Critical comparison of shake-flask, potentiometric and chromatographic methods for lipophilicity evaluation (log P o/w ) of neutral, acidic, basic, amphoteric, and zwitterionic drugs

Abstract

In the present study three different procedures have been compared for the determination of the lipophilicity of the unionized species (log P) of neutral, acidic, basic, amphoteric, and zwitterionic drugs. Shake-flask, potentiometric and chromatographic approaches have been assayed in a set of 66 representative compounds in different phases of advanced development. An excellent equivalence has been found between log P values obtained by shake-flask and potentiometry, while the chromatographic approach is less accurate but very convenient for screening purposes when a high-throughput is required. In the case of zwitterionic and amphoteric compounds, either for shake-flask and chromatographic methods, the pH has to be accurately selected in order to ensure the compound to be in its neutral form.

Influence of the acid-base ionization of drugs in their retention in reversed-phase liquid chromatography

“…z is the charge of the most dissociated form of the acid-base drug. [46] The retention time of the neutral form is highlighted in bold Table 5. Parameters (±sd) and statistics obtained in the fits of the retention time to mobile phase pH of acids and bases with pKa values too low or too high to estimate the retention of the ion from the fitting.…”

Prediction of the n-octanol/water partition coefficients in the SAMPL6 blind challenge from MST continuum solvation calculations

“…The reasons that may explain this behaviour are unclear, but the uncertainty might be attributed to the population of cationic and anionic species during the potentiometric determination of the log P for a compound with distinct titratable sites. In this case, according to previous studies [50], the use of a shake-flask technique would be valuable for comparison purposes with the potentiometric method, because these compounds are prone to exhibit a larger difference between the log P values obtained by using these experimental techniques.…”

Multiple linear regression models for predicting the n‑octanol/water partition coefficients in the SAMPL7 blind challenge

“…1). Thus, it is expected a higher log P N value for SM36 because benzene rings are significant lipophilic fragments [42][43][44], however, it was not the experimental observation for the pair SM35-SM36. Comparison of analogous situations in pairs of molecules: SM29-SM30, SM32-SM33, SM41-SM42, and SM44-SM45 reveals the conventional increase in the experimental log P N resulting from the substitution of methyl for phenyl groups.…”