716 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Table VIII Influence of proportion of oil on the concentration of methyl paraben in the water of an oil/water mixture Preservative concentration in water Total Oil: water ratio preservative concentration Oil phase Kwø 0.11 0.25 0.43 0.66 1.00 in oil/water mixture • w/v oil phase 10 20 30 40 50 Methyl paraben Liquid paraffin 0.1 • (S.G. 0.85) 0.02 0.11 0.12 0.14 0.16 0.20 Methyl paraben Liquid paraffi 0.2% (S.G. 0.85) 0.02 0.22 0.24 0.24 0.24 0.24 Methyl paraben 0.2• Soya oil 80.0 0.027 0.012 0.008 0.006 0.005 In liquid paraffin/water mixtures the concentration of methyl paraben in the water is always higher than the total concentration in the mixture and increases as the proportion of oil is increased until water saturation (0.24•o w/v) is reached. With vegetable oils the water concentration is so far below the total concentration that the aqueous phase is virtually devoid of activity and the concentration falls as the proportion of oil is increased. The same general picture is obtained with many preservatives no matter what the vegetable oil. The inclusion of an emulgent in the system results in a redistribution of the preservative between the total aqueous phase and the oil, the con- centration in the total aqueous now being calculated using the equation C.• = C(0 + 1) K0+I where Ca = concentration of preservative in the total aqueous phase K = oil/aqueous phase partition coefficient. Because the preservative in the water is partly associated with the emulgent, the concentration free in the water is Cw = c^/J which can be shown (31) to be equivalent to C(0+l) Cw = 0 0 + R) (v) a more generally useful expression because Kw ø, the true oil/water partition

PRESERVATIVES FOR PHARMACEUTICALS 717 coefficient, is constant for any oil/preservative/water mixture, whereas K falls as the concentration of emulgent is increased. If it is now assumed that the liquid paraffin/water mixtures of Table VIII are emulsified by the inclusion of 5.0•o Polysorbate 80 the concen- tration of methyl paraben free in the water can now be recalculated (Table IJO using equation (V) the appropriate value of R being 4.5. Table IX Influence of proportion of oil on the concentration of methylparaben free in the water of liquid paraffin/water emulsions emulsified with 5 % Polysorbate 80 Total preservative concentration in emulsion o Oil phase Kw Preservative concentration in water Oil: water ratio 0.11 0.25 0.43 0.66 1.00 % w/v oil phase 10 20 30 40 50 Methyl paraben Liquid paraffin 0.1% (S.G. 0.85) 0.02 0.025 0.027 0.032 0.037 0.044 Methyl paraben Liquid paraffin 0.2 % (S.G. 0.85) 0.02 0.05 0.055 0.063 0.074 0.088 Because in the emulsions the concentrations of methyl paraben in the water are so far below those required for preservation the total concentration would have to be increased. If it is accepted that 0.2•o is required in the water, the total concentrations that would be required in the emulsions containing 10, 20, 30, 40 and 50•o oil would be 0.81, 0.72, 0.67, 0.54 and 0.47•o respectively, which can be shown experimentally to produce an activity in the emulsion approximately equivalent to that produced by 0.2•o methyl paraben in water. The writer has endeavoured to show that once the required activity of a preservative in a product has been established, it can be maintained in spite of predictable losses for the solution provided certain basic parameters of the preservative are known. Even in products which are more complex than an aqueous solution it is often possible to quantify changes in the chemical availability of a preservative with changes in formulation and to modify either the total concentration of preservative to meet the availability requirements or substitute another preservative with more satisfactory