pH-Dependent Liquid鈥揕iquid Phase Separation of Highly Supersaturated Solutions of Weakly Basic Drugs

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• 作者：Anura S. Indulkar ; Karl J. Box ; Robert Taylor ; Rebeca Ruiz ; Lynne S. Taylor
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：July 6, 2015
• 年：2015
• 卷：12
• 期：7
• 页码：2365-2377
• 全文大小：617K
• ISSN：1543-8392

文摘

Supersaturated solutions of poorly aqueous soluble drugs can be formed both in vivo and in vitro. For example, increases in pH during gastrointestinal transit can decrease the aqueous solubility of weakly basic drugs resulting in supersaturation, in particular when exiting the acidic stomach environment. Recently, it has been observed that highly supersaturated solutions of drugs with low aqueous solubility can undergo liquid鈥搇iquid phase separation (LLPS) prior to crystallization, forming a turbid solution such that the concentration of the drug in the continuous solution phase corresponds to the amorphous solubility while the colloidal phase is composed of a disordered drug-rich phase. Although it is well established that the equilibrium solubility of crystalline weakly basic drugs follows the Henderson鈥揌asselbalch relationship, the impact of pH on the LLPS phenomenon or the amorphous solubility has not been explored. In this work, the LLPS concentration of three weakly basic compounds鈥攃lotrimazole, nicardipine, and atazanavir鈥攚as determined as a function of pH using three different methods and was compared to the predicted amorphous solubility, which was calculated from the pH-dependent crystalline solubility and by estimating the free energy difference between the amorphous and crystalline forms. It was observed that, similar to crystalline solubility, the experimental amorphous solubility at any pH follows the Henderson鈥揌asselbalch relation and can be predicted if the amorphous solubility of the free base is known. Excellent agreement between the LLPS concentration and the predicted amorphous solubility was observed. Dissolution studies of amorphous drugs showed that the solution concentration can reach the corresponding LLPS concentration at that pH. Solid-state analysis of the precipitated material confirmed the amorphous nature. This work provides insight into the pH-dependent precipitation behavior of poorly water-soluble compounds and provides a fundamental basis with which to understand the performance of supersaturating dosage forms.