Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Department of Pharmacy, Faculty of Science and Engineering, Åbo Akademi University, 20521 Turku, Finland.
Int J Pharm. 2018 Dec 1;552(1-2):407-413. doi: 10.1016/j.ijpharm.2018.09.070. Epub 2018 Sep 29.
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 60 min 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.
基本氨基酸（AAs）已成功用作与酸性药物共晶形成的共晶形成剂，用于通过球磨（BM）和喷雾干燥（SD）制备共无定形制剂。相比之下，当使用 BM 作为制备技术时，报道说酸性 AAs 即使对于碱性药物，也是共无定形制剂的较差共晶形成剂。在这项研究中，使用碱性药物卡维地洛（CAR）和两种酸性氨基酸谷氨酸和天冬氨酸，探索了使用 BM、SD 和液辅助研磨（LAG）制备共无定形制剂的可能性。X 射线粉末衍射、热分析和傅里叶变换红外光谱用于确定各种 CAR-AA 混合物制备的固态形式。BM 使 CAR-AA 混合物研磨 60 分钟不会导致共无定形，因为 XRPD 揭示了 CAR 和 AA 的结晶度仍然存在。另一方面，所有 SD 样品均成功形成共无定形盐。差示扫描量热法显示所有 SD CAR-AA 混合物的玻璃化转变温度均约为 80°C。通过 LAG 制备的 CAR-AA 混合物显示出 CAR 的一些多晶型转化。内源性溶解测试显示，由于共无定形盐的形成，所有 SD 混合物的溶解速率最高。因此，观察到在所使用的三种制备技术中，仅通过 SD 才能制备碱性药物与酸性 AA 的成功共无定形制剂。
