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The role of chromatography in physicochemical
characterisation
Shenaz Nunhuck, Computational Analytical and
Structural Sciences,
GlaxoSmithKline
During the early phase of drug discovery it is becoming
increasingly important to acquire the physicochemical profile of molecules. It
has long been recognised that there is a strong relationship between
lipophilicity and various “developability” parameters, such as permeability,
solubility, oral absorption, bioavailability, CNS penetration, metabolism,
etc. For this purpose there is a strong interest in developing high throughput
fully automated methods for fast and reliable measurements of lipophilicity.
The HPLC technique has a great potential to determine
various types of lipophilicity through retention time measurements. Various
stationary phases can be used, such as C-18, octanol, immobilised artificial
membrane (IAM), human serum albumin (HSA), alpha-acid glycoprotein (AGP), etc.
The mobile phase pH can be altered for the investigation of the effect of charge
and to obtain a quantitative measure of acid/base character. The dynamic range
can be increased by applying a fast gradient to alter the mobile phase polarity
and thus decrease the analysis time without decreasing precision. The measured
retention times can be converted into reproducible partition data (e.g.
Chromatographic Hydrophobicity Index, CHI) using calibration.
The HPLC based biomimetic lipophilicity measurements such
as protein binding and IAM partitioning has proved to be useful to understand
compound’s distribution in vivo. Parallel HPLC systems and automation make it
possible to determine these various “flavours” of compound lipophilicity in
minutes. These large amounts of HPLC based lipophilicity measurements are
extensively used in the early stages of the drug discovery process during
compounds’ selection processes.
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Physical Chemists by Physical Chemists
