The development of efficient and cost-effective manufacturing routes toward HIV active pharmaceutical ingredients (APIs) is essential to ensure their global and affordable access. Continuous pharmaceutical manufacturing (CPM) is a new production paradigm for the pharmaceutical industry whose potential for enhanced efficiency and economic viability over currently implemented batch protocols offers promise for improving HIV API production. Nevirapine is a widely prescribed HIV API whose continuous flow synthesis was recently demonstrated. This paper presents the technoeconomic optimization of nevirapine CPM, including the continuous flow synthesis and a conceptual continuous crystallization. Arrhenius law parameter estimation from published reaction kinetic data allows explicit modeling of the temperature dependence of the reaction performance, and an experimentally validated aqueous API solubility computation method is used to model crystallization processes. A nonlinear optimization problem for cost minimization is formulated for comparative evaluation of different plant designs. Higher reactor temperatures are favored for CPM total cost minimization, while lower pH (less neutralizing agent) is required to attain the desired plant capacities for cost-optimal configurations compared with batch crystallization designs. Suitable E-factors for pharmaceutical manufacturing are attained when higher solvent recoveries are assumed. Implementing CPM designs significantly lowers the nevirapine cost of goods toward reducing the price of societally important HIV medicines.

• University of Edinburgh
• Virginia Commonwealth University

• API
• Modeling

1. API
2. Continuous crystallization
3. modeling
4. Nevirapine
5. Optimization
6. Process design
7. Research Article
8. technoeconomical