Drug stability

Question 1

Why is drug stability important and who is it important to?

Answer 1

Patient - if drug decomposes, it could be toxic and/or not work
Pharmacist - financial loss if stock degrades

Question 2

Example drugs where hydrolysis of esters can happen?

Answer 2

aspirin, procaine, benzocaine

Question 3

Cyclic esters (lactones) drugs include

Answer 3

Warfarin, Nystatin, Digoxin, Digitoxin

Question 4

Example of a thioester

Answer 4

Spironolactone

Question 5

How does ester hydrolysis occur?

Answer 5

OH from water replaces the ester group
Slow hydrolysis under neutral conditions
Acid or base catalysed

Question 6

By what mechanism does base-catalysed hydrolysis of esters occur?

Answer 6

addition-elimination

Question 7

Storage of ester-containing drugs?

Answer 7

Store in an air-tight container to prevent moisture access

Question 8

Amide drug examples

Answer 8

Nicotinamide, paracetamol, procainamide

Question 9

Carbamate drug examples

Answer 9

Carbochol, Neostigmine, Carbimazole

Question 10

Which is more stable to hydrolysis, carbamates or esters? Why? Any exceptions?

Answer 10

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

Question 11

Penicillin storage

Answer 11

Stored as powders. Pharmacist must add water as appropriate. Patient requested to store in fridge to minimise hydrolysis.

Question 12

Free radical oxidation is a problem for what kind of drugs?

Answer 12

• Phenolic drugs, especially the catechol group
• Aromatic amines
• unsaturated aliphatic compounds

Question 13

Name some phenolic drugs

Answer 13

morphine, paracetamol, catecholamines (adrenaline)

Question 14

Name some aromatic amine drugs

Answer 14

procaine or benzocaine

Question 15

Name some unsaturated aliphatic compounds

Answer 15

oils, fats, ethyl oleate, protriptyline, vitamin A

Question 16

free radical oxidation of catechol is more rapid at

Answer 16

high pH

Question 17

Free radical oxidation of unsaturated aliphatic compounds occurs…

Answer 17

-when butter goes rancid
-rubber goes brittle
it is an autooxidation reaction

Question 18

Formation of free radicals via light

Answer 18

absorption of light energy can promote the electrons in a bond to an “excited state” generating radicals.
Homolytic radicals

Question 19

Sunlight is capable of

Answer 19

causing decomposition in organic compounds with susceptible functional groups

Question 20

Prevention of free radical formation via light

Answer 20

store medicines in foil packaging or brown bottles to protect from light

Question 21

How are free radicals formed by metals?

Answer 21

Transition metals can accept an electron and initiate radical formation
e.g.
Fe3+ +e- —> Fe2+
-C-H- + Fe3+ + electron —> Fe2+ + -C- + -H-

Question 22

How do you prevent free radical formation via metals?

Answer 22

Add a chelating agent eg EDTA

Question 23

How are free radicals formed by oxygen?

Answer 23

in the present of light, oxygen forms peroxide radicals that give rise to oxidation and regradation of medicines

Question 24

How to prevent free radical formation via oxygen?

Answer 24

• 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)

Question 25

Give 3 examples of antioxidants

Answer 25

Vitamin C (ascorbic acid)
BHT (butylated hydroxytoluene)
Vitamin E (alpha-tocopherol)