Dept. of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Dept. of Chemistry, University of Hamburg, Hamburg, Germany.
Eur J Pharm Biopharm. 2013 Nov;85(3 Pt B):1019-30. doi: 10.1016/j.ejpb.2013.04.022. Epub 2013 May 16.
Cocrystal formation allows the tailoring of physicochemical as well as of mechanical properties of an API. However, there is a lack of large-scale manufacturing methods of cocrystals. Therefore, the objective of this work was to examine the suitability of high-shear wet granulation as a manufacturing method for cocrystal granules on a batch scale. Furthermore, the cocrystal granules were characterized regarding their mechanical properties as well as their dissolution behavior. High-shear wet granulation was found to be a feasible manufacturing method for cocrystal granules. Cocrystal formation depended on the exposure time of the solids to the granulation liquid (water), the amount of liquid, the impeller speed of the granulator, and on the excipients (hydroxyl propylcellulose, microcrystalline cellulose, calcium hydrogenphosphate) used in the formulation. Storage stability was strongly influenced by the excipients, since in presence of calcium hydrogenphosphate, the poorly water-soluble salt calcium tartrate monohydrate was formed at high relative humidity. Interestingly, compactability was increased by cocrystal formation compared to that of the reference granules (piracetam and the respective excipients). The drug release was slightly decreased by cocrystal formation, most likely due to the lower solubility of the cocrystal. In the presence of calcium hydrogenphosphate however, no influence of cocrystal formation on either compactability or on drug release were observed, compared with the reference tablets. It was concluded that high-shear wet granulation is a valuable, however complex, manufacturing method for cocrystals. Cocrystal formation may influence compactability and drug release and thus affect drug performance and should be investigated during pre-formulation.
共晶形成允许定制 API 的物理化学性质以及机械性质。然而，缺乏共晶的大规模制造方法。因此，本工作的目的是研究高剪切湿法制粒作为批处理规模共晶颗粒制造方法的适用性。此外，还对共晶颗粒的机械性能和溶解行为进行了表征。高剪切湿法制粒是共晶颗粒的一种可行的制造方法。共晶的形成取决于固体暴露于制粒液（水）的时间、液体的量、制粒机的叶轮速度以及制剂中使用的赋形剂（羟丙基纤维素、微晶纤维素、磷酸氢钙）。储存稳定性受赋形剂的强烈影响，因为在存在磷酸氢钙的情况下，在高相对湿度下形成了水溶性差的盐酒石酸氢钙一水合物。有趣的是，与参考颗粒（吡拉西坦和各自的赋形剂）相比，共晶形成增加了可压缩性。共晶形成导致药物释放略有降低，这很可能是由于共晶的溶解度较低。然而，与参考片剂相比，在存在磷酸氢钙的情况下，共晶形成对可压缩性或药物释放均无影响。得出的结论是，高剪切湿法制粒是一种有价值但复杂的共晶制造方法。共晶形成可能会影响可压缩性和药物释放，从而影响药物性能，因此应在预配方阶段进行研究。
