pre-formulation Flashcards
Key factors affecting product quality
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
When are pre-formulation studies carried out
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
Purpose of pre-formulation studies
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
Data from pre-formulation studies can be used to:
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
Final product
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
Benefits of pre-formulation studies
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
Considerations when developing dosage form
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
Stability test
Test:
1) Chemical / Physiochemical characteristics (e.g. hydrolysis)
2) Non-chemical characteristics
- Particle size
- Polymorphic form
- Dissolution
- Preservative efficacy of multidose formulations (especially liquids)
Bioavailability / Bioequivalence studies - Test for
1) Solubility of active in aqueous media of acid pH
2) GI permeability
Biopharmaceutics Classification System (BCS)
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
Test methods for particle shape
Image analysis
Image analysis
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
Surface area
Affects:
1) Interactions / Forces between particles
2) Area available for reaction e.g. dissolution, degradation
Amorphous solids have greater surface area VS crystalline solids
Test methods for surface area
1) Gas permeability
2) Gas adsorption (BET)
Gas permeability
- How it works
- Limitations
- Applications
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
Gas adsorption (BET)
- How it works
- Calculating specific surface area
- Limitations
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)
Particle density
Also known as: True / Real / Absolute / Skeletal density
Particle density = Weight / True volume
- True volume = Volume occupied by solid, without void space
Apparent density
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
Test method for envelope density
Dry powder displacement
Dry powder displacement
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
Test method for particle density
Gas pycnometry
Gas pycnometry
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
Test method for porosity / Micrometrics
Mercury intrusion porosimetry
Mercury intrusion porosimetry
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
Test for solid-moisture interactions
Dynamic vapor sorption (DVS)
Dynamic vapor sorption (DVS)
- How it works
- Advantages
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
