Stocker Michael W, Harding Matthew J, Todaro Valerio, Healy Anne Marie, Ferguson Steven
School of Chemical and Bioprocess Engineering, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland.
I-Form, The SFI Research Centre for Advanced Manufacturing, School of Chemical and Bioprocess Engineering, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland.
Pharmaceutics. 2022 May 14;14(5):1058. doi: 10.3390/pharmaceutics14051058.
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% / 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.
集成式原料药（API）与药品加工技术能够让临床疗效高但理化性质不佳的分子，通过与辅料直接共同加工制成先进的多组分中间体，从而实现商业化。此外，开发无需分离的框架将能够实现药物的端到端连续加工。这项工作的目的是纯化一个模型API（布洛芬钠）和杂质（布洛芬乙酯）体系，然后直接将其加工成固态制剂，而无需分离出固态API相。提出采用受限搅拌床结晶法，通过周期性或并行操作将不纯API的液流中的杂质含量从4%纯化至0.2%。该液流在中间罐中与聚合物溶液混合，使API能够直接喷雾包衣到微晶纤维素珠粒上。喷雾包衣工艺采用实验设计方法开发，通过改变工艺参数，可以控制药物负载效率以及API在珠粒上的结晶度。实验设计研究表明，溶剂量是控制药物负载效率的主要因素，而多种因素共同影响结晶度。流化床制得的产品非常适合加工成最终药品，随后可以进行包衣以控制药物释放。
