In addition to the aforementioned warnings, the label of a drug packaged in an aerosol container in which the propellant consists in whole or in part of a halocarbon or hydrocarbon shall, where required under regulations of the FDA, bear either of the following warnings:

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 pH levels that favor the undissociated free bases. At such pH levels, 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 pH caused by the slow release of hydroxyl ions by glass. Such a rise in pH can 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 pH of about 7.4 and 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 1 or 2 drops of a solution containing them are added to the eye, the buffering action of the tears is usually adequate to raise the pH and prevent marked discomfort. In some cases pH may vary between 3.5 and 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 pH 7.4, 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 pH levels 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 pH of 7.4 and does not cause precipitation of the drug or its rapid deterioration.

An ophthalmic preparation with a buffer system approaching the physiological pH can 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 pH must 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 1211).

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 pH range 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.

A pharmaceutical grade of methylcellulose (e.g., 1% if the viscosity is 25 centipoises, or 0.25% if 4000 centipoises) 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.

Carefully mix the ground drug or mixture of drugs with a sufficient quantity of the prescribed solvent or solvent mixture to render it evenly and distinctly damp, allow it to stand for 15 minutes, transfer it to a suitable percolator, and pack the drug firmly. Pour on enough of the prescribed solvent or solvent mixture to saturate the drug, cover the top of the percolator, and, when the liquid is about to drip from the percolator, close the lower orifice and allow the drug to macerate for 24 hours or for the time specified in the monograph. If no assay is directed, allow the percolation to proceed slowly, or at the specified rate, gradually adding sufficient solvent or solvent mixture to produce 1000 mL of tincture, and mix (for definitions of flow rates, see under Extracts and Fluidextracts). If an assay is directed, collect only 950 mL of percolate, mix this, and assay a portion of it as directed. Dilute the remainder with such quantity of the prescribed solvent or solvent mixture as calculation from the assay indicates is necessary to produce a tincture that conforms to the prescribed standard, and mix.

Macerate the drug with 750 mL of the prescribed solvent or solvent mixture in a container that can be closed, and put in a warm place. Agitate it frequently during 3 days or until the soluble matter is dissolved. Transfer the mixture to a filter, and when most of the liquid has drained away, wash the residue on the filter with a sufficient quantity of the prescribed solvent or solvent mixture, combining the filtrates, to produce 1000 mL of tincture, and mix.

Tinctures require storage in tight, light-resistant containers, away from direct sunlight and excessive heat.

Suppositories with cocoa butter base require storage in well-closed containers, preferably at a temperature below 30 (controlled room temperature).

Tablets are required to meet a weight variation test (see Uniformity of Dosage Units 905) where the active ingredient comprises a major portion of the tablet and where control of weight may be presumed to be an adequate control of drug content uniformity. Weight variation is not an adequate indication of content uniformity where the drug substance comprises a relatively minor portion of the tablet, or where the tablet is sugar-coated. Thus, the Pharmacopeia generally requires that coated tablets and tablets containing 50 mg or less of active ingredient, comprising less than 50% by weight of the dosage-form unit, pass a content uniformity test (see Uniformity of Dosage Units 905), wherein individual tablets are assayed for actual drug content.

Disintegration is an essential attribute of tablets intended for administration by mouth, except for those intended to be chewed before being swallowed and for some types of extended-release tablets. A disintegration test is provided (see Disintegration 701), and limits on the times in which disintegration is to take place, appropriate for the types of tablets concerned, are given in the individual monographs.

For drugs of limited water-solubility, dissolution may be a more meaningful quality attribute than disintegration. A dissolution test (see Dissolution 711) is required in a number of monographs on tablets. In many cases, it is possible to correlate dissolution rates with biological availability of the active ingredient. However, such tests are useful mainly as a means of screening preliminary formulations and as a routine quality-control procedure.

Classically, tablets have been coated with sugar applied from aqueous suspensions containing insoluble powders such as starch, calcium carbonate, talc, or titanium dioxide, suspended by means of acacia or gelatin. For purposes of identification and esthetic value, the outside coatings may be colored. The finished coated tablets are polished by application of dilute solutions of wax in solvents such as chloroform or powdered mix. Water-protective coatings consisting of substances such as shellac or cellulose acetate phthalate are often applied out of nonaqueous solvents prior to application of sugar coats. Excessive quantities should be avoided. Drawbacks of sugar coating include the lengthy time necessary for application, the need for waterproofing, which also adversely affects dissolution, and the increased bulk of the finished tablet. These factors have resulted in increased acceptance of film coatings. Film coatings consist of water-soluble or dispersible materials such as hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, and mixtures of cellulose acetate phthalate and polyethylene glycols applied out of nonaqueous or aqueous solvents. Evaporation of the solvents leaves a thin film that adheres directly to the tablet and allows it to retain the original shape, including grooves or identification codes.

Where the drug may be destroyed or inactivated by the gastric juice or where it may irritate the gastric mucosa, the use of “enteric” coatings is indicated. Such coatings are intended to delay the release of the medication until the tablet has passed through the stomach. The term “delayed-release” is used for Pharmacopeial purposes, and the individual monographs include tests and specifications for Drug release (see Drug Release 724) or Disintegration (see Disintegration 701).

Extended-release tablets are formulated in such manner as to make the contained medicament available over an extended period of time following ingestion. Expressions such as “prolonged-action,” “repeat-action,” and “sustained-release” have also been used to describe such dosage forms. However, the term “extended-release” is used for Pharmacopeial purposes, and requirements for Drug release typically are specified in the individual monographs.