Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 9-177 WDH, 308 Harvard Street S.E., Minneapolis, Minnesota 55455, United States.
Mol Pharm. 2013 Aug 5;10(8):3128-36. doi: 10.1021/mp400180n. Epub 2013 Jul 22.
Model tablet formulations containing thiamine hydrochloride [as a nonstoichiometric hydrate (NSH)] and dicalcium phosphate dihydrate (DCPD) were prepared. In intact tablets, the water released by dehydration of DCPD mediated the transition of NSH to thiamine hydrochloride hemihydrate (HH). The use of an X-ray microdiffractometer with an area detector enabled us to rapidly and simultaneously monitor both the phase transformations. The spatial information, gained by monitoring the tablet from the surface to the core (depth profiling), revealed that both DCPD dehydration and HH formation progressed from the surface to the tablet core as a function of storage time. Film coating of the tablets with ethyl cellulose caused a decrease in both the reaction rates. There was a pronounced lag time, but once initiated, the transformations occurred simultaneously throughout the tablet. Thus the difference in the phase transformation behavior between the uncoated and the coated tablets could not have been discerned without the depth profiling. Incorporation of hydrophilic colloidal silica as a formulation component further slowed down the transformations. By acting as a water scavenger it maintained a very "dry" environment in the tablet matrix. Finally, by coating the NSH particles with hydrophobic colloidal silica, the formation of HH was further substantially decelerated. The microdiffractometric technique not only enabled direct analyses of tablets but also provided the critical spatial information. This helped in the selection of excipients with appropriate functionality to prevent the in situ phase transformations.
制备了含有盐酸硫胺素[作为非化学计量水合物（NSH）]和磷酸二氢钙二水合物（DCPD）的模型片剂配方。在完整的片剂中，DCPD 的脱水释放的水介导了 NSH 向盐酸硫胺素半水合物（HH）的转变。使用带有面探测器的 X 射线微衍射仪使我们能够快速且同时监测两种相转变。通过从表面到片剂核心（深度剖析）监测片剂获得的空间信息表明，DCPD 脱水和 HH 形成都随着储存时间从表面向片剂核心进行。用乙基纤维素对片剂进行包衣会降低两种反应速率。存在明显的滞后时间，但一旦开始，转化就会在整个片剂中同时发生。因此，如果没有深度剖析，就无法分辨未涂层和涂层片剂之间的相转变行为差异。将亲水性胶体二氧化硅作为配方成分掺入进一步减缓了转化。通过充当水清除剂，它在片剂基质中保持了非常“干燥”的环境。最后，通过用疏水性胶体二氧化硅涂布 NSH 颗粒，HH 的形成进一步大大减缓。微衍射技术不仅能够直接分析片剂，还提供了关键的空间信息。这有助于选择具有适当功能的赋形剂来防止原位相转变。
