PDD 04 and 05: Stability of Dosage Forms Flashcards
What is pharmaceutical stability?
extent to which a product retains the same properties and characteristics that it possessed at the time of manufacture
- product is deemed stable if it remains within its specified limits throughout its intended period of storage and use
What are the 3 components of pharmaceutical stability?
- physical components
- chemical components
- microbiological components
(all components of stability are to be retained within the specified shelf life)
What are the physical components of pharmaceutical stability?
physical properties and appearance
Describe the physical instability of emulsions.
- coalescence
- flocculation
- creaming
- breaking
Describe the physical instability of tablets.
- capping
- chipping
- cracking
Describe the physical instability of capsules.
- cracking
- tackiness
- mottling of coatings
- hardening or softening of shell
What are the chemical components of pharmaceutical stability?
active ingredient retains its chemical integrity and potency
- ie. chemical instability of acetaminophen
What are the microbiological components of pharmaceutical stability?
sterility or resistance to microbiological growth
- ie. microbiological instability of emulsions
What are the factors that influence pharmaceutical stability? (5)
- nature of active ingredients and excipients
- interaction between drug and excipients
- manufacturing process – heat, moisture
- packaging
- storage (environment and time) and handling
What two characteristics define the stability of a pharmaceutical product?
- specifications
- shelf life
What are specifications?
tests → analytical methods → acceptance criteria (depending on each product)
- ie. active ingredient content → HPLC → > 90% of labeled dose
- ie. impurity content → HPLC → < 2% of total dose
- ie. appearance → eye examination → clear colourless solution
What is shelf life?
time interval that a product is expected to remain within approved specifications
How can pharmacists help ensure product stability? (5)
- observe expiration dates and rotate stock
- store under recommended conditions
- observe for evidence of instability
- proper treatment of products subject to additional manipulation – repackaging, dilution or reconstitution, preparation of parenteral products
- patient education
What are the 3 major types of chemical instability?
hydrolysis > oxidation > photolysis
What is hydrolysis?
mediated by water and could be promoted at certain pH values
- susceptible groups include lactams, esters, and amides
What is oxidation?
often mediated through reaction with atmospheric oxygen
- often initiated by trace amounts of impurities
- ie. Cu ions increases vitamin C oxidation by 10,000x
- ie. hydroperoxides in PEG-based suppositories oxidizes codeine to codeine-N-oxide
What is photolysis?
absorption of light with energy sufficient to achieve activation and degradation of the molecule
- molecules containing bonds absorb light – aromatic hydrocarbons, aldehydes, ketones
- degradation can occur under sunlight or room light depending on the absorption spectrum
What are the 3 stabilization methods used to protect drug products from hydrolysis, oxidation and photolysis?
- pharmaceutical packages
- storage conditions
- drug formulation
How can pharmaceutical packages help with stabilization to protect drug products from hydrolysis, oxidation and photolysis? (3)
- blister – reduce air contact
- orange vials – protect from light
- absorbing pack – decrease moisture
How can storage conditions help with stabilization to protect drug products from hydrolysis, oxidation and photolysis?
avoid moisture, light, and high temperature
How can drug formulation help with stabilization to protect drug products from hydrolysis, oxidation and photolysis? (3)
- antioxidants
- chelating agents (ie. to remove metal ions that promote oxidation)
- free radical terminators (BHA, BHT)
What is the law of mass action?
rate of reaction is proportional to product of molar concentration of reactants each to the power of moles of the substance undergoing reaction
- A + B → C + D
- rate ∝ [A]^1 [B]^1
What parameter are we interested in with drug degradation?
loss of reactant (drug A)
What is the order of reaction
sum of powers to which the reactant concentrations are raised in the rate expression (for simple single step reactions)
What is a zero order reaction (pseudo zero order reaction)?
one of the most common orders of reaction in drug stability
- units for k0: concentration/time
- rate of reaction is independent of reactant concentration – therefore rate equation does not contain a concentration term
What is a first order reaction (pseudo first order reaction)?
one of the most common orders of reaction in drug stability
- units for k: 1/time
What is a second order reaction?
sum of powers = 2
Where do pseudo (or apparent) zero order reactions occur?
in suspensions
- because there is excess drug in solid form, which can replace the drug in solution that degrades, drug concentration in solution is constant (until all solid is gone)
What order is a general drug degradation reaction where A is a drug in solution?
first order
What is half-life (t1/2)?
time required for drug concentration to become half (50%) of original concentration
What is shelf life?
time to reach a certain percent of the labelled claim – typically 90-95%
- for pharmaceuticals, acceptable shelf life is never < 90% of original value
Why is the stability of a suspension better than a solution for a given drug?
as temperature increases, number of molecules with sufficient energy to react increases
- Arrhenius demonstrated that reaction rate constant has an exponential dependence on temperature
Arrhenius Equation
- k: rate constant
- Ea: activation energy (cal/mol or J/mol)
- T: absolute temperature (K)
- R: gas constant (J/mol/K or other units)
- A: frequency factor (related to number of collisions)
What is the accelerated stability study?
- designed to increase rate of chemical degradation or physical change of a drug substance or product by using exaggerated storage conditions
- used to support tentative expiration dates in the event that full shelf-life studies are not available
