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首页> 外文期刊>Organic process research & development >Coupling Polymorphism/Solvatomorphism and Physical Stability Evaluation with Early Salt Synthesis Optimization of an Investigational Drug
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Coupling Polymorphism/Solvatomorphism and Physical Stability Evaluation with Early Salt Synthesis Optimization of an Investigational Drug

机译：耦合多态性/溶剂同质性和物理稳定性评估与研究药物的早期盐合成优化

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摘要

The need for effective solid-form screening approaches, especially designed for the early discovery phases, is well recognized within the pharmaceutical industry. Here we report on the early polymorphism and solvatomorphism evaluation of a new drug candidate for selective α_(2C)-adrenoceptor antagonists ORM10921 · HCl. The approach we use is based on the systematic batch-to-batch characterization of the solids generated during the salt synthesis optimization. Within this study three crystalline forms, two anhydrous and one hemihydrate, were discovered and identified by X-ray powder diffraction (XRPD), differential scanning calorimery (DSC), and thermal gravimetry (TGA). Moreover, coupling the gravimetric vapor sorption analysis with a conventional XRPD enabled the relative stability of these solid-state forms at ambient conditions to be established and the most stable form, the hemihydrate, to be selected for further development. Hence, the utilized approach has proven to be an effective and fast tool for initial polymorphism and solvatomorphism tendency evaluation of drug candidates. While it is not obvious that this approach is sufficient for a comprehensive assessment of polymorphism, it demonstrates the importance of mindful solid-state characterization during crystallization process development.
机译：有效的固体形式筛选方法的需求，特别是为早期发现阶段设计的，已在制药行业中得到广泛认可。在这里，我们报告了选择性α_（2C）-肾上腺素能受体拮抗剂ORM10921·HCl的新药候选物的早期多态性和溶剂同型性评估。我们使用的方法基于盐合成优化过程中生成的固体的逐批表征。在这项研究中，通过X射线粉末衍射（XRPD），差示扫描量热法（DSC）和热重分析（TGA）发现并鉴定了三种结晶形式，两种无水和一种半水合物。此外，将重量蒸汽吸收分析与常规XRPD结合使用，可以确定这些固态形式在环境条件下的相对稳定性，并选择最稳定的形式半水合物用于进一步开发。因此，已证明所利用的方法是用于候选药物的初始多态性和溶剂化态势评估的有效且快速的工具。尽管这种方法不足以全面评估多态性，但它证明了结晶过程开发过程中注意固态表征的重要性。

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