Drug stability Flashcards
What is drug stability?
The ability of a pharmaceutical dosage form to remain within established limits of identity,
potency, and purity
Broad categories of drug stability
- Physical
- Microbiological
- Chemical
Why is drug stability important?
Drugs can degrade upon storage
Drugs can inherently degrade at different rates based on their formulation
Drugs can degrade at different rates depending on storage conditions
Drug product:
dosage form in the final formulation intended for marketing
Drug substance
unformulated active drug
Excipient:
Anything other than the drug substance in the dosage form
Shelf-life
The time period during which a drug product is expected to remain within the approved shelf-life specification provided it is stored under listed conditions
Expiration date:
Date listed on the product packaging designating the time prior to which a
drug product is expected to remain within the approved shelf-life specification
Solvolysis
Splitting of molecule by solvent (usually water, hence, hydrolysis
Oxidation
Loss of electrons
Photolysis
Light induced degradation
Dehydration
Loss of water
Epimerization
Conversion of one stereochemical center into another
- Stereroisomers have the same molecular and
structural formula
Hydrolysis
Splitting of a molecule by water
Nucleophile:
“Nucleus loving”
• Likes positively-charged
• Donates electrons to electrophiles
Oxidation reactions
Oxidation is the loss of electrons – Reduction is the gain of electrons
• OILRIG
• For every oxidation, there must be a reduction and vice versa
Photolysis
Photons of light are absorbed by the drug and may cause molecular rearrangement
- The shorter the wavelength, the more energy is present
Energy is inversely proportional to
wavelength
Many drugs degrade upon exposure to light
Functional groups containing double bonds tend to be photolabile, in particular esters and imides
Diastereomers
differ in configuration at a single chiral
center
• Diastereomeric structures are not mirror images of each other
• Have similar, but different physical properties
Tetracycline
Commonly prescribed broad-spectrum antibiotic
• Has a very narrow pH stability (pH 8.2-8.7)
At low pH: At low pH
Epimerizes at low pH to yield 4-epitetracycline which has no antibacterial activity
• Dehydrates to form anhydrotetracycline which has no antibacterial activity
• And does both to form epianhydrotetracycline which is toxic
Physical Stability
- Evaporation of alcohol
- Loss of water
- Saturated solutions can become supersaturated and precipitate
- Emulsions can form biphasic mixture
- Creams can become dry
- Change in product consistency
- Tablets may become hardened – change in dissolution/change in bioavailability
Degradation by microorganisms
Enzymatic processes
• Often a problem in aqueous formulations and those containing natural polymers
Manufacturing side
Raw materials, containers, closures
• Personnel and manufacturing equipment
• Sterilization is often done on containers and some raw materials, but these processes can
negatively impact the final product
Consumer side
Repetitive dosing (ex.-eye drops) • Improper storage
Effects of Drug Instability
- Change in physical appearance
- Change in color, uniformity, odor,
- Change in consumer acceptance
- Change in odor, color, flavor, uniformity
- Change in dissolution/drug release properties
- Possible reduction in bioavailability
- Change in strength of active ingredient
- Loss of labeled strength/potency
- But, could also have unintended activation of prodrugs
- Potential formation of toxic degradants
Which processes are responsible for
elimination?
• B.) Distribution and excretion
The Dark Side of Drug Stability
- Drugs usually lose potency upon storage
- This can be important especially for narrow
therapeutic index drugs
A narrow therapeutic index drug has
a small ratio of plasma drug concentrations where it is toxic relative to where it is effective
Zantac OTC (Ranitidine) recalled
Histamine H2-blocker
• N-nitrosodimethylamine (NMDA) found as a degradation
product
• Probable human carcinogen
• Also found in valsartan, losartan, and irbesartan (angiotensin
II receptor blockers)
• Also recalled 2019
Where is the
histamine H2
receptor primarily
expressed?
GI tract
• Drug (D) reacts with water (W)
to yield degradation products (P)
D + W -> P
A very small concentration of drug [D]
ss lost in a very small amount of time (dt)
• d[D]/dt
As we are losing, not gaining [D], with time
the sign is (-)
• -d[D]/dt
The rate at which drug is lost is proportional
to the concentration of drug and that of water
• -d[D]/dt α [D][W]
• The absolute rate of drug loss is dictated by
a rate constant, k
• -d[D]/dt =-k[D][W]
For intravenous administration:
The drug is injected
• Almost immediately reaches a high concentration
in the plasma
• Then the concentration reduces due to elimination
processes
• Unlike in oral administration, there is no
absorption phase
- first order process
Similarly, for a drug in a container:
The drug is initially at a high concentration
• Then the concentration reduces due to
degradation processes
- zero order process
k (rate constant) dictates the:
rate of elimination (body)
• or rate of degradation (container)
Ke
Constant reflecting the rate of drug elimination to the amount of drug in the body
• Small elimination rate constant, slow elimination from the body
• Large elimination rate constant, fast elimination from the body
• Drug stability: k
Constant reflecting the rate of drug degradation to the amount of drug in the container
• Small rate constant, slow degradation process
• Large rate constant, fast degradation process
Pseudo zero order
A first order reaction that mimics a zero order reaction
Pseudo first order
A second order reaction that mimics a first order reaction
Zero-Order Reactions Proceed
independently of reactant concentration
Rate = Rate constant
-Rate = Rate constant * concentration
- linear
First Order Reactions
• Proceed linearly on the basis on
a single reactant
concentration
Rate = Rate constant * concentration
Some fraction or percentage of the drug is lost per unit
time
- Initial conc. matters
- non-linear and exponential relationship
Half-life (t ½)
Time required for the drug
concentration to decrease by half
-
For zero-order processes, the half-life is
dependent on the concentration
• t½=[D]0/2*k
-It will take more time to reduce higher initial
concentrations by half than lower concentrations
For 1st order processes, half-life is not
dependent on the concentration
• t1/2 = 0.693/k
It will take the same amount of time to reduce
higher initial concentrations by half as it will lower concentrations
We need drug stability studies to:
Establish the shelf-life for a drug product
• Determine proper storage conditions for a drug product
• Identify degradation products that occur during storage
Shelf-life (t90%)
how long it takes to
reach 90% of the original drug concentration
- 90% of drug is left
• For 1st order processes, shelf life is
t90 = 0.105 /k
For zero order, shelf life is
t90%=0.1[D]0 /k
For zero-order processes, like half-life, the
shelf-life is
dependent on the concentration
Pseudo Reaction Order Degradation
- A higher order reaction appears as a lower order reaction
• A first order reaction appears as a zero order reaction
• A second order reaction appears as a first order reaction
Pseudo-zero order: A first order reaction appears to have zero-order kinetics
If the solubility of a drug is exceeded (e.g.-saturated solution), there will be a fixed amount of drug in solution
• The rest remains as excess solid
• Only the drug in solution degrades
• Its concentration in solution is replenished by the pool of solids
• The 1st order degradation rate constant (k1) incorporates the constant concentration into an apparent
degradation constant kapp
Second order reactions:
- Proceed linearly on the basis of two reactant concentrations
- Rate = Rate constant * [concentration1] [concentration2]
Pseudo First Order Degradation
Two reactants, but proceed effectively on the basis of a single
reactant concentration
