Nanocrystal formulations of mebendazole employing quality by design and molecular level insights by atomistic simulations.

Objective: The present study investigates the production of mebendazole nanocrystal formulations by wet media milling.

Significance: Nanocrystal formulations are expected to enhance the dissolution properties of mebendazole, which possesses poor solubility, highly dependent on crystal polymorphism.

Methods: A Box-Behnken design was employed to study the effects of formulation and process variables on the nanocrystal size and ζ-potential. The optimal nanosuspensions were solidified by spay-drying and freeze-drying with and without mannitol, and the effects of the drying method on the reconstitution of the nanosuspension was studied. Additionally, their physicochemical properties were determined, while the mechanism of fracture and stabilizer adsorption were investigated by atomistic simulations.

Results: Poloxamer 407 is the most suitable stabilizer, while the bead size, milling speed, and stabilizer content significantly affect the diameter. The ζ-potential is affected by the stabilizer concentration depending on bead size. Energy-vector diagrams revealed a slip plane in the lattice of form C, while molecular dynamics simulations revealed strong interactions between stabilizer and crystal surface. Both drying processes induce polymorphic transformation to form A, which, however, can be partially prevented by the addition of mannitol in freeze-drying, at the expense of suspension redispersibility. The spray-dried nanosuspensions exhibited substantially enhanced dissolution profile compared to neat mebendazole, probably due to reduction of particle size, despite transformation to the unfavorable form A.

Conclusions: Nanocrystal formulations exhibited significant dissolution enhancement, while experimental design and atomistic simulations provided useful insights into the mechanism of their formation and stability.