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Assessing the Risk of Salt Disproportionation Using Crystal Structure and Surface Topography Analysis

机译：使用晶体结构和表面形貌分析评估盐歧化的风险

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Salt disproportionation is a major issue for pharmaceutical products containing a salt form of a weakly basic drug, because conversion to the free base during processing or storage in the presence of excipients may negatively impact stability and bioperformance of the drug product. Several factors influencing disproportionation tendency have been elucidated; however, a complete mechanistic understanding of this phenomenon is still lacking. Specifically, it is unclear if the crystal structure of the salt plays a role, beyond influencing the salt solubility. Herein, by utilizing model compounds with similar pK(a) and pH(max) values, and hence similar thermodynamic driving forces for disproportionation, we demonstrate that salt crystal structure appears to play a major role in influencing disproportionation tendency. Some salts with low pH(max) values were found to be resistant to disproportionation, while other systems transformed to the free base following contact with the basic excipient, magnesium stearate. For salts that converted to the free base, the new crystal phase was imaged using atomic force microscopy and scanning electron microscopy. Based on these images, it was concluded that conversion occurred via a nucleation and growth process; i.e., transformation involved considerable structural rearrangement. Extensive crystallographic analysis provided some insight, suggesting that the packing and intermolecular interactions around the salt bridge may influence the susceptibility of the salt to conversion to the free base when challenged with a basic microenvironment. Thus, evaluation of disproportionation risk requires consideration not only of pH,a, but also salt crystal structure, whereby different solid state forms of a given salt may present different risk levels for conversion to free base. Further studies of correlations between crystal structure and disproportionation tendency are clearly warranted to ensure the development of robust salt formulations.
机译：盐歧化是含有弱碱性药物的药物产品的主要问题，因为在赋形剂存在下加工或储存过程中的游离基碱可能会产生负面影响和药物产品的生物信息。影响了影响不均匀倾向的几个因素已经阐明了;然而，对这种现象的完全理解理解仍然缺乏。具体地，目前尚不清楚盐的晶体结构在影响盐溶解度之外发挥作用。在此，通过利用具有类似PK（A）和pH（MAX）值的模型化合物，因此类似的热力驱动力用于歧化，我们证明盐晶结构似乎在影响歧化趋势方面发挥着重要作用。发现一些具有低pH（最大值）值的盐抗体，而其他系统转化为与基本赋形剂，硬脂酸镁接触后的游离碱。对于转化为游离碱的盐，使用原子力显微镜和扫描电子显微镜对新的晶相进行成像。基于这些图像，得出结论，通过成核和生长过程发生转化;即，转型涉及相当大的结构重新排列。广泛的晶体分析提供了一些洞察力，表明盐桥周围的包装和分子间相互作用可能影响盐的敏感性，当用基本微环境攻击时，盐在对自由基地转化为自由基地。因此，不仅需要考虑pH，A，含盐晶体结构的评价需要考虑，由此给定盐的不同固态形式可能会呈现不同的风险水平以转化为游离碱。进一步研究晶体结构与歧化趋势之间的相关性，以确保鲁棒盐配方的发展。

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