Drug stability Flashcards
Why is drug stability important and who is it important to?
Patient - if drug decomposes, it could be toxic and/or not work
Pharmacist - financial loss if stock degrades
Example drugs where hydrolysis of esters can happen?
aspirin, procaine, benzocaine
Cyclic esters (lactones) drugs include
Warfarin, Nystatin, Digoxin, Digitoxin
Example of a thioester
Spironolactone
How does ester hydrolysis occur?
OH from water replaces the ester group
Slow hydrolysis under neutral conditions
Acid or base catalysed
By what mechanism does base-catalysed hydrolysis of esters occur?
addition-elimination
Storage of ester-containing drugs?
Store in an air-tight container to prevent moisture access
Amide drug examples
Nicotinamide, paracetamol, procainamide
Carbamate drug examples
Carbochol, Neostigmine, Carbimazole
Which is more stable to hydrolysis, carbamates or esters? Why? Any exceptions?
Carbamates as resonance of the C=O of an amide is less susceptible to nucleophilic attack.
BUT
the 4-membered cyclic amide (beta lactam ring) in penicillins is susceptible to hydrolysis due to the steric strain within the ring
The lactam cleaves to inactive penicillinoic acid
Penicillin storage
Stored as powders. Pharmacist must add water as appropriate. Patient requested to store in fridge to minimise hydrolysis.
Free radical oxidation is a problem for what kind of drugs?
- Phenolic drugs, especially the catechol group
- Aromatic amines
- unsaturated aliphatic compounds
Name some phenolic drugs
morphine, paracetamol, catecholamines (adrenaline)
Name some aromatic amine drugs
procaine or benzocaine
Name some unsaturated aliphatic compounds
oils, fats, ethyl oleate, protriptyline, vitamin A
free radical oxidation of catechol is more rapid at
high pH
Free radical oxidation of unsaturated aliphatic compounds occurs…
-when butter goes rancid
-rubber goes brittle
it is an autooxidation reaction
Formation of free radicals via light
absorption of light energy can promote the electrons in a bond to an “excited state” generating radicals.
Homolytic radicals
Sunlight is capable of
causing decomposition in organic compounds with susceptible functional groups
Prevention of free radical formation via light
store medicines in foil packaging or brown bottles to protect from light
How are free radicals formed by metals?
Transition metals can accept an electron and initiate radical formation
e.g.
Fe3+ +e- —> Fe2+
-C-H- + Fe3+ + electron —> Fe2+ + -C- + -H-
How do you prevent free radical formation via metals?
Add a chelating agent eg EDTA
How are free radicals formed by oxygen?
in the present of light, oxygen forms peroxide radicals that give rise to oxidation and regradation of medicines
How to prevent free radical formation via oxygen?
- Exclude oxygen
- store medicines in well-filled, well-closed containers
- add another gas e.g. nitrogen
- trap radicals with an antioxidant e..g vitamin c (ascorbic acid)
Give 3 examples of antioxidants
Vitamin C (ascorbic acid) BHT (butylated hydroxytoluene) Vitamin E (alpha-tocopherol)
