L32B - Molecular (chemical) Basis For Drug Degredation
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What does much of the synthesis require?
Reactive functional groups
What are examples of reactive functional groups?
• acid chloride and aldelhyde • alkyl halide • a,b unsaturated carbonyls (michael acceptors)
What are is drug degredation usually because?
• photolytic degradation • hydrolysis
What is the general principle for photolytic degradation?
Molecule absorbs a photon (IR, visible or UV light) causing the molecule to go from ground to excited state and can then spontaneously decompose or react
What is the photodegredation of chloramphenicol?
Oxidation of the benzylic carbon - benzylic carbons are more reactive than standard alkyl groups
What are various corticosteroid and antimycotics susceptible to?
Photodecomposition
What does photodecomposition affect for pharmacists? And for pharmacologists?
Pharmacist - formulation, storage, etc. Pharmacologist - stability of stock solutions, reliability of combinatorial libraries etc.
What is photolytic degradation as a negative?
Degrades some medicines and could produce toxic products
How is photolytic degradation avoided?
• amber bottles • blister packs • storage of sensitive drugs in the fridge
What is the main issue probably with with photolytic degredation?
Extemporaneously prepared solutions
What do alternatives solutions use to prevent photolytic degredation?
• addative that is able to competitively absorb light • adding physical quencher
What is a quencher?
Compound that causes physical decay of the excited state before decomposition occurs
What is photolytic degredation as a positive?
Can be used to reduce the effect of pharmaceuticals on the environment
What happens to medicines prescribed that are lost? How are they eliminated?
• end up in the waste water system - significant effect on the environment • photo-assisted wastewater treatment methods used to eliminate them
What is the take home messafe for photolytic degredation?
• can be complex with multiple pathways (radical chem) • involves oxidation (+ benzylic oxidation)
What is hydrolytic degradation?
What do you do to minimise hydrolysis of the strained lactam rin of pediatric penicillin suspension?
Aq suspension, needs to bre prepared immediatly before dispensing - kept in the refrigerator
What are not suited to continuous infusion due to reactivity?
Many beta-lactam drugs
What are biologics like? + degredation?
• largelt protein-based • increasingly gene and cellular or carbohydrate based • degradation/modification of peptide backbones and side chains
What are potential problems of biologics?
• large size and complicated structure • hydrolysis of backbone • oxidation of susceptible side chains
What are examples of oxidation of susceptible side chains?
• 2 Cys residues oxidised to form a dishulphibe bond = protein aggregation • ox of methionine to methionine sulfoxide R-SMe -> R-S(O)Me
What is an example of a substance susceptible to photodecomposition? (2)
Natamycin (antifungal) - typical dosage forms are a cream and eye drops - can degrade by up to 50% over 30 min when exposed to light after they are applied
What is susceptible to hydrolytic degradation?
• ester • amide • lactone • lactam