drug stability Flashcards
what is drug stability
the capacity of a drug to remain within established specifications of identity for a specified time
2 main factors; shelf life, stability after administration
main factors of drug stability
heat, moisture, light, oxidation
problems of instability
Loss of drug through chemical reaction Acid labile groups hydrolysed by GIT Degradation to toxic substances Unpalatability Loss of efficacy Poor bioavailability may occur in raw ingredients, during manufacture and formulation, upon storage or after administration
shelf life
must be able to determine a time interval over which a drug retains sufficient potency
shelf life=time taken to reduce concentration of drug to 90% of its original value
decomposition of drugs
must be aware of chemical groups which may cause stability problems, can prevent or minimise chemical breakdown. more than one decomposition type may be occurring at the same time
physical instability
volatility
uptake or loss of solvent, polymorphism, changes in heterogeneous systems, denaturation, ionisation and solubility, pH dependency, absorbance/partitioning
chemical instability
hydrolysis, oxidation, elimination, racemisation and isomerisation, rearrangement; photochemical, acid catalysed, photodegradation, incompatibilities
functional groups which undergo hydrolysis
alkyl halide, ester (lactone) amide lactam, urea, peptides, sugars)
factors which effect hydrolysis
pH, temp, solvent, structure
pH- acid/base catalyst
probably the most important and widely examined. affects both liquid and solid dosage forms
the hydrolytic rate profile must be measured.
in liquid doses, the pH rate profile may be affected by buffers used in formulation
ionised and unionised forms of the drug molecules can show different susceptibility towards hydrolysis
what is a V plot
generally a plot of log K v pH
shows a minimum rate at about neutrality
acid catalysed hydrolysis
protonation of the carbonyl oxygen activates the carbonyl carbon ready for nucleophilic attack by the water molecule
an alcohol makes a good leaving group
acid hydrolysis is reversible- reverse mechanism is esterification
base catalysed hydrolysis
in this case, the attacking nucleophile is OH. the reaction takes place simply because of the polarisation of the carbonyl group. the carboxylate solute is isolated, which upon addition of an acid liberates the carboxylic acid
the reaction is essentially irreversible since the carboxylate anion shows little tendency to react with an acid
metal ion catalyst
complexes form between polyvalent metal cations (e.g. Ca2+) and lone pairs of electrons on electronegative atoms (e.g. O). this may facilitate hydrolysis by changing the conformation of the molecule.
internal molecular catalyst
another functional group on the molecule may influence the polarisation in a hydrolysis transition state (e.g. aspirin)
temperature (hydrolysis)
an increase in temperature increases the hydrolysis rate. stability studies usually carried out at high temps (60-80 degrees) as hydrolysis can be measured more easily
this is done using the Arrhenius equation
Arrhenius equation
LnK=LnA-Ea/2.303RT Ea- activation energy required when two reactant molecules collide A-frequency factor-independent of temp R-gas constant (8.314Jmol-1 K-1) T- temp in K
can measure the rate of reaction at high temp (as long as the order doesn’t change)
by extrapolating the Arrhenius plot-determine rate at low temps
- if a particular drug formulation proves to be unstable at room temp, it can be labelled with storage instructions
effects of temp on solids (Arrhenius eq)
can be used for solids however complications arise due to; increased melting temps
changing on polymorphic forms
may be loosely bound to water which is lost at a higher temperature
solvent effects and ionic strength
one way to reduce hydrolysis would be to replace some/all of the water in the system with a solvent such as alcohol or propylene glycol. effective in some situations, but in others the rate of hydrolysis increases.
eq used o predict effect of solvent on hydrolysis drug rate
what is often added to control a drugs tonicity
electrolytes
what do dielectric constant values indicate
polarity
below 15 considered non-polar
structure of reactant
drugs are generally poly functional- one group may affect the behaviour of another. much of this has to do with polarisation of bonds
polarisation is due to electronegativity. greater electronegativity leads to increased polarisation.
e.g. O is more electronegative than N, this is why esters hydrolyse more readily than amides
electronic effects
inductive and mesomeric effects can influence the rate of hydrolysis.
mesomeric effect far greater than inductive effects
electron donating./withdrawing groups near a hydrolysable group alter the transition state
steric effects
this is to do with the bulk size and shape of groups. the transition state is tetrahedral
bulky groups may block or shield the hydrolysable group from attack.
Taft’s steric factor
Es-measure of steric effect
-hydrolysis rates are measured under acidic and basic conditions
basic conditions; steric and electronic factors
acidic conditions; only steric factors
controlling hydrolysis
determine pH of max stability from kinetic experiments and formulate at this pH
alter dielectric constant by addition of non-aqueous solvents e.g. alcohol
only that portion of drug which is in solution can hydrolyse- make s drug less soluble by using additives such as citrates, dextrose, sorbitol, gluconate
solubilising in surfactants can protect against hydrolysis
alter the drug
oxidation
addition of oxygen atom
loss of 2 hydrogen atoms
loss of electron
reduction
loss of an oxygen atom
addition of 2 H atoms
gain of electrons
oxidation process
oxidation involves; removal of an electropositive atom e.g. H
removal of a radical or an electron
addition of an electronegative atom or radical
increase in oxidation number
how can oxidative degradation occur (by autoxidation)
a slow irreversible oxidation in the presence of atmospheric O2
chain process-3 steps; initiation, propagation and termination, involving free radicals
may be catalysed by light and trace metals
examples of autoxidation
many substances are prone to oxidation such as fixed oils, fats and waxes used in formulation as well as the drug. drugs which are susceptible to oxidation include steroids, sterols, polyunsaturated fatty acids, phenothiazines and drugs such as simvastatin which contain conjugated double blonds
factors effecting autoxidation
- light- the energy achieved from a light source is capable of forming radical species
- sensitizers- a chemical, upon receiving energy from another molecule, becomes excited and releases light. sensitizers are usually aromatic with many conjugated bonds
- catalyst-oxidising agents that accept the electrons released in oxidative process, e.g. polyvalent metals such as Cu2+, Fe3+, which are present in almost every buffer in trace amounts which get reduced.
- hydrogen ion concentration (pH)- an increase in H+ means it is more difficult to lose electrons. by lowering the pH, the rate of oxidation slows.
5.temperature- generally the rate increases with increasing temperature, however, there are exceptions such as the oxidation of NO decreases with increasing temperature
bond cleavage reactions
heterolytic bond cleavage-both electrons making up the bond, move together when the bond is broken
homolytic bond cleavage- the two electrons making up the bond get distributed equally between the two atoms- each atom gets one electron
what are free radicals
free radicals are species with one unpaired electron in their outer shell.
free radical chain reactions
initiation, propagation, termination
stabilisation against oxidation
very difficult to remove all traces of O2, containers can be purged with N2 or CO2. amber or coloured glass can exclude <470nm
even water contains dissolved )2, moisture on surface of solid preparation may increase oxidation.
chelating agents serve to ‘mop up’ metal ions
antioxidants (inhibitors of oxidative chain)-interact with free radicals during propagation. examples include ascorbic acid, Vitamin E. most are phenols
store at reduced temps
other forms of chemical instability
inversion of stereochemistry geometric isomerism rearrangement of carbon skeleton loss of H2O or CO2 chemical interactions
what do enantiomers do
rotate the plane of polarised light by an equal amount in opposite directions- they are optical isomers
equal mixture of enantiomers
racemate
when are structures chiral
cannot be superimposed on their mirror image- if the molecule contains a carbon atom containing 4 different groups it will not have a plane of symmetry ad must be chiral. the carbon atom is a chiral centre. any structure that has no plane of symmetry can exist as two mirror image forms (enantiomers)
what does racemisation involve
inversion of stereochemistry at a chiral centre to create a 50;50 mixture of enantiomers which is optically inactive
for compounds with 2 or more chiral centres
a change at one chiral centre gives rise to diastereomers (not mirror images)
have different physical, chemical and biological properties
general mechanism (chiral centres)
inversion at a chiral centre occurs readily when the centre is adjacent to a carbonyl group. the process may be acid (enolic) or base (carbanionic) catalysed.
the chiral carbon goes through an sp2 planar transition state during hydrogen migration or loss. because a planar geometry is generated, addition of H can be to either face leading to 50% stereochemical inversion
interconversion of cis and trans forms
initiated by absorption of light (photons)
p-electron of pi bond absorbs light and is promoted to an excited state, temporarily breaking the pi bond which allows free rotation
the double bond then reforms as the electron goes back to the ground state
elimination (dehydration)
elimination of H2O from an alcohol ->alkene
HO- is not a good leaving group. it must be converted unto one by acid catalysts
what may chemical reactions arise from
inappropriate formulation of materials which reacts chemically-> decomposition products
co-administration of drugs in formulations. additions of drugs to transfusion fluids
amine/carbonyl interaction
amine/ester interaction
acid/base interactions (change in pH)
