School of Chemical Engineering and Analytical Science, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
J Pharm Sci. 2011 Mar;100(3):942-8. doi: 10.1002/jps.22334. Epub 2010 Aug 25.
Yellow discoloration was observed at the surface of normally white crystals of a development pharmaceutical fumarate salt, tentatively ascribed to the presence of trace amounts of free base. The impact of impurities on sample properties and behavior can be significant, especially if localized at the surface. No conventional bulk analytical technique could readily provide an explanation for the yellow color, so a surface-sensitive technique, X-ray photoelectron spectroscopy (XPS), was employed to characterize the salt. XPS reveals the presence of free base at the surface through the HN(+)/N ratio. A free radical decarboxylation mechanism is proposed to account for the alterations observed with extended irradiation. The lower intensity carboxyl signal and significantly lower HN(+)/N ratio for the yellow surface samples reveal a higher level of free base at the surface than the white samples. The samples with yellow surfaces could not be successfully milled, which was an important part of the production process for providing material of the required physical quality for product formulation. Identification of residual free base at the surface of the crystalline material, by XPS, was significant for optimization of the crystallization process to yield material of required quality for successful milling at plant scale.
表面原本为白色的富马酸盐结晶药物出现黄色变色现象，初步归因于痕量游离碱的存在。杂质对样品性质和行为的影响可能非常显著，尤其是在表面存在的情况下。没有常规的批量分析技术可以轻易解释黄色的原因，因此采用了表面敏感技术 X 射线光电子能谱（XPS）来对盐进行表征。XPS 通过 HN(+)/N 比证实了表面游离碱的存在。提出自由基脱羧机制来解释延长照射时观察到的变化。黄色表面样品的羧基信号强度较低，HN(+)/N 比明显较低，表明表面游离碱的含量高于白色样品。黄色表面的样品无法成功研磨，这是生产过程中的重要部分，用于提供满足产品配方所需物理质量的材料。通过 XPS 鉴定结晶材料表面残留的游离碱，对于优化结晶过程以生产出适合在工厂规模上成功研磨的所需质量的材料非常重要。
