Mechanism of pharmaceutical degradation: chemical stability

Introduction

The stability of a pharmaceutical product is a relative concept, in that it is dependent on the protectiveness
of the container closure system, the recommended storage conditions and the inherent stability of the active substance, excipients and the specific properties and aspects of the pharmaceutical dosage form.

Stability can be defined as the ability of a pharmaceutical product to withstand physical, chemical or microbiological changes or decomposition when
exposed to various environmental conditions.

The product should be formulated and stored in a way that ensures it remains efficacious and safe, and be of an acceptable quality when used by health care professionals and patients – in short, the pharmaceutical product should be fit for purpose throughout its
unopened and in-use shelf lives.

Shelf life is the term use by pharmacopoeias and regulatory authorities to delineate the period during
which a drug product, following manufacture, remains suitable for its intended use by patients. Typical shelf
lives are 2 or 3 years, but they may be significantly shorter or longer.

The shelf life is established through
rigorous stability testing and must always be qualified by the container closure system and storage conditions.
Some degree of degradation may occur during the shelf life, but the duration is chosen so that an acceptable quantity of drug remains in the product, and any degradation products are at levels which do not pose a risk to the patient.

If a pharmacopoeial monograph has been elaborated for the drug product,
this will typically provide standardized shelf-life acceptance limits for drug assay (usually with a lower limit of at least 90% of the stated content) and for impurities throughout the shelf life of the product.

In the context of this article, ‘pharmaceutical product’ refers to both the active substance and the finished drug product, unless otherwise specified

Whenever the stability of pharmaceutical products is considered, it is important firstly to understand the various chemical and physical mechanisms of degradation.

Chemical stability

Active substances have diverse, and often complex, molecular structures and may therefore be susceptible to different and variable degradation pathways.

Important chemical degradation reactions include hydrolysis, isomerization, polymerization, oxidation,
photochemical reactions and other chemical interactions. The chemical basis for these reactions will be described more fully in another article.

It is therefore beneficial to consider the likely pathways by which an active substance may degrade to assist the development of the formulation, the
choice of manufacturing process, selection of the container closure system and the proposed storage conditions of the drug product so that chemical
degradation is minimized.

Excipients may also degrade or change on storage.

This may subsequently affect the function for which they are being included in the drug product.

For example, hydrolysis of viscosity-modifying polymers can lead to a loss of viscosity; oxidation of preservatives may result in a loss of preservation; water
absorption by hygroscopic excipients may induce dissolution.

Excipients could also degrade to produce
related substances that have toxicity issues.

It is very important to remember that degradation may not occur by only one mechanism; degradation may occur by multiple mechanisms that may interact,
or even act as a catalysis, with each other.

Oxidation

Oxygen is abundant in the air, such that it is inevitable that a pharmaceutical product will be exposed to it during manufacture and storage. Oxidation is a well-known chemical degradation mechanism.

Oxidation may be prevented by removal of the available oxygen, although this is difficult to do completely in practice.

Instead, an inert gas such as
nitrogen or carbon dioxide can be used to displace the oxygen and afford protection to the product.

For example, oxygen-sensitive products can be manufactured under a nitrogen shower or the headspace of containers can be flushed with argon or nitrogen before closure (e.g. as is the case with nicotine).

Alternatively, antioxidants may be included in the formulation. True antioxidants, such as ascorbic acid
or sodium metabisulfite (both typically used in aqueous products), butylated hydroxytoluene (used in medicated chewing gums) and α-tocopherol (used
in omega-3 oils), are thought to scavenge free radicals and block the subsequent chain reactions.

Reducing agents (e.g. ascorbic acid) have a lower redox potential than the active substance and are thus preferentially
oxidized rather than the active substance.

Antioxidant synergists enhance the effects of antioxidants and
chelate the trace metals that initiate oxidation (e.g. sodium edetate is used to stabilize penicillin-, adrenaline- and prednisolone-containing products).

However, the inclusion of an antioxidant should not disguise a poorly formulated product or inadequate packaging, and must be fully and scientifically justified
to the regulatory authorities. Likewise, it is not permissible to include an overage of the active substance (e.g. an amount above the labelled amount) to compensate for degradation.

Protecting the product from light, either by inclusion of a storage warning or by use of amber or opaque containers, may also prevent oxidation, as will storage
at lower temperatures, typically refrigeration.

In aqueous products, oxidation is generally promoted at high pH, and thus decreasing the pH as low as possible will afford some protection.

The container closure system can also provide protection against oxidation.
The oxygen transmission rate is a useful indicator of the protectiveness of the material.

Glass and aluminium packaging offer the most protection against oxidation. Plastic packaging materials have different levels of protection depending on their composition and thickness.

Hydrolysis

Hydrolysis is another common degradation pathway for pharmaceutical products, and is typically the main
degradation pathway for active substances having ester (e.g. benzocaine, aspirin and methylphenidate) and amide (e.g. β-lactam antibiotics and bupivacaine) moieties in their structure.

For most parenteral products and oral solutions, the active substance is formulated as an aqueous solution, and therefore the potential for hydrolysis
is unavoidable.

Suspensions are likely to be more
stable than solutions because much of the active substance is protected within the insoluble particles.

Solid dosage forms are not immune from the risk of hydrolysis. Water is often present in solid dosage forms as moisture, either resulting from the manufacturing process (e.g. when aqueous wet granulation or film coating are used) or inherently present in the
excipients.

The European Pharmacopoeia maximum
limits for water in some common tablet fillers are 15% for maize and pregelatinized starch, 7% for
microcrystalline cellulose and 4.5% to 5.5% for lactose.

Gelatin capsule shells also contain water,
typically up to 15%, as a plasticizer. Active substances (e.g. ethambutol, sodium valproate and ranitidine)
and excipients (e.g. sorbitol, citric acid, sodium carboxymethylcellulose and polyvinylpyrrolidone) may also exhibit hygroscopicity, by which they are
able to absorb water from the atmosphere.

The strategies used to prevent hydrolysis centre around exclusion of water from the pharmaceutical product. For liquid dosage forms, stability can be considerably improved by formulation and storage of the product as a dry powder to be reconstituted before it is dispensed to the patient.

Oral antibiotic solutions typically have a 2- or 3-year shelf life when stored as dry powders, but expire within 7–10 days
once reconstituted into solutions. Freeze-drying of a solution to produce a solid lyophilized cake is also an alternative that is used for some parenteral injections (e.g. diacetylmorphine injections). Lyophilization
(freeze-drying) (see Chapter 29) ensures the product dissolves rapidly during reconstitution, which is critical for a parenteral product.

For solid dosage forms, careful selection of excipients with low moisture content or predrying of excipients before manufacturing can reduce the
likelihood of hydrolytic degradation.

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

Choosing direct compression or dry granulation, rather than aqueous wet granulation, will also reduce the
likelihood of hydrolysis.
Hygroscopic excipients that absorb moisture from the atmosphere should be avoided (e.g. nonhygroscopic mannitol could be used as a replacement
for hygroscopic sorbitol). If the active substance is identified as hygroscopic early enough in the drug development stage, and if feasible, it may be possible
to chemically modify the structure of the active substance to make it less hygroscopic.

Manufacturing under controlled and reduced relative humidity (e.g.
around 30–40% relative humidity) also reduces uptake of moisture by the product.

The container closure system can provide a moisture barrier for the pharmaceutical product. In Europe, solid oral dosage forms (e.g. tablets and capsules) are commonly packed in blister
packs.

The blister materials can have different
compositions that provide differing levels of protection against moisture: poly (vinyl chloride) (PVC) < PVC–poly(vinylidene chloride) (PVdC) < PVC–
polyethylene (PE)—PVdC < PVC–Aclar® laminates.

Alternatively, aluminium–PVC or aluminium– polypropylene films may be used, and are generally regarded as having the highest moisture protection
because of the aluminium layer.

The level of moisture protection of a packaging material can be derived
from the moisture vapour transmission rate, which is a function of the material composition and thickness
(Fig. 49.1).

Fig. 49.1 • Moisture vapour transmission rates (MVTR) of plastic blister materials of differing thickness. PVdC, poly(vinylidene chloride), RH, relative humidity

 

The higher the moisture vapour transmission rate, the less protective is the packaging against moisture.

In contrast to European preferences for blister packs, US patients tend to prefer bottles, which can be manufactured from high-density polyethylene, low-density polyethylene, poly(ethylene terephthalate) or polypropylene.

The relative moisture protection of these materials is as follows poly(ethylene terephthalate) < low-density polyethylene < polypropylene ≪ high-density polyethylene.

Glass bottles or aluminium tubes offer the highest level of protection. A distinct disadvantage of bottles with respect to protection from moisture is that they
are repeatedly opened by the patient during administration, exposing the product to atmospheric moisture.

This can be mitigated by inclusion of a
desiccant cartridge in the bottle, but this must have sufficient water-absorbing capacity for the proposed unopened and opened shelf life, and the risk of the
patient accidentally swallowing the cartridge (e.g. in products used by dementia patients) should also be considered.

Hydrolysis is temperature dependent, so reduction of the storage temperature (e.g. by storing in a refrigerated 2°C to 8°C environment) may also slow
down the rate of hydrolysis, for example, in the case of oral antibiotic mixtures.

The acidity or alkalinity of a solution may affect hydrolysis, so control of the pH by use of a buffer system may reduce hydrolytic reactions (e.g. borate in chloramphenicol eye and ear drops).

Photochemical reactions
Pharmaceutical products will be exposed to the light at some point during their manufacture, storage or use.

Photochemical reactions are typically very complex and will be a concern if the product absorbs light within the range of natural UV–visible sunlight (290 nm to 700 nm), as photodegradants are strongly
linked to safety of the product.

Photodegradation is perhaps more prevalent in solutions, where light can penetrate throughout the entire product; in the case of solid dosage forms, it is typically limited to the surface.

Prevention of photochemical reactions can be achieved by protection of the product from light with use of opaque container closure systems.

Opaque primary packaging of parenteral products can make it difficult for health care professionals to see if the product has precipitated or contains particles, which may present a safety risk
to the patient.

Alternatively, opaque secondary packaging can be used; for example,
ampoules can be packed in cardboard cartons.

Opaque covers can be used to shroud syringe drivers or infusion bags, as well as the giving lines used during
administration.

European regulatory authorities require photostability testing of the product to determine whether it is susceptible to photodegradation and whether the
container closure system intended for marketing affords suitable light protection.

Decreasing the surface area of the product exposed to light, reducing the intensity or wavelength of light,
or adding EDTA or free-radical scavengers to the drug product may also minimize photodegradation.

Formation of adducts and complexes
The drug product typically contains a number of excipients or additives, in addition to either one or more active substances, which may chemically or
physically interact with each other, in addition to any degradation of the active substance.

This may reduce the efficacy of the product as the active substance will not be available for absorption or the
new complex/adduct may pose a safety concern in its own right. A complex is where two or more molecular entities are loosely associated.

An adduct is a new chemical species formed by the direct combination of two molecular entities with no loss of atoms, in contrast to a chemical reaction. Active
substances that contain primary or secondary amines (e.g. pramipexole and memantine) can undergo the Maillard reaction with reducing sugars.

The levels of the memantine–lactose adduct is specifically controlled in the United States Pharmacopeia monograph
for memantine tablets.

Benzocaine in sugar-medicated lozenges can complex with glucose and fructose
produced from the hydrolytic degradation of sucrose.

Formulation of paracetamol with aspirin can lead to transacetylation of the paracetamol with aspirin, as
well as direct hydrolysis of the paracetamol.

Esterification of indometacin in polyoxyethylene (which is also known as polyethylene glycol) suppository bases
has also been demonstrated.

Active substance–excipient adducts should be considered when one is developing analytical methods
used in stability testing as they may be responsible for a lack of mass balance between levels of the active substance and total impurities.

The active substance–excipient adduct may not be solubilized during sample preparation and thus will be unavailable
for analysis.

Conversely, any sample preparation should not degrade adducts into the original constituents, unless this occurs in vivo, otherwise testing may suggest the product is safer or more efficacious than it really is.

The importance of accurately determining the levels of any possible adducts is that they are considered
in the same way as other related substances and degradation impurities, and should be controlled at levels that have been shown to be toxicologically safe.

Isomerization and polymerization
Isomerization involves the conversion of an active substance into its optical or geometric isomer, which may have different pharmacological or toxicological properties.

For example, the loss of activity of adrenaline in parenteral products at low pH is attributed to the conversion from the active (R)- adrenaline to the inactive (S)-adrenaline.

Tetracyclines undergo epimerization in acidic conditions to produce
epitetracycline, which has a reduced therapeutic activity.

Vitamin A is also known to be susceptible
to cis–trans isomerization, with the cis isomer having less activity than the trans isomer.

Polymerization is where two or more molecules combine to form a complex molecule. Concentrated aqueous solutions of aminopenicillins, such as ampicillin and amoxicillin, are known to form dimers on storage, via the self-aminolysis of the β-lactam ring.

Temperature

Temperature appreciably influences the rate of degradation reactions, and may be described by the empirical equation proposed by Arrhenius in 1889

K = Aexp (-Ea÷RT) ….Eq 49.1

where k is the reaction rate, A is the pre-exponential frequency factor, Ea is the activation energy (in joules per mole), R is the universal gas constant and T is
temperature (in kelvins)

Logarithmically transforming Eq. 49.1 produces a linear equation of the form y = mx + c:

lnK = lnA – (Ea/RT) …. Eq (49.2)

This equation can be used as a basis for a plot of the results from stress or forced degradation studies at elevated temperatures to extrapolate the rate constant at different temperatures. This interrelationship can then be used to gain an idea of the stability of the
drug product.

There are a number of limitations to the use of the Arrhenius equation. Both the activation energy (Ea) and the rate constant (k) are experimentally
determined.

These represent macroscopic reactionspecific parameters that are not related to threshold energies and individual molecular reactions involved
in degradation.

Linear specific rates of change must be obtained at all temperatures used in the experimental study, which requires the rate of reaction to be constant over the period stability is evaluated. If the degradation kinetics vary, the specific rate that is assignable to the specific temperature is unable to be identified.

If the reaction mechanism changes with temperature, this would also alter the slope of the reaction curve.
The activation energy must also be independent of the temperature of interest, which may not be
the case if more than one reaction process is occurring.

Some degradation reactions may be more significant at higher temperature than at lower temperature, and vice versa. Some primary degradation products may convert more rapidly to secondary degradation products at higher temperatures, leading to less
accumulation, which may cause subsequent problems with analytical method development and impurity
profile safety.

Elevated temperatures can lead to less moisture in solid dosage forms, and thus less degradation. The amount of dissolved oxygen reduces with increasing temperature, which will decrease oxidative degradation and result in elevated temperature studies predicting better long-term stability than
is the case.

There is also a discontinuity between
theoretical values calculated with the Arrhenius equation and experimental data around the glass transition temperature.

Consequently, the precision of the shelf-life estimates obtained with the Arrhenius equation can
be poor, with studies typically yielding estimates with a wide range of uncertainty. However, from a practical
perspective in the development of pharmaceutical products, the Arrhenius equation is a useful tool for estimating the real-time stability of a pharmaceutical product from elevated temperature studies. It is generally accepted that an increase in temperature
by 10°C will increase the degradation rate by a factor of approximately two to three times.

In other words, the Q10 temperature coefficient (which is a measure
of the rate of change of a biological or chemical system as a consequence of the temperature being increased
by 10°C) will be between 2 and 3.

For those products that are unstable at room temperature, refrigerated storage (2°C to 8°C) is an option to increase stability. However, this option
should not be taken lightly as it increases the complexity and cost of the supply chain as refrigeration will need to be maintained at all times.

Cooling of the product to −20°C or even to −70°C to increase stability adds significantly greater complexity to the storage and distribution of drug products, and specialist distribution companies should be used.

In the case of parenteral products, the product will need to be fully thawed to avoid injection of ice
crystals into the patient. If heat is used to defrost the product, this may lead to the same degradation that freezing was used to avoid.

Some chemicals and biopharmaceuticals are actually less stable when frozen.
The global pharmaceutical market must be considered when the stability of a pharmaceutical product is being evaluated with respect to temperature.

Manufacturers of both active substances
and drug products tend to be located in one geographical location (because of cost and expertise) and ship their products worldwide, rather than
operate multiple manufacturing sites. It is critical that products are transported and stored in their recommended storage conditions, particularly if the
products require cold-chain distribution, and this is a requirement of good manufacturing and distribution
practice (Medicines and Healthcare products Regulatory Agency, 2017).

Corrosion

Corrosion is not considered a traditional degradation mechanism, but the numbers of drug–device combination products that may include electrical components are increasing. Drug–device combination products are now being developed to take advantage of new
developments in device and electrical designs. The correct functioning of an electrical device is particularly critical where delivery of the active substance
is device controlled. For instance, the drug containing hydrogel of a novel patient-controlled iontophoretic
device for the transdermal delivery of fentanyl caused the printed electronic circuit boards to corrode, resulting in self-activation of the device and potential
overdose.

This was overcome by developing separate electronic controller and drug units that are assembled before use, thus avoiding moisture from the hydrogel corroding the circuits (European Medicines Agency, 2015).

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