J. Soc. Cosmetic Chemists 16 369-393 (1965) ¸ 1965 Society of Cosmetic Chemists of Great Britain The Preservation of Ophthalmic Preparations M. R. W. BROWN and D. A. NORTON* Presented at the Symposium on "Preservatives and Antioxidants", organized by the Pharmaceutical Society of Great Britain and the Society of Cosmetic Chemists of Great Britain, in London on 17th November 1964. Synopsis--The chemical and physical factors involved in ophthalmic formulations have been considered briefly. The problems of sterility for ophthalmic preparations have been discussed and the evidence relating to the activity of several preservatives examined. Chlorocresol, chlorbutol, benzalkonium chloride and chlorhexidine were shown to have scientific support for use as ophthalmic preservatives. Ophthalmic preparations should be made so as to preserve them against physical, chemical and biological changes which may make them less effective therapeutically. The pharmacist must formulate such preparations with attention to many factors, most important of which are tonicity, pH, stability, viscosity and sterility. It is proposed briefly to consider the chemical and physical factors involved in ophthalmic formulations and to investigate more fully the problems of sterility and preservation against micro-organisms. PHYSICAL AND CHEMICAL FACTORS Tonicity Lachrymal fluid is isotonic with blood and has a tonicity equivalent to that of 0.9% sodium chloride solution. Riegelman and Vaughan (1) have quoted results of their own, and of other workers, showing that an *School of Pharmacy, Bristol College of Science and Technology, Bristol 7. 369

370 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS ophthalmic solution may safely range from the equivalent of 0.7% to 1.5% sodium chloride. Most ophthalmic drugs have high molecular weights, and may usually be added to an isotonic vehicle without altering the tonicity to painful levels. This applies particularly to eye drops used in small volumes large volumes of eye lotions should be approximately isotonic. Hydrogen ion concentration Normal tears have a pH of about 7.4. They have the capacity to bring the pH of an unbuffered solution at pH as low as 3.5, or as high as 10.5, to within tolerable limits instantaneously (1). Most ophthalmic drugs, e.g. alkaloidal salts, in distilled water or isotonic saline have a negligible buffer capacity although some drugs, notably salts of pilocarpine and epinephrine, may overtax the buffer capacity. The United States National Formulary XI recommends a 2% boric acid solution (about pH 4.7) as a general ophthalmic vehicle. This solution will tend to neutralize alkali leached from the glass container, it has a satisfactory tonicity, and is at a pH where most ophthalmic drugs are stable to auto- claving as well as being therapeutically active. The United States Pharmacopoeia XVI recommends an isotonic phosphate buffer as an ophthalmic vehicle in addition to boric acid solution. Stability The stability of ophthalmic preparations during prolonged storage, and the effects of heat sterilization processes, must be considered during formu- lation. The effects of temperature and pH are particularly important. Buffering certain drugs in the physiological pH range makes them unstable, particularly at high temperatures. Most of the common ophthalmic drugs, however, in 2% boric acid solution can be autoclaved without seriously affecting their therapeutic activity. The U.S.N.F. XI states that the oxidative discolouration of physostigmine, epinephrine and phenylephrine under these circumstances may be reduced by the addition of 0.2% sodium bisulphite to the vehicle. Alkaline drugs such as the sulphonamides and fluorescein sodium should be prepared in sterile distilled water. Viscosity Methylcellulose is sometimes added to ophthalmic solutions to increase contact time with the cornea. Calculated quantities of a concentrated, hydrated stock solution of methylcellulose may be added to normal