Druglikeness Flashcards
Factors Included in Lipski’s rule of 5
Hydrogen Donor Bonds, Hydrogen Bonds acceptor, molecular weight and Log P
What Lipki’s Rule of 5 Outlines
Predicts permeability of substance across semi-permeable membrane. A minimum of 2 of these must be met to be orally absorbed. Number may shift depending on admin route and target area
Lipinski’s Rule In Relation to H bond donors
< 5
Lipinski’s Rule In Relation to H bond Acceptors
< 10
Lipinski’s Rule In Relation to Molecular Weight
< 500 Daltons
Lipinski’s Rule In Relation To Log P
< 5
Example of H bond donors
Water and amide
Example of H bond acceptor
Ketone
Limitation of LipKini’s Rule
Doesn’t account for dissolution, doesn’t account for drugs with transporters/ pumps and doesn’t evaluate hydrophilicity
Biopharmacuetics Classification Systems (BCS)
Measures solubility (hydrophilicity, liberation) and permeability (lipophilicity, absorption). Form of bioequivalence testing (avoids clinical test replication via biowaver, cheaper) and helps in manufacturing process
Number of BSC classes
4
BCS Class 1
High Aqueous Solubility (fast dosage form liberation) and high permeability (fast absorption). Biowaver granted, low risk
BCS Class 2
Low aqueos solubility (slow liberation, rate limiting) and high permiability (fast absorption). No biowaver (risk), most drugs
BCS Class 3
High aqueous solubility (fast liberation) and low permiability (slow absorption, rate limiting). Typically not granted biowavers
BCS Class 4
low aqueos solubility (slow liberation) and low permiability (slow absorption)
BCS High Solubility Def
Highest dose of substance will dissolve <250 ml of water. pH range 1-7.5 at temp 37 degrees Celcius
How is high solubility usually referenced calculated
mg amount of solute dissolved per ml of solvent
BCS High Permeability Def
Minimum of 90% of substance absorbed in humans. Tested either in animals or in vitro
Bioavailability testing in people
Volunteers recieve 1 dose of drug via IV. Plasma drug levels recorded over set time. This is used as reference (straight into circulation = no absorption barriers). Once drug is eliminated from system volunteer recieves oral dose and plasma drug levels monitored over same time. Bioavalaibility = (amount of drug absorbed orally)/(amount of drug absorbed IV)
Bioavailability Testing In Vitro Outline
Celll cultures predict permeability in humans by fraction they absorb
Permeability Coefficient relationship to rate of flux
Proportional. High coefficient = high flux
Relationship between permeability coefficient and concentration on membrane structure
High permeability coefficent = low conc on membrane surface
Apparent permeability Coefficent
Numerical estimate of whether drug’s permeability is high/low. >1x10^-5 cm/s is prediction of high permeability
permeability coefficient is proportional to
Transport rate and initial donor concentration
Permeability coefficient is inveresely proportional to
Surface area exposed
What can substitute for apparent permeability coefficent
LogP. 2< LogP < 5 indicates good permeability, regardless of H bond number, pKa and molecular weight
BCS Classes in relation to dissolution
To be BCS Class 1, 85% of dosage form must dissolve in 30 mins in 90ml of solvent at pHs 1.2, 4.5 and 6.8, using USPC appaaratus at 37 degrees
BCS Functions
Bioequivalence testing between generic and innovator drugs (if same bioavailability granted biowaver, cost and time saving), manufacturing guidance
DCS in realtion to BCS
DCS is stricter. Used in the development of oral products as a guideline
Ideal BCS Class
class 1
How can Class 4 improve both solubility and permeability
Change to structure (eg saltings, crystallisation, solution forming)
BDDCS Outline
Substitutes permiability for metabolism. Better understands drug distribution and deposition
