stability 1/2

Question 1

define stability

Answer 1

Stability is the ability to remain within specifications to ensure the safety, efficacy and acceptability of the medicine.

Question 2

what are the 3 main factors in product stability?

Answer 2

–Physical stability–Microbial stability–Chemical stability

Question 3

how are physical/microbial and chemical stability controlled? and how are they measured?

Answer 3

These factors are controlled in product design and assessed in QC.
•Measure by rate of change.

Question 4

what changes in storage/medicinal could have a major impact on the stability?

Answer 4

–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

Question 5

define expiry date

Answer 5

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.

Question 6

why after opening the packaging will the expiry date be shorter?

Answer 6

as a result of the decreased concentration of drug during usage and the effects of external factors.

Question 7

what is the expiry for the following after them being opened? ; eye drops/Syrups and suspension of antibiotics/

Answer 7

• 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°.

Question 8

which polyform has the highest melting point?

Answer 8

polymorph 1

Question 9

how can you convert between different polymorphs?

Answer 9

Mechanical stress (grinding) may convert powder to different form
–Conversion may occur in suspension

Question 10

is the most stable polymorph always the best?

Answer 10

no- may be too stable sometimes

Question 11

what is a suspension?

Answer 11

Two-phase system comprising solid particles dispersed in a liquid
–Particles 1-1000nm termed colloids
–Particles > 1 μm termed coarse suspensions

Question 12

how does instability occur in suspensions?

Answer 12

instability due to settling

Question 13

what may particularly soluble drugs do to particle size?

Answer 13

Partially soluble drug may change particle size if temperature fluctuates

Question 14

what happens in flocculation?

Answer 14

Weakly bound aggregates (“flocs”)
– Force of attraction > force of repulsion
– Settle quickly
– Large sedimentation volume– Don’t cake/ easily dispersible

Question 15

what happens in a deflocculated system?

Answer 15

•  Deflocculated systems
– Force of repulsion > force of attraction
– Settle slowly
– Small sedimentation volume
– Prone to caking

Question 16

what is flocculation sensitive to?

Answer 16

ph, ionic strength

Question 17

what influences suspension stability?

Answer 17

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

Question 18

what are the physiochemical properties that may effect stability?

Answer 18

solvent and its effect on solubility
-the ratios that they are mixed in may lead to precipitation
ph effect

Question 19

how is chemical stability helpful?

Answer 19

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

Question 20

what are the 3 main types of chemical reaction?

Answer 20

– Hydrolysis– Oxidation– Photodegradation

Question 21

what does an ester hydrolyise to?

Answer 21

carboxylic acid +alcohol/phenol- either OG attacks or =0 attacks an adjacent H

Question 22

if the R groups donate electrons to the carbonyl is the ester less/ more prone to hydrolysis?

Answer 22

less- less delta positive and less attractive nucleophilic centre

Question 23

what effects ester hydrolysis?

Answer 23

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

Question 24

what does an amide hydrolyse to?

Answer 24

carboxylic acid +amine

Question 25

what is an amide hydrolysis mechanism similar to?

Answer 25

ester hydrolysis

Question 26

what effects hydrolysis of amides?

Answer 26

ph/ r1/2 groups

Question 27

is the hydrolysis of an amide or ester more reactive?

Answer 27

ester- amide is less reactive due to the presence of a more basic leaving group and less withdrawing effect of N

Question 28

What is autooxidation?

Answer 28

spontaneous oxidation in air at ambient temperatures

Question 29

is ground state oxygen a di-radical or a singlet?

Answer 29

di-radical-Both unpaired electrons in HOMO have the same spin

Question 30

what is a singlet oxygen?

Answer 30

oxygen from a high energy source- have opposite spin- paired electrons
can react with organic compounds

Question 31

what will molecular oxygen react with?

Answer 31

unpaired electrons- radicals

Question 32

is oxygen a good indicator of stability?

Answer 32

Oxygen, although a diradical is not a good initiator

- light may initiate it

Question 33

what is the most stable radical?

Answer 33

benzyl-allyl-tertiary-secondary-primary-vinyl-methyl

Question 34

how can we have radical stability?

Answer 34

resonance hybrid- benzyl/allyl

Question 35

what are groups prone to oxidation?

Answer 35

phenol/ethers/amines/thiols/thioether

Question 36

how do we minimise oxidation?

Answer 36

• 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

Question 37

why do we use optimum ph when wanting to minimise oxidation?

Answer 37

– Acidic drugs (e.g. phenols and thiols) degrade morerapidly when ionised (pH > 7)– Basic drugs also more stable in acidic conditions

Question 38

what antioxidant would you add to minimise oxidation?

Answer 38

– Water soluble sacrificial agents e.g. ascorbic acid, sodium metabisulphite

Question 39

what radical scavengers could we use-non- polar?

Answer 39

butylated hydroxy toluene
vit e
propyl gallate

Question 40

what can thioethers be oxadised to?

Answer 40

• 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)

Question 41

what are some drugs prone to oxidation?

Answer 41

captopril/ chloropromazine

Question 42

what is photodegeneration?

Answer 42

• Photon promotes transition to excited state

* πbonds absorb UV and visible light leading to promotion to antibonding orbital (π*)

Question 43

where in photodegeneration to degeneration occur?

Answer 43

in the excited state

Question 44

which bonds are promoted to the antibonding orbital and why?

Answer 44

the pi bonds- so that there is free rotation and there can be a mixture of cis and trans

Question 45

what is radical initiation?

Answer 45

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

Question 46

what may be a secondary reaction in radical initiation?

Answer 46

decarboxylation- procaine hydrolyses to 4-amino benzoic acid which decarboxylates to aniline.

Question 47

what is Racemisations?

Answer 47

hydrolysis and reformation of ester
When bond breaks- free rotation
labile group at or near chiral center required
R- adrenaline- s less active form