1 Stability

Question 1

What is drug stability?

Answer 1

The extent to which a product retains, within specified limits and throughout its period of storage and use, the same properties and characteristics it possessed at the time of manufacture. Shelf Life

Question 2

What are the three stability areas of concern?

Answer 2

Chemical, physical and microbiological

Question 3

What are the chemical stability concerns?

Answer 3

That the active ingredients retain chemical integrity and potency within limits.
Degradation leads to inaccuracy in dosing and possible therapeutic failure.
Limits are usually within 2-10% of label. Tighter restrictions if degradants are toxic like tetracycline.

Question 4

What are the physical stability concerns?

Answer 4

Properties like appearance, palatability, uniformity and dissolution are retained.
May lead to reduced bioavailability and reduced efficacy due to physicochemical changes to the active ingredient or exipients.
Polymorphs and loss of volatiles, hardening (dissolution affected). Mottling, caking or colour change may not affect efficacy but elegance and patient confidence.

Question 5

What are the microbiological stability concerns?

Answer 5

Sterility or resistance to microbial growth is retained according to the product specifications.
Preservatives used must retain their efficacy over their entire shelf life.

Question 6

How do classical chemical kinetic principles of degradation compare to pharmaceuticals?

Answer 6

The opposite of the conditions that optimize chemical reactions is done to products (low concentrations, room temperature and pH 7.0)
Pharmaceutical decomposition may take months or years while reactions take minutes to hours.
Range of reactions in products is much than what would be found in chemistry.

Question 7

What is hydrolysis?

Answer 7

The decomposition of drug through a reaction with water.
Water acts as a nucleophilic agent and attacks the electrophilic sites.
Carboxyl derivatives (lactams, esters, amides)

Question 8

What can affect the rate of hydrolysis?

Answer 8

Unstable molecules can increase the rate. More rings=more stable
Other functional groups can affect the stability of the carboxyl group due to inductive, resonance, steric or H bonding effects.

Question 9

What are some drugs that contain functional groups that are subject to hydrolysis?

Answer 9

Acetaminophen (amide), Penicillin (lactam), Atropine (ester), Warfarin (lactone), Erythromycin (acetal), Diazepam (imine)

Question 10

What is oxidation?

Answer 10

The decomposition of drug that is often mediated through atmospheric oxygen. Loss of electrons, loss of hydrogen or gain of oxygen.
Can occur in aqueous and non-aqueous solution and solid state.

Question 11

What does autoxidative mean?

Answer 11

When decomposition is free radical and oxidation occurs spontaneously under ordinary conditions.

Question 12

What do the products of oxidation look like?

Answer 12

Products are usually more electronically conjugated so colour/aroma change is seen.
A product may be unfit even though only a small part is decomposed.

Question 13

What are some drugs that are subject to oxidation?

Answer 13

Steroids (phenols), Isoproterenol (catechol), PEG (ether), Methimazole (thiols), Chlorpromazine (thioether) and Paraldehyde (aldehyde)

Question 14

What are redox reactions?

Answer 14

Oxidation/reduction reactions. Electron transfer processes where oxidation is a loss of electrons.

Question 15

What are the steps of autoxidation?

Answer 15

Initiation, which generates a free radical.
Propagation, where hydroperoxide formation occurs with further release of free radicals.
Termination, where two free radicals combine to form a non-radical or combine with an inhibitor.

Question 16

What is photolysis?

Answer 16

Light provides energy (photon) for initiation of the oxidative process.
Can cause molecule to decompose with release of free radical, energy be retained with a chemical change, energy be converted to heat so no reaction or absorbing molecule emits light of a different wavelength.
Shorter wavelengths have more energy so more energy, higher reaction probability.

Question 17

What is dehydration?

Answer 17

Decomposition of a drug by the loss of water. No chemical change. Changes the crystal habit of the drug (pseudopolymorphism) which may affect solubility, stability and bioavailability.
Tetracycline, prostaglandin E2, hydrates

Question 18

What is racemization?

Answer 18

A change in optical activity. Isomers.

Body can only metabolize l-amino acids. d-isomer is metabolized to bicarbonate instead of glycogen

Question 19

Whats is an example of racemization in drugs?

Answer 19

Dextromethorphan (D) is a cough suppressant that has almost no psychoactive effects at medically recommended doses. Has euphoric, psychedelic properties in high doses.
The L iosomer is an opioid analgesic.

Question 20

What are some miscellaneous forms of chemical degradation?

Answer 20

Hydration, decarboxylation, additions and Schiff’s base formation.
Some form the basis for various drug incompatibilities and instability when drugs are mixed together (admixtures).
Penicillins/cephalosporins with an aminoglycoside antibiotic form an inactive amide.

Question 21

What is a Schiff’s Base?

Answer 21

A drug containing primary amine and one with aldehyde.

Question 22

What is a Maillard reaction?

Answer 22

A drug with an amide functional group and hydroxyl group of a sugar.

Question 23

What is polymorphism?

Answer 23

Polymorphs differ in crystal structure and crystal energies which results in solubility differences and unusable product.
Conversion of soluble polymorph to stable polymorph causes caking.

Question 24

What is vaporization?

Answer 24

Drugs that possess high vapour pressure can be lost through vapourization every time the container is opened.
Changes in tablet content and uniformity may occur.

Question 25

What is aging?

Answer 25

Hardening or softening alters disintegration/ dissolution and bioavailability.

Question 26

What is adsorption?

Answer 26

Drug loss due to packaging materials. Partitioning (nitroglycerin).
IV solutions in PVC plastic, diazepam, insulin, hydralazine.

Question 27

What is shelf life and how is it determined?

Answer 27

General principles of chemical kinetics are used.
Shelf life (t90) is the time when the initial concentration of active ingredient has decreased by 10%.

Question 28

What is the order of a reaction?

Answer 28

Order determines the shape of the concentration-time profile. The rate constant determines its slope.
Concentration change is small so distinction between orders is unimportant.
Zero has constant slope.

Question 29

What is a first order reaction?

Answer 29

Loss of drug is directly proportional to the concentration remaining with respect to time (t1/2)
shelf life=0.105/k1
unit for rate constant is 1/time
Linear when log is taken

Question 30

What is a zero order reaction?

Answer 30

Loss of drug is independent of concentration and constant with respect to time.
Linear slope
shelf life=0.1[D]/k
Rate constant unit is concentration/time
[D]=-kt+[D]0

Question 31

How does temperature affect reaction rate?

Answer 31

Reaction rates are proportional to the number of collisions and temperature.
k=A(e)^(-Ea/RT)
Ea is usually 12-24 Kcal/mol for drug decomposition reactions.

Question 32

How do catalysts affect reaction rate?

Answer 32

They increase the rate constant of a reaction, but not the equilibrium constant. Lowers activation energy. Interact with the reactants to facilitate reaction.

Question 33

How does pH affect reaction rate?

Answer 33

Varies between drug. Must be found experimentally.

Plots are rate constant as a function of pH.

Question 34

What are the different types of pH curves?

Answer 34

V-Shaped Curve, which is seen with non-ionizable substrate subject to hydrolysis.
Sigmoid-Shaped Curve, which is seen with a drug that can undergo acid/base dissociation. Ionizable substrate.

Question 35

How does solvent affect reaction rate?

Answer 35

Water miscible solvents may be needed to solubilize drug. Significant effects on stability but complex and difficult to predict.
Alcohol, PEG, propylene glycol.
Increased solvent polarity increases rates, decreases rates when there is less charge, may affect pKa

Question 36

How does solubility affect reaction rate?

Answer 36

Reduced solubility decreases the amount of drug available for reaction.
When in solution a drug may undergo first order reaction but as a suspension it may undergo zero order kinetics.

Question 37

How can we slow the rate of hydrolysis?

Answer 37

Exclusion of water by formulating as a solid dose form.
Buffer pH to a place where reaction rate is a minimum. (may not always be possible as solubility may reduced so a cosolvent may need to be included).
Storing at a reduced temperature (not freezing).
Changes in solvent composition.
Formation of complexes maybe
Formulation as a suspension since drug will probably degrade through apparent zero order kinetics.