Abstract：
In the pharmaceutical industry, the unexpected appearance of crystalline forms could impact the therapeutic efficacy of an Active Pharmaceutical Ingredient (API). For quality control, a thorough qualitative and quantitative monitoring of pharmaceutical solid forms is essential to ensure the detection and the quantification of crystalline forms, wither different or with the same chemical composition (polymorphs) at a low detection level. The purpose of this paper was to review and highlight the importance of choosing adequate solid-state techniques for detection and quantification APIs that present polymorphism - based on limits of detection (LOD) and quantification (LOQ), pharmacopeias specifications, international guidelines and studies reported in the literature. To this study, the powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Infrared and Raman spectroscopies and solid-state nuclear magnetic resonance (NMR) were the solid-state techniques analyzed. Additionally, the Argentine, Brazilian, British, European, International, Japanese, Mexican and the United States of America pharmacopeias were reviewed. Based on the analysis performed, the advantages and disadvantages of these techniques, as well as the LOD and LOQ values of APIs were reported. In comparison to these solid-state techniques, reference material used for identification analyses should be previously identified with the corresponding polymorph. Without this previous procedure, the patterns, the spectra, and DSC curves of the reference material can only be used to confirm the mixture of solid forms, not being able to specify which polymorphs are contained in the sample. A major advantage of PXRD is the use of the calculated diffraction patterns obtained from the Crystallographic Information Frameworks (CIFs) files which could be used as a reference pattern without any other information, assistance technique, or physical standards. Regarding the quantification aspect, different pharmacopeias suggest various methods such as the PXRD combining with Rietveld method, which can be used to obtain lower LOD values for minority phases in the mixture of different substances without the need for a calibration curve. Raman spectroscopy can detect polymorphs in small particles and solid-state NMR spectroscopy is a powerful technique for quantification not only crystalline but also crystalline-amorphous mixtures. Finally, this review intends to be a useful tool to control, with efficiency and accuracy, the polymorphism of APIs in pharmaceutical compounds.
摘要：
在制药行业,结晶形式的意外出现可能影响活性药物成分(API)的治疗功效。为了质量控制，对药物固体形式进行彻底的定性和定量监测对于确保晶体形式的检测和定量至关重要，在低检测水平下枯萎不同或具有相同的化学组成（多晶型物）。本文的目的是回顾并强调选择适当的固态技术来检测和定量呈现多态性的API的重要性-基于检测限（LOD）和定量（LOQ），药典规范,文献中报道的国际准则和研究。对于这项研究，粉末X射线衍射(PXRD),差示扫描量热法(DSC),红外和拉曼光谱以及固态核磁共振（NMR）是分析的固态技术。此外,阿根廷人,巴西,英国,欧洲,国际,日本人,对墨西哥和美国的药典进行了审查。根据所进行的分析，这些技术的优点和缺点，以及API的LOD和LOQ值。与这些固态技术相比，用于鉴定分析的参考材料应事先用相应的多晶型物鉴定。如果没有前面的程序，模式，光谱，参考材料的DSC曲线只能用于确认固体形式的混合物，无法指定样品中包含的多晶型物。PXRD的主要优点是使用从晶体学信息框架（CIF）文件中获得的计算衍射图案，这些图案可以用作参考图案，而无需任何其他信息。辅助技术,或物理标准。关于量化方面，不同的药典提出了各种方法，如PXRD结合Rietveld法，可用于获得不同物质混合物中少数相的较低LOD值，而无需校准曲线。拉曼光谱可以检测小颗粒中的多晶型物，固态NMR光谱是一种强大的技术，不仅可以量化晶体，还可以量化晶体-无定形混合物。最后,这项审查旨在成为控制的有用工具，效率和准确性，药物化合物中原料药的多态性。
