Pre-formulation studies Flashcards
what is pre-formulation testing
- in drug discovery
- to understand physical, chemical, analytical, and pharmaceutical properties of molecule
- possible ideas for modification of molecule for better performance
- studies on the quality of raw materials (APIs and excipients); ensuring quality, meet specifications
- identify critical material attributes (CMAs) that could impact CQA of a product
why is pre-formulation testing important (singificance)
studies on API
- whether formulations or manufacturing methods can make a viable product
- provide clues on how to achieve desired finished pdt
- confirm stability and bioavailability (minimise risk of formulation/pdt failure)
- more likely to form a better quality product (even though high cost to do such studies)
whats the purpose of conducting preformulation tests
- [primary characterisation] of API/ excipients for physical and chemical properties
- ensure quality of raw materials, confirm the suppliers info (reliable)
- provide impt data that may be impt for subsequent events
what are the benefits for conducting preformulation studies
- set specifications for API (ensuring consistency of batches)
- ensure optimal pdt formed before costly bioavailable and bioequivalence studies are done
- prevent failure during long-term stability (whether ingredients are compatible, stability of API)
- minimise need for in vivo bioavailable/bioequivalence studies
- -> BCS done in vitro
what are the physical measurements available for pre-formulation studies
- Particle shape
- surface area (BET etc)
- density
- solubility
- solid-moisture interactions (DVS)
the various densities for characterising granulations
true (particle, real, absolute, skeletal) density; weight/ true volume
where true volume = vol occupied w/o voids
apparent density;
- bulk
- tapped
- envelope (bulk w/o inter-agglomerate void; means it measure the voids present between particles as well)
BCS determines
- solubility of active in aq media of various pH
- ability of API to cross gut wall (GI permeability)
classes in BCS; and which have a biowaiver (means which classes don’t need to in vivo)
solubility, permeability
I: high, high
II: low, high (focus on in vitro dissolution)
III: high, low (optimise absorption/route)
IV: low, low (maybe molecule modification
class I and III are BCS-based biowaiver
why are stability studies important
monitors ageing non-chemical characteristics:
(1) particle size (large particles will grow, small particles shrink/dissolve in suspension)
(2) polymorphic form (solubility changes when amorphous becomes crystalline)
(3) dissolution rate (esp w polymorphic transformation)
(4) preservative efficacy, sterility; incompatibility
bioavailability of drug is affected by?
disintegration and dissolution in GITransit
absorption in GIT (systemic absorption) –> bloodstream (affected by first-pass clearance)
what to take note whe forming a dosage form?
(1) manufacturability
- scalable
- reproducible
- cost-effective
(2) stability
- during manufacture
- shelf-life (ideal 2 yrs)
- in GIT
(3) bioavailability
- for therapeutic action
- convenience and compliance
what do pre-formulation test focus on?
the physical aspect of raw material; greater influence on the manufacturing process
2 shape factors that can determine flowability in the particle shape method
sphericity = (4 x pi x area)/(perimeter)^2
aspect ratio = length / breadth
how is surface area measured
using gas permeability or adsorption
e.g. BET - determines specific surface area
e. g. estimation from size
disadv: shape factor not taken into account, usually underestimation
how does BET works?
added N2 to a solid at cryogenic temperatures
gas will be adsorbed via weak molecular attractive forces
by measuring pressure, we can find volume of gas adsorbed
p x V = constant –> therefore, p is inversely proportional to V
we know cross-sectional area of each adsorbed gas molecule –> allow us to find s.a. and pore size distribution
how is s.a. calculated by BET method
(1) plot P(n x [P0 -P]) against P/P0
(2) gradient is 1/nm where nm is the monolayer capacity
(3) use nm calculated and input into S = NA X nm x sigma
where NA is avogadro’s number
sigma is the cross-sectional are of one adsorbed gas
specific s.a. usually ranges 0.01 to over 2000 m^2/g
how is envelope density determined
also known as geometric density; ensures intervoids are filled with particles
dry powder displacement
particle size should be >2mm
dry powder = free-flow filler
then have to tap the cylinder to ensure compaction before measuring
envelope density = W1/V1
where W1 is the sample weight of granules used
V1 = vol of envelope = displaced volume
how is true density determined
using gas pycnometry; uses helium
how is gas pycnometry used to determine particle/true density
Vs = Vc + Vr/(1 - P1/P2) Vs = sample volume Vc = vol of empty sample chamber Vr = vol of reference volume P1 = first pressure in sample chamber P2: second lower pressure when gas expand to sample and reference chamber
ideal gas law: vol of sample can be found from the measured change in pressure
p x V = constant (using boyle’s law)–> therefore, p is inversely proportional to V
which method can find the intravoids within a particle
micromeritics: mercury intrusion porosimetry
pore size and volume determined
external pressure needed to force mercury into a pore against the opposing force of mercury’s surface tension
(using capillary law) dp = (-4 x sigma)/p x cos(tetha) dp = pore diameter at pressure, p sigma = surface tension of mercury tetha = contact angle bet mercury and sample
what tests are done for solubility?
form saturated solutions
test for:
- supersaturation: crystal form
- impurities
- equilibrium point: how long does it take to establish eq (poor water soluble drugs take longer time to achieve eq)
- temperature has to be controlled
test done for solid-moisture interactions and how is it done?
Dynamic vapour sorption (DVS)
(1) measure sample and reference dry weight
(2) introduce increasing humidity
(3) record the amt of moisture absorbed
advantages of dynamic vapor sorption (DVS)
- minimal sample size required (10mg)
- rapid analysis due to faster equilibration (compared to dessicators)
- higher accuracy and precision (due to enclosed env and sensitive microbalance)
how to read the graph of the moisture sorption isotherm from DVS?
first part of graph: monolayer
last part of graph: deliquescence seen
deliquescence: substance absorbs moisture from atmosphere until dissolve in absorbed water to form solution
hysteresis loop seen: as water that went into spaces are hard to release upon desorption (entrapped)
benefits of DVS for determining solid-moisture interactions? what does it allows us to understand?
allow us to understand:
- handling and flowability
- processing conditions and performance (e.g. issues of sticking)
- stability of excipient, drug, and pdt
summary: why proper pre-formulation work is important?
- help to improve and facilitate formulation work –> reduces wastage, reworking, and prevent products to fail the specifications
summary: why physical characterisation of particulate are important?
impt for pre-formulation assessment and some may become the CQA of a product
what are some examples of CQAs
- assay
- content uniformity
- dissolution
- degradation
what are some examples of CMAs
- solid-state form
- particle size distribution
- hygroscopicity
- solubility
- moisture content
- residual solvent
- impurity
- chemical stability
- flow properties
- porosity
- specific volume
summary: why knowing physicochemical properties is useful
- develop better products benefiting both the consumer and manufacturer
summary: particles
are a key to good products
