Gupta P, Bansal A K
Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India.
Pharmazie. 2005 Nov;60(11):830-6.
The present study highlights the development of ternary amorphous composites to enhance the solubility of a poorly soluble crystalline drug, celecoxib (CEL). These systems comprised of an 'amorphous drug,' and its 'stabilizer' and 'solubilizer.' The ternary amorphous system of CEL, poly(vinyl pyrrolidone) (PVP) and meglumine (MEG) (7:2:1 w/w) enhanced CEL solubility by approximately equal to 10.2-fold over that for the crystalline drug, and maintained the thermodynamic stability of the amorphous drug. However, MEG alone was unable to stabilize the amorphous CEL against thermally-induced crystallization, and so gave no solubility advantage. The PVP-MEG combination provided a 'synergistic' enhancement of CEL solubility, as compared to their use alone in the amorphous systems. Phase-solubility studies provided greater insight into molecular mechanisms underlying stability and solubility of these amorphous systems. MEG exhibited phase-specific interaction with CEL molecules, when stabilized by PVP in the amorphous state. The higher solubility of CEL from ternary amorphous systems was also thermodynamically favored, as analyzed by van't Hoff plots. A possible molecular level interaction of MEG with PVP-stabilized amorphous CEL seems to be responsible for the solubility advantage of the CEL-PVP-MEG ternary amorphous system.
本研究着重介绍了三元无定形复合材料的开发，以提高难溶性结晶药物塞来昔布（CEL）的溶解度。这些体系由“无定形药物”及其“稳定剂”和“增溶剂”组成。CEL、聚维酮（PVP）和葡甲胺（MEG）（7:2:1 w/w）的三元无定形体系使CEL的溶解度比结晶药物提高了约10.2倍，并保持了无定形药物的热力学稳定性。然而，单独使用MEG无法稳定无定形CEL以防止热诱导结晶，因此没有溶解度优势。与它们在无定形体系中单独使用相比，PVP-MEG组合对CEL的溶解度有“协同”增强作用。相溶解度研究更深入地揭示了这些无定形体系稳定性和溶解度背后的分子机制。当在无定形状态下由PVP稳定时，MEG与CEL分子表现出相特异性相互作用。通过范特霍夫图分析，三元无定形体系中CEL较高的溶解度在热力学上也是有利的。MEG与PVP稳定的无定形CEL之间可能的分子水平相互作用似乎是CEL-PVP-MEG三元无定形体系具有溶解度优势的原因。
