SKIN PENETRATION 619 hydration does not drastically affect the "barrier" function of the stratum corneum (24). The more important point to consider is the thermo- dynamic activity of water in the barrier phase, not just the amount there. The efficiency of varied type vehicles in aiding penetration can be reasonably predicted on the basis of their effect on hydration of the stratum comeurn or how the vehicle alters the activity of water in the stratum comeurn and influences the stratum corneum/vehicle partition coefficient. Greases and oils are the most occlusive vehicles and induce the greatest hydration through sweat accumulation at the skin-vehicle interface (51). This is accentuated by covering with occlusive bandages or plastic. Emulsions of the water-in-oil type are less occlusive than greases. Substances in the vehicle, such as humectants, which have a high affinity for water, would act in proportion to the relative humidity of the environment. If the latter is low, the humectant would tend to dehydrate the stratum comeurn and decrease penetration. Similarly, powders increase surface area, increase the rate of evaporation of water, and so decrease the extent of hydration (51). Temperature Under normal in vivo conditions, substances penetrate the skin only within a very narrow temperature range. Clinical variations derive chiefly from occlusion. In vitro experiments, on the other hand, may be conducted over a much wider range. Blank and Scheuplein (25) studied the rates of penetration of ethanol and 1-pentanol within the range of 0 and 55øC. The flux, or the amount of alcohol penetrating per unit area in unit time, was an exponential function of the temperature. The energies of activation were determined by Arrhenius plots of the log of the permeability constant against the reciprocal of the temperature. The activation energies of the two alco- hols differ measurably from one another and are higher than those ob- tained for diffusion of the same substances in solutions. The magnitude of the activation energies for the penetration of the low molecular weight alcohols through the skin indicates that penetration is a more complex process than diffusion through vehicle-filled channels. The same au- thors observed little alteration of the permeability of the barrier by exposure for several hours to temperatures as high as 60øC. However, Allenby et al. (52) showed that the stratum corneum undergoes irrever- sible structural changes when heated above 65øC or incubated in aqueous media at pH 3 or 9.

620 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Concentration of Penetrant The amount of penetrant percutaneously absorbed per unit surface area per time interval wild usually increase as the concentration of the drug in the vehicle is increased. Diffusion through the skin is virtually always a passive process, governed by Fick's general law of diffusion: e At where Q is the amount of the solute which penetrates A is the area of the membrane t is the time ]8 is the flux or the amount which penetrates per unit area in unit time k• is the permeability constant, and zxC8 is the difference in concentration of the solute on the two sides of the mem- brane. In essence, the driving force or rate of transfer across the membrane is the concentration of the applied drug. The permeability constant is of utmost importance, for by varying the concentration of the penetrant and observing the consistency of /%, one can determine the extent to which Fick's law is applicable under the experimental conditions. When Fick's law is indeed applicable, the k• value provides a satisfactory basis for comparing penetration rates obtained in different laboratories with different concentrations and techniques. Thermodynamically, the activity of the drug in the vehicle is the product of the concentration of drug and the activity coefficient of the drug in the vehicle. For most substances, the rate of penetration is limited by the irapermeability of the skin and, in such cases, the highest thermodynamic potential in the applied phase is necessary to obtain the maximum rate of penetration. For a given concentration of drug in certain vehicles, the activity coefficient of the drug, and con- sequently the thermodynamic activity of the drug in the vehicle at that concentration, may vary by a factor as much as a thousandfold from one vehicle to the next. Solutes held firmly by the vehicle, such as when the drug forms a soluble complex with the vehicle, exhibit low activity coefficients hence, the rate of release from such drug-vehicle combina- tions will be slow. Solutes held "loosely" by the vehicle (less affinity of the vehicle for the drug or solute) exhibit high activity coefficients there- fore, the rate of release from such drug-vehicle combinations will be faster (11). Higuchi (11) initiated the basic equations describing the variables affecting the rate of release of solid drugs suspended in vehicles. He