Safer Solvents can Replace Dichloromethane in Pharmaceutical Manufacturing
For a three-year period, TURI collaborated with Dr. Hsi-Wu Wong and his research team from the UMass Lowell Chemical Engineering Department, Dr. Grace Chen and her research team from the UMass Lowell Plastics Engineering Department, and representatives from Johnson Matthey (now called Veranova) to find and evaluate safer alternatives to dichloromethane (DCM) used in the manufacture of pharmaceuticals. The U.S. Department of Health and Human Services and the U.S. Environmental Protection Agency (EPA) have associated DCM with a variety of health problems, including cancer and damage to the central nervous system. DCM also endures in the environment, with a half-life in water of more than 18 months. The purification of active pharmaceutical ingredients (APIs) often requires the use of column chromatography (CC). This technique uses DCM thereby exposing workers of this industry sector to health and safety risks and also contributes to chlorinated solvent waste.
Three hazardous chemicals rating systems were used to evaluate the safety of possible alternatives: (1) GreenScreen®, (2) Pollution Prevention Options Analysis System (P2OASYS), and (3) the GlaxoSmithKline (GSK) solvent selection guide. The Toxics Use Reduction Act has DCM as a higher hazard substance in 2014. The safer solvents evaluated all had better GreenScreen, P2OASys, and GSK ratings than DCM. The alternatives were also evaluated for their cost as compared to DCM. Two safer alternatives methyl acetate and acetone cost less than DCM, and two safer alternatives ethyl acetate and 1,3 dioxolane had slightly higher cost than DCM.
Thin-layer chromatography (TLC) was used as a screening technique to investigate if an alternative solvent or solvent blend could show comparable separation performance to DCM. Several safer solvent blends (e.g., mixtures composed of methyl acetate and ethyl acetate) with adequate TLC performance were identified. These results provided guidance for the next step of identifying and evaluating safer solvents to separate APIs using column chromatography. The results are documented in a Separations Journal article.
The next step to evaluate the performance of safer solvents as compared to DCM was to conduct the purification of ibuprofen, aspirin, and acetaminophen as model APIs, with a model impurity, caffeine, using a lab-scale column chromatography. Overall, the safer solvents provided better economic potential (lower volumes used and higher API recovery) compared to DCM in addition to health, safety, and environmental benefits (safer ratings and lower E-factor values), with a compromise of API purity and flexibility in separation. Ethyl acetate and methyl acetate demonstrated better performance, with larger windows of operation, higher recovery ratios, and lower E-factors. In conclusion, our research demonstrates the ability of these solvents to be potential good replacements to DCM and thereby addressing the safety concerns in the pharmaceutical manufacturing processes while providing comparable or better performance compared to DCM. The results of the column chromatography tests were published in the ACS Environmental Au journal.
-Greg Morose, Research Manager
