(575c) Systematic Design of Solvent Recovery Systems in Pharmaceutical Processes

The global pharmaceutical market is projected to nearly double in size between the years of 2020 and 2028[1]. This growth has raised concerns around the sustainability of the industry as a majority of pharmaceutical products are formed through organic synthesis routes that require many sequential reaction steps, and large quantities of multiple organic solvents. Product formation processes are followed by downstream operations such as numerous solid-liquid separation and purification steps [2], [3] that generate waste streams containing organic solvents since they are not a part of the reaction stoichiometry. It is common in the pharmaceutical industry for solvents to account for 80-90% of the mass intensity for the process and due to the stringent purity requirements for solvents, these are often discarded after a single use.[4]–[6]. A common method for estimating the “greenness” of a process is to calculate the E-factor which is a measure of the mass of waste generated per mass of product. Due to the various sources of waste generation, the API (Active Pharmaceutical Ingredient) manufacturing process has an E-factor (mass of waste per mass of product) usually between 25 and 100 [7]. Current leaders in the Pharmaceutical industry like AstraZeneca and Glaxo-Smith-Kline (GSK) have implemented Life Cycle Assessment (LCA) metrics to evaluate the emissions associated with their process. It has become important to identify and optimize the “hot spots” of these processes in relation to their life cycle. In the case of the Pharmaceutical industry one such hot spot is the solvent consumption, with the current research being into selecting “greener” solvents. The focus has been put on obtaining higher reaction yields rather than developing systems that can recover, purify, and reuse solvents and thus reduce the amount of fresh solvent required in a process.

This work proposes the development of roadmap and associated software tool for the systematic design of solvent recovery processes that emphasize the importance of physical properties and stream composition-based resource conservation and recovery. The solvent recovery roadmap is generated using a stage-wise superstructure approach consisting of technology models. Each technology is modeled as a set of mass/energy balance and design equations. These models are then formulated as a mixed integer non-linear programming (MINLP) problem in General Algebraic Modeling System (GAMS). By implementing binary variables, used to make “yes” or “no” decisions, we are able to select a path that is simultaneously optimized for minimum cost and environmental impact while meeting quality requirements. The associated software tool is created using MATLAB to generate a graphical user interface (GUI). This GUI is used to allow the user to define the components, composition, and desired quality specifications and display the relevant reports from the GAMS model. These reports include key performance indicators (KPIs) in the pharmaceutical industry such as carbon footprint, process mass intensity (PMI), water usage, and cost per kilogram of solvent recovered. To test the validity of this application, a series of case studies from a major pharmaceutical company were analyzed. The complexity of these case studies ranged from a simple binary system to a five-component system with multiple azeotropic mixtures.

[1] “Pharmaceutical Manufacturing Market Size Report, 2021-2028.” https://www.grandviewresearch.com/industry-analysis/pharmaceutical-manuf... (accessed Mar. 07, 2022).

[2] R. G. Harrison, “Bioseparation Basics,” Chemical Engineering Progress, Oct. 2014. Accessed: Jun. 14, 2016. [Online]. Available: http://www.aiche.org/resources/publications/cep/2014/october/bioseparati...

[3] P. A. Belter, E. L. Cussler, and W.-S. Hu, Bioseparations: downstream processing for biotechnology. USA: Wiley, 1988.

[4] C. Jimenez-Gonzalez, C. S. Ponder, Q. B. Broxterman, and J. B. Manley, “Using the Right Green Yardstick: Why Process Mass Intensity Is Used in the Pharmaceutical Industry To Drive More Sustainable Processes,” Org. Process Res. Dev., vol. 15, no. 4, pp. 912–917, Jul. 2011, doi: 10.1021/op200097d.

[5] M. J. Raymond, C. Stewart Slater, and M. J. Savelski, “LCA approach to the analysis of solvent waste issues in the pharmaceutical industry,” Green Chem., vol. 12, no. 10, pp. 1826–1834, 2010, doi: 10.1039/C003666H.

[6] R. K. Henderson et al., “Expanding GSK’s solvent selection guide – embedding sustainability into solvent selection starting at medicinal chemistry,” Green Chem., vol. 13, no. 4, pp. 854–862, 2011, doi: 10.1039/C0GC00918K.

[7] R. A. Sheldon, “The E Factor: fifteen years on,” Green Chem., vol. 9, no. 12, pp. 1273–1283, 2007, doi: 10.1039/B713736M.