Stability of pharmaceutical products

Stability of pharmaceutical products

Eduard Tichy, Bratislava, 2020

Faculty of Pharmacy, Comenius University

Stability of pharmaceutical productsGood stability of a medicinal product is crucial for its effectiveness, safety and it is also important for the manufacturer and supplier (longer shelf life). Within the lecture following topics will be discussed:

• Definitions of basic terms• shelf life• expiration date

• Chemical stability (it refers mainly to drugs)• chemical degradation reactions, possibility of stabilization

• Physical stability (it refers mainly to dosage forms)

• Microbiological stability

• Stability testing as the tool, how to control stability of drug products• accelerated, long-term stability testing• prediction of stability

All information is possible to find also in recommended textbooks, e. g. Pharmaceutics: The Science of Dosage Form Design 2nd Edition By Michael E. Aulton, Chapter 7, pp 101 – 112 and Chapter 8, pp 129 - 132. It is available online at https://youngpharmacists.com/2014/04/10/pharmaceutics-the-science-of-dosage-form-design-2nd-edition-by-micheal-e-aulton/

https://youngpharmacists.com/2014/04/10/pharmaceutics-the-science-of-dosage-form-design-2nd-edition-by-micheal-e-aulton/

Basic terms which is necessary to know and distinguish:

• Shelf life: a period of time during which, if stored correctly, product is expected to retain acceptable chemical, physical and microbiological stability (SPC: 2 years, 36 months, ...)

• Expiration date (expiry date): the date given on the product packaging which represents the end of the shelf life

Stability of pharmaceutical products

After production and during storage, components of drug product can undergo various chemical degradation reactions:

• hydrolysis• oxidation• dimerization and polymerization• isomeric change• photodegradation• chemical incompatibilities

Stability of pharmaceutical productsChemical stability

• Hydrolysis: the breaking of a molecular bond by reaction with water (esters, amides)


• Oxidation: an increase in the number of carbon-to-oxygen bonds in a molecule or a reduction in the number of carbon-to-hydrogen bonds. Oxidation reaction goes on in 3 stages:• Initiation phase (formation of free radicals due to a presence of

light and/or heavy metals)RH → R∙ + H∙

• Propagation phase (concentration of free radicals incerases greatly, forming of hydroperoxides)

R∙ + O2 → RO2∙

RO2∙ + RH → ROOH + R∙

• Termination phase (the rate of reaction slows, free radicals combine to produce unreactive products)

R∙ + R∙ → R - R


• Dimerization and polymerization: reaction of a drug molecule with another molecule(s) of the same drug• glutaraldehyd (it is active at a

slightly alkaline pH, but at these conditions it is subject of polymerization; glutaraldehyd solution must be formulated at an acidic pH and activated before use by adding of alkaline buffer)


• Isomeric change: different isomers of a drug often have different pharmacological activity or toxicity. A few types of the change can happen:• Racemization (the conversion of an optically active molecule

with one chiral centre into its mirror-image)• Epimerization (racemization at one of more chiral centres)• Geometrical isomerization (the change in the conformation

of groups around a carbon-to-carbon double bound or a cyclic group; the change trans/cis)


• Photodegradation: light-induced degradation (at 300 – 400 nm)


Sometimes photodegradation and thermal degradation of the same substance lead to different products.

• Chemical incompatibilities: reactions drug – drug or drug – excipient. Examples:

• Methylparaben can react with sorbitol resulting in sorbitol hydroxybenzoate esters, which leads to lack of preservative concentration in the system.

• Maillard reaction: amines can react with reducing sugars (e. g. aminoacids with lactose or glucose) resulting in brown reaction products.


There are several possibilities, how to avoid or at least decrease the rate of chemical decomposition reactions:

• Temperature. The decrease of temperature usually decrease the reaction rate; NOTE: oxidation is usually an exception; solubility of gasses in water is higher at at lower temperature). Product may be cooled or freeze:• Cooling in refrigerator 2 - 8°C; BE AWARE of possible changes in drug /

excipients solubility.

• Freezing in freezer to less than - 15°C; freezing may compromise the quality of products containig proteins or vaccines due to changes in their tertiary structure.

• Absence of oxygen. Oxidation rate may be decreased by changes of pH value; by the use inert gases during production and inside the packagining of the product; by the use of antioxidants or chelating agents, which bind metal ions catalyzing oxidation reactions.)

Stability of pharmaceutical productsChemical stability – possibility of stabilization

• Hydrolysis may be prevented by the use of a suitable solvent (aqueous solvent vs. non-aqueous); BE AWARE of potential solubility differences of components of the drug product in various solvents. Another possibility is the change of pH value of the system (hydrolysis is usually catalyzed by H+ or OH- ions). Various buffers may be used.

• Protection from light and prevention of photodegradation is usually solved by the use of proper packaging imperemeable for light (metals).

Stability of pharmaceutical productsChemical stability – possibility of stabilization

During storage, some demonstartion of physical instability of various dosage forms may be observed:

• Solutions, liquids• Sorption of drug or excipients to container or closure

(preservatives).• Extraction of materials into product from container or closure.• Precipitation of drug due to changes of temperature or pH (e. g.

in contact with glass, which may be solved by surface treatment of the glass).

• Suspensions • Caking of sediment (mainly in deflocculated suspensions).• Particle growth during temperature changes.

• Emulsions, creams• Creaming, phase separation.• Reduction in viscosity.

Stability of pharmaceutical productsPhysical stability

• Ointments• Separation of liquids onto surface.

• Solid dosage forms• Polymorfic change in case some of components exists in more

crystalline modifications.

• Change in disintegration time.

• Change in crushing strength, which usually precedes previous instability demonstration.

• Cracking of coated tablets due to absorption of moisture and increase of the core volume.

• Inhalation and nasal aerosols• Change in particle size distribution of emitted dose due to

decrease of pressure in the container in case the non-liquified propellants are used.

Stability of pharmaceutical productsPhysical stability

Deterioration of product due to activity of microorganisms has several impacts:

• It is harmful to the patient; microorganisms themselves or their toxic methabolic products may impair the patient health.

• Activity of microorganisms may have also adverse effect on the product´s properties (chemical and physical characteristics).

• Possibility of microbiological contamination is a critical factor mainly for sterile products (once opened it needs to be used immediately).

Stability of pharmaceutical productsMicrobiological stability

The tool how to control stability of medicinal products is stability testing.

• Purpose of stability testing: to formulate a pharmaceutical product, which is stable during all its shelf life. Two types of stability testing are generally used:

• Accelerated stability testing. It is sometimes called „stress testing“; the product is exposed to extreme temperature / humidity conditions. Stress testing can give a prediction of drug product stability during its shelf life.

• Long-term stability testing. It is used for precise and complete stability evaluation of the drug product during its whole shelf life in correspondence with the climatic area, where the product is intended to be used.

Stability testing

Accelerated stability tests serve to various purposes:

• Preformulation assessment (testing of API before formulation of the drug product with regard to its sensitivity to hydrolysis, oxidation, pH,...).

• Temperature cycling (acceleration of physical instabilities potentially present in the particular drug product: particle growth in suspensions, cracking of emulsions, precipitation of dissolved drugs,...).

• Photostability testing (evaluation of photo sensitivity of drug product and its components; it is performed by exposure to light, provided by artificial-daylight fluorescent lamps, which emit long-wavelength ultraviolet light and visible light).

• Prediction of shelf life by stress testing (Arrhenius equation is used for estimation of expected shelf life of the drug product).

Stability testingAccelerated stability tests

Prediction of stability and shelf life:

Based on Arrhenius theory there is a linear dependency between natural logarithm of the rate constant of any chemical reaction and inverse value of the temperature:

ln k = ln A – (E/R).(1/T) y = a + b.x

k = rate constant of chemical reactionA = frequency factorE = activation energyR = gas constantT = temperature (K)


If parameters (ln A) and (E/R) were known, it would be possible to calculate the reaction rate of decomposition reaction for any temperature and subsequently the time, when the concentration of API reaches the minimal specified limit (usually 95 % of original concentration) or when the concentration of impurities reaches the maximal specified limit.

Prediction of stability: Arrhenius theory - example

ln k = ln A – (E/R).(1/T) y = a + b.x

k = rate constant (k = - (dc/dt) for zero-order kinetic, k = - [dc/(c.dt)] for first-order kinetic, k = - [dc/(c2.dt)] for second-order kinetic)A = frequency factorE = activation energyR = gas constantT = temperature (K)

Hydrolysis of ASA: 1st order kinetic

k = - [dc/(c.dt)]k = - [(c – c0)/(c. (t – t0)]k = (c0 – c)/(c . t)


Temp. (K) Time (d) c (%) k = (c0 – c)/(c . t) ln k 1/T

343 (70°C) 7 87.73 0.0200 -3.91 2.92 x 10-3

333 (60°C) 7 94.97 0.0076 -4.88 3.00 x 10-3

323 (50°C) 7 98.14 0.0027 -5.91 3.10 x 10-3

313 (40°C) 7 99.37 0.0009 -7.01 3.20 x 10-3

298 (25°C) ? 95.00 ? ? 3.36 x 10-3

ln k = 28.402 – 11084.(1/T)

ln k25 = 28.402 – 11084.(1/298)

k25 = 1.52 x 10-4 day-1

k = (c0 – c) / (c . t)

t = (c0 – c) / (c . k)

t = (1 – 0.95) / (0.95 x 0.000152)

t = 346 days (approx. 1 year)


Summary of shelf life calculation:

1. Exposure the formulation to at least 2 different temperatures T for a certain time.

2. Measurement of API or impurity concentration c for each temperature.

3. Calculation of rate constants k for each temperature (the choice of the proper reaction order is crucial!).

4. Plotting the dependency between ln k and 1/T (a straight line).5. Calculation of a straight line equation ln k = a.(1/T) + b.6. Calculation of ln k and subsequently k for the chosen temperature

(e.g. 25°C (298 K)).7. Calculation of API or impurity concentration c for the chosen time

(e.g. 2 years).


Problems with prediction of stability

• At high temperatures, reactions may take place which are not significant or do not go on at normal storage temperatures.

• At high temperatures, the degradation products may react further and so not accumulate.

• Kinetics of drug degradation may also change at different temperatures.

• A possible reduction in the concentration of dissolved oxygen at higher temperatures may affect the reaction rate.

• A reduction of moisture in solid dosage forms may affect the reaction rate.

• Melting of semi-solids at higher temperature may distort results of measurements.


Long-term stability testing

• Stability and shelf life are determined during storage of the product under realistic worst-case conditions of temperature and humidity in controlled-temperature cabinets or rooms.

• Samples are removed at intervals and tested (assay, degradation products, pH, etc.).

• Storage conditions depend on climatic zone, where the product is intended to be marketed.

• At least 3 commercial batches of the product should be tested.

Stability testingLong term stability tests


Climatic zones

• Class I – Temperate climate: i.e. Canada, New Zealand, northern Europe, Russia, UK, etc.

• Class II – Mediterranean and subtropical climate: i.e. Japan, southern Europe, USA, etc.

• Class III – Hot and dry climate: i.e. Argentina, Australia, Botswana, Middle East, etc.

• Class IVa, IVb – Hot and humid climate: i.e. Brazil, Ghana, Indonesia, Nicaragua, the Philipines, etc.


Testing schedule (example according to ICH Q1A (R2))


Questions ?

Stability of pharmaceutical products

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