Section 1 - Drug Stability Flashcards
What is drug stability?
The extent to which a product retains the same properties and characteristics it possessed at the time of manufacture
What does drug stability refer to?
Shelf life
What are the 3 areas of concern with drug stability?
1) Chemical - active ingredients retain chemical integrity and potency
2) Physical - dissolution and appearance are retained
3) Microbiological - sterility or resistance to microbial growth are retained
What can chemical degradation of active ingredients lead to?
- Inaccuracy in dosing
- Possible therapeutic failure
What is the allowed amount of degradation?
2-10%, but tighter control if the degradants are toxic
What can physical degradation lead to?
- Reduced bioavailability
- Reduced efficacy
What can cause physical degradation?
Physicochemical changes to active or excipient ingredients
What are some examples of physicochemical changes that can cause physical degradation?
- Production of polymorphs
- Loss of volatiles
- Dissolution changes from aging
What are some examples of physicochemical changes that don’t affect efficacy, but affect elegance?
- Mottling of tablets
- Caking of suspensions
- Colour changes of solutions
How can products resist microbial growth?
Preservatives, which must retain efficacy over the entire shelf-life
What is hydrolysis?
Decomposition of a drug through a reaction with water
In a hydrolysis reaction, water acts as a _____ and attacks _____
- Nucleophilic agent
- Attacks electrophilic sites of a drug molecule
What are the most common functional groups involved in hydrolysis reactions?
Carboxyl derivatives
Why are penicillins susceptible to hydrolysis?
Because of the steric strain on their 4 membered beta-lactam ring
Oxidation reactions are often mediated through _____
Atmospheric oxygen
What is different about the products of oxidative processes?
They are usually electronically more conjugated, so their colour and scent change
In what types of solutions can oxidation reactions occur?
- Aqueous
- Non-aqueous
- Solid state
Can oxidation reactions cause products to become unfit?
Yes
What are the 3 types of oxidation reactions?
- Loss of electrons
- Loss of hydrogen
- Gain of oxygen
Since oxidation is the loss of electrons, what generally goes along with the loss of electrons?
Change in structure and transfer of protons
What is an autoxidative reaction?
An oxidation reaction that requires a free-radical and occurs spontaneously
What are the 3 steps of an autoxidative reaction and what occurs in each step?
1) Initiation - generation of a free radical
2) Propagation - further release of free radicals
3) Termination - free radicals come together to form a non-radical
What is photolysis?
When light provides the energy for initiation of an oxidative process (although not always oxidative)
What may happen when electromagnetic radiation is absorbed by a molecule?
1) Molecule decomposes with release of free radical
2) Energy is retained, causing a chemical change
3) Energy is converted to heat and no reaction occurs
4) Absorbing molecules emit light of a different wavelength
What are 2 examples of dehydration reactions?
1) Tetracycline -> epidehydrotetracycline
2) Prostaglandin E2 -> prostaglandin A2
Is dehydration a chemical change?
No, it changes the crystal habit of the drug which may result in solubility changes
What can dehydration produce?
Pseudopolymorphs
What are the 5 types of chemical degradation reactions?
1) Hydrolysis
2) Oxidation
3) Photolysis
4) Dehydration
5) Racemization
Polymorphs differ in ______
Crystal structure and crystal energies
Can polymorphs cause a product to be unusable?
Yes, sometimes
What is needed for a drug to be lost through vaporization?
The drug needs a high vapor pressure
What is an example of physical degradation that occurs in tablets?
Hardening or softening, which alters disintegration and bioavailability
What are 4 types of physical degradations?
1) Polymorphism
2) Vaporization
3) Aging
4) Adsorption
What occurs in adsorption?
Drug is lost to packaging materials
Which drug delivery method is most prone to adsorption?
IV
How can adsorption be avoided?
Careful selection of the container
What is t90?
- Shelf life
- The time it takes the initial concentration of the active ingredient to be decreased by 10%
What does the order of the reaction determine?
The shape of the concentration-time profile
What determines the slope of the concentration-time profile?
The rate constant
Which orders of reactions are most common in drug stability?
Zero, first, and second
What is a zero order reaction?
A constant amount of drug is eliminated per unit time; independent of concentration
What is a first order reaction?
The rate of decrease of substrate molecules is proportional to the concentration of substrate molecules remaining
What is a second order reaction?
The overall order of the reaction is the sum of the exponents of the concentration terms
Is it important to make a distinction between the orders of reactions?
No
Which order of kinetics are expiration dates usually based on?
Zero or first
What is the unit for a first order rate constant?
t^-1
What will the slope be of a plot of log[D] vs. time?
-k1 / 2.303
What is constant in a first order reaction?
Half life
What is the shelf life of a zero order reaction equal to?
0.1 [D]o / Ko
What is plotted on the graph for a zero order reaction?
[D] vs. time
What is plotted on the graph for a second order reaction?
1/[D] vs. time
What are 5 factors affecting reaction rate?
1) Temperature
2) Catalysis
3) pH effects
4) Solvent
5) Solubility
What are reaction rates proportional to?
The number of collisions between particles
What will the slope be of a plot of log k against the inverse of absolute temperature?
Slope = -Ea/2.303R
What is the typical range for Ea for drug decomposition reactions?
12-24 Kcal/mol
What are 2 common catalysts of oxidation reactions?
Iron and copper
How can you prevent iron and copper from catalyzing oxidation reactions?
Add something that kelates with them
Reaction rates in aqueous solutions are often dependent on _____
The pH of the solution
What can you learn from studying the pH effects on reaction rates?
- The mechanism
- The stability of the drug
What is plotted on a pH-rate profile?
Rate constant (log k for first order or k for zero order) against pH
When would a V-shaped pH-rate profile be expected?
When the substrate is non-ionizable and is subject to hydrolysis
When would a sigmoid shaped pH-rate profile be expected?
When the drug molecule undergoes an acid/base dissociation (an ionizable substrate)
Do chemically-related compounds generally have similar pH-rate profiles?
Yes
What are the most common solvents used to solubilize a drug?
- Alcohol
- Propylene glycol
- Glycerol
- Polymeric alcohols
Do solvents have a small or large impact on stability?
Large
What impact does solvent polarity have on reaction rate?
- As solvent polarity increases, the rate will increase when there is a charge is developed in the activated complex
- Rate will decrease when there is less charge in the activated complex than the starting materials
- Rate will be unaffected when there is little or no difference in charge between reactants and activated complex
How can solvents change pKa?
By shifting the dissociation equilibrium
How can a drug be stabilized using solubility?
It can be made into an insoluble salt and formulated into a suspension
What does reduced solubility in a suspension mean?
It decreases the amount of drug available for reaction
What is the typical order of reaction for a drug in a solution?
First
What is the typical order of reaction for a drug in suspension?
Zero
What are 2 stabilization strategies?
1) Hydrolysis
2) Oxidation
What is needed for hydrolysis to occur and why?
- Drug must be in solution
- Exclusion of water will slow the rate
How can hydrolysis be achieved?
By formulating the product as a solid dose form (tablet, capsule)
Is total exclusion of water possible?
Not usually
What can allow for control over hydrolysis rate?
Control of pH
Can every drug be frozen?
No, only the ones that show no deleterious effect
What can freezing do to a drug?
- For some, it can increase product stability
- For others, it can increase the rate of degradation (ex: ampicillin)
How can drugs be protected from light?
- Tinted glass
- Opaque plastics
How can oxygen be removed and what is this used for?
- Oxygen is purged with inert gas (usually nitrogen) and sealed
- Used for parenterals
