Co-Crystallization Adducts of Carvedilol with Carboxylic Acids: Design and Characterization ^†

Carvedilol (CARV) belongs to the group of non-selective beta and alpha-1 adrenergic receptor antagonists and is indicated for hypertension and chronic heart failure. The disadvantages related to its poor bioavailability, as a consequence of its low water solubility, are one of the reasons that led researchers to resort to methods to improve its physicochemical properties [1]. Pharmaceutical co-crystals have been shown to positively influence the bioavailability, thermal stability, photostability, and intrinsic dissolution rate of drugs [2,3,4].

The current study aims to address a strategy for modifying the physicochemical properties of a candidate drug with limitations, resulting in binary adducts with an improved biopharmaceutical profile.

This study integrates thermal methods of analysis, such as thermogravimetry (TG) and derivative thermogravimetry (DTG) as well as spectroscopic techniques, including universal-attenuated total reflectance Fourier-transform infrared (UATR-FTIR) spectroscopy and powder X-ray diffractometry (PXRD) applied to investigate the formation of CARV adducts with two carboxylic acids, namely, malonic and succinic acid, in a 1:1 molar ratio (CARV: CARBOXYLIC ACIDS).

The IR spectra of the adducts showed shifts in the CARV characteristic bands toward different wavenumbers compared to the parent substances’ spectra, confirming the formation of co-crystals with the two carboxylic acids. Thermal analysis data reveal a great stability of CARV, characterized by a single decomposition step, starting at 220 °C, with a continuous mass loss in the temperature range of 220–450 °C (DTG_peak at 331 °C), resulting in a residual mass of 29.88%. The co-crystallization products of CARV with carboxylic acids exhibit a different thermoanalytical profile than those of the parent compounds, demonstrating the interaction of the components with the formation of a new chemical entity. The results of the PXRD analysis highlight the following phenomena in the diffraction patterns of the binary adducts: 1. the disappearance of the intense crystalline reflections of the parent substances; 2. the shift in the diffraction peaks of CARV towards other 2θ values and drastic decrease in their intensity; 3. the appearance of new crystalline reflections, all of which suggest the formation of new chemical entities different from the parent compounds, which have the specific crystalline structure identified with the adducts.

The collected data proved to be a valuable source of structural knowledge on co-crystals, promoting strategic design and optimization of the physicochemical properties and pharmacological profiles of drugs at the molecular level, providing significant contributions to scientific research and practical applications.