Deng Jia, Staufenbiel Sven, Bodmeier Roland
College of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, Germany.
College of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, Germany.
Eur J Pharm Sci. 2017 Jul 15;105:64-70. doi: 10.1016/j.ejps.2017.05.013. Epub 2017 May 6.
The purpose of this study was to discriminate three crystal forms of carbamazepine (a BCS II drug) by in vitro dissolution testing and to correlate in vitro data with published in vivo data. A biphasic dissolution system (phosphate buffer pH6.8 and octanol) was used to evaluate the dissolution of the three polymorphic forms and to compare it with conventional single phase dissolution tests performed under sink and non-sink conditions. Similar dissolution profiles of three polymorphic forms were observed in the conventional dissolution test under sink conditions. Although a difference in dissolution was seen in the single phase dissolution test under non-sink conditions as well as in the aqueous phase of the biphasic test, little relevance for in vivo data was observed. In contrast, the biphasic dissolution system could discriminate between the different polymorphic forms in the octanol phase with a ranking of form III>form I>dihydrate form. This was in agreement with the in vivo performance. The dissolved drug available for oral absorption, which was dominated by dissolution and solution-mediated phase transformation, could be reflected in the biphasic dissolution test. Moreover, a good correlation was established between in vitro dissolution in the octanol phase of the biphasic test and in vivo pharmacokinetic data (R=0.99). The biphasic dissolution method is a valuable tool to discriminate between different crystal forms in the formulations of poorly soluble drugs.
本研究的目的是通过体外溶出度试验鉴别卡马西平（一种BCS II类药物）的三种晶型，并将体外数据与已发表的体内数据进行关联。采用双相溶出系统（pH6.8的磷酸盐缓冲液和辛醇）来评估三种多晶型物的溶出度，并将其与在漏槽和非漏槽条件下进行的传统单相溶出试验进行比较。在漏槽条件下的传统溶出试验中观察到三种多晶型物具有相似的溶出曲线。尽管在非漏槽条件下的单相溶出试验以及双相试验的水相中均观察到溶出差异，但与体内数据的相关性很小。相比之下，双相溶出系统能够在辛醇相中区分不同的多晶型物，其排序为III型> I型>二水合物型。这与体内性能一致。双相溶出试验能够反映出以溶出和溶液介导的相转变为主导的可用于口服吸收的溶解药物。此外，双相试验辛醇相中的体外溶出与体内药代动力学数据之间建立了良好的相关性（R = 0.99）。双相溶出方法是鉴别难溶性药物制剂中不同晶型的有价值工具。
