Lacrimal fluid is isotonic with blood,having an isotonicity value corresponding to that of a 0.9%sodium chloride solution.Ideally,an ophthalmic solution should have this isotonicity value;but the eye can tolerate isotonicity values as low as that of a 0.6%sodium chloride solution and as high as that of a 2.0%sodium chloride solution without marked discomfort.

Some ophthalmic solutions are necessarily hypertonic in order to enhance absorption and provide a concentration of the active ingredient(s)strong enough to exert a prompt and effective action.Where the amount of such solutions used is small,dilution with lacrimal fluid takes place rapidly so that discomfort from the hypertonicity is only temporary.However,any adjustment toward isotonicity by dilution with tears is negligible where large volumes of hypertonic solutions are used as collyria to wash the eyes;it is,therefore,important that solutions used for this purpose be approximately isotonic.

Many drugs,notably alkaloidal salts,are most effective at pHlevels that favor the undissociated free bases.At such pHlevels,however,the drug may be unstable so that compromise levels must be found and held by means of buffers.One purpose of buffering some ophthalmic solutions is to prevent an increase in pHcaused by the slow release of hydroxyl ions by glass.Such a rise in pHcan affect both the solubility and the stability of the drug.The decision whether or not buffering agents should be added in preparing an ophthalmic solution must be based on several considerations.Normal tears have a pHof about 7.4and possess some buffer capacity.The application of a solution to the eye stimulates the flow of tears and the rapid neutralization of any excess hydrogen or hydroxyl ions within the buffer capacity of the tears.Many ophthalmic drugs,such as alkaloidal salts,are weakly acidic and have only weak buffer capacity.Where only 1or 2drops of a solution containing them are added to the eye,the buffering action of the tears is usually adequate to raise the pHand prevent marked discomfort.In some cases pHmay vary between 3.5and 8.5.Some drugs,notably pilocarpine hydrochloride and epinephrine bitartrate,are more acid and overtax the buffer capacity of the lacrimal fluid.Ideally,an ophthalmic solution should have the same pH,as well as the same isotonicity value,as lacrimal fluid.This is not usually possible since,at pH7.4,many drugs are not appreciably soluble in water.Most alkaloidal salts precipitate as the free alkaloid at this pH.Additionally,many drugs are chemically unstable at pHlevels approaching 7.4.This instability is more marked at the high temperatures employed in heat sterilization.For this reason,the buffer system should be selected that is nearest to the physiological pHof 7.4and does not cause precipitation of the drug or its rapid deterioration.

An ophthalmic preparation with a buffer system approaching the physiological pHcan be obtained by mixing a sterile solution of the drug with a sterile buffer solution using aseptic technique.Even so,the possibility of a shorter shelf-life at the higher pHmust be taken into consideration,and attention must be directed toward the attainment and maintenance of sterility throughout the manipulations.

Many drugs,when buffered to a therapeutically acceptable pH,would not be stable in solution for long periods of time.These products are lyophilized and are intended for reconstitution immediately before use (e.g.,Acetylcholine Chloride for Ophthalmic Solution).

The sterility of solutions applied to an injured eye is of the greatest importance.Sterile preparations in special containers for individual use on one patient should be available in every hospital,office,or other installation where accidentally or surgically traumatized eyes are treated.The method of attaining sterility is determined primarily by the character of the particular product (see Sterilization and Sterility Assurance of Compendial Articles á1211ñ).

Whenever possible,sterile membrane filtration under aseptic conditions is the preferred method.If it can be shown that product stability is not adversely affected,sterilization by autoclaving in the final container is also a preferred method.

Buffering certain drugs near the physiological pHrange makes them quite unstable at high temperature.

Avoiding the use of heat by employing a bacteria-retaining filter is a valuable technique,provided caution is exercised in the selection,assembly,and use of the equipment.Single-filtration,presterilized disposable units are available and should be utilized wherever possible.

Ophthalmic solutions may be packaged in multiple-dose containers when intended for the individual use of one patient and where the ocular surfaces are intact.It is mandatory that the immediate containers for ophthalmic solutions be sealed and tamper-proof so that sterility is assured at time of first use.Each solution must contain a suitable substance or mixture of substances to prevent the growth of,or to destroy,microorganisms accidentally introduced when the container is opened during use.

Where intended for use in surgical procedures,ophthalmic solutions,although they must be sterile,should not contain antibacterial agents,since they may be irritating to the ocular tissues.

Apharmaceutical grade of methylcellulose (e.g.,1%if the viscosity is 25centipoises,or 0.25%if 4000centipoises)or other suitable thickening agents such as hydroxypropyl methylcellulose or polyvinyl alcohol occasionally are added to ophthalmic solutions to increase the viscosity and prolong contact of the drug with the tissue.The thickened ophthalmic solution must be free from visible particles.