Process design and optimisation for the continuous manufacturing of Nevirapine, an Active Pharmaceutical Ingredient (API) for H.I.V. treatment

Development of efficient and cost-effective manufacturing routes towards HIV active pharmaceutical ingredients (APIs) is essential to ensure their global, 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 technoeconomic optimisation of nevirapine CPM, including the continuous flow synthesis and a conceptual continuous crystallisation. Arrhenius law parameter estimation from published reaction kinetic data allows explicit modelling of the temperature-dependence of reaction performance and an experimentally validated aqueous API solubility computation method is used to model crystallisation processes. A nonlinear optimisation problem for cost minimisation is formulated for comparative evaluation of different plant designs. Higher reactor temperatures are favoured for CPM total cost minimisation, while lower pH (less neutralising agent) is required to attain the desired plant capacities for cost optimal configurations compared to batch crystallisation 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 towards reducing the price of societally- mportant HIV medicines.