Dissolution

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Author:
jcu1
ID:
199206
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Dissolution
Updated:
2013-02-09 18:43:25
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DD3 exam
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Description:
Dr. Sant's first lecture slides
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  1. go through the the cards between slides 1 and 20
  2. 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
  3. Noyes Whitney equation when D, h, A, V are constant?
    dC/dt = Ks (Cs-Ct)
  4. solubilizing coefficient
    Ks = DA/Vh
  5. 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
  6. what is wetting dependent on?
    surface tension (surface free energy change)
  7. wetting agents
    • polysorbate 80
    • poloxamers
    • sodium lauryl sulfate
  8. hydrophobic additive to a tablet that reduces penetration of solvents?
    Mg stearate
  9. examples of a wicking agent?
    microcrystalline cellulose
  10. examples of disintegrants
    • crospovidone
    • starch
  11. polymeric materials that swell rapidly
    carboxymethyl cellulose sodium
  12. purpose of dissolution testing
    to simulate in vivo sink conditions
  13. in sink conditions is the dissolution rate affected by concentration gradient?
    NO
  14. what are some dissolution testing methods?
    • rotating paddle/basket
    • flow through dissolution systems
    • reciprocating cylinder/disk method
  15. 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
  16. what is needed for the dissolution method?
    • constant temp (37.8 C)
    • water/buffer medium
    • predetermined speed
  17. 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
  18. 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
  19. 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
  20. what do the solubility and dissolution of weak electrolytes depend on?
    pKa and solution pH
  21. solubility enhancers for hydrophobic drugs?
    • starch
    • poloxamers
    • cyclodextrins
  22. example of a lubricant
    Mg stearate (hydrophobic layer prevents interaction with water
  23. what do bile salts do? and what is the advantage?
    • form aggregates like micelles with lipophilic drugs
    • --increases solubility
    • --lowers D
    • --inc dissolution rate
  24. what does micronization do?
    inc dissolution rate and absorption by decreasing particle size and inc surface area
  25. 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)
  26. 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)
  27. stable compared to unstable polymorphs
    stable polymorphs have the lowest energy state, highest melting point and the least aqueous solubility
  28. 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
  29. what are amorphous forms?
    • have no internal structure
    • have the highest energy
    • supercooled liquids
    • may eventually convert to more stable crystalline forms
  30. 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
  31. effect of counter ion on salt solubility?
    • smaller counter ion = higher solubility
    • large counter ion may have lower solubility that the free base itself
  32. examples of large counter ions used in sustained release forms?
    • palmoates
    • stearates of weak bases (steroids)
  33. what is permeability?


    • D = diffusion coefficient
    • A = area of absorbing membrane
    • Rm/aq = partition coefficient of drug between membrane and GI fluids
  34. 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
  35. caco-2 cell monolayers and Papp
    model of the human enterocytes lining the intestines

    apparent permeability across the cacao-2 monolayers
  36. logP
    • partition coefficient that measure lipophilicity
    • negative logP = polar, large, poorly lipophilicity
    • positive logP = lipid soluble, well absorbed, susceptible to metabolism
  37. BCS classification categories
    • Class I - soluble/permeable
    • Class II - not soluble/permeable¬†
    • Class III - soluble/not permeable
    • Class IV - not soluble/not permeable
  38. 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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