T2 - Week 3 Flashcards
What are the categories of stability within drug development?
- Stability of the drug substance
- Stability of the drug substance in drug product
What is a drug product?
The finished dosage form that contains a drug substance in association with other active or inactive ingredients
What are the identifications of instability?
- Physical
- Chemical
What are indicators of physical instability of a drug?
- Change in physical properties such as color, odor, taste, or texture
- Microbiological instability when a product grows signs of microbial growth (molds)
What are indicators of chemical instability?
The integrity of the chemical structure of the active ingredient is degraded
What might occur with the drug if it has been chemically degraded?
- Loss in efficacy
- Toxicity concerns
- Therapeutic and toxicological instability
What kind of reaction is degradation?
Decomposition
What factors affect the rate of a decomposition reaction?
- Concentration of reactants
- Reaction temperature
- Presence of catalysts
What are catalysts?
Speeds up chemical reaction by lowering activation energy (threshold)
What are the factors that can cause instability of a drug?
- Moisture and water
- Temperature
- Light
- Excipients
- pH of the environment
- Oxygen
What reactions cause water to destabilize the drug in a drug product?
- Hydrolysis
- Isomerization (Racemization)
- Polymerization
What reactions cause temperature to destabilize the drug in a drug product?
- Hydrolysis
- Oxidation
What reactions cause light to destabilize the drug in a drug product?
- Photolysis
- Oxidation
What reactions cause pH to destabilize the drug in a drug product?
- Hydrolysis
- Oxidation
- Isomerization (Racemization)
What reactions cause oxygen to destabilize the drug in a drug product?
Oxidation
What is the most common drug degradation pathway?
Hydrolysis
What is hydrolysis?
When the OH group of a water molecule provides a nucleophile attack with a susceptible functional group on a drug molecule to degrade the drug (typically C=O groups)
What catalyzes hydrolysis?
H+ (acids) and OH- (base)
What are the susceptible functional groups for hydrolysis?
- Esters
- Amides
- Lactone
- Lactam
- Carbamate
What are common drugs that can be effected by hydrolysis?
- Aspirin (ester linkages)
- Penicillins (Lactam ring)
What are methods to control hydrolysis?
- Reduce or eliminate water from formulation
- Control pH with buffers, HCl or NaOH
How do we reduce or eliminate water from a formulation?
- Using co-solvents
- Suspension of drug in a non-aqueous vehicle
- Protection from humidity by applying a waterproof coating
- Supply the drug product in a dry powder for reconstitution
- Suppress degradation by making the drug less soluble
How do we determine what buffer to select from?
- Determine the optimum pH and adjust at which pH the drug is most stable.
- Design buffers based on the pKa, route and compatibility with the other ingredients in the formulation.
What are the storage conditions to prevent hydrolysis?
- Dry environment: 40-60% humidity not in refrigerator
- Low temperature can stabilize liquid dosage forms
How should drugs be packaged to prevent hydrolysis?
Keep in a tightly closed container
What is oxidation?
Involves either the removal of an electropositive atom (hydrogen), radical or electron, or the addition of an electronegative atom (oxygen) or radical
What are the concurrent reactions caused by autooxidation?
- Initiation
- Propagation
- Termination
What functional groups can be degraded by oxidation?
- Aldehydes
- Alcohols
- Phenols
- Sugars
- Alkaloids
- Unsaturated fats and oils
What are example drugs that can be influenced by oxidation?
- Steroids (hydrocortisone)
- Polyunsaturated fatty acids
- Thiamine
- Catecholamines
What are the methods to control oxidation?
- Using chelating agents that trap trace metals from being oxidized
- Using antioxidants
- Replacing air with nitrogen gas or carbon dioxide to remove dissolved O2
- Controlling pH by buffering because most drug oxidized at acidic pH in protonated form
What are examples of antioxidants used for aqueous products?
Sulfites
What are examples of antioxidants used for oleaginous products?
- Alpha-tocopherol
- Ascorbyl palmitate
How do we store drugs prone to oxidation?
Low temperature because activity of metal ions and hydroxyl ions are reduced
How do we package drug prone to oxidation?
- Light resistant or opaque containers cause light can catalyze oxidations
- Solid oral forms have sealed bottles with foil before dispensing
What happens if a drug is degraded by light?
- Loss in potency
- Discoloration
- Formation of precipitate
What causes the photochemical reaction of a drug?
- The wavelength of the incident light is within the range of absorption of the drug so the drug absorbs radiation and degrades
- Absorption of radiation by excipients in the formulation (photo-sensitizers) which transfer the absorbed energy to the drug, causing it to degrade.
How can photodecomposition occur after a drug is applied?
Sunlight can penetrate skin to a certain depth causing photo-degradation of drugs circulating in the surface capillaries or in the eyes of patients receiving the drug
How do we control photolysis?
Coating tablets with vinyl acetate (polymer) containing oxybenzone an UV absorbers reducing discoloration and degradation
How do we package drugs sensitive to photolysis?
- The use of colored glass containers and storage in a dark.
- Amber glass excludes light of wavelength <470 nm and so affords considerable protection of compounds sensitive to ultraviolet light.
What is isomerization/racemization?
The process of conversion of a drug into its optical or geometric isomers
How can isomers affect the probability for degradation?
- Conversions can result in a loss of therapeutic activity due to isomerization/racemization
- Loss of activity of solutions of adrenaline at low pH.
- In acidic conditions, tetracyclines undergo epimerization to toxic epimer.
What are methods of controlling isomerization/racemization?
- Reducing or eliminating water from formulation
- Control pH with buffers, HCl, or NaOH
What is polymerization?
The process by which two or more identical drug molecules combine together to form a complex long-chain molecule
What is an example drug that is effected by polymerization?
Aminopenicillins (ampicillin sodium) in concentrated aqueous solutions
What is the temperature spec for cold?
<8C or <46F
What is the temperature spec for refrigerator?
2-8C or 36-46F
What is the temperature spec for freezer?
-10- -20C or 14- -4F
What is the temperature spec for cool?
8-15C or 46-59F
What is the temperature spec for room temperature?
20-25C or 68-77F
What is drug stability?
The extent to which a product retains, within specified limits, and throughout its period of storage and use the same properties and characteristics that it possessed at the time of its manufacture or compounding
What the keys of pre-formulation studies?
- Solubility analysis
- Dissolution rate
- Stability
- pKa
- Partition coefficient (Log P)
