Safety Concerns in a Pharmaceutical Manufacturing Process Using Dimethyl Sulfoxide (DMSO) as a Solvent

Abstract

During the process safety analysis of a fluoride displacement reaction, a highly exothermic event was observed when the reaction mixture was heated, which appears to be due to the decomposition of DMSO catalyzed by the HF byproduct from the displacement reaction. Although the T D24 for the decomposition is 42 °C above the reaction temperature and the synthesis reaction is mild, the consequences of the decomposition reaction are severe and could exceed the emergency venting capability of the reactor in the case of uncontrolled heating or an external fire, even at pilot plant scale. The use of several bases, cosolvents, and alternative solvents was investigated. Administrative safeguards, including temperature control system limits and removal of flammable solvents from the area, were identified to establish a basis of safety for a scale up to pilot scale. However, these safeguards would be impractical in a manufacturing facility. Eventually, an N-methyl-2-pyrrolidone (NMP)/tert-butyl methyl ether (MTBE) solvent system was identified, which provided an acceptable process while eliminating the use of DMSO and the associated decomposition reaction. This work shows some of the potential hazards that need to be investigated when using DMSO in a process. While DMSO alone can decompose near its boiling point, the effect of impurities, including byproducts of reactions, can lower the onset and increase the rate of this decomposition. Also, although this process falls into a Stoessel criticality index of 2, which is on the lower risk side of the scale, this case provides a good example where a low probability event needs to be investigated due to the severity of the consequences.

Developing Efficient Nucleophilic Fluorination Methods and Application to Substituted Picolinate Esters

“…Our initial additive screening efforts focused on reaction parameters where DMSO was the solvent medium; however, it became prudent to identify other process-friendly solvents that could alleviate potential scale-up problems associated with DMSO. 11 Amide solvents (e.g., NMP) as well as less toxic solvents (e.g., sulfolane) were evaluated under standard screening reaction conditions, and the fluorination yields were compared to DMSO results ( Figure 4). For this effort, 98% Bu 3 MeNCl was chosen as the additive without further purification or drying efforts.…”

From sugars to FDCA: a techno-economic assessment using a design concept based on solvent selection and carbon dioxide emissions

“…However, their negligible vapour pressure makes them very safe to handle in an industrial plant and easy to recover due to their high thermal and chemical stability. In contrast, DMSO has low toxicity to aquatic life and humans on account of its biodegradability but it undergoes decomposition under acidic or basic conditions at high temperatures 103,104 and to methyl sulfide and dimethyl sulfide under oxidative conditions. 105,106 Table 9 summarises these properties using a scoring technique with the aim of evaluating the safety considerations when using these solvents.…”

Comparison of Perovskite Solar Cells with other Photovoltaics Technologies from the Point of View of Life Cycle Assessment

“…[109] Of the solvents assessed, DMSO has the lowest total impact being the solvent, which is both the most environmentally friendly and least deleterious to human health. [109] Although some issues are acknowledged: [115][116][117][118][119][120][121] DMSO can decompose exothermically near its atmospheric boiling point, and the presence of other chemicals such as acids, bases, several halides, sodium hydride, or perchloric acid can reduce the onset temperature; there is an odor issue with heavy use in water treatment plants, and DMSO can also carry contaminants/toxins on the skin or dissolved materials with it across the membranes.…”