Merged in silico–in vitro validations of atenolol and amlodipine besylate with excipient interactions for the design of solid oral dosage forms

Abstract

Early understanding and estimation of interactions between drugs and excipients is a crucial step in preformulation studies. In silico studies utilising computational methods were followed by in vitro studies and analytical validation to identify stable excipients (SmartEx and Ludipress) for the development of solid oral dosage forms. In silico studies were conducted using the FormulationDE machine learning tool, which utilises artificial intelligence to interpret input data. FormulationDE can predict compatibility outcomes based on functional groups using SHAP (Shapley Additive explanations) force plots. In vitro studies, including isothermal stress testing methods, ATR-FTIR, DSC and drug stability profiles, were conducted to assess the potential for DEIs under long-term storage and physiological conditions. These studies were demonstrated, and samples were analysed using high-performance liquid chromatography to quantify the percentage of drug degradation over time. The in silico studies showed that ATN was compatible with lactose and mannitol, whereas AMB was incompatible with both. The in vitro IST results showed that ATN was compatible with SmartEx, whereas AMB was incompatible with Ludipress and SmartEx. Drug stability profiles were obtained under gastric pH (1.2) and incubation at 37 °C for four hours to evaluate the resilience of the drugs under physiological conditions and to mimic the gastric environment. The drug stability profiles showed that AMB was unstable and ATN was stable under the gastric physiological conditions. This article highlights the importance of integrating in silico with in vitro experimental techniques in preformulation to minimise risk during later stages of formulation development. The results of various studies will guide the future development of ATN-based solid oral dosage forms using SmartEx QD 100 thermoplastic excipients.