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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.

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The stratum corneum, the rate‐limiting barrier in transdermal drug delivery, is chiral in nature and enantiomers behave differently with respect to their transport across the skin, resulting in enantioselective permeation. The permeation characteristics of individual enantiomers of metoprolol free base (MB) were investigated using hairless mouse skin. The influence of chiral permeation enhancers, l‐menthol and (±)‐linalool, on the permeation of MB was also investigated. In the absence of enhancers, the permeation profiles of R‐ and S‐MB from donor solutions containing either RS‐MB or pure enantiomers are comparable (p < 0.05). In presence of enhancers, l‐menthol and (±)‐linalool, the flux values were increased 2.4‐ to 3.0‐fold, respectively, and the permeation profiles of R‐ and S‐MB from donor solutions containing RS‐MB are comparable (p < 0.05). However, when donor vehicle contains pure enantiomers, the permeation enhancing effect of l‐menthol on S‐MB was significantly higher (by 25%) than on R‐MB (p < 0.05). Further, in presence of l‐menthol, the flux of S‐MB from donor solution containing pure S‐MB was 35% higher than the flux of RS‐MB from racemate. No such effect was seen with (±)‐linalool. In all the investigations, no enantiomeric inversion was observed during the permeation process. The lag times were shorter in the case of l‐menthol compared with (±)‐linalool. Chirality 11:536–540, 1999. © 1999 Wiley‐Liss, Inc.

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