Downloaded from orbit.dtu.dk on: Dec 23, 2016 Modelling and synthesis of pharmaceutical processes: moving from batch to continuous Papadakis, Emmanouil; Gani, Rafiqul; Woodley, John Publication date: 2016 Document Version Peer reviewed version Link to publication Citation (APA): Papadakis, E., Gani, R., & Woodley, J. (2016). Modelling and synthesis of pharmaceutical processes: moving from batch to continuous. Kgs. Lyngby: Technical University of Denmark. 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If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. 2016 Modelling and synthesis of pharmaceutical processes: moving from batch to continuous to batch from moving pharmaceutical processes: of Modelling and synthesis Modelling and synthesis of pharmaceutical processes: moving from batch to continuous Emmanouil Papadakis PhD Thesis September 2016 Department of Chemical and Biochemical Engineering Technical University of Denmark Søltofts Plads, Building 229 2800 Kgs. Lyngby Emmanouil Papadakis Denmark Phone: +45 45 25 28 00 Web: www.kt.dtu.dk/ Modelling and synthesis of pharmaceutical processes: moving from batch to continuous Doctor of Philosophy Thesis Emmanouil Papadakis KT-Consortium Department of Chemical and Biochemical Engineering Technical University of Denmark Kgs. Lyngby, Denmark Friday, 30th September 2016 DTU Chemical Engineering Department of Chemical and Biochemical Engineering PREFACE This thesis is submitted as partial fulfilment of the requirements for the Doctor of Philosophy (PhD) degree at the Technical University of Denmark (DTU). The PhD project was carried out at the research group “PSE for SPEED” at the Department of Chemical and Biochemical Engineering from October 2013 to September 2016 under the guidance of Professor Rafiqul Gani as the main supervisor and Professor John M. Woodley as co-supervisor. The project has been financed by the Technical University of Denmark (DTU). First of all, I would like to express my gratitude to my supervisor Professor Gani his support, enthusiasm, inspiring ideas and valuable criticism. I am grateful for all amazing opportunities I’ve been given and for all his time and patience spent on me. I would like to thank Professor John Woodley for his critical comments, feedback and enthusiasm. Finally, I would like to thank Dr. Sven Pedersen, from Novozymes. I would also like to thank Professor Gernaey for all his help, guidance, fruitful discussions and feedback that he provided me. I thank all my current and former co-workers and friends at “PSE for SPEED” and the CAPEC- PROCESS, Soheil, Stefano, Anjan, Mariona, Miguel, Peam, Rebecca, Sawitree, Zainatul and Deenesh. Special thanks to my friends from DTU basketball club, especially I would like thank all the players of the second team that I have the pleasure to coach and enjoying the privilege of being part of a real team. In addition, I would like to thank Cristina, Giannis and Brais for the valuable time spending together on Friday nights. My very good friends from University of Patras, Anna, Giannis and Giorgos and my very good friend, Vaggelis, from my hometown at Kissamos. Finally, I would like to thank my colleagues from Prof. Pistikopoulos group Maria, Ioana, Nikos for all the nice discussions and the pleasant time we had during the conferences. I couldn’t do much without endless support from my whole family, especially my parents (Ioannis and Chrisi) and my brother (Giorgos). They have always believed in me and supported me. I will be forever grateful for everything they did for me. And finally, I would like to thank Marina for being always on my side, for all her love, support during frustration times, our discussions and of course her unlimited patience. Emmanouil (Manolis) Papadakis September 2016, Kgs. Lyngby III ABSTRACT Research in pharmaceutical process development has gained a lot of interest over the last years. Long development times, increasing R&D costs, increasing competition, and short patent duration are some of the driving forces for the increased research efforts in the field. Increased process understanding of the pharmaceutical process has resulted in major improvements in the field. Process systems engineering (PSE) approaches, which have been successfully applied in the design, analysis and optimization of chemical and petrochemical processes, might be also important for the improvement of pharmaceutical processes by providing systematic and structured solutions for the stages of the pharmaceutical process development. In this PhD thesis, the objective is to systematize the pharmaceutical process development in order to enhance process understanding by creating a data-rich environment and to investigate/evaluate opportunities for continuous operation. To achieve the mentioned objectives the use of an integrated framework based on systematic model-based methods and tools is proposed. Computer-aided methods and tools are used to generate process knowledge and to evaluate different operational scenarios. The developed framework is divided into four main sections: the reaction pathway, reaction analysis, separation synthesis and process evaluation-operation based on evaluation. In the first section, the selection of the reaction pathway to produce a desired active ingredient is examined. A reaction database for small pharmaceutical molecules, including information for reactions, the solvent role and processing information, has been developed to assist the reaction pathway selection. In the second section, the reaction analysis, the identified individual reactions during the reaction pathway selection are analysed. The objective of the reaction analysis section is to collect reaction data and by using model-based methods to investigate possibilities of reaction improvement by evaluating the reaction conditions, the operating mode, the solvent role, and the reactor design. In the third section, alternatives for the separation of the reaction mixture are generated based on the driving force principles and evaluated based on performance criteria, such as mass and energy utilization. Finally, the overall process is simulated and evaluated in terms of productivity and environmental impact. Process optimization studies are performed by defining optimization target based on the process analysis. The application of the developed integrated framework is highlighted through four case studies. In the first case study, the overall use of the framework is highlighted using the synthesis of ibuprofen as a motivating example. The second case study focuses on the application of the developed solvent selection methodology for solvent swap problems. The third case study focused on multiphase reaction systems and improvements through the combination of reaction-separation. Finally, model-based analysis-design is performed for the operation improvement of a glucose isomerization plant. V RESUME PÅ DANSK Forskning i farmaceutisk procesudvikling har opnået meget interesse i de seneste år. Lange udviklingstider, øgende F&U-omkostninger, øget konkurrence og korte patentvarigheder er nogle af de drivende kræfter for den øget forskningsindsats på området. Øget procesforståelse af den farmaceutiske proces har resulteret i de store forbedringer på området. Proces systemteknik (engelsk: PSE) fremgangsmåder, som er blevet anvendt med succes i design, analyse og optimering af kemiske og petrokemiske processer, kan også være vigtig for forbedringen af de farmaceutiske processer ved at give systematiske og strukturerede løsninger til faserne af den farmaceutiske procesudvikling. De centrale mål i denne afhandling er at systematisere den farmaceutiske procesudvikling for at forbedre forståelsen af processerne ved at skabe et data-rigt miljø og at undersøge / vurdere mulighederne for kontinuerlig drift. For at nå de nævnte mål foreslås en integreret systematisk platform baseret på systematiske modelbaserede metoder og værktøjer. Computerbaserede metoder og værktøjer bruges til at generere procesviden og/eller at anvende allerede tilgængelige viden til generering af data. Når detaljerede oplysninger for processen er til rådighed, kan ændringer forstås og knyttes til procesparametre og endelig forbundet med produktkvalitet og / eller andre procesydelseskriterier relateret til at omkostninger, bæredygtighed og energi. Platformen er opdelt i fire hovedafsnit, reaktionsstien, reaktionsanalyse, separationssyntese og processimulering / -evaluering og drift. I det første afsnit, er forbedringer relateret til valget af reaktionsveje. En database af reaktioner for små farmaceutiske molekyler, herunder oplysninger om reaktionerne, solventrolle og behandling af oplysninger, er blevet udviklet for at lette valget reaktionsvej. I det andet afsnit er procesforbedringerne relateret til de enkelte reaktioner, som kan forbedres ved at evaluere reaktionsbetingelserne, driftsform,