PHYSICAL AND CHEMICAL DEGRADATION OF PHARMACEUTICAL PRODUCTS. Physical Factors Loss of volatile constituents Loss of water Absorption of water Crystal growth Polymorphism changes Colour changes Chemical factors Hydrolysis Oxidation Carboxylation Decarboxylation Isomerization Polymerization

1. PHYSICAL AND CHEMICAL
DEGRADATION OF PHARMACEUTICAL
PRODUCTS
Prepared by ,
Mr. Snehal Patel
Assistant Professor,
Sumandeep Vidyapeeth,
Vadodara, Gujarat, India.

2. PHYSICAL DEGRADATION OF PHARMACEUTICAL PRODUCT
• Loss of volatile constituents
• Loss of water
• Absorption of water
• Crystal growth
• Polymorphism changes
• Colour changes

3. Loss of Volatile Constitution
• Medicinal agent such as iodine, camphor, menthol, ethyl alcohol,
anesthetic ether and chloroform, have a tendency to evaporate from
the product during the storage.
• Similarly nitroglycerin tablets may loose their potency, owning to
volatilisation of the medication.
• The preventative measure includes keeping the product in well-
closed containers and storing in the cool place.

4. Loss of water
• Loss of vehicle (water) from the product leads to decrease in weight,
raises the dose of drug and increases potency.
• Efflorescent substances, such as borax, caffeine, and quinidine
sulphate, have a natural tendency to loss water.
• Loss of water from the emulsions and semisolids results in cracking.
• Loss of water depends on the temperature and humidity.
• The preventative measure includes keeping the product in well-
closed containers and storing in the cool place.

5. Absorption of water
• Absorption of the moisture from the atmosphere increase the weight
of the product, dilutes the preparation and decreases the potency.
• Deliquescent substances, such as calcium chloride and potassium
carbonate, have a natural tendency to absorb the water.
• Gelatin capsules absorb moisture and becomes soft and sticky.
• Preventive measures include storing of such products in air tight
container and keeping in cool place.

6. Crystal Growth
• Crystal growth is promoted by fluctuation in the ambient
temperature ( day and night or seasonal). These are observed in the
following dosage forms.
1. Solutions
• When temperature is lowered, the solution becomes supersaturated
with respect to drug. Hence precipitation and crystal growth of the
drug is observed.
• For example 10 %w/v calcium gluconate injection is a supersaturated
solution. In order to reduce the risk of crystallization, the IP suggests
the use of calcium saccharate as a stabilizer.

7. Crystal Growth
2. Suspension
• Particles slowly becomes bigger in size and finally may form hard cake.
• These crystal, if present in the injection, may block the hypodermic needle.
• These particles, if present in eye drops, produce gritty texture when applied into
eyes.
Preventive measures includes:
• Selecting suitable storage condition to reduce fluctuations in ambient
temperature.
• Increasing the viscosity of the product, so that diffusion of solute molecules
onto the crystal surface will be hindered.
• Including the surface active agents into the formulation. These agents get
adsorbed on the surface of the crystal and inhibit further deposition of the drug
molecule.

8. Polymorphism changes
• Polymorphism is the ability of a solid material to exist in more than one
form or crystal structure.
• For eg: Cortisone acetate - form II (metastable) is more soluble and
formulated as aqueous suspension. During the storage, it may be
converted into form IV (more stable form). Such changes lead to caking
of the cortisone acetate suspension.
• Normally suspending agents such as methyl cellulose are added to
prevent the conversion owning to enhanced viscosity.

9. Colour changes
• Colour change indicates some kind of chemical and photochemical
degradation of active ingredients, dyes or other ingredients.
• Colour fading of dyes is a fairly common type of instability.
• Aspirin tablets become pink and ascorbic acid tablet turns yellowish
brown. Adrenaline on exposure to air becomes red.
• Preventive measures: The product should be protected from light and
air.

10. Chemical DEGRADATION OF PHARMACEUTICAL PRODUCT
• Hydrolysis
• Oxidation
• Carboxylation
• Decarboxylation
• Isomerization
• Polymerization

11. Hydrolysis
• Drugs with ester and amide groups reacts with one molecule of water and
undergoes hydrolysis.
• A few drugs with undergoes hydrolytic pathway are given below
Protection against hydrolysis
1. Buffers
2. Complexation
3. Removal of water
Esters Amides
Aspirin Chloramphenicol
Procaine Ampicillin
Atropine Cephalosporin

12. Oxidation
• Addition of oxygen or removal of hydrogen from the drug molecule is known as oxidation.
• Oxidation also involves the removal of the electrons from the molecule.
• Drugs that decompose by the oxidation pathway are
1. Ascorbic acid
2. Clove oil
3. Vitamin A
4. Vitamin B12
5. Morphine, etc
• Oxidation is prevented by using anti-oxidants and chelating agents.
• Oxidation reactions are known to occur in presence of oxygen, trace metals, H+ and OH- ions.
Protective measures should aim at eliminating the influence of these factors on the drug.

13. Carboxylation
• Addition of CO2 into a drug compound is known as carboxylation.
• There is a formation of carboxylic acid group (-COOH).
• Preventive measure: Keep the drug in air tight container so that it is
not exposed to the air carbon dioxide.

14. Decarboxylation
• Elimination of CO2 from a compound is known as decarboxylation.
• Drug substances having a carboxylic acid group are sometimes
susceptible to decarboxylation.
• 4-Aminosalicylic acid is a good example.
• Preventive measures: Carbon dioxide gas is passed into the solution
for one minute.

15. 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.
• Preventive measures: The product should be protected from light
and heat. Optimum pH has to be maintained for maximum activity.

16. Polymerization
• Combination of two or more identical molecules to form a much larger and
more complex molecule is known 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.
• Preventive measure: Manufacturer should supply the product as a dry
sterile powder. The instruction should be –to dissolve the drug before use in
CO2 free sterile water for injection.