D10-D11 Chemical stability of medicines Flashcards
why are ALL chemical mechanisms affected by temperature?
greater free energy usually leads to more rapid degradation
what is the most likely cause of drug instability?
hydrolysis
describe the process of hydrolysis
- bonds are broken via nucleophilic attack by water
- certain bonds are more susceptible to hydrolysis than others
what is solvolysis?
- similar to hydrolysis
- bonds are broken by a solvent that is not water
what is hydrolysis catalysed by?
hydroxide ions
hydrogen ions
presence of ions
heat
light
order ester, lactam, imide and amide in order of most susceptible to least susceptible to hydrolysis
most susceptible
lactam
ester
amide
imide
least susceptible
explain how extreme pH can catalyse hydrolysis
- 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
how can we used pH to control stability?
- determine pH at which drug is most stable using kinetic studies
- formulate medicine at that pH
- use a buffer to control pH if needed
how is a cosolvent formed?
by adding a water miscible solvent to the formulation
eg. ethanol, glycerol, propylene glycol
how do cosolvents help with stability and reduce hydrolysis?
- 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)
which environment is more polar, cosolvent or water?
- water is more polar
- solvent is more organic in nature
state some methods to reduce hydrolysis
- using a cosolvent
- make the drug less soluble
- solubilise or ‘hide’ drug away from the aqueous environment
how can a drug be made less soluble in a medicine to reduce hydrolysis?
- 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
how can a drug be solubilised or ‘hidden’ away from the aqueous environment in a medicine to reduce hydrolysis? 2 ways
- formulate a micellar formulation (using surfactants)
- as an inclusion complex (eg. with cyclic saccharides called cyclodextrins)
describe micellar solubilisation as a method of reducing hydrolysis by solubilising / ‘hiding’ away the drug from the medicine’s aqueous environment
- 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
describe cyclodextrin inclusion complexes as a method of reducing hydrolysis by solubilising / ‘hiding’ away the drug from the medicine’s aqueous environment
- many reports that cyclodextrins protect from degradation
- but… hydroxyl groups within cyclodextrin can catalyse hydrolysis and increase degradation
what is oxidation catalysed by?
- temperature
- light
- trace metals
- oxygen and oxidising agents
what environment can oxidation occur in?
- both water and oil
- oils in emulsions are susceptible to oxidation
general definition of oxidation
- loss of electrons by a molecule
- can involve addition of oxygen but not necessarily!
- can occur in anaerobic environments (no oxygen)
what is autoxidation?
- pharmaceutical oxidations that are chain reactions which occur slowly in the presence of oxygen
- free radical reaction (initiation, propagation, termination)
what features of molecules are there that make molecules prone to oxidation?
- 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
state some common features of drug and ingredient molecules that are susceptible to degradation
- many carbon-carbon double bonds
- highly conjugated systems
- electron rich
- lone pair of electrons eg. hydroxyl, carbonyls
state the 3 stages of autoxidation
- initiation
- propagation
- termination
describe the initiation stage of autoxidation
- initiating radical could be something like a peroxide from a surfactant
- interacts with drug to form drug free radical
- X. + RH –> R. + XH
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)
describe the termination stage of autoxidation
- 2 radicals react together to form a stable product in addition reactions
state some methods that can be used to prevent oxidation
- formulate with antioxidants
- formulate with reducing agents
- air replacement
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
why is ascorbic acid a good antioxidant?
- easily oxidised
- due to OH group and double bond
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
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
state some pharmaceutical compounds / products that are susceptible to photolysis
- hydrocortisone!
- prednisolone
- riboflavine
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
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)
what can trace metal ions do?
- catalyse oxidation (and other forms of degradation
eg.
hydrolysis of benzyl penicillin - copper, lead, mercury and zinc ions
how can trace metal catalysis be prevented?
formulate with chelating agents
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)
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
what is isomerisation?
- process of conversion of a molecule (drug or excipient) into its optical or geometric isomer
- different isomers have different biological activities
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
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
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
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)
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)
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
