Investigation of Maillard-Type Drug–Excipient Interaction Between Rivaroxaban and Lactose: Implications for Stability and in-vitro Anticoagulant Activity

The study of drug–excipient interactions (DEI) is a critical aspect of the preformulation stage in pharmaceutical formulation development. The Maillard reaction is particularly reported in amine-containing excipients interacting with drug molecules possessing carbonyl groups, or vice versa, forming intermediate products that may be toxic in nature. The present study highlights the interaction between Rivaroxaban (RVI) and lactose monohydrate (LT) through the Maillard reaction. RVI is an oral anticoagulant with potent activity. The RVI–LT adduct was prepared by incubating RVI with LT at 60 °C in borate buffer (pH 9.2) for 12 hours. The formation of the adduct was assessed using spectroscopic and thermal techniques such as UV–visible spectroscopy, Fourier-transform infrared spectroscopy, differential scanning calorimetry, high-performance liquid chromatography, and liquid chromatography–mass spectrometry. In silico molecular docking experiments were performed to evaluate the effect of adduct formation on the binding of RVI to its pharmacological target, Factor Xa. A significant loss of binding activity of the adduct, compared with native RVI, was revealed by docking experiments, indicating a potential reduction in anticoagulant potency. These were supported by in vitro chromogenic substrate assays for Factor Xa inhibition, with the adduct demonstrating reduced inhibitory activity. The present study identifies the susceptibility of RVI to Maillard-type interactions when formulated with LT, highlighting the imperative of prudent excipient selection in solid dosage forms to ensure therapeutic activity.