A Comprehensive Multi-Method Approach to Investigating Simvastatin Forced Degradation: Integrating in silico Evaluation with HRMS, NMR, and UV-HPLC

Simvastatin, developed in the 1980s, is a widely prescribed medication used to treat hyperlipidemias and lower the risk of cardiovascular diseases, earning its status as a blockbuster drug globally. However, simvastatin has points of instability, and there is limited research regarding the stability of this compound. The objective of this study was to evaluate potential degradation products generated from various stressors, such as pH, humidity, light, and heat, using in silico methods (via Zeneth®) and analytical techniques like high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (¹H NMR). As a result, we identified the main points of reactivity and predicted seven possible degradation compounds in silico. Upon experimentally comparing the pure drug with its commercial formulation, we detected seven of these degradation products - primarily resulting from hydrolysis and oxidation, using HRMS and NMR. Additionally, we assessed the recovery of both formulations through high-performance liquid chromatographyultraviolet (UV-HPLC), indicating that the excipients in the commercial form provide protection against basic agents; however, this protection is less effective under light stress. This study highlights the importance of combining in silico analysis with experimental techniques, emphasizing the need for careful handling of simvastatin, particularly concerning the formation of hydrolysis products, oxidation, and light exposure.