Modelling and synthesis of pharmaceutical processes: moving from batch to continuous

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.