stability 1/2 Flashcards
define stability
Stability is the ability to remain within specifications to ensure the safety, efficacy and acceptability of the medicine.
what are the 3 main factors in product stability?
–Physical stability–Microbial stability–Chemical stability
how are physical/microbial and chemical stability controlled? and how are they measured?
These factors are controlled in product design and assessed in QC.
•Measure by rate of change.
what changes in storage/medicinal could have a major impact on the stability?
–Exposure of medicine to light and/or moisture may induce chemical instability
–Transferring tablets to MCA may allow uptake of moisture affecting disintegration time
–Preparing suspension from capsules involves microbiological risk
define expiry date
means that drug can not be used after this date because the concentration of drug is decreased and become lower than therapeutic concentration.
•In addition, some products of drug degradation are toxic and harmful to patients.
why after opening the packaging will the expiry date be shorter?
as a result of the decreased concentration of drug during usage and the effects of external factors.
what is the expiry for the following after them being opened? ; eye drops/Syrups and suspension of antibiotics/
- Eye drops: can be used for one month after opening the droppers
- Syrups and suspension of antibiotics: can be used for one week by storage in room temperature and for two weeks by storage in 4C°.
which polyform has the highest melting point?
polymorph 1
how can you convert between different polymorphs?
Mechanical stress (grinding) may convert powder to different form –Conversion may occur in suspension
is the most stable polymorph always the best?
no- may be too stable sometimes
what is a suspension?
Two-phase system comprising solid particles dispersed in a liquid
–Particles 1-1000nm termed colloids
–Particles > 1 μm termed coarse suspensions
how does instability occur in suspensions?
instability due to settling
what may particularly soluble drugs do to particle size?
Partially soluble drug may change particle size if temperature fluctuates
what happens in flocculation?
Weakly bound aggregates (“flocs”)
– Force of attraction > force of repulsion
– Settle quickly
– Large sedimentation volume– Don’t cake/ easily dispersible
what happens in a deflocculated system?
• Deflocculated systems – Force of repulsion > force of attraction – Settle slowly – Small sedimentation volume – Prone to caking
what is flocculation sensitive to?
ph, ionic strength
what influences suspension stability?
Viscosity enhancers–Pseudoplastic properties are useful Electrolytes–Reduce zeta potential–Maintain stability through Brownian motion: prevent particles sticking when they collide. surfactants hydrophilic colloids preservatives/ antioxidants sedimentation rate flocculation value • Ease of redispersion • Effect of elevated temperature • Effect of temperature fluctuations • Centrifugation
what are the physiochemical properties that may effect stability?
solvent and its effect on solubility
-the ratios that they are mixed in may lead to precipitation
ph effect
how is chemical stability helpful?
Predict likely degradation based on chemical structure
– Reactivity of functional groups in the drug• Be aware of the main factors affecting degradation rate
• Suggest strategies to improve chemical stability
what are the 3 main types of chemical reaction?
– Hydrolysis– Oxidation– Photodegradation
what does an ester hydrolyise to?
carboxylic acid +alcohol/phenol- either OG attacks or =0 attacks an adjacent H
if the R groups donate electrons to the carbonyl is the ester less/ more prone to hydrolysis?
less- less delta positive and less attractive nucleophilic centre
what effects ester hydrolysis?
ph/ The stability of the leaving group affects the rate; weaker bases are better leaving groups.
if R groups are el withdrawing- increases rate/ el donating- decreases rate
what does an amide hydrolyse to?
carboxylic acid +amine
what is an amide hydrolysis mechanism similar to?
ester hydrolysis
what effects hydrolysis of amides?
ph/ r1/2 groups
is the hydrolysis of an amide or ester more reactive?
ester- amide is less reactive due to the presence of a more basic leaving group and less withdrawing effect of N
What is autooxidation?
spontaneous oxidation in air at ambient temperatures
is ground state oxygen a di-radical or a singlet?
di-radical-Both unpaired electrons in HOMO have the same spin
what is a singlet oxygen?
oxygen from a high energy source- have opposite spin- paired electrons
can react with organic compounds
what will molecular oxygen react with?
unpaired electrons- radicals
is oxygen a good indicator of stability?
Oxygen, although a diradical is not a good initiator
- light may initiate it
what is the most stable radical?
benzyl-allyl-tertiary-secondary-primary-vinyl-methyl
how can we have radical stability?
resonance hybrid- benzyl/allyl
what are groups prone to oxidation?
phenol/ethers/amines/thiols/thioether
how do we minimise oxidation?
- Exclusion of oxygen– Pack under inert gas (e.g. nitrogen)– Tablet strips
- Protect from light – e.g. amber bottles
- Control of peroxides
- Use optimum pH
- Add chelating agent to remove metal ions-EDTA
- Add antioxidant
why do we use optimum ph when wanting to minimise oxidation?
– Acidic drugs (e.g. phenols and thiols) degrade morerapidly when ionised (pH > 7)– Basic drugs also more stable in acidic conditions
what antioxidant would you add to minimise oxidation?
– Water soluble sacrificial agents e.g. ascorbic acid, sodium metabisulphite
what radical scavengers could we use-non- polar?
butylated hydroxy toluene
vit e
propyl gallate
what can thioethers be oxadised to?
- thioethers can be easily oxidized to the sulfoxides (R–S(=O)–R),
- which can themselves be further oxidized to sulfones (R–S(=O)2–R)
what are some drugs prone to oxidation?
captopril/ chloropromazine
what is photodegeneration?
- Photon promotes transition to excited state
* πbonds absorb UV and visible light leading to promotion to antibonding orbital (π*)
where in photodegeneration to degeneration occur?
in the excited state
which bonds are promoted to the antibonding orbital and why?
the pi bonds- so that there is free rotation and there can be a mixture of cis and trans
what is radical initiation?
loss of halogen atom- cl/br
May lead to photosensitization in patient taking chlorpromazine
where it comes close enough to skin to absorb UV light- end up with HCL
what may be a secondary reaction in radical initiation?
decarboxylation- procaine hydrolyses to 4-amino benzoic acid which decarboxylates to aniline.
what is Racemisations?
hydrolysis and reformation of ester
When bond breaks- free rotation
labile group at or near chiral center required
R- adrenaline- s less active form
