Reassessment of paracetamol orthorhombic Form III and determination of a novel low-temperature monoclinic Form III-m from powder diffraction data

Abstract

Paracetamol [N-(4-hydroxyphenyl)acetamide, C8H9NO2] has several polymorphs, just like many other drugs. The most stable polymorphs, denoted Forms I and II, can be obtained easily and their crystal structures are known. Crystals of the orthorhombic, less stable, room-temperature Form III are difficult to grow; they need a special recipe to crystallize and suffer from severe preferred orientation. A crystal structure model of Form III has been proposed and solved from a combination of structure prediction and powder X-ray diffraction (PXRD) [Perrinet al.(2009).Chem. Commun.22, 3181–3183]. The finalRwpvalue of 0.138 and the corresponding considerable residual trace were reasons to check its validity. A new structure determination of Form III using new high-resolution PXRD data led to a finalRwpvalue of 0.042 and an improvement of the earlier proposed model. In addition, a reversible phase transition was found at 170–220 K between the orthorhombic Form III and a novel monoclinic Form III-m. The crystal structure of Form III-m has been determined and refined from PXRD data to a finalRwpvalue of 0.059.