why is preformulation necessary
to identify critical material attributes (CMAs) that could impact the critical quality attributes (CQAs) of a product
example of CMA (critical material attributes)
- solid state form
- particle size distribution
- hygroscopicity (tendency to absorb water from air)
- solubility
- moisture content
- residual solvent
- process impurity
- chemical stability
- flow properties
example of CQA critical quality attribute
- assay
- content uniformity
- dissolution
- degradation products
purpose of preformulation studies
- involve primary characterisation of drug substance and/or excipients for certain fundamental physical and chemical properties
- confirm supplier’s information and ensure quality, especially of raw materials
- provide important data that may dictate many of the subsequent events
assumptions made in preformulation studies
- operate in optimum capacity
- process control managed by good healthy workers
reason for preformulation studies (API)
- to predict viability of various formulations and methods of manufacture
- to provide clues as to how to achieve the desired performance of finished product
- to confirm stability and bioavailability, reduce probability of formulation failure
cost are associated with preformulation studies but studies
- significantly minimise the risk of product failure
- increase the likelihood of producing a better quality product
use of data from preformulation studies
- detect batch to batch variations of starting materials
- enable better specifications to be drawn up for procuring materials
- an excellent database for the assessment of suppliers who can provide materials of consistent quality
- retrospective study of process or product, improve specifications for raw materials
benefits from conducting preformulation studies
- setting specifications for API, to ensure consistent successive batches of finished product
- minimising development cost, ensure optimal product development before commencing costly bioavailability and bioequivalence studies
- avoiding failures during long-term stability; by accurate predictions of chemical and physiochemical stability of API, compatibility with excipients, other actives and container
class I
high solubility and permeability
class II
low solubility and high permeability
focus on in vitro dissolution
class III
high solubility and low permeability
optimise absorption/route
class IV
low solubility and permeability
molecule modification
non-chemical characteristics that can change on aging
- particle size (in suspensions, large particles grow while small particles shrink/dissolve)
- polymorphic form
- dissolution rate (especially with polymorphic transformation)
- preservative efficacy of multidose suspension, both sterile and non-sterile
important factors to consider when developing dosage form
- manufacturability
- stability
- bioavailability
manufacturability
- scalability
- reproducibility
- cost-effectiveness
stability
- during manufacture
- shelf life- ideally 2yr or more (in ambient)
- in GIT
bioavailability
- acceptance for biological activity- therapeutic action
- convenience, for compliance
particle shape factor
- sphericity (4 pi x area/ perimeter ^2)
2. aspect ratio (length/breadth)
surface area measurement and determination methods
by either gas permeability or adsorption
methods:
1. BET- specific surface are (v small pores determined)
2. estimation by size - shape factor not taken into account (tend to underestimate)
the technology of specific surface area by gas adsorption technique
- performed by addition of small known volume of gas (adsorbate, typically N2) to a solid at cryogenic temp (liq nitro temp -298)
- at cryogenic temp, weak molecular attractive forces will cause gas molecules to be adsorbed
- direct relationship between the pressure and volume of gas, by ideal gas law, measuring pressure, can determine volume of gas adsorbed (adsorption isotherm)
- from cross-sectional area of adsorbed gas molecule, surface area and pore size distribution can be derived
Brunauer-emmett teller (BET) theory
first isotherm: assume a random distribution of sites that are empty or that are covered with by one monolayer, two and so on
apparent density
- poured (bulk); freely settled
- tapped: post-tapped
- enveloped: bulk density without inter-agglomerate voids
envelope density
involves the determination of geometric space occupied within the envelope of solid material or aggregate (like interior voids, cracks, pores)
- particle size should ideally exceed 2mm for best results
