Pharmaceutical Salts of Haloperidol with Some Carboxylic Acids and Artificial Sweeteners: Hydrate Formation, Polymorphism, and Physicochemical Properties

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• 作者：Srinivasulu Aitipamula ; Annie B. H. Wong ; Pui Shan Chow ; Reginald B. H. Tan
• 刊名：Crystal Growth & Design
• 出版年：2014
• 出版时间：May 7, 2014
• 年：2014
• 卷：14
• 期：5
• 页码：2542-2556
• 全文大小：707K
• 年卷期：v.14,no.5(May 7, 2014)
• ISSN：1528-7505

文摘

We report novel pharmaceutical salts of an important neuroleptic drug haloperidol (HAL) with some carboxylic acids and artificial sweeteners. The pK_a difference between HAL and the selected carboxylic acids and sweeteners suggests salt formation. All the salts were obtained from conventional solvent evaporative crystallization experiments at ambient conditions. Except formic acid, all the carboxylic acids form salt hydrates. Crystal structure analysis revealed an isostructural crystal packing in succinate, fumarate, and acetate salt hydrates. This study reports a stable polymorph of the known HAL-saccharinate, and two polymorphs of a novel salt with acesulfame. Both polymorphic sets feature significant differences in hydrogen bonding and conformations of HAL. Stability of the polymorphs was deduced by thermal analysis, comparison of the calculated density, and slurry experiments in the case of the HAL-acesulfame salt. The reported salts with artificial sweeteners could offer advantages in terms of masking the bitter taste of the parent HAL base. All the salts showed higher solubility and intrinsic dissolution rate in 10% EtOH鈥搘ater medium compared to HAL. These salts provide a means of increasing the number of solid forms for HAL that facilitate selection of a suitable salt form for development of fast-dissolving HAL formulations.