Rodrigues Sá Couto André, Ryzhakov Alexey, Larsen Kim Lambertsen, Loftsson Thorsteinn
Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, IS-107 Reykjavik, Iceland.
Department of Chemistry and Bioscience, Aalborg University, Frederik Bajers Vej 7H, DK-9220 Aalborg, Denmark.
ACS Omega. 2019 Jan 16;4(1):1460-1469. doi: 10.1021/acsomega.8b02045. eCollection 2019 Jan 31.
A detailed comprehensive study on how the formation of soluble and insoluble carbamazepine/cyclodextrins (CBZ/CD) complexes (with consequent changes in the solid-phase composition) depends on the CD structure is not yet available. Moreover, the study of possible influence of this drug on the tendency of CDs and their complexes to self-aggregate is still lacking. Phase-solubility studies demonstrated that CDs and CBZ form a range of soluble (A-type: αCD, βCD, and hydroxypropylated CDs) and insoluble (B-type: γCD) complexes depending on CD used. HPβCD proved to be the best CD solubilizer for CBZ forming the most stable complex with highest apparent solubility, whereas γCD was shown to be the best native CD. For the native CDs, CBZ solubilization increases with increasing CD cavity diameter (αCD ≪ βCD < γCD). Solid phases collected from phase-solubility studies were characterized by Fourier-transformed infrared spectroscopy, differential scanning calorimetry, and X-ray powder diffraction to elucidate their composition and crystalline structure. They provided similar conclusions being overall supportive of phase-solubility, osmolality, and permeation studies results. Solid CBZ was the only detected component for A-type profiles over the CD concentration range studied, whereas precipitation of poorly soluble CBZ/γCD complexes (B-type) was observed (i.e., at and beyond plateau region). Osmometry and permeation studies were applied to evaluate the effect of CBZ on the aggregate formation and also to elucidate their influence on CD complex solubility and permeation profile. Permeation method was shown to be the most effective method to detect and evaluate aggregate formation in aqueous γCD and HPβCD solutions containing CBZ. CBZ did not affect the HPβCD tendency to self-aggregate but CBZ did modify the aggregation behavior of γCD decreasing the apparent critical aggregation concentration value from 4.2% (w/v) (in pure aqueous γCD solution) to 2.5% (w/v) (when CBZ was present).
关于可溶性和不溶性卡马西平/环糊精（CBZ/CD）复合物的形成（以及随之而来的固相成变化）如何依赖于CD结构的详细全面研究尚未开展。此外，关于这种药物对CD及其复合物自聚集倾向可能产生的影响的研究仍然缺乏。相溶解度研究表明，根据所使用的CD不同，CD与CBZ会形成一系列可溶性（A型：αCD、βCD和羟丙基化CD）和不溶性（B型：γCD）复合物。HPβCD被证明是CBZ的最佳CD增溶剂，能形成最稳定的复合物且具有最高的表观溶解度，而γCD被证明是最佳的天然CD。对于天然CD，CBZ的增溶作用随着CD腔径的增大而增强（αCD≪βCD<γCD）。通过傅里叶变换红外光谱、差示扫描量热法和X射线粉末衍射对相溶解度研究中收集的固相进行表征，以阐明其组成和晶体结构。它们得出了相似的结论，总体上支持相溶解度、渗透压和渗透研究结果。在所研究的CD浓度范围内，对于A型曲线，唯一检测到的成分是固体CBZ，而观察到了难溶性CBZ/γCD复合物（B型）的沉淀（即在平台区及之后）。渗透压和渗透研究用于评估CBZ对聚集体形成的影响，并阐明其对CD复合物溶解度和渗透曲线的影响。渗透法被证明是检测和评估含CBZ的γCD和HPβCD水溶液中聚集体形成的最有效方法。CBZ不影响HPβCD的自聚集倾向，但CBZ确实改变了γCD的聚集行为，将表观临界聚集浓度值从4.2%（w/v）（在纯γCD水溶液中）降低到2.5%（w/v）（当存在CBZ时）。
