US 6,548,307 B2 · Determination of logP coefficients via a RP-HPLC column

Abstract

This invention provides a RP-HPLC method, for the determination of logPoct values, which combines ease of operation and high accuracy, and which has been shown to work for a set of 36 molecules largely comprised of drugs. The general features of the method are: i) compound sparing (≦1 mL of a 30-50 μg/mL solution needed), ii) rapid determinations (20 minutes on average), iii) low sensitivity to impurities, iv) wide lipophilicity range (6 logPoct units), v) good accuracy, vi) excellent reproducibility. A linear free energy relationship (LFER) analysis, based on solvation parameters, shows that the method encodes the same information obtained from a shake-flask logPoct determination. The value generated via this method is referred to as ElogPoct.

Claims8

Dependent claims

A method of determining ElogPoct for chemical compounds which comprises:

a) Introducing said chemical compounds seriatim to the column of a reverse phase high performance liquid chromatograph;
said column being an embedded amide functional group column;
or a C-18 bonded column with low silanol activity;
and
b) Eluting said compounds with a mobile phase containing MOPS buffer and a methanol/octanol mixture in which the proportions of said methanol/octanol mixture to said buffer are from 70 to 15% v/v;
and with flow rates between 0.5 and 2 ml/mm and with the proviso that said mobile phase does not contain an aliphatic amine;
and
c) Measuring the retention time required to elute each sample from said column;
and
d) Calculating ElogPoct from the retention time of each sample using equation 3:
logPoct=1.1021(±0.0291)logkw+0.1344(±0.0653) (Eq. 3).

8 more elements

A method of determining ElogPoct for chemical compounds which comprises:

a) Introducing said chemical compounds seriatim to the column of a reverse phase high performance liquid chromatograph;
said column being an embedded amide functional group column;
or a C-18 bonded column with low silanol activity;
and
b) Eluting said compounds with a mobile phase containing MOPS buffer and a methanol/octanol mixture in which the proportions of said methanol/octanol mixture to said buffer are from 70 to 15% v/v;
and with flow rates between 0.5 and 2 ml/min and with the proviso that said mobile phase does not contain an aliphatic amine;
and
c) Measuring the retention time required to elute each sample from said column;
and
d) Calculation ElogPoct from the retention time of each sample using equation 3:
logPoct=1.1021(±0.0291)logk′w+0.1344(±0.00653) (Eq.3),
wherein said compounds for which ElogP.sub.oct is to be determined are divided into groups according to calculated lipophilicity based on chemical structure and;
ElogP.sub.oct is determined for all samples in a first group and;
said column is equilibrated to the conditions for a second group.

11 more elements

Dependencies are inferred from the claim text.

Determination of logP coefficients via a RP-HPLC column

Life of this patent

Determination of logP coefficients via a RP-HPLC column

Life of this patent

Abstract

Claims8