Product stability and stability testing

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Product stability and stability testing

Michael E. Aulton

Chapter contents

Key points

• Long-term product stability is an important goal that affects the quality and efficacy of pharmaceutical products.

• Pharmaceutical products tend to deteriorate due to chemical, physical and microbiological causes.

• Chemical degradation of the drug in a product is influenced by factors such as the presence of water, oxygen, light or incompatible ingredients in the product.

• Deterioration can be reduced in a number of ways, such as appropriate selection of the solvent or pH, by including specific stabilizing additives, appropriate packaging and storage conditions.

• Careful formulation of the product is necessary to ensure adequate stability.

• Packaging plays an important role in the prevention of product deterioration, for instance protecting the contents from moisture. The packaging must avoid interactions with components of the formulation, such as by sorption.

• Adequate stability of the product needs to be demonstrated during its development before it can be assigned a shelf-life.

• Defined storage conditions of the manufactured product (temperature, humidity and light exposure) need to be appropriate.

• Short-duration stress testing is valuable in predicting the likely stability of a product, but long-term testing under realistic conditions is needed before the product can be marketed.

The stability of pharmaceutical products

Pharmaceutical products tend to deteriorate on storage. The shelf-life of a pharmaceutical product is the period of time during which, if stored correctly, it is expected to retain acceptable chemical, physical and microbiological stability. The expiry date, or expiration date, is the date given on the product’s primary and secondary packaging which represents the end of the shelf-life.

Stabilization of pharmaceuticals

Pharmaceuticals should be formulated and stored in a way that minimizes degradation. The following factors are relevant to most mechanisms of degradation. Oxidation and photodegradation are also important degradation mechanisms and these are dealt with separately later in this chapter.

Temperature

The rate of degradation reactions is markedly influenced by temperature. Storage of the product in a refrigerator (at 2–8 °C) is an option if the product is unstable at room temperature.

Using a freezer (at less than −15 °C) to store unstable formulations is sometimes adopted, however, this makes storage and distribution of the product inconvenient. Also, because a liquid product needs to be thawed before administration, there is the risk of degradation occurring if heat is used to achieve this. Moreover, some drugs, for instance amoxicillin are less stable in solution when frozen than when stored at refrigerator temperature (McDonald et al 1989). Freezing can cause degradation of biopharmaceuticals (see Chapter 46) and live vaccines, though the inclusion of a cryoprotectant, such as trehalose, in the formulation may protect against this.

Finished products are most at risk of exposure to unacceptable temperatures during transportation or storage in vehicles, such as in ambulances (Helm et al 2003, Lucas et al 2004, Priston et al 2005).

Solvent

Replacing an aqueous solvent in a formulation with a non-aqueous one is a potential means of avoiding hydrolysis.

The dielectric constant of a solvent is related to its polarity, more polar solvents having higher values. The dielectric constant can influence the rate at which charged species react. However, the practical considerations of choosing a solvent for a formulation, such as its toxicity and compatibility with the drug, usually outweigh consideration of any effect due to the solvent’s dielectric constant.

Solid dosage forms of a drug, such as tablets or capsules, are usually more stable than liquid ones. However, reactions can occur in water adsorbed onto the surface of a drug particle or other dosage form component. This is why poorly stored aspirin tablets may smell of acetic acid, formed by the hydrolysis of aspirin. Injection formulations of unstable drugs, such as penicillins, can be formulated as freeze-dried powders, which are reconstituted with water or saline (0.9% w/v sodium chloride solution) immediately before administration.

Suspension formulations are often more stable than a solution formulation of the same drug because much of the drug is protected within the insoluble particles.

Acid and base catalysis

A catalyst is a species that accelerates the rate of a reaction without itself being consumed in the reaction. Hydrolysis is often catalysed by hydrogen ions (which exist as H3O+ in solution) or hydroxyl ions. The pH of an aqueous formulation is therefore a critical factor which determines its stability. Specific acid catalysis is catalysis by hydrogen ions and specific base catalysis is catalysis by hydroxyl ions.

Investigation of the relationship between pH and the degradation rate of a drug is performed during the preformulation phase of drug development (Chapter 23). Plotting the logarithm to base 10 of the first-order reaction rate constant against pH may yield useful information about the degradation mechanism. A typical curve is shown in Figure 49.1a. The increase in degradation rate at low pH is due to specific acid catalysis. The increase in rate seen at high pH is due to specific base catalysis. Straight lines with gradients of −1 in the acidic region and +1 in the basic region are characteristic of specific acid and specific base catalysed hydrolysis. The flat region of the curve is largely due to uncatalysed hydrolysis. The product should be maintained at a pH within this region for optimal stability. Cefuroxime and other cephalosporin antibiotics typically show this shape of graph.

For some drugs, such as many penicillins, the uncatalysed reaction with water is relatively less important than that shown in Figure 49.1a, so there is no flat base to the curve and a V-shaped graph results (Fig. 49.1b). In this case, the pH needs to be more precisely controlled than in the previous example because there is a narrower region of optimal stability.

Many drug molecules undergo ionization, to an extent that often depends on the pH. These typically give a curve as shown in Figure 49.1c. The ionized and unionized forms of the drug degrade at different rates. Therefore, the rate of reaction changes as the pH influences the relative proportion of ionized drug present and this gives an inflection point on the graph. Aspirin is an example of a drug which shows this characteristic.

Other species in a formulation besides H3O+ or OH may act as acids and bases and thus catalyse degradation reactions. This is known as general acid catalysis and general base catalysis respectively. Buffer ions are a common cause of this, so careful selection of buffer for use in a formulation is needed. Hydrolysis of the amide bond of the antimicrobial drug chloramphenicol is catalysed by several common buffers, including phosphate and acetate. Borate buffer, however, does not catalyse degradation and is used, for example, to buffer eye drops.

Ionic strength

The ionic strength of a medium is related to the concentration of ionic species in it. Changing the ionic strength by adding electrolyte to a solution has some influence on the rate of many degradation reactions. This effect is not high enough to be of importance in the formulation of drug solutions. However, it can be important in laboratory experiments to investigate the influence of pH on degradation rate. In this case, care should be taken to ensure the ionic strength of the various buffer solutions used is kept the same in order to avoid interference with the results.

Light

Containers made from tinted glass protect the product from light to some extent because they allow less ultraviolet light to penetrate than those which are untinted (Chapter 47). Placing the product in an opaque outer container such as a cardboard box is also an option, but it must be borne in mind that the patient might not return the product to its secondary packaging following use.

Oxygen

Oxidation reactions are less influenced by temperature than most other degradation reactions, so low-temperature storage may be less successful as a stabilization option. Flushing containers with an inert gas such as nitrogen before they are sealed will reduce the amount of oxygen in the product. However this technique will not remove all oxygen and is best suited for single-use containers such as ampoules.

Oxidation reactions are generally promoted by high pH, so aqueous products which are susceptible to oxidation should be formulated at as low a pH as possible.

Heavy metal ions, such as Cu2+ and Fe3+, catalyse oxidation reactions, acting at the initiation and propagation stages. These ions are present at trace levels in all formulations. A chelating agent such as ethylenediamine tetraacetic acid (EDTA) or citric acid has a stabilizing effect by binding to the heavy metal ions and preventing them from acting as catalysts.

Chelating agents are usually used in combination with an antioxidant. Antioxidants act in one of two ways. They may act as oxygen scavengers – oxygen is removed from the formulation by reacting preferentially with the antioxidant. The other mechanism by which antioxidants act is to terminate free radical reactions. The antioxidant forms a free radical which is relatively unreactive and so cannot contribute to free radical propagation. Sodium metabisulphite and ascorbic acid are examples of water-soluble antioxidants used in aqueous formulations. Ascorbyl palmitate, butylated hydroxytoluene and α-tocopherol are oil-soluble antioxidants used in oily formulations.

Physical stability

Common physical causes of instability are summarized in Table 49.1. Most of these are due to changes in the physical properties of the dosage form, either spoiling the product’s appearance or reducing its effectiveness. The other potential problems are loss of drug due to sorption or evaporation, or contamination of the product by extractables from the container.

Molecules of the drug or other formulation component may be lost from a formulation by adsorption onto the surface of the container or closure or by absorption of molecules into plastic or rubber containers or closures. Adsorption and absorption often operate together and are collectively known as sorption. Non-polar molecules are susceptible to sorption to plastics and rubber (Chapter 47). For instance, diazepam is lost from solutions in contact with plastic packaging. Loss of antimicrobial preservative to rubber closures is a problem with injection dosage forms (Chapter 36). Sorption is enhanced where the drug (or preservative) is present at low concentration. If the drug molecule ionizes, the pH of the solution may influence the extent of sorption because the unionized form of the molecule, being less polar than the ionized form, may undergo more sorption.

Glyceryl trinitrate (nitroglycerin) evaporates from tablets, where it can then be lost by sorption to plastic packaging. To avoid this, glyceryl trinitrate tablets need to be packaged in glass bottles with aluminium-lined closures.

Plastic packaging materials may be permeable to water vapour. Aqueous products packaged in plastic containers may therefore lose water on storage and the drug content becomes more concentrated.

The term extractable or extractive is used to describe any material which is released from packaging materials into the dosage form. The common packaging material polyvinyl chloride (PVC) is rendered flexible by the addition of a plasticizer (e.g. diethylhexylphthalate, DEHP) which may migrate into injection solutions. This is a particular problem where the solution contains a non-aqueous solvent or surfactant. Paclitaxel, a cytotoxic drug, needs to be administered in dilute solution by slow intravenous infusion. The injection also contains polyoxyethylated castor oil (a material used to solubilize the drug) with ethanol as a cosolvent. Paclitaxel injection therefore cannot be added to infusion fluids contained in PVC because it induces DEHP extraction. Glass or polyethylene infusion containers should therefore be used instead (Allwood and Martin 1996).

Glass containers can release hydroxyl ions into an aqueous product, changing its pH (Chapter 47). This may especially occur during heating in an autoclave, and surface-treated glass is available to minimize hydroxyl ion extraction for formulations where this is of concern.

Microbiological stability

Deterioration due to the presence of microorganisms can either render the product harmful to the patient or have an adverse effect on the product’s properties (Chapter 50

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