Process Design and Optimization for the Continuous Manufacturing of Nevirapine, an Active Pharmaceutical Ingredient for HIV Treatment

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 minim...

[1]  Roger A Sheldon,et al.  Fundamentals of green chemistry: efficiency in reaction design. , 2012, Chemical Society reviews.

[2]  Dimitrios I. Gerogiorgis,et al.  Technoeconomic Optimization of a Conceptual Flowsheet for Continuous Separation of an Analgaesic Active Pharmaceutical Ingredient (API) , 2017 .

[3]  Roger A. Sheldon,et al.  Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration Level™ concept , 2015 .

[4]  B. Likozar,et al.  Modelling chemical kinetics of a complex reaction network of active pharmaceutical ingredient (API) synthesis with process optimization for benzazepine heterocyclic compound , 2016 .

[5]  Yang Yang,et al.  Combined Cooling and Antisolvent Crystallization in Continuous Mixed Suspension, Mixed Product Removal Cascade Crystallizers: Steady-State and Startup Optimization , 2015 .

[6]  J. Proudfoot,et al.  Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 1. Tricyclic pyridobenzo- and dipyridodiazepinones. , 1991, Journal of medicinal chemistry.

[7]  Ferenc Faigl,et al.  The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds. , 2017, Bioorganic & medicinal chemistry.

[8]  D Tyler McQuade,et al.  Improved synthesis of mono- and disubstituted 2-halonicotinonitriles from alkylidene malononitriles. , 2013, Organic letters.

[9]  Timothy F Jamison,et al.  7‐Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir , 2018, Angewandte Chemie.

[10]  Soo Khean Teoh,et al.  Practical Assessment Methodology for Converting Fine Chemicals Processes from Batch to Continuous , 2016 .

[11]  Volker Hessel,et al.  Eco-efficiency Analysis for Intensified Production of an Active Pharmaceutical Ingredient: A Case Study , 2014 .

[12]  Dimitrios I. Gerogiorgis,et al.  Process modelling, design and technoeconomic evaluation for continuous paracetamol crystallisation , 2018, Comput. Chem. Eng..

[13]  Allan S. Myerson,et al.  Compact and Integrated Approach for Advanced End-to-End Production, Purification, and Aqueous Formulation of Lidocaine Hydrochloride , 2016 .

[14]  J L Sullivan,et al.  Pharmacokinetics of nevirapine: initial single-rising-dose study in humans , 1993, Antimicrobial Agents and Chemotherapy.

[15]  Dimitrios I. Gerogiorgis,et al.  Process Modeling, Simulation, and Technoeconomic Evaluation of Separation Solvents for the Continuous Pharmaceutical Manufacturing (CPM) of Diphenhydramine , 2017 .

[16]  N. Rodríguez-Hornedo,et al.  How cocrystals of weakly basic drugs and acidic coformers might modulate solubility and stability. , 2016, Chemical communications.

[17]  H. Bjørsvik,et al.  Continuous flow synthesis concatenated with continuous flow liquid–liquid extraction for work-up and purification: selective mono- and di-iodination of the imidazole backbone , 2016 .

[18]  Dimitrios I. Gerogiorgis,et al.  Process modelling, simulation and technoeconomic evaluation of crystallisation antisolvents for the continuous pharmaceutical manufacturing of rufinamide , 2018, Comput. Chem. Eng..

[19]  Dimitrios I. Gerogiorgis,et al.  Technoeconomic optimisation and comparative environmental impact evaluation of continuous crystallisation and antisolvent selection for artemisinin recovery , 2017, Comput. Chem. Eng..

[20]  Zoltan K. Nagy,et al.  Multiobjective Optimization of an Unseeded Batch Cooling Crystallizer for Shape and Size Manipulation , 2015 .

[21]  Allan S. Myerson,et al.  Continuous Crystallization of Cyclosporine: Effect of Operating Conditions on Yield and Purity , 2017 .

[22]  Haitao Li,et al.  An Integrated Process Analytical Technology (PAT) Approach for Pharmaceutical Crystallization Process Understanding to Ensure Product Quality and Safety: FDA Scientist’s Perspective , 2015 .

[23]  Klavs F Jensen,et al.  Reconfigurable system for automated optimization of diverse chemical reactions , 2018, Science.

[24]  Peter H Seeberger,et al.  A concise flow synthesis of efavirenz. , 2015, Angewandte Chemie.

[25]  Klavs F. Jensen,et al.  Design of Multistage Counter-Current Liquid–Liquid Extraction for Small-Scale Applications , 2017 .

[26]  Sreeraj Macha,et al.  In vitro–in vivo correlation for nevirapine extended release tablets , 2009, Biopharmaceutics & drug disposition.

[27]  Paul Sharratt,et al.  Achieving Continuous Manufacturing: Technologies and Approaches for Synthesis, Workup, and Isolation of Drug Substance May 20-21, 2014 Continuous Manufacturing Symposium. , 2015, Journal of pharmaceutical sciences.

[28]  Zoltan K. Nagy,et al.  Population balance model based multi-objective optimization and robustness analysis of a continuous plug flow antisolvent crystallizer , 2014, 2014 American Control Conference.

[29]  Allan S. Myerson,et al.  Development of Continuous Anti-Solvent/Cooling Crystallization Process using Cascaded Mixed Suspension, Mixed Product Removal Crystallizers , 2012 .

[30]  Dimitrios I. Gerogiorgis,et al.  Nonlinear Optimization via Explicit NRTL Model Solubility Prediction for Antisolvent Mixture Selection in Artemisinin Crystallization , 2017 .

[31]  Andreas Seidel-Morgenstern,et al.  Design and optimization of coupling a continuously operated reactor with simulated moving bed chromatography , 2014 .

[32]  Romaric Gérardy,et al.  Continuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges , 2018 .

[33]  Dimitrios I. Gerogiorgis,et al.  Plantwide Design and Economic Evaluation of Two Continuous Pharmaceutical Manufacturing (CPM) Cases: Ibuprofen and Artemisinin , 2015 .

[34]  Volker Hessel,et al.  Life cycle assessment of multi-step rufinamide synthesis – from isolated reactions in batch to continuous microreactor networks , 2016 .

[35]  Zoltan K. Nagy,et al.  Parametric, Optimization-Based Study on the Feasibility of a Multisegment Antisolvent Crystallizer for in Situ Fines Removal and Matching of Target Size Distribution , 2016 .

[36]  Paul Watts,et al.  Semi-continuous multi-step synthesis of lamivudine. , 2017, Organic & biomolecular chemistry.

[37]  A. Hill,et al.  Estimated costs of production and potential prices for the WHO Essential Medicines List , 2018, BMJ Global Health.

[38]  D. T. McQuade,et al.  Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine , 2013, Beilstein journal of organic chemistry.

[39]  D. Tyler McQuade,et al.  Increasing global access to the high-volume HIV drug nevirapine through process intensification , 2017 .

[40]  C. Oliver Kappe,et al.  Why flow means green – Evaluating the merits of continuous processing in the context of sustainability , 2017 .

[41]  Concepción Jiménez-González,et al.  Expanding GSK's solvent selection guide ― embedding sustainability into solvent selection starting at medicinal chemistry , 2011 .

[42]  Nilay Shah,et al.  Robust optimisation methodology for the process synthesis of continuous technologies , 2011 .

[43]  Do Yeon Kim,et al.  Operating Strategy for Continuous Multistage Mixed Suspension and Mixed Product Removal (MSMPR) Crystallization Processes Depending on Crystallization Kinetic Parameters , 2016 .

[44]  Tiffany Ellison,et al.  Active Pharmaceutical Ingredients for Antiretroviral Treatment in Low- and Middle-Income Countries: A Survey , 2014, Antiviral therapy.

[45]  Paul Watts,et al.  Flow Processing as a Tool for API Production in Developing Economies , 2017, Journal of Flow Chemistry.

[46]  Colin L Raston,et al.  Multi-step continuous-flow synthesis. , 2017, Chemical Society reviews.

[47]  Alexandros Koulouris,et al.  Optimize Manufacturing of Pharmaceutical Products with Process Simulation and Production Scheduling Tools , 2007 .