STABILITY IN

PREFORMULATION

Presented By
MITHA ANN THAMPY
M PHARM FIRST YEAR
NEHRU COLLEGE OF PHARMACY

CONTENTS

1. STABILITY
2. OBJECTIVES OF STABILITY STUDIES
3. FACTORS AFFECTING STABILITY
4. STABILITY PROBLEMS AND ITS PREVENTION
5. REFERENCES

STABILITY
Stability of pharmaceutical product may be defined

as the capability of a particular formulation in a

specific container/closure system to remain within its
physical, chemical, microbiological, therapeutic and
toxicological specification.
The stability of the drug substance is first assessed in
the preformulation stage.
A drug product must satisfy stability in terms of
chemical, therapeutic, toxicological and physical
characteristics

OBJECTIVES OF STABILITY STUDIES

To gather information during preformulation stage to

produce a stable product.

To determine maximum expiration date.
To get an idea of storage condition.
To determine the packaging components.
To determine the retest period of pharmaceuticals.
To determine transport conditions.

FACTORS AFFECTING STABILITY

Extrinsic factors

- Temperature
- Light
- Gases
- Moisture
Intrinsic factors
- pH
- Complexation
- Microbial Growth
Boundary factors
- Container composition
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EXTRINSIC FACTORS

TEMPERATURE
Speed of reactions increases about 2 or 3 times with

every 10o rise in temperature.

Arrhenius equation explains the effect of temperature
on rate of reaction

Important in case of parenterals

ENERGY OF ACTIVATION AND

REACTION TYPES
2-3 kcal/mole----------

Diffusion or photolysis

<10 kcal/mole---------

Fast reactions stability

problems in
development
10-30 kcal/mole-------

50-70 kcal/mole-----

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Solvolytic process; most

drug degradation

Pyrolytic reactions

LIGHT
Activate molecules and enhance rate of decomposition
Photochemical decomposition due to absorption of

sunlight ( visible - blue, violet and uv 500 300nm )

Exposure of sunlight colour change of product
- degrade packaging
- chemical decomposition of
active ingredient
Test procedure test sample in open petridishes or
clear containers
- control sample in light resistant
containers
- placed into temperature monitored
cabinets for 4 weeks
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 Drugs undergo zero order kinetics

eg. Chlorpromazine, reserpine, colchicine

Drugs undergo first order kinetics
eg. Adriamycin, furosemide, nefidipine
Examples of photochemical degradation
- colour fading of tablets and liquids
- conversion of ergosterol to vitamin D

12

GASES
Oxygen and carbon dioxide affect stability of drug

Oxygen oxidation potency loss / colour change

eg. Ascorbic acid

dehydroascorbic acid
CO2 - potency loss
eg.Sodium hexobarbitone iv injection hydrolysis solution CO2
(basic pH)

hexobarbitone precipitate
(acidic pH )

13

MOISTURE
Absorption of moisture increases the weight of product
- dose diluted decreases potency
eg Deliquescent substances CaCl2 ,K2CO3
Gelatin capsules absorb moisture and become soft
Test procedure expose to various range of humidities
- test carried out on final packaged product
and unpackaged product
- To get information regarding formulation
adjuvant, type of environment suitable for
a drug & type of package needed

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INTRINSIC FACTORS

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pH
Rate of hydrolytic reactions vary with pH

- Hydrogen ion catalyses predominantly at lower pH

- Hydroxyl ion catalysis operates at higher pH range
pH can also influence the rate of oxidation.
- system less readily oxidized when the pH is low.
Test procedure product samples are kept at pH 2 12 at
55 90 0 c for 2 weeks
- plot pH rate profile ( log k vs. pH )
- point of inflection of such a plot represents
pH of optimum stability
- point is useful in the development of
stable dosage form
eg. Aspirin buffered solution is maximum stable at a pH of 2.4,
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above a pH of 10 the decomposition rate rapidly increases.

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COMPLEXATION

Complex formation reduces the rate of hydrolysis

and oxidation.
e.g. caffeine complexes with local anesthetics, such as
benzocaine, procaine and tetracaime - reduction in
rate of hydrolytic degradation.

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MICROBIAL GROWTH
o Threat to stability - degradation of drug dosage

impotency
o Evaluating microbiological stability
chemical assays of preservatives
- Microbial challenge tests

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BOUNDARY FACTORS

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CONTAINER COMPOSITION
The container and closure are particularly important in

affecting product stability.

21

 Glass

- Glass is resistant to chemical and physical change

and is the most commonly used material.
Limitations
1. Its alkaline surface

Overcome
use of Borosilicate glass

2. Ions may precipitate

the use of buffers
insoluble crystals from the glass
3. Permits the transmission of
light which may accelerate
decomposition.

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Amber coloured glass

 Plastics

The problems with plastic are:

1. Migration of the drug through the plastic into the
environment.
2.Transfer of environmental moisture, oxygen, and other
elements into the pharmaceutical product.
3.Leaching of container ingredients into the drug.
4.Adsorption of the active drug or excipients by the plastic.
Overcome:
1. Minimize by overwrapping
2. Leaching can be reduced by coating with Teflon
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 Metals

- Various alloys and aluminium tubes may be utilized as

containers for emulsions, ointments, creams and pastes.

- Limitation: They may cause corrosion and precipitation in
the drug product.
- Overcome: Coating the tubes with polymers may reduce
these tendencies.
Rubber
- It has the problems of extraction of drug ingredients and

leaching of container ingredients.

- The pretreatment of rubber vial stoppers and closures with
water and steam reduces potential leaching.
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STABILITY PROBLEM AND ITS

PREVENTION

Physical instability
Chemical instability
Therapeutic instability
Microbiological instability

25

PHYSICAL DEGRADATION
Loss

of volatile constituents
Loss of water
Absorption of water
Crystal growth
Polymorphism
Colour changes

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LOSS OF VOLATILE CONSTITUENTS

Medicinal agents such as iodine, camphor, menthol, ethanol,

anaesthetic ether, chloroform tendency to evaporate from

product
Nitroglycerine loose its potency volatilisation of medicament
Prevention
1. keep product in well closed container
2. store in cool place

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LOSS OF WATER
Decrease in weight, rises in concentration and

increases potency
Loss of water depends on temperature and humidity
eg. Efflorescent substances borax, quinidine
sulphate, caffeine
Prevention
1. keep product in well closed container
2. store in cool place

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ABSORPTION OF WATER
Absorption of moisture increases the weight of product

- dose diluted decreases potency

eg. Deliquescent substances CaCl2 ,K2CO3
Gelatin capsules absorb moisture and become soft
Prevention
1. keep product in well closed container

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CRYSTAL GROWTH
Fluctuation in temperature causes crystal growth
Seen in - supersaturated solution

e.g. 10% w/v Calcium gluconate solution

- suspension
Prevention
1. select suitable storage condition to prevent
temperature fluctuation
2. increase the viscosity of the product
3. include surface active agents in formulations

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POLYMORPHISM
Polymorphs exhibit significant difference in physicochemical

properties such as solubility, dissolution rate and melting point

Metastable and stable
eg. Cortisone acetate form ll
Cortisone acetate form lV
(metastable)
( stable )
Prevention
1.Suspending agent such as methyl cellulose are added to
prevent the conversion

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COLOUR CHANGES
Indicate some kind of chemical or photochemical

degradation of active ingredients, dyes or other ingredients

eg. 1. Colour fading of dyes
- indigo carmine dye tend to fade in presence of
reducing substances(lactose & dextrose)
- tartrazine tend to fade rapidly in presence of
additives(surfactants) or light
2. Aspirin tablet becomes pink
3. Ascorbic acid tablet turn yellowish brown
4. Adrenaline on exposure to air becomes red
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CHEMICAL INSTABILITY
Hydrolysis

Absorption of CO2
Decarboxylation
Polymerization
Isomerization
Oxidation

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HYDROLYSIS
- means splitting by water

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Drug type

Examples

Esters

Aspirin, alkaloids
Dexmethasone sodium phosphate
Nitroglycerin

Lactones

Pilocarpine
Spironolactone

Amides

Chloramphenicol

Lactams

Penicillins
Cephalosporins

 Prevention

1. By adding Buffers
- maintain pH having maximum stability and
therapeutic activity
- Optimum pH selected should between 3.5 and 5
e.g. Boric acid buffer
2. Complexation
3. Suppression of solubility
- achieved by adding
o Additives e.g. Citrate, dextrose, sorbitol & gluconate
o Converting into salt form
e.g. Penicillin
Procaine Penicillin
o Converting into water insoluble derivative.
e.g Erythromycin propionate, Erythromycin stearate
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4. Removal of water
- achieved by
o Storing drug in dry form
e.g. Streptomycin dry powder for injection
o Use water immiscible vehicle for dispersion of drug
e.g. Aspirin in silicone fluid

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ABSORPTION OF CARBON DIOXIDE

loss potency

eg. Sodium hexobarbitone iv injection

Amphetamine,KOH,NaOH,Ca(OH)2,MgO turbid solution
Prevention
- keep product in well closed container
- Manufacture product as dry sterile powder

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DECARBOXYLATION
Elimination of CO2 from a compound
Encountered when parenteral solutions of NaHCO3

are autoclaved
e.g. Sodium P- amino salicylic acid
Procaine hydrochloride
Prevention
- CO2 gas is passed into the solution for 1 min
prior to sealing

38

POLYMERISATION
combination of 2 or more identical molecules to form

larger and more complex molecule

e.g. dextrose inj autoclaving 5 hydroxymethyl furfural
( straw coloured solution)

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ISOMERISATION
Process of conversation of one isomer into other. This

causes drug deterioration

3 types of isomerisation
1. Optical isomerisation
e.g. (-) Adrenaline

2. Epimerisation
e.g. Ergometrine
3. Geometric Isomerisation
e.g. Vit A palmitate

( ) Adrenaline
( less potent )
Ergometrinine
( less potent )

6- mono- cis derivative +

2,6 di- cis derivative
Prevention: 1. Product is protected from light and heat
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2. Optimum pH has to be maintained for maximum activity

OXIDATION
Removal of electropositive atom, radical or electron or
addition of electronegative atom or radical

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Functional group

Examples

Catechols

Catecholamines (dopamine)

Ethers

Diethylether

Thiols

Dimercaprol (BAL)

Thioethers

Chlorpromazine

Carboxylic acids

Fatty acids

 Prevention : Oxidation is prevented by

1. Adding antioxidants
- break free radical chain reaction at the step of chain
propagation
Aqueous systems
Oil systems
Sodium metabisulfite Ascorbyl palmitate
Sodium thiosulfate
BHT
Ascorbic acid

BHA

2. Adding chelating agents

- form complexes with heavy metal ions and prevent
them from catalyzing oxidative decomposition.
e.g. EDTA derivatives and salts, citric acid & tartaric
acid.
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3. Adding Buffers
- impart stability when oxidation catalysed by H+ or
OH- ions
4. Adding reducing agents
- employed at a concentration of .01 - .1 %
e.g. sodium and potassium metabisulphite
5. Adding surfactants
- Nonionic, cationic and anionic surfactants when
added to solutions containing drugs form micelle and
the drug particles become trapped in the micelle
6. Environmental control measures
- prevent exposure to light
- oxygen free environment
- low temperature storage
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MICROBIOLOGICAL INSTABILITY

44

Water

gram-negative groups: Pseudomonas,

Xanthamonas, Flavobacterium

Air

Mould spores: Penicillium, Aspergillus

Bacterial spores: Bacillus spp. Yeasts

Raw materials
Starches

Micrococci
Coliforms

Pigments
Gums

Salmonella
Actinomyces

Animal
products
Personnel

Salmonella, Coliforms
Coliforms, Staphylococci, Sterptococci

Prevention:
(1) Suitably designing the containers
(2) usually using single dose containers
(3) sticking to proper storage conditions
(4) adding an antimicrobial substance as preservative

Preparation

Preservative

Concentration %w/v

Injections

Phenol
Cresol
Chlorocresol
Chlorhexidine
acetate
Benzalkonium
chloride
Benzoic acid
Methyl paraben
Alcohol

0.5
0.3
0.1
0.01

Eye drops

Mixtures
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0.01
0.1
0.1
12-20

THERAPEUTIC INSTABILITY
Due to drug interactions ( effect of one drug is altered

by prior or simultaneous administration of another

drug or food)
Prevention
- proper adjustment of dosage
Generic name

Bacampicillin

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Potentiates

Decreases

Chloramphenicol
Beta adrenergic Erythromycin
Birth control pills Loperamide
Probenicid
Paromomycin
Sodium benzoate Tetracycline
Troleandomycin

Food
alcoholic
beverages,
acidic
fruits or
juices

REFERENCES
Leon Lachman et.al, The Theory and Practice of Industrial

47

Pharmacy, Varghese Publishing House, Bombay,3rd edition

P. 190
C.V.S Subrahmanyam, Textbook of Physical pharmaceutics,
Vallabh Prakashan, Delhi,2nd edition P. 51 - 69
Dr.Shyamala Bhaskaran, Industrial Pharmacy, Birla
Publications, Ist edition, P. 8 - 11
R.M. Mehta, Pharmaceutics ll, Vallabh Prakashan, Delhi,2nd
edition P. 58
Conditions for Stability from
:http://www.pharmacopeia.cn/v29240/usp29nf24s0c1191.ht
ml
Drug interactions from http://en.wikipedia.org/wiki/Listof
drug interactions

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