Pharmaceutics (Physical Pharmacy)

THE DRUG STABILITY

Definition:

 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.

Importance of Drug Stability Study:

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)

1. Patient Safety:

 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.

2. Legal Requirements:

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

3. Financial Repercussion:

 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.

Factors Affecting Product/Drug Stability:

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 Pharmaceutics (Physical Pharmacy)

The product stability is affected by:

 The stability of active ingredients

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

Expiry Date:
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.

Degradation of Pharmaceutical Products:

Degradation:

It is the condition or process of degrading or being degraded

OR
Decline to a lower quality, condition or level is called as degradation.

Pharmaceutical Degradation:

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.

Types of Pharmaceutical Degradation:

There are two types of pharmaceutical degradation.

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 Pharmaceutics (Physical Pharmacy)

 Physical degradation
 Chemical degradation

Physical Degradation:
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

1. Loss of Volatile Components:

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.

2. Loss of Water:

 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.

3. Crystal Growth:

 In solutions after super saturation of solvent crystal growth occurs e.g.

injection of calcium gluconate
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 Pharmaceutics (Physical Pharmacy)

 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.

4. Absorption of water:

 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.

5. Polymorphic Changes:

 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.

6. Colour Changes:

Colour changes are of two types:

 Loss of color
 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.

Formulation Likely physical instability Effects

Problems
Oral 1. Loss of flavor Change in smell or feel or taste
Solutions 2. Change in taste

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 Pharmaceutics (Physical Pharmacy)

3. Presence of off flavors due to

interaction with plastic bottle
4. Loss of dye
5. Precipitation
6. Discolorization
Suspensions 1. Setting 1. Loss of drug content uniformity
2. Caking in different doses from the bottle
3. Crystal Growth 2. Loss of Elegance
Emulsions 1. Creaming 1. Loss of drug content uniformity
2. Coalescence in different doses from the bottle
2. Loss of Elegance
Tablet Change in Change in drug release
a) Disintegration time
b) Dissolution profile
c) Hardness
d) Appearance
Capsule Change in: Change in drug release
a) Appearance
b) Dissolution
c) Strength
Chemical Degradation:
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

1. Hydrolysis:

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:

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 Pharmaceutics (Physical Pharmacy)

 Esters
 Amides
 Lactams

A. Esters Hydrolysis:

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

B. Amide Hydrolysis:

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

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D16M137
 Pharmaceutics (Physical Pharmacy)

C. Ring Hydrolysis:

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

Protection against Hydrolysis:

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

2. Oxidation:

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 Pharmaceutics (Physical Pharmacy)

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:

 Auto-oxidation
 Photo-oxidation

A. Auto-Oxidation:

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:

 Ascorbic acid
 Morphine
 Epinephrine
 Heparin
 Paraldehyde
 Tetracycline
 Vitamin A
 Vitamin D
 Vitamin K

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 Pharmaceutics (Physical Pharmacy)

B. Photo-Oxidation / Photolysis:

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.
𝐿𝑖𝑔ℎ𝑡 𝐻+

𝐶𝑦𝑎𝑛𝑜𝑐𝑜𝑏𝑎𝑙𝑎𝑚𝑖𝑛𝑒 𝐻𝑦𝑑𝑟𝑜𝑥𝑜𝑐𝑜𝑏𝑎𝑙𝑎𝑚𝑖𝑛 + 𝐶𝑁 −
𝐷𝑎𝑟𝑘 𝐶𝑛−
𝑂𝑥𝑖𝑑𝑎𝑡𝑖𝑜𝑛
𝐵𝑖𝑜𝑙𝑜𝑔𝑖𝑐𝑎𝑙𝑙𝑦 𝐴𝑐𝑡𝑖𝑣𝑒 𝑃𝑟𝑜𝑑𝑢𝑐𝑡𝑠

Pharmaceutical products undergo photolysis are:

 Ascorbic acid
 Riboflavin
 Cyanocobalamin folic acid
 Hydrocortisone
 Prednisolone
 Nifedipine

Protection against Oxidation:

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

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 Pharmaceutics (Physical Pharmacy)

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

3. Isomerization:

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

A. Optical Isomerization:

A change in the optical activity of a drug may result as a change in its

biological activity.

It is further divided into:

 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.
 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.

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D16M137
 Pharmaceutics (Physical Pharmacy)

B. Geometric Isomerization:

 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.

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.

5. Decarboxylation:

Elimination of CO2 from a compound is called as Decarboxylation. Drug

substances having a carboxylic acid group are sometimes susceptible to
Decarboxylation.

E.g. 4-Aminosalicylic acid

Microbial Degradation:

 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.

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 Pharmaceutics (Physical Pharmacy)

 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.

Physical Factors Influencing Chemical Degradation:

1. Temperature:

 Rate of chemical reaction increased by 2 to 3 folds for every 10 0ͦ C 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.
 Thermo labile drugs while heating for sterilization can decompose, as dextrose
injections, sulfonamides.

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D16M137
 Pharmaceutics (Physical Pharmacy)

 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.

2. Light (Photolysis):

 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.

Preventive Measures:

 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 antioxident

3. Radiation:

 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

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 Pharmaceutics (Physical Pharmacy)

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

4. Moisture:

 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.

Preventive Measures:

 Such drugs should be stored in dry conditions

 Formulation process should be carried out in controlled humidity conditions
e.g. formulation of sodium ampicillin.
 Excipients chose must have low moisture contents so that transfer of moisture
from excipients to drug is less.

Methods for Detecting Physical and Chemical Degradation:

 THERMAL ANALYSIS

Following methods can be used for detection,

1. DIFFERENTIAL SCANNING CALORIMETRY (DSC)

2. DIFFERENTIAL THERMAL ANALYSIS (DTA)
3. DIFFERENTIAL THERMOGRAVIMETRY (DTG)

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D16M137