VOLUME 17 : NUMBER 2 : April 1994
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The expiry date is that point in time when a pharmaceutical product is no longer within acceptable specifications for potency and stability. In determining an expiry date, a range of characteristics of the product are studied over time. One important characteristic is the chemical stability of the active ingredient. Temperature has a pronounced effect on the rate of degradation of the active ingredient. As the rate of decomposition usually doubles for every 100C rise in temperature, it is important to comply with the storage conditions specified on the container. The expiry date may be set as a fixed time after manufacture, dispensing or opening of the manufacturer's container. It is good practice not to use drugs past their expiry date.
Key words: drug stability, hydrolysis, oxidation, photodegradation, shelf-life
Aust Prescr 1994;17:46-8
The shelf-life of a drug is the time it is known to stay within acceptable specifications for potency and other important parameters. The expiry date is the date when a given batch reaches the end of its shelf-life. The lower potency limit of the drug is usually set at 90% of the stated label claim. However, for some drugs with a narrow therapeutic margin, like theophylline, a lower limit closer to the label claim may be required. Once opened, the shelf-life of some products, e.g. eye drops, will be determined not by decomposition of the active drug but by the risk of microbial contamination.
After the expiry date, the product does not necessarily become useless, as it may only have reached the potency limit of the active ingredient. If, however, other physicochemical characteristics (such as pH, dissolution rate of tablets and capsules, particle size in creams and suspensions) have changed, or toxic degradation products reach unacceptable levels, use of the product may be harmful.
If the pH of eye drops and other preparations for application to mucous membranes, or injectables, falls outside a fairly narrow range, pain and perhaps tissue damage may result. Similarly, the rate and extent of absorption may be affected by changes in the dissolution rates of tablets and capsules and the particle size of creams, oral suspensions and aerosols.
Use of a product past its expiry date may simply result in a lower dose of active ingredient than that stated on the label. Alternatively, it may result in altered bioavailability, or patient discomfort or present a safety hazard. Consequently, it is good practice not to use drugs after the expiry date.
The expiry date depends on specified storage conditions. Not all drugs have the same rate of decomposition, thus expiry dates will differ. Amoxycillin suspension has an expiry date of 14 days when stored at room temperature (25°C), but trimethoprim/sulphamethoxazole combination tablets have a shelf-life of 5 years when stored below 30°C.
Degradation processes include hydrolysis, oxidation and degradation by light (Table 1). This is because of the chemistry of many of the functional groups in drug molecules and the ubiquitous presence of water and oxygen. Even when factors such as water, oxygen and light have been controlled, degradation will still occur, but at a reduced rate.
The rate of hydrolysis is affected by access to water and is prevented or lowered by reducing exposure to water. If a drug must be formulated in water, the solution is often buffered to a pH where the rate of hydrolysis is minimal. Substances which are particularly susceptible to hydrolysis are often packed in individual dose units e.g. soluble aspirin tablets are individually encased in foil.
Mechanisms of degradation of some commonly used drugs
|chloramphenicol||: eye drops must be refrigerated|
: ointments (water-free) may be stored at room temperature
The specified storage conditions of amoxycillin preparations are related to the presence of water in the product when it is ready for use. Tablets, capsules, unreconstituted syrups and injections have a shelf-life at room temperature of at least two years. However, once reconstituted, the syrups have a shelf-life of 14 days at room temperature, and the injections should be used immediately. The reconstituted syrup has a longer shelf-life than the injection because the syrup is a suspension of amoxycillin with the pH buffered to minimise hydrolysis. Injectable amoxycillin is hydrolysed rapidly as it is a solution with no buffering agent.
Oxidation and photodegradation
Many drugs will react with atmospheric oxygen, so oxidation is a prime cause of degradation. A well known oxidation is the conversion of wine into vinegar; the ethanol is oxidised to acetic acid. Photochemical degradation is usually discussed with oxidation as both processes occur mostly via free radical or free radical-like pathways.
Oxidation is reduced by the exclusion of oxygen. If a drug which is susceptible to oxidation is present in aqueous solution at 1 mg/mL in a 1 mL ampoule, there would be sufficient oxygen in the head-space above the liquid and dissolved in the water to completely decompose the drug. Therefore, oxygen is usually removed from the solution and the head-space by flushing with an inert gas before the ampoule is sealed.
Control of the pH and protection from light may reduce the rate of oxidation of injectable solutions. If appropriate, antioxidants or chelating agents may also be used.
The oxidation of some tablets, e.g. chlorpromazine, is reduced by individual blister packaging. The plastic bubble component of the chlorpromazine packaging is also coloured to provide protection from light.
The absorption of light energy may result in photodegradation. When light is absorbed by a molecule, it is either re-emitted or transformed into physical or chemical energy. Physical energy is usually lost as heat. Chemical energy may be sufficient to cause either cleavage or rearrangement of the molecular bonds. Protection from light is achieved by packaging the products in amber glass bottles or by using coloured film for blister packed products.
The formulation of a drug may have a pronounced effect on the shelf-life because of the effect of excipients used in manufacturing. Some drugs may be quite stable in the pure form, but may undergo degradation rapidly when combined with certain excipients. Excipients affect the stability of drugs by acting as surface catalysts, altering the pH of the moisture layer and/or undergoing direct chemical reactions with the drug.
Occasionally, two drugs which are to be included in one dose form interact. If recognised, the problem can be partially overcome by manufacturing a layered tablet, which minimises the contact of one drug with the other.
Some cold and flu relief products are presented as layered tablets.
Shelf-life is predicted from stability studies. Temperature, humidity, lighting, temperature fluctuations, type of container, effects of opening and closing containers and microbial content form the core of stability study design.
Many parameters need to be considered when designing a stability study and the reason for the incorporation of some parameters may not be immediately apparent. For example, containers are stored upright and inverted to detect any interactions with the container closure.
Storage and transport
Stability is a significant issue, and the importance of temperature on the chemical stability of a pharmaceutical product cannot be over-emphasised. The rate of chemical reactions doubles for every 10°C rise in temperature.
Reconstituted amoxycillin syrup is stable for 14 days if stored at room temperature (25°C) and even longer if refrigerated. If, however, it is stored out of the refrigerator on very hot days, its stability may be reduced to a week or less.
The Australian Pharmaceutical Formulary states that some drugs require ancillary labels when they are dispensed. Two important ancillary labels concerning stability are:
a) Label 6 `Refrigerate do not freeze' — the product should be stored at temperatures between 2°C and 8°C to minimise decomposition; a household refrigerator is suitable for this purpose.
b) Label 7 `Discard contents after / / ' or alternatively `Discard contents .... days after opening. Date opened / / ' — these labels are used if the product has a limited shelf-life due to either decomposition as in the case of amoxycillin suspension, or due to the risk of bacterial contamination such as eye preparations. The recommended shelf-life for eye preparations is usually 30 days after opening.
Table 2 shows some drugs which require one or other or both of the ancillary labels 6 and 7.
For some drugs, e.g. glyceryl trinitrate, the loss of potency on storage is due not only to intrinsic instability, but also to adsorption onto and absorption into containers and other packaging materials.
In the Australian climate, temperature during transport is an important factor. Products which are to be stored in the refrigerator, e.g. vaccines and insulin, should be transported in refrigerated containers or vehicles.
Although not a stability problem as such, the efficacy of some transdermal products such as oestradiol patches may be reduced in humid climates because of the effect of heat and humidity on the adhesive.
The stability of products is variable. A product which is stable in its container may become unstable once the container is opened. Patients should be advised to store their medicines as recommended and to discard them after the expiry date. The hoarding of medicines should also be discouraged.
Connors KA, Amidon GL, Stella VJ. Chemical stability of pharmaceuticals: a handbook for pharmacists. 2nd ed. New York: Wiley, 1986.
Carstensen JT. Drug stability: principles and practices. In: Drugs and the pharmaceutical sciences, vol 43. New York: Dekker, 1990.
Australian pharmaceutical formulary and handbook. 15th ed. Canberra: Pharmaceutical Society of Australia, 1992.
Reynolds JE, Martindale W, editors. Martindale. The extra pharmacopoeia. 29th ed. London: Pharmaceutical Press, 1989.
Some drugs which require one or other or both of the APF ancillary labels 6 and 7
|`Refrigerate do not freeze'||`Discard contents ... days after opening'|
|Amoxycillin suspension||Amoxycillin suspension (14 days)|
|Amoxycillin/clavulanic acid suspension||Amoxycillin/clavulanic acid suspension (7 days)|
|_||Captopril solution (28 days)|
|Cefaclor suspension||Cefaclor suspension (14 days)|
|Cephalexin suspension||Cephalexin suspension (14 days)|
|_||Cyclosporin oral solution (2 months)|
|Erythromycin ethylsuccinate suspension||Erythromycin ethylsuccinate suspension (10 days)|
|_||Glyceryl trinitrate tablets (3 months)|
|Insulin (except vial in use)|
The insulin vial in use can be stored up to room temperature (25°C) for a maximum of 30 days
The following statements are either true or false (click here for the answers)
1. Pharmaceutical products do not degrade until the container has been opened.
2. The stability of a drug may be reduced by excipients in the formulation.