Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA.
Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
AAPS PharmSciTech. 2017 Nov;18(8):3140-3150. doi: 10.1208/s12249-017-0784-3. Epub 2017 May 22.
The purpose of this research was to design and characterize an immediate-release formulation of carbamazepine (CBZ), a poorly soluble anti-epileptic drug, using a porous silica carrier. Carbon dioxide in its supercritical state (2000 psi, 30-35°C) was used as an anti-solvent to precipitate CBZ onto two particle size variants of silica. Adsorption isotherms were used as a pre-formulation strategy to select optimum ratios of silica and CBZ. The obtained drug-silica formulations were characterized by dissolution studies, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). This formulation strategy resulted in a 2.4-fold improvement in dissolution rate when compared to pure drug after 30 min of dissolution testing. PXRD and DSC confirmed the amorphous nature of CBZ in the formulations as well as the differences in polymorphic forms of commercial and supercritical fluid-processed CBZ. Additionally, solid-state NMR spectroscopy showed that the spin-lattice relaxation time for bulk drug (without silica) was ∼7.5 times greater than that for silica-confined CBZ, implying that when CBZ was adsorbed onto mesoporous silica, it is structurally disordered and had higher structural mobility, a characteristic of amorphous solids. The mesoporous silica matrix prevented CBZ crystal growth by imposing spatial constraint on CBZ nuclei and hence resulted in faster dissolution compared to bulk solid drug. Adsorption onto mesoporous silica using supercritical fluid technology may be used as a novel formulation strategy for amorphization of poorly soluble compounds, in turn improving their dissolution rate.
本研究旨在使用多孔硅载体设计并表征卡马西平（CBZ）的即释制剂，CBZ 是一种难溶性抗癫痫药物。超临界二氧化碳（2000 psi，30-35°C）被用作抗溶剂，将 CBZ 沉淀到两种不同粒径的硅载体上。吸附等温线被用作预配方策略，以选择硅和 CBZ 的最佳比例。通过溶解研究、差示扫描量热法（DSC）、粉末 X 射线衍射（PXRD）和扫描电子显微镜（SEM）对获得的药物-硅制剂进行了表征。与纯药物相比，该制剂在 30 分钟的溶解测试后，溶解速率提高了 2.4 倍。PXRD 和 DSC 证实了配方中 CBZ 的无定形性质，以及商业和超临界流体处理的 CBZ 的多晶型形式的差异。此外，固态 NMR 光谱表明，散装药物（无硅）的自旋晶格弛豫时间比硅限制的 CBZ 长约 7.5 倍，这意味着当 CBZ 被吸附到介孔硅上时，它的结构无序且具有更高的结构迁移率，这是无定形固体的特征。介孔硅基质通过对 CBZ 核施加空间约束来防止 CBZ 晶体生长，因此与散装固体药物相比，溶解速度更快。使用超临界流体技术将吸附到介孔硅上可能成为一种新型的制剂策略，用于使难溶性化合物非晶化，从而提高其溶解速率。
