Drug stability

Question 1

What is instability (5)

Answer 1

1. A change in the physicochemical properties of a pharmaceutical product can be:
2. Chemical changes - in the qualitative or quantitative composition
3. Physical changes
4. Microbiological changes
5. These are secondary effects and may have serious consequences for the patient.

Question 2

What is chemical reactivity (3)

Answer 2

1. The use of functional groups to have the desired biological action
2. Functional groups are chemically very reactive - under certain conditions, they will react and undergo molecular rearrangement.
3. Reactivity can have undesirable consequences; therefore, the molecule is considered unstable.

Question 3

What are the instability causes (4)

Answer 3

1. Light
2. Temperature
3. Moisture
4. Oxygen

Question 4

What happens during temperature instability (3)

Answer 4

1. Activation energy (Ea) is often supplied in the form of heat, which causes a chemical reaction to occur.
2. Greater free energy = more rapid reaction
3. 10 °C increase in temperature can cause a 2–5 fold increase in degradation rate

Question 5

What can be used to determine the temperature and degradation rate (4)

Answer 5

1. The Arrhenius equation is often used to predict the relationship between reaction rate and temperature.
2. In k = In A - Ea/RT
3. Ea (activation energy) can be derived from the slope of the Arrhenius plot.
4. This forms the basis of ‘accelerated stability testing’ (i.e. predicting shelf-life)

Question 6

How does light affect drug stability (4)

Answer 6

1. Some chemical reactions can be initiated by light-photochemical reactions.
2. Photolysis is a reaction initiated by light (e.g. photolytic oxidation, photolytic hydrolysis)
3. Photolysis requires the reactant(s) to absorb a specific wavelength of light.
4. Usually, UV light (more energetic than visible light)

Question 7

How is moisture (water) found in pharmaceutics (3)

Answer 7

1. Deliberately included as a vehicle.
2. A crystalline hydrate within the product
3. Present as a contaminant.

Question 8

What is hydrolysis (3)

Answer 8

1. Hydrolysis is the reaction between a molecule and water - a specific case of solvolysis.
2. Involves cleavage of one or more bonds within the molecule
3. Results in the production of smaller, more polar and more reactive fragments

Question 9

What gives rise to nucleophilic attack (4)

Answer 9

1. A covalent bond between two atoms with unequal electronegativity → unequal sharing of electrons
2. Acyl groups: oxygen is more electronegative than acyl carbon, attracts electrons → creates a dipole
3. A dipole is created whenever carbon is double-bonded to an atom more electronegative than itself, e.g. Nitrogen (dipole is weaker)
4. The creation of dipoles gives rise to nucleophilic attack.

Question 10

What happens in a nucleophilic attack (2)

Answer 10

1. A small, negatively charged anion is strongly attracted to the (partially) positively charged carbon atom - which satisfies the electronic requirements of the carbon.
2. To lose the excess electron, the formed anion breaks the weakest bond to lose the most stable anion (leaving group)

Question 11

What is acid-catalysed hydrolysis (4)

Answer 11

1. High [H+] attack by protonation of carbonyl oxygen increases dipole moment, allowing weakly nucleophilic water to attack
2. Proton transfer from water to the leaving group R2 leads to the cleavage of CR2 bond.
3. Electron deficiency at carbo-cation is satisfied by the loss of a hydroxyl proton.
4. Example: ester hydrolysis

Question 12

What is base catalysed hydrolysis (4)

Answer 12

1. High [OH-] direct nucleophilic attack on carbon atom to produce an oxide anion
2. Converts back to a carbonyl by the withdrawal of an electron from the C-R2 bond (loss of an R2O- anion)
3. R2O- anion picks up a proton from the solution
4. For both acid and base catalysed mechanisms, the rate of hydrolysis: Lactam > thioester > ester > amide > imide

Question 13

What functional groups are prone to hydrolysis (5)

Answer 13

1. Lactam (cyclic amide) - e.g. amoxicillin
2. Trioester - e.g. spiranolactone
3. Ester - e.g. aspirin
4. Amide - e.g. paracetamol
5. Imide - e.g. phenytoin

Question 14

What is the importance of hydrolysis (5)

Answer 14

1. One of the most important degradation processes
2. Many drugs feature hydrolysable functional groups.
3. Water is commonly used as a vehicle/solvent in production processes.
4. Water is ubiquitous in the environment.
5. Drugs must be in solution to exert an effect, so they are often water-soluble.

Question 15

How can hydrolysis be prevented (5)

Answer 15

1. Exclude water from the formulation.
2. Remove metal ions - chelating agents are used to remove metal ions.
3. Buffer at pHmin(the pH of maximum stability)
4. Store at low temperature
5. Protect from light

Question 16

What occurs during chelation of metal ions (4)

Answer 16

1. Metal ions are removed.
2. Commonly used chelating agent: Ethylenediamine tetraacetic acid (EDTA)
3. Used as the disodium salt to enhance solubility
4. Thought to adopt a cage-like configuration when fully ionised - nucleophilic groups bind to the metal ion.

Question 17

What is oxidation (9)

Answer 17

1. Oxidation is the reaction between the molecule and oxygen.
2. Change of bonding within a molecule
3. Possible increase in molecular weight
4. Often, a change in colour and/or odour
5. Increase in the number of bonds to oxygen.
6. Decrease in the number of bonds to hydrogen.
7. Loss of electrons
8. Increase in the valence state.
9. Usually, it requires the presence of molecular oxygen or an oxidising agent.

Question 18

What is autoxidation (4)

Answer 18

1. Oxidation involving molecular oxygen is known as autoxidation.
2. Molecular oxygen (O2) has an unpaired triplet electronic configuration in the ground state, which undergoes spontaneous homolytic cleavage to form a molecular oxygen diradical.
3. This radical diradical is VERY reactive.
4. For autoxidation to be significant, there has to be oxygen and time for the radicals to interact.

Question 19

What are the stages of autoxidation (3)

Answer 19

1. Initiation – homolytic fission of a covalent bond in the drug molecule. This can be a relatively low-energy process.
2. Propagation – free radicals reaction to produce more and more free radicals (cascade)
3. Termination – two radicals join to form a covalent bond.

Question 20

How is the stability of radicals from autoxidation described (4)

Answer 20

1. Radicals are unstable & react immediately to form saturated outer shell orbitals.
2. More stable radical = less stable drug
3. Radicals are stabilised by resonance around the molecule - the more complex the molecule, the greater the chance of autoxidation.
4. Rank order for the stability of radical:
   Cyclic > tertiary > secondary > primary

Question 21

What active molecules are prone to oxidation (5)

Answer 21

1. Promethazine
2. Oxetacaine
3. Morphine
4. Hydrocortisone
5. Captopril → captopril disulfide

Question 22

How can oxidation be prevented (4)

Answer 22

1. Remove oxygen
2. Protect from light - Photolytic oxidation is common - use amber or opaque packaging.
3. Remove metal ions - use chelating agents (e.g. EDTA) and use high-quality manufacturing equipment.
4. Include antioxidants in the formulation.

Question 23

What are antioxidants (6)

Answer 23

1. Compounds that supply electrons or easily available protons
2. They are more readily oxidised than the drug.
3. There are 3 types, and they are sulphur compounds.
4. Inorganic & Organic antioxidants
5. Free-radical scavengers
6. Fat-soluble antioxidants

Question 24

What are inorganic antioxidants examples (3)

Answer 24

1. Sodium sulphite
2. Sodium bisulphite
3. Sodium metabisulphite

Question 25

What are organic antioxidants examples (3)

Answer 25

1. Acetylcysteine
2. Thiourea
3. Glutathione

Question 26

What are free radical scavengers and an example (3)

Answer 26

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 → dehydroascorbic acid

Question 27

What can oxidation of fats and oils lead to (6)

Answer 27

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.

Question 28

What are fat soluble antioxidants examples (3)

Answer 28

1. a-Tocopherol
2. Butylated hydroxytoluene (BHT)
3. Butylatedhydroxyanisole (BHA)