Continuous Pharmaceutical Manufacturing (CPM) has the potential to revolutionize the pharmaceutical industry, with many expected benefits in terms of cost, efficiency, and quality. Process modeling and optimization are valuable methodologies for comparative technoeconomic evaluations: this paper pursues total upstream CPM cost minimization via two nonlinear optimization methods. An explicit NRTL solubility estimation method has been used in order to analyze the potential performance of three binary antisolvent mixtures for the crystallization of artemisinin. This Active Pharmaceutical Ingredient (API) is a key antimalarial substance and has been the focus of several CPM studies, including continuous chemistry and separation. Ethanol, acetone, and ethyl acetate are the three antisolvents studied. Used as a binary antisolvent with toluene as the solvent, the composition of the binary antisolvent, the quantity of the binary antisolvent with respect to the process solvent, and the temperature of the overall mixture is cooled to in the crystallization process are formulated as the three key variables in a nonlinear optimization problem. Two solvers are used, NOMAD and NLOPT-BOBYQA. Results show that they have very similar precision (<1% difference), but that the latter is up to 66% faster; NLOPT-BOBYQA was used for the majority of optimization cases. Results show that the size of the temperature gradient of the crystallization has a much stronger effect on the total cost than the quantity of antisolvent used. Nearly pure antisolvent use is favored for yielding lowest total costs for a single crystallizer (pure ethyl acetate is most favored, followed by ethanol, with acetone last). When considering multiple, identically-sized crystallizers in series, results indicate that higher API recovery, E-factor, and Operating Expenditure (OpEx) benefits can be achieved when using two crystallizers, but these metrics worsen with three or more; Capital Expenditure (CapEx) follows the same trend. For sequential crystallizers of varying size, increasing the number of crystallizers also benefits OpEx, E-factor, and API recovery, but CapEx continues to increase, thereby promising technical but no economic benefits.

中文翻译：

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通过显式NRTL模型溶解度预测进行非线性优化，以选择青蒿素结晶中的反溶剂混合物

连续制药制造（CPM）有潜力革新制药行业，在成本，效率和质量方面具有许多预期的好处。过程建模和优化是进行比较技术经济评估的有价值的方法：本文通过两种非线性优化方法追求总的上游CPM成本最小化。为了分析三种二元反溶剂混合物对青蒿素结晶的潜在性能，已使用了显式的NRTL溶解度估算方法。这种活性药物成分（API）是一种重要的抗疟疾药物，一直是包括连续化学和分离在内的几项CPM研究的重点。乙醇，丙酮和乙酸乙酯是研究的三种抗溶剂。用作甲苯的二元抗溶剂，该二元抗溶剂的组成，相对于工艺溶剂的二元抗溶剂的量以及在结晶过程中将整个混合物的温度冷却至以下三个条件：非线性优化问题中的关键变量。使用了两个求解器：NOMAD和NLOPT-BOBYQA。结果表明，它们具有非常相似的精度（相差<1％），但后者的速度最高可提高66％；NLOPT-BOBYQA用于大多数优化案例。结果表明，结晶温度梯度的大小对总成本的影响远大于所用反溶剂的数量。推荐使用几乎纯的抗溶剂剂，以使单个结晶器的总成本最低（最优选纯乙酸乙酯，其次是乙醇，最后是丙酮）。当考虑串联使用多个相同大小的结晶器时，结果表明，使用两个结晶器可实现更高的API回收率，E因子和运营支出（OpEx）效益，但三个或三个以上结晶器会恶化这些指标。资本支出（CapEx）也遵循同样的趋势。对于大小不同的顺序结晶器，增加结晶器数量也会使OpEx，E因子和API回收率受益，但是CapEx会继续增加，因此在技术上却没有经济上的好处。但是这些指标随着三个或更多而恶化；资本支出（CapEx）也遵循同样的趋势。对于大小不同的顺序结晶器，增加结晶器数量也会使OpEx，E因子和API回收率受益，但是CapEx会继续增加，因此在技术上却没有经济上的好处。但是这些指标随着三个或更多而恶化；资本支出（CapEx）也遵循同样的趋势。对于大小不同的顺序结晶器，增加结晶器数量也会使OpEx，E因子和API回收率受益，但是CapEx会继续增加，因此在技术上却没有经济上的好处。