Rational polymorph screening based on slow cooling crystallization of poorly soluble mebendazole

• All of reported anhydrous crystal forms and the three novel solvates of MBZ were crystallized by slow cooling.
• Crystallization temperature and the interaction with solvent via hydrogen bonding were remarkable factors that governed the crystal forms of MBZ.
• Resultant crystal form was influenced by solvent, drug concentration, crystallization temperature, and cooling rate.
• Effect of antisolvent addition on crystallization was clarified.
• Slow cooling crystallization using diverse solvents and solvent mixtures is a rational approach for the polymorph screening of poorly soluble drugs.

During polymorph screening, the possibility of overlooking the most stable form of a poorly soluble drug is relatively high due to its slow nucleation rate. To develop a rational polymorph screening system applicable to poorly soluble drugs, the slow cooling crystallization of one such compound, mebendazole (MBZ), from diverse organic solvents and solvent mixtures was demonstrated. The most stable form of MBZ was selectively crystallized from toluene and alcohol/antisolvent mixtures, which generated a higher crystallization temperature. In contrast, metastable forms and solvates were crystallized from specific solvents at higher degrees of supersaturation. Several crystallization factors, such as solvent, drug concentration, temperature, and cooling rate, were found to affect the resultant MBZ crystal forms. Solvents that generated weak solute–solvent interactions and high crystallization temperatures were required to predominantly crystallize the most stable form. In particular, it was clarified that solvents having weak hydrogen bonding propensity such as toluene and heptane were effective for shortening the induction time for crystallization, thereby rising the crystallization temperature during slow cooling that ensured the crystallization of the stable form. Furthermore, we demonstrated that the cooling rate slower than 3 °C/h was rational to be predominantly crystallized the stable form of poorly soluble mebendazole.