Department of Pharmacy & Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands.
Int J Pharm. 2013 Jan 30;441(1-2):213-7. doi: 10.1016/j.ijpharm.2012.11.041. Epub 2012 Dec 5.
In this article, we report the anomalous dissolution behaviour of amorphous capecitabine. In contrast to what is expected from thermodynamic theory, amorphous capecitabine dissolves significantly slower compared to its crystalline counterpart. Our experiments show that this is due to the "gelling" properties of amorphous capecitabine in an aqueous environment. The "gel", which is immediately formed upon contact with water, entraps the capecitabine and significantly slows down its dissolution. This "gelling" property is hypothesized to be related to the low glass transition temperature (Tg 19°C) of amorphous capecitabine, resulting in an instant collapse ("gelling") in an aqueous environment. From IR and DSC analysis it is shown that this collapsed capecitabine is remarkably stable and does not recrystallize upon an increased water content or temperature. This highly reproducible dissolution behaviour can be applied in the development of a sustained release dosage form as substantially less sustained release excipient is required in order to attain the desired release profile. As capecitabine is a high-dosed drug, this is highly favourable in view of the size and thus clinical feasibility of the final dosage form. Currently, we are developing and clinically testing a sustained release formulation making use of amorphous capecitabine and its remarkable dissolution behaviour.
在本文中，我们报告了无定形卡培他滨异常的溶解行为。与从热力学理论预期的情况相反，无定形卡培他滨的溶解速度明显比其晶型对应物慢。我们的实验表明，这是由于无定形卡培他滨在水环境中的“胶凝”特性。“凝胶”在与水接触时立即形成，将卡培他滨困住并显著减缓其溶解速度。这种“胶凝”特性与无定形卡培他滨的低玻璃化转变温度（Tg 19°C）有关，导致其在水环境中立即崩溃（“胶凝”）。通过红外和差示扫描量热分析表明，这种塌陷的卡培他滨非常稳定，在增加含水量或温度时不会再结晶。这种高度重现的溶解行为可应用于开发缓控释剂型，因为需要更少的缓控释赋形剂即可达到所需的释放曲线。由于卡培他滨是一种高剂量药物，因此从最终剂型的体积和临床可行性来看，这是非常有利的。目前，我们正在开发并临床测试一种利用无定形卡培他滨及其显著的溶解行为的缓控释制剂。
