680 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS the selection of costly ingredients, which may have been influenced by miceIlar or lyotropic mesomorphic behavior. Thus drug, flavor, odor or color changes may be associated with liquid-crystal phase transitions. This is especially true if we rely on optical methods for routine analysis (spectrophotometric, microscopic, light-scattering, etc.) FACTORS AFFECTING THE CMC VALUES The implications of the existence of a cmc range for nafoxidine hydrochloride aqueous solutions allows us to predict many physical-chemical properties. At concentrations above the cmc the solution is non-ideal. It should be emphasized, however, that the critical concentration is not a unique concentration value but a concentration range within which the constitution of the amphipathic solute in solution changes from the molecular (or ionic) disperse state to an equilibrium between molecules (or ions) and aggregates. It is important to distinguish between (a) those factors which influence the cmc ofnafoxi- dine hydrochloride solutions and (b) those properties of nafoxidine hydrochloride so- lutions which are a consequence of micellar behavior in the subsequent physical, chemical and/or biological systems investigated, i.e., properties affected by the cmc. The cmc ranges determined in the studies described were for essentially simple binary systems of drug in water. The micellar behavior for ternary or more complicated systems becomes quite complex. Mention is only made here of the most common fac- tors which can affect cmc values, namely, (a) the presence of additives such as (1) salts (gegenions), (2) polar compounds, (3) insoluble materials or (4) other surfactants (b) the effect of pH and (c) the temperature dependency. These effects are discussed by Shinoda and Sjoblom (15) in greater detail however, the qualitative effect of these fac- tors is important to recognize. Special emphasis is made in recognizing that nafoxidine hydrochloride solutions involve an ionic surfactant, and, as such, one must be careful not to assume that the typical behaviors of nonionic surface-active agents can be ex- pected in these systems. Salts lower the cmc values of ionic surfactants. However the salt effect is not governed by the principle of ionic strength or the Debye-Hiickel relationships. The depression of the cmc depends only on the concentration of ions bearing a charge opposite of that of the surface-active ions (i.e., anions). The nature and concentration of ions of the same charge (cations) are without effect. Correspondingly smaller cmc's for nafoxidine hydrochloride solutions would be observed for bivalent gegenions than for univalent additives. Long-chain alcohols, amines and similar compounds containing a polar group can produce a considerable lowering of the cmc. The effect is increased both by the concentration of the polar additive and by increasing the chain length (i.e., C4OH lower the cmc more than C2OH). Insoluble materials such as hydrocarbons or any other material which can be solubi- lized in the interior of the nafoxidine hydrochloride micelle can cause an increase in the micellar size and thus lower the critical concentration. The interplay of the hydro- philic and oleophilic (may be here considered as hydrophobic) portions of the amphi- pathic nafoxidine ion have a great effect on the cmc. The solubility of the ion-pair (counterion + charged polar head of the amphipathic nafoxidine cation) in the surface

LYOTROPIC MESOPHASE (LIQUID CRYSTAL) 681 region of the micelle is probably a very important factor in determining the size of the micelie and hence its cmc. The selection of aerosol components in cosmetic formulations including a mesomorphic compound may be affected by the above additives. The vapor pressure, spray pattern and concentrate/propellant ratio will depend on the surface activity and phase behavior of the major active ingredient. The addition of salts or alcohols will de- termine the stability and shelf-life of the product. SIGNIFICANCE OF MICELLAR AND MESOMORPHIC PROPERTIES The importance of the miceliar behavior of nafoxidine hydrochloride can be subject to considerably varied interpretation. The presence of a cmc can manifest itself in a wide variety of physiochemical properties, many of which have been described in this report. It is pertinent here to mention those properties affected by miceliar behavior which may significantly influence the use of drug, cosmetic or toiletry products. Shi- noda describes the following properties as being critically affected by micellization: (a) solubilization, (b) surface tension, (c) partial molal volume, (d) refractive index, (e) light scattering, (f) colligative properties, (g) solubility, (h) electromotive force, (i) diffusion, (j) viscosity, (k) dialysis, (1) ultraviolet and infrared absorption and 10 or more other physicochemical phenomena. All are based on a non-ideal or varied be- havior of the surfactant at concentrations above the cmc. The physical and chemical methods employed in preparing the drug and the dosage form were of particular interest to us in the design of the most effective formulation of nafoxidine hydrochloride. In addition, any analytical procedure employed to aid us in dealing with the drug in its varied systems must be subjected to a possible involvement of miceIlar behavior. Having recognized such a contribution in several of the systems investigated in product development has greatly facilitated both an understanding of the phenomena observed and the selection of appropriate methods to study and develop suitable formulations. The growing popularity of cosmetic hair preparations in transparent form has stimu- lated the development of clear gels. Emulsions, microemulsions and lyogels have been made from miceliar and mesomorphic ingredients. The viscoelastic properties of lyotropic mesophases have been utilized to capture rheological cosmetic acceptance based on ease of application (feel) as well as detergent properties in shampoos and soaps. The color and fragrance of such products may be stabilized by concentrating the ingredient(s), often very expensive components, into a mesomorphic phase which is very thermodynamically stable. The clear gel formulation has also been used for lipsticks, skin fresheners and anti- perspirants, as well as hair products. While most of these products involve microemul- sions which are not mesophases, the use of surfactants in high concentration offers spe- cial solubilization opportunities to incorporate other ingredients into the gel formula- tion (especially perfuming). The optical properties of nafoxidine hydrochloride mesophases displayed pearlescent appearances which offer not only an acceptable cosmetic property but can also be used to overcome the problem of discoloration. Surfactant systems can be formulated to in- corporate vanillin, eugenol, indole and other labile additives. While the pearlescent ef-