Boetker Johan P, Rantanen Jukka, Arnfast Lærke, Doreth Maria, Raijada Dhara, Loebmann Korbinian, Madsen Cecilie, Khan Jamal, Rades Thomas, Müllertz Anette, Hawley Adrian, Thomas Diana, Boyd Ben J
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC, Australia.
Eur J Pharm Biopharm. 2016 Mar;100:119-27. doi: 10.1016/j.ejpb.2016.01.004. Epub 2016 Jan 13.
Transformation of the solid-state form of a drug compound in the lumen of the gastrointestinal tract may alter the drug bioavailability and in extreme cases result in patient fatalities. The solution-mediated anhydrate-to-hydrate phase transformation was examined using an in vitro model with different biorelevant media, simulated fasted and fed state intestinal fluids containing bile salt and dioleoylphosphatidylcholine (DOPC) micelles, DOPC/sodium dodecyl sulfate (SDS) mixture, bile salt solution and water. Two anhydrate compounds (carbamazepine, CBZ and nitrofurantoin, NF) with different overall transformation time into hydrate form were used as model compounds. The transformations were monitored using direct structural information from time-resolved synchrotron X-ray diffraction. The kinetics of these transformations were estimated using multivariate data analysis (principal component analysis, PCA) and compared to those for nitrofurantoin (NF). The study showed that the solution-mediated phase transformation of CBZ anhydrate was remarkably faster in the DOPC/SDS medium compared to transformation in all the other aqueous dispersion media. The conversion time for CBZ anhydrate in water was shorter than for DOPC/SDS but still faster than the conversion seen in fed and fasted state micellar media. The conversion of CBZ anhydrate to hydrate was the slowest in the solution containing bile salt alone. In contrast, the solution-mediated phase transformations of NF did only show limited kinetic dependence on the dispersion media used, indicating the complexity of the nucleation process. Furthermore, when the CBZ and NF material was compacted into tablets the transformation times were remarkably slower. Results suggest that variations in the composition of the contents of the stomach/gut may affect the recrystallization kinetics, especially when investigating compounds with relatively fast overall transformation time, such as CBZ.
药物化合物在胃肠道腔内的固态形式转变可能会改变药物的生物利用度，在极端情况下会导致患者死亡。使用体外模型，在不同的生物相关介质中研究了溶液介导的无水物到水合物的相变，这些介质包括模拟禁食和进食状态的肠液（含有胆盐和二油酰磷脂酰胆碱（DOPC）胶束）、DOPC/十二烷基硫酸钠（SDS）混合物、胆盐溶液和水。两种转变为水合物形式的总时间不同的无水化合物（卡马西平，CBZ和呋喃妥因，NF）被用作模型化合物。使用时间分辨同步加速器X射线衍射的直接结构信息监测转变过程。使用多变量数据分析（主成分分析，PCA）估计这些转变的动力学，并与呋喃妥因（NF）的动力学进行比较。研究表明，与在所有其他水性分散介质中的转变相比，CBZ无水物在DOPC/SDS介质中的溶液介导相变明显更快。CBZ无水物在水中的转化时间比在DOPC/SDS中短，但仍比在进食和禁食状态的胶束介质中观察到的转化快。CBZ无水物向水合物的转化在仅含胆盐的溶液中最慢。相比之下，NF的溶液介导相变仅显示出对所用分散介质的有限动力学依赖性，这表明成核过程的复杂性。此外，当将CBZ和NF材料压制成片剂时，转化时间明显变慢。结果表明，胃/肠内容物组成的变化可能会影响重结晶动力学，特别是在研究具有相对较快总转化时间的化合物（如CBZ）时。
