(674a) Safer Solvents for Active Pharmaceutical Ingredients Purification Using Column Chromatography

Dichloromethane (DCM) is a widely used solvent in the polymer, chemical, and pharmaceutical sectors for the separation of chemicals using column chromatography. The annual production of DCM in the United States in 2012 was 260 million pounds. The United States remains highly dependent on this toxic chemical since it is extensively used as an extractant for the decaffeination of coffee in the food industry, as a coating remover, and other applications. In the pharmaceutical sector, DCM has often been utilized in chromatographic applications, particularly liquid chromatography, for the synthesis of active pharmaceutical ingredients (API). For instance, approximately 554,000 pounds of DCM were used by Johnson Matthey in 2019 for API purification. DCM has been linked to a variety of health problems, including cancer and the damage of the central nervous system. Furthermore, DCM is designated as a Higher Hazard Substance under the Massachusetts’ Toxics Use Reduction Act, as a GreenScreen® Benchmark score of BM-1 and has a GSK rating of 4. Replacing this toxic solvent with a safer alternative(s) will provide significant environmental, health, and safety benefits. The major challenge is the performance and cost of the alternative solvents which cannot be compromised so that the businesses can stay competitive.

Replacing DCM by a safer solvent (SS) and/or a safer solvent blend (SSB) alternative has remained a hurdle to researchers over the past several decades. Jessop et al. (2012) reported DCM as one of the problematic solvents which safer substitute has not yet been found. Taygerly et al. (2012) developed a solvent guide to help determine alternatives to DCM in chromatographic applications based on safety, environmental impact, toxicity, and other factors. Chen et al. (2021) developed a methodology, that utilized Hansen Solubility Parameter (HSP), dissolution power, safety, and price, to down-select solvents that were then applied to thin-layer chromatography (TLC) to identify SS and SSB that could serve as an alternative to DCM in the separation of widely used APIs (acetaminophen, aspirin, and ibuprofen) from caffeine. The goal of this study is to use the SS and SSB identified by Chen et al. to determine, through column chromatography, which of them could be safer alternatives to DCM for the separation of widely used APIs from caffeine.

During this research, a Synthwareâ„¢ Chromatography Column of 13.4 mm in diameter and 203 mm in length, with Standard Taper Joint and 1000 ml reservoir was used for the laboratory-scale experiments. Silica Gel 60, 0.060-0.2mm (70-230 mesh) was used as the polar stationary phase, while the baseline solvent (DCM) and each of the SS (ethyl acetate, methyl acetate, 1, 3 dioxolane, and dimethyl adipate) as well as the SSB (dimethyl adipate and ethyl acetate, dimethyl adipate and 1, 3 dioxolane, methyl acetate and ethyl acetate) are used as the mobile phases.

The stationary phase is wet packed while the APIs including caffeine are injected into the column when dissolved into the mobile phase being used to run the column. The compounds (API + caffeine) to silica gel ratio for every experiment was 1:40. The volumes collected for the baseline solvent (DCM) was 80 ml, with 50 mg calibration standards, while those collected for the SS and SSB were 3 ml, with 1 mg calibration standards.

Initial results depict a recovery factor (RF) of 0.66 and 0.73, respectively, for the separation of aspirin and ibuprofen from caffeine with DCM. Both APIs were 100% pure while no caffeine was recovered. When separating acetaminophen from caffeine, no analyte was recovered. All experiments using DCM required large amounts of solvent.

Safer solvents depicted RFs ranging from 0.91 – 0.99 for the separation of ibuprofen from caffeine, 0.75 – 0.93 for the separation of aspirin from caffeine, and 0.2 – 0.29 for the separation of acetaminophen from caffeine. The purity of each API was 99% and higher, except for the cases when 1, 3 dioxolane was used as mobile phase where the purity was 98% and higher. Far smaller amounts of safer solvents were used for the separation of APIs from caffeine compared to the amounts used for DCM.

The RFs for safer solvent blends ranged from 0.68 – 0.89 for the separation of Ibuprofen from Caffeine, 0.63 – 0.97 for the separation of aspirin from caffeine, and 0.23 – 0.28 for the separation of acetaminophen from caffeine. The purity of each API was 99% and higher, and far smaller amounts of SSBs were used for the separation of APIs from caffeine compared to the amounts used for DCM.

The results suggest that the dependence on DCM by pharmaceutical industry can be overcome by redesigning chromatographic applications to SS and/or SSB used in this study as the mobile phase, as more APIs shall be recovered with far less solvent quantities utilized for their recovery. The importance of using these SS/SSB to replace DCM cannot be overemphasized as it will greatly improve the health and safety of employees of this sector, and considerably limit the proliferation of toxic chemicals in the environment.