Racemic Salts and Solid Solutions of Enantiomers of the Antihypertensive Drug Carvedilol

Abstract

The R and S enantiomers of the antihypertensive drug carvedilol (CVD) can display remarkable miscibility in the crystalline state allowing this active pharmaceutical ingredient (API) to form a solid-solution of enantiomers (SSEs) as well as racemic compounds. Although rare and still little explored, these intriguing systems can also be used to design racemic multicomponent crystal forms toward the improvement of undesirable pharmaceutical properties of APIs. In this study, aiming to understand why there is miscibility between the enantiomers during the supramolecular recognition and crystallization processes of the CVD in the presence of salt formers, two SSEs and one racemic salt were prepared from the reaction of CVD with pharmaceutically acceptable HCl, HBr, and oxalic acids. Two monohydrated isostructural salts, hydrochloride (CVD-HCl-H 2 O) and hydrobromide (CVD-HBr-H 2 O), crystallize as racemic SSEs. These unique systems are formed from the miscibility of the R•••R and S•••S homochiral units that propagate into enantiomerically enriched one-dimensional chains through H-bonds with water molecules along the crystal. The oxalate salt (CVD-OXA), in turn, crystallizes as a standard racemic compound since the oxalate anions, which lie in the inversion center, are directly H-bonded to both R and S CVD enantiomers, forming racemic ionic units that extend along the structure. Complementary to the crystallographic study, conformational and Hirshfeld surface analysis were also performed based on the single-crystal X-ray diffraction data. The salt formations were confirmed from the Fourier transform infrared spectroscopy as well as powder X-ray diffraction patterns, and their thermal behaviors were investigated by a combination of differential scanning calorimetry, thermogravimetric, and hot-stage microscopy techniques.

Formation of pharmaceutical salts and cocrystals via vapour-assisted tumbling (VAT) – a solvent efficient process

“…After 1 h, a PXRD was taken of the free flowing powder showing no conversion to the reported Cav:OxA (2:1) salt (CCDC: YOKSUP). 31 A flow of N2 bubbled through MeOH was added to the tumbler and tumbling resumed. Within 1 h, peaks of the reported salt were seen along with broad peaks from an unknown form.…”

“…YOKSUP) was previously made by mixing the components in EtOH/H2O (1:1, v/v) at 70 °C for 20 min before being filtered and dried. 31 Starting from a Cav freebase (CCDC: GIVJUQ01 46 ), after 1 h of tumbling in MeOH vapour, the reported Cav:OxA (2:1) salt quickly formed concomitantly with the freebase along with very broad peaks of an unknown phase.…”

Pharmaceutical Solid Form Formation via Vapour-Assisted Tumbling (VAT) – A Solvent Efficient Process with Potential Industrial Applications

“…After 1 h, a PXRD was taken of the free flowing powder showing no conversion to the reported Cav:OxA (2:1) salt (CCDC: YOKSUP). 30 A flow of N2 bubbled through MeOH was added to the tumbler and tumbling resumed. Within 1 h, peaks of the reported salt were seen along with broad peaks from an unknown form.…”

“…YOKSUP) was previously made by mixing the components in EtOH/H2O (1:1, v/v) at 70 °C for 20 min before being filtered and dried. 30 Starting from a Cav freebase (CCDC: GIVJUQ01 43 ), after 1 h of tumbling in MeOH vapour, the reported Cav:OxA (2:1) salt quickly formed concomitantly with the freebase along with very broad peaks of an unknown phase.…”

Pharmaceutical Solid Form Formation via Vapour-Assisted Tumbling (VAT) – A Solvent Efficient Process with Potential Industrial Applications

“…The solvent reservoir was the removed and dry N2 passed through the tumbler for 2 h. Recovered mass: 9.29 g. A DSC of the final material showed one sharp endotherm at 176.85 °C.Carvedilol freebase (4.30 g, 10.58 mmol) and milled oxalic acid dihydrate (0.68 g, 5.29 mmol) were added to the sample tumbler of the VAT Mk.10b and tumbled under a flow of dry N2 (420 mL min -1 ). After 1 h, a PXRD was taken of the free flowing powder showing no conversion to the reported Cav:OxA (2:1) salt (CCDC: YOKSUP) 30. A flow of N2 bubbled…”