IV. Pre Formulation

DOSAGE FORM CONSIDERATION:
PREFORMULATION
By: LOUJESSA D. ARCELO
DOSAGE FORM CONSIDERATION
The need for dosage forms

General considerations in dosage
form design
Preformulation Studies
Drug and Drug Product Stability
Pharmaceutical ingredients and
excipients
Dosage Form Design

PHARMACEUTICS
study on the: formulation, manufacture, stability, and
effectiveness of pharmaceutical dosage forms
Pharmaceutical ingredients or
excipients
solubilize thicken stabilize
suspend dilute
preserve
suspend emulsify color
flavor
efficacious
appealing closure forms.
Requirements of a proper design &

formulation of dosage form
compatible with one

another - stable,
efficacious,
attractive, easy to
administer & safe
*manufactured
under appropriate
measures of quality
control & packaged
in containers to
make product stable
Consideration
of drug
substances:
*labeled to promote
correct use & stored
under conditions to
maximize shell life
THE NEED FOR DOSAGE

FORMS
THE NEED FOR DOSAGE FORMS

Mechanism for safe
and convenient
delivery of
accurate dosage
Provide liquid
preparations of
insoluble drugs
Conceal bitter,
salty, or
offensive taste
or odor
Protection of
drug from
atmosphere (CT)
Protection of
drug from
gastric acid
(EC)
THE NEED FOR DOSAGE FORMS

Provide clear
liquid dosage
forms
Provide for
inhalation
therapy
Provide ratecontrolled drug

action
Provide for
placement into
bloodstream
Provide topical
drug action
Provide for
insertion into
body cavity
GENERAL CONSIDERATIONS
IN DOSAGE FORM DESIGN
General Considerations in Dosage

Form Design
Determine desired product type
framework for product development.
Develop and examine initial formulations of

the product:
desired features: drug release profile, bioavailability,
clinical effectiveness
pilot plant studies and production scale-up.
MASTER FORMULA
- formulation that best meets the goals of the product
General Considerations in Dosage

Form Design
Factors to consider before formulation
of a medicinal agent in one or more
dosage forms
Therapeutic matters (nature of the illness)
manner it is treated (locally or through
systemic action)
age and anticipated condition of the
patient.
Reliability
Stability
Pharmaceutical
elegance
Safety
Effectiveness
Design
of Drug
Products
Convenience
PREFORMULATION
PREFORMULATION
Is branch of Pharmaceutical science that utilizes
biopharmaceutical principles in the determination of
physicochemical properties of the drug substance.
PREFORMULATION
Safe handling
of ingredients
and
equipments
Proper
sequence of
addition of
ingredients
Optimum
environmental
conditions
Precautions to
be observed
Expected
interaction
Need for
overages
1. Physical Description
Liquid drugs
are used to a
much lesser
extent than
solid drug
Ability to get to
site of action and
elicit a response
Structure,
form,
reactivity
Solids,
liquids,
gases
Chemical
Properties
Biological
Properties
Physical
Properties
Description, particle
size, crystalline
structure, melting
point, solubility
1. Physical Description: ORGANOLEPTIC PROPERTIES
COLOR
ODOUR
TASTE
OFF-WHITE
PUNGENT
ACIDIC
CREAM-YELLOW SULFUROUS
BITTER
SHINY
FRUITY
SWEET
AROMATIC
TASTELESS
ODOURLESS
TASTELESS
2. Microscopic Examination
Particle size
Particle
shape
Particle size
range
Crystal
structure
3. Heat of Vaporization
Vapor pressure
Personnel
exposure
Volatile drugs
can migrate
within a solid
dosage form
4. Melting point depression
Purity
determination
Identity
5. Phase Rule
Phase diagrams constructed determines:
existence & extent of the presence of solid and liquid

phases in binary, ternary & other mixtures
6. Particle Size
affects : physicalchemical properties of drug

substances:
*dissolution rate
stability
flow properties
bioavailability
taste
absorption
content uniformity
texture
sedimentation rate
7. Polymorphism
substances can exist
in more than one
crystalline form
Polymorphic forms
diff. physical-chemical
properties (melting pt.
& solubility)
POLYMORPHS
Crystalline and
Amorphous
Evaluation of:
*crystal structure
(microscopy, IR
spectroscopy, thermal
analysis, x-ray diffraction)
8. Solubility
If solubility is
<1mg/ml
Solubility:
4C and 37C.
8. Solubility
Description
Parts of solvent required for

one part of solute
Very soluble
Freely soluble
Soluble
Sparingly soluble
Slightly soluble
<1
1 - 10
10 - 30
30 - 100
100 - 1000
Very slightly soluble
1000 - 10,000
Insoluble
> 10,000
8. Solubility
Chemical
nature and
type of drug;
chemical
modification
Some aqueous
solubility
required for
therapeutic
efficacy
SOLUBILITY
and PARTICLE
SIZE
SOLUBILITY
and pH
SOLUBILITY
8. Solubility: SALTS
Points to consider:
Salts prepared from strong acids or

bases
Salts prepared from weaker acid or
base
Injections should ideally lie in the pH
range 3-9
Oral syrups should not be too acidic
8. Solubility: SURFACTANT
SURFACTANT
low
concentration?
Very high
concentration?
8. Solubility: EFFECT OF TEMPERATURE
Endothermic
reaction
Exothermic
reaction
8. Solubility: PARTICLE SIZE
Coarse
(#20)
Very coarse
(#8)
Moderately
coarse
(#40)
Fine (#60)
PARTICLE
SIZE
Very fine
(#80)
8. Solubility: PARTICLE SIZE
Dissolution
rate
Suspendability
Penetrability
Uniform
distribution
Lack of
grittiness
8. Solubility and pH
adjustment of
pH of solvent
where drug is
dissolved to
adjust
solubility
Weak acidic
or basic drugs
pH on
solubility and
stability
cosolvents ,
complexation,
micronization,
or solid
dispersion
8. Solubility: INCREASE SOLUBILITY
Addition of
co-solvent
pH change
method
Reduction of
particle size
Temperature
change
method
Addition of
Surfactant
Complexation
CO-SOLVENT
PG, ehtanol,
glycerin, sorbitol,
PEG, Glyceryl
formal, glycofurol,
ethyl carbamate,
ethyl lactate and
dimethyl
acetamide.
pH CHANGE METHOD
For weak acidic

drug?
For weak base
drug?
8. Solubility: CO-SOLVENT
It must be nontoxic. Nonirritating.
It should be
able to cross
the
membrane.
It should be
able to
solubilize the
drug in given
solvent.
ENDOTHERMIC
REACTION?
EXOTHERMIC
REACTION?
Cationic
IONIC
Anionic
NON-IONIC
Zwitterionic
SURFACTANT
CATIONIC
Cetyl Trimethyl
Ammonium
Bromide (CTAB)
Hexadecyl
Trimethyl
Ammonium
Bromide, and
other
Alkyltrimethyl
Ammonium
Salts,
Cetylpyridinium
Chloride (cpc)
ANIONIC
Sodium Dodecyl
Sulphate (SDS),
Ammonium
Lauryl Sulphate
and other alkyl
sulfate salts,
Sodium
Laureth
Sulphate, also
known as
Sodium Lauryl
Ether Sulphate
(SLES).
ZWITTERIONIC
Dodecly
Betamine
and Dodecly
Dimethylam
ine Oxide
8. Solubility: SURFACTANT (HLB SCALE)
0
Most antifoaming agents
W/O Emulsifying agents
sorbitan
ester
Wetting and Spreading agents
TWEEN
12
O/W Emulsifying agents
15
Detergents and Solubilizing agents

18
(polyoxyethylen
ederivative of
span)
9. Dissolution Rate
Time for the drug to dissolve in the fluids at

the absorption site
(rate-limiting step in absorption)
Can affect onset, intensity, and duration of response and
control overall bioavailability of the drug from the dosage
form
Increasing dissolution rate:

decreasing the particle size.
use a highly water soluble salt of the parent substance.
9. Dissolution Rate
Ficks law
(law of
diffusion)
NoyesWhitney
Equation
1st law: relates to a steady state

flow
2nd law: relates to a change in conc.
of drug with time, at any distance,
or a nonsteady state of flow
Describes the relationship between

particle size, diffusion layer
coefficient, and drug saturated
solubility (Dissolution)
10. Membrane Permealibility
drug molecule
must cross a
biologic
membrane
early assessment
of passage of
drug molecules
across biologic
membranes
The biologic
membrane (lipid
barrier)
Membrane
Permeability
pKa, solubility, and

dissolution rate
data can provide an
indication of
absorption.
EVERTED
INTESTINAL
SAC
11. Partition Coefficient
octanolwater
partition
coefficient
12. pKa / Dissociation Constants
Extent of
dissociation or
ionization
Can affect
absorption,
distribution,
and
elimination
Dependent
on pH of
medium
12. pKa / Dissociation Constants
Can be calculated by Henderson Hasselbach
equationFor acidic drugs.pH= pKa+ log [ionized drug]
[unionized drug]
For basic drugs.pH= pKa+ log[unionized drug]

[ionized drug]
DRUG AND DRUG PRODUCT STABILITY

Stability is the extent to which a product retains within specified
limits and throughout its period of storage and use (i.e., its shelf
life) the same properties and characteristics that it possessed at the
time of its manufacture.
Substantial
changes in
physical
appearance of
the dosage form
Undesired
change in
performance
Cause product
failures
INSTABILITY
Drug Stability: Mechanisms

of Degradation
Hydrolysis
(solvolysis
process)
Oxidation
(drug) molecules
interact with water
molecule to yield
breakdown product.
loss of electrons
from an atom or
molecule; involves
free radicals
esters, substituted
amides, lactones,
and lactams
aldehydes, alcohols,
phenols, sugars,
alkaloids &
unsaturated fats &
oils
Photolysis
decomposition
by light
1. suitable packing in
amber-coloured
bottles
2. cardboard outers
3. aluminium foil over
wraps
Drug and Drug Product Stability:

A. Kinetics and Shelf Life
CHEMICAL STABILITY
active ingredient retains chemical integrity

and labeled potency within the specified
limits.
PHYSICAL STABILITY
original physical properties, appearance,

palatability, uniformity, dissolution and
suspendability are retained.
MICROBIOLOGICAL
STABILITY
sterility/resistance to microbial growth
THERAPEUTIC
STABILITY
therapeutic effect remains unchanged
TOXICOLOGIC
STABILIY
no significant increase in toxicity occurs.

B. Rate Reactions
description of the drug

concentration with respect to time
ZERO ORDER
FIRST ORDER
KINETICS
KINETICS
(LINEAR
(NONLINEAR
PHARMACOKINETICS) PHARMACOKINETICS)

C. Q10 METHOD
estimate the shelf
life of a product that
has been stored or
to be stored under a
different set of
conditions.
the rate constant

increases for a
100C temp.
increase
Accelerated
Stability
Studies
Q10
METHOD
ENHANCING DRUG
STABILITY
ENHANCING STABILITY
HYDROLYSIS
OXIDATION
ENHANCING STABILITY
Tablet:
waterproof
protective
coating
pH: pH 5 & 6
Reduction or
elimination of
water
Buffering
agent
HYDROLYSIS
ENHANCING STABILITY
Tightly closed
containers
liquid
formulation:
water replaced
by substitute
liquids.
unstable antibiotic
drugs (aq. prepn
desired)
HYDROLYSIS
injectable
products:
anhydrous
vegetable oils
may be used as
solvent
ENHANCING STABILITY
packaged in
sealed
containers with
air replaced by
inert gas
prepared in
dry state
add
antioxidants
OXIDATION
ENHANCING STABILITY
AQUEOUS PREPARATION
Na2SO3, NaHSO3,
Na2S2O5, ascorbic
acid
OLEAGINOUS/UNCTOUS
PREPNS:
alpha tocopherol,
butylhydroxy
anisole &
ascorbyl
parmitate
ENHANCING STABILITY
purification of
source of
contaminant
TRACE METALS
complexing or
binding metal
(chelating agents)
OXIDATION
LIGHT
light-resistant or
opaque
containers
TEMPERATURE
Cool place
pH
Buffering agent
Ca disod edetate
& EDTA)
STORAGE TEMPERATURE
Conditions
Temperature
Freezer
-20C (-10C)
Refrigerator
2C - 8C
Cold
Not exceeding 8C
Cool
8C 15C
Warm
30C 40C
Excessive Heat
Above 40C
NOTE: Article for storage in cool place stored in refrigerator.

Article for storage in a controlled room temperature may be stored
in a cool place.
Other destructive process in

pharmaceutical preparations
POLYMERIZATION
Reaction between
two or more
identical molecules
with resultant
formation of new &
generally larger
molecule
(formaldhyde)
OTHER PROCESSES
Decarboxylation
decomposition of
RCOOH & release of
CO2
Deamination
removal
of nitrogen
containing group from
organic amine (ex.
Insulin)
ASSIGNMENT.
Enumerate 3 The instability possibilities in
different formulations: (1 whole yellow paper)
1.
Oral Solutions
2.
Parenteral Preparations
3.
Suspension
4.
Emulsion
5.
Semi-solid Preparations
6.
Capsule and Tablets
STABILITY TESTING
Requisite data to demonstrate and

document the products stability
Before approval for marketing, a products stability must

be assessed with regard to its formulation;
the influence of its pharmaceutical ingredients;
the influence of the container and closure;
the manufacturing and processing conditions (e.g., heat);
packaging components;
conditions of storage;
anticipated conditions of shipping, temperature, light, and
humidity;
and anticipated duration and conditions of pharmacy shelf
life and patient use
STABILITY TESTING
Expiration Date
The date placed on the immediate container
label of a drug product that designates the
date through which the product is expected
to remain within specifications
STABILITY TESTING
Duration
Long Term
12 mos.
Storage
Condition
25C2
Humidity
Intermediate
6 mos.
30C2
605% RH
Short Term
6 mos.
40C2
75% RH
605% RH
Scientific data pertaining to the stability

of a formulation
leads to:
*prediction of the expected shelf-life of the
proposed product
*redesign of the drug (to more stable salt or
ester form)
*reformulation of the dosage form.
PHARMACEUTICAL INGREDIENTS
(EXCIPIENTS)
PHARMACEUTICAL INGREDIENTS &

EXCIPIENTS
FOR SOLUTIONS
Stabilizers (antioxidants and

chelating agents) prevent
decomposition
FOR TABLETS
Solvents used to dissolve the

drug substance
Flavors and Sweeteners make
product more palatable
Colorants enhance appeal
Preservatives prevent
microbial growth
Diluents or fillers to increase

bulk of the formulation
Binders adhesion of the
powdered drug and
pharmaceutical substances
Antiadherents or lubricants
assist smooth tablet formation
Disintegrating agents
promote tablet breakup after
administration
PHARMACEUTICAL INGREDIENTS &

EXCIPIENTS
HARMONIZATION OF STANDARDS
United
States Pharmacopeia National

Formulary (USP-NF)
British Pharmacopeia
European Pharmacopeia
Japanese Pharmacopeia
Appearance and Palatability

Flavoring
Pharmaceuticals
Color,
odor, texture, and taste must coincide/balance

In general, LMW salts are salty while HMW salts are bitter.
In organic chemistry, the more hydroxyl group present,
increase sweetness.
Different types of flavors: Natural, Artificial, Spice
Delaney Clause
Flavor
Type of Drug
Cocoa
Bitter drugs
Fruit or citrus
Sour and acid-tasting drugs
Cinnamon, Orange, Raspberry &

others
Salty drugs
Delaney Clause
"No additive shall be deemed to be
safe if it is found to induce cancer
when ingested by man or laboratory
animals or if it is found, after tests
which are appropriate for the
evaluation of the safety of food
additives, to induce cancer in man or
animals."
Flavor Selection Guide
Salty
Bitter
Acrid/Sour
Oily
Sweet
Acid
Butterscotch/Maple
Wild Cherry/Licorice
Chocolate Mint
Raspberry/Fruit
Berry/Acacia Syrup
Peppermint/Anise
Wintergreen
Fruit/Berry/Vanilla
Citrus
Sweetening Pharmaceuticals
Dextrose
Sucrose
Sorbitol
Mannitol
Saccharin
Aspartame
- 1st artificial sweetener (1958 amendment)
w/ requirement for pre-marketing proof of safety.

- Aspartame breaks down in the body into three basic components:
phenylalanine, aspartic acid, and methanol.
-
Acesulfame potassium (nonnutritive sweetener)

- structurally similar to saccharin (USP approved)
-180 200 times as sweet as sucrose, excreted unchanged in

the urine;
- more stable than aspartame
-
Stevia (Stevia rebaudiana bertoni)

new sweetening agent: natural, nontoxic, safe,
30x sweeter than cane sugar/sucrose
Saccharin & cyclamate - used in foods

-generally recognized as safe (before the
amendments passage)
- use on rats: developed incidence of bladder
tumors (cancer)
- continued availability but warning labels be used
-cyclamates (banned) - possible carcinogenicity,
genetic damage, testicular atrophy
Coloring Pharmaceuticals
Coloring
Pharmaceuticals
Used in pharmaceutical preparations for esthetics
Certain agents that are not pharmaceutical
colorants
Sulfur (Yellow)
Riboflavin (Yellow)
Cupric sulfate (Blue)
Ferrous sulfate (Bluish green)
Cyanocobalamin (Red)
Red Mercuric iodide (Vivid Red)
Aniline dyes
Coal tar (pix carbonis)
- thick black viscid liquid
- by product of destructive distillation of coal.
- source of synthetic coloring agents in pharm.
products in the middle of the 19th century
Dyes added to pharmaceutical preps. in the
form of diluted solutions
Lakes - commonly used in the form of fine
dispersions or suspensions.
90% of the dyes used in the products - synthesized from

derivative of benzene (aniline)
FDA - regulates use color additives in foods, drugs, and

cosmetics (Federal Food, Drug, and Cosmetic Act of 1938)
- FD&C color additives - foods, drugs, and cosmetics
- D&C color additives - drugs, some in cosmetics &

medical devices
- external D&C color additives - restricted to external parts

of the body (not including the lips and other parts that
are covered by mucous membrane)
Factors in selecting dyes

Solubility of
prospective dye
Dyes must be
photostable
pH & pH stability
of the preparation
to be colored
PRESERVATIVES
liquid and semisolid preparations

- must be preserved against microbial
contamination.
Sterilization and Preservation
some types of pharmaceutical products

(ex. Ophthalmic and injectable
preparations)
- sterilized by physical methods :
*autoclaving (20min at 15 lb. press. &
121C, dry heat at 180C for 1 hr)
*bacterial filtration.
Preparations that provide excellent growth

media for microbes
- aqueous preparations: syrups, emulsions,
suspensions
- semi solid preparations particularly creams.
- hydro-alcoholic & most alcoholic preparation
*may not require addition of chemical
preservative
prevent microbial growth:

*15% alcohol in acid media
*18% alcohol in alkaline media.
Alcohol-containing pharmaceuticals (elixirs, spirits,
and tinctures) - self sterilizing and do not require
additional preservation.
Preservative Selection
Considerations in selecting preservative in

pharmaceutical preparations:
1.
2.
3.
Prevents the growth of the type of

microorganisms ( contaminants of the
preparations)
Soluble enough in water to achieve adequate
concentrations in aqueous phase with two or more
phase systems
Proportion of preservative remaining
undissociated at the pH of preparation (can
penetrate the microorganism & destroy its
integrity).
4.
5.
6.
7.
Concentration of the preservative does not

affect the safety/comfort of the patient
With adequate stability and not reduced in
concentration by chemical decomposition/
volatilization
Compatible with all other formulative
ingredients and does not interfere with them
Does not adversely affect the preparations
container or closure.
Dosage form
Route of
administration
Compatibility
with
excipients
Container and
closure
compatibility
General Preservative Considerations
Range of
activity
Concentration
required
pH
requirements
Compatibility
Mode of action: Mechanisms preservative interfere

with microbial growth, multiplications, and metabolism:
1. Modifications of cell membrane
permeability & leakage of cell constituents
(partial lysis)
2. Lysis and cytoplasmic leakage

3. Irreversible coagulation of cytoplasmic
constituents
4. Inhibition of cellular metabolism by
interfering with enzyme systems/inhibition of
cell wall synthesis
5. Oxidation of cellular constituents and
Hydrolysis
PRESERVATIVES
Benzoic acid/sodium benzoate
Alcohol
Phenylmercuric nitrate/acetate
Phenol
Cresol
Chlorobutanol
Benzalkonium chloride
Methylparaben/propylparaben
Others
PRESERVATIVES
PRESERVATIVE
PROBABLE MODE OF ACTION
Benzoic acid, Boric acid, phydroxybenzoates
Denaturation of proteins
Phenols and chlorinated phenolic

compounds
Lytic & denaturation action on cytoplasmic

membranes and for chlorinated preservatives,
also by oxidation of enzymes
Alcohols
Lytic & denaturation action on membranes
Quaternary compounds
Lytic action on mebranes
Mercurials
Denaturation of enzymes by combining with

thiol (-SH groups)

IV. Pre Formulation

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IV. Pre Formulation

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DOSAGE FORM CONSIDERATION:

By: LOUJESSA D. ARCELO

DOSAGE FORM CONSIDERATION

The need for dosage forms

Dosage Form Design

Requirements of a proper design &

compatible with one

THE NEED FOR DOSAGE

THE NEED FOR DOSAGE FORMS

THE NEED FOR DOSAGE FORMS

Provide ratecontrolled drug

General Considerations in Dosage

Develop and examine initial formulations of

General Considerations in Dosage

Phase diagrams constructed determines:

existence & extent of the presence of solid and liquid

affects : physicalchemical properties of drug

Parts of solvent required for

Very slightly soluble

Salts prepared from strong acids or

For weak acidic

It must be nontoxic. Nonirritating.

Most antifoaming agents

W/O Emulsifying agents

Wetting and Spreading agents

O/W Emulsifying agents

Detergents and Solubilizing agents

Time for the drug to dissolve in the fluids at

Increasing dissolution rate:

1st law: relates to a steady state

Describes the relationship between

pKa, solubility, and

For basic drugs.pH= pKa+ log[unionized drug]

DRUG AND DRUG PRODUCT STABILITY

Drug Stability: Mechanisms

Drug and Drug Product Stability:

active ingredient retains chemical integrity

original physical properties, appearance,

sterility/resistance to microbial growth

therapeutic effect remains unchanged

no significant increase in toxicity occurs.

Drug and Drug Product Stability:

description of the drug

Drug and Drug Product Stability:

the rate constant

NOTE: Article for storage in cool place stored in refrigerator.

Other destructive process in

Requisite data to demonstrate and

Before approval for marketing, a products stability must

Scientific data pertaining to the stability

PHARMACEUTICAL INGREDIENTS &

Stabilizers (antioxidants and

Solvents used to dissolve the

Diluents or fillers to increase

PHARMACEUTICAL INGREDIENTS &

States Pharmacopeia National

Appearance and Palatability

odor, texture, and taste must coincide/balance

Sour and acid-tasting drugs

Cinnamon, Orange, Raspberry &

Flavor Selection Guide

w/ requirement for pre-marketing proof of safety.

Acesulfame potassium (nonnutritive sweetener)

-180 200 times as sweet as sucrose, excreted unchanged in