drug stability

Question 1

what is drug stability

Answer 1

the capacity of a drug to remain within established specifications of identity for a specified time
2 main factors; shelf life, stability after administration

Question 2

main factors of drug stability

Answer 2

heat, moisture, light, oxidation

Question 3

problems of instability

Answer 3

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

Question 4

shelf life

Answer 4

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

Question 5

decomposition of drugs

Answer 5

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

Question 6

physical instability

Answer 6

volatility
uptake or loss of solvent, polymorphism, changes in heterogeneous systems, denaturation, ionisation and solubility, pH dependency, absorbance/partitioning

Question 7

chemical instability

Answer 7

hydrolysis, oxidation, elimination, racemisation and isomerisation, rearrangement; photochemical, acid catalysed, photodegradation, incompatibilities

Question 8

functional groups which undergo hydrolysis

Answer 8

alkyl halide, ester (lactone) amide lactam, urea, peptides, sugars)

Question 9

factors which effect hydrolysis

Answer 9

pH, temp, solvent, structure

Question 10

pH- acid/base catalyst

Answer 10

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

Question 11

what is a V plot

Answer 11

generally a plot of log K v pH

shows a minimum rate at about neutrality

Question 12

acid catalysed hydrolysis

Answer 12

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

Question 13

base catalysed hydrolysis

Answer 13

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

Question 14

metal ion catalyst

Answer 14

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.

Question 15

internal molecular catalyst

Answer 15

another functional group on the molecule may influence the polarisation in a hydrolysis transition state (e.g. aspirin)

Question 16

temperature (hydrolysis)

Answer 16

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

Question 17

Arrhenius equation

Answer 17

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

Question 18

effects of temp on solids (Arrhenius eq)

Answer 18

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

Question 19

solvent effects and ionic strength

Answer 19

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

Question 20

what is often added to control a drugs tonicity

Answer 20

electrolytes

Question 21

what do dielectric constant values indicate

Answer 21

polarity

below 15 considered non-polar

Question 22

structure of reactant

Answer 22

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

Question 23

electronic effects

Answer 23

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

Question 24

steric effects

Answer 24

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.

Question 25

Taft’s steric factor

Answer 25

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

Question 26

controlling hydrolysis

Answer 26

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

Question 27

oxidation

Answer 27

addition of oxygen atom
loss of 2 hydrogen atoms
loss of electron

Question 28

reduction

Answer 28

loss of an oxygen atom
addition of 2 H atoms
gain of electrons

Question 29

oxidation process

Answer 29

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

Question 30

how can oxidative degradation occur (by autoxidation)

Answer 30

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

Question 31

examples of autoxidation

Answer 31

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

Question 32

factors effecting autoxidation

Answer 32

1. light- the energy achieved from a light source is capable of forming radical species
2. sensitizers- a chemical, upon receiving energy from another molecule, becomes excited and releases light. sensitizers are usually aromatic with many conjugated bonds
3. 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.
4. 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

Question 33

bond cleavage reactions

Answer 33

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

Question 34

what are free radicals

Answer 34

free radicals are species with one unpaired electron in their outer shell.

Question 35

free radical chain reactions

Answer 35

initiation, propagation, termination

Question 36

stabilisation against oxidation

Answer 36

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

Question 37

other forms of chemical instability

Answer 37

inversion of stereochemistry 
geometric isomerism
rearrangement of carbon skeleton
loss of H2O or CO2
chemical interactions

Question 38

what do enantiomers do

Answer 38

rotate the plane of polarised light by an equal amount in opposite directions- they are optical isomers

Question 39

equal mixture of enantiomers

Answer 39

racemate

Question 40

when are structures chiral

Answer 40

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)

Question 41

what does racemisation involve

Answer 41

inversion of stereochemistry at a chiral centre to create a 50;50 mixture of enantiomers which is optically inactive

Question 42

for compounds with 2 or more chiral centres

Answer 42

a change at one chiral centre gives rise to diastereomers (not mirror images)
have different physical, chemical and biological properties

Question 43

general mechanism (chiral centres)

Answer 43

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

Question 44

interconversion of cis and trans forms

Answer 44

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

Question 45

elimination (dehydration)

Answer 45

elimination of H2O from an alcohol ->alkene

HO- is not a good leaving group. it must be converted unto one by acid catalysts

Question 46

what may chemical reactions arise from

Answer 46

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)