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Process development strategy to ascertain reproducible API polymorph manufacture

机译：确定可重复生产的API多晶型物生产的工艺开发策略

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摘要

The present example illustrates the application of a consistent process development strategy to ascertain reproducible active pharmaceutical ingredient (API) polymorph manufacture. Key methodologies are illustrated using a Novartis API and carbamazepine as model substances. In the present example, the Novartis API was synthesized in the final chemical step by hydrolysis followed by acidification. The process was investigated in four steps: First, solid-liquid equilibrium studies were carried out in several solvents and yielded two polymorphs that were characterized by X-ray powder diffraction. Reliable solubility data and the transition temperature (45 degrees C) were extracted from these experiments as well. Second, based on the knowledge of the enantiotropic behavior of the system, a procedure was developed that crystallized the stable polymorph-which was chosen for development-reproducibly by seeding at low supersaturation below 45 degrees C, followed by cooling at a moderate rate. The absence of metastability with respect to the undesired polymorphic form throughout the process was confirmed by applying ATR-FTIR. Third, reaction conditions were modified to obtain the API in solution at undersaturated conditions. Subsequently, the API could be crystallized in a controlled manner as described above. Fourth, filtration, washing, and drying conditions were investigated to avoid scale-up problems. Constant pressure filtration yielded low compressibility of the filter cake allowing a nutsche or centrifuge as appropriate equipment for isolation. On the basis of vacuum thermogravimetry, fast drying kinetics could be determined. Bench scale paddle dryer experiments illustrated an unacceptable increase of bulk density at permanent rotation. Therefore, intermittent rotation was successfully used at production scale. Thus, the presented process development strategy leads to a robust process scale-up from lab to pilot and production plant, yielding the desired product quality with respect to physical properties as well as chemical purity. Using solid-liquid equilibrium studies, the solubility and the transition temperature (79 degrees C) between forms I and III of carbamazepine could be determined in 2-propanol. These results correspond well with findings of other authors. On the basis of vacuum thermogravimetry, fast drying kinetics of 2-propanol from carbamezepine is illustrated. Near-complete drying can be achieved at any pressure below the solvent vapor pressure, which points to solvent free from interactions with the solid drug substance.
机译：本示例说明了一致的过程开发策略在确定可重现的活性药物成分（API）多晶型物制造中的应用。使用诺华API和卡马西平作为模型物质说明了关键方法。在本实施例中，在最后的化学步骤中通过水解然后酸化来合成诺华API。对过程进行了四个步骤的研究：首先，在几种溶剂中进行了固液平衡研究，得到了两种多晶型物，它们通过X射线粉末衍射表征。还从这些实验中提取了可靠的溶解度数据和转变温度（45摄氏度）。第二，基于对系统的对映行为的知识，开发了一种方法，该方法通过在低于45摄氏度的低过饱和状态下进行晶种，然后稳定地冷却，使稳定的多晶型物结晶化（该晶型被选择用于开发）。通过使用ATR-FTIR，证实了在整个过程中相对于不希望的多晶型形式没有亚稳性。第三，修改反应条件以获得在饱和条件下在溶液中的API。随后，可以如上所述以受控方式使API结晶。第四，研究了过滤，洗涤和干燥条件，以避免扩大规模。恒压过滤导致滤饼的可压缩性低，允许将坚果或离心机作为分离的合适设备。基于真空热重法，可以确定快速干燥动力学。台式规模的桨式干燥机实验表明，永久旋转时堆积密度的增加是不可接受的。因此，间歇旋转已成功用于生产规模。因此，提出的工艺开发策略可实现从实验室到中试和生产车间的稳健工艺放大，从而在物理性能以及化学纯度方面产生所需的产品质量。使用固液平衡研究，可以确定在2-丙醇中卡马西平I和III型之间的溶解度和转变温度（79摄氏度）。这些结果与其他作者的发现非常吻合。在真空热重分析的基础上，说明了来自卡马西平的2-丙醇的快速干燥动力学。在低于溶剂蒸气压的任何压力下都可以实现近乎完全的干燥，这表明溶剂不与固体药物发生相互作用。

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