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Solid > Pre-formulation studies > Flashcards

Pre-formulation studies Flashcards

1
Q

what is pre-formulation testing

A
  • 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
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2
Q

why is pre-formulation testing important (singificance)

A

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)
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3
Q

whats the purpose of conducting preformulation tests

A
  • [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
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4
Q

what are the benefits for conducting preformulation studies

A
  • 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
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5
Q

what are the physical measurements available for pre-formulation studies

A
  • Particle shape
  • surface area (BET etc)
  • density
  • solubility
  • solid-moisture interactions (DVS)
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6
Q

the various densities for characterising granulations

A

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)
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7
Q

BCS determines

A
  • solubility of active in aq media of various pH

- ability of API to cross gut wall (GI permeability)

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8
Q

classes in BCS; and which have a biowaiver (means which classes don’t need to in vivo)

A

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

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9
Q

why are stability studies important

A

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

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10
Q

bioavailability of drug is affected by?

A

disintegration and dissolution in GITransit

absorption in GIT (systemic absorption) –> bloodstream (affected by first-pass clearance)

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11
Q

what to take note whe forming a dosage form?

A

(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

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12
Q

what do pre-formulation test focus on?

A

the physical aspect of raw material; greater influence on the manufacturing process

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13
Q

2 shape factors that can determine flowability in the particle shape method

A

sphericity = (4 x pi x area)/(perimeter)^2

aspect ratio = length / breadth

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14
Q

how is surface area measured

A

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

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15
Q

how does BET works?

A

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

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16
Q

how is s.a. calculated by BET method

A

(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

17
Q

how is envelope density determined

A

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

18
Q

how is true density determined

A

using gas pycnometry; uses helium

19
Q

how is gas pycnometry used to determine particle/true density

A 
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

20
Q

which method can find the intravoids within a particle

A

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
21
Q

what tests are done for solubility?

A

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
22
Q

test done for solid-moisture interactions and how is it done?

A

Dynamic vapour sorption (DVS)

(1) measure sample and reference dry weight
(2) introduce increasing humidity
(3) record the amt of moisture absorbed

23
Q

advantages of dynamic vapor sorption (DVS)

A
  • 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)
24
Q

how to read the graph of the moisture sorption isotherm from DVS?

A

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)

25
Q

benefits of DVS for determining solid-moisture interactions? what does it allows us to understand?

A

allow us to understand:

  • handling and flowability
  • processing conditions and performance (e.g. issues of sticking)
  • stability of excipient, drug, and pdt
26
Q

summary: why proper pre-formulation work is important?

A
  • help to improve and facilitate formulation work –> reduces wastage, reworking, and prevent products to fail the specifications
27
Q

summary: why physical characterisation of particulate are important?

A

impt for pre-formulation assessment and some may become the CQA of a product

28
Q

what are some examples of CQAs

A
  • assay
  • content uniformity
  • dissolution
  • degradation
29
Q

what are some examples of CMAs

A
  • solid-state form
  • particle size distribution
  • hygroscopicity
  • solubility
  • moisture content
  • residual solvent
  • impurity
  • chemical stability
  • flow properties
  • porosity
  • specific volume
30
Q

summary: why knowing physicochemical properties is useful

A
  • develop better products benefiting both the consumer and manufacturer
31
Q

summary: particles

A

are a key to good products

Solid (16 decks)

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