Development of an Efficient and Scalable Process for Preparing Timolol N-Nitrosamine Impurities B, C, E, H, I, J, and Their ADMET Evaluation

Abstract

The synthesis of N-nitrosamine impurities in Timolol maleate is a critical aspect of pharmaceutical research and quality assurance. It enables a deeper understanding of impurity formation, facilitates effective risk assessment, and supports the development of robust control strategies. This process is essential for ensuring patient safety, achieving regulatory compliance, and upholding stringent standards of drug quality and reliability. In response to earlier reports, the synthesis of N-nitrosamine impurities of Timolol has become necessary. The present work outlines a streamlined approach for preparing N-nitrosamine impurities B, C, E, H, I, and J in a few simple steps, achieving good yields from readily available raw materials. The process employs diethyl malonate in combination with 3,4-dichloro-1,2,5-thiadiazole as key starting components. Theoretical studies on the ADMET properties showed good oral bioavailability of few impurities, and the impurities may likely exhibit respiratory toxicities.