Stability of drugs and medicines Flashcards

1
Q

various factors affecting stability of drugs and medicines

A

Susceptibility to hydrolysis, oxidation, light degradation and other common chemical degradation reactions.
Identify and minimize drug excipient interactions.
Reaction mechanism and kinetics.
Shelf life by accelerated stability testing (stress testing)

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2
Q

acceptable level of therapeutics

A

therapeutic effect remains unchanged

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3
Q

toxicogical expectations

A

no significant increase in toxicity occurs

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4
Q

Define shelf life

A

*The shelf life is that length of time during which a pharmaceutical product retains acceptable chemical, physical and microbiological stability so that the product remains fit for its intended purpose.

Ideally >3yrs and < 5% loss in potency without exceeding allowed limits of toxic degradation productions

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5
Q

Factors measuring stability

A

-pH - acid and base catalysis tends to raise chemical degradation. Extreme pH changes cause epimerisation
Many (not all) drugs are stable pH4-8 (epimer=one pair of stereoisomers)

Temperature - high temperature can induce oxidation, reduction and hydrolysis

Humidity - promotes hydrolysis, oxidation/reduction reactions and encourage microbial growth

Light - photons provide energy leading to radical formation, oxidation and polymerisation reactions. Photolysis of covalent bonds can also occur

Dosage form - solid usually more stable than liquid dosage form

Oxygen - promotes autoxidation
Metal ions - promotes oxidation

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6
Q

Factors measuring stability

A

-pH - acid and base catalysis tends to raise chemical degradation. Extreme pH changes cause epimerisation
Many (not all) drugs are stable pH4-8 (epimer=one pair of stereoisomers)

Temperature - high temperature can induce oxidation, reduction and hydrolysis

Humidity - promotes hydrolysis, oxidation/reduction reactions and encourage microbial growth

Light - photons provide energy leading to radical formation, oxidation and polymerisation reactions. Photolysis of covalent bonds can also occur

Dosage form - solid usually more stable than liquid dosage form

Oxygen - promotes autoxidation
Metal ions - promotes oxidation

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7
Q

Causes of chemical instability

A
Hydrolysis
Oxidation
Dimerisation and polymerization
Isomeric change
Photodegradation
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8
Q

Hydrolysis

A

Often the most common cause of drug instability. It involves nucleophilic attack of labile bonds by water.
Reactivity ranking: lactam > ester > amide > imide
Hydrolysis is a first order reaction.
pH dependent

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9
Q

Oxidation

A

Oxidation reactions tend to be complex, giving a variety of degradation products.
Oxidation taking place at ambient temperature in presence of molecular oxygen is called autoxidation. This reaction typically involves free radicals:
RH→ R. + H. (initiation)
R. + O2.→ RO2- (propagation)
RO2. + RH → ROOH + R.

The hydroperoxides (ROOH) react further to produce stable oxidation products.
In the termination phase, the availability of oxygen or drug diminishes, the rate of reaction slows and free radicals combine to produce unreactive end-products.
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10
Q

How is oxidation promoted and stopped?

A

Oxidation is promoted by presence of oxygen ,oxidizing agents, light and trace metals

Antioxidants are generally used in formulations to suppress oxidation An effective antioxidant is more readily oxidized than the drug.

Example. Ascorbic acid (vitamin C) undergoes a rapid oxidation in solution to dehydroascorbic acid. The reaction is reversible but dehydroascorbic acid is irreversibly hydrolysed to form diketogulonic acid.

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11
Q

EDTA as a stabilising agent

A

Generally 0.005% and 0.1%
Chelates trace metal ions to minimise metal ion catalysed oxidation
Can also enhance action of preservatives such as benzalkonium chloride

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12
Q

Photodegradation

A

The energy associated with an electromagnetic radiation increases as wavelength decreases (UV > VIS > IR)
Natural sunlight (wavelength range 290-780nm) cause photodegradation of drug through its highest energy range (290-320nm).
Light-induced degradation is called photolysis.

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13
Q

Storage to prevent photodegradation

A

STORAGE statement in BP2013
“In an airtight container, protected from light.
Once the container has been opened, its contents are to be used as soon as possible; any part of the contents not used at once should be protected by an atmosphere of inert gas”

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14
Q

Photolysis occurs via what mechanism(s)

A

Many photolysis reactions involve oxidation, although other mechanisms may occur (for instance, hydrolysis may be catalysed by light).

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15
Q

More ways to affect stability

A
  • isomeric change

- dimerisation and polymerisation

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16
Q

dimerisation and polymerisation

A

Reaction of a drug molecule with another molecule of the same drug may result in the formation of a dimer or a polymer.
e.g. Amoxicillin ; amino group can attack β-lactam ring to give dimer. A potential source of related substance

17
Q

Problems with protein and peptide drugs

A

Examples: Monoclonal antibodies (trastuzumab), Insulin, vaccines (influenza). Mostly parenteral administration.
Same causes of chemical degradation as drugs but with additional concerns:
Denaturation of conformation
Aggregation
Cross-linking

Stability of protein and peptide drugs is dependent on the amino acid sequence

18
Q

Guidelines for API in the finished dosage

A

ICH (International Conference on Harmonisation
FDA (food drug administration)
EMEA (European Agency for the evaluation of Medicinal products)

Problem – Proteins and Peptides are largely excluded. Validating structural conformation and efficacy on large molecules is tricky.
19
Q

Susceptible amino acids to:

1) oxidation
2) deamidisation

A

1) oxidation - Methionine, Cysteine

2) deamidisation -Asparganine, Glutamine

20
Q

Problem with Tryptophan

A

Photosensitive and oxidation prone

21
Q

Explain the strategy for lowering temperature to increase stability

A

Slows down reaction rates for most drugs
Can promote oxidation (liquid dosage)
freezing and thawing can affect protein drugs dramatically

22
Q

How to control pH

A

add buffer components to make use of optimum pH range

23
Q

Why add chelators and antioxidants?

A

e.g. EDTA, ascorbic acid, citric acid, tocopherol

often used in combo to slow down oxidation reactions

24
Q

Why add a co-solvent?

A

reducing the aqueous with another solvent can reduce hyrolysis

25
Q

Why add a co-solvent?

A

reducing the aqueous with another solvent can reduce hyrolysis

26
Q

Why add inert gas?

A

Prevents autoxidation

27
Q

Why add complexing agent?

A

Addition of complexing agent can slow down hydrolysis

e.g. caffeine in the case of procaine

28
Q

Hydrolysis susceptible drugs

A

lidocaine

procaine

29
Q

Oxidation susceptible drugs

A

ascorbic acid
chloramphenicol
calcitonin

30
Q

Isomerisation susceptible drugs

A

tetracycline

adrenaline

31
Q

photolysis susceptible drugs

A

Retinol
Adrenaline
Decarbazine

32
Q

Polymerisation susceptible drugs

A

Amoxicillin

Ceftazidime

33
Q

Sources of microbial contamination

A
  1. Environment :Water , air, ventilation
  2. Raw materials, containers and closures
  3. Personnel
  4. Instruments and apparatus

Deterioration due to microorganisms can render the product not only inactive but also very harmful to the patient
Microbial contamination affects sterility of products. examples:
- Injection products and eye drops have short in-use life once the container is opened.

Strictly controlled through :
manufacturing practice, preservatives packaging and storage instructions

34
Q

Zones of world

Conditions

A

Zone 1: Temperature climate e.g. Canada, north Europe , Russia & uk
Zone 2: Subtropical & Mediterranean e.g. Japan, USA,
Zone 3: Hot & dry climate e.g. Australia , Middle east
Zone 4: Hot & humid e.g. Central Africa, Nigeria, Malaysia

35
Q

Accelerated stability testing

A

In accelerated stability testing, the drug is stored at elevated temperatures (e.g. 40 ,50 ,600C and the reaction rate is calculated in a short time period (from minutes to days depending on the relative stability of the drug). The Arrhenius equation is used to predict the reaction rate at a realistic storage temperature.
`

36
Q

Limitations of accelerated stability testing

A

kinetics of degradation may change at higher temperatures
(ex. at elevated temperatures, the concentration of dissolved oxygen tends to decrease.
Additional complex reactions may take place at higher temperatures

Temperature may change the nature of the dosage form
(ex. melting of some solid ingredients at elevated temperature)

Change in physical properties with unpredictable effect.
(ex. changes in viscosity, reduction of the moisture level in a solid dosage form, etc.)