Lecture 3: product quality and stabilty

Question 1

What does product quality comprise of and what is the significance of it?

Answer 1

content unformity, purity, appearance, efficiency, mechanical properties, packing, stability, taste

meeting these standards is necessary to achieve desired therapeutic effect and minimise risk

Question 2

What is product stability and what is its significance?

Answer 2

The extent to which the pharmaceutical product retains its chemical, physical, therapetic & microbiological properties within specified limits, thoughout the period of storage and use.

need to ensure that a drug remains effective and safe over its intended shelf life

Question 3

What are the pillars of pharamceutical quality & why are they important

Answer 3

1. Patient safety: Ensures accurate dosing, correct form, and no contaminants to avoid adverse effects or complications.
2. Therapeutic efficacy: Ensures correct potency, purity, and release for expected treatment outcomes.
3. Patient compliance: Poor quality meds with side effects erode trust, leading to non-compliance.

Question 4

What is quality assurance?

Answer 4

A system of proceudres, checks, audits and corrective actions used to ensure the consistent and reliable production of high quality pharmaceutical products.
It encompasses the entire product lifecycle.

Question 5

What is quality control?

Answer 5

The process by which entities review the quality of all factors involved in production. It’s concerned with testing & inspection to identify & rectify defects in the product.

Question 6

What is the difference between QA and QC?

Answer 6

1. QA focuses on improving & optimizing the production process to prevent defects
2. QC involves testing & insepction of products to identify & rectify defects.

Question 7

What are the key QC tests to assess phamaceutical quality?

Answer 7

1. Physical tests : appearance test, friability test, disintegration test
2. Chemical tests: chromatography, mulpliple quadrupole mass spectrometers.
3. Microbiological tests (more for creams): Microbial limit tests (non sterile) and USP71 sterility testing (for sterile products)

Question 8

WHat are the 5 elements of good manufacturing practices (GMPs)?

Answer 8

1. Personnel: should have comprehensive roles & responsibilities
2. Products: well defined goals for each production phase
3. Process: documentation should be simple & consistent
4. Procedures: should have guidelines on critical processes
5. Premises should be maintained well.

Question 9

What is stability?

Answer 9

A drug’s capacity to maintain its physical, chemical, microbiological & biopharmaceutical prodperties throughtout its shelf life.

Question 10

What are factors affecting stability?

Answer 10

1. External: temp sensitivity, sunlight, moisture, oxygen, microbiome
2. Internal: chemcial structure, crystal structure, pH, internal microbiome growth

Question 11

How would you package drugs sensitive to sunlight?

Answer 11

Put in opaque containers

Question 12

How would you package drugs that are sensitive to external microbiome contamination?

Answer 12

Single use packaging, consumed immediately after opening
Add preservatives?

Question 13

What is the shelf life of a drug?

Answer 13

It is the time frame during which a drug remains effective and safe

Question 14

What could happen to the durg product once it is expired?

Answer 14

1. Drug loses its efficacy and is no longer potent enough
2. Microbiome growth inside the formulation
3. Chemical breakdown of APIs, producing unwanted products
4. Physical changes to tablets : change colour, cracked etc
5. Packaging can degrade, exposing the medication to the outside environment

Question 15

What is the primary pack?

Answer 15

The primary pack contains the drug product and is in direct contact with it.

Question 16

What is the secondary pack?

Answer 16

It contains the primary pack, as well as ancillary components such as spoons and leaflets

Question 17

What is the tertiary pack?

Answer 17

Contains multiple secondary packs, facilitates handing & transpaort & prevents damage associated with handling, transport and storage

Question 18

What are the pros and cons of multiple unit packs?

Answer 18

1. Pros: cost effective, convenient to take, less environmental impact.
2. Cons: drugs exposed to humidity/air/light when you open it –> degrade, risk of contamination, dosing variability because you have to measure yourself, harder to transport, shorter shelf life.

Question 19

What are the processes of degradation of drugs?

Answer 19

1. Hydrolysis
2. Oxidation
3. Dimerisation and polymerisation
4. Photodegradation
5. Chemical incompatibilities - API may recat with another drug/excipeint

Question 20

What is the most common cause of chemical degradation?

Answer 20

Hydrolysis

Question 21

What is the functional group that is affected by hydrolysis, and what happens to the functional group?

Answer 21

Derivatives of carboxylic acids such as esters and amides
1. Esters hydrolyse to form carboxylic acid + alcohol
2. Amides degrade to carboxylic acid and amine

Question 22

Which is more stable to hydrolysis? Amide or ester?

Answer 22

Amides are more stable than esters because nitrogen in the amide is less electronegative than oxygen which makes it more stable to hydrolysis.

Question 23

Would you recomment an aqueous formulation for aspirin?
(it has an ester group)

Answer 23

No because aspirin is sensitive to hydrolysis due to its ester group, so a liquid formulation would be very unstable.

Question 24

Why chloramphenicol eye drops must be stored in a
refrigerator?
(it has an amide group and Cl atoms adjacent)

Answer 24

The Cl subtsituent in chloramphenicol polarise the amide bond, which makes it very suceptible to hydrolysis
By putting the drops in the fridge, we can slow down the hydrolysis process throughout its shelf life.

Question 25

WHy is benzylpenicillin not available for oral delivery?

Answer 25

It has a beta lactam group which is a cyclic amide, making it suceptible to hydrolysis.
It is especially suceptible in acidic conditions, so in the stomach it will degrade before it can get absorbed into the blood.
It is prepared as a powder by lyophilization, and is dissolved in USP grade water before being injected.

Question 26

How suceptible are dosage forms to hydrolysis?

Answer 26

1. Parenteral & oral solutions: unavoidable, can add stability agents
2. Suspensions: better than previous because the API is protected within the insoluble particles
3. Solid dosage forms: more stable, but not immune because some excipents liek MCC absorb water so the tablet may be hygroscopic (packaging is impt)

Question 27

How will you formulate APIs to overcome hydrolysis?

Answer 27

1. Parenteral: freeze drying of APIs, then add water right before injecting (reconsititution)
2. Suspensions: store as dry powder so they have a long shelf life, then mix in water before consuming (antibiotics)
3. Solid dosage: select non hygroscopic excipients, dry granulation, particle engineering for hygroscopic APIs (coating, surface modification, nanocoating etc)

Question 28

What is dynamic vapor sorption (DVS) used for?

Answer 28

To quantitatively measure hygroscopicity in the lab. Its commonly used in preformulation to monitor the change in water content in drug molecules

Question 29

What is the process by which vitamin C gets degraded?

Answer 29

Ascorbic acid (Vit C) undergoes rapid OXIDATION in solution to form dehydroascorbic acid –> reversible
Dehydroascorbic acid is rapidly HYDROLYSED as the ester linkage to form diketogulonic acid –> irreversible

Question 30

What are the ways inwhich amoxicilin gets degraded?

Answer 30

1. It get get oxidised at the beta lactam ring
2. It can get dimerised by nucleophilic attack on the beta lactam ring by the amino group –> trimer and tetramer can be produced too.

Question 31

Why is glutaradehyde formulated at an acidic pH?
Why is an alkaline buffer added before use?

Answer 31

1. Formulated at an acidic pH to prevent keto enol tautomerism which leads to polymerisation
2. Add alkaline buffer to increas ethe pH to make it a better disinfectant

Question 32

What are the most damaging wavelengths for APIs (photodegradation)?

Answer 32

300nm - 400nm

Question 33

How would you package a product to minimise photodegradation?

Answer 33

Put in opaque or dark bottle to prevent light from entering it.

Question 34

What are the attributes of a drug product that we need to check to ensure physical stability?

Answer 34

1. Appearance
2. Polymorphicform
3. Precipitation
4. Water content

Question 35

Why is appearance of a drug product important?

Answer 35

Changes in tablet and blister pack appearance may be an early sign of chemcial degradation and warrants further investigation.

Question 36

Why is polymorphism an important factor to consider during drug development?

Answer 36

1. The API may change polymorphic forms during the manufacturing and storage
2. Different polymorphic forms have different dissolution rate, stability, bioavailability etc

Question 37

Why is precipitation an important factor to consider during drug development?

Answer 37

1. The API may precipitate if the drug is formulated near saturation point, or it gets saturated due to evaporation
2. Presence of particles is dangerous for parental products - vein irritation, phlebitis, clinically occult pulmonary granulomas, local tissue infarction, severe pulmonary dysfunction, occlusion of capillaries and arteries, anaphylaxis and death.

Question 38

Why is water content an important factor to consider during drug development?

Answer 38

1. Water may facilitate hydrolysis & microbial proliferation
2. Water may affect the mechanical properties of tablets, like tensile strength
3. Gelatin capsules contain water, which can get absorbed by the API

Question 39

Why are efferversant drugs usually not formulated as gelatin
capsules?

Answer 39

1. The capsule shells are bought from commercial sellers so they almost always have water
2. You can prevent water in the capsule, but they will absorb water from the gelatin.