Spontaneous carbonate formation in an amorphous, amine-rich, polymeric drug substance: Sevelamer HCl product quality
Spontaneous carbonate formation in an amorphous, amine-rich, polymeric drug substance: Sevelamer HCl product quality
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DOI：
10.1002/jps.23228
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发表时间：
2012-08-01
影响因子：
3.8
通讯作者：
Faustino, Patrick J.
中科院分区：
文献类型：
--
作者：
Berendt, Robert T.;Samy, Raghu;Faustino, Patrick J.
通过傅里叶变换红外光谱法观察到多个生产商/批次盐酸司维拉姆之间的光谱差异，并进行进一步表征以确定这些差异的原因。原料药是一种聚合物，具有大分子量，为无定形，几乎不溶于水和有机溶剂。因此，需要固态表征方法（光谱和热）来识别和表征样品之间的差异，以评估产品质量的可能差异。盐酸司维拉姆物质的13 C交叉极化魔角旋转核磁共振光谱证明存在含羰基物质，这归因于样品中的碳酸盐杂质。稳定性研究表明，该碳酸盐杂质在原料药暴露于大气水蒸气和二氧化碳时自发形成，即使在环境条件下也是如此。从机理上讲，该行为可能是由于大量伯胺和仲胺基团、HCl盐的吸湿性以及由于原料药的无定形性质而导致的高度分子流动性引起的。(C)2012 Wiley Periodicals，Inc.和American Pharmacologist Association J Pharm Sci 101：26812685，2012
Spectral differences among multiple manufacturers/lots of sevelamer HCl were observed by Fourier transform infrared spectroscopy, and further characterization was performed to identify the cause for these differences. The drug substance is a polymer that possesses a large molecular weight, is amorphous, and is practically insoluble in both water and organic solvents. Thus, solid-state characterization methods (spectroscopic and thermal) were required to identify and characterize differences among the samples to assess possible differences in product quality. 13C cross-polarizationmagic-angle-spinning nuclear magnetic resonance spectroscopy of sevelamer HCl substances demonstrated the presence of a carbonyl-containing species, which was attributed to a carbonate impurity among samples. Stability studies demonstrated that this carbonate impurity formed spontaneously upon exposure of the drug substance to atmospheric water vapor and carbon dioxide, even under ambient conditions. Mechanistically, this behavior likely arises from the large number of primary and secondary amine groups, the hygroscopicity of the HCl salt, and a high degree of molecular mobility due to the amorphous nature of the drug substance. (C) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:26812685, 2012