Drug stability Flashcards
1
Q
What is instability (5)
A
- A change in the physicochemical properties of a pharmaceutical product can be:
- Chemical changes - in the qualitative or quantitative composition
- Physical changes
- Microbiological changes
- These are secondary effects and may have serious consequences for the patient.
2
Q
What is chemical reactivity (3)
A
- The use of functional groups to have the desired biological action
- Functional groups are chemically very reactive - under certain conditions, they will react and undergo molecular rearrangement.
- Reactivity can have undesirable consequences; therefore, the molecule is considered unstable.
3
Q
What are the instability causes (4)
A
- Light
- Temperature
- Moisture
- Oxygen
4
Q
What happens during temperature instability (3)
A
- Activation energy (Ea) is often supplied in the form of heat, which causes a chemical reaction to occur.
- Greater free energy = more rapid reaction
- 10 °C increase in temperature can cause a 2–5 fold increase in degradation rate
5
Q
What can be used to determine the temperature and degradation rate (4)
A
- The Arrhenius equation is often used to predict the relationship between reaction rate and temperature.
- In k = In A - Ea/RT
- Ea (activation energy) can be derived from the slope of the Arrhenius plot.
- This forms the basis of ‘accelerated stability testing’ (i.e. predicting shelf-life)
6
Q
How does light affect drug stability (4)
A
- Some chemical reactions can be initiated by light-photochemical reactions.
- Photolysis is a reaction initiated by light (e.g. photolytic oxidation, photolytic hydrolysis)
- Photolysis requires the reactant(s) to absorb a specific wavelength of light.
- Usually, UV light (more energetic than visible light)
7
Q
How is moisture (water) found in pharmaceutics (3)
A
- Deliberately included as a vehicle.
- A crystalline hydrate within the product
- Present as a contaminant.
8
Q
What is hydrolysis (3)
A
- Hydrolysis is the reaction between a molecule and water - a specific case of solvolysis.
- Involves cleavage of one or more bonds within the molecule
- Results in the production of smaller, more polar and more reactive fragments
9
Q
What gives rise to nucleophilic attack (4)
A
- A covalent bond between two atoms with unequal electronegativity → unequal sharing of electrons
- Acyl groups: oxygen is more electronegative than acyl carbon, attracts electrons → creates a dipole
- A dipole is created whenever carbon is double-bonded to an atom more electronegative than itself, e.g. Nitrogen (dipole is weaker)
- The creation of dipoles gives rise to nucleophilic attack.
10
Q
What happens in a nucleophilic attack (2)
A
- A small, negatively charged anion is strongly attracted to the (partially) positively charged carbon atom - which satisfies the electronic requirements of the carbon.
- To lose the excess electron, the formed anion breaks the weakest bond to lose the most stable anion (leaving group)
11
Q
What is acid-catalysed hydrolysis (4)
A
- High [H+] attack by protonation of carbonyl oxygen increases dipole moment, allowing weakly nucleophilic water to attack
- Proton transfer from water to the leaving group R2 leads to the cleavage of CR2 bond.
- Electron deficiency at carbo-cation is satisfied by the loss of a hydroxyl proton.
- Example: ester hydrolysis
12
Q
What is base catalysed hydrolysis (4)
A
- High [OH-] direct nucleophilic attack on carbon atom to produce an oxide anion
- Converts back to a carbonyl by the withdrawal of an electron from the C-R2 bond (loss of an R2O- anion)
- R2O- anion picks up a proton from the solution
- For both acid and base catalysed mechanisms, the rate of hydrolysis: Lactam > thioester > ester > amide > imide
13
Q
What functional groups are prone to hydrolysis (5)
A
- Lactam (cyclic amide) - e.g. amoxicillin
- Trioester - e.g. spiranolactone
- Ester - e.g. aspirin
- Amide - e.g. paracetamol
- Imide - e.g. phenytoin
14
Q
What is the importance of hydrolysis (5)
A
- One of the most important degradation processes
- Many drugs feature hydrolysable functional groups.
- Water is commonly used as a vehicle/solvent in production processes.
- Water is ubiquitous in the environment.
- Drugs must be in solution to exert an effect, so they are often water-soluble.
15
Q
How can hydrolysis be prevented (5)
A
- Exclude water from the formulation.
- Remove metal ions - chelating agents are used to remove metal ions.
- Buffer at pHmin(the pH of maximum stability)
- Store at low temperature
- Protect from light
16
Q
What occurs during chelation of metal ions (4)
A
- Metal ions are removed.
- Commonly used chelating agent: Ethylenediamine tetraacetic acid (EDTA)
- Used as the disodium salt to enhance solubility
- Thought to adopt a cage-like configuration when fully ionised - nucleophilic groups bind to the metal ion.
17
Q
What is oxidation (9)
A
- Oxidation is the reaction between the molecule and oxygen.
- Change of bonding within a molecule
- Possible increase in molecular weight
- Often, a change in colour and/or odour
- Increase in the number of bonds to oxygen.
- Decrease in the number of bonds to hydrogen.
- Loss of electrons
- Increase in the valence state.
- Usually, it requires the presence of molecular oxygen or an oxidising agent.
18
Q
What is autoxidation (4)
A
- Oxidation involving molecular oxygen is known as autoxidation.
- Molecular oxygen (O2) has an unpaired triplet electronic configuration in the ground state, which undergoes spontaneous homolytic cleavage to form a molecular oxygen diradical.
- This radical diradical is VERY reactive.
- For autoxidation to be significant, there has to be oxygen and time for the radicals to interact.
19
Q
What are the stages of autoxidation (3)
A
- Initiation – homolytic fission of a covalent bond in the drug molecule. This can be a relatively low-energy process.
- Propagation – free radicals reaction to produce more and more free radicals (cascade)
- Termination – two radicals join to form a covalent bond.
20
Q
How is the stability of radicals from autoxidation described (4)
A
- Radicals are unstable & react immediately to form saturated outer shell orbitals.
- More stable radical = less stable drug
- Radicals are stabilised by resonance around the molecule - the more complex the molecule, the greater the chance of autoxidation.
- Rank order for the stability of radical:
Cyclic > tertiary > secondary > primary
21
Q
What active molecules are prone to oxidation (5)
A
- Promethazine
- Oxetacaine
- Morphine
- Hydrocortisone
- Captopril → captopril disulfide
22
Q
How can oxidation be prevented (4)
A
- Remove oxygen
- Protect from light - Photolytic oxidation is common - use amber or opaque packaging.
- Remove metal ions - use chelating agents (e.g. EDTA) and use high-quality manufacturing equipment.
- Include antioxidants in the formulation.
23
Q
What are antioxidants (6)
A
- Compounds that supply electrons or easily available protons
- They are more readily oxidised than the drug.
- There are 3 types, and they are sulphur compounds.
- Inorganic & Organic antioxidants
- Free-radical scavengers
- Fat-soluble antioxidants
24
Q
What are inorganic antioxidants examples (3)
A
- Sodium sulphite
- Sodium bisulphite
- Sodium metabisulphite
25
Q
What are organic antioxidants examples (3)
A
- Acetylcysteine
- Thiourea
- Glutathione
26
Q
What are free radical scavengers and an example (3)
A
- Antioxidants that easily form free radicals which can react with the oxygen diradical and terminate the oxidation process
- Ascorbic acid is a commonly used antioxidant.
- ascorbic acid → dehydroascorbic acid
27
Q
What can oxidation of fats and oils lead to (6)
A
- Deterioration in performance
- Viscosity, emulgent properties
- Unacceptable aesthetics
- Rancidity, discolouration
- Ascorbic acid & sulphur compounds are not fat-soluble.
- Specialised fat-soluble anti-oxidants are required in oil-based pharmaceuticals.
28
Q
What are fat soluble antioxidants examples (3)
A
- a-Tocopherol
- Butylated hydroxytoluene (BHT)
- Butylatedhydroxyanisole (BHA)
