Pre-Formulation Studies Flashcards
What is the purpose of Pre-Formulation Studies
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)
Significance of Pre-Formulation Studies
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)
Use of data from Pre-Formulation Studies
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
Benefits of conducting Pre-Formulation Studies
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
What does the Biopharmaceutics Classification System (BCS) consist of:
- 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
Tests involved in Stability studies
- Chemical
- Physicochemical
- Microbiological (sometimes)
Non-chemical characteristics that can change on aging:
- Particle size
- Polymorphic form
- Dissolution rate
- Preservative efficacy of multidose suspensions
Important considerations when developing a dosage form
1) Manufacturability
- Scalable, reproducible, cost-effectiveness
2) Stability
- During manufacture, shelf-life (2yrs), in GIT
3) Bioavailability
Does the phy/chemical properties of raw materials have a greater influence on the manufacturing process?
Physical aspects
What does Pre-Formulation Studies test for?
1) Particle shape
2) Surface area
3) Particle/bulk density
4) Envelope density
5) True density
6) Solubility
7) Solid-moisture interactions
8) Stability
Method to determine particle shape
Image analysis
Methods to measure surface area (Not routinely used, only when necessary)
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)
How to calculate particle density
Weight/True volume
Methods to measure Envelope Density
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)
Methods to measure True Density
Gas pycnometry
- By ideal gas law, solids vol of sample can be determined by measuring change in pressure
