J. Soc. Cosmetic Chemists, 16, 341-348 (1965) Soluble Brominated Salicylanilides W. E. LANGE, Ph.D.,':' and M. R. MEZIKOFSKY, M.S.t Presented at the American Pharmaceutical Association Meeting, August 8-6, 19•, New York City Synopsis The low aqueous solubility of the brominated salicylanilides (x) limits their use- fulness in cosmetic or pharmaceutical preparations. Nonionic surface active agents and compounds chemically related to • did not increase solubility. Preparation of the salts of • gave compounds with good microbiological activity and aqueous solubility but with limited light stability. Aqueous solutions of formulations utilizing the salts of x showed good sta- bility when they were protected from U.V. light. INTRODUCTION Antimicrobial agents are used in many cosmetic and pharma- ceutical products to protect and preserve them from deterioration due to growth of bacteria, fungi, or yeasts. Many of the higher mo- lecular weight agents such as hexachlorophene, dichlorophene, bithionol, the parabens and substituted salicylanilides have extremely low water solubilities. Because of their low water solubility their use is somewhat limited. Thus, with the great interest today in the salicylanilides it was thought that the preparation of a water soluble compound or mixture would be of value in product formulations. Recently, considerable interest has centered about the halonitro- salicylanilides (1) and halogenated salicylanilides, especially various chlorinated and brominated derivatives (2, 3). The halogenation of the salicylanilide molecule enhances the activity of the parent compound (4). * Massachusetts College of Pharnmey, Boston, Mass. i Gillette Safety Razor Co., Boston, Mass. 341

342 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS In 1959 Stecker (5) reported that a synergistic mixture existed between 5,4•-dibromosalicylanilide and 3,5,4•-tribromosalicylanilide (Diaphene •*) when combined in the proper proportions. By a modified fresh calfskin technique he demonstrated the substantivity and anti- bacterial properties of the mixture (6). At about the same time Mattson (7) reported another similar syner- gistic mixture consisting of 3,5-dibromosalicylanilide (approximately 15%), 3,5,4•-tribromosalicylanilide (approximately 85%), and traces of a monobromosalicylanilide derivative. This mixture is referred to as ET-394'['. The fact that Stecker (6) noted that the brominated salicylanilides were not inactivated by the presence of various emulsifiers and surface active agents suggested the possibility of physical solubilization of ET-394. All attempts to prepare a 0.1% aqueous solution of ET-394 by the addition of various nonionic or anionic surface active agents were unsuccessful. Even the addition of 50% ethanol failed to dissolve ET-394. Attempts to add ET-394 as a solution in polyethylene glycol 600 monolaurate to various combinations of ethanol, surface active agents and water were also unsuccessful. Occasionally a chemical similar in structure to the material under investigation is capable of increasing the compound's solubility. Thus, the use of salicylanilide as a solubilizing agent was attempted, but without StlCCeSS. Recently Russell (8) reported the solubilization of Diaphene to the extent of 0.8% in a mixture of 4% nonionic surface active agent and either 40% detergent or potassium coconut oil soap. Bacteriological testing of these solutions showed activity equal to that of a similar solution containing hexachlorophene. Thus it appeared that the use of complexation or simple physical means would not work to enhance the solubility of ET-394 in water or in 50% ethanol at low surfactant level. On the other hand, it seemed likely that the brominated salicylanilides as their sodium, potassium or ammonium salts might exhibit improved water solubility. EXPI)•RIMENTAL Preparation of Salts Sodium ET-394 was the first salt to be prepared, and its preparation was accomplished in the following manner: Fifteen milliliters of a 10% * Diaphene is a registered trademark of the Stecker Chemicals, Inc., Ho-Ho-Kus, N.J. t Manufactured by The Dow Chemical Company, Midland, Mich.