An insight into carvedilol solid forms: effect of supramolecular interactions on the dissolution profiles

Abstract

Carvedilol, a β-blocker drug used to treat hypertension, is known to exhibit polymorphism. Thus far, the crystal structure of two polymorphs (I and II) and one hydrate have been reported. In this study, three crystal modifications of carvedilol were obtained from crystallization experiments. The structure of another polymorph (III) was elucidated for the first time and the crystal structure of the hydrate was also determined from single-crystal diffraction data. Carvedilol structures are characterized by variations in their molecular conformations, with different orientations of the carbazole moiety. Further conformational details also differentiate them. Carvedilol structures II, III and hydrate were characterized by thermal and microscopic methods. A higher melting temperature polymorph (III), compared to form II, was identified when carvedilol was crystallized from methanol. This polymorph showed a higher intrinsic dissolution rate than polymorph II in hydrochloric acid at pH 1.4 containing sodium lauryl sulfate (0.1% w/v). Although it was not expected due to its greater stability, the higher dissolution rate of polymorph III could be explained by its structural features. The dissolution of carvedilol in acid medium is related to its ability to form protonated molecules. DFT calculations with the WB97XD functional were carried out for evaluation of the classical and non-classical hydrogen bonds between the molecules in carvedilol structures. The energies involved in the intermolecular interactions explain some experimental observations. This result showed that intermolecular interactions influence the solid-state properties of carvedilol. Moreover, polymorph III exhibits a higher dissolution rate than II, showing great potential for formulation strategies of this poorly water soluble drug.