Characterization of co-amorphous carvedilol–maleic acid system prepared by solvent evaporation

Abstract

The aim of this study was to enhance the solubility and stability of the water-insoluble drug carvedilol (CAR) with maleic acid (MLE) to create a co-amorphous system by a solvent evaporation method. Phase diagrams of co-amorphous CAR–MLE, constructed from peak height in the Fourier-transform infrared (FTIR) spectra and the glass transition temperature (Tg) from differential scanning calorimetry (DSC) measurements, revealed that the optimal molar ratio of CAR to MLE was 2:1. The FTIR spectra indicated that the secondary amine-derived peak of CAR and the carboxy group-derived peak of MLE disappeared in the CAR:MLE (2:1) co-amorphous system. DSC measurements showed that the endothermic peaks associated with the melting of CAR and MLE disappeared and a Tg at 43 °C was apparent. Furthermore, the solubility of CAR tested using the shaking flask method for 24 h at 37 °C was 1.2 μg/mL, whereas that of the co-amorphous system was approximately three times higher, at 3.5 μg/mL. Finally, the stability was evaluated by powder- X-ray diffraction at 40 °C; no clear diffraction peaks originating from crystals were observed in the amorphous state until after approximately three months of storage. These results indicate that co-amorphization of CAR with MLE improved the solubility of CAR while maintaining its stability in an amorphous form.

Keywords:

• Carvedilol
• maleic acid
• co-amorphous
• molecular interaction
• solubility
• physical stability

Acknowledgments

The authors are grateful to Dr. Mayumi Ikegami-Kawai at Hoshi University for their insightful comments and suggestions for NMR measurements.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported by Hoshi University Grant-in-Aid for Leading Research Project grants in 2017 and 2018, by the OTC Self-Medication Promotion Foundation 2018, the Mochida Memorial Foundation for Medical and Pharmaceutical Research 2019–2020 (T.F.) and 2021 Grand-in-Aid for 2021 and 2022 fiscal years ‘Research on Test Methods in the Japanese Pharmacopoeia’ by the Pharmaceutical and Medical Device Regulatory Science Society of Japan (E.Y.).