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
6
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-----
10
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
11
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
[Link] 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
14
INTRINSIC FACTORS
15
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,
16
above a pH of 10 the decomposition rate rapidly increases.
17
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.
18
MICROBIAL GROWTH
o Threat to stability - degradation of drug dosage
impotency
o Evaluating microbiological stability
chemical assays of preservatives
- Microbial challenge tests
19
BOUNDARY FACTORS
20
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.
22
Amber coloured glass
Plastics
The problems with plastic are:
1. Migration of the drug through the plastic into the
environment.
[Link] of environmental moisture, oxygen, and other
elements into the pharmaceutical product.
[Link] of container ingredients into the drug.
[Link] of the active drug or excipients by the plastic.
Overcome:
1. Minimize by overwrapping
2. Leaching can be reduced by coating with Teflon
23
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.
24
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
26
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
27
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
28
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
29
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
30
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
[Link] agent such as methyl cellulose are added to
prevent the conversion
31
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
32
CHEMICAL INSTABILITY
Hydrolysis
Absorption of CO2
Decarboxylation
Polymerization
Isomerization
Oxidation
33
HYDROLYSIS
- means splitting by water
34
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
35
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
36
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
37
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)
39
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
40
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
41
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.
42
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
43
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
45
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
46
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 [Link], 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
[Link] 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
:[Link]
ml
Drug interactions from [Link]
drug interactions
48
