Observing Products for Evidence of Instability—
Loss of potency usually results from a chemical change, the most common reactions being hydrolysis, oxidation-reduction, and photolysis. Chemical changes may also occur through interaction between ingredients within a product, or rarely between product and container. An apparent loss of potency in the active ingredient(s) may result from diffusion of the drug into, or its combination with, the surface of the container-closure system. An apparent gain in potency usually is caused by solvent evaporation or by leaching of materials from the container–closure system.
The chemical potency of the active ingredient(s) is required to remain within the limits specified in the monograph definition. Potency is determined by means of an assay procedure that differentiates between the intact molecule and its degradation products. Chemical stability data should be available from the manufacturer. Although chemical degradation ordinarily cannot be detected by the pharmacist, excessive chemical degradation sometimes is accompanied by observable physical changes. In addition, some physical changes not necessarily related to chemical potency, such as change in color and odor, formation of a precipitate, or clouding of solution, may serve to alert the pharmacist to the possibility of a stability problem. It should be assumed that a product that has undergone a physical change not explained in the labeling may also have undergone a chemical change, and such a product is never to be dispensed. Excessive microbial growth, contamination, or both, may also appear as a physical change. A gross change in a physical characteristic such as color or odor is a sign of instability in any product. Other common physical signs of deterioration of dosage forms include the following.
Solid Dosage Forms—
Many solid dosage forms are designed for storage under low-moisture conditions. They require protection from environmental water and therefore should be stored in tight containers (see Containers in the General Notices) or in the container supplied by the manufacturer. The appearance of fog or liquid droplets, or clumping of the product, inside the container signifies improper conditions. The presence of a desiccant inside the manufacturer's container indicates that special care should be taken in dispensing. Some degradation products, for example, salicylic acid from aspirin, may sublime and be deposited as crystals on the outside of the dosage form or on the walls of the container.
hard and soft gelatin capsules—
Since the capsule formulation is encased in a gelatin shell, a change in gross physical appearance or consistency, including hardening or softening of the shell, is the primary evidence of instability. Evidence of release of gas, such as a distended paper seal, is another sign of instability.
uncoated tablets—
Evidence of physical instability in uncoated tablets may be shown by excessive powder and/or pieces (i.e., crumbling as distinct from breakage) of tablet at the bottom of the container (from abraded, crushed, or broken tablets); cracks or chips in tablet surfaces; swelling; mottling; discoloration; fusion between tablets; or the appearance of crystals that obviously are not part of the tablet itself on the container walls or on the tablets.
coated tablets—
Evidence of physical instability in coated tablets is shown by cracks, mottling, or tackiness in the coating and the clumping of tablets.
dry powders and granules—
Dry powders and granules that are not intended for constitution into a liquid form in the original container may cake into hard masses or change color, which may render them unacceptable.
powders and granules intended for constitution as suspensions—
Dry powders and granules intended for constitution into solutions or suspensions require special attention. Usually such forms are antibiotics or vitamins that are particularly sensitive to moisture. Since they are always dispensed in the original container, they generally are not subject to contamination by moisture. However, an unusual caked appearance necessitates careful evaluation, and the presence of a fog or liquid droplets inside the container generally renders the preparation unfit for use. Presence of an objectionable odor also may be evidence of instability.
effervescent tablets, granules, and powders—
Effervescent products are particularly sensitive to moisture. Swelling of the mass or development of gas pressure is a specific sign of instability, indicating that some of the effervescent action has occurred prematurely.
Liquid Dosage Forms—
Of primary concern with respect to liquid dosage forms are homogeneity and freedom from excessive microbial contamination and growth. Instability may be indicated by cloudiness or precipitation in a solution, breaking of an emulsion, nonresuspendable caking of a suspension, or organoleptic changes. Microbial growth may be accompanied by discoloration, turbidity, or gas formation.
solutions, elixirs, and syrups—
Precipitation and evidence of microbial or chemical gas formation are the two major signs of instability.
emulsions—
The breaking of an emulsion (i.e., separation of an oil phase that is not easily dispersed) is a characteristic sign of instability; this is not to be confused with creaming, an easily redispersible separation of the oil phase that is a common occurrence with stable emulsions.
suspensions—
A caked solid phase that cannot be resuspended by a reasonable amount of shaking is a primary indication of instability in a suspension. The presence of relatively large particles may mean that excessive crystal growth has occurred.
tinctures and fluidextracts—
Tinctures, fluidextracts, and similar preparations usually are dark because they are concentrated, and thus they should be scrutinized carefully for evidence of precipitation.
sterile liquids—
Maintenance of sterility is of course critical for sterile liquids. The presence of microbial contamination in sterile liquids usually cannot be detected visually, but any haze, color change, cloudiness, surface film, particulate or flocculent matter, or gas formation is sufficient reason to suspect possible contamination. Clarity of sterile solutions intended for ophthalmic or parenteral use is of utmost importance. Evidence that the integrity of the seal has been violated on such products should make them suspect.
Semisolids (Creams, Ointments, and Suppositories)—
For creams, ointments, and suppositories, the primary indication of instability is often either discoloration or a noticeable change in consistency or odor.
creams—
Unlike ointments, creams usually are emulsions containing water and oil. Indications of instability in creams are emulsion breakage, crystal growth, shrinking due to evaporation of water, and gross microbial contamination.
ointments—
Common signs of instability in ointments are a change in consistency and excessive “bleeding” (i.e., separation of excessive amounts of liquid) and formation of granules or grittiness.
suppositories—
Excessive softening is the major indication of instability in suppositories, although some suppositories may dry out and harden or shrivel. Evidence of oil stains on packaging material should warn the pharmacist to examine individual suppositories more closely by removing any foil covering. As a general rule (although there are exceptions), suppositories should be stored in a refrigerator (see Storage Temperature in the General Notices).
Proper Treatment of Products Subjected to Additional Manipulations—
In repackaging, diluting a product or mixing it with another product, the pharmacist may become responsible for its stability.
Repackaging—
In general, repackaging is inadvisable. However, if repackaging is necessary, the manufacturer should be consulted concerning potential problems. In the filling of prescriptions, it is essential that suitable containers be used. Appropriate storage conditions and, when appropriate, an expiration date and beyond use date should be indicated on the label of the prescription container. Single-unit packaging calls for care and judgment and for strict observance of the following guidelines: (1) use appropriate packaging materials, (2) if stability data on the new package are not available, repackage at any one time only sufficient stock for a limited time, (3) include on the unit-dose label a lot number and an appropriate beyond-use date, (4) if a sterile product is repackaged from a multiple-dose vial into unit-dose (disposable) syringes, discard the latter if not used within 24 hours, unless data are available to support longer storage, (5) if quantities are repackaged in advance of immediate need, maintain suitable repackaging records showing name of manufacturer, lot number, date, and designation of persons responsible for repackaging and for checking (see General Notices), (6) if safety closures are required, use container closure systems that ensure compliance with compendial and regulatory standards for storage.
Dilution or Mixing—
If a product is diluted, or if two products are mixed, the pharmacist should observe good professional and scientific procedures to guard against incompatibility and instability. For example, tinctures such as those of belladonna and digitalis contain high concentrations of alcohol to dissolve the active ingredient(s), and they may develop a precipitate if they are diluted or mixed with aqueous systems. Pertinent technical literature and labeling should be consulted routinely; it should be current literature, because at times formulas are changed by the manufacturer. If a particular combination is commonly used, consultation with the manufacturer(s) is advisable. Since the chemical stability of extemporaneously prepared mixtures is unknown, the use of such combinations should be discouraged; if such a mixture involves an incompatibility, the pharmacist might be responsible. Oral antibiotic preparations constituted from powder into liquid form should never be mixed with other products.
Combining parenteral products necessitates special care, particularly in the case of intravenous solutions, primarily because of the route of administration. This area of practice demands the utmost in care, aseptic technique, judgment, and diligence. Because of potential unobservable problems with respect to sterility and chemical stability, all extemporaneous parenteral preparations should be used within 24 hours unless data are available to support longer storage.
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STABILITY CONSIDERATIONS IN DISPENSING PRACTICE
-lactams are the chemical bonds that are most likely to hydrolyze in the presence of water. For example, the acetyl ester in aspirin is hydrolyzed to acetic acid and salicylic acid in the presence of moisture, but in a dry environment the hydrolysis of aspirin is negligible. The aspirin hydrolysis rate increases in direct proportion to the water vapor pressure in an environment.
increase in temperature. This relationship has been observed for nearly all drug hydrolysis and some drug oxidation reactions. The actual factor of rate increase depends on the activation energy of the particular reaction. The activation energy is a function of the specific reactive bond and the drug formulation (e.g., solvent, pH, additives). As an example, consider a hydrolyzable drug that is exposed to a 20