714 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS hand there is ample evidence that a rise in the pH of a solution of a phenolic or an organic acid reduces cellular uptake and activity (22, 23). Much more readily quantifiable is the effect of nonionic surfactants on the activity of preservatives. Kostenbauder and others (24-26) have assumed that interaction between surfactants and phenolics or organic acids involves complexation and a reduction in the concentration of 'free' preservative, the latter largely but not necessarily completely controlling the activity of the system. The amount of preservative bound to the sur- factant is directly related to the concentration of surfactant, the relation- ship being representable by the equation R = SC+I where R = ratio of total/free preservative C -- constant $ = surfactant concentration. The constant C has a unique value for each surfactant-preservative pair and increases in value as the lipid solubility of the preservative increases (Fig. 3). R is the factor by which the total concentration of preservative 2O c 40- 3o B A 0 I I I I I I I 2 4 6 8 I0 12 I• Cetommcrogol conch (% w/v) Figure 3. The binding of phenolics to Cetomacrogol (27). A, phenol B, cresol C, chlorocresol.

PRESERVATIVES FOR PHARMACEUTICALS 715 must be increased for a g•ven surfactant concentration to maintain a specified concentration free in the water. Even the simplest emulsion contains oil, water and emulgent the latter being partially adsorbed at the o/w interfaces but the majority of it being dispersed throughout the water phase as emulgent micelies. A preser- vative incorporated in an emulsion is distributed between all three com- ponents or phases and the influence of each of the phases on preservative availability and activity is most easily understood by considering simplified models. The influence of the emulgent in the water on preservative avail- ability has already been considered. If now the oil and water phases are considered without reference to the emulgent, the preservative will be distributed between the two phases so that Co Cw- K?v where Co = concentration of preservative in the oil at equilibrium Cw = concentration of preservative in the water at equilibrium Køw = oil/water partition coefficient, a constant at a specified temperature for any oil, water preservative mixture. An enormous range of values for oil/water partition coefficients is recorded (28, 29) some values for the parabens being shown in Table VII and having Table VII Oil/water partition coefficients for parabens (25 ø) Compound Partition coefficient Liquid paraffin/water Soya oil/water Methyl hydroxybenzoate 0.02 Propyl hydroxybenzoate 0.50 Butyl hydroxybenzoate 3.0 7.5 80.0 280.0 a range of 14 000. The coefficients can be used in the equation below (30) for calculation of the way in which the relationship of the total concen- tration of paraben in the oil/water mixture to the concentration in the water depends on the proportion of oil and water (Table VIII). Cw- c(o Koo+I where C = total concentration of preservative Cw = concentration of preservative in the water 0 = oil' water ratio.