J Therm Anal Calorim

DOI 10.1007/s10973-011-2151-z

Influence of temperature and humidity on the degradation process

of ascorbic acid in vitamin C chewable tablets
Gorica Pavlovska Stojne Tanevska

Received: 24 October 2011 / Accepted: 12 December 2011

Akademiai Kiado, Budapest, Hungary 2012

Abstract Ascorbic acid (AA) is the active ingredient of

vitamin C chewable tablets. It is unstable even at room
temperature, and increased temperature and humidity rapidly increase its degradation. To protect the active substance, we made its coating with polymers ethyl cellulose
that provides its thermal protection and protection from
moisture. We bet each particle of AA with a layer of
polymer by the method of fluidization. Extra protection
against thermal effects and penetration of moisture and
oxygen provides the packaging. By using four kinds of
packaging: polypropylene container for tablets, strips of
aluminum and polyvinyl chloride Al/PVC strips, glass
bottles, and strips of aluminum and polyethylene (Al.PE/
PE.Al) of 3, of 6 months and of 12 months. One of the
tablets are stored at room temperature (25 2 C/60%
RH 5%), and the rest in terms of accelerated aging or
increased temperature and humidity (30 2 C/65%
RH 5% and 40 2 C/75% RH 5%). The speed of
degradation of unprotected AA usually get doubled when
there is increasing of the temperature for every 10 C.
Experimentally the concentration of AA was monitored, its
oxidation product-dehydroascorbic acid and its degradation
product-diketogulonic acid.
Keywords Ascorbic acid  Dehydroascorbic acid 
Chewing tablets  Oxidation  Degradation

G. Pavlovska (&)
Faculty of Technology and Technical Sciences-Veles, University
St. Kliment Ohridski-Bitola, Petre Prlichkov 42, 1400 Veles,
Republic of Macedonia
e-mail: pavlovskagorica@yahoo.com
S. Tanevska
Varus, Skupi 15, 1000 Skopje, Republic of Macedonia

Introduction
As generally known, vitamins are essential substances,
which are necessary for normal health and growth. Vitamin
C is a powerful antioxidant essential for human organism
and needs to be entered in a certain amount through the
food every day, to prevent diseases [1]. If this intake is
insufficient or if exist special dietary requirements, it is
necessary to make something to prevent vitamin deficiency. The lack of vitamin C is supplemented by various
agents and is often formulated as film coated dragee that is
readily available in the market [2]. Vitamin C chewable
tablets are a new vitamin product of Jaka 80 AD, Macedonia and are intended primarily for pediatric and geriatric
patients. They are produced according to all regulations in
the pharmaceutical industry [37].
Vitamin C exists in two forms: ascorbic acid (AA)
where mostly exists and dehydroascorbic acid (DHAA),
which is its oxidation product, but has also vitamin properties. AA is stable in acidic environment, while in weak
acid, neutral and basic environment in the presence of
moisture and oxygen can be easily oxidized to DHAA [8
10]. In the presence of moisture and increased temperature
DHAA oxidize into diketogulonic acid (DKGA) irreversibly, which does not have vitamin properties [912]. The
period of half-life in aqueous solution is 6 min at 37 C,
but the extent of AA oxidation to DHAA and its hydrolysis
to DKGA depends on concentration, temperature, pH,
light, etc. [10, 11]. The speed of degradation of unprotected
AA usually is increased double by increasing the temperature for every 10 C.
The aim of this investigation is production of chewing
tablets of vitamin C, according to the prescribed concentration of ascorbic acid, but also preventing its decomposition before their limit date of use. The great instability of

123

G. Pavlovska, S. Tanevska

vitamin C requires special technology in the production of

vitamin C tablets. To protect AA from oxidation and
decomposition, each particle is wrapped by a layer of
polymer that is insoluble in water. Ethyl cellulose (EC) is
probably the most widely used water-insoluble polymer in
the pharmacy and obtains tablets with controlled release of
the active component [1317]. The EC in chewing tablets
is not used for controlled release of active substance AA,
but to protect AA from moisture. Therefore, the method of
application of the EC is different. The tablets with controlled release of active component EC layer is applied
over the whole tablet, while the chewing tablets EC layer is
applied over each particle of AA using a special technology
called fluidization [3, 4, 13, 1820].
The packaging provides additional thermal protection
against impacts and penetration of moisture and oxygen.
There are used four types of packaging: polypropylene (PP)
container for tablets strips of aluminum and polyvinyl
chloride Al/PVC strips, glass bottles, and strips of aluminum
and polyethylene (Al.PE/PE.Al) [21]. Each of these containers has a different degree of moisture permeability and
varying degrees of thermal protection. In pharmaceutical
industry there is increasingly use of thermal analysis for
production of quality active substance and for production of
quality finished pharmaceutical product. Changes of physical parameters (color, strength, friability, moisture) and
changes of chemical properties (oxidation and degradation
product, decomposition) have been monitored, or stability of
the medicine under temperature and moisture changes
[2226].One part of the tablets are stored at room temperature of 25 C 2 C and room relative humidity (RH) of
60% 5%, but in aging conditions, under increased temperature and increased humidity (30 2 C/65% RH
5% and 40 2 C/75% RH 5%) [3, 4, 21, 27].

Experimental conditions
Apparatus
Applying polymer EC is performed in Fluid-bed granulators GLATT AG (Switzerland). Temperature of input air,
air flow, and other parameters in Fluid-bed granulator are
given in Table 1.
Chewable tablets are packed into four primary types of
packaging:

PP container for pills, made of polypropylene with

polypropylene leather
Al/PVC strips, which thermally shapes and the tablets
are packaged individually
Glass bottles, brown glass tetra hydrolytic group with
PVC leather

123

Table 1 Process parameters of Fluid-bed granulators

Parameter

Value

Temperature of incoming air, C

60

Pressure of incoming air, kPa

200

Pressure that is spraying the coating solution, kPa

200

Time of shaking the filters, s

20

Inflicted, mL min-1

510

Temperature of product, C

3035

Temperature of coating solution, C

25

Al.PE/PE.Al strips are strips of aluminum coated with

polyethylene inside. They are thermally welded and the
tablets are packaged individually.

Tablets in Al/PVC strips and Al.PE/PE.Al strips are

packed by packaging machine Uhlmann B1240 (Laupheim,
Germany), and in PP container and glass bottle they are
packed by hand.
Tablets packed in each of these primary containers are
placed in the carton as secondary packaging.
The rapid aging of the tablets (30 2 C/65%
RH 5% and 40 2 C/75% RH 5%) is performed in
separate air chambers for constant conditions WTB Binder
Labortechnik GmbH (Tuttlingen, Germany). In these
chambers we maintain constants conditions as air temperature and relative humidity, according to our needs. For
determination of stability, tablets are put in them and they
are removed after 3, 6, and 12 months.
The strength of the tablets or their fragility is determined
by the camera VAN KEL VK. 200 tablet hardness tester
(North Carolina, USA). This apparatus measures the force
required to break the tablet.
Appliance VAN KEL friability tester is used for friability determination (North Carolina, USA) [28]. For most
tablets, this should not be more than 1% and is calculated
from the ratio of the mass of the tablets before and after
putting in the apparatus.
Disintegration is determined by VAN KEL HAAKE DC
(North Carolina, USA) [28] at a temperature of 37 C in
water medium. We measured the time for which there will
be decomposition of 6 tablets in the corresponding
medium.
The moisture is determined by moisture meter, Sartorius
MA 45 (Germany) [28], and it means a loss of moisture
during drying.
Dissolution apparatus ERWEKA DT 700/1000 LH ZT
302 (Germany) is used for determining the solubility of the
tablets [29]. In 6 cups of this apparatus filled with 900 mL
water at 37 C and turning the wesley of 50 rpm we put 1
tablet. By measuring the AA which has been released from
the tablets, the solubility is determined in 5 min.

Degradation process of ascorbic acid in vitamin C

120

Table 3 Physical parameters of chewing tablets with vitamin C

under 30 2/65% RH 5% after 3, 6, and 12 months

Ascorbic acid/%

100

Parameters
80

Primary packaging
PP
container
for pills

Al/PVC
strips

Glass
bottle

Al.PE/
PE.Al
strips

Color

White

Yellow spots, soft

tablets

White

White

Strength, kp

10.2

10

10.65

100.08

98.12

104.5

Friability, %

0.6

0.6

0.6

Fig. 1 Content and solubility in the coated granulate (diamonds

content of AA, squares AA dissolved in 5 min)

Time of
reintegration,
min

1.4

1.4

1.4

Moisture, %

0.42

2.23

0.4

0.33

Table 2 Physical parameters of chewing tablets with vitamin C

under 25 2 C/60% RH 5% in the beginning and after 3, 6 and
12 months

After 6 months
White

Dark yellow
spots, soft
tablets

White

White

60
40

After 3 months

20
0
3

12

Ethyl cellulose/%

Parameters

Primary packaging
PP container
for pills

Al/PVC
strips

Glass
bottle

Strength, kp

9.5

Al.PE/
PE.Al strips

93.21

Friability, %

0.8

0.7

0.6

White

Time of
reintegration,
min

1.55

1.5

1.4

Moisture, %

0.56

2.42

0.5

0.33

White

Brawn spots, soft

tablets

Yellow
spots

White

Strength, kp

88.3

Color

White

White

White

Strength, kp

10.65

10.65

10.65

10.65

104.5

104.5

104.5

104.5

Friability, %

0.6

0.6

0.6

0.6

Time of
reintegration,
min

1.4

1.4

1.4

1.4

Moisture, %

0.33

0.33

0.33

0.33

10

10.65

98.12

104.5

After 12 months
Color

Determination of AA, DHAA, and DKGA has been

performed using HPLC system VARIAN (California,
USA) consisted of: 9012 tertiary pump and 9050 UV/VIS
detector. Separation is done by MERCK Lichrospher column 100 RP 18 250 mm 9 5 lm. The content of AA and
DHAA were determined by HPLC method for determination of AA and DHAA in plasma, and serum adapted for
the determination of AA and DHAA in tablets [30]. It used
5 mM cethyltrimethylammonium bromide with pH = 4.5
as a mobile phase. AA is determined directly, but DHAA
Fig. 2 Content of AA under
25 2 C/60% RH 5%

Color

9.2

10

90.2

98.12

Friability, %

0.8

0.9

0.6

Time of
reintegration,
min

1.6

1.6

1.45

Moisture, %

0.6

2.53

0.8

0.4

indirectly, after its reduction into AA with dithiothreitol.

By subtraction of non-oxidized AA, which is determined
directly, from the total AA that is determined after the
reduction, is obtained DHAA. DKGA is calculated as the

120

AA/%

100

Initial analysis

80

AA after 3 months

60

AA after 6 months

40

AA after 12 months

20
0
PP container
for pills

Al/PVC strips

Glass bottle

Al,PE/PE,Al
strips

123

G. Pavlovska, S. Tanevska
120

AA/%

Fig. 3 Content of AA, DHAA

and DKGA under 30 2/65%
RH 5%

100
80

AA initial analysis
AA after 3 months

60

AA after 6 months

40

AA after 12 months

20
0

DHAA/%

PP container
for pills

Al/PVC strips

Glass bottle

Al,PE/PE,Al
strips

14
12
10
8
6
4
2
0

DHAA initial analysis

DHAA after 3 months
DHAA after 6 months
DHAA after 12 months
PP container Al/PVC strips
for pills

Glass bottle

Al,PE/PE,Al
strips

DKGA/%

25
20

DKGA initial analysis

15

DKGA after 3 months

10

DKGA after 6 months

DKGA after 12 months

0
PP container Al/PVC strips
for pills

difference of the AA of tablets (given immediately after the

tableting) and the sum of AA and DHAA (given after a
certain standing in the chambers for rapid aging of the pill).
The accuracy of the method is determined by method of
standard accessories. Recovery, that is a ratio of the found
and calculated AA, is above 97% and confirms the accuracy of the method.

Procedure
Betting with EC
To prevent the breakdown of AA and maintain its stability
we coat each particle with 10% solution of EC in 96%
solution of ethyl alcohol. This process is performed in the
Fluid-bed granulators. AA particles are moving pneumatically through power from moderately hot air and spraying
with the prepared EC solution that has previously been
turned into very tiny droplets or atomized in the atomizer.
Particles are immediately dried in a warm current of air
after falling down, and other particles move up. The process repeats. In this way we achieve evenly coating of each
particle of the AA solution of EC.
The resulting granules together with other components
of vitamin C in chewing tablets are tableting with firm
compression.

123

Glass bottle

Al,PE/PE,Al
strips

The stability of the tablets in different packaging

in terms of accelerated aging
The tablets immediately after the tableting are packed in
four different containers: PP container for tablets, Al/PVC
strips, glass bottles, and strips of Al.PE/PE.Al and placed
in chambers for rapid aging. These are special chambers in
which temperature and humidity are increased and are
maintained constantly.
Stability of tablets in each package is accompanied with
the following experimental conditions:

25 2 C/60% RH 5% at room temperature

30 2 C/65% RH 5% air chamber
40 2 C/75% RH 5% air chamber

To determine the stability, we measure the contents of

AA, DHAA, and the DKGA tablets right after the tableting
and the content of the tablets standing 3, 6, and 12 months
in each of the chambers.

Results and discussion

Determination of the optimal layer of EC
EC layer, which bet the AA particles, is insoluble in water
and it is a polymer which can reduce solubility, or reduce

Degradation process of ascorbic acid in vitamin C

Table 4 Physical parameters of chewing tablets with vitamin C
under 40 2/75% RH 5% after 3 and 6 months
Parameters

Primary packaging
PP
container
for pills

Al/PVC
strips

Glass
bottle

Al,PE/
PE,Al
strips

Color

Yellow
spots

Yellow spots,
soft tablets

Yellow
spots

White

Strength, kp

10

88.3

88.3

98.12

Friability, %

1.2

Time of
reintegration,
min

1.5

Moisture, %

0.8

After 3 months

0.6

0.9

1.45

2.73

0.7

0.4

Soft,
brawn
tablets

Soft, brawn
tablets

Yellow
spots

Yellow
spots

After 6 months
Color

Strength, kp
N

78.496

88.3

Friability, %

1.5

1.3

Time of
reintegration,
min

1.5

1.45

Moisture

2.1

3.52

0.9

0.8

Determination of optimum packaging for the stability

of tablets
To determinate the stability of the tablets, there is need to
determinate the content of AA, DHAA, and DKGA of the
tablets after the tableting and the content of the tablets after
standing in each of the chambers for 3, 6, and 12 months.
Table 2 shows the physical parameters (color, strength,
friability, time of reintegration, and moisture) of tablets
stored in a chamber at 25 2 C/60% RH 5%, and in
Fig. 2 are given the contents of AA of the same tablets. The
tablets in all four containers that are kept at 25 2 C/

120

AA/%

100
80

AA initial analysis

60

AA after 3 months

40

AA after 6 months

20
0
PP container
for pills

Al/PVC strips

Glass bottle

Al,PE/PE,Al
strips

DHAA/%

20
15

DHAA initial analysis

DHAA after 3 months

10

DHAA after 6 months

5
0
PP container
for pills

Al/PVC strips

Glass bottle

Al,PE/PE,Al
strips

100
80

DKGA/%

Fig. 4 Content of AA, DHAA

and DKGA under 40 2/75%
RH 5%

the release of AA. That means you can come to a partial or

complete exhaustion of the existing quantity of AA.
Experimentally EC layer is determined to prevent decomposition of AA, but will not reduce its release. Therefore,
there is an application layer of polymer with 3, 6, 9, and 12
w/w %. Then, determination is made to the content of AA
and determining the solubility of the tablets or the release
of AA (Fig. 1).
With the increasing layer of EC of 312 w/w %, AA
content decreases from 9788%. Reducing the solubility or
release of AA is even greater and it is amounting form
100% for 326.812 w/w % polymer layer. This means
that for full use AA or have its 100% relief may only be
used with 3 w/w % of polymer layer.

DKGA initial analysis

60

DKGA after 3 months

40

DKGA after 6 months

20
0
PP container
for pills

Al/PVC strips

Glass bottle

Al,PE/PE,Al
strips

123

G. Pavlovska, S. Tanevska

60% RH 5%, the physical parameters after 3, 6 and

12 months remain unchanged. In the tablets of the four
containers in these conditions there are no oxidation and
degradation products of AA.
The biggest changes in physical parameters of tablets
are given in tablets stored in a chamber at 30 2 C/65%
RH 5% there are with a tablet in Al/PVC strips. After
only 3 months standing in this chamber the tablets of Al/
PVC strips change the color from white to yellow, after
6 months into dark yellow, and in 12 months they are
brown (Table 3). These tablets get soft so it cannot be
determined strength, friability, and time of reintegration.
The percentage of moisture in tablets of 0.33 increases
from 2.23 after 3 months, to 2.53 after 12 months. There
are minor but not negligible changes in packaging in a PP
container and glass bottle, and almost negligible in the
Al.PE/PE.Al packaging. Initial physical parameters correspond with this given in Table 2. Physical parameters
change is associated with chemical changes in a pill. In the
tablets in Al/PVC strips there is a profound reduction of
AA (20%) which disintegrated to DKGA, and in the tablets
in glass bottle AA only oxidized into DHAA (12%), but in
not yet disintegrated to DKGA (Fig. 3). In PP container for
pills there is a reduction of AA, but it is very small and AA
only oxidized into DHAA, while in the tablets in Al.PE/
PE.Al strips there are almost no oxidation and degradation
products of AA (\1%).
The most rigorous are the conditions in the third
chamber 40 C 2/75% RH 5% so here are the
greatest physical and chemical changes. Brown color and a
high percentage of moisture in the tablets PP container for
pills and Al/PVC strips indicate possible chemical changes
in tablets in these packaging (Table 4). It is indeed so, in
tablets in PP container for pills and Al/PVC strips after
6 months, much of the AA is disintegrated by DKGA (33%
DKGA in PP container, and 83% DKGA in Al/PVC strips).
In tablets in glass bottle after 6 months over 10% of AA is
disintegrated to DKGA, which means that this type of
packaging does not protect AA from disintegration in these
conditions of increased temperature and humidity. Under
these rigorous conditions, only Al.PE/PE.Al strips provides
full protection of AA (Fig. 4).

Conclusions
Since AA is a very unstable substance with increased
temperature and humidity, chewable tablets are obtained
with special technology-fluidization. In this process each
piece of AA bets with a layer of polymer EC that is not
soluble in water, to protect from moisture and temperature
changes. The optimum layer thickness is established and it

123

is 3 w/w % of its EC that provides protection from moisture

and temperature, but simultaneously does not reduce its
solubility. Additional protection of AA to limit the use of
the pill provides their primary packaging. It is made an
examination of the impact of temperature and humidity on
the degradation processes of AA tablets packaged in four
different containers. Increased temperature and humidity in
the chambers of aging are causing large oxidation and
degradation processes of AA in three types of tablets
packing. Only Al.PE/PE.Al strips provides full protection
of the AA in increased temperature and humidity.

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