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The interrelationships between solubility, lipophilicity
and pKa for ionisable molecules
Knowledge of lipophilicity and solubility is important at various
stages of drug discovery, selection and pre-formulation. This talk will describe
how solubility and lipophilicity are influenced by the ionisation properties of
the compound. Examples will be used to show the relationships between intrinsic
compound properties and pH-dependent compound properties. Also, some new instrumental
techniques for studying these properties for ionisable drug molecules will be discussed.
Noting the correlation between PAMPA permeability and logP
dodecane-water values, we have developed a new way to measure logP dodecane-water
on Sirius GLpKa. The method involves acid base titration with UV detection, and
requires less than 0.4mg of sample per assay. The results compare well with pH-metric
values.
We have also introduced CheqSol (patent applied for), a new
pH-UV method for measuring equilibrium solubility. CheqSol gets a result in 20 minutes
for many samples, and confirms it several times in a one-hour assay. It has been
validated by comparison with shake-flask for about 25 acidic and basic drugs. CheqSol
also measures kinetic solubility in the same experiment. Kinetic solubility is higher
than equilibrium solubility for samples that form supersaturated solutions, but
identical for samples that do not supersaturate.
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for
Physical Chemists by Physical Chemists
