Polymorphs and isostructural cocrystals of dexamethasone: towards the improvement of aqueous solubility

Abstract

Dexamethasone (DEX) is a corticosteroid drug used to treat arthritis and asthma and considered a promising drug for the treatment of COVID-19. The major drawback of DEX is its poor aqueous solubility (89 mg L⁻¹). In order to enhance its solubility, polymorph and cocrystal screening was performed, which resulted in the crystallization of the metastable polymorph (commercial Form A) along with two novel cocrystals with catechol (CAT) and resorcinol (RES). These solid forms were characterized by powder-XRD, DSC, and finally single-crystal XRD. The commercial Form A (P2₁2₁2₁, Z′ = 1, new) and reported Form B (P2₁2₁2₁, Z′ = 2) were harvested concomitantly during crystallization from CH₃CN. While Form A constitutes a trimer ring motif, Form B maintains a dimer synthon between two symmetry independent DEX molecules and they are designated as synthon as well as packing polymorphs. The presence of CAT/RES breaks dimer/trimer synthons in the cocrystal lattice of the drug molecule and forms a hydrogen-bonded sandwich between two anti-parallel DEX chains. In addition, both DEX–CAT and DEX–RES are proved to be isostructural cocrystals based on their identical lattice parameters and molecular packing arrangement. Aqueous solubility (24 h) experiments indicated that commercial Form A was 1.5-fold more soluble than Form B and inversely correlated with their melting points. DEX–CAT and DEX–RES cocrystals improved the aqueous solubility by 2–5-fold than commercial Form A, although both the cocrystals transformed to the mixture of polymorphs during solubility experiments. The improved solubility of the DEX–CAT cocrystal may offer more bioavailability of DEX.