pre-formulation

Question 1

Key factors affecting product quality

Answer 1

1) Suitability of formulation
- Including appropriate specifications for finished product, ingredients & container
2) Validated & controlled manufacturing procedure
3) Stability under storage conditions & throughout product life
4) Good & consistent bioavailability

Question 2

When are pre-formulation studies carried out

Answer 2

1) Drug discovery
- Understand physical, chemical, analytical & pharmaceutical properties of the candidate molecule
- Provide ideas for modification of candidate molecule to improve performance

2) Manufacturing
- Ensure final product meets release specifications & is of consistent quality

Question 3

Purpose of pre-formulation studies

Answer 3

Pre-formulation studies carried out on APIs to:

1) Predict viability of various formulations and methods of manufacture
2) Provide clues as to how to achieve desired performance of finished product
3) Ensure stability & bioavailability throughout storage/shelf-life

Overall:

1) Primary characterization of drug substances and/or excipients for certain fundamental physical & chemical properties
2) Confirm suppliers’ information & ensure quality, especially of API

Question 4

Data from pre-formulation studies can be used to:

Answer 4

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

Question 5

Final product

Answer 5

1) Meet product specifications
2) Meet intended delivery of drug as designed –> reach site of action at intended concentrations
3) Consistency
- Within batch, batch to batch, different manufacturing sites
4) Physically & chemically stable throughout shelf-life
5) Acceptable to consumer in terms of convenience & palatability

Question 6

Benefits of pre-formulation studies

Answer 6

1) Can set API specifications
2) Minimize developmental costs
3) Avoid failure during long-term stability
- By accurate prediction of chemical & physical stability of API and compatibility of materials
4) Biowaiver

Question 7

Considerations when developing dosage form

Answer 7

1) Manufacturability
- Scalability
- Reproducibility
- Cost-effectiveness

2) Stability - Must remain stable throughout:
- Manufacture
- Shelf-life
- In GIT

3) Bioavailability
- Must be able to dissolve & disintegrate to be absorbed in GIT
- Must be able to reach site of action to elicit therapeutic effect
- Convenience –> compliance

Question 8

Stability test

Answer 8

Test:

1) Chemical / Physiochemical characteristics (e.g. hydrolysis)
2) Non-chemical characteristics
- Particle size
- Polymorphic form
- Dissolution
- Preservative efficacy of multidose formulations (especially liquids)

Question 9

Bioavailability / Bioequivalence studies - Test for

Answer 9

1) Solubility of active in aqueous media of acid pH

2) GI permeability

Question 10

Biopharmaceutics Classification System (BCS)

Answer 10

Class I

• High solubility & permeability
• Ideal

Class II

• Low solubility, high permeability
• Focus on in vitro dissolution

Class III

• High solubility, low permeability
• Optimize absorption/route

Class IV

• Low solubility & permeability
• Molecule modification

Question 11

Test methods for particle shape

Answer 11

Image analysis

Question 12

Image analysis

Answer 12

Obtain pixelated image of particle 
Calculate area (no. of pixels x area of 1 pixel) & perimeter from pixelated image of particle 

Sphericity = (4π Area) / Perimeter^2
- Sphericity = 1 --> perfect circle 
Elongation factor / Aspect ratio = Length / Breadth 
- Aspect ratio = 1 --> sphere/cube
- Aspect ratio = 2-3 --> needle shape

Limitation
- Particle will be oriented such that centre of gravity is lowest –> may overestimate particle size

Question 13

Surface area

Answer 13

Affects:

1) Interactions / Forces between particles
2) Area available for reaction e.g. dissolution, degradation

Amorphous solids have greater surface area VS crystalline solids

Question 14

Test methods for surface area

Answer 14

1) Gas permeability

2) Gas adsorption (BET)

Question 15

Gas permeability

• How it works
• Limitations
• Applications

Answer 15

How it works:
Pass gas through body of powder
Larger surface area –> gas passes through more slowly

Limitations:

1) Not very precise
2) Shape factor not taken into account
3) Tends to underestimate

Applications:
1) Not commonly used today

Question 16

Gas adsorption (BET)

• How it works
• Calculating specific surface area
• Limitations

Answer 16

How it works:

1) Cool to cryogenic temperature
2) Addition of small volume of known gas (adsorbate)
- Usually nitrogen
3) At cryogenic temperatures, weak molecular attractive forces will cause gas molecules to be adsorbed
4) Based on BET, as adsorbate is introduced, if pressure remains constant, indicates that gas is being adsorbed
- When pressure starts to increase –> monolayer completely formed

Calculating specific surface area:

1) Cross-sectional area (σ) of 1 adsorbate molecule known
- Nitrogen: σ = 16.2 Å^2
2) Determine monolayer capacity (i.e. No. of moles of gas molecules required to form monolayer on surface of 1g of adsorbent
3) Determine no. of adsorbate molecules needed to form monolayer
- No. of adsorbate molecules = Avogadro’s constant x Monolayer capacity
4) Calculate specific surface area
- Specific surface area = No. of adsorbate molecules x Cross-sectional area of 1 adsorbate molecule

Limitations:

1) Very small pores determined
2) Only used for rough estimation, not for precise values (surface area may be exaggerated)

Question 17

Particle density

Answer 17

Also known as: True / Real / Absolute / Skeletal density

Particle density = Weight / True volume
- True volume = Volume occupied by solid, without void space

Question 18

Apparent density

Answer 18

Poured/Bulk density: Density obtained when poured into container/cylinder

Tapped density: Density obtained after tapping until no change in volume

Envelope/Geometric density: Bulk density without inter-agglomerate space

Question 19

Test method for envelope density

Answer 19

Dry powder displacement

Question 20

Dry powder displacement

Answer 20

Ideal particle size: > 2mm (more accurate)

How it works:

1) Test sample of known weight (W1)
2) Place test sample in bed of free-flowing filler of known volume (V0)
- Free-flowing filler: Quasi-fluid composed of small, rigid spheres
3) Filler is agitated (tapping) to completely embed sample
4) Measure volume after tapping (V1)
5) Envelope density = W1/V1

Question 21

Test method for particle density

Answer 21

Gas pycnometry

Question 22

Gas pycnometry

Answer 22

How it works:

1) Sample of known weight added to sample cell
2) Sample & reference chamber pressurized to certain pressure
3) Known volume of helium added & monitor pressure
4) Sample volume can be determined from equation P1V1 = P2V2

Question 23

Test method for porosity / Micrometrics

Answer 23

Mercury intrusion porosimetry

Question 24

Mercury intrusion porosimetry

Answer 24

How it works:

1) Intrusion of non-wetting mercury at high pressure –> forces mercury into porous structure of material
2) Mercury entering interparticle voids indicated by decrease in volume
3) Pore size determined based on external pressure needed to force mercury into a pore against opposing force of the liquid’s surface tension

Question 25

Test for solid-moisture interactions

Answer 25

Dynamic vapor sorption (DVS)

Question 26

Dynamic vapor sorption (DVS)

• How it works
• Advantages

Answer 26

How it works:

1) Expose sample to varying humidity, at constant temperature
2) Water activity (rate of adsorption/desorption) can be determined

Advantages:

1) Minimal sample size needed (10 mg)
2) Rapid analysis due to faster equilibration
3) Higher accuracy & precision