PHYSICAL CHEMICAL ANALYSIS OF PERCUTANEOUS ABSORPTION PROCESS 89 was maintained constant. Thus all ointments containing finely ground suspensions of the drug (thermodynamic activity equal to that of the solid drug) will produce the same rate of penetration. This again presupposes that the rate determinining step is essentially in the passage of the barrier phase. For highly insoluble systems this would not be true as we will see later. In order to obtain the maximum rate of penetration it is evident that the highest thermodynamic potential possible for the penetrating substances must be used. For simple organic compounds the activity of the pure form of the material at environmental temperature places, however, an upper limit on the available thermodynamics activity. Any higher activity would represent supersaturation with respect to the form. With more complex compounds, however, different crystalline modifications may exist having different free energies, thus different thermodynamic activities, at room temperature. In such instances the selection of the most energetic species will result in fastest penetration. These systems are, however, metastable and may show a gradual change in properties. TABLE 1--LIMITING ACTIVITY COEffiCIENTS or $ARIN IN ORGANIC SOLVENTS AND WATER Perfluorotributylamine ........ 66.6 Hexadecane .................. 15.6 Water ....................... 14 Tributylamine ............... 10.4 Tetralin ..................... 4.3 2-Pyrrolidone ................ 2.8 Diethylene glycol ............. 2.4 Carbon tetrachloride .......... 2.4 Phenyl ether ................. 2.38 Diisooctyl adipate ......... 1.84 Methyl salicylate .......... 1.74 N-methylacetamide ........ 1.44 Dibutyl phthalate ......... 1.42 Butryolactone ............. 1.3l Isoamyl alcohol ........... 1.07 Ethyl lactate ............. 0. 536 Benzyl alcohol ............ 0. 446 m-Cresol ................. 0. 044 Since activities are important rather than any absolute concentration, it is obvious that, for a given concentration of the penetrating substance, vehicles which have lower affinity (poorer solvent power) will normally produce faster penetration. It is not commonly realized how dependent such activity coefficients are on solvents. In Table 1, I have listed values in some solvents for sarin, a nerve gas, which we determined a few years ago. It is evident that these values encompass three orders of magnitude. It is to be expected that the same degree of difference will be found in the rates of absorption of the fluorophosphate from these solutions. In practical language one might say that solutes held firmly by the vehicle will exhibit low activity coefficients and slow rates of penetration. Good pharmaceutical examples of this behavior are the relative rates of release (penetration) of phenols from mineral oil or petrolatum bases and from camphor or polypropylene glycol bases. The latter preparations are mild and bland whereas the former are quite corrosive at equal concentrations. This is due to the reduction in the thermodynamic activity of the phenols caused by the ketone or the polyethers. Such complex formations usually

9O JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS cause marked diminution in the rate of penetration of the bound compound. Similarly, the absorption rate of iodine has been greatly reduced by use of PVP to control its toxicity. For the same reason the rates of absorption of acidic and basic drugs are strongly influenced by the effective pH of the vehicle. The activity co- efficient of the molecular form of such drugs is a rapidly changing function of pH for pH values greater than pKa for acidic compounds and less than pKw - pKb for alkaloidal drugs. Thus, for example, the rate of absorption of histamine would be 10 times greater from a base buffered at pH = 7.5 than from tl'at at 6.5 and 100 times greater than that from base at 5.5. Such estimations are valid irrespective of the nature of the assumed barrier and mode of transfer provided only the nonionized species is involved in the absorption process. Substances showing lower melting points generally permit higher con- centration in solution and would thus tend to give faster penetrating systems. It is difficult, therefore, to produce rapid absorption of high melting chemicals such as sulfonamides whereas most semipolar, low melt- ing or liquid organic compounds are fairly rapidly absorbed. Effective Multilayer Barriers. These simple relationships are not valid for systems where the penetrating substance has an extremely low affinity for the lower water-bearing tissues. In this instance the rate determining step no longer involves transition through the barrier but transfer from the barrier phase to the deeper tissues. The situation becomes evident by comparison of Fig. 2 with Fig. 4 where such a situation exists. In the latter Deeper Tissue Barriel Layer Figure 4.--Schematic diagram showing Surface Layer • Conc. plot enetrating system having little or no gradient in the barrier layer. instance the drop in the chemical potential of-the penetrating agent occurs largely below the barrier layer. In the former case the drop occurred mainly in the barrier itself. Systems which follow Fig. 4 usually exhibit a relatively low rate of penetration. This is obviously due to the highly unfavorable partition coefficient in moving from the epidermal layers to the watery deeper tissues.