High Pressure Differential Scanning Calorimetry Investigations on the Pressure Dependence of the Melting of Paracetamol Polymorphs I and II

A high pressure differential scanning calorimeter (HP‐DSC) has been used to investigate the pressure dependence of the melting of the monoclinic (Form I) and orthorhombic (Form II) polymorphs of paracetamol (acetaminophen). DSC scans obtained at ambient pressure show that the stable monoclinic form melts at 442 K while the metastable orthorhombic form melts at 430 K. HP‐DSC scans obtained for pressures up to about 450 MPa show that the melting temperatures of both Forms I and II increase with increasing pressure, but the latter more rapidly than the former. This results in a cross‐over at about 250 MPa, where the two forms have approximately the same melting temperature, while at higher pressures Form II becomes the more stable phase. Although no solid-solid transitions have been observed, the coordinates of the I-II-liquid triple point have been found experimentally (p = 258.7 MPa and T = 489.6 K) for the first time, and confirm those predicted by Espeau et al. from a topological p-T diagram based on theoretical arguments and experimental data at ambient pressure. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2784-2794, 2007