D10-D11 Chemical stability of medicines Flashcards
1
Q
why are ALL chemical mechanisms affected by temperature?
A
greater free energy usually leads to more rapid degradation
2
Q
what is the most likely cause of drug instability?
A
hydrolysis
3
Q
describe the process of hydrolysis
A
- bonds are broken via nucleophilic attack by water
- certain bonds are more susceptible to hydrolysis than others
4
Q
what is solvolysis?
A
- similar to hydrolysis
- bonds are broken by a solvent that is not water
5
Q
what is hydrolysis catalysed by?
A
hydroxide ions
hydrogen ions
presence of ions
heat
light
6
Q
order ester, lactam, imide and amide in order of most susceptible to least susceptible to hydrolysis
A
most susceptible
lactam
ester
amide
imide
least susceptible
7
Q
explain how extreme pH can catalyse hydrolysis
A
- many drugs are weak acids / bases
- tend to be most water-soluble when in ionised form but this is also when they are most unstable
- therefore, extreme bases allow for drugs to be soluble in medicines but they are extremely unstable due to being in ionised form
8
Q
how can we used pH to control stability?
A
- determine pH at which drug is most stable using kinetic studies
- formulate medicine at that pH
- use a buffer to control pH if needed
9
Q
how is a cosolvent formed?
A
by adding a water miscible solvent to the formulation
eg. ethanol, glycerol, propylene glycol
10
Q
how do cosolvents help with stability and reduce hydrolysis?
A
- cosolvent is more organic and so favours unionised form of drug (reduces hydrolysis because drug favours unionised form)
- increases solubility of more stable unionised form of weak acid / base
- can reduce pH extreme required for solubility
- products of degradation reactions can be less soluble than reactants so the degradation doesn’t occur (it’s limited)
11
Q
which environment is more polar, cosolvent or water?
A
- water is more polar
- solvent is more organic in nature
12
Q
state some methods to reduce hydrolysis
A
- using a cosolvent
- make the drug less soluble
- solubilise or ‘hide’ drug away from the aqueous environment
13
Q
how can a drug be made less soluble in a medicine to reduce hydrolysis?
A
- add excipients to make suspensions (citrates, dextrose or sorbitol) or chemically modify the drug
- drugs can only degrade by hydrolysis if they’re in solution
14
Q
how can a drug be solubilised or ‘hidden’ away from the aqueous environment in a medicine to reduce hydrolysis? 2 ways
A
- formulate a micellar formulation (using surfactants)
- as an inclusion complex (eg. with cyclic saccharides called cyclodextrins)
15
Q
describe micellar solubilisation as a method of reducing hydrolysis by solubilising / ‘hiding’ away the drug from the medicine’s aqueous environment
A
- non-polar compounds solubilised in the oily interior of micelles protected from hydrolysis (and other degradation processes)
- more polar compounds (situated nearer the surface of the micelle) surface charges of micelle head groups repel the drug inside the micelle
16
Q
describe cyclodextrin inclusion complexes as a method of reducing hydrolysis by solubilising / ‘hiding’ away the drug from the medicine’s aqueous environment
A
- many reports that cyclodextrins protect from degradation
- but… hydroxyl groups within cyclodextrin can catalyse hydrolysis and increase degradation
17
Q
what is oxidation catalysed by?
A
- temperature
- light
- trace metals
- oxygen and oxidising agents
18
Q
what environment can oxidation occur in?
A
- both water and oil
- oils in emulsions are susceptible to oxidation
19
Q
general definition of oxidation
A
- loss of electrons by a molecule
- can involve addition of oxygen but not necessarily!
- can occur in anaerobic environments (no oxygen)
20
Q
what is autoxidation?
A
- pharmaceutical oxidations that are chain reactions which occur slowly in the presence of oxygen
- free radical reaction (initiation, propagation, termination)
21
Q
what features of molecules are there that make molecules prone to oxidation?
A
- molecules with hydroxyl group which have a lone pair that can be given up (loss of electrons is oxidation)
- lots of rings joined together and conjugated molecules because they can lose electrons but still form stable structures
22
Q
state some common features of drug and ingredient molecules that are susceptible to degradation
A
- many carbon-carbon double bonds
- highly conjugated systems
- electron rich
- lone pair of electrons eg. hydroxyl, carbonyls
23
Q
state the 3 stages of autoxidation
A
- initiation
- propagation
- termination
24
Q
describe the initiation stage of autoxidation
A
- initiating radical could be something like a peroxide from a surfactant
- interacts with drug to form drug free radical
- X. + RH –> R. + XH
25
describe the propagation stage of autoxidation
- drug free radical interacts with oxygen to form peroxy radical (ROO.) which reacts with drug to form hyperoxide (ROOH)
26
describe the termination stage of autoxidation
- 2 radicals react together to form a stable product in addition reactions
27
state some methods that can be used to prevent oxidation
- formulate with antioxidants
- formulate with reducing agents
- air replacement
28
explain how formulating with antioxidants can prevent oxidation
- function by providing more electrons (or hydrogen)
- terminate chain reaction and are more easily oxidised than the drug
eg.
ascorbic acid (vitamin C)
propyl gallate
butylated hydroxy toluene
29
why is ascorbic acid a good antioxidant?
- easily oxidised
- due to OH group and double bond
30
explain how formulating with reducing agents can prevent oxidation
- more readily oxidised than the drug
eg. sodium metabisulfite
- used to prevent decomposition of adrenaline injections
- sulphite easily gives up electrons and mops up free radicals to prevent oxidation
31
explain how air replacement can prevent oxidation
- for formulations prone to decomposition by oxidation
- air in container can be replaced by an inert gas
eg. nitrogen or carbon dioxide
32
state some pharmaceutical compounds / products that are susceptible to photolysis
- hydrocortisone!
- prednisolone
- riboflavine
33
explain photolysis
- molecules absorb light and increase in energy and have double bonds somewhere
- energy increases and can increase heat so degradation speeds up
energy may be:
- retained or transferred
- converted to heat
- result in the emission of light
- cause decomposition (photolysis) or the generation of free radicals
34
how does energy and wavelength intertwine in photolysis?
- energy of radiation increases with decreasing wavelength (degradation ability is greater with shorter wavelength, UV>visible>IR)
- higher energy range is responsible for photolysis of drugs (avoid direct sunlight if drug or ingredients are susceptible)
35
what can trace metal ions do?
- catalyse oxidation (and other forms of degradation
eg.
hydrolysis of benzyl penicillin - copper, lead, mercury and zinc ions
36
how can trace metal catalysis be prevented?
formulate with chelating agents
37
how does formulating with chelating agents prevent trace metal catalysis?
- chelating agents are capable of forming complex salts with metal ions by donation of lone electron pairs
- they form a shell around the ion and replace water of hydration to inactivate the ion in solution (not precipitated)
38
give an example of a chelating agent
EDTA
- forms a complex and replaces the hydration of those metal ions
- prevents the metal ions from catalysing oxidation or hydrolysis
39
what is isomerisation?
- process of conversion of a molecule (drug or excipient) into its optical or geometric isomer
- different isomers have different biological activities
40
how could activity be lost in adrenaline solutions at low pH?
- due to racemisation
- R converted to S at low pH
- this mixture is less effective than the pure R sample
41
how can isomerisation be avoided / prevented?
- difficult
- knowledge of conditions in which the isomerisation processes occur (eg. extreme pH, oxidising conditions)
- try to formulate in conditions where these occur slowly
42
what is freeze drying?
- aka lyophilisation
- removal of the moisture from a frozen product under vacuum (removes potential for hydrolysis and oxidation)
- preserves integrity
- water comes off during the freeze process by sublimation
43
state some uses of freeze drying in practise
- dry products such as blood plasma, antibiotics, vaccines (smallpox), enzymes (hyaluronidase) and microbial cultures
- generally applied to peptides and proteins
- porous sugars and proteins are leftover (reconstitution step is required - add water before giving to patient)
44
advantages of freeze drying
- low temperatures and vacuum conditions inhibit hydrolysis and oxidation
- the porous solid produced is more readily soluble (easy to reconstitute back into liquid medicine again)
45
disadvantages of freeze drying
- the porosity, solubility and dryness of the solid make it very hygroscopic (rapidly absorbs moisture if exposed to air)
- can be slow, complicated and expensive (needs a lot of optimisation in order to get the conditions correct)
- relatively difficult for solutions containing non-aqueous solvents
