DMSO is a standard process solvent in API manufacturing, but residual DMSO stays in the isolated solid cake and must be controlled to release. Its high boiling point and full water miscibility make it harder to remove than low-boiling solvents. Under ICH Q3C(R6), DMSO is a Class 3 solvent.
The Regulatory Limit
Class 3 solvents have low toxic potential and no known human health hazard at typical exposure, which places DMSO alongside water and ethanol rather than in the restricted Class 2 group. The limit below is the number a process team designs the drying step against.
| Parameter | Value |
|---|---|
| Solvent | Dimethyl sulfoxide (CAS 67-68-5) |
| ICH Q3C class | Class 3 |
| Permitted daily exposure (PDE) | 50 mg/day |
| Concentration limit (≤ 10 g/day dose) | 5000 ppm (0.5%) |
| Boiling point | 189 °C |
Table 1: ICH Q3C classification and limit for DMSO
For doses above 10 g/day, the allowable residual concentration is recalculated from the 50 mg/day PDE. USP general chapter <467> and European Pharmacopoeia 2.4.24 adopt the same limit, and residual DMSO data are filed in the Drug Master File and NDA or ANDA submission.
Detection and Removal
Release testing runs by headspace GC with flame ionization detection (HS-GC-FID). Because DMSO boils at 189 °C, the headspace oven must be held at 80–120 °C with 30–60 minute vial equilibration to transfer it efficiently onto a polar column; a developed method reaches a limit of quantitation around 5–50 ppm, well below the 5000 ppm release limit. DMAc and DMF are unsuitable dissolution solvents because they elute near DMSO, so water or a semi-volatile diluent is used.
With a vapor pressure near 0.6 mmHg at 20 °C, DMSO strips slowly from a solid API. The standard step is vacuum drying at 40–80 °C for 12–48 hours in tray, conical, or rotary vacuum dryers. Recrystallization or anti-solvent washing is often more efficient, because DMSO is fully miscible with water and ethanol and is displaced from the crystal lattice on the filter. For heat-sensitive APIs and amorphous dispersions, spray drying or freeze-drying removes solvent during isolation.
DMSO Solvates vs Residual Solvent
Not every DMSO in an API is a residual solvent. When DMSO is incorporated into the crystal lattice as a stoichiometric solvate, as in trametinib, it is not classified under ICH Q3C; the solvate is part of the drug substance and is regulated through its own monograph. Distinguishing a solvate from adsorbed solvent is therefore the first analytical question, because it decides whether the 5000 ppm limit applies at all.
References
- ICH Harmonised Tripartite Guideline Q3C(R6): Impurities — Guideline for Residual Solvents, 2019.
- United States Pharmacopeia, General Chapter <467> Residual Solvents.
- Rocha, T. C.; et al. Development and validation of a GC-FID headspace method for DMSO residual solvent determination. J. Pharm. Biomed. Anal. 2019, 164, 432–439.