Crystallization of a Metastable Solvate and Impact of the Isolation Method on the Material Properties of the Anhydrous Product,Organic Process Research & Development

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Crystallization of a Metastable Solvate and Impact of the Isolation Method on the Material Properties of the Anhydrous Product
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2018-04-04 00:00:00 , DOI: 10.1021/acs.oprd.8b00062
Kalyan V. Vasudevan ₁ , Frederick Osei-Yeboah ₁ , Kenny K. Tran ₁ , Daniel Patience ₁ , Erwin Irdam ₁ , Daw-Iong Kwok ₁ , Matthew L. Peterson ₁

Affiliation

We report the crystallization of a metastable small-molecule solvate and the effect of the isolation method on the physical and material properties of the resulting anhydrous material. The anhydrous crystalline products obtained from two different isolation routes using either a temperature-driven form change or a solvent-wash-mediated form change were analyzed by a suite of material-sparing characterization methods probing both physical form and material properties such as particle size distribution and powder flow behavior. The temperature-driven desolvation method was found to be time-consuming and undesirable. A relatively rapid desolvation approach was obtained using an ethyl acetate wash-mediated process. However, this method leads to powder with a broader particle size distribution, poorer flowability, higher interparticulate friction, and lower bulk density compared with the powder obtained by the temperature-driven desolvation process. The direct impact of the method of isolation on the material properties of the drug substance highlights the importance of not only understanding the crystallization process and form landscape but also the ability to implement systematic characterization to identify key powder properties of drug candidates early in the drug development process.

中文翻译：

亚稳溶剂化物的结晶及其分离方法对无水产物材料性能的影响

我们报告了亚稳态小分子溶剂化物的结晶以及分离方法对所得无水材料的物理和材料性质的影响。通过一套材料保留表征方法，分析了从两种不同的分离途径（使用温度驱动的形式变化或溶剂洗涤介导的形式变化）获得的无水结晶产物，这些方法同时考察了物理形式和材料特性（例如粒度分布）和粉末流动行为。发现温度驱动的去溶剂化方法是费时的并且是不期望的。使用乙酸乙酯洗涤介导的方法获得了相对快速的去溶剂化方法。但是，这种方法会导致粉末的粒度分布更宽，流动性更差，颗粒间的摩擦更大，与通过温度驱动的去溶剂化工艺获得的粉末相比，堆积密度更低。分离方法对原料药的材料特性的直接影响凸显了不仅要了解结晶过程和形成形态的重要性，而且要具有在药物开发早期进行系统表征以鉴定候选药物关键粉末特性的能力的重要性。过程。

更新日期：2018-04-04

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