FORMULATION AND PROPERTIES OF CHLORHEXIDINE 263 tions, the latter being more effective and less liable to lower the available chlorhexidine. The solubilizing properties of surfactants are put to good effect in formulating concentrates for dilution with hard water. Thus, a 7.5•o chlorhexidine gluconate concentrate, intended for dilution to 0.005•o to be used as a premilking udder wash in the prevention of bovine masfitis, required the presence of about 2•o of an ethoxylated (9 mol.) nonylphenol, Lissapo! NXU, in order to prevent precipitation with almost all the hard water likely to be found on farms, while at the same time conferring ade- quate cleansing action. Reverting to pharmaceutical preparations, one risk is the incompati- bility of the chlorhexidine preservative with the salts of alkaloids, frequently the hydrochlorides, hydrobromides or nitrates, used in eye medication. Common ion effect also governs the issue, yet most of them give clear solutions with chlorhexidine acetate 0.01•o, though there are some failures at 0.02•o. Chlorhexidine gluconate at 0.05•o gives a clear solution with normal saline at 20øC. A typical example of the need to check the 'incom- patibility' before reaching a decision is seen with silver nitrate-chlorhexidine preparations, a recent innovation for the treatment of burns (8). Quite surprisingly it was found that silver nitrate at 0.5•o did not precipitate chlorhexidine nitrate from a 0.2•o gluconate solution when present far in excess of solubility product requirements. It was likely that complex forma- tion was the reason. CHLORHEXIDINE AVAILABILITY When chlorhexidine is converted, wholly or partly, to an insoluble salt by reaction with an excipient or with hard water, a loss of antibacterial action is to be expected. The problem of chlorhexidine availability is more involved when it is held in solution in the presence of a surfactant, the need for which may arise for various reasons, e.g. wetting agents or cleansers in skin-disinfecting solutions or in instrument disinfectants, and co-emulsifiers in creams. In the last application the situation is complicated because release of antibacterial at the skin surface from a diphasic oil-in-water cream system is governed inter alia by its concentration in the aqueous phase and the pos- sible influence of any co-emulsifier that partitions into it. The co-emulsifier may or may not be above its critical micelle concentration, and this also has a bearing on the availability. The effect of varying the concentration of a nonionic surfactant Lubrol W, a polyethyleneglycol monoalkyl ether allied to Cetomacrogol 1000

264 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS B.P.C., in a 0.1•o chlorhexidine gluconate solution was studied by Barnes (9) using the inhibitory zone method, in duplicate, to assess the available activity. It was clear that the adverse effect of the surfactant increased greatly with concentration though in practice the chlorhexidine strengths are usually higher than that of the surfactant. The loss in availability at equal concentra- tions (0.1 •o each in Fig. 2) was about 30•o, not too serious a matter with so potent an antibacterial agent. However, a paraffin-water emulsion contain- ing 0.1 •o chlorhexidine gluconate with cetostearyl alcohol and LubroI W as the co-emulsifiers lost over 90•o of its apparent availability when the latter was at 1 •o strength, thus illustrating the importance, as with liquid prepara- tions, of keeping surfactants to the minimum concentration consistent with long-term stability. A modification of the above experiment on creams in which the LubroI W was held at 1•o, varying the chlorhexidine gluconate between 0.1•o and 1.0•o, is summarized in Table II. From Table 11 it seems that an o/w cream containing 1 •o chlorhexidine gluconate and 1 •o Lubrol W shows only about 20•o activity. It was found in a control test with an aqueous solution of the same strength that there was about 40•o available chlorhexidine, and reference to Fig. 2 reveals that a tenfold aqueous dilution (i.e. 0.1•o each) gives nearly 70•o availability. Thus, it appears that the liquid preparations are more effective than corre- sponding creams. As chlorhexidine gluconate is insoluble in fats it is there- fore mostly present in the aqueous phase and similarly Lubrol W is known 7O BO 5O 40 :50 2O 0 I I I I I I I I I I I I .... l o i 2 3 4 % oeubrol W Figure 2. Effect of a polyoxyethylene glycol monoalkyl ether on availability of chlorhexidine gluconate. O-- O, 0.1% w/v chlorhexidine gluconate in water O-- O, 0.1% w/v chlorhexidine gluconate in o/w cream.