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A fast HPLC method was developed to study the hydrophobicity extent of pharmaceutically relevant molecular fragments. By this strategy, the reduced amount of sample available for physico‐chemical evaluations in early‐phase drug discovery programs does not represent a limiting factor. The sixteen acid fragments investigated were previously synthesized also determining potentiometrically their experimental log D values. For four fragments it was not possible to determine such property since their values were outside of the instrumental working range (2 < pKa < 12). An RP‐HPLC method was therefore optimized. For each scrutinized method, some derived chromatographic indices were calculated, and Pearson's correlation coefficient (r) allowed to select the so‐called "φ0 index" as the best correlating with the log D. The wspH${}_w^spH$ was fixed at 3.5 and a modification of some variables [organic modifier (methanol vs. ACN), stationary phase (octyl vs. octadecyl), presence/absence of the additives n‐octanol, n‐butylamine, and n‐octylamine], allowed to select the best correlation conditions, producing a r = 0.94 (p < 0.001). Importantly, the φ0 index enabled the estimation of log D values for four fragments which were unattainable by potentiometric titration. Moreover, a series of molecular descriptors were calculated to identify the chemical characteristics of the fragments explaining the obtained φ0. The number of hydrogen bond donors and the index of cohesive interaction correlated with the experimental data. [ABSTRACT FROM AUTHOR]

Benzodiazepines (BZDs) are often prescribed to schizophrenic or depressed patients, as a part of polypharmacy regimens. An HPLC method has been developed for the simultaneous determination of 15 BZDs in human plasma. Separation was obtained by using a C8 RP column and a mobile phase composed of 65% aqueous phosphate buffer at pH 3.0 and 35% ACN. The UV detector was set at 220 nm and clomipramine was used as the internal standard. A careful pretreatment procedure of plasma samples was developed, using SPE with C1 cartridges, which gives high extraction yields (> 97%). The LOQs were always lower than 7.6 ng/mL and the LODs always lower than 2.6 ng/mL for all analytes. The method was successfully applied to plasma samples from depressed and schizophrenic patients undergoing polypharmacy with one or more BZDs. Precision data, as well as accuracy results, were satisfactory and no interference from other drugs was found. Hence, the method seems to be suitable for the therapeutic drug monitoring (TDM) of patients undergoing therapy with one or more BZDs.