Racemate and Enantiomers of Ketoprofen: Phase Diagram, Thermodynamic Studies, Skin Permeability, and Use of Chiral Permeation Enhancers

Abstract

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.

Effect of chiral enhancers on the permeability of optically active and racemic metoprolol across hairless mouse skin

“…These results suggest that the chiral nature of the stratum corneum and epidermis did not give rise to enantioselective permeation. These findings are in agreement with the reported studies on propranolol, 15 ephedrine, 1 and ketoprofen 6 where no enantioselective permeation across the skin was observed. The lack of enantioselectivity may be attributed to various factors such as (a) high drug concentration, (b) presence of organic solvent in the donor solution which causes conformational changes in keratin/lipid molecules, and (c) a different pH of the donor solution from that of the skin.…”

“…16 Further, the lipophilicity of prodrug is significantly higher than that of propranolol. 16 Extrinsic factors such as differences in physicochemical properties of enantiomers and racemate 5,6 and presence of chiral excipients 17 were reported to cause enantioselective permeation. In the present studies, the melting point of the pure enantiomers of MB (43.9°C) was slightly lower than RS-MB (49.9°C).…”

Kuromoji (Lindera umbellata) Essential Oil Inhibits LPS-Induced Inflammation in RAW 264.7 Cells

“…Previous reports suggest that linalool and some terpenoids can enhance the permeability of numerous drugs through biological tissues such as skin and mucus membranes. [31][32][33] Various terpenoids show PPAR ligand activity. They regulate inflammatory processes such as diabetes mellitus, hyperlipidemia, and cardiovascular disease, which are associated with low-grade chronic inflammation.…”

Metabolic chiral inversion of 2-arylpropionic acid derivatives (profens)

“…Other authors claim that no relevant enantiomeric inversion of (R)-to (S)-form has been registered [4,26,27].…”