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Technoeconomic Optimization of Continuous Crystallization for Three Active Pharmaceutical Ingredients: Cyclosporine, Paracetamol, and Aliskiren
Industrial & Engineering Chemistry Research ( IF 3.8 ) Pub Date : 2018-07-12 , DOI: 10.1021/acs.iecr.8b00679 Samir Diab 1 , Dimitrios I. Gerogiorgis 1
Industrial & Engineering Chemistry Research ( IF 3.8 ) Pub Date : 2018-07-12 , DOI: 10.1021/acs.iecr.8b00679 Samir Diab 1 , Dimitrios I. Gerogiorgis 1
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Mixed suspension, mixed product removal (MSMPR) crystallizers are widely implemented for the continuous crystallization of active pharmaceutical ingredients (APIs), allowing enhanced efficiency, flexibility, and product quality compared to currently dominant batch crystallizer designs. Establishing cost-effective continuous crystallization process configurations for societally and economically important APIs is essential to ensure the successful implementation of end-to-end continuous pharmaceutical manufacturing (CPM) campaigns. Process modeling and optimization allow rapid, systematic comparative technoeconomic evaluations. This paper pursues total cost minimization of different crystallizer configurations of three APIs—cyclosporine, paracetamol, and aliskiren hemifumarate—whose continuous MSMPR crystallization has been experimentally demonstrated. Nonlinear optimization for total cost minimization is implemented for one to three crystallizers for different plant API capacities with crystallizer temperatures and residence times as decision variables. Optimization results show that the optimal number of crystallizers is dependent on plant capacity; implementing one crystallizer is preferred for all three APIs at 102 kg year–1, while multiple crystallizer implementation is more cost-beneficial at increased capacities. These trends are observed due to the increasing dominance of operating expenditures on total costs at increased capacities, making the benefits of implementing more crystallizers (enhanced yields, reduced utility loads) worth the increased capital expenditures. Process modeling and optimization allows rapid technoeconomic evaluation of MSMPR crystallizer configurations for different APIs toward systematic selection of optimal continuous crystallizer designs for continuous manufacturing.
中文翻译：
三种活性药物成分连续结晶的技术经济优化：环孢菌素，扑热息痛和阿利吉仑
混合悬浮液，混合产品去除（MSMPR）结晶器被广泛用于活性药物成分（API）的连续结晶，与目前占主导地位的批量结晶器设计相比，可以提高效率，灵活性和产品质量。为社会和经济上重要的API建立具有成本效益的连续结晶工艺配置对于确保成功实施端到端连续药物制造（CPM）活动至关重要。过程建模和优化可以进行快速，系统的比较技术经济评估。本文力求将三种API（环孢霉素，扑热息痛，和阿利吉仑半富马酸盐-其连续MSMPR结晶已通过实验证明。针对总成本最小化的非线性优化是针对一到三个结晶器来实现的，这些结晶器具有不同的工厂API容量，并且以结晶器温度和停留时间为决策变量。优化结果表明，结晶器的最佳数量取决于工厂的生产能力。对于10种所有三个API，最好实现一个结晶器每年2千克– 1千克，而多台结晶器的实施在增加产能的情况下更具成本效益。观察到这些趋势的原因是，随着产能的增加，运营支出在总成本中的支配地位越来越高，使得实施更多的结晶器（提高产量，减少公用事业负荷）带来的好处值得增加资本支出。工艺建模和优化允许针对不同API的MSMPR结晶器配置进行快速的技术经济评估，从而为连续制造提供系统的最佳连续结晶器设计选择。
更新日期：2018-07-14
中文翻译：
三种活性药物成分连续结晶的技术经济优化：环孢菌素，扑热息痛和阿利吉仑
混合悬浮液，混合产品去除（MSMPR）结晶器被广泛用于活性药物成分（API）的连续结晶，与目前占主导地位的批量结晶器设计相比，可以提高效率，灵活性和产品质量。为社会和经济上重要的API建立具有成本效益的连续结晶工艺配置对于确保成功实施端到端连续药物制造（CPM）活动至关重要。过程建模和优化可以进行快速，系统的比较技术经济评估。本文力求将三种API（环孢霉素，扑热息痛，和阿利吉仑半富马酸盐-其连续MSMPR结晶已通过实验证明。针对总成本最小化的非线性优化是针对一到三个结晶器来实现的，这些结晶器具有不同的工厂API容量，并且以结晶器温度和停留时间为决策变量。优化结果表明，结晶器的最佳数量取决于工厂的生产能力。对于10种所有三个API，最好实现一个结晶器每年2千克– 1千克，而多台结晶器的实施在增加产能的情况下更具成本效益。观察到这些趋势的原因是，随着产能的增加，运营支出在总成本中的支配地位越来越高，使得实施更多的结晶器（提高产量，减少公用事业负荷）带来的好处值得增加资本支出。工艺建模和优化允许针对不同API的MSMPR结晶器配置进行快速的技术经济评估，从而为连续制造提供系统的最佳连续结晶器设计选择。
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