ArticlePharmaceutical research2026
From Crystal Structure to Dissolution Enhancement: Cocrystal Engineering of Resmetirom to Address Its Solubility Challenge.
Article in Pharmaceutical research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
purposeResmetirom (RSM), the first FDA-approved drug for non‑cirrhotic steatohepatitis, suffers from poor aqueous solubility, limiting its oral bioavailability. This study aims to enhance the solubility of RSM through cocrystal engineering guided by Hansen Solubility Parameters (HSP).
methodsHSP as an initial miscibility filter combined with hydrogen-bond complementarity for cocrystal screening. Five novel cocrystals (Resmetirom-(S)-( +)-2-Amino-1-butanol (RSM‑S‑AB), Resmetirom-4-Aminopyridine (RSM‑AP), Resmetirom-Piperazine (RSM‑Pip), Resmetirom-Pyrimidine (RSM‑Pyr), Resmetirom-(R)-( +)-9-(2-Hydroxypropyl) adenine (RSM‑R‑HPA)) were obtained and characterized by PXRD, DSC, TGA, FT‑IR, and SCXRD. Hirshfeld surface analysis was employed to investigate intermolecular interactions. Equilibrium solubility and intrinsic dissolution rate (IDR) were measured in ultrapure water.
resultsAll five cocrystals exhibited enhanced equilibrium solubility compared to pure RSM, with RSM‑S‑AB showing the greatest improvement (~ 30-fold). SCXRD revealed that the solubility enhancement stems from an extended hydrogen‑bonding network, a more open crystal packing, and additional polar groups introduced by the coformers. Lower melting points of all cocrystals further indicated reduced lattice energy.
conclusionsCocrystal engineering guided by HSP and hydrogen‑bond complementarity successfully improved the aqueous solubility of RSM. The elucidated structure-solubility relationships provide a practical approach for optimizing the solid forms of poorly soluble drug candidates.
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