Optimizing solubility: kinetic versus thermodynamic solubility temptations and risks.

The aim of this study was to assess the usefulness of kinetic and thermodynamic solubility data in guiding medicinal chemistry during lead optimization. The solubility of 465 research compounds was measured using a kinetic and a thermodynamic solubility assay. In the thermodynamic assay, polarized-light microscopy was used to investigate whether the result referred to the crystalline or to the amorphous compound. From the comparison of kinetic and thermodynamic solubility data it was noted that kinetic solubility measurements frequently yielded results which show considerably higher solubility compared to thermodynamic solubility. This observation is ascribed to the fact that a kinetic solubility assay typically delivers results which refer to the amorphous compound. In contrast, results from thermodynamic solubility determinations more frequently refer to a crystalline phase. Accordingly, thermodynamic solubility data--especially when used together with an assessment of the solid state form--are deemed to be more useful in guiding solubility optimization for research compounds.

Characterization of a new solvate of risedronate.

Three new forms of the osteoporosis drug sodium risedronate, sodium [1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonate, were identified and designated as the J, K, and M phases. Form J is an acetic acid disolvate with the chemical composition Na(+) [C(7) H(10) NO(7) P(2)](-) · 2CH(3) COOH, as determined by single-crystal structure analysis. This novel solvate is easily formed by the recrystallization of sodium risedronate from acetic acid. Dissolution of the new disolvate was characterized in distilled water, a compendial buffer, simulated gastric fluid sine pepsin (pH 1.2), and a biorelevant buffer system FaSSIF-V2 (pH 6.8). It was demonstrated that solubility of the disolvate in physiological buffers differed significantly from that of the original molecule, with delayed dissolution under simulated esophageal and gastric conditions, but rapid and complete dissolution under simulated intestinal conditions. These studies suggest that through the generation of novel solvates, the biopharmaceutical properties of poorly soluble drug candidates can be improved.

Prediction of blood-brain barrier penetration of poorly soluble drug candidates using surface activity profiling.

The aim of this study was to determine whether transepithelial transport across the blood-brain barrier (BBB) [expressed as the logarithm of blood/brain partitioning coefficient (logbb)] could be correlated to surface tension properties for a series of new chemical entities (NCEs) having extremely low solubility in aqueous media. Surface tension data were generated by the "Du Nouy maximum pull force method" using an automated, small volume Kibron Delta 8 Multi-channel tensiometer. Using the surface pressure/concentration profiles, parameters such as the maximum surface pressure, cross-sectional area and the air-water partitioning coefficient were calculated for the individual compounds and correlated with their in vivo logbb values. A good linear correlation (R(2)=0.8669) between logbb and cross-sectional area was observed, suggesting a morphological analogy between the molecular orientation at the air-water interface and the anisotropic cellular bilayer of the blood-brain barrier.