J. Soc. Cosmet. Chem. 24 259-278 (1973) ¸ 1973 Society of Cosmetic Chemists of Great Britain Some observations on the formulation 'and properties of chlorhexidine N. SENIOR* Presented on the 11th April 1972 in Oxford, at the Symposium on 'Skin--Environmental responses and protection', organized by the Society of Cosmetic Chemists of Great Britain. Synopsis--The selection of the most appropriate salts of the ANTISEPTIC CHLORHEXIDINE and the influence of formulation adjuncts on drug availability are discussed. The rapid, broad spectrum bactericidal action in association with the wide safety margin, freedom from SENSITIZATION and drug resistance risks are factors influencing its current wide usage in medical and surgical practice. Hospital applications include bactericidal handwashing, pre- operative SKIN disinfection, prevention of cross-infection and the DISINFECTION of inanimate objects. Chlorhexidine is employed advantageously in antibacterial TOILET PREPARATIONS and its properties are ideal for safe and effective DEODORANT compositions. In DENTAL applications it is adsorbed on the enamel, plaque and mucins and accordingly it may be valuable in the prevention or treatment of oral infections and in the control of dental caries. INTRODUCTION Chlorhexidine, 1,6-di-(4-chlorophenyldiguanido)hexane, was first synthesized by Rose and Swain (1) who, with the guidance of Davies, Francis and Martin (2), selected it from a series of bisbiguanides possessing marked bactericidal action against a wide range of micro-organisms (2). Since this work, which took place in the early 1950s, there have been many publications on its medical and veterinary applications and there *Imperial Chemical Industries Ltd (Pharmaceuticals Division), Macclesfield, Cheshire. 259

260 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS NH N•-t CI .NH.C, NH.C. NH.(CH•)•oNH, C. NH. Co NH. NH H • CI. Figure 1. Chemical structure of ehlorhexidine available commercially as gluconate solution (B.P.), acetate (B.P.C.) and hydrochloride (B.P.). must be few hospitals in the British Isles and Commonwealth in which it is not used in one form or another. A multiplicity of simple and complex compositions have been investigated by various professions in turn-- formulators, practising pharmacists, bacteriologists, dermatologists, sur- geons, urologists, gynaecologists and ophthalmologists, and the overall conclusion is that chlorhexidine is at the forefront of modern antibacterial agents because of its broad spectrum, rapid action, effectiveness at high dilution, innocuous nature and low incidence of resistant strains. SELECTION OF SALTS When a drug exerts basic properties it is often a rewarding policy to examine a comprehensive series of salts of various chemical types, studying the requirements of all interested parties before reaching a decision on which ones to manufacture. In the first place, the development chemist seeks the salt which is most readily isolated and his choice is therefore governed by the ease with which it is crystallized to give high purity and good yield. The formulator views the subject from a different aspect in seeking a salt of low solubility in water for some applications, for instance those requiring prolonged antibacterial action with only a limited concentration of avail- able antibacterial in contact with the tissues (depot effect). Too low a solubility, however, may lead to difficulty in isolating a pure salt and also to inadequate release of active agent. On the other hand, and particularly when swift bactericidal effect is sought, an extensively soluble salt is a prime objective. The practising pharmacist making his own formulations prefers a rapidly and extensively soluble salt for convenience and economy in pro- viding strong aqueous concentrates, while the manufacturer of proprietary compositions has a similar attitude, seeking rapidly to prepare fluid formula- tions in bulk at ambient temperatures. Having regard to these several re- quirements many chlorhexidine salts were eaxmined, of which Table I shows a selection. There were two main methods of preparation•doublo