Exam 4 Flashcards
Why shouldn’t you store medicines in a humid environment?
Water often reacts and degrades drugs.
Why are some drugs stored under nitrogen?
To prevent oxidation
How do elevated temperatures impact stability?
Elevated temperatures enable accelerated breakdown of a drug
A solution drug will be stable only….
- at a given concentration
- for a certain time
- at a certain temperature
- at a certain degree of light exposure
A solid drug will be stable only…
- for a certain time
- at a certain temperature
- at a certain degree of light exposure
Which kind of solutions experience compatibility issues?
solutions with longer infusion times (antibiotics, insulins, some vasopressors)
Which decomposes faster – solutions or solids?
Solutions decompose 10-100 times faster.
Which kinds of drugs are typically refrigerated for longer stability?
IV drugs
Which IV drugs crystalize if kept cold?
furosemide and phenytoin
How are medications supplied to protect from light?
amber vials
What are the possible negative impacts of light exposure?
photodegradation and an increase in toxicity
Which drugs have to be protected from light during administration?
Vitamin K, Nitroprusside, Doxycycline
Define stability:
Stability is the extent to which a product retains the same properties and characteristics throughout its period of storage and use (shelf life)
Which chemical reactions cause drug degredation?
oxidation-reduction, hydrolysis, photolysis
How can oxidation be prevented?
- protection from temperature changes
- control pH with buffers
- light protection
- lower temperatures
- chelating agents
How do chelating agents prevent oxidation?
Chelating agents such as EDTA remove metal ions which can cause oxidation
What is the function of antioxidants?
Antioxidants can remove free radicals produced by oxidation.
Which compounds are likely to by hydrolyzed?
carbonyls, amides, cyclic amides
How can hydrolysis be prevented?
- remove moisture with absorbents
- lyophilization
- non-hygroscopic salts
- control temp
- control pH
What is a hygroscopic salt?
A solid that absorbs water
Define photolysis
Photolysis mean the drug is sensitive to light exposure and react to form new compounds in light
Name 3 drugs that undergo photolysis
vitamin c, nitroprusside, phytonadione injection
List functions of dosage forms:
- provide an accurate dose
- promote drug dissolution
- promote delivery to the site of action
- ensure drug stability
- control drug delivery to the body
- determine dosing interval
What does a carboxylic acid ester produce once it undergoes hydrolysis?
a carboxylic acid and an alcohol
What are the products of the hydrolysis of aspirin under basic conditions?
salicylic acid and acetic acid
What mechanism allows aspirin to be used for preventing strokes?
acetylation of cyclooxygenase
What is a prodrug?
A prodrug is a pharmacologically inactive chemical derivative of a drug.
- Prodrugs are often created to improve the drug’s solubility or absorption
- In the body, the prodrug is converted to the active “parent” drug chemically or enzymatically
How can hydrolysis of ester and lactones be prevented?
- protect from moisture
- protect from heat
- control pH in solution formulations
How can you protect esters and lactones from moisture?
Use solid dosage forms such as tablets and capsules
What is the mechanism of ester and lactone hydrolysis dependent on?
pH
What kind of intermediate does the amide hydrolysis mechanism have?
tetrahedral intermediate
What does the hydrolysis of amides produce?
carboxylic acid and an amine
Which degrades slower: amides or esters?
amides
How can hydrolysis of amides and lactams be prevented?
- protect from moisture
- protect from heat
- control pH in solution formulations
What drugs are amides and lactams commonly found in?
proteins and B-lactam antibiotics
What can promote oxidation?
exposure to oxygen, metal ions, light or heat
What are the two major types of oxidation?
auto-oxidation and chain oxidation (free radical reactions)
Which is slower: chain oxidation or auto-oxidation?
auto-oxidation
Define auto-oxidation
Auto-oxidation is the uncatalyzed oxidation of a drug by molecular oxygen
What are the three reactions that make up chain oxidation?
initiation, propagation, termination
Define initiation for chain oxidation
Generation of free radicals by:
- auto-oxidation
- exposure to heat
- exposure to light
- exposure to metal ions
Define propagation
reaction of free radicals with oxygen or other species, with generation of new free radicals
Define termination
re-combination of free radicals to form stable products
What are the toxicity concerns with hydroquinone?
superoxide and hydroxyl radical (HO.) generated from it
How can oxidation be minimized?
- protecting from air, light, and metals
- excipients added to the formulation
How can oxidation and photolysis be prevented?
- protect from oxygen (nitrogen fill)
- protect from heat
- protect from light
- include anti-oxidants
- include metal chelators
What kind of kinetics describe drug degradation kinetics?
first-order
Define half-life
the time required for the drug concentration to decrease to one-half of its initial value
define shelf-life
the period of time that a drug product maintains its properties within specified limits
Define expiration date
- the end of the shelf-life
- FDA requires expiration dating of all drug products
What is shelf-life based on?
t90
What is t90?
The time for the drug concentration to decrease to 90% of its initial value
What is the common target shelf-life?
two years
What kind of intermediate does the amide hydrolysis mechanism have?
tetrahedral intermediate
What is an example of zero-order kinetics?
- degradation of a drug in suspension
- rate of drug degradation is constant – independent of concentration
What are the stability issues for biologics?
- they tend to be more fragile than small molecule drugs
- biologics are larger than small molecules, so there are more bonds that can break
- biologics can also lose activity if they unfold
- biologics can aggregate
Why is aggregation a stability issue for biologics?
- it can increase or decrease potency
- it leads to increased potential for adverse immune response
List examples of biologics:
- recombinant proteins
- vaccines
- stem cells
- gene therapy
Which are more fragile: protein drugs or small molecule drugs?
Protein drugs tend to be more fragile than small molecule drugs
How do protein drugs degrade?
- chemical degradation
- physical degradation
List characteristics of chemical degradation of protein drugs:
- breaks the correct covalent bonds and forms incorrect ones
- hydrolytic reactions
- oxidation reactions
List characteristics of physical degradation of protein drugs:
- changes protein structure, usually without breaking covalent bonds
- unfolding
- aggregation
What are examples of hydrolytic reactions for chemical protein degradation?
- asparagine deamidation
- peptide bond hydrolysis (clipping)
What are examples of oxidation reactions for chemical protein degradation?
- methionine oxidation
- disulfide bond scrambling
What may be more relevant than solubility alone?
dose solubility volume
The solubility of a drug should be considered together with its dose.
True
How did Amidon define high solubility?
- If the largest human dose is soluble in 250 mL (or less) of water throughout the physiological pH range of 1-8 at 37 C.
What does bioavailability depend on?
- having the drug in solution
- drug’s permeability
What is a high jejunal permeability?
- at lease 2-4 x 10^-4
- corresponds to a fraction absorbed of 90% or better
What drug are enteric polymers used for?
omeprazole
What are characteristics of enteric polymers?
- don’t dissolve in the stomach
- release drug in small intestine
What is a matrix tablet?
a drug embedded in polymer matrix
Describe erosion
the polymer and AED go away at the same time
Describe diffusion
- outer layer of polymers swell to form gel layer
- AED diffuse through gel
Explain how elementary osmotic pumps (EOPs) work?
- drug has osmotic core, semipermeable membrane, and a delivery orifice
- water seeps through membrane to dissolve the drug
- the dissolved drug is slowly released through the delivery orifice throughout the whole day
What makes a double chamber different?
- one chamber holds the drug
- the other chamber swells with water, pushed the drug compartment out
Describe the serum concentration of an immediate release drug:
- the serum concentration levels wavers in and out of the therapeutic range.
- this increases the risk of experiencing adverse effects and toxicity
How does the serum concentration curve of delayed release compare to that of immediate release?
- they have the same shape, but the delayed release curve is shifte to the right since it took time prior to release
How does the serum concentration curve of extended release compare to that of immediate release?
- the extended release curve has a much broader, shorter peak
- stays within the therapeutic range
What was the issue with generic concerta?
It was being substituted for Concerta even though it didn’t have the OROS system.
What is the significance of the dry mouth graph that compares IR to XL?
It shows that extended release products reduce the frequency of patients experiencing adverse effects.
Which group are most pharmaceutical advances in?
Group A - involves incremental tweaking of existing products
What are the categories for the inventive ideation model?
change, copy, combine, separate, convert (with the problem in the center)
What are the primary principles of the Lean Start Up?
- practice makes perfect
- quick and dirty prototype testing
- aim for the minimum viable product
- use customer feedback
Describe disruptive innovation:
- radical changes
- produced by outsiders – not well established leaders
- valued by niche customers
- no one sees it coming – fitbit
What is the increased life expectancy likely due to?
drug development
What is the dip in life expectancy due to?
COVID
Describe the solubility of antiviral drugs?
- anti-viral drugs are typically very insoluble
What is sofosbuvir?
- Sofosbuvir is a prodrug.
- it is converted to the triphosphate and inhibits the NS5B polymerase
One way to improve solubility and bioavailability is to make an amorphous dosage form; how is this done?
melt extrusion
melt extrusion
- melt API and matrix powder
- mix together
- cool and disperse the homogenous mixture
What are two methods to improve solubility and bioavailability?
melt extrusion and spray drying
What is the purpose of abuse-deterrent technologies?
- make product manipulation more difficult
- make abuse of manipulated product less attractive
What are examples of abuse-deterrent technologies?
- improve taper resistance – OxyContin
- incorporate deterrent – Suboxone
How is OxyContin abuse-deterrent?
the new formulation can’t be crushed into powder and it turns into a gel upon trying to dissolve it
What is the function of polyethylene oxide?
- it turns into a gel when water is added
How does PEO work?
PEO forms a net structure with water to produce a gel.
