Process Research & Development, Merck & Co., Inc., Kenilworth, NJ, USA.
Analytical Sciences, Pharmaceutical Sciences, Merck & Co., Inc., Kenilworth, NJ, USA.
J Pharm Sci. 2021 Sep;110(9):3238-3245. doi: 10.1016/j.xphs.2021.05.013. Epub 2021 Jun 2.
The physical properties of active pharmaceutical ingredients (API) are critical to both drug substance (DS) isolation and drying operations, as well as streamlined drug product (DP) processing and the quality of final dosage units. High aspect ratio, low bulk density, API 'needles' in particular are a hindrance to efficient processing, with a low probability that conventional crystallization routes can modify the challenging morphology. The compound evaluated in this manuscript demonstrated this non-ideal morphology, with the added complexity of shear sensitivity. Modest shear exposure resulted in conversion of the thermodynamically stable crystalline phase to the amorphous phase, with the amorphous phase then undergoing accelerated chemical degradation. Slow filtration during DS isolation resulted in uncontrolled and elevated amorphous levels, while subsequent DP operations including blending, densification and compression increased amorphous content still further. A chemically stable final dosage unit would ideally involve a high bulk density, free flowing API that did not require densification in order to be commercialized as an oral dosage form with direct encapsulation of a single dosage unit. Despite every effort to modify the crystallization process, the physical properties of the API could not be improved. Here, an innovative isolation strategy using a thin film evaporation (TFE) process in the presence of a water soluble polymer alleviated filtration and drying risks and consistently achieved a high bulk density, free flowing co-processed API amenable to direct encapsulation. Characterization of the engineered materials suggested the lower amorphous levels and reduced shear sensitivity were achieved by coating surfaces of the API at relatively low polymer loads. This particle engineering route blurred conventional DS/DP boundaries that not only achieved improved chemical stability but also resulted in a optimized material, with simplified and more robust processing operations for both drug substance and drug product.
原料药（API）的物理性质对原料药（DS）的分离和干燥操作、简化药物产品（DP）的加工以及最终剂量单位的质量都至关重要。高纵横比、低堆密度、特别是 API“针状”物，这对高效处理造成了阻碍，而常规结晶途径改变这种具有挑战性的形态的可能性很低。本文评估的化合物表现出这种不理想的形态，加上对剪切敏感的额外复杂性。适度的剪切暴露导致热力学稳定的晶相转化为非晶相，然后非晶相经历加速化学降解。在 DS 分离过程中缓慢过滤导致不可控和升高的非晶态水平，而随后的 DP 操作，包括混合、致密化和压缩，进一步增加了非晶态含量。理想情况下，具有化学稳定性的最终剂量单位将涉及高堆密度、自由流动的 API，不需要致密化即可作为口服剂型商业化，直接封装单个剂量单位。尽管尽了一切努力来改变结晶过程，但 API 的物理性质仍无法得到改善。在这里，一种使用薄膜蒸发（TFE）工艺在水溶性聚合物存在下的创新分离策略缓解了过滤和干燥风险，并始终实现了高堆密度、自由流动的共处理 API，可直接封装。对工程材料的特性分析表明，较低的非晶态水平和降低的剪切敏感性是通过在相对较低的聚合物负载下涂覆 API 表面来实现的。这种颗粒工程途径模糊了传统的 DS/DP 边界，不仅实现了改善的化学稳定性，而且还得到了优化的材料，药物物质和药物产品的处理操作更加简化和稳健。
