A cost-effective, scalable, and environmentally benign process is herein reported for the synthesis of pantoprazole sodium sesquihydrate: 5-(difluromethoxy)-2-[{(3,4-dimethoxy-2-pyridinyl)methyl}sulfinyl]-1 H -benzimidazole sodium sesquihydrate. At least two of the three main synthetic steps (coupling and oxidation) have been carried out for the first time in water, with no need to isolate and purify the intermediates, affording the corresponding pantoprazole sodium in good yield and purity. Minimum organic solvents, in terms of both the number of solvents and the volume of solvent used, are employed to make this process both economical and environment friendly. Furthermore, in situ transformation of pantoprazole sodium heterosolvate, due to the association between molecules of water and solvent used, to pantoprazole sodium sesquihydrate is described.

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Pantoprazole sodium, a substituted benzimidazole derivative, is an irreversible proton pump inhibitor which is primarily used for the treatment of duodenal ulcers, gastric ulcers, and gastroesophageal reflux disease (GERD). The monographs of European Pharmacopoeia (Ph. Eur.) and United States Pharmacopoeia (USP) specify six impurities, viz. ; impurities A, B, C, D, E and F, respectively for its active pharmaceutical ingredient (API). The identification and synthesis of all impurities except impurity E are well described in the literature; however, there is no report related to impurity E. The prospects to the formation and controlling of impurity E up to ≤0.03% in the synthesis of pantoprazole sodium sesquihydrate (PAN) were discussed in detail for the first time. The present work described the journey towards the successful development of an optimal preparation procedure of dimer impurity E. The most plausible mechanism involved in the formation of impurity E has been proposed.