718 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS characteristics. That is, provided the parameters of preservatives are adequately quantified it is possible to elevate preservation from a hit-and- miss strategy to a more precise science. (Received: 15th June 1971) (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) REFERENCES Lord, C. F. and Husa, W. J. Antimolding agents for syrups. J. Am. Pharm. Assoc. Sci. Ed. 43 438 (1954). Report by the Royal Swedish Medical Board into microbiological contamination of medical preparations (1956). Report of Working Party of National Health Service Laboratories, Denmark. Dansk. Tidsskr. Farm. 42 1, 50, 71,125, 257 (1967). World Health Organization. Microbiological contamination of non-sterile drugs. Working paper WHO/Pharm./69.433 (1969). Dony, J. Condition microbiologique du m•dicament non sterile. XIX Journ•es pharma- ceutiques Franfaises, 25 (1969). Sykes, G. The basis for 'sufficient of a suitable bacteriostatic' in injections. J. Pharm. Pharmacol. 10 Suppl. 4OT (1958). Crompton, D. O. Ophthalmic prescribing. Austral. J. Pharm. 1020 (1962). Crompton, D. O. Sterility of eye medicaments. Lancet i 41 (1964). Williams, R. and Boehm, E. E. Sterility of eye medicaments. Lancet ii 790 (1963). Kohn, S. R., Gershenfeld, L. and Barr, M. Effectiveness of antibacterial agents presently employed in ophthalmic preparations as preservatives against Pseudomonas aeruginosa. J. Pharm. Sci. 52 967 (1963). Ridley, F. Sterile drops and lotions in ophthalmic practice. Brit. J. Ophthal. 42 641 (1968). Hygienic manufacture and preservation of toiletries and cosmetics. J. $oc. Cosmet. Chem. 21 719 (1970). U.S. Pharmacopoeia XVIII. p. 845. Antimicrobial agents--effectiveness. (1970) (Bethesda, Md). Bean, H. S. and Walters, V. The viability of Escherichia coli in aqueous solutions of benzylchlorophenol. J. Pharm. Pharmacol. 7 661 (1955). Brown, M. R. W. and Garrett, E. R. Kinetics and mechanisms of action of antibiotics on micro-organisms. J. Pharm. Sci. 53 179 (1964). Garrett, E. R. and Brown, M. R. W. The action of tetracycline and chloramphenicol alone and in admixture on the growth of E. coli. J. Pharm. Pharmacol. 15, 185T (1963). Bean, H. S. and Farrell, R. The persistence of Pseuabmonas aeruginosa in aqueous solutions of phenols. J. Pharm. Pharmacol. 19 Suppl. 183S (1967). Hamdi, F. J. Studies in the interaction of some phenols with plastics. M.Phil. Thesis, University of London (1968). Tilley, F. W. An experimental study of the influence of temperature on the bactericidal activities of alcohols and phenols. J. Bacteriol. 43 521 (1942). Cohen, B. Effect of temperature and hydrogen-ion concentration upon viability of E. coli and Ebethella typhi in water. J. Bacteriol. 7 183 (1922). Salton, M. R. J. The action of lytic agents on the surface structures of the bacterial cell. Proceedings of the Second International Congress on Surface Activity 274 (1957). (Butter- worth, London). Lundy, H. W. The effect of salts upon the germicidal action of phenol and secamyl- tricresol. J. Bacteriol. 35 633 (1938). Oka, S. Studies on transfer of antiseptics to microbes and their toxic effect. Bull. Agr. Chem. Soc. Japan 24 59 (1960). Patel, N. K. and Kostenbauder, H. B. Interaction of preservatives with macromolecules I. J. Am. Pharm. Assoc. Sci. Ed. 47 289 (1958). Pisano, F. D. and Kostenbauder, H. B. Interaction of preservatives with macromolecules II. J. Am. Pharm. Assoc. Sci. Ed. 48 310 (1959). Miyawaki, G. M., Patel, N. K. and Kostenbauder, H. B. Interaction of preservatives with macromolecules III. J. Am. Pharm. Assoc. $ci. Ed. 48 315 (1959). Sheikh, A. W. Studies on the influence of a surface active agent on the activity of some preservatives. Ph.D. Thesis, University of London (1971).

PRESERVATIVES FOR PHARMACEUTICALS 719 (28) Hibbott, H. W. and Monks, J. Preservation of emulsions--p-hydroxybenzoic ester partition coefficient. J. $oc. Cosmet. Chem. 12 2 (1961). (29) Bean, H. W., Heman-Ackah, S. M. and Thomas, J. The activity of antibacterials in two- phase systems. J. $oc. Cosmet. Chem. 16 15 (1965). (30) Bean, H. S. and Heman-Ackah, S. M. Influence of oil: water ratio on the activity of some bactericides against Escherichia cell in liquid paraffin and water dispersions. J. Pharm. Pharmacol. 16 Suppl. 58T (1964). (31) Bean, H. S., Kenning, G. H. and Malcolm, S. A. A model for the influence of emulsion formulation on the activity of phenolic preservatives. J. Pharm. Pharmacol. 21 Suppl. 173S (1969). DISCUSSION MR. R. J. MCBRIDE: It is good to see you advocating 100K mortality level within a fixed time limit as a standard for a preservative suitable for use in preserving ophthalmic solutions. We believe that the time period of 3 h is too slow, however, especially for multidose solutions used in eye clinics, and we prefer the time of 1 h, suggested by Kohn et al (10). Our own work has shown that this 1 h sterilization time can be achieved against high inocula of Pseudomonas aeruginosa in preserved fluorescein sodium, pilocarpine hydrochloride, atropine sulphate, physostigmine sulphate, or salicylate and sodium bicarbonate ophthalmic solutions. T•E LECTURER: I suppose for ophthalmic solutions it is a question of toxicity I really do not know the optimal time. I would make the point that if you do not get 100•o mortality you are liable to have subsequent multiplication. For injections we have been obtaining sterilization times 1 h by incorporating 0.1• chlorocresol, and there have been no criticisms. It was only when we had 0.1• chlorocresol which did produce roughly a 10 min kill in ophthalmic solutions, that the problem of toxicity arose we now know that this was due to an unfortunate use in ophthalmic surgery. The major problem is one of toxicity rather than producing sterility. DR. R. M. E. RICHARDS: The use of mixtures of antibacterial agents for the preserva- tion of pharmaceuticals has not often been reported in the literature. Nevertheless mixtures of antibacterial agents are in frequent use in commercial preparations. Accord- ing to Remington (32) they now account for almost 50•o of the preservative systems in commercially available ophthalmic solutions produced in the U.S.A. Remington also predicts the increase of the use of mixtures of antibacterials in extemparaneous com- pounding. Would you please comment on the parameters to be observed in choosing a mixture of antibacterials in pharmaceutical preservation. THE LECTURER: AS far as I see, the advantages are that a mixture broadens the spectrum of micro-organisms which may l•e dealt with and it may increase the capacity of the preservative system. For example, if one uses shall we say, two of the parabens-- methyl paraben, propyl paraben, the probability is that with the more active compound (propyl parabort) the cell-aqueous phase partition coefficient will be in fayour of much of the propyl compound going into the cell, leaving the system deficient in activity. If one would also include the methyl compound this would tend to increase the capacity. There are great theoretical difficulties in handling these mixtures of preservatives--if they work, use them. I think the reason that so little has appeared in the literature is the (32) Remington, P. J. Pharmaceutical scieaces 14th edn. 1570 (1970) (Mack Publishing Co.. Easton, Pennsylvania).