Crystallization kinetics and molecular dynamics of binary coamorphous systems of nimesulide and profen analogs

Coamorphous drug delivery systems have emerged as a promising formulation technique for improving the solubility and oral bioavailability of poorly soluble drugs. The selection of a suitable coformer is the key to obtaining a successful coamorphous formulation. This study aims to investigate the impacts of coformers with similar chemical structures but different physical properties on the crystallization behavior and molecular dynamics of binary amorphous systems. The addition of three profen analogs, ibuprofen (IBU), ketoprofen (KETO) and indoprofen (INDO) leads to significantly different effects on the crystallization kinetics of amorphous nimesulide (NIME). The crystal growth rates for amorphous NIME are substantially accelerated in the presence of IBU, but drastically reduced in the presence of INDO, while the incorporation of KETO results in a negligible effect. Broadband dielectric spectroscopy is employed to characterize the molecular dynamics of neat amorphous NIME and coamorphous systems. The addition of three structural analogs alters the molecular mobility of amorphous NIME in different ways, which is consistent with the trend observed for their impacts on the crystallization kinetics, suggesting that the relative mobility between the components of coamorphous mixtures governs the physical stability. In addition, it is found that the temperature dependence of the α-relaxation times for NIME with and without coformers is superimposed once the temperature is scaled by Tg/T, whereas the crystallization kinetics do not overlap on a Tg/T scale. This deviation can result from a complex interplay of thermodynamic and kinetic factors involved in multicomponent amorphous systems. This study provides insights into the crystallization kinetics and molecular dynamics of coamorphous systems containing drug analogs, which can potentially offer more flexibility for the control of physical stability without sacrificing therapeutic efficacy.