238 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS 0.12 - 0.10 E '•- 0.08 E x • 0.06 • 0.04 "'-' 0.02 0.00 0 25 50 75 100 % Saturation Figure 6. Methylparaben flux as a function of the percent saturation (activity) for 1-propanol treatment. Table III Theophylline Solubilities and Permeation Data Flux (Ixmol/cm2/h) Solubility @ 37øC Solvent (mg/cm 3) n Mean 95% C.I. a PEG 400 9 0.011 Glycerin 5 0.014 0.012 DMIS 6 0.029 0.024 Propylene glycol 6 0.044 0.032 Water l0 b 12 0.13 0.12 1-Propanol 4.1 6 0.21 0.17 Ethanol 4.8 6 0.29 0.27 Methanol 8.4 6 0.65 0.54 Average lag time +_ standard error (h) 56 1.5 ñ 0.1 0.011 • x • 0.012 0.016 0.033 0.057 0.14 0.25 0.32 0.75 Confidence interval. Calculated using 8.07 mg/cm 3 at 32øC (reference 10).

SKIN PENETRATION 239 Table IV Methylparaben Solubilities and Permeation Data Flux (•tmol/cm2/h) Solubility @ 37øC Solvent (mg/cm 3) n Mean 95% C.I. • PEG 400 330 9 0.055 0.049 • • • 0.061 Glycerin 6 0.11 0.094 • • • 0.12 DMIS 6 0.16 0.14 • I.t • 0.18 Propylene glycol 260 6 0.55 0.49 • •t • 0.61 Water 3.5 12 0.67 0.60 • • • 0.73 1-Propanol 360 6 0.68 0.61 • Ix • 0.76 Ethanol 380 6 1.36 1.1 • I.t • 1.6 Methanol 470 6 9.1 7.7 • I.t • 10 Average lag time _+ standard error (h) 93 3.3 -+ 0.1 Confidence interval. equal in the absence of solvent-induced skin damage. Significant differences in flux are a measure of the effect of specific skin/solvent interactions. Permeation data for saturated solutions of theophylline and methylparaben in each sol- vent are collected in Tables III and IV. The same data are graphically presented in Figure 7. Theophylline flux from suspension in propylene glycol was similar to a value reported by Sloan et al. (10) using hairless mouse skin (0.032 -+ 0.005 •xmol/cm2/h) at 32øC. Limited flux data for propylparaben (propylene glycol flux: 0.55 ptmol/cm2/h + SE 0.05 dimethylisosorbide flux: 0.17 •tmol/cm2/h -+ SE 0.03) parallel data for corre- sponding methylparaben systems. The average coefficient of variation in flux values was 14% for methylparaben and 15% for theophylline. The large variation in measured lag times (average CV of 26%) limited their usefulness for quantitative assessment. Methyl- paraben flux was greater than that of theophylline from each donor solvent. In the absence of solvent-induced changes in membrane permeability, the flux values for each solute should have been constant. However, examination of the data in Tables III and IV reveals significant differences in the flux values between solvents for both solutes. Permeant solubility per se is not a factor in the results. Theophylline solubility in water was not measured, but can be estimated as approximately 10 mg/cm 3 (10). Its flux from saturated solution in water is about half that from ethanol, although its solubility is about twice as great (Table III). On the other hand, theophylline solubility in methanol is intermediate between that of water and ethanol, yet skin penetration from methanol was highest. Similarly, methylparaben flux from 1-propanol is more than ten times greater than from polyethylene glycol 400, although solubility in these solvents is nearly identical (Table IV). Furthermore, methylparaben flux from water and propylene glycol are comparable despite a difference in solubility of nearly two orders of magni- tude. To quantitate the solvent interaction, the data were normalized to an arbitrary refer- ence. Water was selected as the reference solvent since it allows comparison to most other skin permeation studies. The larger. number of replicates for aqueous systems (n = 12) resulted in a smaller flux confidence interval. Flux ratios for the fuzzy rat skin are presented in Table V. The alcohols consistently increased solute flux up to a max-