Racemate and enantiomers of ketoprofen: phase diagram, thermodynamic studies, skin permeability, and use of chiral permeation enhancers.
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 degreesC 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 l-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.
Kommuru
T R
TR
Division of Basic Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe, Louisiana 71209, USA.
Khan
M A
MA
Reddy
I K
IK
D000080462:Acyclic Monoterpenes; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000493:pharmacokinetics; D002627:Chemistry, Physical / Q000379:methods; D004347:Drug Interactions; D066298:In Vitro Techniques; D007660:Ketoprofen / Q000737:chemistry* / Q000493:pharmacokinetics*; D008297:Male; D008610:Menthol / Q000494:pharmacology*; D051379:Mice; D008812:Mice, Hairless; D039821:Monoterpenes; D010539:Permeability / Q000187:drug effects; D012869:Skin Absorption / Q000187:drug effects*; D012996:Solutions; D013237:Stereoisomerism; D013729:Terpenes / Q000494:pharmacology*; D013816:Thermodynamics; D014961:X-Ray Diffraction
D000080462:Acyclic Monoterpenes; D000894:Anti-Inflammatory Agents, Non-Steroidal; D039821:Monoterpenes; D012996:Solutions; D013729:Terpenes; D008610:Menthol; D007660:Ketoprofen; C018584:linalool