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

摘要

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 ℃/h was rational to be predominantly crystallized the stable form of poorly soluble mebendazole.