Pre-Formulation Studies

Question 1

What is the purpose of Pre-Formulation Studies

Answer 1

1) Pri characterisation of drug substances &/or excipients for phy & chemical properties
2) Confirm supplier’s information & ensure quality (esp of raw materials)
3) To understand the phy, chemical & pharmaceutical properties of candidate molecules & provide ideas for modification for better performance (ie. stability, solubility)
4) Provide impt data that may dictate subsequent events
5) Identify critical material attributes (CMAs) that could impact critical quality attributes (CQAs)

Question 2

Significance of Pre-Formulation Studies

Answer 2

On API…

• To predict viability of various formulations & methods of manufacture
• To provide clues as to how to achieve the desired performance
• To confirm stability & bioavailability
• Significantly minimise risk of product failure
• Increase likelihood of better quality product (which can then be sold at a higher price)

Question 3

Use of data from Pre-Formulation Studies

Answer 3

1) Detect batch-to-batch variations
2) Enable better specifications to be drawn up for procuring materials
3) Provide database for assessment of suppliers who can provide materials of consistent quality
4) Retrospective study of process/product

Question 4

Benefits of conducting Pre-Formulation Studies

Answer 4

1) Setting specifications for API
- > Ensure consistent successive batches of the finished product
2) Minimise development costs
- > Ensure optimal product before commencing costly bioavailability & bioequivalence studies
3) Avoid failures during long-term stability
4) Minimise the need for in vivo bioavailability/bioequivalence studies

Question 5

What does the Biopharmaceutics Classification System (BCS) consist of:

Answer 5

• Solubility of active itself in aqueous media of various pH
• Gastrointestinal permeability

Class I: Optimal
Class II (High P): Focus on in vitro dissolution
Class III (High S): Optimize absorption/rate
Class IV: Molecule modification

Question 6

Tests involved in Stability studies

Answer 6

• Chemical
• Physicochemical
• Microbiological (sometimes)

Question 7

Non-chemical characteristics that can change on aging:

Answer 7

• Particle size
• Polymorphic form
• Dissolution rate
• Preservative efficacy of multidose suspensions

Question 8

Important considerations when developing a dosage form

Answer 8

1) Manufacturability
- Scalable, reproducible, cost-effectiveness

2) Stability
- During manufacture, shelf-life (2yrs), in GIT

3) Bioavailability

Question 9

Does the phy/chemical properties of raw materials have a greater influence on the manufacturing process?

Answer 9

Physical aspects

Question 10

What does Pre-Formulation Studies test for?

Answer 10

1) Particle shape
2) Surface area
3) Particle/bulk density
4) Envelope density
5) True density
6) Solubility
7) Solid-moisture interactions
8) Stability

Question 11

Method to determine particle shape

Answer 11

Image analysis

Question 12

Methods to measure surface area (Not routinely used, only when necessary)

Answer 12

1) BET (Gas adsorption technique)
- Add adsorbate (ie. N2) to solid @ cryogenic temp
- > Weak molecular attractive forces will cause gas molecules to be adsorbed
- > Specific surface can be determined from amount of adsorbate required for monolayer adsorption
- > S = (6.022x10^23/mol) (16.2A [for N2]) (mol of molecule needed to make monolayer)

Question 13

How to calculate particle density

Answer 13

Weight/True volume

Question 14

Methods to measure Envelope Density

Answer 14

Envelope/Geometric density:
Involves determination of the geometric space occupied within envelope of a solid material/aggregate

Envelope density = W1/V1
(W1 = Weight of sample,
V1 = Displacement vol)

Question 15

Methods to measure True Density

Answer 15

Gas pycnometry

• By ideal gas law, solids vol of sample can be determined by measuring change in pressure

Question 16

What is mercury intrusion porosimetry used for?

Answer 16

To quantify a material’s porous microstructures
- Involves intrusion of non-wetting mercury at high pressure, forcing mercury into porous structures

• Pore size determined based on external pressure needed to force mercury into a pore against the opposing force of the liquid’s surface tension

Question 17

Why is testing for Solubility important?

Answer 17

Affects bioavailability of drug -> Rate of drug release -> Therapeutic efficacy

Question 18

How is Solubility determined?

Answer 18

From saturated solutions

Question 19

Why is testing for Solid-moisture Interactions important?

Answer 19

• Moisture affects handling & flowability
• Moisture affects processing conditions & performance
• Stability of excipients, drugs & pdcts

Question 20

How is Solid-moisture Interactions determined?

Answer 20

Dynamic vapor sorption (DVS)

- Weight imbalance reflects moisture absorbed by substance

Question 21

Advantage of Dynamic vapor sorption (DVS)

Answer 21

• Minimal sample required (10mg)
• Rapid analysis due to fast equilibration
• Higher accuracy & precision