A new polymorph of metacetamol

Abstract

Metacetamol is a structural isomer of the widely used drug paracetamol and is being considered as a promising alternative to the latter because of its lower toxicity. Due to the importance of the well-known polymorphism of paracetamol, an investigation of the polymorphism of metacetamol was successfully undertaken. A new polymorph of metacetamol has been discovered and extensively characterised using a variety of analytical techniques (IR-and Raman spectroscopy, UV-visible optical spectroscopy, X-ray powder and single-crystal diffraction, TGA and DSC). A procedure for the reliable and reproducible preparation of the new polymorph is described. Its properties and crystal structure are compared with those of the previously known polymorph, as well as with those of paracetamol. CrystEngComm This journal isScheme 1 Molecular structures of metacetamol (left) and paracetamol (right) containing the same characteristic functional groups.

The Pressure-Temperature Phase Diagram of Metacetamol and Its Comparison to the Phase Diagram of Paracetamol

“…Although the enthalpy values are higher than those reported by Perlovitch et al, 9 the ratio ∆ I→L H /∆ II→L H equals 1.22, which is close to the value of 1.19 found in the article by McGregor et al 1 During one of the second heating runs by DSC, after the recrystallization into form II marked by c1 in Figure 2 serendipitously an additional exothermic effect was observed marked by c2, which was ascribed to the conversion of form II into form I. It can be seen that after this conversion form I melts at its ordinary melting point (c3 in Figure 2).…”

“…Its crystalline dimorphism has been demonstrated by McGregor et al, who recently published the structure of a new polymorph, form II, which is monoclinic with space group P2 1 . 1 They also confirmed the structure of the known polymorph, form I, which is orthorhombic with space group Pna2 1 The present study has been carried out in the framework of a more general study on the pressure-temperature behavior of polymorphism in small organic molecules and in particular in active pharmaceutical ingredients (APIs). Often, polymorphism of active ingredients is tested by a few calorimetric measurements in a differential thermal analyzer (DSC) and transition temperatures are reported with the accuracy of the equipment stated in the manual.…”

“…1 However, they did provide the recorded DSC curves on heating and on reheating of the same specimen and therefore the surface areas of the melting peaks of the two forms could be determined. The surface ratio of 1.19 equals the ratio ∆ I→L H /∆ II→L H, leading to ∆ II→L H = 137 J g -1 using the known value of ∆ I→L H previously found by Perlovich et al 9 A summary of the calorimetric results can be found in Table 1.…”

The Crystal Structure of Orthocetamol Solved by 3D Electron Diffraction

“…In the crystal structure of orthocetamol, chain alternation causes the NH donors to always point towards the aromatic rings and they do not establish any relevant intermolecular interaction (Figure S6c). Among unsubstituted acetamidophenols, the NH⋅⋅⋅OH interaction is absent only in the monoclinic polymorph of metacetamol in which, however, OH⋅⋅⋅O‐based chains are missing, too …”

The Crystal Structure of Orthocetamol Solved by 3D Electron Diffraction

“…[13] This has directly led to an increase in research into related structures,p articularly orthocetamol, which has been shown to demonstrate lower hepatotoxicity. [15] Although the crystal structures of both para-and metacetamol have been solved, [16] no structure of orthocetamol has been reported until now.Remarkably,orthocetamol was first reported in 1876, [17] that is,b efore the discovery of X-rays. [15] Although the crystal structures of both para-and metacetamol have been solved, [16] no structure of orthocetamol has been reported until now.Remarkably,orthocetamol was first reported in 1876, [17] that is,b efore the discovery of X-rays.…”