W7.1_Drug Stability Flashcards
What is the importance of drug stability to patients and pharmacists?
- Importance to patients: ineffective medicines or toxic by-products from decomposition
- Importance to pharmacists: financial loss if stock expires (after BBD/best before date)
- Drugs require long shelf-life and appropriate storage conditions
Explain the effect of pH in ester hydrolysis. What is the overall reaction called? Describe the process of acid and base catalysed hydrolysis of esters through the diagrams.
Hydrolysis of esters: slow under neutral conditions, but catalysed by acid/base
-> Addition-elimination reaction (overall substitution)
Acid-catalysed hydrolysis of esters (diagram)
Base-catalysed hydrolysis of esters (diagram)
Ex. aspirin (to salicylic acid and ethanoic acid)
What is the purpose of a pH rate profile. Compare the hydrolysis rates of cyclic esters and amides. Refering to the diagram, describe the hydrolysis of cyclic amides.
- pH rate profile -> find most stable pH and decide formulation (free acid/base or salt)
- Hydrolysis of cyclic ester-containing drugs (lactones) (ex. nystatin, clarithromycin)
- Hydrolysis of amides: more stable due to resonance (ex. paracetamol, lidocaine)
- Hydrolysis of cyclic amides
- Beta-lactam ring (in penicillins) makes them less stable
- Due to steric strain in 4-membraned ring -> lactam cleaves into inactive penicilloic acid
What are the ways to minimise hydrolysis (4)?
- More stable formulation forms such as solid (ex. penicillins are powders, pharmacists add water to give a suspension right before sale)
- Formulate medicines at pH where rate of hydrolysis is low (from pH rate profile)
- Store medicines in fridge as low temperatures favours stability
- Store/packaging in airtight container/blister packs to keep out water
What are the susceptible functional groups in free radical oxidation (3)? Describe free radicals and how it can be catalysed (3).
- Susceptible functional groups: phenol group especially catechols (morphine, paracetamol, catecholamines), aromatic amine (prilocaine, primaquine), drug/excipients with unsaturated groups especially alternating double-bonds (ethyl oleate, vitamin A, omega-3 fish oils)
- Free radical: reactive species with an unpaired electron (7 in total) in the second shell
- Catalysed by light, oxygen, metals
Describe the process of free radical oxidation by light, oxygen, and metal. What are their preventing methods (2/2/1)?
Formation by light:
- Absorption of light energy -> cleave a susceptible bond to give radical and H*
- ex. homolytic bond cleavage: R-H -light-> R* + H*
- Prevention: store medicines in blister packs, brown bottles/cardboard cartons to protect from light
Formation by oxygen:
- R* radical from light reacts with O=O to give a reactive peroxide radical (R-O-O)
- Oxidation and degradation of drugs (ex. through autoxidation of polyunsaturated compounds)
- Prevention: store in well-filled/tightly-closed containers, add inert gas (ex. N2) to exclude O2
Formation by metals:
- Transition metals accept an electron and initiate radical formation in drug
- ex. R-H + Fe3+ -> Fe2+ + R + H+
- Prevention: add a metal chelating agent such as ethylenediaminetetraacetate (EDTA)
Explain the pH influence in oxidation of catechol. Describe the special processes of oxidations in aromatic amine and polyunsaturated compounds by referring to the diagrams.
- Oxidation of catechol is more rapid at basic pH through dimer (ex. adrenaline formulated as tartaric acid salt to keep an acidic pH)
- Oxidation of aromatic amines can cause dimer coupling
- Oxidation of polyunsaturated compounds can cause autoxidation reaction (occurs when butter goes rancid/rubber goes brittle)
How can adding antioxidants prevent free radical oxidation?
- Prevention by adding antioxidants: radicals shared across the structure -> forms stabilised radicals that stop the chain reaction -> avoid self-propagation (ex. vitamin C, BHT, vitamin E)
