Impurity-Aware Route Design for Mefenamic Acid Crystallization using Computer-Aided Retrosynthesis

The presence of impurities during the crystallisation of active pharmaceutical ingredients is a major process engineering challenge because they can affect product purity, safety, efficacy, and consistency.^1,2 In mefenamic acid (MFA) manufacturing, impurities inherited from reaction steps can influence crystal quality attributes.³ Current MFA synthesis relies on Buchwald coupling, whichgenerates benzoic acid through dehalogenation, and relies on excess toxic 2,3-dimethylaniline, both known impurities to affect MFA crystal morphology.

This study leverages state-of-the-art computer-aided retrosynthesis (CAR),^4,5 to develop a greener-by-design and safer multistep synthesis for MFA. The main objective is to identify an effective, greener, and feasible route for the selected API while avoiding the presence of impurities that are toxic and affect crystal quality attributes.

The CAR identified two viable routes. The first is similar to the current synthesis. However, when constrained against toxic and crystallisation-relevant compounds, CAR proposed a one-step route for MFA from safe building blocks, eliminating the need to remove hazardous materials and simplifying the purification to the final crystal product. In addition, as the CAR route avoids 2-chlorobenzoic acid, the formation of benzoic acid impurity that affects the crystal morphology is minimised.

In summary, CAR identified a synthetic route for MFA that eliminated the use of hazardous and toxic compounds, improving the safety and greenness of the reaction. By reducing impurity inheritance upstream, the proposed route offers process advantages, lowering the burden on downstream purification and enabling more robust crystallisation with improved control of final crystal quality.

Acknowledgement:

This project was funded by the UKRI (10038378) and ERC (HORIZON-HLTH-2021-IND-07, 101057430).

References:

1. Fysikopoulos et.al. Comput. Chem. Eng., 2019, 122, 275-292.
2. Mustoe, et.al. Int. J. Pharm., 2025, 681, 125625.
3. Li et.al., Chemical Engineering Research and Design, 2023, 202, 126-146.
4. I. Teixeira, B. Benyahia, Chemical Engineering Research and Design, 2025, 216, 367-375.
5. I. Teixeira, et.al., JACS Au, 2024, 4, 4263-4272.