Racemate and enantiomers of ketoprofen: Phase diagram, thermodynamic studies, skin permeability, and use of chiral permeation enhancers
Racemate and enantiomers of ketoprofen: Phase diagram, thermodynamic studies, skin permeability, and use of chiral permeation enhancers
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DOI：
10.1021/js9704644
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发表时间：
1998-07-01
影响因子：
3.8
通讯作者：
Reddy, IK
中科院分区：
文献类型：
--
作者：
Kommuru, TR;Khan, MA;Reddy, IK
研究了内源性和外源性因素对手性药物经皮转运的影响。选择酮洛芬（KP）作为模型手性药物。研究了S-和RS-KP的熔融特性与通量值之间的可能关系。手性增强剂薄荷醇和芳樟醇的潜在用途也进行了研究。对KP的各个对映体和外消旋体进行了热分析。各对映异构体的熔融温度比外消旋化合物的熔融温度低22 ℃。熔融吸热峰温度作为对映体组成的函数作图，得到二元相图。相图表明存在外消旋化合物，并通过使用报道的方法计算在dyphritic区的液相线来验证。粉末X-射线衍射研究也证实了KP的外消旋体是外消旋化合物。在体外使用并排扩散池测定单个对映体和KP的外消旋体通过小鼠皮肤的渗透性。R-和S-KP从外消旋体和纯对映体的水溶液中的转移显示渗透速率没有显著差异，表明KP从这些溶液穿过小鼠皮肤的转移速率与药物的立体化学无关。在转移过程中未观察到外消旋化迹象。芳樟醇的促渗率高于I-薄荷醇，但不显著。通过MTMT概念预测的对映异构体与外消旋体通过皮肤的通量的比率（1.97）与实验测定的通过小鼠皮肤的比率（1.79）非常一致。
The role of intrinsic and extrinsic factors on transport of a chiral drug through the skin was studied. Ketoprofen (KP) was chosen as a model chiral drug. A possible relationship between the melting characteristics and the flux values of S- and RS-KP was investigated. The potential use of chiral enhancers, menthol and linalool, was also investigated. Thermal analyses were carried out for individual enantiomers and the racemate of KP. The melting temperature of each enantiomer was 22 degrees C lower than that of the racemic compound. Peak temperatures from the melting endotherms were plotted as a function of enantiomeric composition to give the binary phase diagram. The phase diagram suggested the presence of a racemic compound, and it was verified by calculations of the liquidus curve in the dystectic region using reported methods. Powder X-ray diffraction studies also confirmed that the racemate of KP is a racemic compound. The permeability of individual enantiomers and the racemate of KP through mice skin was determined in vitro using side-by-side diffusion cells. Transfer of R- and S-KP from aqueous solutions of both the racemate and pure enantiomer showed no significant differences in the rates of permeation, indicating that the rate of transfer of KP across the mice skin from these solutions was independent of the stereochemistry of the drug. No evidence of racemization during the transfer process was observed. The permeation-enhancing ratio of linalool was higher, but not significant, than that of I-menthol. The predicted ratio of enantiomer to racemate flux through the skin by the MTMT concept (1.97) is in close agreement with the experimentally determined ratio (1.79) across mouse skin.