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Integrated Purification and Formulation of an Active Pharmaceutical Ingredient via Agitated Bed Crystallization and Fluidized Bed Processing
Pharmaceutics ( IF 5.4 ) Pub Date : 2022-05-14 , DOI: 10.3390/pharmaceutics14051058
Michael W Stocker 1 , Matthew J Harding 1, 2 , Valerio Todaro 3 , Anne Marie Healy 3 , Steven Ferguson 1, 2, 4, 5
Affiliation  

Integrated API and drug product processing enable molecules with high clinical efficacy but poor physicochemical characteristics to be commercialized by direct co-processing with excipients to produce advanced multicomponent intermediates. Furthermore, developing isolation-free frameworks would enable end-to-end continuous processing of drugs. The aim of this work was to purify a model API (sodium ibuprofen) and impurity (ibuprofen ethyl ester) system and then directly process it into a solid-state formulation without isolating a solid API phase. Confined agitated bed crystallization is proposed to purify a liquid stream of impure API from 4% to 0.2% w/w impurity content through periodic or parallelized operations. This stream is combined with a polymer solution in an intermediary tank, enabling the API to be spray coated directly onto microcrystalline cellulose beads. The spray coating process was developed using a Design of Experiments approach, allowing control over the drug loading efficiency and the crystallinity of the API on the beads by altering the process parameters. The DoE study indicated that the solvent volume was the dominant factor controlling the drug loading efficiency, while a combination of factors influenced the crystallinity. The products from the fluidized bed are ideal for processing into final drug products and can subsequently be coated to control drug release.

中文翻译:

通过搅拌床结晶和流化床工艺对活性药物成分进行一体化纯化和配制

原料药和药物产品的一体化加工使临床疗效高但理化特性差的分子能够通过与赋形剂的直接协同加工实现商业化,生产先进的多组分中间体。此外,开发无隔离框架将使药物的端到端连续处理成为可能。这项工作的目的是纯化模型 API(布洛芬钠)和杂质(布洛芬乙酯)系统,然后直接将其加工成固态制剂,而无需分离固体 API 相。提出了限制搅拌床结晶以将不纯 API 的液体流从 4% 提纯到 0.2% w / w通过定期或并行操作处理杂质含量。该流与中间罐中的聚合物溶液结合,使 API 能够直接喷涂到微晶纤维素珠上。喷涂工艺是使用实验设计方法开发的,允许通过改变工艺参数来控制药物装载效率和 API 在微丸上的结晶度。DoE 研究表明,溶剂体积是控制载药效率的主要因素,而多种因素共同影响结晶度。流化床的产品非常适合加工成最终的药物产品,随后可以进行包衣以控制药物释放。
更新日期:2022-05-14
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