Exploring the Structural Landscape for a Thrombopoietin Receptor Agonist Avatrombopag Maleate: An Innovative Trihydrate Forms with Improved Solubility Found

Abstract

Avatrombopag maleate (AVAT), a second-generation oral thrombopoietin (TPO) receptor agonist, is currently in development for the therapeutic management of thrombocytopenia. The present study introduces a novel comparative analysis that elucidates the intricate relationship between the crystallographic structures and the diverse physicochemical properties inherent to the complex polymorphic forms of the Avatrombopag (AVA) maleic salt. Seven solid-state forms, including two polymorphic forms (AVAT-B, AVAT-C), a new trihydrate (AVAT-3H), and four solvates (AVAT-A, AVAT-dimethyl sulfoxide (AVAT-DMSO), AVAT-dimethylformamide (AVAT-DMF), and AVAT-tetrahydrofuran (AVAT-THF)), were synthesized and analyzed in detail. Although the powder diffraction patterns for polymorphs AVAT-A, AVAT-B, and AVAT-C have been previously reported, our study marks the inaugural report of their crystallographic structures. Trihydrate and three new solvates were initially identified and subjected to a comprehensive characterization through thermal analysis, X-ray diffraction, etc. Thermal stability and transformation in aqueous solutions for different forms were conducted. Surprisingly, it was found that all five other solid forms except AVAT-B would be transformed to AVAT-3H when suspended in aqueous solution. All solvates retained their original framework structure after the removal of part of the solvent and could not lose all solvents until decomposition. AVAT trihydrate did not lose water upon storage under ambient conditions. Furthermore, the solubility profiles of AVAT-B, AVAT-C, and AVAT-3H were meticulously determined. By integrating the distinct molecular conformations with the respective intermolecular and intramolecular interactions as well as the packing arrangements, we were able to elucidate the underlying factors influencing their phase behavior. The insights gained from this analysis were instrumental in simulating crystal growth, thereby facilitating a comprehensive understanding of the specific interactions that govern the phase behavior of these compounds.