Identification, synthesis, and characterization of potential genotoxic impurities of sildenafil citrate drug substance

Abstract

Background Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specifil phophodiesterase type 5 (PDE5). Sildenafil enhances the effect of nitric oxide by inhibiting phosphodiesterase type 5, which is responsible for the degradation of cGMP in the corpus cavernosum. The possible genotoxic impurities of sildenafil were synthesized, i.e., sildenafil sulfonyl methyl ester, sildenafil sulfonyl ethyl ester, and sildenafil sulfonyl isopropyl ester. The present work describes the synthesis and characterization of these sulfonyl ester compounds related to sildenafil. Results All the synthesized sildenafil sulfonyl esters have proved to be beneficial for the pharmaceutical industry in view of the regulatory importance. Conclusion A simple, efficient, and repeatable method was developed for the preparation of sildenafil sulfonyl esters in view of the regulatory importance of the potential genotoxic impurities in the active pharmaceutical ingredient. A detailed study of various impurities in sildenafil was conducted. Different process-related sulfonyl esters in sildenafil were identified, synthesized, and characterized by using various spectroscopic techniques like liquid chromatography-mass spectrometry (LCMS), mass, 1H NMR, and FT-IR. These efforts to synthesize and characterize them effectively have proved to be beneficial.

Research progress on the impurities identification and determination in pharmaceuticals

“…Some researchers increase the content of impurities in the sample through forced degradation experiments to reduce the workload of preparation. 88 There are also researchers who obtain a large amount of impurities through synthesis methods, [89][90][91] but this method needs to derive the structure of the impurities, then design the synthesis route, and finally verify the synthesized impurities. It has many steps, takes a long time, and the success rate is not high.…”