Mechanically Activated Anticonvulsant Lacosamide: Study of Long-Term Changes in Physico-Chemical and Pharmacokinetic Properties

Introduction: The development of new drugs typically requires approximately 10–15 years; therefore, the modification of known pharmaceutical molecules using mechanochemistry - a "green" technology enabling controlled alteration of material properties - has become highly relevant. In the context of increasing drug resistance, including that observed in epilepsy, targeted structural modification of compounds is of particular importance. Aim: To investigate the effect of high-intensity mechanical loading on the physicochemical properties of lacosamide, a third-generation antiepileptic drug, and to establish the relationship between mechanoactivation, solid-state transformation, and the temporal evolution of properties within the framework of the kinetic theory of strength. Materials and methods: Lacosamide powder was subjected to mechanoactivation in a laboratory rotor mill under controlled temperature conditions. The obtained samples were analyzed using static and dynamic light scattering, X-ray powder diffraction (XRD), ATR-FTIR spectroscopy, and principal component analysis (PCA). Results: Mechanical treatment induced particle fragmentation, accumulation of crystal lattice defects, and rearrangement of intermolecular interactions, without altering the chemical structure. The temperature curve enabled identification of the elastic and plastic deformation stages. Scanning electron microscopy (SEM) confirmed morphological changes from needle-like crystals to particles with smooth surfaces. A main finding was the experimental confirmation of the long-term evolution of the mechanically activated state over a 37-month observation period. The system did not revert to its initial state but exhibited prolonged thermally activated rearrangement, interpreted within the framework of the S.N. Zhurkov equation as stress relaxation. Conclusions: Mechanochemical modification represents a controllable approach for altering the solid-state properties of pharmaceutical substances without changing their chemical nature. The proposed kinetic assessment of the activated state durability is valuable for predicting stability and for the development of novel dosage forms, which is of significant importance for both pharmacy and medicine in general.