Role of Salt and Excipient Properties on Disproportionation in the Solid-State
Role of Salt and Excipient Properties on Disproportionation in the Solid-State
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DOI：
10.1007/s11095-009-9918-y
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发表时间：
2009-08-01
影响因子：
3.7
通讯作者：
Taylor, Lynne S.
中科院分区：
文献类型：
--
作者：
Guerrieri, Peter;Taylor, Lynne S.
大约50%的活性药物成分（API）是以盐的形式生产和配制的，这是因为它们具有更高的溶解速率或更好的固态特性。在加工过程中和产品的整个使用寿命期间，必须保持药物的适当固态形式。本研究的目的是调查的过程中的影响因素，从而盐转化回游离形式的drug.Infrared和拉曼光谱法被用来检测和定量的物理混合物与赋形剂的游离碱的形成。的pH值-溶解度关系的基础上测得的盐的溶解度和性质的游离form.The甲磺酸盐的两个模型药物化合物被发现不成比例的游离碱形式时，物理混合与某些常见的基本赋形剂，并暴露于适度的相对湿度。相比之下，萘磺酸盐对反硝化的抗性更强。萘磺酸盐的溶解度比相应的甲磺酸盐低3个数量级以上，并且显示很少或没有可检测的游离碱形成。具有较高溶解度的甲磺酸盐显示出显著水平的向游离碱的转化。看来，盐的溶解度和pH（max）（存在离子化和非离子化物质饱和的溶液的pH）以及碱溶解度在确定盐对歧化的敏感性方面起重要作用。转化程度还受赋形剂性质的影响，包括碱度、溶解度、物理状态和表面积。
Approximately 50% of active pharmaceutical ingredients (APIs) are manufactured and formulated as salts, due to their enhanced dissolution rates or improved solid state properties. It is essential to maintain the appropriate solid state form of the drug during processing and over the lifetime of the product. The aim of this study was to investigate the contributing factors in the process of disproportionation, whereby the salt converts back to the free form of the drug.Infrared and Raman spectroscopy were used to detect and quantify the formation of free base in physical mixtures with excipients. The pH-solubility relationships were determined based on measured salt solubilities and properties of the free form.The mesylate salts of two model pharmaceutical compounds were found to disproportionate to the free base form when physically mixed with certain common basic excipients and exposed to moderate relative humidities. In contrast, the napsylate salts were much more resistant to disproportionation. The napsylate salts had solubilities more than 3 orders of magnitude lower than the respective mesylate salts, and showed little to no detectable formation of free base. The mesylate salts with higher solubilities showed significant levels of conversion to the free base.It appears that both the solubility and pH(max) (the pH of a solution where there is saturation of both ionized and unionized species) of the salts, as well as the base solubility, play important roles in determining the susceptibility of salts to disproportionate. The extent of conversion was also affected by excipient properties, including basicity, solubility, physical state and surface area.