18- sar part 4 pKa Flashcards
what are the percentages of of ionizable groups
- 75 % of drugs are bases
- 20 % of drugs are acids
- Only 5 % are non-ionizable
what controls water solubility
pKa of a drug
Solubility in water is pH dependant
pKa with acids
pKa of the acid
pKa with bases
value of conjugate acid of that base
when are acids neutral and charged
- Neutral when pH < pKa
- Charged when pH > pKa
when are bases neutral and charged
- Charged when pH < pKa
- Neutral when pH > pKa
what do you do when a group amphiprotic
Check both pKa values, make equations for both
what is the max and min range for water
max 15.7
min -1.7
what does it mean when the pKa is less than -1.7
If pKa is less than -1.7 group is fully deprotonated
what does it mean when the pKa is more than 15.7
If pKa is more than 15.7 group is fully protonated
what is the max water solubility
when drug is in charged form
what is the requirement for a drug to cross the membrane
when pKa within 2 or 3 units of 7.4 → make it easy for the drug to be in either charged or neutral form
- needs to be neutral when going across membrane, then becomes charged again when exits into water
what is the relation between pH, water and lipid solubility
for lipids: as pH increases (5-10) the solubility decreases
for water: as the pH increases, the solubility increases
what is drug permeability and what is it influenced by
Rate at which a drug passes through lipid membranes
Influenced by solubility, LogP, molecular weight
what are the two permeability methods and what are they
caco-2 - using human colon cancer cells (similar to intestine), difficult to do, clinic
PAMPA - artificial membrane, easier
explain the assay methods
- Place sample in Buffer 1
- Measure the rate at which it is transported into buffer 2
- you measure the time it takes from drug to go from buffer 1 to 2 and used as estimate for body now
- same thing but different layer between buffers- lipid for PAMPA, monolayer of cells for Caco-2
what system does the FDA use for benchmark values
BCS, Biopharmaceuticals Classification System
square of classes
what is class 1
high solubility and high permeability
ideal for oral dosing, receive DFA waiver for bioavailability
what is class 2
low solubility and high permeability
- Drugs tend to be lipophilic
- Special formulations can be used to solubilize
what is class 3
high solubility and low permeability
- Drugs tend to be hydrophilic
- Prodrugs used to improve permeability
what is class 4
low solubility and low permeability
- cancer drugs
- Development is expensive
- Development is risky (high failure rate)
- i.v. dosing
