Screening, packing systematics, Hansen solubility parameters and desolvation of resmetirom (MGL-3196) solvates

Resmetirom (MGL-3196) can form masses of solvates with a variety of solvents. In this study, a series of solvates, including those reported in patents and newly discovered solvates, were prepared by experimental screening. Hansen solubility parameters (HSPs) were used to investigate the formation rules of MGL-3196 solvates, and the results showed that the formation of MGL-3196 solvates was most related to the parameterΔδt. When the Δδt value between MGL-3196 and solvent was less than 14.23 MP0.5 a, MGL-3196 tended to form solvate with an accuracy of 84.09%. The precise crystal structures of six solvates and one solvent-free form (form A) were acquired by single crystal X-ray diffraction (SCXRD). After analyzing the structures of obtained solvates in-depth from the aspects of conformation, dimeric synthon, molecular packing, porosity and isostructuralism, the six solvates were classified into alcohol solvates (group 2), ester solvates (group 3) and other types of solvates (group 1). Generally, these three groups of solvates had completely different crystal structures. The solvates in group 1 and group 3 were channelized and isostructural in which solvents could be substituted without great influence on the structure, while in the alcohol solvates (group 2) solvents were fixed by strong hydrogen bonds to be a part of the crystal structure. Moreover, when solvates were desolvated, two metastable solvent-free forms (i.e., B and C) were crystallized and then transformed to form A through a structural rearrangement. The possible mechanisms for the phase transformation during different desolvation processes were finally proposed. All results shall provide an understanding and inspiration on the screening and production of polymorphic and pseudopolymorphic forms of MGL-3196 for the pharmaceutical industry.