The control of impurity content in active pharmaceutical ingredients is of utmost importance for the pharmaceutical industry. While crystallization is oftentimes used as an efficient and cost-effective means of achieving this purification, structurally similar impurities can be very difficult to separate via crystallization. The impact of nonadsorbing polymers on the crystallization of the compound of interest can be leveraged to enhance the purification of pharmaceutical molecules. Here we discuss a case study in which an impurity formed in a pilot plant batch at a level of 3% could not be adequately rejected using conventional crystallization processes. We used a polymer additive to modify the crystallization to enhance impurity rejection. The process was implemented on scale to successfully deliver the product with less than 0.1% of the impurity. We explain the observed influence of the polymer additive on the crystallization of the product by carrying out additional investigations and considering the effect of the additive on the energy barrier to nucleation and growth kinetics of the impurity crystals. This work demonstrates the utility of polymer additives in the crystallization process development of pharmaceutical compounds.

中文翻译：

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聚合物添加剂在药物化合物结晶中增强杂质排除的用途

活性药物成分中杂质含量的控制对制药业至关重要。尽管结晶常常被用作实现该纯化的有效且经济的手段，但是结构上相似的杂质可能很难通过结晶分离。可以利用非吸附性聚合物对目标化合物结晶的影响来增强药物分子的纯化。在这里，我们讨论了一个案例研究，其中使用常规结晶工艺无法充分排除在中试工厂批次中形成的3％杂质。我们使用了一种聚合物添加剂来修饰结晶，以提高杂质抑制率。该流程已大规模实施，以成功交付小于0的产品。1％的杂质。我们通过进行其他研究并考虑添加剂对杂质晶体成核和生长动力学的能垒的影响，来解释观察到的聚合物添加剂对产物结晶的影响。这项工作证明了聚合物添加剂在药物化合物结晶过程开发中的实用性。