Preformulation studies Flashcards
When is preformulation studies needed?
- lead optimisation
- pre-clinical studies
- volunteer studies
- phase II clinical studies
- phase III clinical studies
- scaling up for launch
(i.e. drug development phase)
role of preformulation studies in formulation:
understand the physical, chemical, analytical and pharmaceutical properties of the candidate molecule and provide ideas for modification, its physical state for better performance
- study qualities of raw materials of a formulation, APIs and excipients
- ensure final product quality, meet release specifications and be of consistent quality
Purpose of preformulation studies
- primary characterisation of drug substances and/or excipients for certain fundamental physical and chemical properties
- confirm suppliers’ information and ensure quality, especially of raw materials
- provide important data that may dictate many of subsequent events
Significance of preformulation studies on API:
- to predict vaibility of various formulations and methods of manufacture
- to provide clues as to how to achieve desired performance of the finished product
- confirm stability and bioavailability, reduce probability of formulation failure
- studies minimise risks of product failure and increase likelihood of producing better quality product
Uses of data from preformulation studies:
- detect batch to batch variations of starting materials
- enable better specifications to be drawn for procurement of materials (reduce cost or increase product quality)
- database for assessment of suppliers who can provide materials of consistent quality
- allow for retrospective study of process/product – improve specifications for raw materials
Key factors influencing product quality
- suitability of formulation
- validated and controlled manufacturing procedure
- stability under considerations of storage and duration of claimed shelf life
- good and consistent bioavilability
- Check if lining of container reacts with surface of the product – cost may be much higher for some plastics
- ensure that impurity levels are controlled
Expectations from preformulation studies:
meet intended delivery of drug as designed – reach site of action with intended concentration
meet product specifications
Unit to unit consistency
Chemically and physically stable throughout shelf life
manufactured at acceptable cost
acceptable to patient in terms of convenience and palatability
benefits of conducting preformulation studies:
setting specifications for API – ensure consistent successive batches of finished product
minimise development costs, ensure optimal product developed before costly bioequivalent and bioavailability studies
avoid failures during long-term stability tests
minimise need for invivo bioavailability/booequivalence studies
nonchemical characteristics that change on aging:
particle size
polymorphic form
dissolution rate
efficacy of multidose suspensions – both sterile and non sterile
manufacturability considerations when developing dosage forms :
scalability
reproducibility
cost-effectiveness
Stability considerations when developing dosage forms :
during manufacture
shelf life
within GI tract
Bioavailability considerations when developing dosage forms:
Acceptable for biological activity – think about therapeutic action
convenience – compliance
Types of preformulation tests:
Testing of particle shape Testing of surface area Testing of particle/bulk densities Testing of true density by gas pycnometry/mercury intrusion porosimetry Solubility testing Testing of solid-moisture interactions
Problems with testing of particle shape:
particle tends to lie on an area where you will always get the lowest center of gravity
how does the gas adsorption method work to determine surface area
addition of small known volumes of inert gas at cryogenic temperatures and weak molecular attractive forces will cause gas molecules to be adsorbed
- measures direct relationship between pressure and volume of gas by ideal gas law – measurement of pressure can determine volume of gas adsorbed
cross sectional area of adsorbed gas molecule helps derive surface area and pore size distribution
