Accessing Phase-Pure and Stable Acetaminophen Polymorphs by Thermal Gradient Crystallization

Abstract

We employ a simple and reproducible methodology based on thermal gradient crystallization to access forms I and II of acetaminophen. This methodology provides insight into the role of heat flux in the control over polymorphism and phase transitions. We report the crystallization of different polymorphs of acetaminophen as a function of the thermal gradient parameters (magnitude of the gradient, sample velocity) in a thin film geometry. The thin-film samples were displaced at well-defined velocities (1 ≤ v ≤ 75 μm/s) to control both the direction and the rate of crystal growth. We carried out a detailed structural analysis combining polarized optical microscopy and X-ray diffraction (specular and grazing-incidence) to characterize the crystalline forms isolated by the thermal gradient technique. The resulting polymorphic forms have been found to exhibit high phase purity and remarkable stability over time.