Stability Flashcards
Define stability
the extent to which a dosage form retains within specific limits, and throughout its period of storage and use, the same properties and characteristics that is possessed at the time of its manufacture
What are some factors affecting drug stability?
Environmental factors:
- temperature
- light
- humidity
- oxygen
- carbon dioxide
Dosage form factors:
- particle size
- pH
- solvent system composition
- compatibility of anions and cations
- primary container
- additives
- molecular binding
- diffusion of drugs and excipients
What are the four reasons you should be concerned about drug stability?
- Ensure that the patient receives the intended drug and dose
- Prevent appearance of contaminants or toxic compounds
- Exclude any decrease in bioavailability as a result of chemical or physical changes in the product
- Eliminate possibility of poor compliance as a result of appearance change to the product
Define shelf-life
The period of time which, if stored correctly, the product is expected to retain acceptable chemical, physical, and microbiological stability
Define expiry/expiration date
The date given on the product packaging which represents the end of the shelf life (expressed as month/year on packaging)
What is the condition for expiration?
On the day of expiry the drug must still retain 90% of its labeled potency
How many expiry dates are given for dry products meant to be reconsituted?
2 → expiration date assigned to both the reconstituted and dry product
What are the different types of stability?
Physical → viscosity, appearance, odour, colour, suspend-ability
Chemical → pH, drug content
Microbiological → sterility, microbial load, preservative effectiveness
Therapeutic → activity, potency
Toxicological → identification of degradation products
What are signs of physical instability for solutions, suspensions, emulsions/creams, ointments, transdermal patches, and nasal aerosols?
Solutions → precipitation of drug or degradation products
Suspensions → caking of sediment, particle reduction
Emulsions/creams → creaming, cracking, reduction in viscosity
ointments → separation of liquid onto surface
Patches → change in drug release rate, change in adhesive characteristics
Nasal aerosols → change in particle size distribution
What is primary evidence of instability in capsules?
Hardening or softening
What are some things that would show evidence of instability of tablets?
Powdering, chipping, mottling, discolouration, and fusion
What are some evidences of instability for powders and granules?
- caking
- colour change
- swelling dur to premature effervescent reaction
What are some evidences of instabilities for lozenges and troches?
- clumping
- tackiness
- discolouration
What are the signs of instability for liquid dosage forms in general and more specifically emulsions and suspensions?
Generally → clarity, precipitation, mold/bacteria growth, odour, and loss of volume
Emulsions → odour, colour change, creaming, coalescence, phase separation and mold/bacteria growth
Suspensions → non-uniformity, settling, caking, crystal growth, mold/bacteria growth, odour, loss of volume
What are some of the ways you can enhance stability of emulsions?
- decrease droplet size (ideally <5um)
- Obtain optimal ratio of oil to water (40-60% product volume)
- increase viscosity of external phase
Which is more susceptible to chemical degradation; solution or suspension?
Solution
What are the pharmacist’s responsibilities according to USP 1191?
- dispense oldest stock first
- store products under recommended conditions
- watch products for evidence of instability
- properly treat and label products that are repackaged, diluted or mixed with other products
- dispense products in proper container closure system
- inform and educate patients concerning proper storage and use of products → how to dispose of expired prescriptions
What is the aim of microbiological stability?
Prevent the presence and growth of pathogenic microorganisms which can spoil product
What is meant by CFU?
Colony-forming unit
What are sources of microbial contamination?
- raw materials, including water
- manufacturing environment
- manufacturing personnel
What are the two means of preventing microbial contamination?
- Sterilization
- Adding preservatives
What are the general considerations regarding preservative selection? (4)
- should be effective against broad spectrum (Gram positive and negative)
- must be soluble at needed concentration
- must not affect safety or efficacy of the product
- must be stable and compatible with other excipient and packing materials
What is usually the most critical parameter for determining shelf life?
Chemical stability → drug content of 90% of theoretical value is the MAXIMUM allowable reduction
What is an overage and when is it possible?
Overage = combating the 10% reduction of theoretical value by adding more drug than required
Only possible where degradation products are non-toxic and dose is not critical
What are the types of degradation reactions? (6)
- hydrolysis
- oxidation
- isomerization
- polymerization
- photo-degradation
- chemical incompatibilities
What are the chemical groups susceptible to hydrolysis? (4)
- esters (aspirin, benzocaine, procaine, atropine, scopolamine)
- amides (lidocaine, acetaminophen)
- lactams (penicillin, cephalosporin)
- lactones (simvastatin)
What are the factors effecting hydrolysis?
- pH
- buffer salts
- ionic strength
- presence of co-solvents
- complexing agents
- surfactants
What is often included in oxidation and what can prevent it?
Oxidation often includes a chain reaction of free radicals
Antioxidants can prevent initiation OR propagation (by forcing termination)
What are the important isomerization processes?
Racemization
Epimerization
How can you help stabilize solvents?
- replacing aqueous solvent with non-aqueous
- solid dosage forms are usually more stable than liquids (dry powder for reconstitution, suspensions)
How can you protect dosage forms from oxygen?
- reduce the size of containers, use single use containers
- add antioxidants (ascorbic acid, BHA, vitamin E)
- Add chelating agents (EDTA or citric acid)
- Sealing container with inert gas
Give 3 examples of chemical incompatibilities
- Transesterfication of methylparaben and sorbitol to form a mixture of esters
- Transesterfication of aspirin with phenylephrine HCl, acetaminophen or with polyethylene glycol
- Lactose and amine drugs can form a glycosyl amine to form a 1-amino-2-keto sugar (Maillard reaction)
Define reaction rate and give the formula
The velocity with which a reactant or reactants undergo chemical change → describes the change in concentration of a drug as a function of time
rate = +/- d[A]/dt
What is the rate of degradation?
Describes a decrease in concentration, rate expression has a negative sign
How can you figure out what the order of reaction is?
order is given by the sum of the powers of the concentration term(s) in the rate expression
What is the relationship between decomposition and concentration in a zero order reaction?
Decomposition or loss of the drug is independent of the concentration of any reactants
d[A]/dt = -k0
What are the units used in a zero order?
Units of mass or concentration/time
What is the difference between the equations for half-life and shelf-life for zero order reactions?
Half-life → t0.5 = 0.5[A0]/k0
Shelf-life → t90% = 0.1[A0]/k0
A drug suspension (125mg/mL) decays according to zero order kinetics with a reaction rate constant of 0.5mg/mL/h.
What is the concentration remaining after 3 days?
What is the half life?
3 days → 89 mg/mL
Half-life → 125 hours
What is the relationship between concentration and decomposition in a first order reaction?
Which units are used?
Decomposition or loss of drug is directly proportional to the concentration of the reacting substance
units: 1/time or inverted time
What is the between the reactions for half-life and shelf-life in first order reactions?
Half life → t0.5 = -ln0.5/k1 = 0.693/k1
Shelf-life → t0.9 = -ln0.9/k1 = 0.105/k1
An ophthalmic solution of a drug, present at 5 mg/mL exhibits first order degradation with a rate constant of 0.0005/day.
How much drug remains after 120 days?
What is the half life?
after 120 days → 4.71 mg/mL
Half-life → 1386 days
What is a pseudo-zero order reaction and how is this acheived?
Suspensions often display kinetics that appear to be zero order but are actually first order
Solid suspended in drug has zero order
When the drug starts to dissolve, the solution degrades by first order
What happens when drug concentration exceeds solubility?
you have a zero order reaction
An aqueous solution of drug X contains 200mg of drug per 5mL. The solubility of drug at 25 degrees is 1g/350mL in water and the first order rate constant for degradation at that temperature is 3.9 x 10-6 sec-1.
What is the zero order rate constant?
What is the shelf-life of the suspension?
Rate constant → 1.11 x 10^(-8) g/mL sec-1
Shelf-life → 4.2 days
What is the Arrhenius equation and what is it used for?
Allows for the calculation or rate constants at various temperatures based on the activation energy for the reaction
k = Ae-Ea/RT
A new cancer drug exhibits 1st order degradation kinetics with a rate constant of 0.0001/hr at 60 degrees and 0.0009 at 80 degrees.
What is it’s activation energy?
25.6 Kcal/mol
What is the Q10 shelf-life estimation and what can it be used for?
Based upon activation energy rather than reaction order
Q10 = (kT + 10)/ kT
What are the Q10 values and their activation energy corresponding to possible, likely and conservative?
Possible → Q10 = 2, Ea = 12.2
Likely → Q10 = 3, Ea = 19.4
Conservative → Q10 = 4, Ea = 24.5
How do we estimate shelf-life decreases at different temperatures?
t90 (T2) = (t90 x T1)/ Q10(delta T)/10
An antibiotic has a shelf life of 48 hours at 5 degrees.
What is the estimated shelf life at room temperature of 25 degrees? (set Q10 = 3)
5.33 hours
What is the purpose of stability testing?
Provide evidence on how the quality of a drug substance/product varies with time under the influence of a variety of environmental factors like temperature, light and humidity
AND to establish a retest period for the drug substance or shelf-life and recommended storage conditions
What is the statement from the International Conference on Harmonization on stability testing?
Establishes the sent of criterial including methods of assessment that a drug substance/product must conform to in order to be acceptable for use
What is involved in stability testing during product development phase?
Formulator designs the stability studies to predict or establish the shelf-life and storage conditions for future batches
What is involved in step 1 of stability testing?
Step 1: stability of drug SUBSTANCE
- analytical and/or biological method development for accessing stability
- determination or degradation products
- mechanism of drug breakdown and conditions under which it breaks down
What is involved in step 2 of stability testing?
Step 2: Stability of drug PRODUCT
- design long-term stability studies based on drug substance stability data
- storage of product at normal and accelerated conditions
- preparation of lab scale batches
- storage in proposed packaging
- compatibility studies with excipients
- elimination of excipients that could induce degradation
What is involved in step 3 of stability testing?
Step 3: Stability of LARGE SCALE batches
- development of stability protocol
- large scale batch is representative of 1/10th of a commercial scale batch
- batches are prepared in a similar fashion using similar excipients, methods and equipment
- tested using well established analytical or biological methods to pre-determine specifications
- detailed statistical analysis performed on each batch to determine shelf life and degree of variability between batches
What is involved in step 4 of stability testing?
Step 4: Stability of COMMERCIAL batches
- AIM: determine that each unit dose/package from every batch should remain within specification limits during shelf-life
- stability program is designed and implemented based on information obtained during stability testing
- frequency of testing of commercial scale batches over their shelf-life is usually less than for large scale batches used to determine shelf-life
What are the considerations when assigning a beyond-use date?
- nature of the drug and it’s degradation mechanism
- dosage form and it’s components
- potential for microbial proliferation
- container it’s packaged in
- expected storage conditions
- intended duration of therapy
