Pharmaceuticals 9th March 2023 5 min read

The quest for viable and sustainable alternatives to DMF

The Context

Dimethylformamide (DMF, N,N-dimethylformamide, CAS 68-12-2) is an amide of formic acid used as a polar organic solvent. DMF is considered a CMR substance (Carcinogens - Mutagens - Reprotoxic) and was therefore included in the SVHC Candidate List (Substances of Very High Concern) on 19 December 2012.

On 22nd November 2021, the European Union (EU) published Regulation (EU) No 2021/2030 with an amendment to Annex XVII of REACH as regards N,N-dimethylformamide, which entered in force on 9th December 2021.

DMF was added as Entry 76 in Annex XVII to Regulation (EC) No 1907/2006 with the following restrictions:

The Need

Despite the pressure from regulatory authorities, DMF continues to play an important role in organic synthesis, along with other dipolar protic solvents including dimethylacetamide (DMAc) and N-methyl-2-pyrrolidone (NMP), all classified as CMR.

It is challenging for the pharmaceutical industry to avoid the use of this solvent. DMF is an effective solvent and can be difficult to replace in a chemical synthesis where the impurity profile and yield are crucial to the success of the process. Nonetheless, it is widely agreed that effort should be invested to avoid/limit the use of DMF where possible to achieve more sustainable chemistry. 

What do we do?

Pharmaceutical manufacturing processes can run for 10-15 years (or longer), therefore solvent selection is important when considering the change in the regulatory landscape and trend towards green chemistry. 

Recently, more sustainable and less harmful alternative dipolar aprotic solvents including DMSO, DMC, GVL, NBP and Propylene carbonate have gained increasing interest. 

IMCD Regulated Synthesis has championed several of these alternatives by showcasing examples of chemistries that excel when run in these solvents. For example, in peptide solid phase synthesis, TamiSolve® NxG-PS has been reported to offer superior performance to DMF in specific cases.

Likewise, in cross-coupling chemistry, GVL was shown to outperform DMF in a number of equivalent reactions showing great promise as a viable alternative.

So what ‘Greener’ dipolar aprotic options are available? 

ICH Q3C Class 3 solvent, low toxicity, with low environmental burden. Click here to explore

To find out more about our exciting alternatives to DMF, please contact us or register for one of our Greener Solutions seminars

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