Chemical Stability

Define Stability.

the chemical and physical integrity of the dosage unit and, when appropriate, the ability of the dosage unit to maintain protection against microbiological contamination

ALSO

the extent to which a product retains, within specified limits, and throughout its period of storage and use (i.e. its shelf life), the same properties and characteristics that it possessed at the time of manufacture”.

Define Shelf life.

• Time from date of manufacture that a drug product will remain in its approved product specifications while stored under defined conditions. 

• time lapse from initial preparation to the specified expiration date

Where can you find the shelf life of a dosage form?

The monograph specifies identity, strength, quality, and purity throughout the shelf life of the product

USP monographs state percent ranges for labeled strengths of active ingredients, where the lower number is the shelf life value

What is BUD?

Date after which an article shall not be used.

How do we find BUD?

• Unless otherwise specified in the individual monograph, for non-sterile solid/liquid products repackaged into unit-dose or single unit containers the Beyond-use date shall be no later than 

(a) the expiration date on the manufacturer’s container, or 

(b) 1 year from the date the drug is dispensed, whichever is earlier.

Chemical Stability

Each active ingredient retains its chemical integrity and labeled potency, within the specified limits.

THROUGHOUT THE SHELF LIFE

Physical Stability

The original physical properties, including appearance, palatability, uniformity, dissolution, and suspendability, are retained.

THROUGHOUT THE SHELF LIFE

Microbiological Stability

Sterility or resistance to microbial growth is retained according to the specified requirements. Antimicrobial agents that are present retain effectiveness within the specified limits.

THROUGHOUT THE SHELF LIFE

Therapeutic Stability

The therapeutic effect remains unchanged.

THROUGHOUT THE SHELF LIFE

Toxicological Stability

No significant increase in toxicity occurs.

THROUGHOUT THE SHELF LIFE

Factors that can impact product stability:

• Temp → High temp = Inc chemical degradation

• pH → influences rate of drug decomposition

• Moisture → can catalyze chemical rxns & Promotes microbial growth

• Light → Energy/thermal effect = OXIDATION

• Dosage form → Solid > Liquid

• Drug Incompatibility →

• Oxygen

How do we prevent drug container interactions?

• Non-PVC tubing minimizes leaching

• Contact of undiluted concentrate with plasticized PVC equipment or devices is NOT recommended

• Diluted TAXOL solutions should be stored in bottles or plastic bags and administered through polyethylene lined administration sets

• Preconditioned tubing for insulin

Elements for establishing an EXPIRATION date for a drug product

• Characteristics of the drug

  • Active drug content

  • Degradants

• Characteristics of the dosage form

  • – Appearance, color, pH, odor, coating integrity

    – Moisture content, content uniformity

    – Friability (tablets)/brittleness (capsules), tablet hardness

    – Dissolution characteristics

    – Viscosity (for liquids)

    – Particle size eg suspensions and emulsions

    – Emulsion phase separation – creams and liquids.

    – Lack of microbial contaminations (creams, liquids, etc

What are the chemical routes of degradation?

• Hydrolysis

• Oxidation

• Photodegradation

• Drug-drug or Drug-Excipient incompatibilities

What is hydrolysis?

• Breaking of molecular bonds by reaction with water

• Most common cause of chemical degradation since drugs formulated in aqueous media or will be exposed to water during dissolution

• Esters, Amides, Lactams, Lactones

Catalysts of Hydrolysis

• Presence of water

• pH

• Presence of general acids and bases used as buffers/salts (citrate, acetate, phosphate)

• Temperature

Hydrolysis rate can be reduced by:

• Temperature (0-5 °C)

• Humidity <40%

• Desiccant in packaging

• Multi-layered tablets

• Film coating

• Buffers for solutions

• Suspensions for liquids

What is Oxidation?

• Increase in the number of C-O bonds in a molecule (loss of electrons) or a reduction in the number of C-H bonds

• Catalyzed by trace metals, light, heat

• Can lead to:

  • Hydroxylation

  • Dehydrogenation

  • Carboxylation

  • Deamination

  • Demethylation

• Most rxns involve free radicals (unpaired electrons)

• Initiation, propagation, termination

Drugs Susceptible to Oxidation

• Catechols → Methyldopa, Epi

• Thiol;s → 6-Mercaptopurine, Captopril

• Phenothiazines → Promethazine

• Polyunsaturated molecules → Vit A, Ergocalciferol, cholecalciferol

Oxidation Catalysts

• Cu+2, Fe+2,+3 ions - Trace amounts of heavy metals

• Sunlight and fluorescent light (UV from both)

• O2, oxidizing agents

• Heat

Oxidation can be reduced by:

–Nitrogen, carbon dioxide, to replace air in container

–Temperature 0-5 °C

– Protect from light

–Chelating agents – EDTA (ethylene diamine tetracetic acid

What do Antioxidants do?

They interrupt the propagation by interacting with the free radical

Suicide substrate - more susceptible to oxidation and are preferentially oxidized to consume the available oxygen

Drug-Drug/Drug-Excipient Incompatibilities

Amines: Many drugs contain the amino (-NH2) functional group which is highly reactive with a number of other chemicals. Examples include:

• Carboxylic acid

• Carboxylate Ester

• Large Anions

• Aldehyde

• Esters: Beside reacting with amines, esters can also react with alcohols to undergo an alcoholysis reaction (Transesterfication).

– Formulation of aspirin (an ester) in polyethylene glycol or the preparation of an aspirin with either morphine or codeine (contain alc.)