Drug stability Flashcards
what does stability mean and what could it affect?
can mean
- physical
- chemical
- microbiological
can affect shelf life
what factors can affect stability?
- drug.excipient properties
- compatibility with excipients
- dosage form
- packaging
- environmental conditions
what changes can occur physically for solutions, suspension, emulsion and cream and ointments?
for liquid and semisolid formulations solutions; precipitation suspension; caking and Ostwald ripening emulsions and creams; creaming, cracking, Ostwald ripening ointments; bleeding
what is Ostwald ripening?
for solid or liquid solutions a change that occurs over time where small crystals or solid particles will dissolve and redeposit onto large crystals or solid particles
what can microbiological stability result in?
can result in microbiological growth inside the preparation
what physical stability changes should solid dosage forms keep?
tablets
- should watch and retain size, colour, shape and uniform coating
capsules
- high moisture content of gelatin shell; can be affected by air humidity
- cross-linking; can also affect chemical stability
what physical stability changes can other dosage forms undergo?
patches
- appearance and adhesive properties
- drug release issues
inhaled aerosols
- changes in size distribution so therefore emitted dose and appearance
what can loss of a drug or components of the product be due to?
the evaporation of a volatile compound; can affect UoC
adsorption on the surface of the container/closure
absorption into plastic or rubber container; dosage migrates into packaging
difference between absorption and adsorption?
adsorption is molecules or ions gathering on the surface
absorption is where a liquid is soaked up onto paper, sponge etc.
what molecules is sorption more likely for?
non-polar molecules
- worse if conc of drug/excipient is low; increase consequences
- sorption of preservatives on rubber closures decreases physical stability and microbiological stability
what can increase the evaporation risk?
- expiry date decreases from 2 years -> 8 weeks
- adding anything else to the bottle
- repackaging
what are examples of impurities leaching/ additives from packaging?
- plasticiser from PVC bags
e.g. Taxol and Taxotere
if solvent contains ethanol or surfactants - release of OH- ions from glass containers into solutions
e.g. autoclave sterilisation
what changes can occur from microbial contamination?
- stability of sterile products
- the shelf life once opened
e. .g eye drops go from 24 months -> 1 month
how to calculate zero order form a graph?
- select two pairs of data at different places on the curve; choose an early and late start point e.g. time 0hr and 2hrs is one pair and 16hr and 24hr is another pair
- each pair, calculate the gradient (want gradient to be constant)
- C1-C2/ T1-T2
- for both pairs, should have similar values but a different value
how to calculate if it is a first order reaction from graph?
- select two pairs of data at different places on the curve; choose an early and late start point e.g. time 0hr and 2hrs is one pair and 16hr and 24hr is another pair
- for a first order reaction, written as y = lac
- should be same value
how to calculate if a graph is second order reaction?
- select two pairs of data at different places on the curve; choose an early and late start point e.g. time 0hr and 2hrs is one pair and 16hr and 24hr is another pair
- calculate the gradient of these two pairs
- you should see this isn’t zero order as conc. do not change even though time interval is same but time has increased
what are the mechanisms of drug degradation?
- hydrolysis
- oxidation
- isomerisation
- dimerisation and polymerisation
- photochemical drug degradation
what is hydrolysis?
drug degradation resulting from reaction with water
- can be catalysed by acids or bases in solution
- requires the drug to be in solution and accessible
how can reaction rate of hydrolysis be decreased?
can be decreased by:
- decreasing solubility; adding additives
- formulation as a suspension
what does hydrolysis require and what should you be careful of?
requires the drug to be in solution be careful of: - impact of moisture content - impact of shell material - impact of packaging
what is oxidation accelerated in the presence of?
light/heat; free radicals formation
trace metals; impurities and contamination during processing
how can oxidation reactions of drugs be controlled?
- adding antioxidants
- BHA, BHT. gallate’s
- ascorbic acid and sodium ascorbate - adding reducing agents
- sodium metabisulphite - control temp, pH, protect from light
- packaging impermeable to gases
what is photochemical degradation?
it is degradation reaction catalysed by light
- photosensitive drugs undergo this
- they absorb light at around 300-400 nm
e. g- carbonyl, nitro, alkene, acyl chloride - generally photo-oxidation; free radicals involved
why can photochemical degradation occur?
can be due to incompatibilities within the formulation
e.g adrenaline and sodium metabisulphite
the OH is replaced with a H and a SO3- atom
how can photochemical degradation be prevented?
can be prevented by
- adequate packaging
- > primary pack; amber pack, opaque blister pack; has direct contact with dosage form
- > secondary pack; cardboard box
- polymeric coating containing UV-light blocking agent
e. g. oxybenzene
what is dimerisation and polymerisation?
dimerisation; combination of two drug molecules
polymerisation; combination of multiple molecules to make a long chain of repeating units
what is dimerisation of B-lactams responsible for?
responsible for dimerisation of amino-penicillins in concentrated solutions
- susceptibility increases with increasing basicity of side chains
therefore responsible for penicilloyl-specific allergens
what is isomerisation?
conversion from one isomer to another
- optical isomers
- change from one enantiomer to another
- > racemization: single chiral centre
- > epimerisation: more than one chiral centre - geometric
- differences in conformation around C=C
- > change from cis to trans - structural isomers
- same formula but bonds in a different order
what is the difference between homogenous and heterogenous?
homogenous- single phase (solutions)
heterogenous- dispersed systems (suspensions)
what is the definition of molecularity and order?
molecularity is the number of molecules taking part in a reaction
- unimolecular ; a molecule transformed into a product
- bimolecular ; two molecules taking part
order is the number of concentrations that define the rate
- rate is proportional to reactants
what is the general equation for the reaction rate?
-dC/dt = k(C)^order
what is meant by zero order reaction?
rate doesn’t depend on reactant conc.
- reactant conc. is constant
- conc. won’t change over time until disperse phase has been used
- will get a straight line
how can you calculate half life for zero order?
t50% = Co/2k
what kind of graph is first order reaction?
it is not a straight line
gradient becomes less steep
more of a curve off as % drug conc. becomes more constant
but as a natural log graph it should be a straight line
how do you calculate the half life for first order kinetics?
lnCo/2 = lnCo - kt
t50% = ln2/k
what is an example of pseudo-first order?
drug + h20 = products
in a dilute solution, water is in EXCESS, so conc, remains CONSTANT. this reaction is theoretically second order, is in reality a FIRST ORDER reaction. the rate constant will be defined as k, to show its a pseudo-first order
- dilute solution in a lot of water
- not a big change in water conc. in preparation even if all drugs reacts
- conc. won’t change much as reactant is in first order
what will a second order reaction graph look like?
if you plot a natural log graph it will not be a straight line
plot a 1/C graph and will produce a positive gradient on graph straight line
how do we calculate the half life for a second order reaction?
half life = 2/Co = 1/Co + kt50%
so t50% = 1/(Co x k)
examples of some stabilising agents?
sodium alginate, sodium carboxymethyl cellulose (CMC), gelatin, pectin
