Stability of drugs Flashcards
(33 cards)
Lactams are more susceptible to hydrolysis than esters. True or false?
True
Which are the most susceptible to hydrolysis, esters of amides?
Esters
Imides are less susceptible to hydrolysis than amides. True or false?
True
Hydrolysis is a zero order reaction. True or false?
False
First order
Hydrolysis is pH dependent – so the lower the logK, the higher the rate of hydrolysis and so the more the drug will degrade. True or false?
False
The higher the logK the more the drug will degrade
Oxidation is promoted in the presence of oxygen. What else promotes oxidation?
Presence of oxidising agents, light and trace metals
Highly conjugated metals are susceptible to photodegradation. True or false?
True
Energy increase as wavelength increases. True or false?
False
Energy increases with decreasing wavelength
What is light induced degradation called?
Photolysis
Isomeric change may affect pharmacological and toxicological activity. True or false?
True
The L form of adrenaline is more active than the D form. True or false?
True
Optical rotation is used to detect isomeric change because there is no change in mass spec etc. it is not useful. True or false?
True
The chemical stability of proteins and peptides is dependent on amino acid composition and sequence. True or false?
True
How do inert gases stabilize pharmaceutical preparations?
They protect from auto oxidation
Why is procaine more prone to hydrolysis than lidocaine?
procaine is an ester so more prone to hydrolysis than lidocaine which is an amide
What is the eqn for half-life of a first order reaction?
T1/2 – ln(2)/k
What is the eqn for shelf life of a first order reaction?
T90 = ln(1.11)/k
What are the limitations of accelerated stability testing?
kinetics of degradation may change at higher temps, additional complex reactions may take place at higher temps, temp may change nature of dosage form, change in physical properties with unpredictable effect
What is the acceptable level of therapeutics?
therapeutic effect remains unchanged
Toxicological expectations?
no significant increase in toxicity occurs
Define shelf life
*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
Factors affecting stability
- pH - acid and base catalysis tends to raise chemical degradation. Extreme pH changes cause epimerisation
- 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
Explain hydrolysis
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
Explain oxidation
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.
