Frank H. Clarke

The relationship of pKa and acute skin irritation in man.

The relationship between pKa and skin irritation in man is studied for a homologous series of benzoic acid derivatives, which permeate through human skin at comparable rates (15–88 µg/cm2/hr). Skin irritation and pKa are correlated for pKa ≤ 4. Laser Doppler velocimetric assessment of skin blood flow, color meter readings, erythema, edema, and the primary irritation index are all linearly correlated and related to pKa, erythema at 24 hr appears to be the most sensitive parameter to variation in pKa when pKa ≤ 4.

Quantitative Evaluation of Aqueous Isopropanol Enhancement of Skin Flux of Terbutaline (Sulfate). I. Ion Associations and Species Equilibria in the Formulation

It has been reported previously that saturated terbutaline sulfate in aqueous isopropanol significantly enhances the terbutaline flux through human skin in vitro. This paper demonstrates that the effect of isopropanol on the permeant species in the formulation contributes to the flux enhancement. This demonstration is based on studies involving measurements of conductivity and pKa as well as NMR spectroscopy in isopropanol-water mixtures. Increasing isopropanol concentration inhibits the proton dissociation of terbutaline and results in the ion associations between the protonated terbutaline and its counterion, sulfate anion. The species present in the formulation include protonated terbutaline, the negatively charged terbutaline-sulfate (1:1) ion pair, and the neutral terbutaline-sulfate (2:1) ion triplet. The results of the studies provide the basis for a quantitative evaluation of the species equilibria in solutions of terbutaline sulfate. The saturated terbutaline sulfate in 60% isopropanol produces the maximum concentration of the neutral ion triplet. This result is almost parallel to the terbutaline skin flux, which maximized at 60–80% isopropanol.

Relationship of PKA and Acute Skin Irritation in Humans

AbstractThe relationship between pKa and skin irritation in humans was studied for a homologous series of benzoic acid derivatives with predicted permeation through human skin at comparable rates (15-90 μg/cm2/hr). Skin irritation and pKa are strongly correlated, and, for pKa ≤4, skin irritation rapidly increases. Laser Doppler velocimetric assessment of skin blood flow, color meter readings, erythema, edema, and the primary irritation index are all linearly correlated and related to pKa; erythema at 24 hr appears to be the most sensitive variable.