Technoeconomic Mixed Integer Nonlinear Programming (MINLP) optimization for design of Liquid-Liquid Extraction (LLE) cascades in continuous pharmaceutical manufacturing of atropine
Technoeconomic Mixed Integer Nonlinear Programming (MINLP) optimization for design of Liquid-Liquid Extraction (LLE) cascades in continuous pharmaceutical manufacturing of atropine
复制标题
阿托品连续制药生产中液液萃取 (LLE) 级联设计的技术经济混合整数非线性规划 (MINLP) 优化
DOI：
10.1002/aic.16738
复制
发表时间：
2019
期刊：
影响因子：
3.7
通讯作者：
Diab S
中科院分区：
文献类型：
--
作者：
Diab S
连续药品制造 (CPM) 比目前业界采用的主流方法具有更高的运营和经济效益。所展示的阿托品连续流合成有助于对其上游连续制造进行建模和优化。本研究对连续液液萃取 (LLE) 流程上部结构实施了 MINLP 优化，以最大限度地降低上游阿托品 CPM 工厂的总成本。稳态过程模型根据回归动力学参数考虑反应器设计，包括研究最大允许 PFR 反应器尺寸，以最大限度地发挥 API 流合成的优势。连续 LLE 建模考虑了相间的溶质分配、UNIFAC 模型的液液平衡以及 LLE 设计的传质相关性。所考虑的上部结构的最佳 LLE 设计配置除了级联中的逆流外，还需要以并流方式将新鲜溶剂添加到第一个容器中。优化结果表明，甲苯是最佳溶剂选择，对于 103kgAPI 年−1 的工厂产能，总成本为 3.944 × 106GBP。
Continuous Pharmaceutical Manufacturing (CPM) offers operational and economic benefits over the currently dominant methods implemented by industry. The demonstrated continuous flow synthesis of atropine facilitates modeling and optimization of its upstream continuous manufacturing. This study implements MINLP optimization of a continuous Liquid‐Liquid Extraction (LLE) flowsheet superstructure for total cost minimization of an upstream atropine CPM plant. The steady‐state process model considers reactor design from regressed kinetic parameters including investigation of maximum allowable PFR reactor dimensions to maximize the benefits of API flow synthesis. Continuous LLE modeling considers solute partitioning between phases, UNIFAC‐modeled liquid–liquid equilibria and mass transfer correlations for LLE design. Optimal LLE design configurations from the considered superstructure require fresh solvent added to the first vessel in co‐current flow in addition to the countercurrent flow in the cascade. Optimization results indicate toluene as the best solvent choice, with total costs of 3.944 × 106GBP for a plant capacity of 103kg API year−1.