Buhler 2003-Vademecum For Vitamin Formulations

Zum
Inhalt
Vademecum
for Vitamin
Formulations
by
Volker Bhler
2 nd revised edition
Wissenschaftliche Verlagsgesellschaft mbH Stuttgart 2001
4
Dr. Volker Bhler
In den Weingrten 14
D-67157 Wachenheim
Deutsche Bibliothek Cataloguing in Publication Data

Vademecum for vitamin formulations / by Volker Bhler. 2., rev. ed..
Stuttgart : Wiss. Verl.-Ges., 2001
ISBN 3-8047-1834-5
All rights reserved. No part of this book may be translated or reproduced in any form without written
permission of the publisher.
The use of general descriptive names, trade names, trademarks, etc., in this publication, even if the former
are not especially identified by the Trade Marks and Merchandise Marks Act, may accordingly be used
freely by anyone.
While the advice and information in this book are believed to be true and accurate at the date of going to
press, neither the author nor the publisher can accept any legal responsibility for any errors or omissions
that may be made. The publisher makes no warranty, express or implied, with respect to the material
contained herein.
2001 by Wissenschaftliche Verlagsgesellschaft mbH, Birkenwaldstr. 44, D-70191 Stuttgart
Printed in Germany
Preface
Vitamin products began to be developed
several decades ago. Nevertheless, there
is still much that is obscure in the pharmaceutical technology of vitamins. This
derives from the specific problems associated with this class of substances. The
multivitamin products are unique in combining such a large number of active substances with entirely different chemical
structures and physical properties. This
is compoundes by the fact that virtually
all the vitamins are more or less unstable
when formulated and some of them interact to result in decomposition.
There has been a large number of publications on the pharmaceutical technology
of vitamin formulations. The intention of
this text is not merely to review the literature. Although a wide selection of publications has been quoted in order to
give an overview, our own work represents a large proportion of the text and
this is reflected by the many formulations
which are specified, almost all of which
were developed in the food products/
pharmaceuticals applications laboratories
of BASF AG, Ludwigshafen, FRG. However, not all of them have been examined for chemical stability.
On this basis, the present text aims to
make the process of development of vitamin products intelligible and thus to aid
pharmacists engaged in this work.
The entries have been arranged alphabetically to provide rapid access to the information, and this is facilitated by crossreferences and the key words which are
printed in italics.
Spring 1988
Volker Bhler
In the second edition of this book some amendements and actualizations were
introduced. This concerns e. g. the situation of the Pharmacopoeias and other legal
conditions. Furthermore several new formulations of vitamin combinations (e. g.
multivitamin syrup, vitamin C + E tablets, vitamin B complex injectable, multivitamin
effervescent tablets, multivitamin tablets with minerals) and a great chapter of multivitamin solutions were added to impart an even better knowledge about the pharmaceutical technology of vitamins.
Since this book has the structure of a dictionary and many crosslinks between the
individual sections are included it was decided to offer it also in an electronic form of
the attached CD-ROM.
An alphabetical index of all formulations listed in the book was added.
September 2000
Volker Bhler
Index of Formulations
The following vitamin formulations are includes in this book as typical examples.
Further formulae are available in the literature [279].
Formulation
Acetylsalicylic acid + Vitamin C tablets
(400 + 200 mg)
Beta-carotene + Vitamin C + Vitamin E
chewable tablets (10 + 500 + 250 mg)
Beta-carotene tablets (15 mg)
Beta-carotene tablets (5 mg)
Calcium D-pantothenate tablets (250 mg)
Multivitamin + copper + zinc mixture
and tablets
Multivitamin effervescent tablets
(1-2 RDA)
Multivitamin instant granules
Multivitamin syrup (1-2 RDA/20 ml)
Multivitamin tablets with minerals
(2 RDA)
Multivitamin tablets
Multivitamin two chamber ampules
Nicotinamide tablets (200 mg)
Pyridoxal phoshate solution for
lyophilization
Suspension for a water-soluble
film-coating of tablets
Suspension for automatic sugarfilm-coating of tablets
Suspension of ethylcellulose for
film-coating of tablets
Tretinoin cream with dexpanthenol
Vitamin A chewable tablets
(100,000 I.U.)
Vitamin A chewable tablets
(50,000 I.U.)
Vitamin A drops (50,000 I.U/ml)
Vitamin A drops, unstabilized
(50,000 I.U./ml)
Vitamin A tablet (75,000 I.U.)
Vitamin A/D/E emulsion
(for veterinary use)
Vitamin A/D/E emulsion for injection
(for veterinary use)
Vitamin A + D concentrate for
processing (100,000 + 20,000 I.U./ml)
Vitamin A + D drops
(25,000 + 2,500 I.U./ml)
page
8
9
31
16
21
134
76
62
120
75
76
130
80
99
46
119
43
35
71
102
93
112
35
19
41
89
103
Formulation
Vitamin A + E chewable tablets
(30,000 I.U.+ 30 mg)
Vitamin A + E drops
(25,000 I.U.+ 50 mg/ml)
Vitamin A + E drops
(825,000 I.U.+ 50 mg/ml)
Vitamin B complex + C effervescent
tablets
Vitamin B complex + C syrup
Vitamin B complex injectable
Vitamin B complex tablets
Vitamin B1 tablets (100 mg)
Vitamin C + Rutin tablets
Vitamin C capsules (100 mg)
Vitamin C chewable tablets (100 mg)
Vitamin C effervescent tablets
(1000 mg)
Vitamin C effervescent tablets
(500 mg)
Vitamin C sustained release tablets
(200 mg)
Vitamin C tablets (100 mg)
Vitamin C tablets (500 mg) with trace
elements
Vitamin C + D + calcium effervescent
tablets
Vitamin C + E chewable tablets
Vitamin C + E chewable tablets
(500 + 20 mg)
Vitamin E acetate solutions
(20 mg/ml)
Vitamin E chewable tablets (200 mg)
Vitamin E chewable tablets (50 mg)
Vitamin E tablets (100 mg)
Vitamin K1 solution (10 mg/ml)
page
114
96
89
123
15, 34
32
15, 125
67, 125
37
105
99
57
117
28
107
53
30
28
40
119
12, 51
36
109
129
74
7
12
113
24, 70
21
128
92
Alfacalcidol
A
A, vitamin
see retinol, retinyl acetate, retinyl palmitate and retinyl propionate.
Acetiamine
Vitamin C+E chewable tablet

Tocopheryl acetate dry powder
adsorbate 50 % [1]
Ascorbic acid for direct
compression
Sorbitol
Orange flavo(u)r
Saccharin, sodium salt
Cyclamate, sodium salt
550.0 mg
400.0 mg
800.0 mg
10.0 mg
0.3 mg
3.0 mg
Aerosil
Acetiamine (syn. thianeurone or diacetamine) is a thiamine derivative which is
rarely used in pharmaceuticals. It differs
from other thiamine derivatives in being
lipid-soluble.
Aerosil is a registered trademark [4] for

highly disperse silica. The type usually
employed in vitamin products is Aerosil 200.
Alfacalcidol
Adsorbate
An adsorbate is a dry powder consisting
of a carrier (e. g. silica gel) onto which a
defined percentage of a usually liquid
vitamin has been bounded by adsorption.
Examples are adsorbates of tocopheryl
acetate and dexpanthenol. Adsorbates
are produced to allow these vitamins to
be incorporated into solid drug forms.
Adsorbates are usually unsuitable for direct tabletting if their particle size distribution includes excessively fine material
and/or the expressibility is too high. They
can, nevertheless, be compressed directly
if the concentration of the adorbate in the
tablet is not too high, as in the following
composition for a vitamin C+E chewable
tablet.
Alfacalcidol (syn. 1-alpha-hydroxy-cholecalciferol) is a synthetic substance hormonal form of cholecalciferol.

The substance takes the form of white
crystals which are insoluble in water but
soluble in oil and are encapsulated, for
example, as vitamin D3. Alfacalcidol has
the same vitamin action as cholecalciferol.
Analgesics
Analgesics
Antagonist
It is sometimes appropriate to combine

some analgesics, such as acetylsalicylic
acid or paracetamol, with ascorbic acid.
A typical example is the following composition for a mixture for direct tabletting:
Some sustances act as vitamin antagonists, i.e. they may reduce or abolish the
vitamin activity. The table below lists
some examples.
Acetylsalicylic acid + vitamin C tablet

(400 mg/200 mg)
Acetylsalicic acid
400 mg
220 mg
Ascorbic acid, for direct
compression
Sorbitol
150 mg
Cellulose, microcrystalline [2]
50 mg
Copovidone
20 mg
Crospovidone
35 mg
Magnesium stearate
3 mg
Polyethylene glycol 6000, powder 20 mg
Vitamin antagonists (selection)

Vitamin
Antagonist
Retinol
Thiamine
Liquid paraffin
Ethanol, sugars in
large amounts
Ethanol, contraceptives, antibiotics
Ethanol, antibiotics,
sugars in large
amounts
Levodopa, isoniazid,
hydralazine and
others [172]
Contraceptives
Ethanol, contraceptives, phenytoin,
primidone
Nicotine, ethanol,
acetylsalicylic acid,
corticoids, indomethacin
Liquid paraffin
Liquid paraffin,
contraceptives, iron
Antibiotics, sulfonamides
Riboflavin
Nicotinamide
Pyridoxine
Cyanocobalamin
Folic acid
Analysis
In the analysis of vitamins a distinction
has to be made between examination of
pure substances and that of products. The
analysis of pure substances will comply
with current pharmacopeias. This will
often also apply to single-vitamin products.
Determination of the contents of vitamins
in combination products is nowadays
mainly carried out by highpressure liquid
chromatography (HPLC), which can frequently be used to determine several vitamins at the same time.
Analysis in products is of importance to
formulating pharmacists since the stability of the vitamins is a major problem, and
this can be monitored only by analysis.
Aneurine
Aneurine is a former name for thiamine.
Ascorbic acid
Cholecalciferol
Tocopherol
Biotin
Vitamin antagonists should not be combined or taken with vitamin products. If

this is unavoidable for more than a short
period, the daily requirement of the relevant vitamin will be increased.
Antioxidants
Since many vitamins are sensitive to oxidation, it is important to use antioxidants
in the relevant vitamin products [13, 14,
209, 241]. Antioxidants for vitamins are
listed in the table below.
Ascorbic acid
Apocarotenal
Antioxidants for vitamins

Vitamin
Antioxidant
Retinol,
cholecalciferol
and ergocalciferol
Butylated hydroxyanisole or butylated

hydroxytoluene, alpha-tocopherol and
propyl gallate
Propyl gallate
Sodium sulfite,
propyl gallate
Alpha-tocopherol,
ascorbyl palmitate
Butylated hydroxyanisole, nordihydroguaiaretic acid
B vitamins
Ascorbic acid
Beta-carotene
Folic acid
The modes of action of the individual

antioxidants differ. Thus, for example,
tocopherols, butylated hydroxytoluene,
and propyl gallate trap free radicals, and
sodium sulfite and ascorbyl palmitate are
reducing agents or oxygen traps. The two
groups may complement each other's action, and their actions are potentiated by
synergists, such as lecithin, citric acid or
ethylenediaminetetraacetic acid.
Ascorbic acid can also be used as a water-soluble antioxidant in other products.
Beta carotene, vitamin C and vitamin E
are considered as physiological antioxidants. A typical formulation of such preparation is given in the table below.
Apocarotenal (syn. beta-apo-8'-carotenal) is a carotenoid as found in nature

and, when used to colo(u)r food products,
has the E number E 160 e. It takes the
form of brown crystals which are insoluble in water. Apocarotenal is soluble to
the extent of about 5 % in oils.
In sugar-coating, apocarotenal has proved to be the carotenoid colorant which
is most stable to light. It can be dissolved
in the coating suspension as a 5 % coprecipitate with polyvinylpyrrolidone. The
coating is darker than that obtained with
beta-carotene.
Aquocobalamin
see hydroxocobalamin.
Ascorbic acid
Beta-carotene + vitamin C + vitamin E

chewable tablet (10 mg/500 mg/250 mg)
Beta carotene dry powder 10 %
Ascorbic acid, crystalline
Sodium ascorbate, crystalline
Vitamin E acetate 50 % SD
Sorbitol, crystalline
Ludipress
Fructose
Polyethylene glycol 6000,
powder
Manufacturing:
Direct compression
100 mg
250 mg
280 mg
500 mg
600 mg
500 mg
350 mg
50 mg
Ascorbic acid (syn. L(+)-ascorbic acid)

and its salts, e.g. sodium or calcium ascorbate, are vitamin C.
Ascorbic acid is a white, odo(u)rless, macro- or microcrystalline powder with a
strongly acid taste. It dissolves to the
extent of about 30 % in water, is not
hygroscopic and has a relatively high reduction potential. This is why it undergoes many chemical interactions with
other vitamins and has to be regarded as
Ascorbic acid
one of the unstable vitamins. Ascorbic
acid decomposes in two ways, both of
which involve the reversible step to produce dehydroascorbic acid:
1. Anaerobic hydrolysis resulting in carbon dioxide and furfural (q.v. for reaction scheme), and brown resins produced from the latter.
2. Aerobic degradation, in which oxidation produces oxalic acid (q.v. for
reaction scheme).
The rates of these decomposition reactions vary with the pH [15, 125, 253], as
shown by the following figure.
Effect of the pH on the decomposition of

ascorbic acid [15].
Liquid drug forms containing ascorbic

acid have been examined for their stability by a number of authors. For oral
solution, particular attention must be
paid to the pH, the addition of chelating
agent to counter the catalytic action of
heavy metals on oxidation, the absence of
oxidizing agents including oxygen, the
solvent, and the possible stabilizing action of sugars [16]. It is possible to stabilize ascorbic acid solutions with, for
example, sucrose, glucose, fructose, ethy-
10
lenediaminetetraacetic acid (EDTA), citric acid, propyl gallate, glycerol, and
propylene glycol.
For examples of use in vitamin B complex + C syrup, see B complex and dexpanthenol. The table below shows the
best stabilizers for an aqueous ascorbic
acid solution of pH 2.7 [20]:
The best stabilizers for ascorbic acid solutions in water
Storage
Stabilizer
Ratio of
ascorbic
acid to
stabilizer
Under air
Ethylenediaminetetraacetic acid
Sodium sulfite
Citric acid
Glucose
100 : 1
100 : 1
10 : 1
10 : 1
Under
nitrogen
Sodium sulfite
Maltose
Propyl gallate
100 : 1
10 : 1
100 : 1
A syrup containing no sucrose with a

sherry flavo(u)r, composed of glycerol
and sorbitol, containing 25 mg or
100 mg ascorbic acid per teaspoon
(4 ml), with an excess of 20 %, can have
the following composition [22]:
Composition of auxiliaries for a vitamin C
syrup
Sherry essence
Citric acid
Water
Glycerol
70 % sorbitol solution
0.4 g
10.0 g
10.0 g
75.0 g
ad 1000.0 g
After storage for one year at room temperature, the loss of ascorbic acid was
about 15 %. The relative losses were
less at higher than at lower concentrations. The stability of the ascorbic acid
11
Ascorbic acid
was somewhat better in the glycerol/sorbitol base than in a sucrose syrup.

When the effects of glucose, sucrose and
sorbitol on the stability of vitamin C in
multivitamin drops were compared, o difference was found between sorbitol and
sucrose at pH 4.5 and 7.0. The stability
was worse with glucose [152].
Addition of carboxymethylcellulose and/
or tragacanth reduced the stability of ascorbic acid in oral solutions [21].
In the production of injectables it is
absolutely necessary to minimize the
contents of heavy metals, e.g. iron and
copper, and oxygen. Thus, only water
which has been freshly distilled over
glass or silver, and from which the oxygen has been completely removed by
boiling immediately before use, should
be used. The ascorbic acid solution must
be processed under an inert gas atmosphere. All the vessels and the apparatus
which come into contact with the solution must be made of glass or stainless
steel.
The optimum pH for stability of ascorbic
acid solutions is between 5.5 and 6.5.
Sodium bicarbonate is best for adjusting
to this pH.
The solution is dispensed, under a stream
of carbon dioxide, into brown ampules
which have been carefully cleaned and

sterilized. The ampules are then immediately sealed and sterilized.
Ascorbic acid is generally much more
stable in solid drug forms than in liquid
products. In uncolo(u)red or uncoated tablets, it is the hydrolysis and the associated discoloration, which becomes evident
much sooner than the oxidation. There
are contradictory reports in the literature
on the effect of auxiliaries on the stability
of vitamin C tablets (see table below).
The reason for these differences is probably that these auxiliaries usually exert
only an indirect effect on the hydrolysis
of ascorbic acid. This is evident from the
fact that ascorbic acid granules of a particular composition differ greatly in colo(u)r stability when produced using an
aqueous solution of polyvinylpyrrolidone
on the one hand in a fluidized bed and on
the other hand in a traditional granulator.
The granules from the fluidized bed show
no change in colo(u)r for more than
12 months while those from the traditional process, which have been well dried,
show a brownish colo(u)r after only
6 months. This means that great care
must be taken with the contact between
water and ascorbic acid during and after
the granulation of the product.
Effect of auxiliaries on the stability of ascorbic acid tablets

[16]
[23]
[21]
[24]
[129]
Very suitable
Mannitol
Cellulose,
microcryst.
Polyvinylpyrrolidone
Lactose
Lactose
Starch
Dextrin
Mannitol
Lactose
Sucrose
Sorbitol
Lactose
Suitable
Sucrose
Lactose
Sucrose
Starch
Less suitable
Glucose
Calcium
hydrogen
phosphate
Starch
Mannitol
Starch
Glucose
Aluminium
oxide
Ascorbyl palmitate
12
The ideal solution to this problem is direct tabletting or compaction [261]. Unfortunately, the physical properties of ascorbic acid mean that it is unsuitable for
direct tabletting at concentrations above
50 % in the tabletting mixture.
However, at lower concentrations there is
no problem if the ascorbic acid has the
particle size distribution which is appropriate for the particular formulation. This
is shown by the following example of a
vitamin C composition for direct tabletting [176]:
Ascorbic acid
(90 % below 150 m)
Starch, mechanically treated,
Type 1500
Stearic acid
Silica, highly dispers [4]
40.0 %
57.5 %
2.0 %
0.5 %
Slight modification of the tablet composition may allow the ascorbic content to be
increased [257].
An example of vitamin C + vitamin E
chewable tablets is given in the following
table.
Vitamin C + vitamin E chewable tablets
(500 mg + 20 mg)
Ascorbic acid, powder
Sodium ascorbate, crystalline
Vitamin E acetate dry
powder 50 %
Ludipress LCE
Polyethylene glycol, powder
Orange flavour
Mango flavour
Aspartame
Manufacturing:
Direct compression
375 mg
142 mg
40 mg
840 mg
40 mg
25 mg
25 mg
20 mg
For further examples of use in solid drug

forms see compaction, effervescent tablets, copovidone, glucose, minerals,
multivitamin solid preparations, sodium

ascorbate, tabletting pressure, instant
granules, tartaric acid, and vitamin mixture.
If there is to be more than 50 % ascorbic
acid in the tablet, it is advisable to use a
type meant for direct compression, commercially available with a vitamin C content of 90 to 98 %. However, the use of
this type of ascorbic acid may be advantageous in other cases, too, as shown by
the examples given under adsorbate,
analgesics, direct compressible vitamins,
and trace elements.
Also commercially available are coated
types of ascorbic acid. These are coated
with, for example, 3 to 5 % ethylcellulose, silicone oil or fat. The use of these
types of ascorbic acid may in some cases
improve the stability. However, this often
does not apply to tablets since the coating
is insufficient to withstand the mechanical stress of tabletting and maintain the
protection against chemical interactions
with other vitamins or moisture [25].
Apart from its use as a vitamin, ascorbic
acid is used in, for example, food products as a reducing agent and water-soluble antioxidant (E number E 300).
Ascorbyl palmitate
Ascorbyl palmitate (syn. palmitic acid

ester of L(+)-ascorbic acid) is a white,
virtually odo(u)rless powder.
Ascorbyl palmitate is used as a fatsoluble
antioxidant with the E number E 304, acting as an oxygen trap or reducing agent
13
Axerophthol
to stabilize fats, oils, and beta-carotene.

It can also act as a synergist with other
antioxidants by regenerating them and
thus prolonging their action.
The concentration range generally used
in fats and oils is 0.05 to 0.1 %. The
concentration can be higher in beta-carotene products, with use being made of the
synergism with lecithin and tocopherol.
Avicel
Avicel is a registered trademark [2] for

microcrystalline cellulose.
The Avicel types used most often form

solid drug forms containing vitamins are
PH 101, PH 102 and PH 200, the particles in the latter being somewhat more
coarse than those in the former.
Axerophthol
older name for retinol or vitamin A alcohol.
B1, vitamin
14
B
B1, vitamin
B complex
see cocarboxylase, thiamine hydrochloride, thiamine mononitrate.
The following vitamins are regarded as

belonging to the vitamin B complex:
k thiamine,
k riboflavin,
k niacin,
k pantothenic acid,
k pyridoxine,
k cobalamin,
k folic acid.
Not all the commercially available vitamin
B complex products contain all these vitamins. This particularly applies to folic acid
and/or pantothenic acid, which considerably simplifies formulation.
In the case of liquid drug forms, if possible, cyanocobalamin should not be combined with the other vitamins in the same
solution. The main reason for stability
problems with folic acid and D-pantothenates is the pH, which should be about 4
for the other B vitamins. The main adverse factor with cyanocobalamin is the
chemical interactions with the other vitamins. In general, pyridoxine hydrochloride, riboflavin-phosphate, sodium, and
nicotinamide can be regarded as involving the fewest problems amongst the
vitamins of the B complex. Thiamine hydrochloride occupies an intermediate position.
Thought has to be given to the possible
use of antioxidants, chelating agents, and
solvents, the protection from light, the
minimization of chemical interactions,
and the consequent overages [33]. The
following formulation for a vitamin B
complex + C syrup attempts to take account of all these (see also dexpanthenol
and cyanocobalain).
B2, vitamin
see riboflavin, riboflavin-phosphate sodium.
B3, vitamin
see niacin, nicotinamide, nicotinic acid.
B5, vitamin
see calcium pantothenate, dexpanthenol,
sodium pantothenate.
B6, vitamin
see pyridoxal phosphate, pyridoxine hydrochloride.
B12, vitamin
see cyanocobalamin, hydroxocobalamin.
B13, vitamin
see orotic acid.
BC, vitamin
see folic acid.
15
Thiamine hydrochloride
27 mg
Riboflavin-phosphate
sodium
27 mg
Nicotinamide
125 mg
Dexpanthenol
55 mg
Pyridoxine hydrochloride
27 mg
Ascorbic acid
400 mg
Orange flavo(u)r
50 mg
Ethylenediaminetetraacetic
acid, disodium salt
10 mg
II. Propylene glycol + water
(2 + 1)
30 ml
III. Parabens
250 mg
Sorbitol
15 mg
Sucrose
100 mg
Water
70 ml
Dissolve I in II; prepare solution III by
heating, allow to cool and mix with I/II.
Adjust the pH to 4.2 or 4.3, Dispense under
nitrogen.
The syrup has been stored in the dark at
room temerpature for 1 year and analyzed
by HPCL. The measured losses were as
follows:
15 %
Riboflavin-phosphate sodium
13 %
Nicotinamide
0%
Dexpanthenol
14 %
4%
Ascorbic acid
12 %
Benzoylthiamine disulfide
I.
The stability is distinctly better in solid

drug forms. There are no problems with
direct tabletting of the B complex when
sufficient amounts of auxiliaries are used
[198], as is shown by the two variants of
a mixture for direct tabletting in the following table.
For another formulation of vitamin B
complex tablets, see thiamine mononitrate. For an example of vitamin B complex
+ C effervescent tablets, see tartaric
acid.
See vitamin derivatives for the forms of
vitamins which are best for solid and
liquid products.
Variant 1 Variant 2
Thiamine
mononitrate
Riboflavin
Nicotinamide
Calcium
pantothenate
Pyridoxine
hydrochloride
Cyanocobalamin,
0.1 % gelatincoated [3]
Cellulose,
microcryst. [2]
Polyvinylpyrrolidone K 30
Silica,
highly disperse[4]
24 mg
24 mg
80 mg
15 mg
15 mg
50 mg
40 mg
25 mg
16 mg
10 mg
16 mg
10 mg
280 mg
175 mg
16 mg
10 mg
3 mg
2 mg
Benfotiamine
Benfotiamine is a white, crystalline powder.

It is occasionally used as vitamin B1. The
highest stability is shown by aqueous solutions of pH 3.8 since hydrolysis increases at higher and lower values [171].
Benzoylthiamine disulfide
Benzoylthiamine disulfide is a fine white
powder.
This thiamine derivative is occasionally
used and is said to have a prolonged action. Its stability in tablets is better than
that of thiamine hydrochloride or thiamine mononitrate [21]. In aqueous solution at pH 7.4, benzoylthiamine disulfide
Benzyl alcohol
is unstable compared with thiamine sulfide [225].
Benzyl alcohol
Benzyl alcohol is a clear colo(u)rless liquid with an aromatic odo(u)r, which is

soluble to the extent of about 4 % in
water and freely soluble in oils.
It is used as a preservative in aqueous
and oily vitamin injectables especially
in veterinary products. The concentration
is normally below 2 %.
For examples of use, see emulsion and
two-chamber ampules.
16
sponds to 6 mg beta-carotene [27]. Betacarotene is sensitive to heat, oxidation
and light, although it can be more stable
than vitamin A.
Beta-carotene is mainly used in solid
drug forms and soft gelatin capsules.
For use as a colorant (E number E 160 a)
in sugar-coating, it can be incorporated
in the coating suspension in the form of a
dry powder which is dispersible in cold
water, or of a 5 % coprecipitate with polyvinylpyrrolidone. It is less suitable for
film-coatings containing no sucrose, because it rapidly undergoes photolytic decomposition in this form.
For tablets, hard gelatin capsules and
granules, beta-carotene is used as provitamin A in the form of dry powders (e.g.
10 % beta-carotene) in order to avoid vitamin A. The following example of a
beta-carotene composition for direct tabletting illustrates this:
Beta-carotene
(see formula below)

Beta-carotene (syn. all-trans-beta-carotene,
provitamin A) is a brownish-violet crystalline powder with a characteristic odo(u)r
and taste. It is insoluble in water, ethanol
and cold oils. It is soluble to the extent of
about 3 % in chloroform. It can be dissolved
in hot oils or fats, because heat causes
partial isomerization, which improves the
solubility. In nature, too, all-trans-beta-carotene is mixed with isomers.
The pure all-trans compound is normally
stated to have a vitamin A activity of
1.67 million I. U./g. However, according
to the German Society for Nutrition, the
vitamin A activity of 1 mg retinol corre-
Beta-carotene tablet (5 mg)

Beta-carotene dry powder, 10 %
Ludipress [1]
Magnesium stearate
50 mg
150 mg
1 mg
For further examples of use in tablets, see

antioxidants, crospovidone, minerals and
multivitamin solid preparations.
For the production of soft gelatin capsules, it is best to use the oily suspensions
of beta-carotene which are compercially
available.
In solid drug forms, it is preferably stabilized with the antioxidant/synergist
mixture of tocopherol, ascorbyl palmitate, and lecithin (e.g. 1+5+10).
17
The presence of ascorbic acid may have
an adverse effect on the stability of betacarotene dry powders.
In liquid drug forms, beta-carotene can
be used as a colorant by addition of a
dry powder which is dispersible in cold
water to, for example, suspensions or
emulsions. A 4 or 5 % solution for injection can be prepared using 25 % of the
solubilizer PEG hydroxystearate [28].
BHA
see butylated hydroxyanisole.
BHT
see butylated hydroxytoluene.
Binders
Binders are auxiliaries which are used in
granules and, especially, tablets in order
to increase tablet hardness. The binders
most commonly used in vitamin tablets
are listed below.
Bioavailability
Virtually the only ones suitable, because
of the solubility in water, for effervescent
tablets are polyvinylpyrrolidone, copovidone, and possibly polyethylene glycol.
Bioavailability
Investigations into the behavio(u)r of vitamin products in the body are less common in the literature than are those on
some other pharmaceuticals. This may be
connected with the fact that, in the past,
the analysis of some vitamins in biological fluids was difficult. On the other
hand, a bioavailability study on a multivitamin product involves an effort which
can scarcely be justified.
The bioavailability of the hydrophilic vitamins from normal products (without delayed release) is usually good.
Examination of the bioavailability of the
lipophilic vitamins is more important. It
can be greatly influenced by the auxiliaries
solubilizers, solvents, food additives, etc.
[264]. The figure below shows the difference caused by auxiliaries in vitamin A
solutions injected into chickens.
Binders commonly used for vitamin products

Starch
Polyvinylpyrrolidone (povidone)
Cellulose, microcrystalline
Carboxymethylcellulose
Copovidone
Gelatin
Hydroxypropyl(methyl)cellulose
Polyethylene glycol
(Sucrose)
(Sorbitol)
(Mannitol)
In direct tabletting the binders like copovidone are added dry, not all being suitable for this purpose (e.g. gelatin), while a
solution of the binder is normally used
for granulation.
Bioavailability of vitamin A in chickens 14

days after parenteral administration.
In solid forms with beta-carotene, the

particle size of the latter may also affect
the bioavailability (see particle size distribution).
Bioflavonoids
Sustained-release vitamin products are
relatively uncommon. This effect can be
achieved as follows:
1. Addition of more than 20 % galactomannan delays the release of ascorbic
acid from 250 mg vitamin C tablets
[30].
2. Mannitol and aminoacetic acid delay
the release of cyanocobalamin from
tablets [31].
3. Embedding of vitamin B2 in tragacanth, gum arabic, and ethylcellulose
in a tablet core which is provided with
a riboflavin-containing ethylcellulose
coating extends the period of release
[32].
4. Mixing of vitamins with a spray dried
combination of polyvinylacetate and
providone (8+2) and compression to
give tablets may delay the release
markedly.
Bioflavonoids
Bioflavonoids (syn. flavonoids) are a
group of substances formerly called vitamin P. The basic chemical structure of
the bioflavonoids is that of flavone:
The most important bioflavonoids are rutin, quercetin, and hesperidin. Rutin is
virtually the only bioflavonoid which is
used as active ingredient in pharmacy
and it is said to have the highest vitamin
P activity (synergistic action with ascorbic acid).
Bioflavonoids are also used as auxiliaries, because they inhibit the oxidation
of ascorbic acid catalyzed by heavy metals [29].
18
For examples of the use of rutin in tablets, see minerals.
Biotin
Biotin (syn. D(+)-biotin, vitamin H) is a

white powder which is very slightly soluble in water (below 0.1 %).
Biotin is used almost exclusively in multivitamin products. The optimum pH for
the stability of aqueous biotin solutions is
between 5 and 8. Biotin is not sensitive to
weak oxidizing agents (e.g. air) reducing
agents and visible light. Strong oxidizing
agents, UV light, and acids may adversely affect the stability of biotion.
A stable 1 % dry powder is normally used
in solid drug forms, e.g. one based on
calcium hydrogen phosphate.
Butylated hydroxyanisole
Butylated hydroxyanisole (syn. tertbutyl4-methoxyphenol, BHA) is a white or

pale yellowish, wax-like powder with a
mild, typical odo(u)r. It is insoluble in
water but freely soluble in ethanol, propylene glycol, and peanut oil.
BHA is an antioxidant which is often
used for vitamins A and D and has the
E number E 320. It acts as a free radical
trap. The concentrations normally used
are in the range 0.01 to 0.1 %.
19
It is also suitable in concentrations of
0.02 to 0.05 % for the stabilization of
folic acid [35].
BHA has on occasion been banned in
Japan for toxicological reasons.
Butylated hydroxytoluene
The figure below compares the stability
of vitamin A in a vitamin A/D/E emulsion with and without addition of BHT.
Vitamin A/D/E emulsion (for veterinary
use)
Composition
Retinyl propionate
Cholecalciferol
Tocopheryl acetate
PEG-35 glyceryl
triricinoleate [1]
Benzyl alcohol
Water
23.0 g
0.2 g
5.5 g
10.0 g
1.0 g
ad 100 ml
Stability
Butylated hydroxytoluene (syn. 2,6-ditert-butyl-p-cresol, BHT) is a white crystalline powder. It is insoluble in water
and propylene glycol but freely soluble in
ethanol and oils.
BHT is the antioxidant which is used
most often in pharmaceutical vitamin
products containing vitamins A and D.
Like BHA, it traps free radicals in the
presence of oxygen or oxidizing agents.
The antioxidant action of BHT for vitamin A is greater than that of BHA. The
effect is even greater on combination of
BHA with BHT [36]. The concentrations
in vitamin solutions may be between 0.01
and 0.5 %.
For further examples of use, see emulsion, PEG glyceryl trihydroxystearate and
syrup.
C, vitamin
20
C
C, vitamin
see ascorbic acid, calcium ascorbate, sodium ascorbate.
Calcitriol (syn. 1-alpha-25-dihydroxycholecalciferol) is the biologically active

form of vitamin D3. It is occasionally
used in vitamin D capsules.
Calcifediol
Calcium ascorbate
Calcifediol (syn. 25-hydroxycholecalciferol) is a metabolite of cholecalciferol and

is thus an intermediate in the formation
of 1-alpha-25-dihydroxy-cholecalciferol
in the body (= calcitriol). It is possible
by solubilization to incorporate it into
aqueous vitamin D solutions, but this is
rarely employed.
Calciferol
see ergocalciferol.
Calcitriol
Calcium ascorbate (syn. calcium salt of

vitamin C, calcium salt of L(+)-ascorbic
acid) is a white, odo(u)rless powder with
a very slightly bitter taste. It has the E
number E 302.
In terms of vitamin C activity, 1.0 g calcium ascorbate is equivalent to 0.826 g
ascorbic acid.
The product is not suitable for liquid drug
forms, because aqueous solutions are too
unstable and calcium oxalate may precipitate out on storage.
In solid drug forms, such as tablets, calcium ascorbate maintains its colo(u)r
somewhat better than ascorbic acid. However, once again the humidity must be
kept below 30 % during production and
the water content of the tabletting mixture must be minimized in order to suppress hydrolysis.
Calcium hydrogen phosphate

Calcium hydrogen phosphate (syn. dibasic calcium phosphate, anhydrous or dihydrate) is a fine white odo(u)rless powder which is insoluble in water.
21
Calcium pantothenate
Calcium hydrogen phosphate is used as a

lowcost filler in tablets, coated tablets
and hard gelatin capsules. Since the particles are very fine, the material is normally granulated.
Calcium hydrogen phosphate which has
been granulated with polyvinylpyrolidone
is very suitable for direct tabletting. A
typical example of this type of use is
the composition for vitamin E chewable
tablets which follows.
Vitamin E chewable tablet (50 mg)
Tocopheryl acetate,
dry powder 50 %
spray-dried with gelatin [1]
Calcium hydrogen phosphyte,
granulated with 5 % polyvinylpyrrolidone K 30
100 mg
300 mg
3 mg
For further examples of the use of calcium hydrogen phosphate, see calcium
pantothenate and crospovidone.
For some vitamin tablets it is important
to know that the dihydrate slowly loses
water at elevated temperature.
Calcium oxalate
Oxalic acid is formed by the oxidation of
ascorbic acid.
If a liquid drug form contains a calcium
salt, e.g. calcium pantothenate, in addition to ascorbic acid, the calcium oxalate
may crystallize out after storage for some
time.
Calcium pantothenate (syn. calcium Dpantothenate, calcium salt of D-pantothenic acid, formerly vitamin B5) is a white,
virtually odo(u)rless powder with a
slightly bitter taste.
It is freely soluble in water.
1.0 g calcium D-pantothenate is equivalent to 0.919 g D-pantothenic acid.
Calcium pantothenate is used almost exclusively in solid drug forms. Particular
attention must be paid to the fact that the
hygroscopicity of the substance may affect the stability of such products. It decomposes rapidly in the presence of ascorbic acid if a certain amount of moisture is present. This is why the water
conent of multivitamin tablets containing
calcium pantothenate must be as low as
possible and the tablets must be packed
in air-tight containers. However, it is often better to use an adsorbate of dexpanthenol in place of calcium pantothenate
in multivitamin tablets. Another possibility is to incorporate calcium pantothenate into the gelatin in soft gelatin capsules or into the coating of coated tablets in
order to prevent chemical interactions
with other vitamins.
The following calcium pantothenate tablet composition is an example for direct
tabletting.
Calcium D-pantothenate tablet (250 mg)
Cellulose, microcryst. [2]
Crospovidone
Stearic acid
Magnesium stearate
275 mg
150 mg
50 mg
20 mg
3 mg
3 mg
For further examples of the use of calcium pantothenate in solid drug forms,
see B complex, multivitamin solid preparations, thiamine mononitrate, and tartaric acid.
Capsules
Calcium pantothenate is unsuitable for
liquid forms, because it is reasonably stable only at a pH of 5.7 to 6.2 [159, 220].
Dexpanthenol or sodium pantothenate are
substitutes. Multivitamin solutions which
contain calcium pantothenate in addition
to ascorbic acid may precipitate calcium
oxalate on storage [37].
Capsules
see hard and soft gelatin capsules.
Carbon dioxide
Carbon dioxide can be used as an inert gas
for some vitamin solutions. Its advantage
over nitrogen is that its solubility in water is
distinctly higher than that of oxygen. However, account has to be taken of the effect
on the pH of the solution.
22
Carbon dioxide can also occur as a product of the anaerobic hydrolysis of ascorbic acid [72, 73, 124]. This may have
very undesirable results, with blisterpacks or polyethylene bottles becoming
distended, and, in extreme cases, ampules
bursting. The maximum formation of carbon dioxide takes place at pH 4.1 as does
the maximum loss of ascorbic acid, as
shown by the preceding figure [72].
The use of carbon dioxide as an inert gas
in vitamin C solutions has two effects:
prevention of oxidation by oxygen and
suppression of hydrolysis (Law of mass
action). For examples of its use, see inert
gas.
In pharmacy, carboxymethylcellulose is
used in the form of the sodium salt,
which dissolves in water and dilute
ethanol.
For granulation for use as a binder, it is
possible to prepare a 5 or 6 % aqueous or
aqueous-ethanolic solution. For use as a
dry excipient in tablets binder, it is necessary to incorporate about 5 to 10 % of
the weight of the tablet.
Certain types of carboxymethylcellulose
(e.g. Nymcel) can be used as disintegrants by drymixing about 2 to 6 % into
the tablets. An even better disintegrant is
the crosslinked form croscarmelose.
Carboxymethylstarch
Formation of carbon dioxide and loss of

ascorbic acid in vitamin C solutions (25 %
in water, 93 h, 55 C).
Carboxymethylstarch can be used in the

form of the sodium salt as a tablet disintegrant. Examples of trade names are
Explotab or Primojel.
Sodium carboxymethylstarch is normally
added in a concentration of 2 to 8 % to
the dry mixture before tabletting.
23
Carotene
Natural carotene is the chief representative of the carotenoids and comprises a
mixture of three chemical substances (alpha-, beta- and gamma-carotene), each of
which in turn comprises a number of
stereoisomers (see formulas above). All
have provitamin A activity although the
strength varies.
To date, only beta-carotene has been important in vitamin formulations, because
it has, in the all-trans form, the highest
provitamin A activity and the synthetic
product is identical to the natural product.
Carotenoids
The term carotenoids comprises a group
of substances including more than one
hundred pigments of vegetable and animal origin [145].
The chief representatives are beta-carotene, apocarotenal, canthaxanthin, lycopene, astaxanthin, capsanthin, zeaxanthin
and citranaxanthin. The E numbers are
E 160 a to f.
In pharmacy, beta-carotene, canthaxanthin and apocarotenal have some importance as pigments, in particular for sugarcoating or for colo(u)ring soft gelatin
capsules and suppositories.
Cellulose
In contrast to sugar-free film-coating, the

coating obtained by sugar-coating has a
reasonably stable colo(u)r if the thickness
and amount of carotenoid are adequate.
The effect of light is the main problem.
In sugar-coated tablets, apocarotenal has
proved to be the most stable to light of
the three substances.
Skin-tanning agents containing canthaxanthin are no longer produced in Germany.
Casein
Casein (syn. milk protein) is used as an
auxiliary in some dry powders of vitamins A and E. In these formulations,
casein acts as an emulsifier to assist in
making the dry powders dispersible in
cold water.
Account must be taken of the possibility
of incompatibility with ascorbic acid,
which results in a pink coloration of tablets, for example, due to the formation
of a complex with ascorbic acid [38].
Cellulose
Cellulose is a polysaccharide with betaglycosidic linkages between the glucose
units.
Chelating agents
24
Microcrystalline or microfine cellulose is

a white, odo(u)rless powder which is insoluble in water, ethanol, and propylene
glycol.
It is marketed in various forms and particle sizes and with various names (e.g.
Avicel [2], Vivacel and Elcema [4]).
These differences mean that the various
types of cellulose are not necessarily interchangeable. The E number is E 460.
Microcrystalline and microfine cellulose
are used in vitamin tablets as fillers, binders and, to a certain extent, as disintegrants. A typical example of use is the
following vitamin E composition for direct tabletting to chewable tablets:
50 %, spray-dried with gelatin [1]
400 mg
130 mg
10 mg
Microcrystalline or microfine cellulose is

suitable for direct tabletting, as in this
example; it can also be incorporated by
granulation.
Owing to its insolubility, cellulose is
scarcely suitable for effervescent tablets.
It is not known to have adverse effects on
the stability for vitamins.
For further examples of use of microcrystalline cellulose in tablets, see analgesics, B complex, calcium pantothenate,
copovidone, crospovidone, direct compressible vitamins, nicotinamide, pyridoxine hydrochloride, thiamine hydrochloride, and thiamine mononitrate.
Chelating agents
Chelating agents (syn. complexing
agents) form chelates for complexes
with metal ions.
Heavy metals may act as catalysts to have

an adverse effect on the stability of many
vitamins (e.g. B1, B6 and C), which is
why they are often inactivated by chelating
agents, especially in liquid products.
The chelating agents which are most
commonly used in vitamin solutions are
citric acid and ethylenediaminetetraacetic acid.
Chemical interactions
see interactions.
Chloroflavin
Chloroflavin is a degradation product of
riboflavin, which may be produced in
multivitamin or B complex solutions,
especially due to interactions with thiamine hydrochloride. Nicotinamide and
ascorbic acid may increase the formation
of chloroflavin, which may even result in
a precipitate.
Cholecalciferol
Cholecalciferol (syn. colecalciferol, vitamin D3) is a white crystalline powder

which is insoluble in water but soluble
in ethanol and oils. It is one of the lipophilic vitamins.
1.0 g cholecalciferol is equivalent to
40 million international units of vitamin D.
Since vitamin D3 is of animal origin, it is
nowadays more important then vitamin
25
D2 (= ergocalciferol), whose vegetable
synthetic precursors are less easily obtainable.
In solid drug forms containing vitamin D,
the primary problem is homogeneous distribution in the formulation and, which is
an associated problem, the content uniformity, since the daily requirement is
only about 5 g. This problem may be
solved by using a highly diluted dry powder, i.e. one embedded in gelatin. The
usual concentrations in these compositions are between 100,000 and 850,000
I. U./g. Compositions of this type together with vitamin A esters are also commercially available (e.g. vitamin A/D3
dry powder 500,000/50,000 I. U./g). In
this form, cholecalciferol can be satisfactorily tabletted and is distinctly more stable than vitamin A. Nevertheless, it has
to be remembered that it is sensitive to
light, oxygen, heat, and humidity.
Vitamin D dry powders virtually always
contain an antioxidant (e.g. butylated hydroxytoluene and/or butylated hydroxyanisole).
The main problem with liquid drug forms
is the insolubility. A solubilizer may remedy this. The amounts of the solubilizer
PEG glyceryl trihydroxystearate required
for various vitamin D concentrations are
shown in the figure below. The concentrations are based on the finished solubilizate.
Solubilization of cholecalciferol using PEG40 glyceryl trihydroxysterate [1].
Cholecalciferol-cholesterol
The stability of vitamin D solubilizates is
substantially independent of the pH. However, isomerization may occur in very
acid solutions [39]. Addition of an antioxidant in the manufacture of an aqueous
vitamin D syrup using polysorbate 80
may be advantageous [40]. Solutions of
vitamin D in propylene glycol are reasonably stable [166], but they, too, have to
be protected from light, oxygen and heat.
Cholecalciferol-cholesterol
Cholecalciferol-cholesterol (syn. vitamin

D3-cholesterol) is a molecular compound
of cholecalciferol with cholesterol produced by crystallizing equimolar amounts
of the two substances. The white crystals
are insoluble in water but dissolve in oils.
The vitamin D activity of cholecalciferolcholesterol is equivalent to about 20 million international units per gram.
Vitamin D3 is more stable in this form
than as pure cholecalciferol or ergocalciferol [41].
Low-concentration compositions which
are based on lactose, for example, are
used for solid drug forms.
Choline
Choline
Although choline was in the past regarded as a B vitamin, it is not a true vitamin
since it is synthesized in the human liver.
The choline derivatives used in pharmacy
include:
k choline chloride,
k choline bitartrate,
k lecithin,
k choline orotate,
k choline stearate.
Choline chloride and bitartrate are hygroscopic white powders and are stable
in solid drug forms only if humidity is
excluded. Likewise, aqueous solutions
are stable for only a limited time. Choline
bitartrate is often preferred to choline
chloride on the grounds of taste.
Choline salts are used rarely in vitamin
products.
26
This is why citric acid is an effective stabilizer for ascorbic acid solutions stored
under air, with a possible ratio of ascorbic
acid to citric acid being 10 : 1 [20].
Citric acid can also be used in oily solutions of the lipophilic vitamins or in soft
gelatin capsules.
Citric acid is also used as the acid component in effervescent tablets. Its advantage over tartaric acid, and especially
ascorbic acid, is that smaller amounts
are required. The liberation of carbon
dioxide takes place more rapidly than
when tartaric acid is used [259].
Coated tablet
see sugar-coating.
Coatings
see film-coating and sugar-coating.
Cobalamin
Cobalamin is vitamin B12. The most important derivatives are cyanocobalamin
and hydroxocobalamin.
Citric acid
Cocarboxylase
Citric acid is a white, odo(u)rless substance with an acidic taste; it is freely

soluble in water and ethanol, and insoluble in fats.
Citric acid and its esters are among the
most important synergists. They are frequently combined with antioxidants in
vitamin products. The essential action
comprises inactivation of traces of metals
by the formation of stable chelate rings,
e.g. with copper or iron.
Cocarboxylase (syn. thiamine pyrophosphate, thiamine diphosphate) is the actual

coenzyme form of vitamin B1. Both the
tetrahydrate and the hydrochloride of cocarboxylase are white, crystalline powders resembling thiamine hydrochloride.
Aqueous solutions of cocarboxylase are
markedly less stable than those of thiamine hydrochloride in the pH range 4 to
7 since hydrolysis results in thiamine mo-
27
Colorants
nophosphate, thiamine, and phosphate

[42, 235].
Thus, products for injection are best manufactured by lyophilization.
Addition of the following stabilizes lyophilizates: 4 % nicotinamide [233], 30 % arginine [234], adenosine [237], valine [238],
mannitol and polyvinylpyrrolidone [239].
The loss of vitamin from a 0.5 % aqueous
cocarboxylase solution of pH 4 or 5 after
storage at 40 C for 2 months was reduced by addition of 0.1 % maleic acid and
0.05 % EDTA from 90 % without this
addition to 2 % [236]. Cocarboxylase is
rarely used in solid drug forms, because it
is cleaved to thiamine monophosphate in
the gastrointestinal tract, and the direct
coenzyme activity of this compound is
much weaker than that of cocarboxylase.
But advantages are the faint taste and
odo(u)r.
Coenzyme
Most of the hydrophilic vitamins act as
coenzymes.
Vitamins as coenzymes
Thiamine
Riboflavin
Niacin
D-pantothenic
acid
Pyridoxal
Cobalamin
Folic acid
Biotin
Coenzyme of the decarboxylases and aldehyde

transferases
Constituent of the flavin
coenzymes
Constituent of codehydrases
Constituent of coenzyme A
Coenzyme of transaminases and amino acid decarboxylases
Coenzyme for fatty acid,
amino acid and nucleotide
metabolism
Coenzyme for C1-metabolism
Coenzyme of carboxyltranferases
Colorants
Colorants can be divided either into soluble colo(u)ring agents, colo(u)r lakes
and pigments or into synthetic substances
and natural substances (or those identical
to the natural substances).
Examples of soluble colo(u)ring agents
used in pharmacy are the substances listed in the table below.
Colo(u)ring agents for aqueous solutions
Colo(u)ring agent
E number
Amaranth
Azorubine
Beta-carotene dry powder
CWD*
Cochineal red
Erythrosine
Indigotine
Orange yellow
(= Sunset Yellow)
Patent blue V
Quinoline yellow
Riboflavin
Tartrazine
E 123
E 122
E 160 a
E 124
E 127
E 132
E 110
E 131
E 104
E 101
E 102
* Cold-water dispersible
Colo(u)r lakes or pigments are more often used in solid drug forms [249]. These
are aluminium oxide lakes of the soluble
colo(u)ring agents, or pigments in the
form of iron oxides (E number E 172)
and titanium dioxide (E number E 171).
The main areas of use are sugar-coating
and film-coating (for examples of use,
see these entries).
For direct colo(u)ring of tablets, it is advisable to prepare a premix of the lubricant with the colo(u)r lake in the ratio
1+1 to 1+4, and to process this mixture in
the same way as the lubricant. It is thus
possible to obtain a concentration of 0.5
to 3.0 % of colo(u)r lake in the tablet as
shown by the following composition of a
yellow vitamin B6 tablet.
Colo(u)r stability
Vitamin B6 tablet (30 mg)
I. Pyridoxine hydrochloride
30.0 mg
180.0 mg
Ludipress [1]
II. Magnesium stearate
1.2 mg
Sicovit tartrazine lake
2.8 mg
Mix mixture II with components I and
compress.
Colo(u)ring agents and colo(u)r lakes

vary in their stability in tablet coatings
containing vitamins. Thus, for example,
of the customary synthetic colorants, only
quinoline yellow, patent blue and tartrazine have been found to be relatively
stable in vitamin C coated tablets [67].
Similar incompatibilities have been
found in food products and solutions containing vitamin C [222224].
Iron oxide pigments are increasingly
being preferred for sugar-coating and in
film-coating.
Carotenoids (e.g. beta-carotene, apocarotenal) can be used as oily dispersions
for colo(u)ring soft gelatin capsules. Account must be taken of their sensitivity to
light [262].
Colo(u)r stability
The colo(u)r stability of vitamin products
is of particular importance with vitamins
B1, B12 and C.
Thiamine hydrochloride may be oxidized
to thiochrome in aqueous solutions. The
rate of this oxidation may be increased in
the presence of riboflavin and nicotinamide. It results in darkening of the solution.
Cyanocobalamin solutions in water are
pink. A breakdown of cyanocobalamin
is evident from a drecrease in the colo(u)r
intensity.
The colo(u)r stability of ascorbic acid in
uncolo(u)red tablets is limited. Traces of
the furfural degradation products which
28
have been produced by hydrolysis cause
the originally white tablets to become
yellow or brown.
When colorants are used in vitamin products, account must be taken of their
possible reactions with vitamins (e.g. ascorbic acid) and light, which may cause
the colo(u)r to pale rapidly. The colorants
beta-carotene and riboflavin, in particular, readily undergo photolysis.
Compaction
For vitamins sensitive against hydrolisis
(e.g. vitamin C) the compaction is an
excellent granulation technology for the
manufacturing of tablets to avoid the use
of solvents and the residues of water.
Normally a roller compactor is used for
this purpose [270].
A typical formulation of a tablet with
compacted vitamin C is given in the table
below [261].
Vitamin C effervescent tablet (1000 mg)
Ascorbic acid, compacted with
1000 mg
4 % of povidone K 30
Tartaric acid
200 mg
Sorbitol
200 mg
Sodium bicarbonate
172 mg
Polyethylene glycol 6000
60 mg
Manufacturing: Direct compression
Compartmented ampules
see two-chamber ampules.
Complexes
Two types of complexes can be distinguished in vitamin products:
1. Metal complexes
Complexing agents are used to bind and
(heavy) metals which are present in order
29
to protect and improve the stability of the
vitamins. For details, see chelating
agents.
2. Vitamin complexes
Nicotinamide and ascorbic acid are complexing agents. Examples of typical vitamin complexes are the yellow nicotinamide ascorbate, ascorutin from ascorbic
acid and rutin, the pink amino acid/ascorbic acid complex [38], and the thiamin/menadione adduct [256]. Nicotinamide forms complexes with folic acid
[109] and riboflavin [126] and thus increases their solubility in water. Other
substances form complexes with these
two vitamins [127, 139, 140], as shown
by the following figure for folic acid with
and without the ethanolamide of gentisic
acid [107, 127].
Solubility of folic acid in water.
Copovidone
Copovidone
Copovidone (syn. PVP/VA copolymer) is

a copolymer of 60 parts by weight of
vinylpyrrolidone and 40 parts by weight
of vinyl acetate.
It is a white or yellowish powder which is
marketed under the name Kollidon
VA 64 [1, 263 b]. In contrast to polyvinylpyrrolidone, the hygroscopicity of copovidone is slight, as is evident from the
graph which follows next.
Moreover, it is suitable as a binder for
granulation and direct tabletting. This is
shown by the example of a vitamin C
composition for direct tabletting to chewable tablets.
Uptake of water by copovidone after

7 days (25 C).
Corn starch
Vitamin C chewable tablet (100 mg)
105 mg
70 mg
Sucrose, ground
32 mg
Sucrose, crystalline
20 mg
6 mg
Copovidone
6 mg
Polyethylene glycol 6000, powder
5 mg
Orange flavo(u)r
2 mg
Strawberry flav(u)r
1 mg
Silica, highly disperse
0.5 mg
0.3 mg
For further examples of its use, see analgesics, instant granules, mannitol, multivitamin solid preparations, nicotinamide,
pyridoxine hydrochloride, retinyl acetate,
riboflavin, tocopheryl succinate and vitamin mixture. The second area of use of
copovidone is for film-coating since it is
an excellent film-forming agent. The
films have the advantage of low hygroscopicity and high elasticity. For examples
of this use, see ethylcellulose, film-coating and sugar-coating.
Corn starch
30
with dexpanthenol in a cream (for an
example see dexpanthenol).
Cremophor
Cremophor is a registered trademark for a
number of emulsifiers and solubilizers
for use in pharmaceuticals and cosmetics
[1].
The types which are particularly used as
solubilizers for lipophilic vitamins are
Cremophor EL (PEG glyceryl triricinoleate) and Cremophor RH 40 (PEG glyceryl trihydroxystearate).
Croscarmelose
Croscarmelose is crosslinked carboxymethylcellulose, with is marketed under the
registered trademark. Ac-Di-Sol [2], for
example. It is insoluble in water and is a
very good disintegrant for tablets.
The concentrations which are normally
used are between 1 and 5 % based on
the weight of the tablet.
see starch.
Crospovidone
Creams
Vitamins are also used in dermatologicals
and cosmetics [4346]. These are preferably in the form of creams. The vitamins
which are commonly used in creams include
k retinol and retinyl palmitate [4851],
k dexpanthenol [52, 191],
k tocopherol (or tocopheryl acetate) and
k tretinoin.
A typical panthenol cream for healing
wounds may contain 5 % dexpanthenol.
It is also possible to combine tretinoin
Crospovidone (syn. insoluble polyvinylpyrrolidone) is a white hygroscopic powder. It does not dissolve in any solvent so
that its molecular weight cannot be determined. It is sold under the registered
trademarks Kollidon CL [1, 263] and
Polyplasdone XL [5].
The non-micronized form of crospovidone is used in concentrations between
1 and 5 % as a disintegrant in vitamin
tablets (for european food E 1202), as is
evident from the following example of
the composition of a beta-carotene tablet
with a very short disintegration time.
31
Cyanocobalamin
Beta-carotene tablet (15 mg)

Beta-carotene
dry powder 10 % [1]
Calcium hydrogen phosphate,
granulated with 5 % polyvinylpyrrolidone K 30
Crospovidone
Talc
Calcium arachinate
150 mg
175 mg
100 mg
25 mg
20 mg
5 mg
2 mg
Micronized crospovidone can also be

used as a suspension-stabilizer and as
dessicant to stabilize the vitamins by reduction of the free water content. This
can be utilized for oral vitamin powders.
For an example of use, see instant granules.
Cyanocobalamin
Cyanocobalamin is the most important

vitamin B12 derivative in pharmaceutical
technology. Like hydroxocobalamin, it is
a dark-red crystalline powder which, despite having a relatively poor solubility in
water (1 or 2 %), is one of the hydrophilic
vitamins. A saturated solution in 90 %
ethanol contains about 0.5 %.
Vitamin B12 is one of the most sensitive

and thus least stable vitamins.
In liquid drug forms, the solubility is no
problem, because the usual doses are
very low. The stability of vitamin B12
solutions is influenced by a number of
factors, as follows:
1. Light
Cyanocobalamin undergoes rapid photolytic decomposition (for details, see
light). The adverse effects of light can
be eliminated or at least minimized by
appropriate measures during production
and packaging.
2. pH
The optimal pH is between 4.5 and 5.0 [18].
3. Heat
Cyanocobalamin solutions are sensitive
to heat and thus there are large losses
on heat-sterilization, which is therefore
not recommended.
4. Oxidizing agents
Vitamin B12 solutions must not contain oxidizing substances. The effects of oxygen
must be eliminated by use of an inert gas.
5. Chemical interactions with vitamins
In combined vitamin products, e.g. multivitamin solutions, it is not possible to avoid
the chemical interactions of cyanocobalamin with other vitamins. It reacts with thiamine and its breakdown products. Nicotinamide promotes this reaction. Iron (III)
salts are said to have a stabilizing effect.
Vitamin B12 is also broken down by dehydroascorbic acid. However, the reaction of
cyanocobalamin is distinctly less than that
of hydroxocobalamin [53].
All these factors may results in the stability of cyanocobalamin being very poor
in combination with vitamins in liquid
products [33]. The best ways of stabilizing cyanocobalamin solutions has proved to be the addition of cyanide ions
[118] or of low molecular weight povidone [263 a]. The latter is demonstrated
in the following formulation.
Cyclamate
32
Vitamin B complex injectable

I Thiamine hydrochloride
Riboflavin monophosphate Na
Nicotinamide
Cyanocobalamin
EDTA sodium
Propylgallate
Kollidon 17PF
II Parabens
Citric acid
NaOH solution, 1 mol/l
Hydrochloric acid, 0.1 mol/l
Propylene glycol
Water
11.0 mg
6.6 mg
44.0 mg
4.4 mg
8.8 g
0.2 mg
0.5 mg
99.0 mg
1.6 mg
22.7 mg
0.216 ml
0.720 ml
0.200 ml
0.864 ml
Stability (9 months, room temperature):

92 %
Vitamin B1
94 %
Vitamin B2
91 %
Vitamin B6
Nicotinamide
100 %
Vitamin B12 (with Kollidon)
87 %
Vitamin B12 (without Kollidon) < 50 %
It is advisable for oral products to take

the form of instant granules, effervescent
granules, etc. The solution for products
for injection is to use two-chamber ampules or compartmented ampules with
separated solutions, only one of which
contains cyanocobalamin. Another possibility is to produce injectables by lyophilization.
The forms used for solid products are, by
reason of the stability and the low dosage, dry dilutions with the substance embedded in starch or gelatin or triturated
with mannitol or galactomannan, some
of which are commercially available.
The concentration of cyanocobalamin in
these formulations is normally 0.1 to
1.0 %. For the multivitamin tablets, the
best way of preventing the chemical interactions with vitamins B1 and C is to
embed the substance in gelatin. This is
shown by the figure below which compares the stability of the substance when
mixed with an excess of ascorbic acid

and either triturated with mannitol or embedded in gelatin and then stored [3].
Comparison of the stability of cyanocobalamin dry powders (mixed with ascorbic

acid, room temperature).
For examples of the use of cyanocobalamin in solid drug forms, see B complex,
instant granules, multivitamin solid preparations, thiamine mononitrate, and tartaric acid.
Cyclamate
Sodium cyclamate (syn. sodium salt of

cyclohexylsulfamic acid) is a white powder which is soluble in water. It is used as
a sweetener, being 1530 times stronger
than sucrose. The advantage of cyclamate over saccharin is that it has virtually not bitter taste.
In some countries, sodium cyclamate is
not approved for use in food products.
Apart from the sodium salt, in some cases
the acid or the calcium salt is used.
For examples of use in formulations, see
adsorbate, copovidone, direct compressible vitamins, polyvinylpyrrolidone, sorbitol, trace elements, and tartaric acid.
33
Daily requirement
D
D2, vitamin
see ergocalciferol.
D3, vitamin
see alfacalcidol, calcifediol, calcitriol,
and cholecalciferol.
Daily requirement
there are some considerable differences
in the opinions about the amounts of the
individual vitamins required each day by
humans.
A number of countries have fixed RDAs.
Care is needed when examining these
figures, because some lists of RDAs are
minimum amounts, while some are of

optimal amounts. In addition, there are
quantitative differences between the figures given for the RDAs in countries using
the same definition and this has resulted
in a great lack of uniformity. As an example, the following table lists the RDAs
of the American Food and Drug Administration (FDA) for the optimal amounts
for adults, the recommendations of the
National Academy of Sciences (USA)
and the recommendations of the Federal
Board of Health in Berlin (BGA).
In the case of beta-carotene, 6 mg as
provitamin A is considered as equivalent
to 1 mg retinol (= 3333 I. U.) [27]. In
some cases, one gram of beta-carotene
is regarded as having a vitamin A activity
of 1.67 million I. U.
Daily requirements of vitamins by adults

Vitamin
FDA, 1986
[203]
National Academy
of Sciences 1998
(USA)
BGA recommendations 1983 [204]
A
B1
B2
Nicotinamide
D-pantothenic acid
B6
B12
Folic acid
C
D
E
H
K
5000 I. U.
1.5 mg
1.7 mg
20 mg
10 mg
2 mg
6 g
0.4 mg
60 mg
400 I. U.
30 mg
0.3 mg
1000 I. U.
1.2 mg
1.3 mg
1.6 mg
5 mg
1.3 mg
2.4 g
0.4 mg
60 mg
200 I. U.
10 mg
80 g
20006000 I. U.
0.752.25 mg
0.82.6 mg
927 mg
412 mg
13 mg
39 g
0.20.8 mg
3090 mg
100 600 I. U.
624 mg
75225 g
50150 g
Dexpanthenol
These figures are of importance for pharmacists, because the formulations of multivitamin products are often based on
them so that each dose contains exactly
the relevant daily requirement or a multiple thereof. Thus, for example, it is
customary in the FRG for vitamin products with up to three times the daily
requirement per dose to be declared as
food products (see also food products
and marketing).
Dexpanthenol
Dexpanthenol (syn. D-panthenol, D-pantothenyl alcohol, provitamin B5) is quantitatively converted into D-pantothenic
acid in the body. Thus 1.0 g dexpanthenol is equivalent to 1.068 g D-pantothenic
acid.
Dexpanthenol is a colo(u)rless liquid
which is soluble in water but, due to its
very high viscosity, is not easy to process.
For this reason, dilutions in propylene
glycol or water are also commercially
available.
Stability of dexpanthenol and calcium pantothenate in multivitamin drops (6 weeks,

45 C).
34
Dexpanthenol is particularly used in liquid and semisolid drug forms, because it
is much more stable in them than is, for
example, calcium pantothenate [21, 220].
This especially applies to combinations
with other vitamins where the pH-dependent hydrolysis and the chemical interactions with other vitamins are of great importance. The preceding figure shows the
difference in stability between dexpanthenol and calcium pantothenate in multivitamin drops [41].
It is clear from this figure that, unlike
calcium pantothenate, dexpanthenol is relatively stable in aqueous solutions when
the pH is below 5. This is very important
for use in vitamin B complex solutions.
For comparison with sodium pantothenate, see under this entry.
In the following example of a vitamin B
complex + C syrup, the loss of dexpanthenol after storage at room temperature
for 12 months was 10 % (see also B complex).
I. Thiamine hydrochloride
Nicotinamide
Dexpanthenol
Orange flavo(u)r
acid, sodium salt
Propyl gallate
Sorbic acid
Sorbitol
Glycerol
Propylene glycol
Water
II. Sucrose
Water
60 mg
55 mg
250 mg
120 mg
55 mg
800 mg
25 mg
5 mg
50 mg
200 mg
5.0 g
10.0 g
9.0 g
10.0 g
5.0 g
64 g
36 g
Mix solution I with syrup II, adjust the pH

to 4.04.3, and store under nitrogen.
35
Direct compressible vitamins
Another possibility for the stabilization

of dexpanthenol in an aqueous medium
is to add D-pantolactone [158].
This particularly applies to the extensive
use of dexpanthenol in products for external use, it being particularly used in
ointments and creams to promote wound
healing [191]. It can also be combined
with tretinoin, as is shown by the following composition for a cream.
Tretinoin cream containing dexpanthenol
I. Tretinoin
Luvitol EHO [1]
II. Cremophor A 6 [1]
Cremophor A 25 [1]
Glyceryl monostearate
Cetyl alcohol
Tegiloxan 100 [7]
III. Butylated hydroxytoluene
Propylene glycol
Dexpanthenol
Preservative
Water
0.05 g
8.0 g
3.0 g
1.5 g
3.0 g
3.0 g
0.5 g
0.04 g
4.0 g
2.5 g
0.5 g
73.8 g
Heat mixture II to 75 C, and stir in solution

I. Heat mixture III until a clear solution is
obtained, add hot mixture I/II, and stir while
cooling.
In multivitamin soft gelatin capsules and

coated tablets, it is possible to incorporate dexpanthenol in the gelatin or sugarcoating in order to avoid chemical interactions with other vitamins.
For use in tablets and hard gelatin capsules, dexpanthenol adsorbates on silica gel
are commercially available.
Dextrin
Dextrin is a product of the breakdown of
starch and is used like gum arabic as a
protective colloid in the production of
vitamin dry powders. It can also act as a
filler in the tabletting of ascorbic acid
[21].
Dextrose
see glucose.
Direct compressible vitamins

Since their physical properties mean that
not all vitamins are suitable for direct
tabletting, a number of modifications
have been worked out specifically for
this purpose and are commercially available. This is of particular interest for
high-dose vitamins, because a direct tabletting auxiliary may solve the problem
when the concentration of the relevant
vitamin in the tablet is low.
The most important commercially available vitamins for direct compression are
vitamins A, C, D and E. Corresponding
B vitamin products are only of minor importance in Europe.
In place of vitamin A, the usual dry powders can be used for direct tabletting with
varying success. It is possible with some
modified products to manufacture small,
high-dose tablets, e.g. having the following composition.
Vitamin A tablet (75,000 I. U.)
Retinyl acetate dry powder
500,000 I. U./g [1]
Talc
163 mg
82 mg
5 mg
For another example of its use, see sorbitol.

In the case of vitamin C, types containing
2 to 10 % auxiliaries are commercially
available for direct compression. The
amount of auxiliaries which are needed
for direct tabletting depends on the ascorbic acid type [198, 261]. An example
is the following composition for a tablet.
Direct tabletting
36
Vitamin C tablet (500 mg)

compression
Sorbitol
powder
Orange flavo(u)r
530 mg
50 mg
37 mg
10 mg
5 mg
For further examples of ascorbic acid for

direct tabletting, see adsorbate, compaction and trace elements. The brochures of
the manufacturers of vitamin C products
for direct compression also contain suggested formulations.
In the case of vitamin E, spray-dried dry
powders containing 25 to 50 % tocopheryl acetate are most suitable for direct
tabletting. For examples of their use, see
calcium hydrogen phosphate, Ludipress,
multivitamin products, and sorbitol.
Direct tabletting
Direct tabletting or direct compression
means the compression of a powder mixture without previous granulation. The
active ingredients and auxiliaries are mixed and compressed. Many vitamins are
unsuitable above a certain concentrations
in the tablet for this type of processing,
because the particles are very fine, or the
flow properties are poor, or the hardness
of the resulting tablets is inadequate, or
they are in the form of liquids or pastes.
On the other hand, direct tabletting is the
best way of producing tablets for a variety
of vitamins, for reasons of stability, because
this process avoids contact with solvents
especially water and the possibility of
solvent residues. Thus, direct tabletting auxiliaries and direct compressible vitamins
are increasingly being used for the manufacture of vitamin products [198].
For examples of the use of direct tabletting, see adsorbate, ascorbic acid, B
complex, beta-carotene, calcium hydrogen phosphate, calcium pantothenate,

cellulose, compaction, copovidone, crospovidone, direct compressible vitamins,
direct tabletting auxiliaries, colorants,
minerals, sodium ascorbate, nicotinamide, tabletting pressure, pyridoxine hydrochloride, retinyl actate, riboflavin, sorbitol,
trace elements, and thiamine mononitrate.
Direct tabletting auxiliaries

A number of auxiliaries or auxiliary formulations are marketed with the object of
facilitating or making possible direct tabletting. Some of these products are listed in the table below.
Direct tabletting auxiliaries (selection)
Trade name
Basis
Manufacturer
Avicel types
Cellulose
Di-Tab
Calcium
phospate
Cellulose
FMC,
USA
Amstar,
USA
Degussa,
FRG
Mendell,
USA
Mendell,
USA
Elcema types
Emcompress
Emdex
Calcium
phosphate
Glucose
Karion Instant
Sorbitol
Merck,
FRG
Ludipress
Lactose +
povidone +
crospovidone
Lactose +
povidone
BASF
FRG
STA-RX 1500
Starch
Tablettose
Lactose
Zeparox
Lactose
Staley,
USA
Meggle,
FRG
Dairy
Crest,
USA
Ludipress LCE
BAS,
FRG
37
Dissolution
The following composition is an example

of a vitamin B1 tablet.
Ludipress
Magnesium stearate
55 mg
290 mg
5 mg
2 mg
Distinct differences in the disintegration

and dissolution times emerged when various direct tabletting auxiliaries were
used in a vitamin B6 tablet by way of
example. Avicel had the best results
[254].
For some applications it is straightforward to prepare direct tabletting auxiliaries rather than buy them. This applies to,
for example, calcium hydrogen phosphate or corn starch if they are granulated with 3 to 10 % polyvinylpyrrolidone
K 30. For examples of use, see crospovidone and calcium hydrogen phosphate.
Discoloration of a vitamin product is evidence of decomposition or instability of

the components. The possible causes are
listed in the preceding table. Many of
these colo(u)r changes occur most commonly in vitamin combination products
[19].
Disintegrants
The disintegrants which are most commonly used in vitamin tablets are listed
in the table which follows. Most of these
substances can be considered as dissolution agents too.
Disintegrants* in vitamin tablets
Substance
Concentration in the tablet
Carboxymethylstarch
Croscarmelose
Crospovidone
Starch
2 6 %
2 8 %
1050 %
1 5 %
1 5 %
540 %
* For details, see the individual disintegrants.
Discoloration
Possible changes in the colo(u)r of vitamin
products
Vitamin
Colo(u)r change/cause
Darker colo(u)r due to formation of thiochrome

Loss of colo(u)r due to
B2
photolysis
Decoloration due to oxidaB12
tion or photolysis
C
Yellow or brown colo(u)r
due to hydrolysis
E (alcohol)
Darker colo(u)r due to oxidation
Beta-carotene Change to a more reddish
colo(u)r due to isomerization, decoloration due to
photolysis
B1
Dissolution
The dissolution test is used to determine
the release of active ingredient or to examine the bioavailability in vitro. It may
be necessary to examine the solid forms
of the individual vitamins in different
ways, because they are absorbed at very
different points in the gastrointestinal
tract.
All in all, this test is not of importance
for all vitamins, specially the oil-soluble
vitamins.
This is evident from the fact that, for
example USP XXIV does not require
that the dissolution test be carried out
on all of the preparations listed in the
following table.
Dose
38
Dissolution test in USP monographs of solid

vitamin preparations (selection)
Preparation
Dissolution required
Ascorbic acid tablets

Beta carotene capsules
Calcium pantothenate tablets
Nicotinamide tablets
Oil-Soluble vitamin tablets
Oil- and water-soluble
vitamin tablets
Pyridoxine HCl tablets
Riboflavin tablets
Thiamine HCl tablets
Vitamin A capsules
Vitamin E capsules
Water-soluble vitamin tablets
+
+
+
+
+
+
Dose
see daily requirement.
D-panthenol
see dexpanthenol.
D-pantothenic acid
see pantothenic acid.
Drops
Vitamin drops have become relatively
rare, because the stability of the vitamins
is considerably greater in a syrup, for
example, and even more so in solid
forms.
Dry powders
In connection with vitamins, dry powders
are produced from vitamins and auxiliaries by embedding, granulating, tritura-
ting or mixing, with the content of auxiliary being at least 50 %.

The possible reasons for producing and
using vitamin dry powders in drug forms
are as follows:
1. The vitamin is a liquid and has to be
converted into a solid form for use in
tablets, hard gelatin capsules, etc. Typical examples are adsorbates or granules of tocopheryl acetate and dexpanthenol.
2. The stability of the vitamin in adsorbates is inadequate, resulting from the
increase in direct contact with oxygen
due to the large surface area, and the
expressibility is too great. In this case,
microencapsulation is carried out, e.g.
in a gelatin/carbohydrate matrix which
has a relatively low permeability to
oxygen . Typical examples are dry
powders of vitamins A and D.
3. The stability of the vitamin in triturations or adsorbates is inadequate, resulting from promotion of chemical
interactions by contact with other vitamins. This is countered by embedding the vitamin in a gelatin matrix,
for example.
One example is vitamin B12 which
decomposes in direct contact with ascorbic acid [25].
4. The dose of the vitamin in the drug
forms is normally so low that inhomogeneities may be produced on mixing
with other vitamins and/or auxiliaries.
This problem is solved by preparing
dry dilutions in the form of triturations
(e.g. vitamin B12) or embedding the
vitamin in a gelatin/carbohydrate matrix (e.g. vitamins D and B12).
5. The odo(u)r or taste of the vitamine is
offensive in the drug form. Such undesired organoleptic properties can be
greatly reduced by embedding in a
matrix. Typical examples are dry powders of vitamin B1 or B2.
39
There has been a large number of publications on the methods of producing dry
powders [14, 41]. The principal processes
are spray-drying, spray-cooling, the adsorbate technique and the double-emulsion process.
Apart form these dry powders vitamins,
which have been coated or granulated in
Dry powders
various ways to improve the stability or
for direct tabletting, are commercially
available. The auxiliary content in these
products does not exceed 10 %. Typical
examples are vitamin B2 and, especially,
vitamin C.
E, vitamin
40
E
E, vitamin
see tocopherol, tocopheryl acetate, tocopheryl nicotinate, tocopheryl PEG succinate, tocopheryl succinate, and tocopheryl succinate calcium.
EDTA
see ethylenediaminetetraacetic acid.
Effervescent tablets
Effervescent tablets are a popular form
for vitamins, especially for vitamin C
and multivitamin products. The effervescence is caused by the liberation of carbon dioxide, which is brought about by
use of sodium bicarbonate (and sodium
carbonate) together with citric, tartaric
or ascorbic acid.
The stoichiometric ratios of the amounts
of sodium bicarbonate to these acids are
as follows [259]:
1 g sodium bicarbonate is equivalent to
0.76 g anhydrous citric acid, 0.90 g tartaric acid or 2.09 g ascorbic acid.
In practice, these components are often
granulated, as in shown by the example
of the composition of a vitamin C effervescent tablet to the right.
Direct tabletting of effervescent tablets is
also possible, but strict care must be taken about the relative humidity during
production and packaging.
This particularly applies to vitamin C
effervescent tablets, its being necessary
not to exceed 30 % relative humidity in
order to avoid problems when tabletting
and with discoloration [34]. To produce
effervescent tablets with a high vitamin C
content by direct tabletting, it is necessary to use types of ascorbic acid designed

for this purpose [261].
Vitamin C effervescent tablet (500 mg)
I. Sodium bicarbonate
500 mg
Tartaric acid
400 mg
II. Polyvinylpyrrolidone K 25 8 mg
Isopropanol
q.s.
III. Ascorbic acid, crystalline
550 mg
Sucrose (0.5 mm)
661 mg
IV. Polyethylene glycol 6000,
powder
67 mg
Orange flavo(u)r
10 mg
1 mg
Granulate mixture I with solution II, pass
the granules through a 0.5 mm screen, and
dry at 70 C. Also dry mixture III at 60 C,
and mix with I//II and IV. Compress to
effervescent tablets at a relative humidity
not exceeding 35 %.
For further examples of effervescent tablets, see compaction, multivitamin solid

preparations and tartaric acid.
Elcema
Registered trademark [4] for various types of microfine cellulose.
Emulsion
The emulsion is a drug form which is
used for vitamins, too. This particularly
applies to the solubilization of the lipophilic vitamins, in which a transparent
microemulsion is produced.
Less fine emulsions (macroemulsions)
are produced in the form of creams, lotions and high-concentration vitamin am-
41
E number
pules for veterinary use. This is shown by

the following example of a formulation
for a physically stable emulsion for injection which contains 500,000 I. U. vitamin
A, 75,000 I. U. vitamin D and 50 mg
vitamin E acetate per ml.
Vitamin A/D/E emulsion for injection (for
veterinary use)
A number of other auxiliaries used in

vitamin products are included in the following list of E numbers [47].
E numbers of food additives (selection)
Antioxidants
E 300E 304
Retinyl propionate
23.0 g
Cholecalciferol
0.2 g
Tocopheryl acetate
5.5 g
PEG-15 hydroxysterate
15.0 g
0.5 g
Benzyl alcohol
1.0 g
Water
ad 100 ml
Heat all the components, apart from water, to
60 C and slowly stir in the water, which is at
the same temperature. The pale yellow lowviscosity emulsion can be sterilized by filtration or by heat. After heat-sterilization, the
ampules should be briefly shaken while hot
in order to eliminate any phase separation.
E 306E 309
E 310E 312
On the chemical stability of this emulsion, see prediction of stability.
E 413
E 414
E 415
E 440 a + b
E 461
E 466
E number
All substances which appear on the European Community List of Approved
Food Additives have been given a number, called the E number. Only vitamins
which act as auxiliaries have an E number [47].
E numbers of vitamins acting as auxiliaries
E 101
E 101 a
E 160 a
E 300
E 301
E 302
E 304
E 307
Riboflavin
Riboflavin-Phosphate sodium
Carotene
Ascorbic acid
Sodium ascorbate
Calcium ascorbate
Ascorbyl palmitate
Tocopherol and tocopheryl
acetate
E 320
E 321
Ascorbic acid and

ascorbates
Tocopherols
Gallates (e.g. propyl
gallate)
(BHA)
(BHT)
Thickening or gelling agents

E 400E 405
E 410
E 412
Alginic acid and alginates

Locust bean gum
(galactomannan)
Guar gum
(galactomannan)
Tragacanth
Gum arabic
Xanthan
Pectins
Methylcellulose
Emulsifiers, stabilizers
E 322
E 470
E 471
E 472 af
E 475
Lecithins
Salts of fatty acids
Mono- and diglycerides
of fatty acids
Mono- and diglycerides
of fatty acids esterified
with fruit acids
Polyglycerol esters of
fatty acids
Acidifying agents, acidity regulators

E 322
E 325E 327
E 330E 333
E 334E 337
Carbon dioxide
Lactates
Citric acid and citrates
Tartaric acid and tartrates
Ergocalciferol
42
E numbers of food additives (contd.)
Ergocalciferol
Others
E 420
E 421
E 422
E 460
Sorbitol
Mannitol
Glycerol
Microcrystalline or
powdered cellulose
Colorants
E 101
E 102
E 104
E 110
E 122
E 123
E 124
E 127
E 131
E 132
E 140
E 141
E 142
E 150
E 151
E 160 af
E 161 ag
E 162
E 163
E 170
E 171
E 172
Lactoflavin (riboflavin)
Tartrazine
Quinoline yellow
Orange yellow S
Azorubine
Amaranth
Cochineal red A
Erythrosine
Patent blue V
Indigotine I
(indigo carmine)
Chlorophylls a + b
Copper complexes of
chlorophyll and chlorophyllins
Acid brilliant green
Caramel
Brilliant black BN
Carotenes and carotenoids
Xanthophylls
Beetroot red (betanin)
Anthocyanins
Calcium carbonate
Titanium dioxide
Iron oxides and hydroxides
Ergocalciferol (syn. calciferol, vitamin

D2) is a white crystalline powder which
is insoluble in water. it is soluble in
ethanol.
Ergocalciferol is one of the lipophilic
vitamins and has a biological vitamin D
activity of 40 million international units
per gram. The importance of D2 is much
less than that of cholecalciferol (= vitamin D3), because the vegetable starting
materials for the synthesis of vitamin D2
are less readily obtainable.
The problems associated with formulating ergocalciferol are the same as those
with cholecalciferol (for details, see that
entry).
Preservatives
E 200E 203
E 210E 213
E 214E 219
E 220E 227
Sorbic acid and sorbates

Benzoic acid and benzoates
P-hydroxybenzoic esters
(parabens)
Sulfur dioxide and sulfites.
Binders, disintegrants
E 1201
E 1202
Povidone
Crospovidone
Solubilization of vitamin D2 using PEG-40

glyceryl trihydroxystearate.
43
The solubilization reveals a difference.
The preceding graph shows the amounts
of the solubilizer PEG glyceryl trihydroxystearate required to prepare clear solutions of ergocalciferol. The figures are
based on the solubilisates.
Also beta-cyclodextrin improves the solubility of ergocalciferol [266].
The isomerization products, which may
occur in ergocalciferol solutions, include
isotachysterol, precalciferol and isocalciferol [58].
Ethanol
Ethanol is popular, especially in countries with a low duty on alcohol, as a
solvent for the granulation of vitamins
or for the production of vitamin solutions
containing up to 25 %. At concentrations
above 15 % ethanol can also act as a
preservative.
Ethylcellulose
Ethylcellulose is a white, free-flowing,
odo(u)rless powder. It is insoluble in water, glycerol and propylene glycol, and
virtually non-hygroscopic (for the graph
of water adsorption, see hygroscopicity).
Apart from its use as a binder, ethylcellulose is used for film-coatings of vitamin
tablets. The following example of a composition of a coating suspension is for use
in a fluidized bed.
Ethylcellulose is also used for coating
crystals, e.g. of ascorbic acid, to improve
the stability.
Suspension of ethylcellulose for film-coatings
Ethylcellulose
5g
Copovidone
5g
Titanium dioxide
20 g
Talc
13 g
Colo(u)r lake
18 g
Isopropanol
98 g
Water
41 g
300 g of the suspension are passed through a
mill and then mixed with 210 g isopropanol
and 90 g water before being used for coating 2 kg of cores (200 mg, 9 mm).
acid
Ethylenediaminetetraacetic acid (syn.

EDTA) is used in the form of the disodium
or the disodium calcium salt. Both are
white powders which are soluble in water.
EDTA salts are used as chelating agents
to bind heavy metals in aqueous solutions
of vitamins in order to eliminate or diminish their catalytic action on the oxidative breakdown of some vitamins. Hence
EDTA may perform the function of a
synergist.
EDTA is only slightly soluble in oil and
is thus scarcely suitable for oily systems.
The vitamins which are listed in the table
below can be stabilized by addition of,
for example, 0.01 % or 3 mmol/l EDTA
to the solution.
Stabilization of vitamins in solution by EDTA
Ascorbic acid [5960, 248]
Thiamine hydrochloride [6364]
Pyridoxine hydrochloride [65]
Nicotinamide [59]
Tocopherol [66]
Expiration date
44
For examples of the use of EDTA in
formulations, see B complex, dexpanthenol, polyvinylpyrrolidone, and sorbitol.
Expiration date
Stabilization of ascorbic acid by EDTA in a

multivitamin solution.
The preceding figure demonstrates the

stabilizing effect using the example of
ascorbic acid in a multivitamin solution
[59].
However, this stabilization of ascorbic
acid by EDTA will often be effective
only if the solution has not been treated
and covered with an inert gas, or the
solution contains oxidizing agents, because heavy metal ions only catalyze the
oxidative breakdown of ascorbic acid
[20].
The expiration date of a vitamin product

depends on its physical and chemical stability. The chemical stability is usually
the limiting factor, which can be dealt
with by a variety of measures, including
overages if everything else fails. The expiration date is fixed on the basis of stability tests and predictions of the stability, normally being the last date at which
it is certain that the vitamin content is not
below 90 % of the declared figure.
Expressibility
The expressibility or extrusion of oily
vitamins from dry powders is of importance in assessing the suitability of such
powders for use in tablets [258]. If the
extrusion is high, the tablets have a
greasy appearance (e.g. vitamin E)
and/or reduced chemical stability (e.g.
vitamin A). The expressibility is usually
distinctly less with gelatin-based dry
powders than with simple adsorbates.
45
Film-coating
F
F, vitamin
see fatty acids.
Fat-soluble vitamins
see lipophilic vitamins.
Fatty acids, polyunsaturated

The polyunsaturated fatty acids are also
called omega fatty acids. The omega 3fatty acids consist mainly of eicosapentaenic acid (EPA) and docosahexaenic
acid (DHA), and the omega 6-fatty acids
consist mainly of linoleic acid, g-linolenic acid and arachidonic acid. Together
with other unsaturated fatty acids it was
formerly called vitamin F.
Polyunsaturated fatty acids are oxidized
by oxygen to resins, which can be retarded by the addition of antioxidants. Omega fatty acids are frequently incorporated
in soft gelatin capsules for pharmaceutical or nutraceutical use.
Fdration Internationale
Pharmaceutique
The Fdration Internationale Pharmaceutique (abbreviated to F. I. P.) is an international association of pharmacists.
Two recommendations of the industrial
pharmacy section of the F. I. P. are of
some importance for vitamin products:
1. Overages for vitamins
The recommended overages of the individual vitamins in various drug
forms were published in 1965. For
details, see overage.
2. Microbiological status
A report in 1975 published a proposal
about the microbiological status of
pharmaceuticals. For details, see microbiology.
Fillers
Where the concentration of active ingredient in tablets and hard gelatin capsules
is low (e.g. vitamins A, B and D), a filler
in powder form is required. The fillers
used most widely in vitamin products
are listed in the table below.
Important fillers for vitamin tablets and
capsules
Corn starch
Glucose
Lactose
Mannitol
Sorbitol
Sucrose
Direct tabletting auxiliaries also usually

act as fillers.
Film-coating
Whereas sugar-coating was more often
used in the past, nowadays film-coating
of tablets is increasingly preferred, because it can be carried out more quickly
and with more automation. Film-coatings
are produced with film-forming agents
which are virtually always synthetic.
Coatings containing natural shellac are
now of minor importance and they can
be produced satisfactorily and reproduci-
Fish liver oil
46
bly only if a synthetic film-forming

agents (e.g. copovidone) is also used.
The coating agents which are most widely used are cellulose derivatives, such as
hydroxypropylmethylcellulose, cellulose
acetate phthalate, methacrylic acid derivatives, copovidone, polyethylene glycols
and polyvinylpyrrolidone. A distinction
must be made between coatings which
are soluble in and those which are resistant to gastric juice. The latter are of
little importance for vitamin tablets. It is
possible, and often advantageous, to
combine various film-forming agents. A
typical composition for an aqueous suspension for a water-soluble film-coating
with copovidone/hypromellose is as follows:
Suspension for a water-soluble film-coating
for tablets
I Copovidone
Hypromellose 6 mPa.s
Water
II Pigments (white + red)
Talc
Water
Total:
53 g
12 g
79 g
732 g
54 g
54 g
216 g
1200 g
Mix solution I with suspension II to obtain

the final coating suspension
For a other examples, see ethylcellulose

and sugar-coating.
The importance of organic solvents for
film-coating continues to decrease.
In the case of multivitamin tablets, sugarcoating is preferable to film-coatings, because the latter are more permeable to
oxygen and humidity and thus have a
distinctly poorer stabilizing effect. This
also applies to colo(u)ring of the coatings
with carotenoids, which are stable to
light only in sugar-coatings. A satisfactory compromise is a film-coating containing a combination of sucrose and a syn-
thetic film-forming agent (see sugar-coating).
Fish liver oil

Fish liver oil was formerly used as an
important source of vitamins A and D,
especially for children. Nowadays in Europe it is of only importance, in the form
of soft gelatin capsules, it contains a relatively high proportion of unsaturated
fatty acids (vitamin F).
It is advisable, to stabilize the vitamins in
fish liver oil, to add a combination of
antioxidants, e.g. tocopherol or butylated
hydroxytoluene with ascorbyl palmitate,
in order to prevent the oxidation of the
unsaturated fatty acids, since the fatty
acid peroxides decompose vitamins A
and D.
Flavonoids
see bioflavonoids.
Flavo(u)ring
Flavo(u)ring is an important factor with
most oral vitamin products, because some
vitamins have an unpleasant taste and/or
odo(u)r. Fruit flavo(u)rings are often
used, in solid or liquid form (orange,
stawberry, lemon, maracuya etc.), as
well as sugars or sweeteners. For example, in order to mask the acid taste of
ascorbic acid, it is possible to add fructose, sucrose, saccharin and/or cyclamate, or to replace part of the ascorbic
acid by sodium ascorbate or calcium ascorbate.
For examples of the flavo(u)ring of formulations, see adsorbate, ascorbic acid,
B complex, copovidone, dexpanthenol,
direct compressible vitamins, effervescent
tablets, instant granules, multivitamin
47
products, sodium ascorbate, polyvinylpyrrolidone, sorbitol, tartaric acid and
trace elements.
Polyvinylpyrrolidone can also be used to
improve the odo(u)r and flavo(u)r, e.g. of
vitamin B complex syrup.
The B vitamins can also be embedded in
gelatin for incorporation in tablets.
Flowability agents
Since many mixtures for tabletting have
poor flow properties, it is necessary to
add a flowability agent to them. The
commonest flowability agents are highly
disperse silica, talc, and starch. Some
lubricants may also improve the flow
properties of a powder mixture.
Folic acid
sufficiently. If this is impossible, the
composition of the solubilizate must be
altered:
1. Addition of silicone oil in very low
concentration.
2. Addition of polypropylene glycol
2000.
3. Addition of Poloxamer 231.
4. Modification of the solvent composition.
5. Change of the solubilization technique
(vice-versa method, see solubilization).
Folic acid
Fluidized bed
The technique of fluidized bed granulation is of considerable importance in the
production of vitamin tablets or granules,
because it is the least deleterious way of
granulating vitamins with water or a solvent, and of drying them.
This is most evident in the case of vitamin C. Granules from a fluidized bed
remain white for a long time on storage
whereas granules of the same composition produced by wet granulation rapidly
discolo(u)r.
Foaming
Undesired foaming may occur during the
solubilization of lipohphilic vitamins.
There is no generally applicable solution
to this problem. If it occurs, tests are to
be carried out to determine whether the
technique of solubilization can be modified, by reducing the stirring speed or
similar measures, to reduce the foaming
Folic acid (syn. pteroylglutamic acid, vitamin Bc or vitamin M) is a yellowish or

orange crystalline powder which has virtually no taste or odo(u)r. The solubility
of folic acid in 1 l of water is 1 or 2 mg at
25 C and 100 mg at 100 C. There is a
great increase in solubility when the pH
is increased above 6 (for diagram, see
complexes, curve 1). Of the customary
organic solvents, only methanol acts as
a solvent to a limited extent.
In liquid drug forms, folic acid is particularly sensitive to reducing agents (e.g.
ascorbic acid) and light. The stronger
oxidizing agents and heavy metals may
also adversely affect the stability of folic
acid. Effective antioxidants are nordihydroguaiaretic acid and butylated hydroxyanisole [35]. The optimal pH for stability is between 6.0 and 9.8. It is very
difficult to combine it with most of the
B vitamins because of the pH. In the case
Food products
of products for injection, this problem
may be solved by separate solutions (see
two-chamber ampules).
Hydrolysis of folic acid results in pterincarbaldehyde and p-aminobenzoylglutamic acid [68].
Nicotinamide distinctly increases the solubility of folic acid (see complexes). Riboflavin and ascorbic acid have adverse
effects on the stability.
It was possible by use of microcrystalline
cellulose in solid drug forms to achieve
satisfactory stability with a decrease of
only 1 % a year [69].
In multivitamin tablets it is possible to
avoid the chemical interactions with the
other vitamins by producing multilayer or
laminated tablets or by incorporating the
folic acid in the coating.
Food products
Nowadays a number of vitamin products, especially multivitamin formulations, are marketed in pharmaceutical
forms as food products or dietetics in
many countries. In the FRG, this is normally permitted with vitamin doses up
to three times the daily requirement (for
details, see marketing). It has to be remembered when developing these forms
that not all auxiliaries and vitamin derivatives used in pharmaceuticals are permitted for use in food products. Legal
requirements must be observed in such
cases. In the FRG, for example, only the
vitamin derivatives listed in the foregoing table are permitted in dietetic
food products.
48
Vitamin derivatives permitted in food products (FRG)
Beta-carotene
Ascorbic acid
Sodium ascorbate
Potassium ascorbate
Calcium ascorbate
Ascorbyl palmitate
Thiamine mononitrate
Riboflavin
Nicotinamide
Nicotinic acid
Sodium pantothenate
Tocopherol
Tocopherol acetate
Tocopheryl succinate
Retinyl acetate*
Retinyl palmitate*
Ergocalciferol*
Cholecalciferol*
Cholecalciferol-cholesterol*
* Only permitted in margarine, dietary products
and baby food.
In the FRG, some auxiliaries are not permitted in food products, examples being
microcrystalline cellulose, polyethylene
glycol, many solubilizers, etc.
In the USA new labeling requirements
developed by the Food and Drug Administration (FDA) are reported. Products
containing ingredients such as vitamins
or minerals intended to supplement the
diet will have to be labeled as dietary
supplements [273].
Freeze-drying
see lyophilization.
Friability
see tablet friability.
49
Fructose
Fructose (syn. D()-fructose, levulose) is

a white powder which is freely soluble in
water.
Fructose is the sweetest sugar. Its sweetening power is about 1.7 times that of
sucrose.
Fructose is suitable as a filler and flavo(u)ring in some solid vitamin formulations. at high concentrations it improves
the stability of ascorbic acid solutions
[70]. however, it has to be remembered
that fructose is a reducing agent. Fructose granules containing, for example,
3.5 % polyvinylpyrrolidone are very suitable for the direct tabletting of vitamin
tablets [71].
Fructose stabilizes sodium ascorbate solutions when present in about 10 % of the
amount of sodium ascorbate [20].
Fursultiamine
Furfural
Furfural occurs in vitamin C products,
together with carbon dioxide, as a result
of the hydrolysis of dehydroascorbic acid
[72, 73].
The resins which are formed from furfural and are very intensely colo(u)red have
serious effetcs on white vitamin C tablets, in particular, but solutions may
also become perceptibly discolo(u)red.
Fursultiamine
Fursultiamine (syn. thiamine tetrahydrofurfuryl disulfide) is a vitamin B1 derivative which is rarely used, is only sparingly soluble in water and thus is usually
employed only for solid drug forms.
Lyophilisates are stabilized by sodium
dextran sulfate [247].
Galactomannan
50
G
Galactomannan
Galactomannan is the main constituent of

locust bean gum (E number E 410) and of
guar gum (E 412). It is a polysaccaride
composed of galactose and mannose. The
galactomannan from locust bean gum
contains mannose and galactose in the
ratio of about 1 : 4 (see formula) while
in guar gum a galactose unit is bonded to
every second mannose molecule.
Galactomannan does not form a clear
solution in cold water, and is thus used
only in solid vitamin products as a filler.
It is mainly used for producing cyanocobalamin triturations.
In 250 mg vitamin C tablets, contents of
galactomannan exceeding 20 % cause release to be delayed [30].
Gelatin
Gelatin is the water-soluble product of
the breakdown of the scleroprotein collagen by boiling. It contains at least 95 %
protein and is virtually odo(u)rless and
tasteless. At 25 C, gelatin adsorbs up to
10 times its weight of water but does not
dissolve. It dissolves immediately at
37 C.
See hygroscopicity for the water-adsorption curve.

The various types of gelatin can have the
following functions in vitamin products:
1. Binder
In recent years, the use of 2 to 20 %
gelatin solutions for granulation has
decreased in favo(u)r of other polymers. The reasons include the difficulty of manipulating the gelatin solutions, the greater risk of microbiological
contamination, and the variability in
the pharmaceutical properties. A gelatin solution is best prepared by braking up the gelatin, leaving it to swell
in cold water for 15 minutes, and then
heating the mixture until it has dissolved.
2. Disintegrant
Formaldehyde-gelatin was formerly
used as a tablet disintegrant.
3. Matrix for vitamin dry powders
Dry powders of lipophilic, and in
some cases also hydrophilic, vitamins
are often produced using a gelatin matrix, because this stabilizes, both mechanically and chemically, that vitamins in them. A typical example is
51
Glycerol
the following qualitative composition
of the matrix for a vitamin A dry
powder.
Matrix for a vitamin A dry powder

Gelatin
Sucrose
Starch
Sodium aluminium silicate
4. Soft gelatin capsules

In this drug form, gelatin is used as a
flexible encapsulating material which
envelops the liquid, nonaqueous contents and stabilizes the vitamins contained therein.
5. Hard gelatin capsules
Hardened gelatin, in form of two-piece capsules, is used as a material for
encapsulating powder mixtures and,
more recently, solidified melts or
even non-aqueous liquids.

I. Ascorbic acid, crystalline
Glucose monohydrate
II. Polyvinylpyrrolidone K 90
Isopropanol + water (1+1)
III. Polyethylene glycol 6000,
powder
Flavo(u)r
110 mg
500 mg
4 mg
q.s.
6 mg
q.s.
For another example of its use in tablets,

see effervescent tablets.
Glucose is useful in sugar-coating in the
form of what is called a smoothing syrup.
Glucose can act as a stabilizer in liquid
drug forms using vitamins. Thus, for example, ascorbic acid is much more stable
in a glucose syrup than in pure water
[17]. However, this does not apply to
cyanocobalamin [74].
Glycerol
Glucose
Glucose (syn. dextrose, grape sugar, alphaD-glucopyranose) is a white, odo(u)rless

powder which is soluble in water and has
a slightly sweet taste. For the adsorption of
water, see hygroscopicity.
In solid drug forms containing vitamins,
glucose monohydrate is used as a filler,
especially in lozenges and chewable tables. In addition to this function, it acts as
a binder to a certain extent, which may
reveal itself in an increase in the tablet
hardness. The following composition for
a vitamin C tablet is an example of its
use.
Glycerol (syn. glycerine) is a colo(u)rless, syrupy liquid with a sweet taste. It

is highly hygroscopic and is miscible
with water, ethanol and propylene glycol.
It has the E number E 422.
In the production of solid drug forms,
glycerol is used in tablet coatings and
gelatin capsules as a wetting agent and
plasticizer. For examples of use, see filmcoating.
In liquid vitamin products, glycerol increases the viscosity, reduces the rate of
diffusion, and thus may improve the stability of vitamin B1 [75], vitamin B12 [74,
76] and vitamin C [17, 22, 75, 77]. The
sweet taste is usually regarded as advantageous. For examples of use, see ascor-
Granulation
bic acid, dexpanthenol, sorbitol and syrup.
Addition of glycerol may allow the
amount of solubilizer in a multivitamin
solution to be reduced [246].
At contents above about 30 %, glycerol
acts as a preservative.
Granulation
The types of granulation which are most
commonly used for vitamin products are
as follows:
1. Wet granulation with binder solution
The vitamins, or only a part thereof,
and a filler are granulated with the
solution of a binder in a granulator or
in a fluidized bed.
For examples, see effervescent tablets,
glucose, instant granules, lactose,
starch, thiamine hydrochloride, and
tocopheryl succinate.
2. Wet granulation with pure solvent
The procedure is identical to that in
section 1, but a dry binder must be
added to the granulating mixture, or
it must have sufficient intrinsic binding capacity, such as with nicotinamide.
For examples, see hydroxypropyl(methyl)cellulose and tartaric acid.
3. Dry granulation
Dry granulation is also called briquetting or roller compaction and entails
the dry material being compressed to
form large pieces which are then reduced to the desired particle size. The
mixture must contain a binder in order
to give the granules the necessary
hardness.
This process has the great advantage
that it operates without solvents, and
thus their adverse effects on the stability of some vitamins can be avoided.
This particularly applies to ascorbic
52
acid [261]. However, a possible disadvantage is that the particle size distribution is wider than for granules produced by wet granulation.
Granules
Possible reasons for preparing granules in
connection with vitamins are as follows:
1. Granules containing vitamins and auxiliaries are used for producing tablets
and hard gelatin capsules.
2. Granules containing vitamins and auxiliaries are themselves used as a drug
form with instant granules being most
important.
3. Granules of one or more auxiliaries
(e.g. calcium hydrogen phosphate or
lactose) are used as direct tabletting
auxiliaries.
The advantages of granules over a physical mixture of the same composition are
the good flow properties, the greater binding capacity in tablets, and the homogeneous distribution of the components,
which is not changed by mechanical
stress, such as shaking or compressing.
A binder is almost always required for
the production of granules and is incorporated by dry or wet granulation.
Gum arabic
Gum arabic (syn. arabic acid, gum acacia) is composed of linked units of arabinose, galactose, rhamnose and D-glucuronic acid. It has the E number E 414.
For solid drug forms containing vitamins,
it is possible to use gum arabic as a
matrix for vitamin dry powders or in
syrups used for sugar-coating.
Gum arabic forms highly viscous solutions which are used in liquid forms.
53
Heat
H
H, vitamin
see biotin.
Hard gelatin capsules

Hard gelatin capsules (syn. two-piece
capsules) consist of two halves which
can be assembled together and sometimes
have different colo(u)rs. They are available in various sizes which are shown
actual size in the figure below.
Hard gelatin capsules are filled either
with a powder mixture, with granules,
with a melt or with lipophilic, anhydrous
liquids. In the latter case, it is necessary
to employ a process to seal the join between the two halves of the capsule.
A typical example is provided by the
ascorbic acid capsules described below
[61].
Vitamin C capsules (100 mg)
Ascorbic acid
Mannitol + silica,
highly disperse
(99.5 + 0.5)
Size of hard gelatin capsules.
100 mg
q.s.
Hard gelatin capsules have the following

advantages over tablets: the technology
of filling is simpler than that of tabletting, and the mechanical stress on the
powder mixture during the filling of the
capsules is less than that during compression, which may have beneficial effects
on the stability of some vitamins.
The disadvantage of hard gelatin capsules
over tablets is the high surface of the
filled powder and therefore the higher
risk of oxidation by oxygen.
Hardness
see tablet hardness.
Heat
Thermal decomposition (thermolysis) is
of importance with virtually all the vitamins. In addition, heat promotes all the
other decomposition actions, such as hydrolysis, interactions, oxidation, photolysis, reduction, etc. This is why unnecessary increases in temperature should be
avoided during manufacture of the pro-
Heavy metals
54
ducts. The effects of heat sterilization

and drying processes on the stability of
the vitamins must always be checked,
and they may have to be replaced by
less deleterious methods (e.g. sterilization by filtration, fluidized bed drying, lyophilization). There are many publications
on thermal decomposition.
Publications on the thermolysis of vitamins
(selection)
Vitamin
Reference
Vitamin A
Beta-carotene
Vitamin B1
D-pantothenic acid
Vitamin B12
Folic acid
Vitamin D
215
216
42, 217 219, 250
220
193
221
210
The increase in the rate of decomposition

of vitamins is utilized in stress tests for
checking stability.
For further information and references,
see prediction of stability.
Heavy metals
In connection with vitamins, the term
heavy metals means, in particular, the
elements lead, cadmium, iron, cobalt,
copper, manganese and nickel. Even
tiny amounts (ppb range) of ions of these
elements have a catalytic effect on the
oxidative breakdown of many vitamins,
those affected being listed in the table
which follows.
Vitamins sensitive to heavy metals
Retinol and its esters
Thiamine
Riboflavin
Pantothenic acid and its salts
Ascorbic acid and its salts
Folic acid
Cholecalciferol
Ergocalciferol
Rutin
The catalytic effects of the heavy metals

vary in potency. This can be demonstrated by taking ascorbic acid as an example [16].
Catalytic effect of heavy metals on the oxidation of ascorbic acid
Cu2+ > Pb2+ > Zn2+ > Co2+ > Fe2+ >
Mn2+ > Ni2+
In the case of thiamine, a potent catalytic

effect is shown by traces of copper, in
particular; the adverse effects of other
metals are only slight in comparison
[250].
The adverse effects of heavy metals on
the stability of vitamins are countered by
adding a chelating agent, which forms
complexes with the metal ions, to the
products.
High-pressure liquid
chromatography
High-pressure liquid chromatography
(syn. HPLC, high performance liquid
chromatography) is nowadays the most
important method for quantitative deterHPLC of vitamin products
Vitamin
Reference
Vitamin A
Vitamin B1
Vitamin B2
Vitamin B6
Vitamin B12
Nicotinamide
Pantothenate
Dexpanthenol
Folic acid
Vitamin C
Vitamin D
Vitamin E
Vitamin H
Vitamin K1
78,
87,
87,
87,
89,
87,
89,
92,
88,
87,
79,
81,
89,
86,
80, 81, 82, 165

88, 90, 91, 94, 165
88, 90, 91, 94, 165
88, 90, 91, 94, 165
91, 94, 165, 276
88, 90, 91, 94, 165
93, 165, 275
165
91, 94, 96, 165
88, 165
80, 81, 83, 84, 85, 165
165
95, 165
165
55
mination of vitamins in pharmaceutical
formulations [165]. The accuracy of the
results is distinctly better than that of
methods previously used. This is an important factor in the development of a
vitamin product, because this is impossible without a series of stability tests.
The table above lists references describing the HPLC methods for the determination of each of the vitamins in their
products.
HPLC is increasingly being used for determination of the pure vitamins, too
[117, 164, 170].
Hydrolysis
Hydrolysis
Hydrolysis is one of the important ways
in which vitamins may be broken down.
This particularly applies to preparations
of thiamine hydrochloride, calcium pantothenate, dexpanthenol, nicotinamide,
pyridoxal phosphate, and ascorbic acid
(for the chemical reaction of the latter
see below). The rate of hydrolysis almost
always depends on the pH, as is illustrated by the following example of thiamine
hydrochloride [97].
HPLC
see high-pressure liquid chromatography.
Humidity
The humidity is of great importance in
the production of solid forms of vitamins. In the case of ascorbic acid tablets, effervescent tablets, and multivitamin tablets, the relative atmospheric
humidity should, if possible, not exceed
30 %, otherwise high-concentration ascorbic acid compositions adhere to the
punches during tabletting, and the adsorbed moisture always has adverse effects
on the stability of many vitamins [34,
141]. It is for this reason indispensable
for the rooms in which these vitamin
products are tabletted to be air-conditioned. As an emergency measure, it is
possible to pass dry air through the closed tabletting machine.
(see also water content and stability)
Rate of thiamine hydrolysis at 96.4 C.
The hydrolisis of ascorbic acid finally

forms carbon dioxide and a yellow to
brown colo(u)r caused by resins of furfural. Traces of water are sufficient to
start this reaction shown the figure below.
The stability of dexpanthenol solutions
also varies between the acid and alkaline
ranges, because the hydrolysis differs.
This is shown by the figure below.
Hydrophilic vitamins
56
Hydrophilic vitamins
The hydrophilic vitamins (those which
are soluble in water) are distinguished
from the lipophilic vitamins and comprise
the following:
k thiamine,
k riboflavin,
k nicotinamide,
k pantothenic acid,
k pyridoxine,
k cobalamin,
k folic acid,
k ascorbic acid,
k biotin.
However, the solubility in water may
vary widely.
Hydroxocobalamin
Hydrolysis of dehydroascorbic acid.
Stability of dexpanthenol solutions at 45 C.
(see formula below)

Hydroxocobalamin (syn. vitamin B12a)
resembles cynaocobalamin in that it takes
the form of dark-red crystals which are
soluble in water and ethanol.
Hydroxocobalamin is used in the form of
the acetate virtually only in liquid drug
forms, especially injectables. In these it is
in equilibrium with the ionic isomer
aquacobalamin [119]. The stability problems are greater than with cyanocobalamin, because it cannot be stabilized by
cyanide ions [118]. Hydroxocobalamin is
less stable than cyanocobalamin in he
presence of ascorbic acid [53, 62]. On
the other hand, in a multivitamin infusion
solution ascorbic acid is decomposed in
the presence of hydroxocobalamin, which
does not occur with cyanocobalamin
[226].
Stable solutions for injection which also
contain vitamins B1 and B6 have been
produced at a pH of 4.3 to 4.4 (acetate
buffer) with the addition of stabilizers
(antioxidants, chelating agents) [193,
57
Hygroscopicity
227]. Addition of 0.4 % L-aspartic acid

and 2.7 % sodium chloride distinctly improved the stability of a 0.1 % hydroxocobalamin solution [228]. Maleic acid
[197] and fumaric acid [230] also have
stabilizing effects. Iron chloride and citric acid, and iron (III) ammonium citrate
have been described as photostabilizers
[229].
The action of hydroxocobalamin can be
prolonged by preparing a complex with
polyvinylpyrrolidone [240].

160 mg
Lactose
20 30 mg
L-HPC
1020 mg
HPMC
04 mg
II. Water
q.s.
III. Magnesium stearate
1 mg
Talc
1 mg
Granulate mixtures I with II, add III, and
compress.
Direct tabletting of vitamin C tablets is

possible with hydroxypropylcellulose
[98].
Hydroxypropyl(methyl)cellulose
Hygroscopicity
Hydroxypropylcellulose (syn. HPC) and

hydroxypropylmethylcellulose (syn. Hypromellose, HPMC) are marketed under
the registered trademarks L-HPC [8]
and Klucel [12], and Pharmacoat [8]
and Viscontran MHPC [11]. They are
used as binders and disintegrants for
both granulation and direct tabletting.
Hydroxypropyl(methyl)cellulose is also
used as coating agent (see also film-coating).
Both substances are slightly hygroscopic
(for the water adsorption curve, see hygroscopicity).
The following composition is recommended for a vitamin B6 tablet [8]:
Uptake of water by calcium D-pantothenate at 80 % relative humidity.
Hygroscopicity
58
With the exception of dexpanthenol and

the pantothenates, the hygroscopicity of
the vitamins is low. The preceding graph
shows the uptake of water by calcium
pantothenate when stored at a relative
humidity of 80 %, the substance having
encrusted after a few days.
This contrasts with ascorbic acid which
has absorbed less than 0.05 % water after
storage for 1 day at a relative humidity of
80 %.
The hygroscopicity of auxiliaries is of
greater importance. The figures which
follow show the uptake of water after 7
days at 25 C by some commonly used
additives in vitamin products [116].
Hygroscopicity of auxiliaries.
59
Hygroscopicity
Hygroscopicity
60
61
Instant granules
I
Incompatibilities
see interactions, oxidation and reducing
agents.
Inert gas
An inert gas (e.g. nitrogen or carbon dioxide) is often used to prevent oxidation of
vitamins by oxygen. This is advisable for
all liquid drug forms containing vitamins
which are sensitive to oxygen (vitamins A,
B1, B12, C and D). The dissolved oxygen
must be driven out by passing the inert gas
through the solution, and the solution is
then packaged under inert gas.
The stabilizing effect of carbon dioxide as
an inert gas is shown by the example of an
ascorbic acid solution which follows [99].
Stabilization of an ascorbic acid solution by

carbon dioxide.
Injectables
Some vitamin combinations (e.g. multivitamin or vitamin B complex) in liquid
drug forms entail very great or even in-
soluble problems of stability. This is why

it is advisable for injection solutions to
contain as few vitamins as possible. Single-vitamin injectables are preferable.
If a combination product is indispensable,
consideration should be given to compartmented ampules, two-chamber ampules or freeze-dried injectables (lyophilization). This particularly applies if the product is to contain vitamin B12, for example.
For examples of formulations, see cyanocobalamin and two-chamber ampules.
Instant granules
Since the problems of stability with liquid multivitamin products are very
great, and some of them are insoluble,
there is a continual search for alternatives. Possibilities are solid forms such as
instant granules, oral powders, effervescent granules or effervescent tablets, since these are likewise taken in the liquid
form.
The formulations of instant granules and
oral powders may actually be the same,
the difference being in the application
form and the packaging (in a bottle which
is to be filled with water, or in individual
envelopes for dissolving).
An example of this type of use is the
following composition of multivitamin
instant granules. It may be sold as an
oral powder, in which case the patient
adds 100 ml water to 30 g and shakes
vigorously to obtain a homogeneous suspension/emulsion. The suspension stabilizers are sucrose and micronized crospovidone [260].
Interactions (chemical)
62
Multivitamin instant granules

I. Vitamin A/D dry powder
250,000/50,000 I. U./g
CWD
19.0 mg
2.6 mg
Riboflavin
3.3 mg
Nicotinamide
11.0 mg
2.2 mg
Cyanocobalamin 0.1 %,
gelatin-coated [3]
6.6 mg
115.0 mg
Tocopheryl acetate dry
powder 50 %, spray-dried
21.0 mg
Sucrose, finely ground
2000.0 mg
Crospovidone, micronized
500.0 mg
(Kollidon CL-M)
Preservative
20.0 mg
Orange flavo(u)r
100.0 mg
Calcium D-pantothenate
150.0 mg
II. Copovidone
200.0 mg
Ethanol approximately
0.7 ml
Pass mixture I through a 0.8 mm screen,
granulate with solution II, and dry the granules in an oven.
After storage of this formulation at room

temperature for 12 months, no higher
losses than 5 % were detected (exception
ascorbic acid: 9 %).
2.
3.
4.
5.
6.
7.
8.
9.
Interactions (chemical)
It is very important to take account of the
chemical interactions between the individual vitamins in the formulation of products containing several vitamins, but not
all the details of them are known. They
are much more pronounced in liquid than
in solid forms. The following chemical
interactions are known:
1. Thiamine hydrochloride is oxidized
by riboflavin to give thiochrome
with the formation of chloroflavin
[100]. Both may precipitate. Ascorbic acid may to a certain extent prevent the precipitation of thiochrome
10.
11.
12.
13.
[100], but this may result in the formation of more chloroflavin [37].
The interaction between thiamine
and riboflavin is intensified by nicotinamide.
Cyanocobalamin is slowly decomposed by thiamine breakdown products
[102104].
Nicotinamide reduces the stability of
thiamine [268].
Nicotinamide greatly potentiates the
reaction between cyanocobalamin
and thiamine [105]. This interaction
may be substantially prevented by
addition of iron (III) chloride [55
57].
Folic acid is degraded by thiamine
and riboflavin [107, 108]. However,
this reaction takes place very slowly
below pH 5 [107].Nicotinamide virtually triples the solubility of folic acid [109]. The solubility of riboflavin is also improved
by nicotinamide.
Ascorbic acid reduces folic acid
[68].
Cyanocobalamin is degraded by dehydroascorbic acid [18, 62, 110]. To
prevent this reaction, it is necessary
to stop the oxidation of ascorbic acid
to dehydroascorbic acid [18]. The
presence of copper ions plays an important part in this [111].
Ascorbic acid reduces the stability of
calcium pantothenate [112].
Ascorbic acid and nicotinamide together form the yellow complex nicotinamide ascorbate which, fortunately, does not alter the chemical
stability of either vitamin.
Riboflavin catalyzes the aerobic degradadation of ascorbic acid. This
interaction can be prevented by excluding light and oxygen [113].
Addition of nicotinamide to a solution of ascorbic acid and riboflavin-
63
phosphate sodium increases the photolysis of the latter. Tryptophan has a
stabilizing effect [101].
14. Ascorbic acid reduces the stability of
beta-carotene dry powders in solid
drug forms.
15. Ergocalciferol is isomerized by ascorbic acid, folic acid, thiamine hydrochloride, and pyridoxine hydrochloride [114].
16. Ascorbic acid in solution reduces the
halflife of thiamine, as shown by the
figure below [115].
Iron
the only possibility is to prepare an oral
powder or instant granules.
International units
The international units (I. U.) provide information on the biological activity of
vitamins. Nowadays international units
are officially used only for vitamins A
and D (see table below).
International units
Vitamin A
1 I.U.
1 I.U.
1 I.U.
1 I.U.
=
=
=
=
0.300 g
0.344 g
0.550 g
0.359 g
retinol
retinyl actetate
retinyl palmitate
retinyl propionate
Vitamin D
1 I.U. = 0.025 g cholecalciferol and
ergocalciverol
Provitamin A
Chemical interaction between thiamine and

ascorbic acid at 80 C.
It is easier than in liquid drug forms to

avoid chemical interactions in solid
forms by using some vitamins (e.g. cyanocobalamin) embedded in gelatin, in
place of the pure substance. Reducing
the water content may also be very important. Other possibilities are the use of
multilayer or laminated tablets or the incorporation of individual vitamins into
the coating or capsule shell instead of
the interior of the drug form.
There are few possibilities for preventing
interactions in liquid drug forms. In the
case of ampules, alternatives are compartmented ampules, two-chamber ampules or lyophilization. For oral products,
Normally, 1 I.U. vitamin A is stated to

be equivalent to 0.6 g beta-carotene.
The German Society for Nutrition uses
1.8 g per 1 I.U. for calculation [27].
Vitamin E
Officially, the I. U. no longer exists.
However, it is still used:
1 I.U. = 1.00 mg DL-alpha-tocopheryl
acetate
1 I.U. = 0.91 mg DL-alpha-tocopherol
1 I.U. = 0.74 mg D-alpha-tocopheryl
acetate
1 I.U. = 0.67 mg D-alpha-tocopherol
The USP units are identical to the I. U.
Iron
Iron salts are, as are other trace elements,
frequently combined with vitamins. It
should be noted that the effect of iron
Isomerization
(III) ions on the stability of some vitamins e.g. thiamine may differ from
that of iron (II) ions, as is evident from
the figure below [54].
Effect of iron salts on the stability of thiamine solutions.
Moreover, the aerobic degradation of ascorbic acid is catalyzed by irons ions

[16], and iron ascorbate has a dark violet
colour.
On the other hand, addition of 0.05 %
iron (III) chloride to liquid drug forms
may prevent chemical interactions between cyanocobalamin and thiamine hydrochloride in the presence of nicotinamide. This is explained by the oxidation
of the thiamine degradation products so
that they are no longer available to decompose cyanocobalamin [5557].
It is perfectly possible to add iron salts to
vitamins in solid drug forms [56]. For
examples of this use, see trace elements.
For the use of iron oxides for coloration,
see colorants.
64
Isomerization
Isomerization is observed with vitamins
A, D, K and beta-carotene.
1. Vitamin A, beta-carotene
Both with retinol and its esters and with
beta-carotene, isomerization takes place
mainly in aqueous solubilizates with a pH
below 6, and in oily solutions exposed to
heat. All-trans-retinol is converted mainly into the 13-cis and 9-cis isomers (see
retinol palmitate).
2. Vitamin D
Ergocalciferol and cholecalciferol may
undergo isomerization in solid forms
[58] and in acid solutions [39, 120122].
In solid drug forms the rate of isomerization of ergocalciferol may be increased
by ascorbic acid [114], but it is reduced
by polyethylene glycol 4000 [183].
3. Vitamin K
Menadione sodium bisulfite isomerizes in
neutral solution to give methylnaphthoquinone sulfonate [123].
Isopropanol
In countries where the duty on ethanol is
high, isopropanol (syn. 2-propanol) is frequently used as a solvent for granulation
or for film-coatings instead of ethanol.
Even though there is a general trend to
avoid, where possible, the use of organic
solvents in the production of pharmaceuticals, for many vitamins it is not
straightforward, for reasons of stability,
to change to using water in the usual wet
granulation. Alternatives are aqueous
granulation in a fluidized bed, dry granulation or direct tabletting.
For examples of the use of isopropanol,
see effervescent tablets, glucose, lactose,
ethylcellulose, starch, and tartaric acid.
65
Isotretinoin
Isotretinoin
Isotretinoin (syn. 13-cis-vitamin A acid,
13-Z-retinoic acid) is one of the retinoids. It is employed not as vitamin A,
but as an agent for the oral treatment of
acne in particular.
K, vitamin
66
K
K, vitamin
Kollidon
see menadione, menadione sodium bisulfite and phytomenadione.
Kollidon is the registered trademark for

soluble polyvinylpyrrolidone (povidone)
with K values between 12 and 90, crospovidone and copovidone [1].
67
Lecithin
L
Lactoflavin
see riboflavin.
Lactose
it acts primarily as a filler. However, it

also functions as a binder to a certain
extent, as is evident from the figure above, which shows the relation between the
compressive force and the tablet hardness [116].
The following formulation of vitamin B1
is a typical example of a vitamin tablet
containing lactose.
Lactose (syn. milk sugar) is a glucosegalactose disaccharide. It is a white

odo(u)rless powder which is soluble in
water. Lactose with 1 molecule of water
of crystallization (monohydrate, loss on
drying = about 5 %) is often used, but
anhydrous lactose is also commercially
available. Neither type is hygroscopic up
to a relative humidity of 80 % (for water
adsorption curve, see hygroscopicity).
The main area of use of lactose with
vitamins is in solid drug forms, in which
100 mg
Lactose monohydrate
200 mg
10 mg
Isopropanol
q.s.
III. Crospovidone
9 mg
Magnesium stearate
2 mg
1 mg
Granulate mixture I with solution II,
mix with III, and press to tablets.
Lactose, or lactose-based preparations,

are also used for direct tabletting (see
direct tabletting auxiliaries).
In vitamin products, the incompatibility
with primary and some secondary amines, which is described in the literature,
can be virtually neglected. On the contrary, ascorbic acid may be stabilized by
lactose [21, 129], as may vitamin A and
thiamine [105].
Lecithin
500 mg anhydrous lactose placebo tablets.
Lecithin is one of the monophosphatides

and is mainly composed of a- and blecithin and cephalin. It is a wax-like,
pale yellow or brown, odo(u)rless hygroscopic material. It is soluble in ethanol and fixed oils. Lecithin swells in water
with the formation of a colloidal solution.
Light
68
Sensitivity of vitamins to light
Vitamin
Lecithin is used either as an emulsifier in

food products or as a synergist to increase the effect of antioxidants (E number E 322). The synergistic action of lecithin derives predominantly from its metal-inactivating properties. It is assumed
that the cephalins have the main effect,
and this is particularly attributed to the
N-containing radical attached to the
phosphoric acid moiety. The effect decreases with increasing water content of
the substrate. The best effects of lecithin
as a synergist have been found in the
stabilization of fats, oils, and beta-carotene. Thus the following mixture of antioxidants is very suitable for beta-carotene formulations.
Retinol and esters

Beta-carotene
Thiamine (UV light)
Riboflavin
Pyridoxal phosphate
(concentration-dependent)
Cynaocobalamin
Folic acid (pH-dependent)
Ascorbic acid
Cholecalciferol, ergocalciferol
Tocopherol (UV light)
Biotin (UV light)
Phytomenadione
Rutin
Tretinoin
Reference
130
41
133
101
232
37, 172
134
135, 136
113
251, 252
41
41
255
The figure below shows the photolytic

effect of visible light on a cyanocobalamin solution [134].
Mixture of antioxidants for beta-carotene

preparations
Tocopherol
Ascorbyl palmitate
Lecithin
1 part
45 pars
515 parts
When lecitihin is used as an emulsifier, it

is advisable to add 0.05 % tocopherol as
antioxidant to stabilize it.
Light
Both visible and ultraviolett light may
have serious adverse effects on the chemical stability due to photolysis of the
vitamins listed in the following table.
Photolysis of a cyanocobalamin solution

(11 g/ml).
This is why it is worthwhile in general to

protect vitamin products from light. In
some cases, addition of auxiliaries (e.g.
methionine for ascorbic acid, tryptophan
for pyridoxine hydrochloride or sucrose
for beta-carotene may stabilize the effects of light.
69
Lipophilic vitamins
The lipophilic vitamins (syn. oil-solube vitamins, fat-soluble vitamins) are distinguished from the hydrophilic vitamins and comprise those listed in the table below.
Lipophilic vitamins
Vitamin A
Provitamin A
Vitamin D
Vitamin E
Vitamin K
(Acetiamine)
(Riboflavin tetrabutyrate)
(Ascorbyl palmitate)
Solubilization is necessary to obtain

aqueous solutions of these vitamins.
Liver extract
Lubricants
The lubricants do not all belong to the
same class of substances and thus some
of their effects differ. This is why different concentrations may be used. The
amount of PEG 6000 usually required is
a multiple of that of magnesium stearate.
However, PEG 6000 has the advantage
that it is the only one of these lubricants
which is soluble in water, which may be
of great importance for effervescent tablets, for example.
Lubricants are not normally added to vitamin tablet compositions before granulation, otherwise they lose part of their
activity. Lubricant concentrations which
are too high may adversely affect the
tablet hardness ad tablet disintegration.
Once again, polyethylene glycol is an exception, as is evident from the figure
which follows
Liver extracts are occasionally combined

with vitamins in tonics or restoratives.
They may have adverse effects on the
stability of the vitamins.
Lubricants
It is almost always necessary to add a
lubricant to a mixture which contains vitamins and is to be tabletted using the
high-speed rotary machines customary
nowadays. The lubricants most commonly used in vitamin tablets are listed in the
table below.
Lubricants commonly used in vitamin
tablets
Magnesium stearate
Talc
Polyethylene glycol (PEG 6000,
powder)
Stearic acid
Calcium arachinate
Calcium stearate
Hydrogenated castor oil
Effect of the lubricant concentration on the

hardness of placebo tablets containing
Ludipress.
Mixing with magnesium stearate for too

long also reduces the tablet hardness.
For notes on uses, see under the individual lubricants. For an example of calcium arachinate in tablets, see crospovidone.
Ludipress
70
Ludipress
Ludipress [1] is the registered trade mark
of a direct compression auxiliary.
The Ludipress grade for normal tablets
combines the properties of a filler (lactose), binder (povidone) and disintegrant
(crospovidone). The special grade for lozenges, chewable tablets and effervescent
tablets without any disintegrant is called
Ludipress LCE.
An example of its use with vitamins is
the following composition of a vitamin E
chewable tablet.
Ludipress LCE
Silica, highly dispers
400 mg
tables). The aim is to improve the stability of the vitamins by ensuring that water
is absent during storage. For example,
lyophilization ensures satisfactory stability of cyanocobalamin in the presence of
ascorbic acid [142].
The carriers which are commonly used
for the lyophilisates are glucose, glycine,
gum arabic, lactose, mannitol, low molecular-weight polyvinylpyrrolidone, and
sucrose [143].
Lysine
190 mg
10 mg
For further examples of its use, see antioxidants, ascorbic acid, beta-carotene,
direct tabletting, auxiliaries, colorants,
multivitamin products, sodium ascorbate,
tabletting pressure, and vitamin mixture.
Lumichrome
see riboflavin.
Lumiflavin
see riboflavin.
Lyophilization
The technology of lyophilization (syn.
freeze-drying) is used for the manufacture of vitamin products (especially injec-
Lysine (syn. L-lysine, 2,6-diaminohexanoic acid) is an essential amino acid and

thus is occasionally combined with B
vitamins or multivitamin products in the
form of the hydrochloride.
It reduces the colo(u)r stability of these
formulations.
Stable vitamin B complex solutions or
granules containing lysine are reported
to be produced by using 5 % polyvinylpyrrolidone K 17, 0.05 % propylgallate,
and 0.005 % ethylenediaminetetraacetic
acid [64, 144]. Stable solutions are also
possible in multivitamin compartmented
ampules [150]. The use of nitrogen as
an inert gas increases the colo(u)r stability.
71
Mannitol
M
Macrogol
see polyethylene glycol.
Macrogol glyceryl hydroxystearate
xiliaries, hydroxypropyl(methyl)cellulose,
lactose, mannitol, minerals, multivitamin
solid preparations, nicotinamide, tabletting pressure, pyridoxine hydrochlorid,
retinyl acetate, riboflavin, and starch.
Mannitol
see PEG glyceryl trihydroxystearate.
Macrogol hydroxystearate
see PEG hydroxystearate.
Magnesium stearate
Magnesium stearate is a fine white,

odo(u)rless and tasteless powder which
feels greasy. It is insoluble in water and
ethanol.
Magnesium stearate is the most widely
used lubricant for tablets, in which the
concentration does not normally exceed
1 % by weight. Higher concentrations
may have adverse effects on tablet hardness, tablet disintegration, and possibly
bioavailability. Insufficient concentrations may also be disadvantageous. It can
be combined with other lubricants (stearic acid, talc, etc.).
It is not known to be incompatible with
any vitamin.
For examples of use in formulations, see
analgesics, beta-carotene, calcium pantothenate, colorants, direct tabletting au-
Mannitol (syn. mannite) is a white crystalline powder which is freely soluble in

water but slightly soluble in ethanol. It is
not hygroscopic, and it has the E number
E 421.
Mannitol is mainly used in solid drug
forms and as a carrier for lyophilization.
In tablets, it acts not only as a filler, but
also as a binder, since it increases the
tablet hardness. This is why it is preferred for use in chewable tablets and lozenges. The pleasantly sweet, somewhat
cooling taste is an additional advantage
in this drug form. An example of its use
is the following vitamin A composition
for direct tabletting to chewable tablets.
Vitamin A chewable tablet (100,000 I. U.)
Retinyl acetate or palmitate dry
powder 325,000 I. U./g
cold-water-dispersible [1]
Mannitol
Copovidone
Magnesium stearate
355 mg
350 mg
25 mg
5 mg
3 mg
Marketing
72
Mannitol is not known to be incompatible

with any vitamin. The stability of vitamins A, B1 and C in tablets is improved
by mannitol [24].
For an example of its use in hard gelatin
capsules, see this entry.
Marketing
The laws applying to the marketing of
vitamin products differ between countries. Thus, for example, in the USA all
normal vitamin products are classified as
food. In the FRG they can be categorized as food products, OTC products, products available only in pharmacies, or
prescription drugs. The table which follows explains these categories, which are
not only based on the vitamin dose.
Classification of vitamin products (FRG)

Category
Permissible
vitamins
including
beta-carotene
Dosage
Form supplied
Foodstuffs
All, apart from

A and D
Max. 3 times
the daily
requirement
Preferentially
food products
(fruit juice,
confectionery,
etc.), but tablets
and capsules
possible
OTC drugs
All
A: max.
6000 I. U./dose.
D: max.
400 I. U./dose.
Other vitamins:
no limits
All drug forms

possible. For
cough and
throat remedies
containing vitamin C: lozenges
Drugs
available
only in
pharmacies*
All
A: max. 50,000 All drug forms

possible
I. U./dose.
D: max. 1000
I. U./dose.
Other vitamins:
no limits
Approval of the Pharmacies

Federal Board
of Health necessary (analysis, toxicity,
stability). Clinical trials also
necessary for
medical indications defined by
law
Prescription
drugs**
All
No limits
As for drugs
available only
in pharmacies
All drug forms

possible
Registration
Approval of the
Federal Board
of Health necessary (analysis, toxicity,
stability)
Marketing
channels
Food stores,
supermarkets,
healthfood
stores,
drugstores,
pharmacies
Supermarkets,
drugstores or
health food stores with specialist staff; pharmacies
Pharmacies
The manufacturer can classify an OTC drug as a drug available only in pharmacies, with the dosage
remaining the same, if there appear to be advantages in this.
** The manufacturer may decide to classify a drug which is available only in pharmacies as a prescription
drug.
73
Menadiol
Microbiology
Solubilizers can be used to improve the
solubility of menadione by as much as a
factor of 10 [26] and to influence the
photostability [26, 106, 138].
Menadione sodium bisulfite

Menadiol (syn. vitamin K4) can be used
in the form of the diacetate, dibutyrate,
tetrasodium diphosphate, or disodium
disulfate.
The diacetate and dibutyrate are insoluble
in water while the tetrasodium diphosphate and the disodium disulfate are soluble in water. Hence the two latter are
preferred for aqueous solutions (e.g. injectables).
Menadiol and its esters are sensitive to
light and oxygen.
Menadione
Menadione sodium bisulfite (syn. watersoluble vitamin K3) is a white powder,

which is soluble in water.
It is used for the preparation of aqueous
solutions (injectables). The product is not
only sensitive to light and oxygen but
also decomposes in alkaline solutions to
give menadione which may precipitate
out, and in neutral solutions it isomerizes
to methyl naphthoquinone sulfonate
[123].
Micelles
Menadione (syn. vitamin K3) is a pale
yellow powder, which is virtually insoluble in water (about 11 mg/100 ml). Solutions containing about 2 % can be obtained with vegetable oils.
The solubility of menadione means that it
is used virtually only in oily products. In
just the same way as the other vitamin K
derivatives, it is sensitive to light and
oxygen. Since phytomenadione is even
more soluble in oil than is menadione,
the former is usually preferred.
see solubilization.
Microbiology
The recommendations of the Fdration
Internationale Pharmaceutique on microbiological purity were applied to vitamin
products during many years [146]. Since
1999 the requirements of the European
Pharmacopoeia are valid as listed in the
table which follows.
Minerals
74
Grades of microbiological purity according to Ph.Eur. 1999, 5.1.4 (selection)

Category
Products
Requirements
Injections
and other sterile preparations
Sterility as defined in the Pharmacopoeia
Preparations for topical use

and for use in the respiratory
tract
Total viable aerobic count: Not more

than 102 micro-organisms (aerobic
bacteria plus funghi) per gram or per
millilitre.
Absence of Pseudomonas aeroginosa,
determined on 1 g, or 1 ml.
Absence of Staphylococcus aureus,
determined on 1 g, or 1 ml.
3A
Preparations for oral

and rectal administration
(synthetic origin)
Total viable aerobic count:

Not more than 103 bacteria and not more
than 102 funghi per gram or per millilitre.
Absence of Escherichia coli
(1 g or 1 ml).
When synthetically prepared vitamins or

auxiliaries are used, it is normally no
problem to comply with these recommendations. In the case of natural materials,
such as starch, gelatin, or D-alpha-tocopherol, more attention has to be paid to
the microbiological status (category 3 B).
Minerals
A distinction is made between the minerals, on the basis of the physiologically
essential amounts, into the macroelements which are required in gram
amounts (sodium, potassium, calcium,
phosphorus, magnesium, and chlorine)
and the trace elements, where the requirements are in the microgram to milligram range.
An example of a combination of calcium
with vitamins C and D and rutin is the
following composition for direct tabletting to effervescent tablets.

Vitamins C + D + calcium effervescent
tablet
Calcium carbonate
Ascorbic acid
Citric acid
Sodium bicarbonate
Rutin
Cholecalciferol dry powder
100,000 I. U./g
powder
Polyvinylpyrrolidone K 25 or
copovidone
flavo(u)ring
600 mg
1000 mg
1000 mg
300 mg
50 mg
4 mg
300 mg
100 mg
3 mg
q.s.
For an example of the combination of

minerals with multivitamins in tablet
form see in the table below.
75
Multivitamin tablets with minerals
(2 RDA)
Beta-carotene dry powder 10 %
50 mg
3 mg
Riboflavin
3 mg
3 mg
Nicotinamide
22 mg
12 mg
compression
100 mg
Calcium phosphate, dibasic
550 mg
Ferrous fumarate
80 mg
Magnesium oxide
160 mg
Cupric sulfate
2 mg
Manganese sulfate
14 mg
Potassium chloride
50 mg
Zinc sulfate
37 mg
60 mg
Crospovidone
50 mg
Stearic acid
6 mg
Magnesium stearate
5 mg
Total tablet weight
12200 mg
M anufacturing: Direct compression
Chemical stability: After the storage at
room temperature the following vitamin
contents were found:
6 months 12 months
98 %
96 %
Vitamin B1
98 %
92 %
Vitamin B2
100 %
99 %
Vitamin B5
97 %
96 %
Vitamin B6
Vitamin C
95 %
94 %
Moisture content of granules

The moisture content of granules means
not only the absolute water content of the
granules but also, and more importantly,
the relative humidity in the space above
the granules in a closed system. The latter parameter provides more information
than does the absolute water content about the absorbency and hygroscopicity of
the relevant powder mixture. It is important to know the moisture content of granules for tabletting, because it may affect
Multivitamin solid preparations

the mechanical properties, the behavio(u)r on compression, the accuracy of
dosing and the stability of vitamins.
Multivitamin products
One of the greatest challenges to pharmacists is the development of a multivitamin product which is as stable as possible and may be combined with trace elements.
The many factors which have adverse
effects on the stability of vitamins (see
stability) make this much more difficult
in aqueous forms than in solid or oily
products. This explains the preference
given to tablets, capsules, instant granules, two-chamber ampules, compartmented ampules, and lyophilisates. The many
publications on multivitamin products
have never revealed a clear solution to
the multiplicity of problems; they have
been able only to throw light on individual aspects [19, 24, 25, 56, 59, 75, 76,
99, 105, 143, 144, 147150, 152156,
198, 246, and many others].
Multivitamin solid
preparations
(tablets, capsules, granules)
The most stable multivitamin formulations are tablets and soft gelatin capsules.
The tablets can be sugar-coated, filmcoated or not coated. If the free water
content is limited no difference of the
stability will be found between coated
and not coated tablets. In such case the
main function of the coating is the taste
masking effect.
The vitamin derivatives given in the following table can be recommended for
tablets because they have a low content
of free water to avoid the hydrolisis and
Multivitamin solid preparations

the chemical interactions, or because
they are the most stable derivatives
against the mechanical stress of tabletting
and because they have a good flowability.
Vitamin
tablets
derivatives
for
multivitamin
Vitamin A acetate dry powder (gelatin

matrix)
Beta-carotene dry powder (gelatin
matrix)
Riboflavin powder 100 % (not needles)
Nicotinamide
Cyanocobalamin dry powder 0.1 % or
1.0 % (gelatin matrix)
Ascorbic acid, crystalline or powder
(not fine powder)
Vitamin D dry powder (gelatin matrix)
Vitamin E acetate spray dried powder.
Many formulations showed that there is

no significant influence of the auxiliaries
(binders, fillers, disintegrants, lubricants
etc.) on the stability of the vitamins if the
free water content is limited.
The most important technology for the
production of multivitamin tablets is the
direct tabletting procedure because it is
the best method to obtain a low content
of free water in the tablet.
The following two formulations of normal multivitamin tablets and multivitamin effervescent tablets are typical examples for direct tabletting..
76
Multivitamin tablet
Composition
500,000 I. U./g
Riboflavin
Nicotinamide
Cyanocobalamin 0.1 % coated [3]
50 %, spray-dried
Ludipress [1]
or Avicel PH 101 [2]
Copovidone
Magnesium stearate
Orange flavo(u)r
Stability
10.0 mg
2.2 mg
2.2 mg
16.5 mg
11.0 mg
2.2 mg
6.0 mg
85.0 mg
31.0 mg
300.0 mg
21.0 mg
3.0 mg
7.2 mg
5.2 mg
The losses of vitamins measured by HPLC

after storage at room temperature for 12
months were as follows:
8%
5%
Vitamin B2
6%
Vitamin B6
10 %
Vitamin B12
All other vitamins
0%
Multivitamin effervescent tablet (12 RDA)
Composition
Beta-carotene dry powder
10% CWD
23 mg
Vitamin E acetate 50 % dry powder 40 mg
2 mg
Riboflavin powder
2 mg
Nicotinamide
22 mg
11 mg
2 mg
Cyanocobalomin 0.1 % dry powder 6 mg
85 mg
477 mg
Ludipress LCE
Sodium bicarbonate
600 mg
Tartaric acid
400 mg
90 mg
Orange flavour
60 mg
Aspartame
30 mg
77
Multivitamin solutions
For further examples of multivitamin tablets with minerals/trace elements see

minerals and vitamin mixture.
For an example of a multivitamin oral
powder, see instant granules.
The use of an inert gas (nitrogen, argon etc.) reduces the oxidation of vitamin A.
A good protection agains light reduces
the isomerisation during storage.
Thiamine
Thiamine hydrochloride should be
used as vitamin derivative because
the solubility of the mononitrate is
low.
A good protection against light reduces the degradation.
The use of an inert gas (nitrogen, argon etc.) reduces the oxidation.
The chemical interactions between the
vitamins B1, B2 and B3 forming brownish solutions (thiochrome etc.) and
with vitamin C can only partially be
avoided by the use of solvents like
propylene glycol or glycerol.
The optimal pH is 2.03.5. The compromize of 4 is even acceptable.
The addition of povidone K 25 or 30
masks the bitter taste but flavo(u)ring
is recommended.
The presence of strong reducing
agents as antioxidants like bisulfite
must be avoided.
Because it is extremely difficult to get an

acceptable chemical stability of multivitamin solutions a summary of recommendations is given about the individual vitamins in such preparations.
Vitamin A
The best derivative of vitamin A for
the solubilisation is retinyl palmitate.
The acetate crystalizes to fast and the
solubilisates of propionate are sensitive against light (formation of turbity).
Only if a very high concentration of
vitamin A is required retinyl propionate should be used in combination
with light protection.
The selection of the best solubilizer
(Cremophor RH 40 for oral liquids,
Solutol HS 15 for injectables) is important to obtain a good solubilization
and to avoid chemical interactions of
the solubilizer with vitamin A. Informations about the needed amounts of
solubilizer see retinyl palmitate and
retinyl propionate.
The temperature of 65 C needed for
the solubilization procedure normally
does not cause a stability problem.
The best antioxidant is butylated hydroxytoluene BHT (or/and butylated
anisole BHA). Tocopherol is less efficient and needs much higher concentrations.
A low pH causes isomerisation but the
compromise of pH 4 is needed for the
other vitamins.
Riboflavin
If the concentration of riboflavin is
low it is preferable to use normal riboflavin as vitamin derivative instead of
the phosphate sodium salt because it is
more stable. But the solubility of normal riboflavin is only max. 7 mg/
100 ml.
The chemical interactions with vitamin B1 and nicotinamide cannot be
avoided forming brownish solutions
(see thiamine).
The optimal pH is 34. Therefore the
compromize of pH 4 is good.
The presence of strong reducing
agents as antioxidants like bisulfite
must be avoided.
The addition of povidone K 25 or 30
masks the bitter taste but flavo(u)ring
is recommended.
Nicotinamide
The use of nicotinic acid as vitamin
derivative is not very common due to
the strong increase of the periferic
blood circulation (flash effect). Normally nicotinamide is preferred.
The intensification of the chemical interactions between vitamin B1 and B2
by nicotinamide cannot be avoided.
The yellow colour formation with vitamin C is not visible in presence of
the vitamins A and B2.
Antioxidants don't stabilize nicotinamide.
Pantothenic acid, dexpanthenol
The best vitamin derivative for multivitamin liquids is the provitamin dexpanthenol because calcium and sodium pantothenate require a neutral
pH.
The optimal pH of dexpanthenol is
about 5. The compromise of pH 4 is
even acceptable.
Antioxidants don't stabilize dexpanthenol.
Pyridoxine
The best vitamin derivative is pyridoxine hydrochloride.
compromize of 4 is good.
Antioxidants don't stabilize vitamin
B6.
Cyanocobalamin
The addition of low molecular weight
povidone (Kollidon 17 PF) increases
78
the chemical stability in paternal solutions of cyanocobalamin. It should be

tested if povidone K 25 or povidone
K 30 shows the same effect in oral
solutions.
The chemical interactions with vitamin C cannot be avoided.
compromize of pH 4 is good.
A good protection agains light reduces
the degradation.
The use of an inert gas reduces the
oxidation.
The chemical interaction with nicotinamide cannot be avoided.
Folic acid
The solubility if folic acid in water at
room temperature depends strongly on
the pH. At pH 4 the solubility is less
than 0.5 mg/100 ml. At pH 6.0 about
400 mg and at pH 6.4 more than
1500 mg are soluble in 100 ml of water.
A good protection against light reduces the degradation.
The best antioxidants is BHT or/and
BHA.
Vitamin C
The hydrolisis as main degradation of
vitamin C can be delayed by addition
of propylene glycol, glycerol, sugar,
fructose, sorbitol or glucose.
The best vitamin derivative is ascorbic
acid.
The pH 4 as compromize would be
acceptable.
The chemical interactions with vitamin B1, B3 and B12 cannot be avoided
forming coloured solutions.
The use of an inert gas reduces the
oxidation.
79
If there is any risk of contamination
with traces of heavy metals EDTA and
citric acid stabilize vitamin C.
Strong reducing agents like sodium
bisulfite are excellent stabiliziers of
vitamin C but they cannot be used in
multivitamin preparations because
most of the other vitamins are degradaded by these substances.
Vitamin D
The most common vitamin derivative
is cholecalciferol because it is cheaper
due to its availability in the market.
An excellent solubilizer for oral preparations is PEG glycerol trihydroxystearate. Informations about the needed amounts of solubilizers, see cholecalciferol.
According to our experience the stability of vitamin D is no major problem
if the stability of vitamin A was optimized in the formulation.
The pH 4 as compromize is acceptable.
The best antioxidant is BHT or/and
BHA.
The use of an inert gas (nitrogen, argon etc.) reduces the oxidation.
Vitamin E
Only the derivative tocopheryl acetate
is suitable for multivitamin liquids.
Tocopherol is not stable enough.
An excellent solubilizer for oral preparations is PEG glycerol trihydroxystearate. Informations about the needed amounts of solubilizer, see tocopheryl acetate.
The pH 4 as compromize is acceptable.
For examples of multivitamin liquid formulations see B complex, cyanocobalamin, syrup, and two-chamber ampules.
Natural vitamins
80
N
Natural vitamins
In terms of their structure, virtually all
the vitamins, and very many of the vitamin derivatives which are used, can be
designated naturally occuring. Based on
the mode of production, the vast majority
of vitamins are synthetic. This results in
the designation identical to the natural
product.
A few of the vitamins which are marketed are of natural origin. These include,
for example, vitamin C extracted from
plants, provitamin A extracted from algae, vitamins A and D3 in fish liver oil,
and a mixture of alpha-, beta-, gammaand delta-tocopherol from soybeans.
Vitamins produced by microbiological
methods or semi-synthetically occupy an
intermediate position. An example of the
latter is D-alpha-tocopheryl acetate,
which is obtained by methylation of the
various D-tocopherols obtained from soybean oil to give D-alpha-tocopherol, followed by acetylation.
In terms of pharmacy, the synthetic vitamins scarcely differ from those of natural origin.
NDGA
see nordihydroguaiaretic acid.
Niacin
The name niacin is used either for nicotinic acid alone (USA) or as a term which
covers the vitamin formerly called vitamin PP or B3 and which includes nicotinamide and nicotinic acid.
Nicotinamide
Nicotinamide (syn. niacinamide, formerly vitamin PP or B3) is a white crystalline

powder with a faint odo(u)r. It is freely
soluble in water and glycerol.
Nicotinamide is one of the most stable
vitamins and gives rise to the fewest problems in pharmaceutical technology. It is
not sensitive to light, oxidizing agents or
reducing agents.
In liquid drug forms, account has to be
taken of the fact that nicotinamide may
potentiate the chemical interactions between vitamins B1/B12 and B2. However,
this has little effect on the stability of
nicotinamide itself. The pH can be between 4 and 8. Hydrolysis to nicotinic
acid takes place below pH 4 and above
pH 8. For examples of its use, see B
complex, dexpanthenol, and two-chamber
ampules.
The advantages of nicotinamide in solid
drug forms are that direct tabletting is
possible and that it has a certain binding
action. The latter may also result in undesired agglomeration of the pure substance. The following nicotinamide tablet
Nicotinamide tablet (200 mg)
Nicotinamide
Copovidone
Magnesium stearate
200 mg
100 mg
10 mg
2 mg
2 mg
81
composition for direct tabletting is an
example of its use.
When nicotinamide is combined with gelatin-coated dry powders of, for example,
vitamin A, it may destroy the structure of
the gelatin and thus release the entrapped
vitamin and reduce its stability [162].
For examples of solid combinations with
other vitamins, see B complex, instant
granules, multivitamin solid preparations,
thiamine mononitrate, and tartaric acid.
Nicotinamide ascorbate
Nicotinamide ascorbate is a complex of
nicotinamide and ascorbic acid. According to the Food Chemicals Codex III,
the molecular ratio is 1+2 and the weight
ratio is 1+3. The complex has also been
reported to have a molecular ratio of 1+1
[160].
It is a lemon-yellow, odo(u)rless powder
which is freely soluble in water.
Nicotinamide ascorbate is used only in
solid drug forms. It is very suitable for
multivitamin tablets since direct tabletting is possible and it has a high bulk
density.
Nicotinic acid
Nicotinic acid (syn. niacin, formerly vitamin PP or B3) is a white crystalline

powder which is slightly soluble in cold
water.
Unlike nicotinamide, nicotinic acid is not
used widely in vitamin products for human consumption, because it strongly stimulates peripheral blood flow (and causes flushing).
Nordihydroguaiaretic acid
Nitrogen
Nitrogen is the most commonly used inert gas for preventing the adverse effects
of oxygen on vitamin stability. The nitrogen must be passed through the solution
in order to displace the dissolved oxygen,
and the solution must be blanketed with
nitrogen before the container is closed.
Since the solubility of oxygen is more
than twice that of nitrogen, the displacement of the former is time-consuming.
Carbon dioxide is more advantageous in
the regard.
The use of an inert gas is important for
the vitamins A, B12, C, and D which are
sensitive to oxidation by atmospheric
oxygen.
Nordihydroguaiaretic acid (syn. NDGA)

comprises white crystals which are freely
soluble in ethanol, glycerol and propylene glycol and less soluble in hot water.
Up to 1 % solutions in oils can be obtained.
Nordihydroguaiaretic acid is a natural antioxidant of vegetable origin. It is mainly
used for stabilizing fats and oils. It may
also indirectly protect vitamins A and D
from oxidation in oily solutions by preventing the formation of lipid peroxides,
which are able to oxidize the vitamins
[51]. Folic acid is likewise stabilized by
addition of 0.02 to 0.05 % NDGA [35].
The concentrations normally used are in
the range 0.01 to 0.1 %.
For an example of its use in a multivitamin syrup, see sorbitol.
Octotiamine
82
O
Octotiamine
Octotiamine comprises, as does benfotiamine, colo(u)rless crystals.

This vitamin B1 derivative is rarely used
but is said to have a certain prolongation
of action.
Odo(u)r
see flavo(u)ring.
palmitate together with an antioxidant,

e.g. tocopherol.
Oily dilutions of vitamins A and D and
provitamin A in peanut oil are commercially available for processing. They facilitate the incorporation of these (otherwise crystalline) substances into oil products (e.g. soft gelatin capsules, oily solutions or emulsions).
Other oily components which are commonly used in vitamin products are
short-chain saturated triglycerides (Miglyol [9]).
Oil-soluble vitamins
see lipophilic vitamins.
Oils
Ointments
The oils used as auxiliaries in vitamin

products are usually vegetable oils (fatty
acid glycerides). The oil which is most
commonly used for this purpose is peanut
oil, because it has no adverse effects on
the stability of vitamins, and is one of the
most stable vegetable oils. Castor oil and
sesame oil are very occasionally used for
parenteral products.
Pharmaceuticals containing oils together
with vitamins which are sensitive to oxidation (e.g. vitamins A or D) must be
stabilized with an antioxidant combination, because the lipid peroxides which
are initially formed by autoxidation will
cause secondary decomposition of the
vitamins [51]. Decreases in the vitamin
A content in oils and emulsions essentially derive from reactions of this type. The
breakdowns of vitamin A can be considerably delayed by addition of ascorbyl
Ointments based on fats and containing

vitamins are uncommon. For bioavailability reasons, creams (oil-in-water emulsions) are almost always used.
Omega fatty acids

see fatty acids, polyunsaturated.
Orotic acid
Orotic acid (syn. formerly vitamin B13) is

no longer regarded as a vitamin. Nevertheless, it or choline orotate or nicoti-
83
namide orotate is still present in some
multivitamin products and geriatric preparations.
The solubility of orotic acid in water is
about 1.7 mg/ml. Aqueous solutions can
be stabilized by amines [242]. Monoethanolamine improves solubility and stabilizes 1.0 to 2.5 % solutions when added to
orotic acid in the ratio 0.8 : 1.0. The stability of this solution was still satisfactory
after the pH had been adjusted to between 4 and 5 with citric acid [243].
OTC vitamin products

see marketing.
Overage
The adverse effects on the stability of almost all the vitamins when they are converted into preparations explain why in
many countries relatively high overages
are applied. The industrial pharmacy section of the Fdration Internationale Pharmaceutique (F. I. P.) many years ago recommended the overages [212], as shown
in the first of the two tables, and the actual
US Pharmacopeia permits the overages for
multivitamin preparations, as given in the
second of the tables which follow.
However, the registration authorities in
many countries have recently started to
insist that the expiration periods are to be
shortened rather than accepting high
overages in pharmaceuticals. This appears sensible in some respects, because
the accurate specification of the vitamin
content is one of the most important criteria distinguishing a pharmaceutical vitamin product from a food product. However, it is likely that the general upper
limit of 10 % for overages, which has
been laid down by the Federal Board of
Health in Berlin, is impracticable for
Overage
many multivitamin products. The overages permitted in the USA for singlevitamin products are listed in the third
table which follows.
Overages of vitamins in single-vitamin products (F. I. P. recommendations 1966)
Vitamin
Overage ( %)
Liquid Solid
forms
forms
Vitamin A (low-dose)
Vitamin A (high-dose)
Vitamin D (low-dose)
Vitamin D (high-dose)
Vitamin E
Vitamin K
Vitamin B1
Vitamin B2
Vitamin B6
Vitamin B12
Folic acid
Vitamin C (oral)
Vitamin C (parenteral)
50
30
50
10
10
30
10
10
10
30
30
10
50
10
50
30
50
10
10
30
10
10
10
10
10
10
10
Overages of vitamins in combination

products, e.g. multivitamin products (USP
XXIV)
Vitamin
Overage ( %)
Liquid Solid
forms
forms
Vitamin A
Vitamin D
Vitamin E
Vitamin B1
Vitamin B2
Vitamin B6
Vitamin B12
Folic acid
Nicotinamide
Vitamin C
Vitamin K1
150
150
150
150
50
50
350
50
50
150
65
65
65
50
50
50
50
50
50
50
30
65
Oxalic acid
84
Overages in single-vitamin products permitted by US Pharmacopeia XXIV

Product
Maximum overage
Vitamin A capsules
Vitamin E capsules
Thiamine mononitrate elixir
Thiamine hydrochloride elixir
Thiamine hydrochloride tablets
Thiamine hydrochloride injection
Riboflavin injection
Riboflavin tablets
Pyridoxine hydrochloride tablets
Pyridoxine hydrochloride injection
Calcium D-pantothenate tablets
Cyanocobalamin injection
Folic acid tablets
Folic acid injection
Vitamin C tablets
Vitamin C injection
Beta-carotene capsules
20 %
20 %
15 %
35 %
10 %
10 %
20 %
15 %
15 %
15 %
15 %
15 %
15 %
10 %
10 %
10 %
25 %
Oxalic acid
Oxalic acid is the final product of the
aerobic (= oxidative) decomposition of
ascorbic acid. Therefore it is limited to
max. 0.2 % in ascorbic acid according to
Ph.Eur. 1997.
Calcium oxalate may crystallize out of
vitamin C solutions containing calcium
on prolonged storage [37].
Stabilization is possible by addition of
oxalic acid to ascorbic acid solutions
[70, 161].
Aerobic breakdown of ascorbic acid.
Oxidation
Many of the vitamins are sensitive to
oxidation in their formulations, a distinction being made between the action of
oxygen and that of oxidizing agents.
85
Oxygen
Sensitivity of vitamins to oxidation

Vitamin
Oxygen
Oxidizing
agents
Vitamin A
Provitamin A
Vitamin B1
()
Vitamin B6
Vitamin B12
Vitamin C
Folic acid
Vitamin D
Tocopherol
In aqueous solution the rate of oxidation

may depend on the pH. The figure which
follows shows that vitamin B1 is virtually
insensitive to atmospheric oxygen at the
pH of about 4 which is normally employed. However, when the pH increases
to 5, the effect of oxygen is evident when
it is excluded by use of an inert gas [54].
The ways of minimizing the oxidation of
vitamins and thus improving their stability in the products are as follows:
1. Addition of an antioxidant.
2. Exclusion of oxidizing agents.
3. Use of nitrogen or carbon dioxide as

inert gas.
4. Addition of a chelating agent, which
binds any traces of heavy metals
which are present and thus prevents
their catalytic effect on oxidation.
Effect of nitrogen on the stability of thiamine in vitamin B complex solution (storage at 22 C for 1 year).
Oxygen
Atmospheric oxygen is detrimental to the
stability of some vitamins, and this must
always be remembered during development, production and packaging. For details, see inert gas and oxidation.
P, vitamin
86
P
P, vitamin
Pangamic acid
see bioflavonoids.
Packaging
Careful attention to packaging is important with many vitamin products, because
it may affect the stability and the expiration date. The greatest care during development and manufacture of a product is
useless if inappropriate packaging cancels out all these efforts. This applies to
all vitamins which are sensitive to light,
humidity and oxidation by atmospheric
oxygen. Gastight and opaque packaging
is thus generally advisable to improve
vitamin stability. For vitamin tablets the
normal blister pack material cannot be
recommended [265, 269]. The new blister pack material Topas having an excellent water vapour impermeability
could be an acceptable choice for vitamin
tablets [278].
For liquid preparations only glass flasks
should be used as packaging [272].
In some cases it is a further advantage to
use an inert gas while the containers are
being filled.
It is advisable with effervescent tablets to
design packaging containing a desiccant
[267].
In certain circumstances, account has to
be taken of chemical or physical reactions with plastic materials (e.g. polyethylene) or their additives [151]. Vitamin A may be adsorbed onto polyvinyl
chloride containers [213, 214].
Pangamic acid (syn. formerly vitamin

B15) is only rarely used in multivitamin
products or geriatric agents since there is
doubt about its effect [137].
Panthenol
see dexpanthenol.
Pantothenic acid
Pantothenic acid (syn. D-pantothenic

acid, formerly vitamin B5) is a viscous
and extremely hygroscopic liquid which
is miscible with water.
Pantothenic acid is very unstable both as
the pure substance and in drug forms.
Hence it is not used as such in pharmacy.
87
Calcium pantothenate is mostly used in
solid forms, and the provitamin dexpanthenol or sodium pantothenate is used in
liquid and semisolid products.
1.0 g D-pantothenic acid is equivalent to:
k 0.936 g dexpanthenol,
k 1.088 g calcium D-pantothenate,
k 1.099 g sodium D-pantothenate.
Parabens
The most important parabens (syn. parahydroxybenzoic esters, PHB esters) are
methylparaben and propylparaben, which
are marketed under the names Nipagin
M and Nipasol M [10].
Methylparaben consists of white needles,
of which about 0.1 g dissolve in 100 ml
water at 20 C. It is more soluble in oils,
and is freely soluble in ethanol.
Propylparaben consists of white crystals,
of which only 1 part dissolves in 2,500
parts of water at 20 C. It is more soluble
in hot water, and is freely soluble in
ethanol.
Both substances are used as preservatives
(E number E 218 and 216). They are
often used together in the ratio 7+3, because their preservative effects are complementary. The normal concentrations
of the combination are 0.1 to 0.2 % in
aqueous solutions and 0.2 to 1.0 % in
oily formulations. For an example of
their use in syrups, see B complex and
sorbitol.
With parabens, as with all preservatives,
account has to be taken of the fact that
solubilizers and emulsifiers may reduce
their efficacy. Thus, for example, addi-
Particle size distribution

tion of 0.3 % methylparaben + propylparaben (7+3) is insufficient to kill in 10
days all the microorganisms added to an
aqueous solution which contains 4 %
PEG glyceryl trihydroxystearate.

The particle size distribution of the vitamins and auxiliaries is of importance in
the production of solid drug forms. It is
necessary to take account of the fact that
the particle size of a particular product
often differ between manufacturers and
the product may be marketed in several
variants (e.g. vitamin A dry powder, pyridoxine hydrochloride, ascorbic acid,
sodium ascorbate, etc.).
The particle size distribution is not always stated in the same manner. The
screens are usually defined in m or
mesh.
Screen definitions
Screen openings
2000 m
850 m
600 m
425 m
300 m
250 m
212 m
180 m
150 m
125 m
75 m
63 m
53 m
45 m
38 m
Mesh [128]
10
20
30
40
50
60
70
80
100
120
200
230
270
325
400
The optimal particle size distribution of a

vitamin for direct tabletting depends on
that of the other components. The upper
limit for soft gelatin capsules is 180 m
Peanut oil
(= 80 mesh) if the vitamins are to be
suspended, not dissolved.
With some lipophilic vitamins (e.g. betacarotene) the particle size may also have
an effect on absorption in the body. The
bioavailability increases with the fineness of the crystals, as is evident from the
experiment on chickens described below.
A low vitamin A content in the liver was
increased only slightly, compared with a
control group, after administration of an
oily beta-carotene dispersion with crystals between 1 and 5 m in size. Administration of a dry powder containing 0.1
to 0.4 m beta-carotene crystals greatly
increased the bioavailability.
88
tions and emulsions of lipophilic vitamins, as well as for soft gelatin capsules. The use of peanut oil as a solvent in
eyedrops containing tretinoin as active
ingredient results in a stable product
[255].
Vitamin A, vitamin D and beta-carotene
are already commercially available as dilutions or dispersions in peanut oil for
processing. These products usually contain an antioxidant to stabilize both the
peanut oil and the vitamins.
PEG
see polyethylene glycol.
PEG glyceryl trihydroxystearate
Bioavailability of beta-carotene of various

crystal sizes in chickens (24 h after oral
administration).
Peanut oil
Peanut oil is a yellow oil which is widely
used as a diluent or solvent for oral solu-
PEG-40 glyceryl trihydroxystearate (syn.

macrogol glycerol hydroxystearate, polyethylene glycol 40 glyceryl trihydroxystearate, polyoxyl-40 hydrogenated castor
oil) is composed of a hydrophilic and
hydrophobic portion. The structure of
the nominal main constituent can be
seen below.
The substance takes the form of a white
paste or semiliquid which is virtually
odo(u)rless and tasteless in aqueous solution. It is miscible in any ratio with both
water and lipophilic vitamins. This makes
it one of the best non-ionic solubilizers
for oral and topical vitamin products
(HLB value 1416).
PEG-40 glyceryl trihydroxystearate is
marketed for pharmaceutical purposes
89
PEG glyceryl triricinoleate
under the registered trade names Cremophor RH 40 [1] or Arlatone 975 [6],
for example.
A typical example of its use is the following composition of vitamin A+E
drops.
Vitamin A+E drops 825,000 I. U. + 50 mg
per ml)
Retinyl palmitate
Tocopheryl acetate
PEG-40 glyceryl trihydroxystearate [1]
Antoxidant
Preservative
Flavo(u)ring
Water
1.5 g
5.0 g
20.0 g
q.s.
q.s.
q.s.
ad 100 ml
In order to obtain a clear solubilizate, it is

necessary to mix the vitamins with the
solubilizer at elevated temperature and
to stir the hot solution of the preservatives and flavo(u)rings slowly into the
mixture.
A concentrate containing 100,000 I. U.
vitamin A and 20,000 I. U. vitamin D
per ml which is commonly used in pharmacy for the production of liquid drug
forms has the following composition, for
example:

PEG glyceryl triricinoleate (syn. macrogol glycerol ricinoleate, polyethylene glycol-35 glyceryl triricinoleate, polyoxyl-35
castor oil) is a viscous yellow liquid
which is miscible in any ratio with water
and the lipophilic vitamins. The substance is composed of a hydrophilic and a
hydrophobic portion. The main component has a chemical structure analogous
to that of PEG glyceryl trihydroxystearate.
It is a non-ionic solubilizer which has a
HLB value of 12 to 14 and is marketed
for pharmaceutical purposes under the
trade name Cremophor EL, for example.
The amounts required for the solubilization of tocopheryl acetate are evident
from the figure which follows, in which
all the data are based on the solubilizate.
Vitamin A+D concentrate for processing

(100,000 + 20,000 I. U. per ml)
Retinyl palmitate
Cholecalciferol
Water
6.5 g
55 mg
0.3 g
26.0 g
ad 100 ml
For further examples of its use, see cholecalciferol, ergocalciferol, solubilizers,

syrup, tocopheryl acetate, and vitamin
derivatives.
Solubilization of vitamin E acetate.
The amounts needed for the solubilization of retinyl palmitate are about the
same as for PEG glyceryl trihydroxystearate (for graph, see vitamin derivatives).
An example of its use for the solubilization of vitamin K1 is described under
phytomenadione.
PEG hydroxystearate
90
PEG hydroxystearate
PEG hydroxystearate (syn. macrogol hydroxystearate, PEG-15 hydroxystearate,

polyethylene glycol 660 hydroxystearate)
is a white paste which is miscible in any
ratio with water and the lipophilic vitamins. The substance is marketed as a
solubilizer for parenteral products under
the trade name Solutol HS 15 [1]. One
of the great advantages of the substance
for pharmacy is its low viscosity below
20 mPa.s (30 % in water). The amounts
of solubilizer, based on the solution, required to prepare clear aqueous solutions
of retinyl palmitate and retinyl propionate are evident from the figure which
follows.
PEG sorbitan oleate

see polysorbate.
pH
The pH is one of the most important
factors for the stability of vitamins, because in most cases their decomposition
(hydrolysis, oxidation, chemical interactions, etc.) depends on the pH. This particularly applies to vitamin products containing water. Unfortunately, the pH optima for the individual vitamins differ so
much that a compromise is always necessary in a multivitamin solution and in
some cases relatively large losses have
to be accepted.
pH optima for the vitamins
Solubilization of vitamin A with PEG hydroxystearate.
An analogous plot for vitamin K1 is to be

found under phytomenadione. An injection solution containing 4 or 5 % betacarotene in water can be prepared using
about 25 % PEG hydroxystearate [28].
For an example of its use in a high-dose
vitamin A+D+E veterinary ampule, see
emulsion.
Vitamin A
Vitamin B1
Vitamin B2
Nicotinamide
D-pantothenates
D-panthenol
Vitamin B6
Vitamin B12
Folic acid
Vitamin C
Vitamin D
Vitamin E
Biotin
above 6
24
35
48
68
56
35
45
69
57
48
48
68
Only vitamins D and E and nicotinamide

can be regarded as being free of problems.
Vitamin A (e.g. retinyl palmitate) starts
to undergo isomerization below pH 6,
which reduces the vitamin A activity.
91
With thiamine hydrochloride the pH
should not exceed 4.5 and is preferably
below 4.0 (see hydrolysis and oxidation).
Dexpanthenol is much more suitable for
combination with other B vitamins than
are the D-pantothenates, which require
too high a pH [159].
In the case of ascorbic acid, there are two
ranges in which the stability is satisfactory or good (for graph, see ascorbic acid).
The recommended compromise for a
multivitamin solution is a pH between
4.0 and 4.5. A vitamin B complex solution containing only vitamins B1, B2, B6,
nicotinamide, and dexpanthenol has grea-
Pharmacopeias
ter stability at a somewhat lower figure
(e.g. 4.0).
The preceding figures show clearly the
differences in the dependence of the stability on the pH for thiamine hydrochloride, dexpanthenol, and ascorbic acid on
the one hand, and of vitamin A on the
other hand [41].
The measured pH values of aqueous solutions of the hydrophilic vitamins are
sometimes outside the optimal pH ranges.
pH of vitamins in water
Vitamin
Thiamine
hydrochloride
Thiamine
mononitrate
Riboflavin
Stability of vitamin B1, C, and dexpanthenol in vitamin B complex + C ampules (6

weeks, 45 C).
Concentration
2.5 %
pH
2.73.3
2.0 %
6.06.7
saturated
5.57.2
(4 mg +
10 ml water)
Riboflavinphosphate
sodium
2.0 %
Pyridoxine
hydrochloride
5.0 %
Dexpanthenol
5.0 %
Calcium
pantothenate
5.0 %
Sodium
pantothenate
10.0 %
Nicotinic acid
1.0 %
Nicotinamide
5.0 %
Ascorbic acid
5.0 %
Sodium ascorbate 10.0 %
4.06.0
2.33.5
9.511.0
6.88.0
9.010.5
3.03.5
6.08.0
2.22.5
6.08.0
Pharmacopeias
Stability of vitamin A in a multivitamin solution (6 weeks, 45 C).
The common vitamins and their important derivatives are all to be found in the
current pharmacopoeias in the form of
monographs on the pure substances and,
in some cases, on preparations. The USP
XXIV also contains monographs of vitamin combination products, e.g. Oil-
Phase separation
and Water-soluble Vitamins tablets and
Oil-soluble Vitamins Capsules.
The requirements for the pure vitamins and
the methods of determination in the European Pharmacopoeia (e.g. Ph.Eur. 3nd edition) are not always identical with those
outside Europe (USA, Japan, etc.).
Phase separation
Phase separation may occur with normal
emulsions and with solubilizates (= microemulsions) of the lipophilic vitamins.
This phenomenon is observed after prolonged storage if the solubilizer content is too
low or the temperatures were very low or
extremely high. Separation of solubilizates
of vitamin A propionate may also be induced by prolonged exposure to light.
Phase separation occurs during the head
sterilization of solubilizates in ampules.
This can be dealt with by briefly and vigorously shaking the solution which is still
warm from sterilization, which returns it
to the original homogeneous distribution.
In addition, phase separation may be observed if the solubilizate is prepared in
the incorrect sequence, too rapidly, or
using cold water (see also emulsion and
solubilization).
PHB esters
92
Phytomenadione (syn. phylloquinone,
phyllomenadione, phytonadione, vitamin
K1) is one of the lipophilic vitamins. Only
the trans form occurs in nature. USP XXIV
specifies that synthetic products must not
contain more than 20 % cis isomer, the
latter having no vitamin K activity.
Phytomenadione is a clear viscous yellow
liquid which is virtually odo(u)rless. It is
insoluble in water but disolves in absolute ethanol and oils.
Phytomenadione is preferentially used in
liquid pharmaceuticals in the form of oil
solutions for solubilizates. Both types of
formulation are sensitive to heat and
light. The pH of aqueous solutions should
be weakly acid and reducing agents must
be excluded. An example of a suitable
solubilizer is PEG glyceryl triricinoleate,
which can be used to prepare a clear
solution of the following composition:
Vitamin K1 solution (10 mg/ml)
Phytomenadione
PEG-35 glyceryl triricinoleate
Water
1.0 g
6.5 g
ad 100 ml
The recommended solubilizer for the preparation of solutions for injection is PEG
hydroxystearate [1]. The figure below
shows the concentrations of solubilizer
required in the solution.
see parabens.
Photolysis
Degradation by light (see this entry).
Phytomenadione
Solubilization of phytomenadione with

PEG hydroxystearate.
93
A phytomenadione dry powder must be
used to prepare solid drug forms (e.g.
adsorbate on silica gel or spray-dried
material).
Plasdone
Plasdone is a registered trademark for a
soluble polyvinylpyrrolidone which may
have various K values [5].
Polyethylene glycol
Polyethylene glycols (syn. PEG, macrogol, polyoxyethylene) are available with

molecular weights between 200 and
20,000. Both the properties and the uses
vary with the molecular weight. PEG absorbs hardly any water up to a relative
humidity of 80 % (for plot of the water
adsorption, see hygroscopicity). The types of PEG used most commonly in vitamin products are as follows:
1. PEG-400 is a colo(u)rless liquid used
as a solvent. It may improve the stability of some vitamins (see solubilizer).
2. PEG-1500 and -4000 are white powders or microbeads which are chiefly
used in semisolid drug forms.
3. PEG-6000 is a powder which is mainly used in solid forms. Its solubility
in water makes it suitable as a glidant
and lubricant, especially in effervescent tablets, but it also has a good
lubricant action in other tablets. The
amounts required are distinctly higher
than those of fatty acids and their
salts, such as magnesium stearate.
This is evident from the examples of
its use, which can be found under the
headings analgesic, ascorbic acid, ef-
Polysorbate
fervescent tablets, copovidone, direct
compressible vitamins, minerals, multivitamin solid preparations, sorbitol,
trace elements, and tartaric acid.
As a film-forming agent, PEG-6000 is
commonly combined with other polymers. For examples of its use, see filmcoating.
PEG may stabilize ergocalciferol in solid
forms by reducing its contact with acidic
substances and thus diminishing isomerization [58].
Polyplasdone
Polyplasdone XL is a registered trademark for crospovidone [5].
Polysorbate
Various types of polysorbate may be used
in vitamin products. By far the most useful is polysorbate 80 (syn. PEG-20 sorbitan oleate), which is marketed under the
name Tween 80 [6].
Polysorbate 80 consists of a hydrophobic
and a hydrophilic part, and the main
component of the hydrophobic part is
polyethylene glycol-20 sorbitan oleate.
It is a yellow viscous liquid which has a
bitter fatty taste and is miscible in any
ratio with water and the lipophilic vitamins.
Polysorbate 80 is one of the most commonly used non-ionic solubilizers for
oral and topical pharmaceuticals. The
HLB value is about 15. The following
composition of a clear aqueous solution
is an example of its use for the solubilization of vitamin A.
Vitamin A drops (50,000 I. U./ml)
Retinyl palmitate
Polysorbate 80
Water
3.0 g
12.0 g
ad 100 ml
(Povidone)
The amounts of polysorbate 80 required
to solubilize tocopheryl acetate are
shown in the graph below.
Solubilization of vitamin E acetate with

polsorbate 80.
For further examples of its use, see solubilizer and sorbitol.

It proved possible to reduce the amount
of polysorbate in a multivitamin solution
by addition of glycerol [246].
Because of the somewhat unpleasant taste, particular care has to be taken with
flavo(u)ring when polysorbates are used.
Polysorbates may, as may all non-ionic
surfactants, reduce the effectiveness of
preservatives.
(Povidone)
Soluble polyvinylpyrrolidone (syn. Povidone, PVP, polyvidone) is a white powder which is freely soluble in water,
ethanol, glycerol, and propylene glycol.
It is hygroscopic (for graph of the water
adsorption, see hygroscopicity). For insoluble polyvinylpyrrolidone, see crospovidone.
94
Povidone of various molecular weights
and of pharmaceutical quality is commercially available under the name Kollidon [1, 263 d] and Plasdone [5]. The
average molecular weight is normally
characterized by use of the K value
[175]. The functions of the individual
types in vitamin products vary:
1. Povidone with a K value between 11
and 18 is used as a carrier for lyophilization and for improving vitamin stability and taste in aqueous solution
[64]. The following mixture of auxiliaries for a vitamin B complex solution has been reported to be very suitable for this purpose [144, 263 a].
Auxiliaries for the preparation of a vitamin

B complex solution in water
Povidone, K value 17
Propyl gallate
Ethylenediaminetetraacetic acid,
disodium salt
Benzyl alcohol
Ethanol
Propylene glycol
Strawberry flavo(u)r
5.0 %
0.05 %
0.005 %
0.02 %
0.3 %
2.0 %
1.0 %
0.5 %
0.1 %

and 33 can be used as a water-soluble
binder in all types of vitamin tablets,
including effervescent tablets. The applies both to granulation and to direct
tabletting. 2 to 5 % Povidone K 2333,
based on the weight of the tablet, is
normally used for this purpose. For
examples of its use in formulations,
see B complex, effervescent tablets,
calcium hydrogen phosphate, compaction, crospovidone, lactose, minerals,
starch, thiamine mononitrate, thiamine hydrochloride, and tartaric acid.
95
In addition Povidone with K values
between 23 and 33 is used as a granulation auxiliary for mixed powders for
hard gelatin capsules and for instant
granules.
Both low molecular-weight Povidone
with a K value of 17 and Povidone K
25 improve the flavo(u)r and stability
of vitamin B solutions [64].
For examples of its use in the formulation of a B complex syrup, see dexpanthenol.
Povidone with a K value between 23
and 33 can also be used as a filmforming agent, and possibly as a plasticizer, in combination with cellulose
derivatives in film-coating or in sugar-coating. However, the hygroscopicity of Povidone is a limitation on
this use.
and 95 is an even more effective binder than the types of lower molecular
weight. Hence the amounts required in
tablets or granules usually do not exceed 2 %. Wet granulation is mainly
used for this purpose in order to distribute the binder uniformly. For examples of its use, see glucose.
Povidone K 25K 90 can be used as
binder in european food e.g. in vitamin
tablets. For this purpose it got the E number E 1201.
PP, vitamin
see niacin, nicotinamide, and nicotinic
acid.
Precipitate
Precipitates in solution of vitamin combinations may have a variety of causes.
Prediction of stability
Examples of precipitates in vitamin solutions
1. Crystallization of the preservative (e.g.
parabens).
2. Crystallization of calcium oxalate where
ascorbic acid and calcium ions are
combined (e.g. calcium pantothenate)
[37].
3. Precipitation of cholecalciferol from a
solubilizate due to inadequate amounts
of solubilizer.
4. Crystallization of colo(u)rless decomposition products when cyanocobalamin is
combined with other B vitamins.
5. Precipitation of yellow chloroflavin from
combinations of thiamine hydrochloride,
riboflavin, nicotinamide, and ascorbic
acid [100].
6. Precipitation of thiochrome form combinations of thiamine hydrochloride and
riboflavin and, possibly, nicotinamide
[100].
Since the stability is the main problem in
manufacturing vitamin products, there is
very great interest in shortening the process of examination of this factor, e.g. by
stress tests, in order to gain rapid information on the effect of various factors on
the long-term stability.
Since the kinetics of thermal decomposition (thermolysis) of most of the vitamins
in their products are first order (or zero
order), it is very often possible to use the
principle of the stress test for prediction
of stability.
A very simple example is the stability of
vitamin A in the formulation of a vitamin
A+D+E injection emulsion which is detailed under the heading emulsion, the
figure which follows showing what happened over a period of 24 months.
96
Vitamin A+E drops, non-stabilized (25,000
I. U. + 50 mg/ml).
Composition
Retinyl palmitate
Tocopheryl acetate
Water
ad
Stability of vitamin A in vitamin A+D+E

emulsion.
The plot of the vitamin A content in the

emulsion on storage for 24 months was
linear, with losses of 6 % at the recommended temperature of 6 C in a refrigerator and of 16 % at 23 C. Even without
mathematical analysis, these two plots
show that it will be possible to estimate
the stability at 6 C from short-term storage at 23 C. This may be of interest for
testing the stability of future batches of
the emulsion. However, it would be
worthwhile also to test one or two higher
temperatures to shorten the duration of
the tests.
A number of publications deals with detailed investigations of the prediction of
stability of vitamin products. The following results are derived from these:
1. Vitamin A
In multivitamin drops the decomposition follows zero order kinetics [185]
or a prediction of stability can be
made using the Arrhenius equation
[186]. First order kinetics were found
in multivitamin tablets [187, 188], apparently other mechanisms of breakdown applying in this case. The latter
is sometimes observed in vitamin A
products such that the kinetics of decomposition in the first one or two
months differ from those thereafter. A
typical example of a non-stabilized vitamin A+E solution demonstrates this.
1.5 g
5.0 g
20.0 g
100 ml
Stability
2. Vitamin B1
The kinetics of breakdown of thiamine
in a vitamin B complex syrup containing trace relements were found to be
first order [186, 189]. The same applies to 2.5 and 5 % solutions of thiamine hydrochloride in water [205].
Stability of thiamine in a vitamin B complex syrup [189].
97
The results with multivitamin tablets
[187, 190] and multivitamin drops
[152] were analogous.
3. Dexpanthenol
The Arrhenius equation was found to
apply to dexpanthenol in a vitamin B
complex syrup containing trace elements, a multivitamin syrup and multivitamin drops [185, 186, 189].
4. Cyanocobalamin and folic acid
The kinetics of breakdown of both
vitamins in a multivitamin syrup are
first order [185]. The same applies to
cyanocobalamin tablets but not to a B
complex syrup containing iron [186].
The kinetics of breakdown of folic
acid mixed with microcrystalline cellulose were found to be zero order
[69].
5. Hydroxocobalamin
First order kinetics of decomposition
were found for solutions of pure hydroxocobalamin in various buffer systems [193].
6. Vitamin C
The kinetics of breakdown of ascorbic
acid in multivitamin tablets were
found to be zero order [190] or first
order [187]. This also applied to a
multivitamin syrup [185], ampules
containing 10 % ascorbic acid [194]
and multivitamin drops containing
sucrose, sorbitol or glucose [152].
Small changes in the concentrations of
the substances used in the formulation
may be expected to have no significant
effect on the prediction of stability. However, it must be remembered that each
prediction of stability or each stress test
applies only to the tested formulation and
not necessarily to any other. The kinetics
of decomposition may vary both qualitatively and quantitatively in products of
different composition, as shown by the
examples of vitamin A and B12 above.
Moreover, in a stress test it is not possi-
Preservatives
ble to raise the temperature indefinitely,
because further reactions may start above
a particular temperature (e.g. in the presence of sucrose) and alter the kinetics of
breakdown.
Prescription vitamin products

see marketing.
Preservatives
It is usually necessary to protect watercontaining vitamin products from the
growth of microorganisms (fungi, yeasts,
bacteria). This is normally achieved by
addition of a preservative (see table below).
Other substances are used as preservatives in products for injection, such as benzyl alcohol, chlorobutanol, phenylmercury compounds, and thiomersal.
Preservatives commonly used in oral vitamin products
Preservative
E number Concentration
Parabens
E 214
E 219
E 200
E 203
E 210
E 213
E 422
E 300
Sorbic acid and

salts
Benzoic acid ad
salts
Propylene glycol
Ethanol
Glycerol
Ascorbic acid
0.030.2 %
0.1 %
0.10.2 %
above 15 %
above 15 %
above 30 %
min. 3 %
The following two points must always be

taken into account when preservatives are
used.
1. Their effectiveness depends on the
pH.
2. Addition of emulsifiers or solubilizers
may markedly reduce the preservative
Propylene glycol
effect. A possible reason is that part of
the preservative is trapped in the micelles.
Propylene glycol
Propylene glycol (syn. 1,2-dihydroxypropane, 1,2-propanediol) is a colo(u)rless

liquid which is miscible in any ratio
with water and ethanol and has a sweet
taste.
Propylene glycol is one of the most commonly used organic solvents in liquid
vitamin products, because it improves
the stability of some vitamins. This particularly applies to thiamine hydrochloride, ascorbic acid, cholecalciferol, ergocalciferol and phytomenadione [1719,
59, 75, 144, 147, 163, 166],
The concentrations of propylene glycol in
the products may vary widely. The beneficial effect on vitamin stability appears
to increase with increasing content of
propylene glycol.
For examples of its use, see B complex,
cyanocobalamin, dexpanthenol, polyvinylpyrrolidone, sorbitol, syrup, and twochamber ampules.
Propyl gallate
Propyl gallate is a white powder, about

0.35 g of which dissolves in 100 ml water. It is freely soluble in ethanol and
98
approximately 1 % solutions in oils can
be prepared.
Propyl gallate is an antioxidant, acting as
a free radical trap (E number E 310). Its
use is not confined to lipophilic vitamins.
Addition of 0.005 % stabilizes a vitamin
B complex solution, especially the thiamine [64, 144].
Ascorbic acid is also stabilized by addition of propyl gallate [20]. The effect of
the addition of propyl gallate on the stability of retinyl palmitate in various lipophilic solvents is shown in the table
which follows [167].
Stabilization of vitamin A in lipophilic solvents by propyl gallate
Solvent
Vitamin loss after

170 h under air
without with
antioxi- 0.05 %
dant
propyl
gallate
Peanut oil
Ethyl oleate
Ethyl stearate
Liquid paraffin
76.2 %
74.3 %
46.9 %
79.8 %
31.3 %
31.3 %
31.3 %
44.6 %
In aqueous solutions, too, propyl gallate

combined with other antioxidants improves the stability of vitamin A. Addition of
tocopherol, butylated hydroxyanisole and
propyl gallate to a syrup containing vitamins A, B1 and C reduced the loss of
vitamin A on storage at room temperature for 180 days from 20 % to 6 % [168].
For examples of the use of propyl gallate
in formulations, see dexpanthenol and
polyvinylpyrrolidone.
Provitamin A
see beta-carotene and carotene.
99
Provitamin B5
see dexpanthenol.
PVP
see polyvinylpyrrolidone (povidone).
Pyridoxal phosphate
Pyridoxal phosphate (syn. pyridoxal 5'phosphate, PLP, vitamin B6) is the form
of vitamin B6 which acts as coenzyme. It
is a pale yellow crystalline powder which
has virtually no odo(u)r and is only
slightly soluble in water. It is soluble in
alkaline solutions, e.g. 1 % sodium bicarbonate. It is virtually insoluble in propylene glycol. It is also commercially available as the sodium salt.
Pyridoxal phosphate is hydrolyzed in the
stomach, and thus is used almost exclusively in injectables. The stability in solutions for injection is distinctly less than
that of pyridoxine hydrochloride or other
vitamin B6 derivatives [169]. Dilute solutions of pyridoxal phosphate are very
sensitive to light [232] and it is relatively
rapidly hydrolyzed under both acidic and
alkaline conditions, with heat increasing
the rate. For this reason, lyophilization is
recommended. An example of a solution
for freeze-drying is as follows.
Solution of pyridoxal phosphate for lyophilization
Pyridoxal phosphate
Sodium hydroxide
Carrier
Water
500 mg
75 mg
q.s.
min. 5 ml
Pyridoxine hydrochloride (syn. pyridoxol

hydrochloride, vitamin B6 hydrochloride)
is a fine white powder which is freely
soluble in water, is virtually odo(u)rless
and has a slightly salty and acidic taste. It
also dissolves in ethanol and propylene
glycol.
Pyridoxine hydrochloride poses few problems in pharmacy, because it undergoes
no chemical interactions with other vitamins and is insensitive to oxygen and
reducing agents.
The stability of pyridoxine hydrochloride
is good in virtually all solid drug forms.
It can be granulated without problems
and tablets containing up to 70 % can be
produced by direct tabletting, as shown
by the following composition of a vitamin B6 tablet.
Copovidone
Magnesium stearate
250 mg
100 mg
13 mg
5 mg
Even higher concentrations of pyridoxine

hydrochloride in tablets can be achieved
by using it in a coarsely crystalline form
[198].
A tablet formulation containing 40 mg
pyridoxine hydrochloride is an approved
standard in the FRG [176].
For examples of further uses in solid drug
forms, see B complex, colorants, hydroxypropyl(methyl)cellulose, instant granu-
les, minerals, multivitamin solid preparations, starch, thiamine mononitrate, and
tartaric acid.
Pyridoxine hydrochloride is also quite
stable in liquid drug forms [172] if no
oxidizing agents are present and it is not
exposed to light. Since (heavy) metals
may reduce the stability of vitamin B6
somewhat [172], it is advisable to add
100
a chelating agent. In a vitamin B complex + C syrup (for formulation, see B
complex) the loss of vitamin B6 was
found to be 4 % after storage at 23 to
25 C for 12 months. In a similar formulation (see dexpanthenol) there was found
to be no decrease in the pyridoxine
content after 9 months at room temperature.
101
Retinyl acetate
R
RDA
The RDA (recommended daily allowance) indicates the vitamin requirement
each day. Various institutions in a number of countries have drawn up lists
which differ at some points. The RDA
list of most importance worldwide was
drawn up by the Food and Drug Administration (FDA) in the USA. For details,
see daily requirement.
Reducing agents
Some vitamins are sensitive to reducing
agents. These include, for example, thiamine, riboflavin, cyanocobalamin, folic
acid, phytomenadione, and rutin.
Although the reducing agent sodium sulfite stabilizes ascorbic acid, it immediately decomposes vitamin B1. Ascorbic
acid itself reduces folic acid and riboflavin.
Release
see dissolution.
noids are not used as vitamin A, all of

them being used for the topical or oral
therapy of acne and psoriasis.
Retinol
Retinol (syn. all-trans-retinol, vitamin A,

vitamin A alcohol, axerophthol) is a viscous yellow liquid which has a typical
odo(u)r and slowly crystallizes as yellow
needles. It is insoluble in water but is
freely soluble in oils, ethanol, and paraffin. Retinol and its esters are lipophilic
vitamins.
1.0 g all-trans-retinol is equivalent to
3.33 million I. U., or 1 I. U. vitamin A is
equivalent to 0.300 g retinol.
Since retinol is even less stable than its
esters, virtually only retinyl acetate, retinyl palmitate, and retinyl propionate are
used in pharmaceuticals.
Retinyl acetate
Retinoic acid
see isotretinoin, retinoids, and tretinoin.
Retinoids
Retinoic acid (= vitamin A acid) and its
derivatives are called retinoids. The most
important retinoids are tretinoin (alltrans-retinoic acid), isotretinoin (13-cisretinoic acid), and etretinate. The reti-
Retinyl acetate (syn. vitamin A acetate,

all-trans-retinyl acetate, axerophthyl acetate) consists of yellow crystals which are
greasy or sticky and have a mild, characteristic odo(u)r. They dissolve in oils and
ethanol. They are insoluble in water.
Retinyl palmitate
102
In theory, 1.0 g all-trans-retinyl acetate is

equivalent to 2.907 million I. U. vitamin
A. Commercial products containing at
least 2.8 million I. U./g are available. In
addition, oily and dry dilutions can be
obtained.
Retinyl acetate is rarely incorporated as
the pure substance in pharmaceuticals.
Normally, a commercially available dry
powder containing 250,000 to 500,000
I. U./g is used in solid forms. The flow
properties of these dry powders make
them suitable for tabletting or for filling
hard gelatin capsules. the vitamin A in
the dry powders is usually embedded in
gelatin/carbohydrate, with the addition of
an antioxidant, this process protecting the
vitamin much better form light, oxygen,
humidity, and mechanical stress than
would be the case with an adsorbate.
Nevertheless, in tablets a loss in activity
of 10 to 20 % per year must be expected.
Since nicotinamide has been reported to
damage the structure of gelatin, vitamin
A dry powders should, if possible, not
come into direct contact with nicotinamide [162].
The following composition of a vitamin
A chewable tablet is an example of the
use of a retinyl acetate dry powder for
direct tabletting.
Vitamin A chewable tablet (50,000 I. U.)
500,000 I. U./g [1]
Mannitol
Copovidone
Magnesium stearate
Flavo(u)ring
170 mg
170 mg
25 mg
5 mg
3 mg
q.s.

forms, see direct compressible vitamins,
multivitamin solid preparations, and sorbitol.
Retinyl acetate is hardly ever used in
liquid drug forms, because it may crystallize out of oily solutions and is more
difficult to solubilize than are retinyl palmitate and retinyl propionate.
Retinyl palmitate
(see formula below)
Retinyl palmitate (syn. vitamin A palmitate, all-trans-retinyl palmitate, axerophthyl palmitate) is a brillant yellow,
partly crystalline oily mass with a characteristic odo(u)r. The crystals melt at body
temperature. They are freely soluble in
oils and ethanol but insoluble in water.
In theory, 1.0 g all-trans-retinyl palmitate
is equivalent to 1.82 million I. U. The
commercial product has a minimum content of 1.7 million I. U./g. Oily and dry
dilutions are also obtainable.
One of the main problems with vitamin A
is its chemical stability. It is sensitive to
humidity, oxygen, heat, light, and heavy
metals. This is why all formulations and
some of the commercial types of vitamin
A contain an antioxidant. However, if a
dry inert gas is used to prevent all contact
with oxygen and moisture, the stability of
pure retinyl palmitate is found to be the
same whether an antioxidant is present or
not. Only thermal decomposition is then
responsible for the measured losses, as
shown by the figure on the next page
[173].
103
Retinyl palmitate
Vitamin A+D drops (25,000 + 2,500 I. U./ml)
Retinyl palmitate
Cholecalciferol
Parabens
Sorbic acid
Water
Stability of pure retinyl palmitate with and

without butylated hydroxytoluene (storage
under nitrogen at 23 C in the dark).
1.8 g
7.5 mg
0.5 g
11.0 g
0.2 g
0.2 g
10.0 g
ad 100 ml
The stability of vitamin A in this formulation on storage at 22 to 25 C for 12

months is shown in the graph which follows.
Liquid drug forms containing vitamin A

palmitate may be oily solutions (e.g. for
soft gelatin capsules) or aqueous systems.
The latter are necessarily micro- or macroemulsions containing a solubilizer or
emulsifier. In the following figure the
amounts of three different solubilizers
needed for vitamin A palmitate are presented.
Stability of vitamin A in vitamin A+D
drops (25,000 + 2,500 I. U./ml).
Solubilization of retinyl palmitate with

PEG hydroxystearate (1), PEG glycerol trihydroxystearate (2) or PEG glycerol triricinoleate (3).
A typical example of a clear aqueous

formulation is the following composition
for vitamin A+D drops.
The pH of aqueous solubilizates of vitamin A should not be lower than 6.0,

otherwise isomerization occurs until an
equilibrium has been reached between
two-thirds all-trans-retinyl palmitate and
one-third cis isomers. The main isomer is
the 13-cis form, which has only 75 % of
the vitamin A activity of the all-trans
form. Other cis isomers which are formed
(e.g. 9-cis and 9,13-dicis) have even lower vitamin A acitvity (15 o 24 %). This
is a particular problem in multivitamin
solutions, where the pH must always be
between 4 and 5.
The most effective antioxidant for vitamin A solutions has proved to be butylated hydroxytoluene.
Retinyl propionate
Losses of vitamin A in a syrup on storage
at room temperature for 180 days were
reduced from 20 % to 6 % by addition of
16.8 % tocopherol, 1 % butylated hydroxytoluene and 1 % propyl gallate (all percentages based on retinyl palmitate)
[168]. The purity of the auxiliaries (e.g.
sucrose) may also affect the stability of
vitamin A. Purification of a sucrose syrup
with an ion exchanger distinctly improved the stability of vitamin A [174]. In
addition, aqueous vitamin A solubilizates
should be (produced and) packaged under
an inert gas.
For further examples of its use and notes
on retinyl palmitate in liquid forms, see
PEG glyceryl trihydroxystearate, PEG
hydroxystearate, polysorbate, solubilizer,
vitamin derivatives, and two-chamber
ampules.
For solid drug forms, retinyl palmitate is
used in the form of dry powders.
Those which are dispersible in cold water
and contain 250,000 to 325,000 I. U. vitamin A per gram are particularly used for
multivitamin products in the form of effervescent tablets, effervescent granules,
instant granules, and lozenges. For examples of use, see instant granules and
mannitol.
Retinyl propionate
Retinyl propionate (syn. vitamin A propionate, all-trans-retinyl propionate, axerophthyl propionate) is a yellow, oily liquid, which does not crystallize at room
temperature and is readily miscible with
oils. It also dissolves in ethanol.
In theory, 1.0 g all-trans retinyl propionate is equivalent to 2.78 million I. U.
104
vitamin A. Commercial products contain
at least 2.5 million I. U./g.
As it is readily solubilized, has a high
vitamin content and is of an oily consistency, retinyl propionate is mainly used
for highly concentrated veterinary injectable solutions or emulsions. An example
of a worldwide commercialized formulation see emulsion.
Using PEG glycerol triricinoleate or
PEG hydroxystearate, it is possible to
obtain very high concentrations in clear
aqueous solubilizates.
Solubilization of retinyl propionate with

PEG hydroxystearate (1), PEG glycerol trihydroxystearate (2) and PEG glycerol triricinoleate (3).
A disadvantage of the retinyl propionate

solubilizates compared with similar preparations containing retinyl palmitate is the
greater sensitivity to light, which affects the
physical stability. This problem is dealt
with by effective protection form light.
Otherwise, the factors affecting the stability of liquid formulations of vitamin A
propionate are the same as those for retinyl palmitate (q.v.).
It is perfectly possible to produce relatively stable aqueous forms containing retinyl propionate. This is evident from the
A+D+E veterinary ampule, whose formulation is to be found under the heading
emulsion. The losses of vitamin A from
this product on storage for 2 years were
16 % at room temperature and only 6 % at
6 C.
105
Riboflavin
Riboflavin
Nevertheless, direct tabletting of the
needles is possible up to a content of
about 25 %, e.g. if the following composition is used for the tablets.

Riboflavin
Sorbitol
Copovidone
Silica, highly disperse [4]
Magnesium stearate
Riboflavin (syn. vitamin B2, lactoflavin)

is a fine orange-yellow, strongly staining
powder which has virtually no odo(u)r
and a bitter taste. It is sparingly soluble
in water (7 mg/100 ml); it is somewhat
more soluble in ethanol.
When used in solid drug forms, the form
and size of the riboflavin crystals exert a
certain effect. Usually it consists of fine
needles with a maximum length of
20 m, but also a granular type of pure
riboflavin can be found in the market [1].
If it is in the form of needles it can be
electrostatically charged and will agglomerate. This makes it difficult to screen
and mix. Applying the granular type of
riboflavin these problems do not exist.
Riboflavin crystals (magnification 1900 ).
100 mg
250 mg
19 mg
10 mg
5 mg
However, granulation is normally employed in the production of riboflavin

tablets. In solid forms vitamin B2 is reasonably stable, but they should be packed
and stored with the exclusion of light. To
minimize the chemical interactions with
ascorbic acid, the water content in multivitamin tablets should be as low as possible. For further examples of use in solid
drug forms, see B complex, instant granules, multivitamin solid preparations,
thiamine mononitrate, and tartaric acid.
A 10 mg riboflavin tablet is an approved
standard in the FRG [176].
The low solubility of riboflavin in water
means that it is used less in liquid products. Riboflavin solutions are sensitive
to reducing agents, heavy metals and
light. the action of light on acidic and
neutral solutions produces lumichrome,
and on alkaline solutions produces lumiflavin [133]. Heat promotes these reactions.
The recommended way of increasing the
vitamin B2 concentrations in liquid drug
forms is to use riboflavin-phosphate sodium which is much more soluble.
Apart from its use as a vitamin, riboflavin
is frequently used as a yellow colorant,
identical to the natural product, in solid
and liquid products, and foods (E number
E 101).
Riboflavin-phosphate sodium (syn. vitamin B2 sodium phosphate, sodium riboflavin-5'-phosphate, sodium lactoflavin5'-phosphate) is, like riboflavin, an orange-yellow, strongly staining, microcrystalline powder with a slight odo(u)r and
a bitter taste. The solubility in water depends on the pH as shown by the figure
below.
It is also freely soluble in ethanol.
1.0 g sodium riboflavin-5'-phosphate is
equivalent to about 0.73 g riboflavin.
106
be taken of the sensitivity to light since
this is even more pronounced than in the
case of riboflavin and is increased by
heat and increasing pH. Reducing agents
and heavy metals are also detrimental to
solutions of riboflavin-phosphate sodium.
For examples of its use in formulations,
see B complex, dexpanthenol, and twochamber ampules.
The vitamin B complex + C syrups mentioned under the headings dexpanthenol
and B complex lost 9 % and 13 %, respectively, of vitamin B2 after storage at room
temperature in the dark for 12 months.
Riboflavin tetrabutyrate
Riboflavin tetratbutyrate (syn. vitamin B2

tetrabutyrate, riboflavin 2', 2', 4', 5'-tetrabutyrate) is a fat-soluble riboflavin derivative which is used, especially in Japan, as a therapeutic antioxidant.
Rutin
Riboflavin-phosphate sodium is used virtually only in vitamin solutions or in drug

forms which are to be dissolved in water
(e.g. effervescent tablets, instant granules) as a substitute for the sparingly soluble riboflavin. Particular account has to
Rutin (syn. vitamin P, rutoside) is a bioflavonoid. It is a pale yellow, microcrystalline powder which has no odo(u)r or
taste. It is very slightly soluble in water,
and slightly soluble in ethanol. It dissolves in alkaline media with the formation
of salts.
The preferred use of rutin is in solid drug
forms, in which it is usually combined
107
Rutin
tion of a vitamin C + rutin tablet below is
taken from the literature [244].
For an example of the combination with
other vitamins and minerals in effervescent tablets, see minerals.
Aqueous solutions of rutin are very sensitive to oxygen. On the other hand, alcoholic solutions with a minimal water content are relatively stable at pH 9 [245].
Vitamin C + rutin tablet
with other vitamins. Reducing agents,

heavy metals and light should be avoided.
On the other hand, rutin is able to stabilize vitamin C by preventing the oxidation of ascorbic acid which is catalyzed
by heavy metals [29, 177]. The combina-
I. Rutin
Ascorbic acid
Corn starch
II. 10 % starch paste
III. Talc
Magnesium stearate
20 mg
200 mg
70 mg
q.s.
5 mg
5 mg
Saccharin
108
S
Saccharin
Since pure saccharin is sparingly soluble
in water, it is the sodium salt which is
chiefly used in pharmacy.
Suitable selenium compounds are sodium

selenite and selenium yeast. In a typical
product, 200 mg DL-alpha-tocopheryl
acetate and 20 g sodium selenite might
be incorporated in soft gelatin capsules.
Sicovit
This salt takes the form of colo(u)rless

crystals with an intensely sweet taste. It is
freely soluble in water, and also dissolves
in 90 % ethanol.
Saccharin and the sodium salt are used as
sweeteners. Their sweetness is 300 to 500
times that of sucrose. One possible disadvantage is the bitter aftertaste which is
detectable above a certain concentration.
Saccharin is used in solid and liquid vitamin products, principally in tablets. The
other sweeteners used in solutions are
those which improve the stability of the
vitamins (sucrose, glucose, sorbitol, fructose, glycerol, propylene glycol, etc.).
For examples of its use, see adsorbate,
copovidone, effervescent tablets, minerals, multivitamin solid preparations, sodium ascorbate, polyvinylpyrrolidone,
trace elements, and tartaric acid.
Sicovit is the registered trademark for a

number of synthetic colorants and iron
oxide pigments [1].
Silica
In connection with vitamins, silica (syn.
silica gel, silicon dioxide) is used either
as a carrier for the production of dry
powders (e.g. adsorbates) or in the highly
disperse form (e.g. Aerosil 200) as a
flowability agent in tablets or hard gelatin capsules. For examples of the use of
highly disperse silica, see ascorbic acid,
B complex, calcium hydrogen phosphate,
copovidone, crospovidone, direct tabletting auxiliaries, hard gelatin capsules,
lactose, Ludipress, mannitol, sodium ascorbate, nicotinamid, retinyl acetate, riboflavin, starch, and thiamine mononitrate.
Sodium ascorbate
Selenium
Selenium is a trace element, and is sometimes combined with vitamin E. The
reason for combining these two substances is the synergistic action of tocopherol
and selenium as biological antioxidants.
109
Sodium pantothenate
Sodium ascorbate (syn. sodium L-ascorbate, sodium salt of L(+)-ascorbic acid) is

a white crystalline powder with a slightly
salty taste. It is freely soluble in water
(about 90 g in 100 ml). When used as an
auxiliary in food products, it has the E
number E 301.
In terms of vitamin activity, 1.12 g sodium ascorbate is equivalent to 1.0 g ascorbic acid.
Sodium ascorbate is used in pharmaceuticals much less than is ascorbic acid,
because it is less stable. However, the
two are often combined in tablets in order to diminish the acid taste. An example of a vitamin C composition for direct
tabletting is as follows:
Sodium ascorbate granular
Ludipress
Stearic acid
Orange flavo(u)r
210 mg
70 mg
195 mg
14 mg
5 mg
3 mg
3 mg
solution is above 6. For an example of its

use in multivitamin ampules, see twochamber ampules.
The best stabilizers for aqueous sodium
ascorbate solutions are listed in the table
above [20].
Sodium pantothenate
Sodium pantothenate (syn. sodium Dpantothenate) is a fine white powder

which is virtually odo(u)rless, and is freely soluble in water.
In terms of vitamin activity, 1.0 g sodium
D-pantothenate is equivalent to 0.909 g
D-pantothenic acid.
Sodium ascorbate is used somewhat more

in liquid drug forms than in tablets, especially in injectables when the pH of the
Best stabilizers for use in sodium ascorbate
solutions in water (pH 5.4)
Storage
Stabilizer
Ratio
sodium
ascorbate:
stabilizer
Under air
Glycerol
Sodium chloride
Fructose
Glycerol
Sodium chloride
Fructose
100 : 1
Under
nitrogen
10 : 1
10 : 1
10 : 1
10 : 1
10 : 1
10 : 1
Stability of sodium pantothenate and dexpanthenol in solution.
Sodium sulfite
Since its hygroscopicity is even greater
than that of calcium pantothenate, and
because its stability is reduced below
pH 6, sodium pantothenate is used only
in liquid and semisolid forms, in which
the pH can be adjusted appropriately. If
this is impossible (e.g. combinations with
other B vitamins) sodium pantothenate
should be replaced by dexpanthenol.
The preceding figures show the dependence of the stability of the two substances on the pH in aqueous solutions,
which backs up this recommendation
[157].
Sodium sulfite
Sodium sulfite has been used as a stabilizer for ascorbic acid solutions at 1 % of
the amount of ascorbic acid [20].
However, it is rarely suitable for combinations of vitamins, because many of
them, e.g. thiamine, are decomposed by
reducing agents.
Soft gelatin capsules

The importance of soft gelatin capsules
in connection with vitamins appears to
exceed that applying to other active substances. This is most true in the case of
multivitamin products and of lipohpilic
vitamins. The reason is the high stability
of the vitamins in soft gelatin capsules,
which is not usually reached in other
drug forms.
The anhydrous vitamins are dissolved or
suspended in an oil, and are protected
from oxygen by the gelatin shell and the
high viscosity of its contents.
The gelatin contains glycerol or sorbitol
as plasticizer, which also have benefical
effects on the stability of some vitamins.
Protection from light is achieved by colo(u)ring the capsules.
110
It is quite possible for the stability of the
critical vitamins A and B1 in soft gelatin
capsules to reach levels which allow,
with an overage of 15 % in a multivitamin capsules, an expiration date 2 years
after manufacture to be guaranteed.
Calcium pantothenate poses a problem
due to its interaction with acidic vitamin
C. This can be solved by incorporating
dexpanthenol into the gelatin casing. In
soft gelatin capsules, too, the low water
content of thiamine mononitrate means
that it is more stable than the hydrochloride.
In general, the particle size of hydrophilic
vitamins which are to be suspended must
not exceed 180 m.
Solubility
The lipophilic vitamins dissolve in oils
and are insoluble in water, and vice versa
for the hydrophilic vitamins. However,
the solubility of the latter in water varies
widely.
Solubility of the hydrophilic vitamins in
water
Vitamin
Solubility
(g/100 mg)
Riboflavin
Riboflavin-phosphate
sodium
Nicotinamide
Sodium pantothenate
Dexpanthenol
Cyanocobalamin
Ascorbic acid
Sodium ascorbate
Folic acid
Biotin
100
23
0.007 0.01
510
100
40
100
100
20
12
30
7090
0.00021.5
0.04
111
The solubility of the hydrophilic vitamins
is rarely a problem in formulation, because the very slightly soluble riboflavin
can be replaced by its freely soluble derivative riboflavin-phosphate sodium.
The solubility of folic acid depends
greatly on the pH (for graph, see complexes). The solubility of biotin also increases with increasing pH so that the sodium
salt forms a 20 % solution in water.
Lipophilic vitamins can be dissolved in
water only by solubilization.
Solubilization
There are various principles of solubilization. In the case of the vitamins, the only
principle employed is that of producing a
microemulsion by formation of micelles
using non-ionic surfactants (solubilizers).
All these compounds have a lipophilic
component, in the form of a fatty acid,
and a hydrophilic portion, in the form of
polyethylene glycol and/or glycerol or
sorbitan. When the solubilizer is dissolved in water, there is formation, above
the critical micelle concentration (e.g.
0.02 % for PEG hydroxystearate), of
spherical micelles, which become ellipsoidal at somewhat higher concentrations. In the micelles the lipophilic parts
of the molecule are directed inwards and
the hydrophilic parts are directed out-
Micelle formation on solubilization.
Solubilization
wards towards the surrounding liquid.
The diameter of a micelle, for example
in a 1 % aqueous solution of PEG hydroxystearate, is 12 nm. At and above a temperature of 60 C there is a rapid increase,
reaching 30 nm at 70 C.
When vitamin A, for example, is solubilized, the molecules of the vitamin are
trapped in the interior of the micelles.
As long as they are not too heavily loaded with vitamin A, the micelles remain
small enough to be invisible to the naked
eye. Above a certain size the solution
appears opalescent.
It has to be remembered that in a solubilizate the surface area of the inner lipophilic phase is very large. This means
that oxygen, inter alia, has a larger area
to attack, which results in vitamins A, D
and K1 being less stable in solubilizates
than in oily solutions.
In practice, the method of solubilization
is crucial. The heating of the vitamin
with the solubilizer and, where appropriate, an antioxidant must always be
in the absence of water, and only when
the mixture has reached 60 to 70 C
(usually), can the water be added (or
vice versa), slowly and with vigorous
stirring, to form the outer phase. If this
procedure is not followed, the micelles
are very often too large, and thus the
solutions are turbid, or at least opalescent. Addition of polyethylene glycol
Solubilizer
to the solubilizer permits the temperature to be reduced.
Not all derivatives of the lipophilic vitamins are equally suited for solubilization. The most suitable are the undiluted
vitamin derivatives listed in the table
which follows.
Vitamin derivatives suitable for solubilization
Retinyl palmitate
Retinyl propionate
Ergocalciferol
Cholecalciferol
Tocopheryl acetate
Phytomenadione
Retinyl acetate is less suitable, because

its solubilizates are physically and chemically less stable [174]. Solubilization
of tocopherol is likewise inadvisable because of its low chemical stability. For a
comparison between retinyl palmitate
and retinyl propionate, see PEG hydroxystearate and vitamin derivatives.
For examples of solubilization in formulations, see the individual lipophilic vitamins and solubilizers.
Solubilizer
It is necessary to use a solubilizer to
produce aqueous solutions of the lipophi-
112
lic vitamins A, D, E, and K1. The most
suitable solubilizers have proved to be
those listed in the table below.
Solubilizers commonly used for vitamins
Polysorbate 80
PEG glyceryl trihydroxystearate
PEG hydroxystearate
These solubilizers form micelles (see solubilization).

The following three formulations are suitable for preparing a clear solution containing 50,000 I. U. vitamin A per ml.
Vitamin A drops, unstabilized
(50,000 I. U./ml)
1. Retinyl palmitate
3.0 g
PEG 40 glyceryl trihydroxystearate [1]
11.0 g
Water
ad 100 ml
3.0 g
10.0 g
5.0 g
Water
ad 100 ml
3.0 g
Polysorbate 80 [6]
12.0 g
Water
ad 100 ml
After storage in the dark at about 23 C

for 12 months, all three solutions were
Stability of vitamin A drops with various solubilizers (50,000 I. U./ml).
113
still clear and the losses were as shown in
the preceding figure [173].
It is obvious that the chemical stability of
vitamin A depends on the solubilizer system.
The amounts of solubilizer required for
the solubilization of vitamin E acetate
may differ widely from those for vitamin
A. The following three formulations, for
example, can be used to prepare a clear
solution containing 20 mg tocopheryl
acetate per ml.
Vitamin E acetate solutions (20 mg/ml)
1. Tocopheryl acetate
2g
Polysorbate 80 [6]
8g
Water
ad 100 ml
2g
PEG 35 glyceryl
triricinoleate [1]
12 g
Water
ad 100 ml
2g
13 g
Water
ad 100 ml
Increasing the vitamin E concentration

reduces the differences in the amounts
of solubilizer required, until they become
approximately identical. For further details of the solubilizer concentrations required, see cholecalciferol, ergocalciferol, PEG glyceryl triricinoleate, PEG hydroxystearate, phytomenadione, polysorbate, tocopheryl acetate, and vitamin
derivatives.
The addition of a solubilizer may also
reduce the rate of breakdown of ascorbic
acid in aqueous solution [179].
When a solubilizer is used, it is always
necessary to check the effectiveness of
the preservatives since these are adversely affected by all solubilizers.
Solvents
Solutol HS 15
Solutol HS 15 is a registered trademark
for PEG 15 hydroxystearate [1].
Solvents
The most important solvent is water. Organic solvents are becoming increasingly
less important in the manufacture of vitamin products. However, it is necessary
to distinguish between solid drug forms,
in which the hydrophilic solvent which is
used should be absent from, or present
only in traces in the final product, and
liquid drug forms, including soft gelatin
capsules, which are meant to contain a
hydrophilic or hydrophobic solvent as an
ingredient.
In the case of solid forms, the organic
solvents ethanol or isopropanol are frequently preferred for granulation or filmcoatings in order to avoid the adverse
effects of water. Other organic solvents
including methylene chloride are only
rarely used nowadays, for toxicological
reasons.
The hydrophilic organic solvents used in
liquid vitamin forms are mainly propylene glycol, ethanol, glycerol or low molecular-weight polyethylene glycol. Suitable hydrophobic solvents for oily solutions are oils (e.g. peanut oil), short-chain
saturated triglycerides (e.g. Miglyol
[9]), ethyl stearate or liquid paraffin.
Solvents do affect the stability of vitamins. The most pronounced changes in
stability brought about by solvents occur
with ascorbic acid: the greatest improvement in the stability compared with water, which is apparently the worst solvent
for this vitamin, is obtained with propylene glycol or glycerol [1719].
The solvent may also affect the chemical
stability of B vitamins [19, 75]. Vitamin
Sorbic acid
114
A behaves similarly, the stability in

aqueous solutions being worse than in
oily formulations.
Sorbic acid
Sorbic acid is a white crystalline powder

with a characteristic odo(u)r. It is slightly
soluble in water, and dissolves in ethanol.
Sorbic acid and its salts are used as preservatives in pharmaceuticals and food
products, the relevant E numbers being
as follows.
E numbers of sorbic acid and its salts
Sorbic acid
Sodium sorbate
Potassium sorbate
Calcium sorbate
E 200
E 201
E 202
E 203
In oral vitamin solutions without an added solubilizer, an adequate preservative

effect is normally ensured with 0.1 or
0.2 % sorbic acid. The pH of the solution
should be in the acidic range, because
sorbic acid and its salts lose their preservative effect in alkaline media. In the
presence of a solubilizer the concentration which is needed must be determined
by experiment. The effect may be intensified by combination with other preservatives.
For an example of use in a syrup, see
dexpanthenol and syrup.
Sorbitol
(see formula to the right)
Sorbitol (syn. D-glucitol) is a white crystalline or spray-dried powder which is
odo(u)rless and has a slightly sweet taste.

It is freely soluble in water (sorbitol syrup) and less soluble in ethanol. Above a
relative humidity of 65 % sorbitol is hygroscopic (for water adsorption plot, see
hygroscopicity). Sorbitol is an important
auxiliary for vitamin products, because it
stabilizes some vitamins.
Sorbitol is used in solid drug forms as a
filler, also having a certain binding effect, which increases the tablet hardness.
Hence it is commonly used in lozenges
and chewable tablets.
Sorbitol is able to adsorb thiamine mononitrate, riboflavin, and pyridoxine hydrochloride up to certain concentrations.
These adsorbates are more suitable for
direct tabletting than are the physical
mixtures [181]. In some tablet formulations it is advisable to compare crystalline and spray-dried sorbitol, because it is
perfectly possible for them to result in
tablets with different properties.
The following composition for direct tabletting to vitamin A+E chewable tablets
may be regarded as a typical example of
the use of crystalline sorbitol.
Vitamin A+E chewable tablet (30,000 I. U.
+ 30 mg)
66 mg
500,000 I. U./g
65 mg
Sorbitol, crystalline
425 mg
Polyethylene glycol 6000, powder 15 mg
Orange flavo(u)r
15 mg
9 mg
115
forms, see adsorbate, analgesics, direct
compressible vitamins, riboflavin, trace
elements, and tartaric acid.
Sorbitol is used in liquid drug forms mainly to stabilize vitamins. Thiamine hydrochloride and riboflavin [153], cyanocobalamin [74, 76], and ascorbic acid [17,
77, 153, 184] are stabilized in syrups or
solutions containing sorbitol.
In a multivitamin syrup containing vitamin concentrations corresponding to
the RDAs, the following composition of
auxiliaries was found to be the most beneficial for the stability of vitamins B1
and C [75].
Composition of auxiliaries for a multivitamin syrup
50 mg
100 mg
Ethylenediamineetraacetic acid,
calcium disoldium alt
10 mg
Parabens
200 mg
Polysorbate 80
8 ml
Water
8 ml
Glycerol
24 ml
Propylene glycol
24 ml
75 % sorbitol solution
ad 100 ml
The stability of vitamins B1 and C in

multivitamin drops of pH 4.5 was about
the same when sorbitol and sucrose were
used. The results with glucose were less
good [152].
For further examples of its use in liquid
formulations, see ascorbic acid, B complex, and dexpanthenol.
Spray-drying
Spray-drying is of only indirect importance in the manufacture of vitamin products. Together with spray-cooling, it is
Stability
an important technique in the production
of dry powders of some vitamins.
In the case of vitamin E, spray-drying can
be used to produce a dry powder containing more than 50 % oily tocopheryl acetate. Only by use of a dry powder of this
type is it possible to produce high-concentration vitamin E tablets (for an example, see cellulose and Ludipress).
Stability
There can scarcely be a group of pharmaceuticals which involves as many problems with stability as do the vitamins.
The problems are compounded by the
fact that, unlike other active substances,
often a single product combines many
vitamins. A multivitamin product contains at least ten vitamins and may be
supplemented by a number of minerals
or trace elements.
Even in single-vitamin products, apart
from those of the vitamin E esters, there
may be adverse effects on the stability of
the vitamins owing to at least one of the
following factors: light, oxidation, reduction, and heavy metals. Vitamin B12 gives
rise to the most difficulty, but vitamins
A, B1, C and D must also be regarded as
highly sensitive.
The stability problems are usually very
much greater with liquid drug forms than
with solid forms because chemical interactions and hydrolisis cannot be avoided
in the presence of water. As the chemical
structures of the vitamins differ, a distinction has to be made between the
problems of physical and chemical stability. The important factors for solutions
differ somewhat from those for tablets, as
shown by the table on the next page.
A stress test is almost always helpful for
examining the effects of these factors
(see prediction of stability).
Starch
116
Factors affecting vitamin stability

Liquid
forms
Solid forms
Physical
stability
Solubility
Solubilization
Vitamin
derivative

Method of
tabletting
Moisture content of granules
Vitamin
derivative
Chemical
stability
pH
Solvent
Vitamin
derivative
Antioxidant
Chelating
agent
Light
Sugar
Solubilizer
Interaction
Packaging
Water content
Vitamin
derivative
Tablet coating
Method of
tabletting
Interaction
Packaging
In solid drug forms the most important

factors for the chemical stability are the
content of free water in the formulation
and the adsorption of water form the atmospheric humidity [277]. All other influences almost always are connected
with these factors. Crystalline water e.g.
in lactose monohydrate normally does
not cause any problem as it is not available as free water.
Starch
Corn, wheat, and potato starch, in pure
and modified forms, are used in pharmacy. All pure starches are composed of
linear amylose chains and branched amylopectin chains.
The molecular weight of amylose is
50,000200,000, and that of amylopectin
is 150,0002,000,000.
Starches are fine, white, odo(u)rless powders which are virtually insoluble in cold
water and ethanol. They swell in hot
water. They are somewhat hygroscopic
(for water adsorption plot for corn starch,
see hygroscopicity).
Starches are used almost exclusively in
solid drug forms containing vitamins as
fillers, binders, and disintegrants. Corn
starch is most often used.
For use as binder, in wet granulation,
normally a 10 to 25 % starch paste in
warm water is prepared for the traditional
techniques, and one containing less than
10 % starch is prepared for fluidized bed
granulation.
When used as filler, the starch can be
added not only after, but also before the
granulation as shown by the following
example of a vitamin B6 tablet.
117
Sterilization

Corn starch
II. Polyvinylpyrrolidone K30
Isopropanol + water (1+1)
III. Silica, highly disperse
Magnesium stearate
40 mg
300 mg
15 mg
q.s.
2 mg
1 mg
Starch can also be used for direct tabletting, in which a modified type is often
preferred (for examples of use, see ascorbic acid and tocopheryl succinate).
For use as a disintegrant, either 20 to
40 % starch is incorporated into the interior of the tablet, or 5 to 15 % is added
after granulation. The amylopectin is responsible for the disintegrant action since
it swells with water. Hence amylopectin
derivatives have been developed, e.g.
carboxymethylamylopectin, which are
more powerful disintegrants than is pure
potato starch.
Granules which are very suitable as a direct
tabletting auxiliary can be produced by
granulating corn starch with 5 % polyvinylpyrrolidone K 30 in a fluidized bed.
Stearic acid
The commercially available stearic acid

always contains a certain percentage of
palmitic acid. It is a white powder.
Stearic acid is used in the same way as its
magnesium salt in tablets as a lubricant.
For examples of its use, see ascorbic
acid, calcium pantothenate, and sodium
ascorbate.
Sterilization
The head sterilization of vitamin injectables may give rise to problems since
any energy input increases the rate of
thermolysis of the less stable vitamins,

e.g. vitamin A or cyanocobalamin. This
is evident by the results of heat-sterilization given in the following two tables.
Influence of heat sterilisation on the vitamin A stability
Solution
Loss of vitamin A
(120 C, 20
min)
Oily, 50,000 I. U./ml

(0.1 % BHT)
Aqueous, 50,000 I. U./ml
(0.1 % BHT)
Aqueous, 100,000 I. U./ml
(0.3 % BHT)
3.9 %
5.6 % (pH 5.4),
3.8 % (pH 6.5)
4.8 % (pH 5.6),
4.6 % (pH 6.5)
Vitamin losses on heat sterilization of a

vitamin B1 + B6 + B12 solution in water
Vitamin
Vitamin loss
(120 C, 20
min)
B1 (3 %)
B6 (3 %)
B12 (0.006 %)
0%
0%
40 %
Radiolysis of vitamins on sterilization by

gamma irradiation has been reported in
some publications.
Publications on the effects of gamma irradiation on vitamins
Vitamin
Reference
Vitamin A
Vitamin B1
Vitamin B2
Vitamin B6
Nicotinamide
Folic acid
Vitamin C
Cyanocobalamin
Hydroxocobalamin
200
196
196
196
201
196
196
199
195
231
Stress test
Gamma sterilization of vitamins in dry
formulations results in no decomposition,
which is why this is particularly recommended for lyophilisates. It is also possible in a few cases to use gamma rays to
sterilize a vitamin solution without losses: there were no changes in the molecular structure of retinyl palmitate in oily
solutions at a radiation dose of 5 Mrad =
50 kGy [200]; likewise there were virtually no losses form 20 % aqueous calcium
pantothenate solutions. However, reduction of the calcium pantothenate concentration to 1 % resulted in extensive (70 %)
radiolysis [201].
Filtration is the least deleterious method
of sterilization, causing virtually no vitamin losses. Care must be taken that no
traces of metals from the apparatus pass
into the solutions, because these may catalyze vitamin breakdown.
Also the microwave sterilization is reported as an able method [274].
Stress test
A stress test of vitamin products is a
short-term storage test at elevated temperature. Its main aim is to reveal the effects of various auxiliaries and/or other
factors on vitamin stability in a short
time. A typical example is the examination of the effect of glucose, sucrose and
sorbitol at various pH values on the stability of vitamins B1 and C in multivitamin drops [152]. For further details, see
prediction of stability.
118
Sucrose
Sucrose (syn. saccharose, sugar) is available in the form of a white powder or

colo(u)rless crystals. It is very freely soluble in water, and also dissolves in 70 %
ethanol. Sucrose is not hygroscopic up to
a relative humidity of 80 % (for water
adsorption plot, see hygroscopicity).
Sucrose is used as a syrup in liquid oral
drug forms, because the increase in viscosity and the reduction in diffusion improve the stability of some vitamins, e.g.
vitamin A [178], vitamin B1 [152, 206],
and vitamin C [17, 70]. A syrup containing sorbitol may sometimes be better.
No great differences in the stability of
vitamins B1 and C in multivitamin drops
were found between the use of sucrose
and sorbitol when the pH was 4.5. Glucose was much less satisfactory [152].
The purity of the sucrose syrup has an
effect on the stability of vitamin A. Purification of the sucrose on an ion exchanger greatly improved the stability [174].
For examples of use, see B complex, dexpanthenol, and syrup.
Sucrose has a variety of functions in solid
drug forms. It can be used as a filler, a
binder, a masking flavo(u)r, e.g. in vitamin C tablets, a stabilizer, and as a coating agent in sugar-coating. For examples
of its use, see effervescent tablets, copovidone, instant granules, tartaric acid,
and sugar-coating.
119
Sugar
Various types of sugar are used in liquid
and solid vitamin products.
Types of sugar in vitamin products
Lactose
Sucrose
Glucose
Fructose
Sorbitol
Mannitol
Maltose
Xylitol
For details of the use of sugar, see under

the individual headings.
Sugar-coating
Traditional sugar-coating is still of value
for multivitamin tablets, and cannot always be replaced by film-coating, because the colo(u)red covering offers effective protection against light and humidity. In addition, it is possible with the
sugar-coated tablet, much as with the soft
gelatin capsule, to incorporate one or
more vitamins into the covering instead
of into the core. This eliminates chemical
interactions and avoids unfavo(u)rable
pH values. The maximum stability of
vitamins A, D, calcium D-pantothenate,
vitamin B12 and folic acid was achieved
when hey were separated from the other
vitamins by incorporation in the sugarcoating [155]. In this case, it may be
better to use dexpanthenol than calcium
pantothenate.
A possible alternative to the traditional
sugar-coating is an automated version
[192].
The following sugar film-coating suspension is very suitable for use in a continuously operation Accela-Cota.
Substained release tablets

Suspension for automated sugar film-coating
Sucrose
Copovidone
Beta-carotene 1 % CWD [1]
Talc
Titanium dioxide
Water
400 g
100 g
80 g
30 g
60 g
100 g
ad 2400 g
When coating vitamin C cores, it is necessary to remember that ascorbic acid

reduces most colorants [222224]. Thus
an uncolo(ur)ed subcoating is absolutely
necessary. However, the individual colorants differ in stability even when this
measure is employed [67].
Substained release tablets

The sustained release effect is almost not
known for vitamin tablets. The only exception is vitamin C for which a formulation is given in the following table:
Vitamin C sustained release tablets
(200 mg)
200 mg
Polyvinyl acetate + Povidone
K 30, 8+2), spray dried
200350 mg
Magnesium stearate
9 mg
Release of vitamin C from sustained release
tablets:
Synergists
Synergists
Synergists are generally defined as substances which increase the effect of another substance. In the specific case of
antioxidants, synergists are substances
which increase their effects either by regenerating the antioxidant, which has
been consumed during the reaction, or
by providing a pH suitable for the action
of the antioxidant. Chelating agents are
included among the synergists because
they form complexes with substances,
e.g. heavy metals, which promote oxidation and thus prevent the latter. The
boundaries between antioxidants and synergists are not well-defined; there are
many transitional cases.
Synergists important in vitamin products
are citric acid, lecithin, and ethylenediaminetetraacetic acid. In addition, ascorbyl palmitate has a synergistic action on
tocopherol.
Syrup
The problems with the stability of liquid
oral products containing vitamin combinations increase with the number of vitamins present. Syrups produced with sucrose, sorbitol or glucose are still the best
in these cases, because the high viscosity
reduces the diffusion in the system.
Nevertheless, it is in any case advisable
to find an alternative to the liquid drug
form, for example effervescent or instant
granules, or effervescent tablets, which
are likewise taken in the liquid form by
the patient.
For further details, see sucrose, glucose,
and sorbitol.
120
For examples of the uses of syrups, see
ascorbic acid, B complex, dexpanthenol,
and sorbitol.
For an example of a multivitamin syrup
see the table below.
Multivitamin syrup (12 RDA/20 ml)
I. Vitamin A palmitate
1.7 mio I. U./g
100 mg
Vitamin D 40 mio I. U./g
0.5 mg
Vitamin E acetate
1000 mg
PEG glyceryl
trihydroxystearat
45 g
II. Water
100 g
III. Sucrose
450 g
Methyl parabene
2g
Citric acid
800 mg
IV. Glycerol
96 g
Water
250 g
V. Thiamine hydrochloride
150 mg
Riboflavin 5-phosphate Na
150 mg
Nicotinamide
550 mg
150 mg
Ascorbic acid
3000 mg
Sorbic acid
1g
Propylene glycol
50 g
Total amount
1000 g
Manufacturing: Heat I and II separately to
60 C and mix both well stirring. Dissolve
III in the hot solution IV. Mix the cool
solutions I/II, III/IV and V and adjust the
pH to about 4. Pass nitrogen through the
syrup before and during filling in flasks.
Chemical stability:
After the storage at room temperature the
following vitamin contents were found by
HPLC
9 months 12 months
Vitamin A
86 %
73 %
88 %
83 %
Vitamin B1
96 %
92 %
Vitamin B2
Vitamin C
78 %
77 %
121
Tablet friability
T
Tablet(s)
Tablet disintegrants
Tablets are the most widely used form

containing vitamins. There is no doubt
that this is partly due to the relatively
high stability of vitamins in this form,
compared with drops, syrups, injectables,
and other solutions.
see disintegrants.
Tablets commonly used for vitamins

Normal tablets
Chewable tablets
Lozenges
Effervescent tablets
Laminated tablets
Multilayer tablets
Cores for coated tablets
The stability of vitamins in tablets with

film-coating and, in particular, with sugar-coating is usually improved due to
the reduction in the permeability to oxygen, or, when one or two vitamins are
incorporated into the coating, due to the
elimination of chemical interactions.
This is also the aim of laminated or multilayer tablets.
The vitamin compositions which are suitable for tablets sometimes differ from
those used in solutions. For details, see
vitamin derivatives.
In addition to the many formulations given
in this book, a large number of suggested
formulae for vitamin tablets can be found in
the literature supplied by the individual vitamin manufacturers and in the general literature [e.g. 71, 180, 202, 279].
Tablet coating
see film-coating and sugar-coating.
Tablet disintegration
The disintegration of a vitamin tablet in
an aqueous medium into its primary particles can be regarded as the first step in
the bioavaibility of vitamins, and thus is
an important criterion of the quality of a
vitamin tablet. The current pharmacopeias specify the apparatus to be used for
measuring it.
Both the nature of the test medium and
the desirable disintegration time depend
on the type of vitamin tablet:
1. All tablets which are to be swallowed (e.g.
film- or sugar-coated tablets and normal
tablets) are tested in simulated gastric fluid
(or water). The maximum disintegration
time is 15 minutes.
2. Chewable tablets and lozenges are tested
in water. The disintegration time is between 15 and 60 minutes.
3. Effervescent tablets are tested in water.
The maximum dissolution time is usually
3 minutes.
The formulations suggested in this book

met these requirements.
Since for other active drug substances the
importance of the control of the tablet
disintegration has been reduced and is
more and more substituted by the dissolution test a similar situation can be observed in the case of vitamin tablets.
Tablet friability
The friability is an important parameter
for assessing the physical properties of
Tablet hardness
tablets. It is measured by the percentage
loss when tested by rolling and shaking.
The equipment used for this test is usually of the rotary type (friabilator).
Friability of 0.8 to 1.0 % regarded as the
upper limit for normal tablets. It is almost
always possible to develop a formulation
for vitamin tablets which meets this requirement.
The friability in the Roche friabilator is
below 1 % for all the tablet formulations
detailed in this book.
Tablet hardness
The hardness is one of the most important parameters for characterizing the
physical properties of a tablet. It is determined by measuring the force acting
along the diameter of a tablet at the instant it fractures. The hardness is usually
reported in kg or N (1 kg is equivalent to
9.81 N). The results of measurement of
hardness may depend on the apparatus,
and thus may not be generally applicable.
Tablets with a very high content of oily
vitamins are least hard. It is usually possible to solve this problem, as shown by
the example of the vitamin E tablet detailed under the heading Ludipress,
which had a measured hardness of 60 to
70 N.
Large amounts of added magnesium stearate may adversely affect the tablet hardness.
The hardness of chewable tablets and
lozenges usually is greater than that of
normal tablets to prevent disintegration
in the mouth. This is achieved by higher
concentrations of binders or fillers, such
as mannitol or sorbitol.
The formulae for tablets suggested in this
book all had a hardness between 50 and
150 N in a Heberelin/Schleuniger apparatus.
122
Tabletting
A variety of methods is available for
tabletting vitamins. For details, see direct
tabletting, granulation, tablets, and tabletting pressure.
Tabletting pressure
The pressure applied during the production of tablets may affect the chemical
stability of the vitamins they contain.
This particularly applies to the unstable
lipophilic vitamins A, D and K1 which
are used as dry powder. A high tabletting
pressure may expel a certain amount of
the oily vitamins A or K1 from the dry
powder matrix, which increases the contact with atmospheric oxygen and other
vitamins. There may also be fracturing of
the dry powder particles, which has the
same effect on the vitamins.
A high tabletting pressure alters the appearance of dexpanthenol or vitamin E
tablets, for example. That tablets acquire
a greasy, i.e. somewhat shiny, appearance, due to extrusion of the vitamins
from their dry powders, and their hardness diminishes. On the other hand, these
tablets, in particular, require a minimum
pressure to reach an adequate hardness.
The effect of the tabletting pressure on
the tablet hardness, the tablet disintegration and the tablet friability has been
examined on the vitamin C formulation
(see next page).
The hardness and the disintegration are
not always directly proportional to the
compressive force over a range as wide
as in this case. If, for example, the ascorbic acid content of the following formulation is increased from 30 % to 45 %, the
hardness will exponentially increase with
the compressive force and the figure at
23 kN will be much higher.
123
Tartaric acid
Tartaric acid
Formulation
Ascorbic acid, fine powder
Ludipress
Magnesium stearate
60 mg
139 mg
1 mg
Properties
Tartaric acid is used as an auxiliary in

effervescent tablets where it brings about
the effervescent effect by reacting with
sodium bicarbonate to liberate carbon dioxide. In some formulations, tartaric acid
has proved to be better at producing satisfactory tablets than has citric acid,
which is used for the same purpose.
The liberation of carbon dioxide may
take place somewhat slower with tartaric
acid than with citric acid unless another
acid, such as ascorbic acid, is present in
the formulation [259].
Effects of the tabletting pressure on the
properties of a vitamin C tablet (60 mg).
Talc
Talc is magnesium hydroxide polysilicate. It is a white powder, which has a
slightly greasy feel, and is insoluble in
water.
Talc is used as glidant and lubricant in
vitamin tablets. The usual concentrations
are in the range 1 to 4 % of the tablet
weight. As with all lubricants, talc should
be added to the tablet mixture after granulation and before compression.
For examples of its use in tablets, see
crospovidone, direct compressible vitamins, and hydroxypropyl(methyl)cellulose.
Talc is also used in film-coatings as an
antistick agent. For examples of its use,
see ethylcellulose, film-coating, and sugar-coating.
Vitamin B complex + C effervescent tablet

I. Thiamine mononitrate
Riboflavin
Nicotinamide
Tartaric acid, powder
Sodium bicarbonate
Sucrose, crystalline
Sorbitol
II. Isopropanol + methylene
chloride (1+1)
III. Ascorbic acid, crystalline
Riboflavin
powder
Cyanocobalamin 0.1 %,
gelatin-coated [3]
Orange flavo(u)r
Granulate mixture I with II, screen,
with III, and compress.
30 mg
5 mg
10 mg
66 mg
16 mg
350 mg
450 mg
750 mg
30 mg
200 mg
q.s.
500 mg
2 mg
50 mg
10 mg
10 mg
2 mg
5 mg
mix
Taste
An example of its possible use is the
preceding composition for a vitamin B
complex + C effervescent tablet.
For further examples of its use, see compaction, effervescent tablets and multivitamin solid preparations.
Taste
see flavo(u)ring.
Thermolysis
see prediction of stability and heat.
Thiamine disulfide
Thiamine disulfide (syn. vitamin B1 disulfide, aneurine disulfide) is a white crystalline powder. When anhydrous, it is
sparingly soluble in water, but crystals
which contain water are freely soluble.
Thiamine disulfide is only rarely used in
vitamin products in the FRG.
Thiamine hydrochloride (syn. vitamin B1

hydrochloride, thiamine chloride hydrochloride, aneurine hydrochloride) is a
white microcrystalline powder with a typical odo(u)r and a bitter taste. It is very
124
freely soluble in water. About 5 % solutions in glycerol and about 1 % solutions
in ethanol can be prepared.
Thiamine hydrochloride is preferred to
other vitamin B1 derivatives in liquid
drug forms because of its solubility. The
stability in solution gives rise to difficulty. Quite stable formulations containing
vitamin B1 and no other vitamins can be
prepared by maintaining a very low pH
[220], excluding light and oxidizing
agents, and possibly adding an antioxidant and chelating agent. A reducing
agent such as sodium sulfite must not be
used as antioxidant, because it will immediately decompose thiamine. A 1 %
thiamine solution was obtained by using
5 % low-molecular-weight polyvinylpyrrolidone to improve the taste, 0.05 % propyl gallate and 0.005 % ethylenediaminetetraacetic acid and adjusting the pH to
4; it had been stable by organoleptic and
chemical criteria, for 2 years [64]. There
are also some other substances which are
able to improve the stability of thiamine
solutions. These include sucrose and glycerol [206].
It is much more difficult, and may be
virtually impossible to develop a multivitamin or B complex + C syrup with a
stable vitamin B1 content, because there
are numerous chemical interactions with
other vitamins. Comparison of glucose,
sorbitol and sucrose in multivitamin
drops revealed that sorbitol was the best
stabilizer of vitamin B1 at pH 3.2. Solutions containing sorbitol and sucrose at
pH 4.5 were of approximately equal stability. The results with glucose were always worse [152].
The losses of thiamine from the formulations of vitamin B complex + C and
multivitamin syrups detailed under the
headings B complex, dexpanthenol and
syrup after storage in the dark at room
temperature for 12 months were 15, 19
125
and 17 %, respectively. This means that
with an overage of 20 % thiamine hydrochloride these products may be expected
to have a shelf-life of only 18 months, at
the outside. The purity of the thiamine
hydrochloride also appears to influence
its stability in injectables [207].
This is why a more stable alternative to a
multivitamin solution should always be
sought, e.g. instant granules, an oral
powder or effervescent granules.
The only solid drug forms, in which thiamine hydrochloride is normally used, are
pure vitamin B1 products and simple B
complex tablets, because it contains 3 or
4 % water, unlike thiamine mononitrate,
and this promotes undesired chemical interactions. The following composition is
an example of its use in a vitamin B1
tablet.
(or thiamine mononitrate)
100 mg
Lactose, monohydrate
100 mg
100 mg
10 mg
Isopropanol
q.s.
III. Crospovidone
10 mg
1 mg
Granulate mixture I with solution II, mix
with III, and compress.
After these tablets had been stored at

30 C and 70 % relative humidity for 6
months, there was no loss of vitamin
and no difference was found between
thiamine hydrochloride and thiamine mononitrate.
For further examples of its use in tablets,
see direct tabletting auxiliaries, lactose,
and thiamine mononitrate.
Thiamine mononitrate (syn. vitamin B1

nitrate, thiamine nitrate, aneurine nitrate)
is a white, microcrystalline powder with
a bitter taste. 2 or 3 % solutions in water
can be prepared and it is slightly soluble
in ethanol.
Thiamine mononitrate is used only in
solid drug forms, in which its stability is
equal to or greater than that of thiamine
hydrochloride [131]. The grater stability
derives from the very low water content
of the nitrate, which means that it is less
prone to chemical interactions than is the
hydrochloride, which contains water.
This is particularly evident in vitamin B
complex and multivitamin tablets [156].
Composition
Thiamine hydrochloride or thiamine mononitrate
Riboflavin
Nicotinamide
Cyanocobalamin 0.1 % gelatincoated [3]
25 mg
25 mg
80 mg
40 mg
16 mg
16 mg
286 mg
16 mg
3 mg
Thiamine stability
The losses of the thiamine derivatives
after storage at 40 C for 6 months were
as follows:
Thiamine hydrochloride:
68 % decrease
Thiamine mononitrate:
17 % decrease
Thiamine pyrophosphate
The stability of thiamine mononitrate has
also been found to be greater in multivitamin soft gelatin capsules [41, 208].
The same applies to hard gelatin capsules [208].
The difference in stability between vitamin B1 hydrochloride and mononitrate
in the preceding vitamin B complex formulation for direct tabletting has been
determined.
For further examples of its use in vitamin
tablets, see B complex, instant granules,
multivitamin solid preparations, thiamine
hydrochloride, and tartaric acid.
Thiamine pyrophosphate
see cocarboxylase.
Thiochrome
Thiochrome is a colo(u)red product of the

oxidation of thiamine derivatives [132],
as may occur in multivitamin solutions
due to chemical interactions with other
Oxidation of vitamin E.
126
vitamins or to oxidation (not by atmospheric oxygen). The solution turns
brown and sometimes a precipitate may
be formed.
Tocopherol
Alpha-tocopherol (syn. vitamin E) has

the highest activity of the vitamin E derivatives. The commercially available
forms are D-alpha and DL-alpha-tocopherol.
The former is the RRR form, and is obtained from a natural mixture of tocopherols (alpha, beta, gamma and delta) by
methylation. The all-racemic DL form is
a synthetic product. Both types are oily,
yellow to brownish liquids. Tocopherol is
insoluble in water, and soluble in fats and
oils. It is one of the lipophilic vitamins.
1 mg DL-alpha-tocopherol = 1.1 USP
units vitamin E
1 mg D-alpha-tocopherol = 1.49 USP
units vitamin E
(1 USP unit is equivalent to 1 former
international unit vitamin E)
127
Tocopherols are very sensitive to oxidation and thus rapidly darken when exposed to oxygen. This is why tocopherol is
only very rarely used as vitamin E in
pharmacy. It is employed as an antioxidant (free radical trap) in pharmaceuticals, food products (E number E 307),
and plastics with tocopherol quinone
being produced.
Tocopherol is particularly used in vitamin products for the stabilization of vitamin A. Addition of 3 % tocopherol to a
vitamin A solubilizate results in very satisfactory stability [209]. The loss of vitamin A in a syrup stored at room temperature for 180 days was reduced from
20 % to 6 % by addition of 16.8 % tocopherol, 1 % butylated hydroxyanisole and
1 % propyl gallate (all figures being based on vitamin A) [168].
Tocopheryl acetate
thus one of the few stable vitamins. This
is also why it has no antioxidant effect,
unless it is hydrolyzed by saponification.
It can be incorporated into soft gelatin
capsules, or oily products either undiluted or mixed with oils (e.g. peanut oil).
A dry powder must be used for solid drug
forms (adsorbate, spray-dried material,
etc.). Commercially available products
mainly contain 33 or 50 % and some of
them are dispersible in cold water. For
examples of its use, see adsorbate, ascorbic acid, calcium hydrogen phosphate,
instant granules, Ludipress, multivitamin solid preparations, and sorbitol.
A solubilizer is necessary when tocopheryl acetate is used in aqueous solutions.
The figure which follows shows the
amount of PEG glyceryl trihydroxystearate [1] needed for solubilization.
Tocopheryl acetate
Tocopheryl acetate (syn. D- or DL-alphatocopheryl acetate, vitamine E acetate) is

a pale yellow, viscous, oily liquid which
is freely soluble in fats and oils. It is
insoluble in water.
1 mg DL-alpha-tocopheryl acetate =
1.0 USP unit vitamin E
1 mg D-alpha-tocopheryl acetate =
1.36 USP units vitamin E
(1 USP unit = 1 former international unit)
Tocopheryl acetate differs from tocopherol in being insensitive to oxidation, and
Solubilization of tocophyerol acetate with

PEG glyceryl trihydroxystearate.
For further examples of the use of tocopheryl acetate in aqueous solutions, see
butylated hydroxytoluene, emulsion, PEG
glyceryl trihydroxystearate, PEG glyceryl triricinoleate, and two-chamber ampules.
Tocopheryl nicotinate
128
Tocopheryl nicotinate
Tocopheryl nicotinate (syn. alpha-tocopheryl nicotinate) consists of pale beige crystals which are insoluble in water. Only the
DL form is available commercially.
Tocopheryl nicotinate is hardly ever used
as a vitamin, being employed to treat
disturbances of peripheral blood flow.
The main drug forms are capsules and
topical products.
Tocopherylquinone
Tocopherylquinone is produced during
the oxidation of tocopherol (q.v.).
Tocopheryl PEG succinate

Tocopheryl PEG succinate (syn. succinic
ester of tocopherol and polyethylene glycol)
is a white powder. It is a water-soluble form
of tocopheryl succinate [211]).
Tocopheryl succinate calcium
Tocopheryl succinate (syn. DL-alpha-tocopheryl succinate, DL-alpha-tocopheryl hydrogen succinate) is a white powder which
is insoluble in water but soluble in oils.
1 mg DL-alpha-tocopheryl succinate =
0.89 USP units vitamin E
(1 USP unit = 1 former international unit)
Tocopheryl succinate can, unlike tocopheryl acetate, be converted directly
into tablets without the necessity to prepare a dry powder [271], as shown by the
formulation which follows.
Vitamin E tablet (100 mg)
I. Tocopheryl succinate
112 mg
II. Copovidone
2 mg
Water
q.s.
III. Lactose, monohydrate
300 mg
corn starch
100 mg
Granulate I with solution II, mix with III,
and compress.
129
Calcium tocopheryl succinate (syn. DLalpha-tocopheryl calcium succinate) is a
white powder which is insoluble in water,
like tocopheryl succinate. Its uses and
pharmaceutical properties are similar to
those of tocopheryl succinate.
Trace elements
In contrast to the minerals, also called
macroelements, the trace elements are
essential for the human body but only in
g to mg quantities. The most important
trace elements are listed in the table below.
Important trace elements
Chromium
Cobalt
Copper
Iodine
Iron
Manganese
Molybdenum
Selenium
Zinc
Inclusion of trace elements in vitamin

products frequently leads to problems
with stability, because some of them are
heavy metals which catalyze the oxidative breakdown of some vitamins.
This is why trace elements and vitamins
should not be present in the same solution in liquid drug forms.
If direct combination of the two classes
of substances in solid forms is necessary,
the problem with stability can be greatly
reduced by minimizing the water content.
This is shown by the following example
of a vitamin C plus trace elements composition for direct tabletting, which showed no loss of vitamin C on storage at
room temperature for 12 months, even
though ascorbic acid is the vitamin
which is most sensitive to heavy metals.
Tretinoin
Vitamin C tablet (500 mg) with trace elements
Ascorbic acid, for direct compression (min. 95 %)
Sorbitol
powder
Iron (II) sulfate
Manganese sulfate
Copper sulfate
Zinc oxide
Magnesium carbonate
Orange flavo(u)r
Colorant
525.0 mg
60.0 mg
40.0 mg
10.0 mg
1.0 mg
10.0 mg
0.4 mg
0.4 mg
0.05 mg
10.0 mg
5.0 mg
q.s.
Of course, it is also possible to keep the

trace elements separate. This is possible
by producing separate granules of the
vitamins and of the trace elements, which
are then converted into a normal tablet, a
bilayer tablet or a laminated tablet. The
trace elements can also be incorporated
into the tablet coating. The most elaborate but most effective method, which is
suitable for multivitamin solid preparations in particular, is the production of
separate vitamin and trace element tablets or capsules, which are then packaged in combination.
Tretinoin
Tretinoin (syn. all-trans retinoic acid, alltrans vitamin A acid) is one of the retinoids. Because of its toxicity, it is not
used as vitamin A but is used for the
topical treatment of acne.
For an example of its use, see dexpanthenol.
Tween
130
Tween
Tween is a registered trademark for polysorbates [6]. The type which is most
commonly used for the solubilization of
vitamins is Tween 80.
Two-chamber ampules
It is necessary when developing parenteral products containing vitamin combinations (e.g. multivitamin injectables) to
take measures to improve the very poor
stability of some vitamins in this type of
drug form. Apart from lyophilization, one
option is the use of compartmented or
two-chamber ampules [34, 147, 150].
The reasons for separating two solutions
are mainly the different pH values required by the various vitamins and the chemical interactions between the vitamins.
The two-chamber ampules, which are nowadays commercially available, are
usually of the design shown in the figure
which follows.
During injection from the two-chamber
ampule, the screwing-in of the plunger
pushes the central partition forwards until
it reaches the bypass. The mixing of
the solutions then starts and continues
until the plunger reaches the partition
and advances it further.
The following example of multivitamin
two-chamber ampules can, of course,
also be used for compartmented ampules
[147].
Two-chamber ampule for multivitamin solutions.

Multivitamin two-chamber ampule
Chamber 1
Retinyl palmitate
Cholecalciferol
Tocopheryl acetate
Sodium ascorbate
Folic acid
Nicotinamide
Polysorbate 80
Benzyl alcohol
Propylene glycol
Water
pH optimum for chemical
stability:
Chamber 2
10,000 I. U.
500 I. U.
30 mg
300 mg
1 mg
20 mg
100 mg
10 mg
100 mg
1 ml
6.87.6
Nicotinamide
Dexpanthenol
Cyanocobalamin
Iron citrate
Benzyl alcohol
Water
pH optimum for chemical
and physical stability:
10 mg
10 mg
55 mg
10 mg
15 mg
15 g
46 g
10 mg
1 ml
4.5
131
Vitamin Bc
V
Viscosity
Vitamin B2
Depending on the vitamin product an increase in the viscosity may be desirable

or undesired.
A high viscosity of oral solutions is
usually regarded as an advantage, because it stabilizes some vitamins. This is
particularly evident in multivitamin solutions such as syrups. The reason is not
only the protection conferred by the sucrose or sorbitol but also the reduction of
diffusion in a viscous solution. This effect may also explain why the rate of
decomposition of ascorbic acid in viscous solutions of the solubilizer polysorbate 80 is markedly reduced [179].
The viscosity of parenteral solutions
ought not to exceed 30 mPa.s. This requirement may be a problem with solubilizates. PEG 15 hydroxystearate has
proved to be the most favourable solubilizer in this respect, because even a 30 %
solution does not reach this viscosity limit.
see riboflavin and riboflavin-phosphate

sodium.
Vitamin B3
former name for nicotinamide and nicotinic acid.
Vitamin B5
former name for pantothenic acid.
Vitamin B6
see pyridoxal phosphate and pyridoxine
hydrochloride.
Vitamin B12
see cyanocobalamin and hydroxocobalamin.
Vitamin A
see retinol, retinyl acetate, retinyl palmitate, and retinyl propionate.
Vitamin A acid
see isotretinoin and tretinoin.
Vitamin B1
see cocarboxylase, thiamine hydrochloride, and thiamine mononitrate.
Vitamin B13
former name for orotic acid.
Vitamin B15
former name for pangamic acid.
Vitamin Bc
see folic acid.
Vitamin C
132
Vitamin C
Vitamin derivatives
see ascorbic acid, calcium ascorbate and

sodium ascorbate.
By choosing the correct vitamin derivatives for the intended drug form, it is possible to optimize both the processing and
the physical and chemical stability. Thus
a wide variety of vitamin compositions
are commercially available for virtually
every type of product. A distinction has
to be made between a chemical derivative and a physically modified composition.
Vitamin D2
see ergocalciferol.
Vitamin D3
see cholecalciferol.
Uses of commonly used chemical derivatives of vitamins (pure substances)

Vitamin derivative
Solid
forms
Soft gelatin
capsules
Solutions
Semisolid
forms
Retinol
Retinyl acetate
Retinyl palmitate
Retinyl propionate
Beta-carotene
Cocarboxlase
Riboflavin
Riboflavin-phosphate Na
Nicotinamide
Sodium pantothenate
Dexpanthenol
Pyridoxal phosphate
Cyanocobalamin
Hydroxocobalamin
Folic acid
Ascorbic acid
Sodium ascorbate
Calcium ascorbate
Cholecalciferol
Ergocalciferol
Tocopherol
Tocopheryl acetate
Biotin
Phytomenadione
(+)
+
+
+
()
+
+
+
+
(+)
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
(+)
(+)
+
+
133
Vitamin derivatives
Solubilization of retinyl palmitate and propionate with PEG-40 glyceryl trihydroxstearate.
Uses of commonly used physical vitamin derivatives

Vitamin derivative
Solid
forms
Soft
gelatin
capsules
Solutions
Semisolid
forms
Retinyl
Retinyl
Retinyl
Retinyl
(+)
Beta-carotene, dry powder (CWD)

Beta-carotene, oily dispersion
Thiamine mononitrate, dry powder

Riboflavin, dry powder
Pyridoxine hydrochloride, dry powder
Dexpanthenol adsorbate
Dexpanthenol in propylene glycol
Cyanocobalamin, dry powder
Ascorbic acid, coated
Ascorbic acid for direct compression
Ascorbic acid, fine powder
Ergocalciferol, dry powder
Ergocalciferol, oily solution
+
+
+
+
+
+
+
+
+
+
Cholecalciferol, dry powder

Cholecalciferol, oily solution
Tocopheryl acetate, dry powder

Biotin, dry powder
Phytomenadione, dry powder
+
+
+
+
(oily)
+
(oily)
+
()
+
(oily)
+
(oily)
acetate, dry powder

acetate, oily solution
palmitate, dry powder (CWD)
palmitate, oily solution
Vitamin E
The preceding table lists the most important chemical derivatives of vitamins and
their uses.
The greater stability is the reason for
using vitamin A esters in place of retinol,
vitamin E esters in place of tocopherol,
and dexpanthenol in place of D-pantothenates in multivitamin solutions, and thiamine mononitrate in place of the hydrochloride in multivitamin tablets, ascorbic
acid in place of calcium ascorbate in
solutions, etc. However, the physical differences are also important: riboflavinphosphate sodium is more soluble than
riboflavin and solubilizates of much higher concentration can be prepared with
vitamin A propionate rather than with
the palmitate, as shown by the figure
above [173].
The physical vitamin derivatives, whose
uses are listed in the table which follows,
mainly have the aim of facilitating processing or even of making it possible.
Vitamin E
see tocopherol, tocopheryl acetate, and
tocopheryl succinate.
Vitamin F
see fatty acid, polyunsaturated.
Vitamin H
see biotin.
134
available for the production of vitamin
preparations e.g. multivitamin tablets. A
typical formulation is given in the table
which follows.
Multivitamin + copper + zinc mixture and
tablets
Vitamin mixture:
Riboflavin
Nicotinamide
Cyanocobalamin gelatin
coated (0.1%)
Folic acid
Ascorbic acid
Vitamin E acetate dry
powder (50 %)
Copper oxide
Zinc sulphate
3.9 %
0.4 %
10.1 %
2.9 %
1.2 %
2.6 %
0.1 %
63.4 %
9.1 %
0.3 %
6.0 %
Tablets:
Vitamin mixture
Silicagel, highly disperse
Ludipress
Copovidone
Magnesium stearate
Talc
1000 mg
5 mg
150 mg
120 mg
25 mg
10 mg
10 mg
Vitamin P
see bioflavonoids and rutin.
Vitamin mixture (premix)

In the market individual vitamin mixtures
produced according to the requirements
of the pharmaceutical manufacturer are
Vitamin PP
see nicotinamide and nicotinic acid.
135
Water-soluble vitamins
W
Water content
In just the same way as the humidity, the
water content may have strong adverse
effects on the stability on many vitamins
in solid drug forms. Only when free water is present, can chemical interactions,
hydrolisis or oxidation catalyzed by heavy metals take place, for example.
The residual water content in the product
may derive from the processing, such as
wet granulation, from high humidity during manufacture, and/or from the water
content of the vitamins or auxiliaries.
A certain residual moisture content is
necessary in tablets for the development
of stable binding between the solid particles. The processes used for minimizing
it must be non-deleterious but efficient,
such as granulation and drying in, for
example, a fluidized bed. Another way
of minimizing the water content of tablets is direct tabletting. Dry granulation
without a solvent may be another way of
achieving this. Unfortunately, the latter
process does not always result in tablets
having the same good physical properties
as those obtained with traditional wet
granulation.
The content of free water in uncolo(u)red

vitamin C tablets, effervescent tablets and
all solid multivitamin forms ought not to
exceed 0.2 % [34]. It may be up to 1 % in
other vitamin tablets without greatly affecting the stability [24]. The effects of
residual water are seen earliest in uncolo(u)red vitamin C tablets, which may
quickly turn yellow or brownish due to
hydrolysis of ascorbic acid.
The high water content of thiamine hydrochloride (3 or 4 %) is the reason why
it is not used in multivitamin tablets or
capsules. Thiamine mononitrate, which
contains virtually no water, is preferred
for these.
The water content in liquid products also
affects the stability of the disolved vitamins (see also solvents). The stability of
vitamin A in ethanol/water solubilizates
increases with decreasing water content
[182]. The same is true of other vitamins
in multivitamin solutions where glycerol
and propylene glycol are used [59, 75].
Water-soluble vitamins
see hydrophilic vitamins.
137
List of Suppliers
List of Suppliers
[1]
[2]
[3]
[4]
[5]
[6]
BASF AG, Division ME, D-67056 Ludwigshafen

FMC Corp., Food and Pharmaceutical Products Div., 2000 Market Street, Philadelphia,
PA 19103, USA
BASF Health & Nutrition A/S, Malmparken
5, DK-2750 Ballerup
Degussa AG, Industrie- und Feinchemikalien, Postfach 13 45, D-63 457 Hanau
ISP Corp., 140 West 51st St., New York, NY
10 020, USA
Atlas Chemie, Goldschmidtstrae 100, D45 127 Essen
[7]
Th. Goldschmidt AG, Goldschmidtstrae

100, D-45 127 Essen
[8] Shinetsu Chem. Company, Cellulose Div.,
Asahi-Tokai Building; 61, 2-chome, Otemachi, Chiyoda-Ku, Tokyo, Japan
[9] Hls AG, Postfach, D-45 764 Marl
[10] Nipa Laboratories Ltd., Nipa Industrial Estate,
Llantwit Fardre, Nr Pontypridd, Mid-Glamorgan CF38 2SN, Wales, Great Britain
[11] Henkel KgaA, Postfach 1100, D-40 191 Dsseldorf
[12] Hercules Aldag GmbH, Curslacker Neuer
Deich 66, D-21 029 Hamburg
139
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Vitamin C+E chewable tablet

Aerosil is a registered trademark [4] for

Alfacalcidol (syn. 1-alpha-hydroxy-cholecalciferol) is a synthetic substance hormonal form of cholecalciferol.

It is sometimes appropriate to combine

Acetylsalicylic acid + vitamin C tablet

Vitamin antagonists (selection)

Vitamin antagonists should not be combined or taken with vitamin products. If

Antioxidants for vitamins

Butylated hydroxyanisole or butylated

The modes of action of the individual

Apocarotenal (syn. beta-apo-8'-carotenal) is a carotenoid as found in nature

Beta-carotene + vitamin C + vitamin E

Ascorbic acid (syn. L(+)-ascorbic acid)

Effect of the pH on the decomposition of

Liquid drug forms containing ascorbic

A syrup containing no sucrose with a

was somewhat better in the glycerol/sorbitol base than in a sucrose syrup.

which have been carefully cleaned and

Effect of auxiliaries on the stability of ascorbic acid tablets

For further examples of use in solid drug

multivitamin solid preparations, sodium

Ascorbyl palmitate (syn. palmitic acid

to stabilize fats, oils, and beta-carotene.

Avicel is a registered trademark [2] for

The Avicel types used most often form

see cocarboxylase, thiamine hydrochloride, thiamine mononitrate.

The following vitamins are regarded as

The stability is distinctly better in solid

Benfotiamine is a white, crystalline powder.

Benzyl alcohol is a clear colo(u)rless liquid with an aromatic odo(u)r, which is

(see formula below)

Beta-carotene tablet (5 mg)

For further examples of use in tablets, see

Binders commonly used for vitamin products

Bioavailability of vitamin A in chickens 14

In solid forms with beta-carotene, the

Biotin (syn. D(+)-biotin, vitamin H) is a

Butylated hydroxyanisole (syn. tertbutyl4-methoxyphenol, BHA) is a white or

Calcitriol (syn. 1-alpha-25-dihydroxycholecalciferol) is the biologically active

Calcifediol (syn. 25-hydroxycholecalciferol) is a metabolite of cholecalciferol and

Calcium ascorbate (syn. calcium salt of

Calcium hydrogen phosphate

Calcium hydrogen phosphate is used as a

Formation of carbon dioxide and loss of

Carboxymethylstarch can be used in the

In contrast to sugar-free film-coating, the

Microcrystalline or microfine cellulose is

Microcrystalline or microfine cellulose is

Heavy metals may act as catalysts to have

Cholecalciferol (syn. colecalciferol, vitamin D3) is a white crystalline powder

Solubilization of cholecalciferol using PEG40 glyceryl trihydroxysterate [1].

Cholecalciferol-cholesterol (syn. vitamin

Citric acid is a white, odo(u)rless substance with an acidic taste; it is freely

Cocarboxylase (syn. thiamine pyrophosphate, thiamine diphosphate) is the actual

nophosphate, thiamine, and phosphate

Coenzyme of the decarboxylases and aldehyde

Colo(u)ring agents and colo(u)r lakes

Solubility of folic acid in water.

Copovidone (syn. PVP/VA copolymer) is

Heat mixture II to 75 C, and stir in solution