Synthon-Based Crystal Engineering of Mebendazolium Tosylates: Solid-Form Design, Structure−Property Relationships, and Enhanced Solubility from Experimental and DFT Studies

Abstract Salt formation is a well-established crystal engineering strategy to modulate the physicochemical and pharmacokinetic properties of active pharmaceutical ingredients. In the case of mebendazole (MBZ), a broad-spectrum anthelmintic, this approach has been successfully employed to prevent tautomerism and polymorphic interconversion in the solid state. Herein, we report two new MBZ salts obtained by recrystallization of MBZ Form C with p-toluenesulfonic acid, namely MBZ tosylate monohydrate and MBZ tosylate anhydrous, crystallizing in the C2/c (15) and P212121 (19) space groups, respectively. Consistent with supramolecular design principles, both structures are assembled through the charge-assisted recurring R22(8) supramolecular synthon between mebendazolium and tosylate ions. Importantly, salt formation suppresses tautomeric transformations and prevents phase segregation into pure MBZ forms, including the pharmaceutically inactive desmotrope MBZ A. The anhydrous salt can be selectively obtained either de novo using anhydrous p-toluenesulfonic acid or through dehydration and recrystallization of the monohydrate phase. Thermal studies revealed that the monohydrate endothermically dehydrates at 125.55 °C, whereas the anhydrous salt remains stable up to 188.56 °C. Under ambient conditions, the anhydrous phase remains unchanged, while the monohydrate gradually converts into the anhydrous form. Both salts exhibit enhanced dissolution behavior compared to MBZ Form C, the pharmaceutically preferred form. Crystal packing analysis combined with DFT calculations, Hirshfeld surface analysis and energy framework estimations, reveals the key role of intermolecular interactions in stabilizing both phases and highlights that the R22(8) supramolecular motif drives the assembly of the components into stable materials. Overall, the anhydrous salt emerges as a promising candidate for future pharmaceutical developments.