Add time:08/06/2019         Source:sciencedirect.com

The physicochemical properties of the base and hydrochlo-ride salt of the poorly water-soluble drug α-pentyl-3-(2-quinolinylmeth-oxy)benzenemethanol (REV 5901) were investigated in order to select an appropriate form of the drug for dosage form development. The pH-solubility profiles of both the base and the salt at 37°C were identical and were in agreement with a pKa value of 3.67 determined by the UV spectral method. The solubility of the drug (~0.002 mg/mL at pH 6) increased gradually with a decrease in pH and reached a value of 0.95 mg/mL at pH 1; at pH values < 1, the solubility decreased due to the common-ion effect. The pHmax, i.e., the pH of maximum solubility of the drug was, therefore, 1.0. The role of the pHmax In the selection of a salt or base form of a compound was investigated. Due to the conversion of the salt to the base at the surface of the dissolving solid at pH values >pHmax, the dissolution rates of both the base and the salt were identical. In the solid state, the salt existed in anhydrous and monohy-drate forms; the anhydrous salt converted to the hydrate at > 40% relative humidity, and the hydrate lost water at 40–60°C. The thermal properties of the salt were indicative of its potential instability, which was confirmed by accelerated stability studies. The base existed in a stable crystalline solid form, and also in an oily liquid form which converted to crystals on standing. In consideration of the better stability of the base, the variability in the hydration of the salt, and the absence of a higher dissolution rate of the salt, the base was selected for the dosage form design.

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