Drug Properties, Physiochemical Incompatibilities and Stability Flashcards
drug properties are physical characteristics that can alter ___
bioavailability
define solubility
the max amount of substance that can dissolve in a given amount of solvent @ a specified temp and pressure
what is the word used when two liquid dissolve in each other
miscible
what is the word used when two liquids do not dissolve in each other?
immiscible
give an example of 2 liquids that are miscible
water and ethanol
give an example of 2 liquids that are not miscible
water and oil
explain why aqueous solubility is important for drugs
b/c drugs can only be absorbed into the bloodstream in the aq (dissolved) form
could a drug still have the desired effect if it didn’t dissolve in aq?
no
what are the 2 main ways to measure solubility?
quantitative and qualitative
what are the 6 factors that affect solubility?
- temperature
- solvent pH and solute Pka
- presence of other solutes
- chemical structure
- surface area
- melting/boiling point
the solubility of inorganic electrolytes depends on their __ properties and their interactions between their
ions with __ through a process called __
crystal; water; hydration
what needs tone overcome during hydration for ions to break free of their lattice structure and dissolve?
the heat of hydration needs to be high enough
salts that increase the solubility of a drug are called
salt-in
salts that decrease the solubility of a drug are called
salt-out
the effects of additives on drug solubility depend on its interactions with what 3 things?
water, the solute (drug) and the solvent
how can different functional groups influence solubility?
by affecting the molecular cohesion/interaction with water
polar FG groups ___ (raise/lower) solubility of solute. How?
raise; by forming H bonds with the water
non-polar groups ___ (raise/lower) solubility of solute
lower
ionization of a FG ___ (raises/lowers) solubility
raises
why does ionization of a FG raise solubility?
charged groups are more polar and therefor more hydrophilic and soluble in water
list the FG position of otrtho, meta, para in order from least to most soluble in water
para; ortho; meta
effect of pH is crucial to drugs with __ groups
ionizable
acidic drugs are more soluble in __ solutions and less soluble in __ solutions
basic; acidic
give an example of an acidic drug
NSAIDs
basic drugs are more soluble in __ solutions and less soluble in __ solutions
acidic; basic
why does surface area affect solubility?
b/c placing a solute molecule in the solvent requires solute-solvent contact points
a larger surface area means a ___ (higher/lower) solubility
higher
why does larger surface area result in greater solubility?
larger cavity required, more contact points made, making it easier for the solvent to dissolve the solute
the melting point of solids and the boiling point of liquids reflects what?
the strength of the interactions between the molecules in the compound
As melting and boiling points increase, what happens to solubility?
decreases
drug partition between 2 immiscible solvents is based on __ solubility
affinity
the partition coefficient (logP) measures what?
the spreading of solute between the aq and organs phases of an immiscible mixture
the P in the partition coefficient is represented by the rate of ___ over __
solubility in organic over solubility on aqueous
drug incompatibilities arise when __
a drug is mixed with other drugs/products and the result is unsuitable products
drug incompatibilities can result in the alteration of physical and chemical __ and the ___ of the active drug
structures; therapeutic effect
what are 2 potential concerns if a drug incompatibility causes a change in the chemical/physical structure of the drug?
reduced solubility and/or stability
during which steps of the drug making process can incompatibilities occur?
preparation, storage, Administration
what are the types of interactions that can happen in drug incompatibilities? (3)
- pharmacological / pharmacodynamics
- pharmacokinetic
- physiochemical
physiochemical interactions could involve an interactions with one/more of what 4 factors?
- other drugs
- solvents
- inactive materials (excipients)
- devices and packaging
what is poly pharmacy?
the concurrent use of multiple medications (all to treat one disease)
what are the 3 types of drug incompatibilities?
- physical (pharmaceutical)
- chemical
- therapeutic
what types of products are made by physical drug incompatibilities?
non-uniform, unacceptable, or unpalatable products
what is a dosing issue relative to physical incompatibilities?
the non-uniformity makes it difficult to accurately measure
what type of drug incompatibility can result in insolubility, immiscibility, precipitation, liquefaction, adsorption, and complexation of materials?
physical (pharmaceutical)
physical drug incompatibilities are preventable using __
pharmaceutical skills
chemical drug incompatibilities are due to chemical interactions involving the __
active ingredient
If an active ingredient is involved in one of the following reactions: hydrolysis, polymerization, effervescence, oxidation, decomposition, precipitation, what sort of drug incompatibility can arise?
chemical
a drug incompatibility that occurs immediately after compounding is called __
immediate
a drug incompatibility that occurs later on after compounding is called __
delayed
a therapeutic drug incompatibility occurs when
the prescribers intended purpose does not math the therapeutic outcome
what are the 2 classes of drug incompatibility prevention?
chemical and physical
what are the six methods of prevention against physical incompatibilities?
- sequence of mxing
- change solvents
- change AI type/form
- change volume
- emulsification and addition of suspension agents
- addition, replacement, or removal of unnecessary ingredients
low solubility can result in crystallization. The mechanism of drug crystallization is often involves what factor?
pH
some IV drugs are unable to be safely mixed due to __
drug crystallization
pH of commercially available infusion fluids can vary between __ to ___ pH units. What is the issue with this?
1-2; pH is measured on a log scale, so 1-2 units is actually a big difference, so the drug. may be compatible with 1 batch, but not another
what is a common solubility issue associated with pH
crystallization
how can the mixing of drugs be done more safely with respect to concerns of pH affecting solubility?
using equations that relate pka to solubility to predict the solubility
what are the 7 causes of drug incompatibilities?
- pH change
- alteration of solvent characteristics
- cation–anion interactions
- effect of salts
- chelation
- ion-pair formation
- adsorption
a change in pH often leads to what physical/ chemical change of the drug?
precipitation
provide an example of in vitro (in drug) effects of pH change
change in solubility/stability of the active ingredients or excipients
solubility of Ca and phosphate in TNP is __ dependent
pH
is a low or high pH more suitable for solubility?
low (acidic)
what are some (3) in vivo (in patient) effects of pH change?
can neutralize H ions in the stomach, increasing the pH; change rate of gastric emptying; change pH of urine
in vivo pH can be altered with ingestion of __, __ and __
antacids, food, weak electrolytes
what is the effect of antacids containing Ca on gastric emptying?
slows
what is the effect of antacids containing Mg on gastric emptying?
speeds up
explain the incompatibility cause of : alteration of solvent characteristics
the solvent can be altered by become diluted (if involved in co-solution with water) and can also be altered by becoming supersaturated if the drug (solute) concentration is too high
cation–anion interactions result in the formation of _ through the methods of __, __, or __
insoluble complexes; complexation, precipitation, phase separation
explaiin how salting out decreases solubility
highly hydrated non-organic ions deprive organic ions/molecules from getting enough water to dissolve
the release of CO2 from carbonated beverages when NaCl is added is an example of the effects of ___ on solubility
salts
what is chelation?
complex between a metal atom/ion and an organ anion
in chelation, what is the e- acceptor and donor?
acceptor is the metal and donor is the organic
chelation results changes in __ and __
solubility and absorption
T/F chelation can result in either increased or decrease absorption
true
deferiprone is used for treatment of __ by forming a chelate with
iron toxicity; iron
EDTA is used for treatment of __ and __ poisoning
lead; mercury
tetracycline forms chelates with which metal ions?
Ca, Fe, Mg, Al
how does tetracycline use its ability to chelate with Mg ?
uses to target the ribosomes of the bacteria which are rich in Mg
what is an adverse effect of tetracycline forming a chelate with ca?
discolouration of teeth
explain ion-pair formation
production of neutral species when opposing charges on atoms interact through electrostatics
ion-pair formation results in the charges being __
“buried”
the products of ion-pair formation are ___ enough to dissolve in non-aqueous solvents
lipophilic
provide an example of ion-pair formation
absorption of highly charged drugs
what is adsorption?
sticking of dissolved drugs onto surface of adsorbents
medical adsorbents are used for __
removing toxic substances form the gut
what elements of a drug can act as adsorbents?
the excipients and the packaging
proteins/peptides are adsorbed on what type of surfaces?
glass
define stability
the extent to which a product retains its same properties throughout its storage and use as it had when it was first mad e
what are the 5 types of stability?
- chemical
- physical
- microbial
- therapeutic
- topological
describe what is meant by “chemical stability”
the active ingredient of the drug maintains its chemical integrity and labeled potency within specified limits
describe what is meant by “physical stability”
the original physical properties are maintained (appearance, palatability, uniformity, dissolution, and suspend ability)
describe what is meant by “microbial stability”
preservatives maintain effectiveness and microbial growth is resisted
describe what is meant by “therapeutic stability”
the therapeutic effect is unchanged
describe what is meant by “topological stability”
no significant increase in toxicity
what is the temp range for “freezer”?
-25 to -10
what is the temp range for “cold”
less than 8
what is the temp range for “controlled cold temp?”
2 to 8
what is the temp range for “cool”
8 to 15
what is the temp range for “room temperature”?
basic temperature of the workspace
what is the temp range for “ controlled room temp”
20-25
what is the temp range for “warm”
30-40
what is the temp range for “excessive heat”?
greater than 40
a drug that must be stored is a “dry place” must not be stored in a spot with greater than ___ % relative humidity
40
what are 2 consequences of drug degradation?
potency loss and change in physical appearance
what 5 FG are prone to degradation?
amides, amides, lactones, esters, lactams
what are the 5 ways in which drugs can degrade?
- hydrolysis
- oxidation
- isomerization
- photo-chemical
- polymerization
what 5 FG are susceptible to hydrolysis?
ester, amide, imide, lactam, carbamate
Hydrolysis can be catalyzed by 2 different atoms, leading to 2 different kinds of catalysis; what are they?
H = acid catalyzed OH = basic catalyses
give an example of hydrolysis that happens in penicillin
breaking of the beta lactic ring
what are 2 ways you can prevent degradation by hydrolysis?
- make the drug @ the pH of most stability
2. alter the dielectric constant of the solo by adding non-aq solvents
oxidation is caused by the addition/removal of a ___
electronegative atom
oxidation is catalyses by which atoms?
oxygen and heavy metals
oxidation can be automatic, with one step (____), or can happen in a chain rxn of ___, ___, ___
autooxidation; initiation,propogation, termination
give 4 examples of compounds suseptible to degradation by oxidation
steroids & sterols, polyunsaturated fats and phenothiazines
what are 4 ways we can prevent degradation by oxidation?
- replace oxygen with CO2 or N2 in drug containers
- avoid heavy metals
- store at reduced temp
- add in antioxidants when making the drug
describe the effect of degradation by isomerization
conversion to different optical/geometric isomers, which lowers the therapeutic effect
what is the effect of isomerization on epinephrine?
racemisation in acidic soln
what is the effect of isomerization on tetracycline?
epimerization in acidic solo
cephalosporins undergo isomerization that is catalyses by __
base
vitamin A undergoes what type of isomerization?
cis-trans
describe photosensitivity in drug degradation
sunlight penetrates the skin and degrades the drug circulating in the surface capillaries
phenothiazines, hydrocortisone, prednisolone, riboflavin, ascorbic and folic acid are sensitive to what type of drug degradation?
photochemical
what are 2 ways we can prevent degradation by the photochemical route?
- using amber vials that block wavelengths bellow 470nm
2. coating tablets with a polymer film that contains ultraviolet absorbers
describe the process of degradation by polymerization
2/more identical drug molecules combine to make a complex compound
amino-penicillins are sensitive to what type of degradation?
polymerization
how can degradation by polymerization be prevented?
monitor polarity of the aq solvent
what are 5 factors that affect the drug stability of liquids?
- pH
- temp/light
- ionic and solvent effect
- oxidizing agents
- surfactants
what are 3 factors that affect drug stability of solids?
- temp/light
- moisture
- oxidizing compounds
what is the relationship of zero order rate of degradation to concentration?
no relationship (independent of each other)
what is the relationship of first order rate of degradation to concentration>
rate is dependent on 1 concentration
what is the relationship of second order rate of degradation to concentration?
rate is dependant on 2 concentrations
drug suspension with poorly water soluble drugs are __ order of degradation
zero
zero order drug degradation have __ rate of depletion of drug
constant
the half-life of second order degradation is dependent on the ___ of reactants
initial concentrations
what can be used to calculate shelf-life?
degradation kinetics (accelerated stability testing0
what theory / set of equations are used to calculate stability and shelf-life?
Arrhenius
