Influence of preparation technique on co-amorphization of carvedilol with acidic amino acids

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Abstract

Basic amino acids (AAs) have successfully been used as co-formers with acidic drugs for the preparation of co-amorphous formulations using ball-milling (BM) and spray-drying (SD). In contrast, acidic AAs have been reported as poor co-formers for co-amorphous formulations, even for basic drugs, when using BM as a preparation technique. In this study the basic drug carvedilol (CAR) and the two acidic AAs, glutamic acid and aspartic acid, were used to explore the possibilities of producing co-amorphous formulations using BM, SD and liquid assisted grinding (LAG). X-ray powder diffraction, thermal analysis and Fourier-transform infrared spectroscopy were used to determine the solid state form of the various CAR-AA mixtures prepared. BM the CAR-AA mixtures for 60min did not result in co-amorphization as XRPD revealed remaining crystallinity of both CAR and the AA. On the other hand, successful co-amorphous salt formation was obtained for all SD samples. Differential scanning calorimetry showed that all the SD CAR-AA mixtures had a single glass transition temperature of approximately 80°C. The CAR-AA mixtures prepared by LAG showed some polymorphic conversion of CAR. Intrinsic dissolution testing showed the highest dissolution rate for all SD mixtures due to co-amorphous salt formation. Hence it was observed that of the three preparation techniques used, successful co-amorphous formulations of a basic drug with an acidic AA could only be prepared by SD.

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