drug stability

Question 1

drug stability definition

Answer 1

 Drug stability is defined as, “the capacity or capability of a particular formulation in a specific
container to remain within a particular physical, chemical, microbiological, therapeutical and
toxicological specifications.”
 Drug stability refers to the time from the date of manufacture and packing of the formulation until its
physical, chemical and biological activity is not less than a pre-determined level of the potency and
physical characteristics.

Question 2

importance of drug stability

Answer 2

The study of stability of pharmaceutical products and stability testing techniques is important for three
main reasons.
 Patient Safety
 Legal Requirement
 Financial Repercussion (an unintended consequences of an event or an action)

Question 3

patient safety

Answer 3

 Safety of patient is very important issue.
 The present trend of pharmaceutical industry is the production of highly specific chemically complex
and potent drug.
 It is important that the patient receives a uniform dose of the drug throughout the whole shelf life of
the drug.
 It is the duty of manufacturer to minimize or if possible prevent the decomposition of the product
especially of parenteral solutions injections.

Question 4

legal requirements

Answer 4

 The considerations must be given to the legal requirement concerned with the identity, strength, purity
and the quality of the drug.

Question 5

financial rerpercussion

Answer 5

 The sale of unstable product is difficult for the manufacturer and therefore subsequent withdraw and
reformation of the drug may lead to considerable financial loss.

Question 6

factors affecting product/ drug stability

Answer 6

 The stability of active ingredients
 Interaction between active ingredients and excipients or container or closure
 Environmental conditions

Question 7

expiry date

Answer 7

It is the date which is fixed by the manufacturer for a certain product after which the harmful events
may result into:
I. Loss of potency
II. Development of toxic products
In classic terms, the drugs stability refers to:
I. Physical stability
II. Chemical stability
III. Biochemical Stability
The stability studies data may have one of the two errors.
I. Type I Error: Expiry date is set too early.
II. Type II Error: Expiry date is set too late.

Question 8

degradation

Answer 8

 It is the condition or process of degrading or being degraded.
 Decline to a lower quality, condition or level is called as degradation.

Question 9

pharmaceutical degradation

Answer 9

The incapacity or incapability of a particular formulation in a specific container to remain within a
particular chemical, microbiological, therapeutical, physical & toxicological specification is called as
pharmaceutical degradation.

Question 10

types of pharmaceutical degradation

Answer 10

There are two types of pharmaceutical degradation.
 Physical degradation
 Chemical degradation

Question 11

physical degradation

Answer 11

It is the degradation which results into the change of physical nature of drug. The formulation is totally
changed by way of appearance, organoleptic properties, hardness, brittleness, particle size. Physical
degradation includes:
 Loss of volatile components
 Loss of water
 Absorption of water
 Crystal growth
 Polymorphic changes
 Colour changes

Question 12

loss of volatile components

Answer 12

Volatile components such as alcohol, ether, camphor, iodine, volatile oil etc. escape from the
formulation e.g. Nitroglycerine from drugs evaporates.
Measures to Prevent Loss of Volatile Components:
 Such products should be placed in well closed container.
 To decrease temperature as increase in temperature will increase volatility, product should be placed
in a cool place.

Question 13

loss of water

Answer 13

 Loss of water from o/w emulsions thus the stability changes.
 Water evaporates from efflorescent salts such as Borax and sodium bisulphate etc.
 Water evaporates causing crystal growth.

Measures to Prevent Loss of Water:
 Water loss may be prevented by storing the product in well closed container.

Question 14

crystal growth

Answer 14

 In solutions after super saturation of solvent crystal growth occurs e.g. injection of calcium gluconate
 In suspension crystals settle down and caking occurs and suspension becomes unstable e.g. ophthalmic
preparations.

Prevention of Crystal Growth:
 In case of solutions stabilizers are employed.
 In case of suspension minimum temperature flocculation should be managed.
 Incorporation of surface active agents.
 By increasing viscosity of suspending medium.

Question 15

absorption of water

Answer 15

 Hygroscopic drugs such as glycerin suppositories absorb
 Water from atmosphere causing physical degradation.
Preventive measure for absorption of water:
 Product should be placed in well closed container.

Question 16

polymorphic changes

Answer 16

 In polymorphic changes crystals form change. A stable crystal form is lost.
Measures to prevent polymorphic changes:
 Formulated product should contain a stable crystalline form of the drug.

Question 17

color changes

Answer 17

color changes are of two types:
o Loss of color
o Development of color
 Loss of color is due to pH changes.
 Development of color is due to reducing agents, water and U.V rays
Prevention of Colour Changes:
 pH should not be changed.
 Exposure to light should be avoided.

Question 18

oral solution

Answer 18

1. Loss of flavor
2. Change in taste
3. Presence of off flavors due to
   interaction with plastic bottle
4. Loss of dye
5. Precipitation
6. Discolorization

effect
Change in smell or feel or taste

Question 19

suspentions

Answer 19

1. Setting
2. Caking
3. Crystal Growth
4. Loss of drug content uniformity in different
   doses from the bottle
5. Loss of Elegance

Question 20

emulsion

Answer 20

1. Creaming
2. Coalescence
3. Loss of drug content uniformity in different
   doses from the bottle
4. Loss of Elegance

Question 21

tablet

Answer 21

Change in

1. Disintegration time
2. Dissolution profile
3. Hardness
4. Appearance

Change in drug release

Question 22

capsule

Answer 22

Change in:
1. Appearance
2. Dissolution
3. Strength

Change in drug release

Question 23

chemical degradation

Answer 23

It is the separation of chemical compound into elements or simpler compounds. Change in the chemical
nature of the drug is called as chemical degradation. Chemical degradation includes:
 Hydrolysis
 Oxidation
 Decarboxylation
 Isomerization
 Polymerization

Question 24

hydrolysis

Answer 24

 Hydrolysis means splitting of pharmaceutical product by the action of water.
 It is the main problem with the pharmaceutical systems such as emulsions, suspensions, solutions etc.
 This is carried out by water vapours from atmosphere.
 Hydrolysis is catalyzed by hydrogen ions or hydroxyl ions and also by acidic or basic species
commonly encountered as components of buffers.
 The main classes of drugs that undergo hydrolysis are the:
o Esters
o Amides
o Lactams

Question 25

esters hydrolysis

Answer 25

Upon hydrolysis of esters acyl-oxygen is cleaved and acid and alcohol is produced.

Examples of drugs undergo hydrolysis are:
 Procaine
 Tetracaine
 Atropine
 Physostigmine
 Aspirin

Question 26

amide hydrolysis

Answer 26

 Although amides are relatively stable than esters but these are susceptible to specific and general acid-
base hydrolysis.

 Amide hydrolysis usually involves the cleavage of the amide linkage to give an amide giving alcohol
and amine as hydrolyzed products.

Examples of drugs undergo amide hydrolysis are:
 Dibucaine
 Ergometrine
 Chloramphenicol
 Niacinamide
 Barbiturates

Question 27

ring hydrolysis

Answer 27

 Compounds containing ring undergo hydrolysis to make hydrolyzed products.
 For example, β-lactam antibiotics such as penicillins which are cyclic amides or lactams undergo rapid
ring opening due to hydrolysis.

Drugs that undergo ring cleavage are:
 Nitrazepam
 Chlorodiazepoxide
 Cephalosporin

Question 28

protection against hydrolysis

Answer 28

Hydrolysis or solvolytic reactions may be retarded:
1. By packing drugs into controlled humidity containers
2. By incorporating a suitable desiccant in the pack
3. By addition of buffers in liquid dosage forms
4. By minimizing buffer concentration to the minimum required for maintaining pH
5. By altering dielectric constant of system by using non-aqueous solvents such as alcohol, glycerin and
propylene glycol
6. By adding complexing agents like caffeine to the drug solutions like procaine and benzocaine
7. By converting drugs into suspensions
8. By formulating drugs (like penicillin and its derivatives) in form of dry syrups, dry powders, injections
or dispersed tablets instead of a liquid dosage form (solutions or suspensions) etc.
9. By refrigerating the drugs

Question 29

oxidation

Answer 29

 Instabilities in a number of pharmaceutical preparations are due to oxidative degradation of the active
ingredients of these preparations when exposed to atmospheric oxygen.
 Removal of an electropositive atom, radical or electron, or the addition of an electronegative atom or
radical is called as oxidation.
 Oxidation is of two types:
o Auto-oxidation
o Photo-oxidation

Question 30

auto-oxidation

Answer 30

 It is the most common form of oxidative degradation that occurs in many pharmaceutical preparations
and involves a free radical chain process.
 In an auto-oxidative degradation, only a small amount of oxygen is required to initiate the reaction and
thereafter oxygen concentration is relatively important.
 The free radicals produced during the initial reaction are highly reactive and further catalyze the
reaction to produce additional free radicals and causing a chain reaction.
 Heavy metals such as copper, iron, cobalt and nickel catalyze the oxidative degradation. Some solvents
like water, and heat and light influence this process.
 Drugs that undergo oxidative decomposition are:
o Ascorbic acid
o Morphine
o Epinephrine
o Heparin
o Paraldehyde
o Tetracycline
o Vitamin A
o Vitamin D
o Vitamin K

Question 31

photo-oxidation/photolysis

Answer 31

 Exposure to light may produce oxidation-reduction, ring rearrangement or modification and
polymerization.
 The shorter the wave-length of light, the greater is the effect of light in initiating the chemical reaction
because of higher energy.
 The thermal (induced by light) reaction may continue even after the light source has been withdrawn.
Cyanocobalamine
Light H+
↔
Dark Cn−

Hydroxycobalamin + CN−
Oxidation
→ Biologically Active Products

 Pharmaceutical products undergo photolysis are:
o Ascorbic acid
o Riboflavin
o Cyanocobalamin folic acid
o Hydrocortisone
o Prednisolone
o Nifedipine

Question 32

protection againt oxidation

Answer 32

Oxidative degradation in a number of drug preparations can be retarded by:
1. Including anti-oxidant in the preparation
a. Anti-Oxidants for aqueous System
i. Sodium sulphite
ii. Sodium metabisulphite
iii. Ascorbic acid
iv. Sodium thiosulphate
b. Anti-Oxidants for Oily System
i. Tocopherol
ii. Ascorbyl palmitate
iii. Hydroquinone
iv. Propyl gallate
v. Butylated hydroxy anisole (BHA)
vi. Butylated hydroxy toluene (BHT)
2. By increasing effectiveness of anti-oxidants by:
a. Citric acid
b. Tartaric acid
3. By insuring pH
4. By replacement of air from the container by an inert gas such as nitrogen
5. By retarding hydrogenation of fats and oils
6. By protecting drugs from light
7. By using amber colored chambers
8. By storing the product in dark
9. By coating of tablets with polymer films containing UV absorbers

Question 33

isomerization

Answer 33

 It is the process by which one molecule is transformed into another molecule which has exactly the
same atoms, but the atoms are rearranged e.g. A-B-C → B-A-C
 Conversion of an active drug into a less active or inactive isomer having same structural formula but
different Stereochemical configuration
 This is done to increase therapeutic effects of drugs or sometimes resulting in loss of therapeutic
activity.

Types of Isomerization:
 Optical Isomerization
 Geometrical Isomerization

Question 34

optical isomerization

Answer 34

 A change in the optical activity of a drug may result as a change in its biological activity.
 It is further divided into:
o Racemization: It involves the optically active form of a drug into its enantiomorph. E.g.
adrenaline solutions at low pH due to conversion of its therapeutically active levorotatory form
to the less active dextrorotatory form, epinephrine shows the same effect.
o Epimerization: It occurs with the compound having more than one asymmetric carbon atom in the molecule. E.g. epimerization of tetracycline in acidic conditions to form less active epi-
tetracycline.

Question 35

geomtric isomerization

Answer 35

 Loss of activity due to the difference in potency exhibited by Cis and Trans isomers of some organic
compounds.
 For example, Active form of VITAMIN A molecule has all Trans configuration. In aqueous solution
as a component of multivitamin preparation, in addition to oxidation vitamin A Palmitate isomerizes
and form 6-mono cis and 2, 6 di-cis isomers, both have low potency.

Question 36

polymerization

Answer 36

4. POLYMERIZATION:
    Combination of two or more identical molecules to form a much larger and more complex molecule
   is called as polymerization.
    E.g. Degradation of antiseptic formulations and aldehydes is due to polymerization. Formaldehyde
   solution may result into formation of white deposit when stand in cold.

Question 37

decarboxylation

Answer 37

5. DECARBOXYLATION:
    Elimination of CO2 from a compound is called as Decarboxylation.
    Drug substances having a carboxylic acid group are sometimes susceptible to Decarboxylation.

Question 38

microbial degradation

Answer 38

 Contamination of a product may sometimes cause a lot of damage and sometimes may not be anything
at all. Thus it is dependent on the type of microbe and its level of toxicity it may produce.
 If parenteral or ophthalmic formulations are contaminated, it may cause serious harm.
 Pyrogens which are the metabolic products of bacterial growth are usually lipo polysaccharides and
they represent a particularly hazardous product released by gram negative bacteria. If administered
inadvertently to a patient, they may cause chills and fever.

Prevention of Microbial Degradation:
 Suitably designing the containers
 Usually using single dose containers
 Sticking to proper storage conditions
 Adding an antimicrobial substance as preservative.

Question 39

physcial factors influsencing chemical degradation

Answer 39

1-temperature
2-light (photolysis)
3-radiation
4-moisture

Question 40

temperature

Answer 40

 Rate of chemical reaction increased by 2 to 3 folds for every 100C rise in temperature.
 So while formulating a product at elevated temperature, storing a product at high temperature or
sterilizing a product by heating temperature effects should be in view.
 Thermolabile drugs while heating for sterilization can decompose, as dextrose injections,
sulfonamides.
 So as the temperature increases the number of effective collisions with sufficient energy to react
chemically increases and hence chemical degradation increases.
 In some cases, low temperature may increase chemical degradation e.g. Rate of polymerization of
formaldehyde increases at temperature below 15.
 Rate of decomposition of thermo labile drugs may be decreased by storing them in a cool place e.g.
Biological products i.e. insulin, oxytocin, vasopressin inj. and penicillin.

Question 41

light (photolysis)

Answer 41

 Exposure of drug to light of particular wave length can result into:
o Oxidation reduction reactions
o Ring rearrangements
o Polymerization
 As far as photolysis is concerned there are two types of molecules on the basis of mechanism of
degradation which they undergo:
o Photosensitive/Photo labile molecule which absorb energy from light and undergo a chemical
reaction themselves and the degradation is photochemical.
o Photosensitizes molecules which absorb light but don’t themselves undergo a chemical
reaction directly, but pass on their energy to other molecules that undergo a reaction. Such
degradation is not a photochemical but a thermal chemical reaction.

 A photochemical reaction is independent of temperature and continues even after the illumination is
stopped.

Question 42

preventive measures light

Answer 42

 Store the product in a clear glass container and then enclose in opaque rapper.
 Use light resistant containers e.g., ambered colour glass.
 Use stabilizer
 Use anti-oxident

Question 43

radiation

Answer 43

 Radiation, mostly gamma rays are used for sterilization of thermo labile compounds
 Following products are sterilized by using radiation may show degradation after irradiation
o Antibiotics ——- Streptomycin
o Alkaloids ———- Atropine
o Steriods ———– Progesteron
o Biological Products——-Insulin
 Decomposition is due ionization and formation of free radicals
 Drugs in solution form show more decomposition than pure solids on exposure to radiation

Question 44

moisture

Answer 44

 Moisture absorbed on to the surface of a solid drug increase the rate of decomposition
 Mostly this type of decomposition is due to hydrolysis e.g. Aspirin, Penicillin, and Streptomycin.

Question 45

preventive moisture

Answer 45

 Moisture absorbed on to the surface of a solid drug increase the rate of decomposition
 Mostly this type of decomposition is due to hydrolysis e.g. Aspirin, Penicillin, and Streptomycin.