(140a) A Reaction Database for Small Molecule Pharmaceutical Processes Integrated with Process Information: Future Developments | AIChE

(140a) A Reaction Database for Small Molecule Pharmaceutical Processes Integrated with Process Information: Future Developments


Gani, R. - Presenter, Technical University of Denmark
Papadakis, E., Technical University of Denmark
Kumar Tula, A., Auburn University
To resolve process engineering issues during the development of synthetic routes for new drugs at an early stage of process development, access to chemical information is needed, which can be provided through knowledge databases, experience, literature review and/or computer-aided tools [1,2]. The available data (knowledge) is used for similarity search, reaction data analysis, synthesis route planning, drug discovery-development and prediction of physicochemical properties [3]. A computer-aided tool for reaction synthesis based on efficient retrieval of chemical information that are organized in chemical reaction databases have been developed. The reaction data in the developed databases consist of individual reactions and chemical information for the associated molecules involved in the reactions.

At the current stage, the database covers 350 chemical and biochemical reaction systems with the data-information mentioned above. Extension of the database is an-going objective and involves several tasks. One current task is to develop and use algorithms for efficient collection of reaction data integrated with process information. This task is crucial and very demanding and requires tests to verify the accuracy of the data and check for their consistency, in the same way phase equilibria data are checked through established consistency tests. Another task is to create an efficient interface for data import-export integrated with tools for synthesis-design of pharmaceutical processes.

The overall objective is for the reaction database to cover a very wide range chemical and biochemical reaction systems and integrate it with generic model-based prediction tools that combines reaction pathways synthesis algorithms, solvent selection tools [5] consistency tests for reaction kinetics data, prediction of missing thermodynamic properties, process synthesis/design algorithms [6, 7], process analysis [6] and optimization tools [8]. Such an integrated computer aided tool will enhance the amount of data-information available, thereby reducing time and cost for problem solution. Also, the tool would provide useful insights for multi-objective optimization involving decision making related to screening of different alternatives for potential active ingredients candidates at the early stage of drug/process development.

This presentation will give a description of the developed reaction database where the objective is to collect-store data for reactions involved in the synthesis of small molecules in pharmaceutical processes together with a search engine to retrieve the data when required. For example, in studies involving the synthesis-design of reaction-separation schemes and/or the role of organic solvents in reaction performance improvement. The goal is to provide a data rich environment by making useful process information available during the early stage synthesis of pharmaceutical products. The database is structured based on a specially developed ontology in terms of reaction classification (reaction types); compounds participating in the reaction; need-use of organic solvents and their function; information for single step and multistep reactions; target products; reaction conditions and reaction kinetic data. Information related to reactor scale-up together with information on downstream separation and other relevant information for each reaction are also available in the database, including the references for the collected data. Additionally, the information available in the database allows the calculation of well-known “green” sustainability metrics [4]. The application of the database will be illustrated through the synthesis of ibuprofen, for which data on different reaction pathways are available whose performances are compared using “green” sustainability metrics.

[1] Caron, S.; Thomson, N.M. Pharmaceutical process chemistry: Evolution of a contemporary data-rich laboratory environment. J. Org. Chem. 2015, 80, 2943–2958.

[2] Gasteiger, J. Chemoinformatics: Achievements and challenges, a personal view. Molecules 2016, 21, 151.

[3] Warr, W.A. A short review of chemical reaction database systems, computer-aided synthesis design, reaction prediction and synthetic feasibility. Mol. Inform. 2014, 33, 469–476.

[4] Papadakis, E.; Anantpinijwatna, A.; Woodley, M.J.; Gani R. A reaction database for small molecule pharmaceutical processes integrated with process information. Processes. 2017, 5(4), 58.

[5] Gani, R.; Jiménez-González, C.; Ten Kate, A.; Jones, M.; Powell, L.; Atherton, J.H.; Cordiner, J.L.A modern approach to solvent selection product formulations. Chem. Eng. 2006, 113, 30-43

[6] Tula, A.K.; Eden, M.R.; Gani, R. Process synthesis, design and analysis using a process-group contribution method. Comput. Chem. Eng. 2015, 81, 245-259

[7] Emenike, V. N.; Schenkendorf, R.; Krewer, U. A systematic reactor design approach for the synthesis of active pharmaceutical ingredients. Eur. J. Pharm. Biopharm. 2018, 126, 75-88.

[8] Diab, S.A.; Jolliffe, H.G.; Gerogiorgis, D. I. Plantwide technoeconomic analysis and separation solvent selection for continuous pharmaceutical manufacturing: Ibuprofen, artemisinin, and diphenhydramine. Comput. Chem. Eng. 2018, 41, 85-120