Structural Diversity and Stability of Mycophenolic Acid with Insights into Coformer induced Polymorphism and Solid-State Characterization

Abstract

The solid-state behaviour of mycophenolic acid (MPA) was investigated systematically to examine its polymorphism and salt formation. Three coformer-induced polymorphic forms (MPA-FII, FIII, FIV) and a sodium salt (MPA-Na2-5H2O) of MPA were obtained using solvent-oriented crystallization. Structural characterization using single-crystal (SC-XRD) diffraction identified differences in molecular conformation and crystal packing. The powder X-ray (P-XRD) diffraction revealed the phase purity of the prepared (MPA-FII and MPA-Na2-5H2O salt) forms. Among the three new polymorphs, only MPA-FII were able to reproduce on a bulk scale. Heat-cool-heat experiments yielded the phase pure bulk material of MPA-FII. Thermal analysis, hygroscopic testing, and solid-state stability studies were employed to assess the behavior of these forms. The phase quantification studies were conducted to understand the stability of MPA-FII in different solvent media. Solubility and dissolution experiments were performed to compare solid-state performance among the polymorphs (MPA and MPA-FII) and the MPA-Na2-5H2O salt. Energy calculations revealed that MPA-FIV exhibits the most negative lattice energy among the investigated polymorphs, followed by MPA, MPA-FII, and MPA-FIII. The results provide a clear and detailed set of experimental data explaining the salient features of different solid forms of MPA.