j. Soc. Cosmet. Chem., 29, 659-683 (November 1978) Thermodynamics and physical properties of a lyotropic mesophase (liquid crystal) and miceliar solution of an ionic amphiphile ARTHUR R. MLODOZENIEC Hoffmann-La Roche Inc., Nutley, NJ 07110. Received April 25, 1978. Presented at Annual Scientific Seminar, Society of Cosmetic Chemists, May 1978, Chicago, Illinois. Synopsis Concentrated aqueous surfactant solutions can be phase examined to determine the extent of anisotropy present under varying THERMODYNAMIC conditions. This study describes the PHYSICAL PROPERTIES of nafoxidine hydrochloride, an IONIC AMPHIPHILE which exhibits both thermotropic and lyotropic mesomorphism. Micelies, ordered fluids and liquid crystals were detected in stepwise aggrega- tion as the kinetics of MICELLIZATION was investigated during a drug development program. Utilizing microscopic and thermal analysis, the phase behavior of a concentrated amphiphile system was studied. Turbidimetric and nephelometric data were utilized to determine the presence of "middle" (nematic), viscous isotropic and "neat" (smectic) mesophases. At lower concentrations, the micelle-monomer equilibrium was investigated utilizing classical spectrophotometric and surface activity measurements. Thermodynamically stable phases have been individually identified which form emulsions, gels and lyogels. The solubility characteristics of a drug, cosmetic or toiletry product may be obscured if the molecule exhibits the LYOTROPIC MESOPHASE and micellar behavior of a surfactant. These are important to the cosmetic chemist who is charged with developing a stable product. INTRODUCTION Often in the development of a cosmetic or pharmaceutical product formulation, the interaction of a major ingredient with water represents the most critical performance characteristic of the product. Occasionally, the compound is surface active and possesses some very unique physicochemical properties which may result in anomalous behavior in various aqueous systems. An example of such a case is nafoxidine hydro- chloride, shown in Figure 1. Investigations of colloidal solutions of this drug have shown that the properties of aqueous systems of the drug exhibit a more or less abrupt change at critical values of concentration. At lower concentrations the drug behaves as an ideal solution. Higher concentrations lead to miceIlar behavior and lyotropic mesophases. Nafoxidine hydrochloride may also be classified as a weak surfactant, although its solubilizing action does not 659

660 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS cl © H/• 0 HYDROPHILIC Ii . ii or chorge-beormg heod OLEOPHILIC or hydrocorbon group Figure 1. The surfactant cation of nafoxidine hydrochloride may be represented schematically as shown above. The conventional formula on the left is drawn to compare to the Hirschfelder model shown photographed on the right. Amphiphiles are commonly divided into regions of hydrophilic (•) and of oleo- philic (if) characters which are linked by amphiphilic (c-') layers. meet the usual criteria for such specific activity. It is a long-chained aromatic (diphenyl dihydronaphthalene) derivative, the oleophilic portion, 9, of a cyclic amine salt (pyrro- lidine), the hydrophilic portion, •, as described in Figure 1. It is essentially water solu- ble only in acidic solution. The salt ionizes to form the long-chain cation and simple chloride anion. Since the concentration of protonated amine cation is dependent on the ionic equilibrium between free amine and the charged amine, a striking pH de- pendency is expected and has been found experimentally. The cation of nafoxidine hydrochloride is surface active. The chloride ion is the counter-ion or gegenion and is important as an electrolyte in colloidal solutions of the drug. The presence of other additives, especially electrolytes, greatly influences the solubility and phase behavior of the drug in aqueous media. If a hot saturated solution of the compound is cooled, the deposition of liquid crystalline states is observed. Alco- holic solutions of the drug do not show anisotropic behavior and a high degree of hydration appears to be a necessary prerequisite for the occurrence of the lyotropic mesophases. Phase examination of aqueous systems of nafoxidine hydrochloride reveals the presence of thermodynamically stable phases other than the mobile isotropic solutions (monomer and miceliar). The dissolution of the drug follows a typical profile: Crystal ) Neat Phase ) Middle Phase • True Solution H20 (Smectic) H20 (Nematic) H•O The kinetics of molecular association in the reverse reaction of the above dissolution scheme is quite complex. Miceliar aggregation in dilute concentrations of the drug can be followed at lower temperatures (25 and 37øC). However stepwise aggregation of the drug through all the phases could not be observed. The lyotropic mesophase system for aqueous solutions of amphiphilic compounds used by Luzzati (1) and Winsor (2) were employed to describe nafoxidine hydrochloride behavior.