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Noyes Whitney equation for dissolution
dC/dt = DA(Cs –Ct)/Vh
- dC/dt = rate of mass transfer (dissolution)
- D = diffusion coefficient
- A = surface area of the particle
- Cs = saturation concentration on particle surface area
- V = volume of solution
- h = diffusion layer thickness
Noyes Whitney equation when D, h, A, V are constant?
dC/dt = Ks (Cs-Ct)
Ks = DA/Vh
drug release from solid dosage form is dependent on?
- wetting: contact angel between solid and liquid phases (0 deg=complete; 180 deg=no wetting)
- penetration of solvent: hydrophilic vs hydrophobic material
what is wetting dependent on?
surface tension (surface free energy change)
- polysorbate 80
- sodium lauryl sulfate
hydrophobic additive to a tablet that reduces penetration of solvents?
examples of a wicking agent?
examples of disintegrants
polymeric materials that swell rapidly
carboxymethyl cellulose sodium
purpose of dissolution testing
to simulate in vivo sink conditions
in sink conditions is the dissolution rate affected by concentration gradient?
what are some dissolution testing methods?
- rotating paddle/basket
- flow through dissolution systems
- reciprocating cylinder/disk method
why is there a need for different dissolution apparatus designs?
What are the most common ones for tablets and capsules?
- b/c the surface area for powders isn't constant
- b/c diffusion layer thickness changes with agitation
most common: rotating basket and rotating paddle
what is needed for the dissolution method?
- constant temp (37.8 C)
- water/buffer medium
- predetermined speed
how do you pick dissolution media?
- what you the conditions in the body would be
- ex: fasted/fed pH's, volumes, buffers, gastric vs intestine material
factors that affect dissolution rate:
- diffusion layer thickness and agitation
- solubility and dissolution of weak electrolytes
- excipients and bile salts
- particle size and surface area
- solid state properties of a drug
what does the force of agitation do?
changes the thickness of the dissolution layers and the dissolution rate
- low RPM: passive flow; different concentration layers
- high RPM: turbulent flow; particles forced onto the side and upwards
what do the solubility and dissolution of weak electrolytes depend on?
pKa and solution pH
solubility enhancers for hydrophobic drugs?
example of a lubricant
Mg stearate (hydrophobic layer prevents interaction with water
what do bile salts do? and what is the advantage?
- form aggregates like micelles with lipophilic drugs
- --increases solubility
- --lowers D
- --inc dissolution rate
what does micronization do?
inc dissolution rate and absorption by decreasing particle size and inc surface area
what are the solid state properties of a drug?
- crystalline vs. amorphous (amorphous more soluble)
- salt vs. free base (salt more soluble)
- presence of counter ions (lower strength ions means higher dissolution rate)
what is polymorphism?
when a compound exists in 2 or more crystalline states
each polymorph has unique properties (i.e. solubility, dissolution rate, melting point, color, stability)
stable compared to unstable polymorphs
stable polymorphs have the lowest energy state, highest melting point and the least aqueous solubility
example of drug that was thought to have only one polymorph, but then ended up having 2 that made it fail dissolution testing (led to forced recall)?
what are amorphous forms?
- have no internal structure
- have the highest energy
- supercooled liquids
- may eventually convert to more stable crystalline forms
weak acid and base in acidic and basic solution and solubility?
- weak acids more soluble in basic pH
- weak bases more soluble in acidic pH
effect of counter ion on salt solubility?
- smaller counter ion = higher solubility
- large counter ion may have lower solubility that the free base itself
examples of large counter ions used in sustained release forms?
- stearates of weak bases (steroids)
what is permeability?
- D = diffusion coefficient
- A = area of absorbing membrane
- Rm/aq = partition coefficient of drug between membrane and GI fluids
unstirred water layer
exists in the GI system next to the intestinal membrane
- high solubility drug: diffusion across UWL fast and permeability is rate limiting
- low solubility drug: diffusion across UWL rate limiting, solubility controls permeability
caco-2 cell monolayers and Papp
model of the human enterocytes lining the intestines
apparent permeability across the cacao-2 monolayers
- partition coefficient that measure lipophilicity
- negative logP = polar, large, poorly lipophilicity
- positive logP = lipid soluble, well absorbed, susceptible to metabolism
BCS classification categories
- Class I - soluble/permeable
- Class II - not soluble/permeable
- Class III - soluble/not permeable
- Class IV - not soluble/not permeable
BCS classification implications
- Class I - get bioequivalence and bioavailability waivers for IR products
- Class 2 - rate limiting = dissolution; need solubility enhancement, inc dose
- Class 3 - rate limiting = permeability; inc dose
- Class 4 - most challenging