Mechanism degradation of pharmaceutical product: physical stability

Introduction

The appearance, physical attributes and functionality of the pharmaceutical product are as important as chemical stability. There is a wide variety of finished drug products, and it is fair to say that the various pharmaceutical forms can each present different and
unique stability challenges.

Appearance

The appearance, taste, smell and feel of a drug product should not change during its shelf life. Changes in appearance may be an early sign of chemical degradation and warrant further investigation.

Examples of changes include discolouration of solutions, tablet
coatings and gelatin capsules becoming tacky, mottled or even cracking (which may be critical for somenmodified-release or gastro-resistant tablets or capsules), aggregation of powders, cracking or creaming of creams and emulsions, ointments and gels becoming
gritty, and the cracking of oral films.

The odour of a pharmaceutical product may also indicate degradation has occurred. The degradationn of aspirin in products is accompanied by the characteristic vinegary smell of acetic acid.

The appearance of the packaging is also important for stability. For example, the distension of blister pockets can indicate that the active substance or the
excipients have degraded releasing a gas as a degradation product (e.g. carbon dioxide in the case of effervescent tablets).

Polymorphic form

Polymorphic form is only a concern where the active substance exhibits polymorphism, is present in the
solid form within the dosage form and the product safety, efficacy and performance may be affected by
the polymorphic form.

The same concern applies if the active substance exists in different solvates.

Typically, polymorphism and solvate
formation may affect the dissolution behaviour of solid dosage forms, either by increasing or decreasing the dissolution rate, which may in turn influence efficacy or safety.

Precipitation and particle size

Active substances or excipients in oral and parenteral solutions may precipitate during storage, particularly
if the solution has been formulated near its saturation point or has become saturated through evaporation
of the solvent.

This will result in the poor appearance
of the drug product but may also have more serious consequences with respect to efficacy and safety.

Precipitation may cause the drug product to become inhomogeneous, leading to issues with dose uniformity and dissolution rate, and ultimately bioavailability.

The presence of large numbers of particles in a parenteral product is a potentially life-threatening risk as it may result in vein irritation, phlebitis,
clinically occult pulmonary granulomas, local tissue infarction, severe pulmonary dysfunction, occlusion of capillaries and arteries, anaphylaxis and death (Tran
et al., 2006).

Consequently, pharmacopoeial standards
are in place to limit particulate matter in parenteral products. The change in particle size of the dose emitted from nasal sprays and inhalation products
can also affect dose delivery and reduce the efficacybof the product.

Ostwald ripening may also occur whereby larger crystals are formed from the dissolution of smaller crystals, leading to a gritty and coarse texture. In some products (e.g. paracetamol
and pseudoephedrine solutions), large crystals in excess of 10 mm can form on storage.

Rheological properties

A change in the rheological properties of a liquid or semisolid drug product can affect the dosing and administration of a drug product. For example,
a change in the viscosity of an oral solution may influence how easily and accurately the solution is drawn up into an oral syringe or is poured into a
spoon. The rheological properties of a cream or ointment can influence how easily it is spread on the skin or mucous membranes, and whether application
is painful or likely to cause further damage to the affected area (e.g. as is the case with haemorrhoid preparations).

Water content

The amount of water in a drug product may be important as it can facilitate chemical degradation (as described earlier) and microbial proliferation.

However, it can also lead to other issues, such as a reduction in tablet hardness and increased tackiness of film coatings and capsules. The permeability of
plastic packaging materials to moisture has been previously described; in addition to drug product absorbing moisture from the atmosphere through
these plastic materials, the evaporation of water or solvents from solutions contained in plastic containers or bottles can also occur, leading to the active substance becoming more concentrated in the solution, and eventually precipitating.

Gelatin capsules contain approximately 15% water, and the capsule contents may absorb water from the capsule shell, particularly if the contents are hygroscopic or deliquescent.

Acidity and alkalinity

Preservative efficacy and protection against microbial spoilage may be influenced by changes in pH. Sodium
benzoate is effective only in acidic conditions (pH 2–5); it is almost without effect in alkaline conditions.

Benzyl alcohol has little activity above pH 8 and optimum activity below pH 5. In contrast, the parahydroxybenzoates (parabens) are effective over a wide pH range (Rowe et al., 2016).

A change in the pH of parenteral solutions or products applied to mucous membranes (e.g. nasal, eye, vaginal and rectal) may result in adverse reactions,
such as local irritation of the mucous membranes, pain on injection and phlebitis.

Resistance to crushing, friability, disintegration and dissolution

The resistance to crushing of a tablet can change on storage, the tablet becoming either less or more resistant. There are a number of mechanisms underpinning this change, such as absorption of water, which acts as a plasticizer for some of the excipients, and long-term elastic or plastic formative changes resulting
from the energy applied to the tablet during compression. In addition to changes to the crushing resistance,
there may be changes in friability, disintegration and dissolution. Tablets that become more friable can
more easily break during handling, transportation (e.g. in a bottle) and removal from the packaging (e.g.
when they are ‘deblistered’), and this is a quality issue.

Tablets that are more resistant to crushing may take longer to disintegrate and dissolve.

Gelatin capsules, including gelatin enrobing of tablets, may undergo irreversible cross-linking of the
polymeric gelatin chains. These ‘pellicles’ are insoluble and may retard or even prevent dissolution of the dosage form.

Redispersibility and reconstitution
Suspensions (oral, parenteral or inhalation) may be prone to sedimentation and even caking on storage; this is where the suspended solid material falls out of suspension to form a compacted layer at the bottom
of the container that is difficult to resuspend. The ability of the solid material to remain suspended or
to redisperse easily on shaking is critical to ensure anuniform drug product and reproducible dosing.

Caking may be problematic for drug
products requiring reconstitution before administration, as it is difficult for the liquid to penetrate and suspend or dissolve the solid caked mass. This leads
to dose uniformity issues (e.g. with oral antibiotic suspensions) and the increased likelihood of a large amount of particulate matter being injected (e.g. with powders for injection, such as diamorphine).

Functionality

Where pharmaceutical products have a physical, mechanical or electrical mechanism that allows the product to operate and deliver the active substance,
its functionality should not change during storage.

For example, transdermal patches can lose adhesiveness, resulting in the failure to adhere and remain in contact with skin, which can impact the delivery of
the drug. Conversely, the adhesive can become so tacky that it is difficult to remove the release liner before administration of the patch onto the skin.

The plungers of prefilled oral and injection syringes should remain easily moveable within the syringe barrel, without excessive plunger pressure being required, to ensure an accurate dose can be easily given; the plunger should not become completely seized within the barrel.

Absorption, adsorption and leaching

Pharmaceutical products, particularly liquid formulations, have the potential to either adsorb onto or absorb into the container closure system, leading, for example, to a loss of active substance or preservative.

Non-polar molecules are susceptible to sorption to plastics and rubber. For instance, glyceryl trinitrate evaporates from tablets and may be lost by absorption/ adsorption onto plastic packaging, and is typically packed in glass bottles with aluminium-lined caps to prevent this. Diazepam can be lost from solutions in contact with plastic packaging, as are some preservatives in contact with rubber closures. The pH of the solution may influence the extent of sorption if the active substance is ionizable, as the un-ionized form is more likely to undergo adsorption/absorption.

Where liquid products are stored in a plastic container closure system, there is the potential for the plasticizers or other components in the plastic to leach into the product over time, which may give rise to toxicity issues. This is normally investigated during product development, whereby the materials
of the container closure system are stored in the liquid product (or simulated product) at extreme conditions to see what compounds can potentially
be extracted from the container materials.

It is critical to know what chemicals have been added to the plastic materials during manufacture so that the range
of compounds for which analysis is performed can be narrowed. The study is then repeated at the recommended and elevated conditions to see whether
the extractable compounds actually leach into the product from the container. These materials may
then need to be monitored during formal stability studies.

For example, paclitaxel injection may use a polyoxyethylated castor oil and ethanol solvent system, which can extract the plasticizer diethylhexyl phthalate from PVC containers.

Glass containers may release soluble mineral substances into aqueous products, which can be determined by measuring the hydrolytic resistance
of the glass. The mineral substance can result in a change in the pH of the solution, which can then catalyse chemical degradation. The European Pharmacopoeia classifies glass containers depending on the composition of the glass, any surface treatment and its hydrolytic resistance.

The European Pharmacopoeia provides corresponding recommendations of
the types of products for which they are suitable.

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