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Impact of Solid-State Form on the Disproportionation of Miconazole Mesylate
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-12-20 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00694 Mitulkumar A. Patel 1 , Suman Luthra 2 , Sheri L. Shamblin 3 , Kapildev Arora 3 , Joseph F. Krzyzaniak 3 , Lynne S. Taylor 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-12-20 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00694 Mitulkumar A. Patel 1 , Suman Luthra 2 , Sheri L. Shamblin 3 , Kapildev Arora 3 , Joseph F. Krzyzaniak 3 , Lynne S. Taylor 1
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Approximately 50% of solid oral dosage forms utilize salt forms of the active pharmaceutical ingredient (API). A major challenge with the salt form is its tendency to disproportionate to produce the un-ionized API form, decreasing the solubility and negatively impacting product stability. However, many of the factors dictating the tendency of a given salt to undergo disproportionation remain to be elucidated. In particular, the role of the solid-state properties of the salt on the disproportionation reaction is unknown. Herein, various solid forms of a model salt, miconazole mesylate (MM), were evaluated for their tendency to undergo disproportionation when mixed with basic excipients, namely tribasic sodium phosphate dodecahydrate (TSPd) and croscarmellose sodium (CCS), and exposed to moderate relative humidity storage conditions. It was observed that the rate and extent of salt disproportionation were significantly different for the various solid forms of MM. As expected, the amorphous salt was highly susceptible to disproportionation, while the dihydrate salt form was resistant to conversion under the conditions tested. In addition, binary excipient blends of amorphous and anhydrous forms exhibited a reduced extent of disproportionation at a higher relative humidity storage condition. This was due to the competitive kinetics between disproportionation to the free base and conversion to the dihydrate salt form. The results of this study provide important insights into the impact of solid-state form on susceptibility to disproportionation that can be utilized for rationally designing robust pharmaceutical formulations.
中文翻译：
固态形式对甲磺酸咪康唑歧化的影响
固体口服剂型的约50％利用活性药物成分（API）的盐形式。盐形式的主要挑战是其不成比例地产生未电离的API形式的趋势，降低了溶解度并对产品的稳定性产生负面影响。但是，许多决定给定盐发生歧化趋势的因素仍有待阐明。特别地，盐的固态性质对歧化反应的作用尚不清楚。在本文中，评估了各种固体形式的模型盐，甲磺酸咪康唑（MM）与基本赋形剂（即磷酸氢二钠十二水合物（TSPd）和交联羧甲基纤维素钠（CCS））混合并暴露于中度相对相对时发生歧化的趋势。湿度存储条件。观察到，对于各种固体形式的MM，盐歧化的速率和程度显着不同。如所期望的，无定形盐高度易歧化，而二水合物盐形式在测试条件下抗转化。另外，无定形和无水形式的二元赋形剂混合物在较高的相对湿度存储条件下显示出歧化程度降低。这是由于歧化成游离碱与转化成二水合物盐形式之间的竞争动力学。这项研究的结果为固态形式对歧化敏感性的影响提供了重要的见解，可用于合理设计健壮的药物制剂。
更新日期：2017-12-20
中文翻译：
固态形式对甲磺酸咪康唑歧化的影响
固体口服剂型的约50％利用活性药物成分（API）的盐形式。盐形式的主要挑战是其不成比例地产生未电离的API形式的趋势，降低了溶解度并对产品的稳定性产生负面影响。但是，许多决定给定盐发生歧化趋势的因素仍有待阐明。特别地，盐的固态性质对歧化反应的作用尚不清楚。在本文中，评估了各种固体形式的模型盐，甲磺酸咪康唑（MM）与基本赋形剂（即磷酸氢二钠十二水合物（TSPd）和交联羧甲基纤维素钠（CCS））混合并暴露于中度相对相对时发生歧化的趋势。湿度存储条件。观察到，对于各种固体形式的MM，盐歧化的速率和程度显着不同。如所期望的，无定形盐高度易歧化，而二水合物盐形式在测试条件下抗转化。另外，无定形和无水形式的二元赋形剂混合物在较高的相对湿度存储条件下显示出歧化程度降低。这是由于歧化成游离碱与转化成二水合物盐形式之间的竞争动力学。这项研究的结果为固态形式对歧化敏感性的影响提供了重要的见解，可用于合理设计健壮的药物制剂。
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