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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
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Noyes Whitney equation when D, h, A, V are constant?
dC/dt = Ks (Cs-Ct)
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solubilizing coefficient
Ks = DA/Vh
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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
- swelling
- disintegration/disaggregation
- dissolution
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what is wetting dependent on?
surface tension (surface free energy change)
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wetting agents
- polysorbate 80
- poloxamers
- sodium lauryl sulfate
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hydrophobic additive to a tablet that reduces penetration of solvents?
Mg stearate
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examples of a wicking agent?
microcrystalline cellulose
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examples of disintegrants
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polymeric materials that swell rapidly
carboxymethyl cellulose sodium
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purpose of dissolution testing
to simulate in vivo sink conditions
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in sink conditions is the dissolution rate affected by concentration gradient?
NO
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what are some dissolution testing methods?
- rotating paddle/basket
- flow through dissolution systems
- reciprocating cylinder/disk method
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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
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what is needed for the dissolution method?
- constant temp (37.8 C)
- water/buffer medium
- predetermined speed
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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
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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
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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
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what do the solubility and dissolution of weak electrolytes depend on?
pKa and solution pH
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solubility enhancers for hydrophobic drugs?
- starch
- poloxamers
- cyclodextrins
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example of a lubricant
Mg stearate (hydrophobic layer prevents interaction with water
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what do bile salts do? and what is the advantage?
- form aggregates like micelles with lipophilic drugs
- --increases solubility
- --lowers D
- --inc dissolution rate
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what does micronization do?
inc dissolution rate and absorption by decreasing particle size and inc surface area
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what are the solid state properties of a drug?
- polymorphism
- crystalline vs. amorphous (amorphous more soluble)
- salt vs. free base (salt more soluble)
- presence of counter ions (lower strength ions means higher dissolution rate)
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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)
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stable compared to unstable polymorphs
stable polymorphs have the lowest energy state, highest melting point and the least aqueous solubility
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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)?
ritonavir
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what are amorphous forms?
- have no internal structure
- have the highest energy
- supercooled liquids
- may eventually convert to more stable crystalline forms
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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
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effect of counter ion on salt solubility?
- smaller counter ion = higher solubility
- large counter ion may have lower solubility that the free base itself
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examples of large counter ions used in sustained release forms?
- palmoates
- stearates of weak bases (steroids)
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what is permeability?
- D = diffusion coefficient
- A = area of absorbing membrane
- Rm/aq = partition coefficient of drug between membrane and GI fluids
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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
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caco-2 cell monolayers and Papp
model of the human enterocytes lining the intestines
apparent permeability across the cacao-2 monolayers
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logP
- partition coefficient that measure lipophilicity
- negative logP = polar, large, poorly lipophilicity
- positive logP = lipid soluble, well absorbed, susceptible to metabolism
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BCS classification categories
- Class I - soluble/permeable
- Class II - not soluble/permeable
- Class III - soluble/not permeable
- Class IV - not soluble/not permeable
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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
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