Área de Análisis de Medicamentos, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario and Instituto de Química Rosario (IQUIR, CONICET-UNR), Suipacha 531, Rosario S2002LRK, Argentina.
Área de Análisis de Medicamentos, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario and Instituto de Química Rosario (IQUIR, CONICET-UNR), Suipacha 531, Rosario S2002LRK, Argentina.
J Pharm Biomed Anal. 2019 Jun 5;170:8-15. doi: 10.1016/j.jpba.2019.03.021. Epub 2019 Mar 14.
The assessment of polymorphism is a problematical issue for regulatory agencies, because variations among crystalline forms of active pharmaceutical ingredient (API) can lead to changes in the efficacy and safety of formulated product. Such conversions are very hard to be detected, thus, the development of techniques for the identification, characterization and quantification of polymorphs results essential in all stages of the manufacturing process. The presence of excipients in formulated products may change the crystal stability of an API, by catalyzing a polymorphic transformation or stabilizing the less stable form. As paradox, all suitable analytical techniques (spectroscopies, thermal analysis, NMR and DRX, and others) for polymorphic analysis are affected by excipients. A deep understanding of the polymorphism-excipient relationship is in full accordance with Quality by Design (QbD) paradigm, the systematic approach focused in quality building into a product based in the full understanding of the products and process. In this work, a novel approach based on thermal stress, MIR monitoring, multivariate curve resolution with alternating least squares (MCR-ALS) and kinetic analysis was developed and applied to monitor polymorphism behavior of model API in formulated products. Commercial tablets, physical mixtures and commercial API, were processed and analyzed under the proposed approach. Commercial tablets of MFA revealed a fast conversion to Form II, contrasting to the behavior of the pure API. Physical mixtures showed similar behavior to commercial tablets, thus reduction in transformation times was related to MFA-excipients physical interaction, even at surface level. Calorimetric studies support the conclusion obtained. The developed approach could be extended to others APIs and other stress sources (humidity, solvents, mechanical forces and its combinations), being a valuable tool for QbD environment.
多态性评估是监管机构面临的一个问题，因为活性药物成分（API）的晶体形式的变化可能导致配方产品的功效和安全性发生变化。这些转化非常难以检测，因此，开发用于鉴定、表征和定量多晶型的技术对于制造过程的所有阶段都是至关重要的。赋形剂在配方产品中的存在可能通过催化多晶型转变或稳定不稳定形式来改变 API 的晶体稳定性。具有讽刺意味的是，所有适合多态性分析的分析技术（光谱学、热分析、NMR 和 DRX 等）都受到赋形剂的影响。深入了解多态性-赋形剂关系完全符合质量源于设计（QbD）的理念，这是一种系统的方法，专注于在充分了解产品和工艺的基础上构建产品质量。在这项工作中，开发并应用了一种基于热应力、MIR 监测、交替最小二乘法（MCR-ALS）和动力学分析的多变量曲线分辨的新方法，用于监测模型 API 在配方产品中的多态性行为。对商业片剂、物理混合物和商业 API 进行了处理和分析。MFA 的商业片剂迅速转化为 II 型，与纯 API 的行为形成对比。物理混合物的行为与商业片剂相似，因此转化时间的减少与 MFA-赋形剂的物理相互作用有关，即使在表面水平也是如此。量热研究支持所得到的结论。所开发的方法可以扩展到其他 API 和其他应激源（湿度、溶剂、机械力及其组合），是 QbD 环境的有价值的工具。
