Drug stability Flashcards
(28 cards)
1
Q
What is instability (5)
A
- A change in the physicochemical properties of a pharmaceutical product, these 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, will react and undergo molecular rearrangement
- Reactivity can have undesirable consequences therefore the molecule is considered to be unstable
3
Q
What are the 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
- 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)
- Creation of dipoles gives rise to nucleophilic attack
10
Q
What happens in nucleophilic attack (2)
A
- A small, negatively charged anion is strongly attracted to the (partially) positively charged carbon atom - satisfies the electronic requirements at the carbon
- To lose the excess electron, the formed anion formed 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 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 withdrawal of an electron from the C-R2 bond (loss of an R2O- anion)
- R2O- anion picks up a proton from 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 are often water-soluble
15
Q
How can hydrolysis be prevented (5)
A
- Exclude water from the formulation
- Remove metal ions - chelating agents 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 number of bonds to oxygen
- Decrease in number of bonds to hydrogen
- Loss of electrons
- Increase in valence state
- Usually requires 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 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 chance of autoxidation
- Rank order for 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), 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
What are organic antioxidants examples (3)
1. Acetylcysteine
2. Thiourea
3. Gluthathione
26
What are free radical scavengers and an example (3)
1. Antioxidants that easily form free radicals which can react with the oxygen diradical and terminate the oxidation process
2. Ascorbic acid is a commonly used antioxidant
3. ascorbic acid → dehydriascrobic acid
27
What can oxidation of fats and oils lead to (6)
1. Deterioration in performance
2. Viscosity, emulgent properties
3. Unacceptable aesthetics
4. Rancidity, discolouration
5. Ascorbic acid & sulphur compounds are not fat-soluble
6. Specialised fat-soluble anti-oxidants are required in oil-based pharmaceuticals
28
What are fat soluble antioxidants examples (3)
1. a-Tocopherol
2. Butylatedhydroxytoluene (BHT)
3. Butylatedhydroxyanisole (BHA)
