1 - Stability Flashcards
Define drug stability
extent to which a product retains, which in specified limits and throughout its period of storage and use, the same properties and characteristics it possessed at the time of manufacture
What are the 3 areas of concern when describing drug stability
- chemical (active ingredients retain chemical integrity and potency within limits)
- physical (properties such as dissolution and appearance are retained)
- microbiological (sterility or resistance to microbial growth retained)
(Chemical) - product specifications have limits usually ______% of the label
+- 2-10%
What can physical degradation lead to?
-can lead to reduced bioavailability and reduced efficacy
What does microbiological stability refer to?
basically keeping a product sterile or resisting microbial growth
Describe hydrolysis (chemical degradation)
- decomposition of a drug through a rxn with water
- water acts as a nucleophilic agent and attacks electrophilic sites of drug molecule
What are the most common functional groups involved in hydrolysis?
carboxyl derivatives
- lactams
- esters
- amides
Describe oxidation (chemical degradation)
- often mediated through atmospheric oxygen
- most are free radical and occur spontaneously under ordinary conditions (auto oxidative)
- color/aroma changes seen (oxidative processes are usually more conjugated)
In what solutions/states can oxidation occur in?
- aqueous solution
- non-aqeous solution
- solid state
Oxidation is viewed as ?
- loss of electrons
- loss of hydrogen
- gain of oxygen
Give examples of functional groups subject to oxidation
- phenols
- catechol
- ether
- thiols
- thioether
- aldehyde
Describe photolysis (chemical degradation)
-light provides energy (photon) for initiation of an oxidative process
When electromagnetic radiation absorbed by a molecule the following may occur: (4 things)
1) molecule decomposes with release of free radical
2) energy retained - chemical change
3) energy converted to heat and no reaction occurs
4) absorbing molecules emit light of different wavelength
Dehydration ?
loss of a water molecule
Is dehydration a chemical change?
No - just changes the crystal habit of the drug (pseudo polymorphism) which may result in solubility changes
Formation of a pseudopolymorph may affect _____ due to solubility changes.
It may also affect _____.
bioavailability
stability
Racemization
changes in optical activity may result in very significant changes in biological activity
Can the body metabolize l or d amino acids?
It can only metabolize l-amino acids
Can DXM (dextromethorphan) be dangerous?
not at medically-recommended doses (there are almost no psychoactive effects)
-but at high doses - has euphoric, psychedelic, and dissociative properties
What is the recreational use of DXM referred as?
robo-tripping
Triple Cs
______ is an opioid analgesic
levomethorphan
B-lactam group of penicillins/cephalosporins with amino group of an amino glycoside antibiotic = ???
inactive amide
Drug containing primary amine and one with aldehyde functional group = ???
Schiff’s base
Drug with amine functional group and hydroxyl group of a sugar = ??
Maillard reaction
Polymorphism is a type of ____ degredation
physical
How do polymorphs differ and result in solubility differences?
they differ in crystal structure and crystal energies
Polymorphism may result in an ___ product
unusable
*could result in caking of product
What are 4 examples of physical degradation?
- polymorphism
- vaporization
- aging
- adsorption
Explain vaporization (physical degradation)
- some drugs have high vapour pressure and drug is lost through vaporization
- severe changes in tablet content and uniformity may occur
Explain aging (physical degradation)
- changes can occur in the disintegration/dissolution properties of the formulation
- hardening or softening alters the disintegration/dissolution and bioavailability
Explain adsorption (physical degradation)
drug loss to packaging materials as well as documented in IV solutions in PVC plastic
How are adsorption problems avoided?
-care must be taken in container selection
Define shelf life (t90)
the time when the initial concentration of active drug bas decreased by 10%
Order of a rxn must be determined _____
experimentally
T or F: Expiration dates are usually based on zero or first order kinetics.
true
First order calculations: plot of Log[D] vs time gives a straight line with a slope equal to ?
-K1/2.303
formula for shelf life for first order calculations
t90 = 0.105/k1
units for a first order rate constant ?
t^-1 or 1/time
loss of drug directly ____ to the concentration remaining with respect to time
proportional
t1/2 is ____ for first order calculations
constant
see slide 27 for first order equation
ok
Zero order calculations: plot of concentration vs time is ____ and gives a slop of __
linear
Ko
shelf life formula for zero order calculations
t90 = 0.1[D]o/ko
unit of rate constant for zero order rxns
concentration/time
zero order rxns: loss of drug _____ of concentration and ____ with respect to time
independent
constant
see slide 30 for zero order equation
ok
List factors affecting rxn rate
- temperature
- catalysis
- pH effects
- solvent effects
- solubility effects
Explain how temperature affects rxn rate
rxn rates are proportional to the number of collisions so expect rxn rate to increase with increasing temperature
Explain how a catalyst has increases rate of rxn
a catalyst is a substance which increases rate constant of a rxn but does not change the equilibrium constant
Is a catalyst transformed or consumed?
Neither - it interacts with the reactants to facilitate reaction
A catalyst decreases ??
activation energy
How does pH affect reaction rates?
certain pH’s can be better for certain rxn rates
they can measure rxn rate while changing pH and keeping other variables (temp, ionic strength, and solvent composition) held constant
and then determine what pH indicates the best rxn rate
What do you plot for a pH profile for a first order rxn?
log k vs pH
What do you plot for a pH profile for a zero order rxn?
k vs pH
What kind of pH profiles can you see?
1) V-shaped curve
- seen with non-ionizable substrate subject to hydrolysis
- in this case put rxn at the lowest rxn rate (so it will go the slowest)
2) sigmoid shaped curve
- seen when the drug molecule can undergo acid/base dissociation so this is the typical curve for an ionizable substrate
- we want it buffered somewhere near the tail of the curve see diagram for pic
- we don’t want the rxn to go too fast or too quickly
Always pick the pH that allows the lowest reaction rate
okay man
water miscible solvents that can be added into formulation to solubilize the drug - examples?
- alcohol
- propylene glycol
- glycerol
- polymeric acids (PEG)
increase in solvent polarity ____ the rates when a charge is developed in the activated complex
accelerates
increase in solvent polarity _____ the rates when there less charge in the activated complex
decreases
Give some examples of how you could stabilize drug products
-prepare insoluble salt and formulate it as a suspension
What does reduced solubility in a suspension do?
decreases amount of drug available for rxn
T or F: drug can undergo apparent first order rxn in solution and then when formulated as a suspension, it decomposes through apparent zero order kinetics
true
What are two stabilization strategies?
hydrolysis
oxidation
Drug must be in ____ for hydrolysis to occur
solution
Therefore exclusion of water will ____ the rate
slow
control of ___ allows some control over hydrolysis rate
pH
Storing a product at a ____ temperature may be used to increase product stability
reduced
*note this does not mean freezing - can only freeze a limited amount of drugs
What can’t you freeze?
emulsions
protein drugs
ampicillin
T or F: complexes can accelerate decomposition and some may alter solubility and variability
true
If you have a complex - how can you overcome decomposition?
- can formulate it as a suspension
- this may be a useful tactic since drug will probably degrade through apparent ZERO order kinetics
List 4 ways you can overcome oxidation
1 - protect from light
2 - exclusion of oxygen
3 - addition of antioxidants
4 - control of pH
How can you protect something from light?
- amber glass
- opaque plastics
- foil wrapping on IV infusions
How can you exclude oxygen?
- useful for parental
- purge with inert gas (usually nitrogen) and sealed
How can you add antioxidants?
-inclusion of a chelating agent such as EDTA which will consume trace amounts of metal ions which can function as catalysts (can be useful)
**an antioxidant is a material which is more easily oxidized than the product or free radical inhibitors ??
da fuck man
What is usually a good pH range that will provide no deleterious effect on product and is physiologically acceptable?
3-4
