Serendipitous discovery of a novel polymorph of an immunosuppressant drug azathioprine: phase transformation, solubility, dissolution and stability study

Abstract

A novel polymorph of an immunosuppressant drug azathioprine (AZP) is prepared (F-III) along with two solvates (2-methoxyethanol (MEE) and 1,4-dioxane (DOX)) and a monohydrate of AZP. The crystal structures were determined and further characterized by powder XRD and thermal and spectroscopy analysis. So far two polymorphs of AZP have been reported in the literature with crystal structure details, namely F-I and F-II. The novel polymorph F-III crystallizes in the monoclinic crystal system with the centrosymmetric P2₁/c space group. AZP F-III crystallizes serendipitously during cocrystallization experiments using DL-malic acid as a coformer. The single-crystal data showed distinct cell lengths and cell angles to confirm the novel polymorph of AZP. The conformational analysis of the novel polymorph shows unique torsion angles as compared to reported forms, demonstrating the conformational polymorphic form of AZP. The thermal analysis data revealed a lower melting point of F-III compared to that of F-I and both the forms decompose upon melting. The solubility results in different buffer media revealed that F-III exhibits a slightly higher solubility than F-I; the dissolution profile of F-III displayed a similar drug release in acidic, phosphate and purified water media. The polymorph stability under accelerated conditions showed the instability of F-III under accelerated humidity conditions (90–95% RH, 40 °C). Further, F-III exhibited solvent-dependent stability at room temperature. Finally, a process for developing F-III is established on a lab scale by a simple recrystallization method in a combination of solvents.