Degradation of Pharmaceutical Products

Question 1

What is drug stability?

Answer 1

Drug stability refers to the extent to which a drug substance or product retains the same properties and
characteristics that it possessed at the time of its manufacture, within
specified limits and throughout its period of storage and use.

Question 2

Define chemical stability.

Answer 2

This is a critical quality of a pharmaceutical product that describes the ability of the formulation to resist chemical changes.

Question 3

Define physical stability.

Answer 3

This is the extent to which a pharmaceutical product resists physical change with regards to its
appearance, color, odor, size, shape, and other physical properties, overtime under specified environmental conditions.

Question 4

Define microbial stability.

Answer 4

Microbial stability refers to the ability of a product to resist microbial growth or maintain sterility, and the maintenance of the effectiveness of antimicrobial agents or preservatives within specified limits.

Question 5

Define therapeutic stability.

Answer 5

The extent to which a drug is able to keep its therapeutic properties through out its shelf life.

Question 6

Define toxicological stability.

Answer 6

The ability of a drug product to resist any increase in its toxicity during its shelf life.

Question 7

Mention 7 types of chemical degradation.

Answer 7

1. Hydrolysis
2. Oxidation
3. Dimerisation
4. Photodegradation
5. Polymerisation
6. Isomerisation
7. Dehydration
8. Chemical incompatibilities
9. Hydration
10. Decarboxylation

Question 8

What is the shelf life of a product?

Answer 8

The time it takes for 10% of the active ingredient to degrade.

Question 9

With a suitable example, explain hydrolysis.

Answer 9

Hydrolysis is the chemical reaction in which water molecules break one or two bonds in a pharmaceutical compound.
Examples:
i. Aspirin, which breaks down into salicylic acid and acetic acid.
[Note equation and mechanism of reaction]
ii. Penicillin, which forms penilloic acid in water.

Question 10

Mention 5 functional groups that are susceptible to hydrolysis.

Answer 10

1. Esters
2. Lactones
3. Amides
4. Imides

This is because they contain a leaving group with high electronegativity.

Question 11

Why is Penicillin administered by IV?

Answer 11

Penicillin breaks down faster under acidic conditions (like in the stomach).

Amoxicillin is a penicillin with a modified structure that allows it to be taken orally.

Question 12

Highlight the methods of preventing hydrolysis of pharmaceuticals.

Answer 12

1. Modification of chemical structure e.g. substituting ester bonds with amide bonds (less electronegative)
2. Proper pharmaceutical packaging. e.g. using single-use packaging like blister packs.
3. Use of desiccant in multi-use packaging e.g. silica gel
4. Storage in cool and dry conditions.

Question 13

With a suitable example, explain oxidation.

Answer 13

Oxidation reactions involve an increase in the number of carbon-to-oxygen bonds in a molecule or a reduction in the number of carbon-to-hydrogen bonds.
Example: Ascorbic acid
[Note equation of reaction]

Question 14

Mention 2 groups that are susceptible to oxidation

Answer 14

• OH groups in alcohols, such as glycerol from fats
• Nitrogen and Sulphur-containing groups.

Question 15

Mention 5 functional groups that undergo oxidation, their resulting oxidative product and a sample drug.

Answer 15

i. Phenolic hydroxy to carbonyl group in adrenaline
ii. Phenolic hydroxyl to dimeric product in morphine
iii. Amine to N-Oxide in Morphine
iv. Thioether to S-Oxide in promethazine
v. Thiol to Disulfide in Captopril

Question 16

Highlight the methods of preventing oxidation of pharmaceuticals.

Answer 16

1. Use of antioxidants e.g. Ascorbic acid, Butylated Hydroxyanisole (BHA) and Butylated Hydroxytoluene (BHT), Citric acid, Tartaric acid.
2. Using higher grades of coated plastics or glass containers that provide better oxygen barriers
3. Purging containers with an inert gas like helium or nitrogen to drive out oxygen before sealing
4. Heat-sealing to form airtight seal around mouth of containers.

Question 17

With a suitable example, explain dimerisation.

Answer 17

It is an addition reaction in which two
molecules of the same compound react with each other to give an adduct or a dimer. Amoxicillin undergoes dimerisation.

Question 18

Define the terms Dimer and Adduct.

Answer 18

A dimer is an oligomer consisting of two monomers joined by bonds that can either be strong or weak, covalent or intermolecular

An adduct is the product of direct addition of two distinct molecules
resulting in a single reaction product containing all atoms of all parts. E.g. glucose and fructose
to give sucrose
[Note equation]

Question 19

Highlight 5 methods of preventing dimerisation of pharmaceuticals.

Answer 19

1. Solvent selection
2. pH control: maintain pH away from the pKa
3. Ionic strength
4. Light exposure
5. Temperature
6. Stabilisers such as antioxidants and chelating agents
7. Supply as dry dowder

SPILTS

Question 20

With a suitable example, explain polymerisation.

Answer 20

This is the process by which two or
more identical molecules combine together to form a much larger and more complex molecule.

E.g. Ampicillin sodium
in aqueous solution.
Formaldehyde solution may result into a formation of white deposit when
kept in cold.

Question 21

Highlight the methods of preventing polymerisation of pharmaceuticals.

Answer 21

1. Supply as dry sterile powder with the instruction “to be reconstituted with CO2 free sterile water”
2. Aldehydes should be formulated in acidic pH.