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FUN D > D10-D11 Chemical stability of medicines > Flashcards

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

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2
Q

what is the most likely cause of drug instability?

A

hydrolysis

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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
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4
Q

what is solvolysis?

A
  • similar to hydrolysis
  • bonds are broken by a solvent that is not water
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5
Q

what is hydrolysis catalysed by?

A

hydroxide ions
hydrogen ions
presence of ions
heat
light

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6
Q

order ester, lactic, imide and amide in order of most susceptible to least susceptible to hydrolysis

A

most susceptible

lactam
ester
amide
imide

least susceptible

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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
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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
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9
Q

how is a cosolvent formed?

A

by adding a water miscible solvent to the formulation

eg. ethanol, glycerol, propylene glycol

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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)
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11
Q

which environment is more polar, cosolvent or water?

A
  • water is more polar
  • solvent is more organic in nature
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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
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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
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14
Q

how can a drug be solubilised or ‘hidden’ away from the aqueous environment in a medicine tor educe hydrolysis? 2 ways

A
  • formulate a micellar formulation (using surfactants)
  • as an inclusion complex (eg. with cyclic saccharides called cyclodextrins)
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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
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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
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17
Q

what is oxidation catalysed by?

A
  • temperature
  • light
  • trace metals
  • oxygen and oxidising agents
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18
Q

what environment can oxidation occur in?

A
  • both water and oil
  • oils in emulsions are susceptible to oxidation
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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
Q

describe the propagation stage of autoxidation

A
  • drug free radical interacts with oxygen to form peroxy radical (ROO.) which reacts with drug to form hyperoxide (ROOH)
26
Q

describe the termination stage of autoxidation

A
  • 2 radicals react together to form a stable product in addition reactions
27
Q

state some methods that can be used to prevent oxidation

A
  • formulate with antioxidants
  • formulate with reducing agents
  • air replacement
28
Q

explain how formulating with antioxidants can prevent oxidation

A
  • 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
Q

why is ascorbic acid a good antioxidant?

A
  • easily oxidised
  • due to OH group and double bond
30
Q

explain how formulating with reducing agents can prevent oxidation

A
  • 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
Q

explain how air replacement can prevent oxidation

A
  • for formulations prone to decomposition by oxidation
  • air in container can be replaced by an inert gas
    eg. nitrogen or carbon dioxide
32
Q

state some pharmaceutical compounds / products that are susceptible to photolysis

A
  • hydrocortisone!
  • prednisolone
  • riboflavine
33
Q

explain photolysis

A
  • 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
Q

how does energy and wavelength intertwine in photolysis?

A
  • 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
Q

what can trace metal ions do?

A
  • catalyse oxidation (and other forms of degradation

eg.
hydrolysis of benzyl penicillin - copper, lead, mercury and zinc ions

36
Q

how can trace metal catalysis be prevented?

A

formulate with chelating agents

37
Q

how does formulating with chelating agents prevent trace metal catalysis?

A
  • 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
Q

give an example of a chelating agent

A

EDTA
- forms a complex and replaces the hydration of those metal ions
- prevents the metal ions from catalysing oxidation or hydrolysis

39
Q

what is isomerisation?

A
  • process of conversion of a molecule (drug or excipient) into its optical or geometric isomer
  • different isomers have different biological activities
40
Q

how could activity be lost in adrenaline solutions at low pH?

A
  • due to racemisation
  • R converted to S at low pH
  • this mixture is less effective than the pure R sample
41
Q

how can isomerisation be avoided / prevented?

A
  • 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
Q

what is freeze drying?

A
  • 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
Q

state some uses of freeze drying in practise

A
  • 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
Q

advantages of freeze drying

A
  • 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
Q

disadvantages of freeze drying

A
  • 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

FUN D (8 decks)

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