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Dissolution, factors affecting drug dissolution, methods to evaluate dissolution, advantages and disadvantages, recent approaches--these are the topics covered in this presentation.

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  1. 1. DISSOLUTIONPresented by: Muhammed Fahad
  2. 2. DISSOLUTIONDefinition:• Dissolution is a process in which a solid substancesolubilizes in a given solvent i.e. mass transfer fromthe solid surface to the liquid phase.• Dissolution is the rate determining step forhydrophobic, poorly aqueous soluble drugs.E.g. Griseofulvin, spironolactone2DISSOLUTION
  4. 4. Why dissolution studies?1. To show that the release of drug from the tablet isclose to 100%.2. To show that the rate of drug release is uniformbatch to batch.3. And to show that release is equivalent to thosebatches proven to be bioavailable and clinicallyeffective.DISSOLUTION 4
  5. 5. Mechanism of Dissolution1. Diffusion layer model2. Danckwert’s model3. Interfacial barrier model5DISSOLUTION
  6. 6. Dissolution mechanisms2 steps:1. Interfacial reaction  cause liberation of solidparticles into boundary layer (Cs).2. Migration of solute from boundary layer into bulk ofsolution (C) by diffusion & convection.• Overall rate of dissolution depends on the sloweststep.• Usually Step (2) is the RDS.6DISSOLUTION
  7. 7. Fick’s law:orwhere k = rate constantDISSOLUTION 7
  8. 8. 1. Diffusion Layer Model• Also called ‘film theory’.• Formation of a thin film at the interface, called asstagnant layer.• 2 steps are involved:1) Interaction of solvent with drug surface to forma saturated drug layer , called stagnant layer.2) Diffusion of drug molecules from stagnant layerinto bulk of the system.8DISSOLUTION
  9. 9. Diagram Representing Diffusion through the Stagnant Layer9DISSOLUTION
  10. 10. Noyes- Whitney’s equation:dC/dt = dissolution rate of the drug,k = dissolution rate constant,Cs = concentration of drug in the stagnantlayer, andCb = concentration of drug in the bulk of thesolution at time t10DISSOLUTION
  11. 11. Modified Noyes-Whitney’s equation:• Where,• D = diffusion coefficient (diffusivity) of the drug• A = surface area of the dissolving solid• Kw/o = water/oil partition coefficient of the drug.• V = volume of dissolution medium• h = thickness of the stagnant layer• (Cs – Cb)= concentration gradient for diffusion of drug.11DISSOLUTION
  12. 12. 12DISSOLUTION
  13. 13. 2. Danckwert’s Model• Also called “Penetration or Surface Renewal Theory”.13DISSOLUTION
  14. 14. • m = mass of solid dissolved, and• γ = rate of surface renewal (or the interfacialtension)14DISSOLUTION
  15. 15. 3. Interfacial Barrier Model• Drug dissolution is a function of solubility rather thandiffusion.• Intermediate concentration exist at the interface as aresult of solvation.• Dissolution rate per unit area, G is given by,where Ki = effective interfacial transport constant.15DISSOLUTION
  16. 16. Powder Dissolution:The Hixson-Crowell Cube Root Law• Applicable for drug powders of uniform size.• Rate of dissolution based on cube root of wt. ofparticles.M0 = initial mass of powderM = mass of powder dissolved in time, tk = cube root dissolution rate constantDISSOLUTION 16
  17. 17. Particulate Dissolution• Used to study influence of particle size & surfacearea on dissolution.• Here, surface area is not made constant.• Weighed powder introduced in dissolution medium agitated by propeller.• Rate of dissolution increases with decrease inparticle size.• Effective and absolute surface area.17DISSOLUTION
  18. 18. PROCESS OF DISSOLUTIONStates of matter:• Solid, liquid & gaseous states.• Dissolution involves relocation of a solute moleculefrom an environment where it is surrounded by otheridentical molecules, into a cavity in a liquid.18DISSOLUTION
  19. 19. Energy changes:• For spontaneous reactions, ΔG must be –ve.• ‘G’ is a measure of the energy available to a systemto perform work.ΔG = ΔH – TΔSWhereΔH = change in enthalpy of the systemΔS = change in entropy of the systemT = temperature• ΔS is usually positive for spontaneous reactions.19DISSOLUTION
  20. 20. Intrinsic Dissolution rate• Rate which is independent of rate of agitation, areaof solute available, etc.• Intrinsic Dissolution Rate (IDR): rate of masstransfer per area of dissolving surface.• It is independent of boundary layer thickness andvolume of slolvent .DISSOLUTION 20
  21. 21. • Thus,IDR = k1Cs• IDR measures the intrinsic properties of the drugonly as a function of the dissolution medium, e.g.its pH, ionic strength, counter ions, etc.)DISSOLUTION 21
  22. 22. Measurement of dissolution ratesApparatus Classification in USP:1. Apparatus 1 (rotating basket)2. Apparatus 2 (paddle assembly)3. Apparatus 3 (reciprocating cylinder)4. Apparatus 4 (flow-through cell)5. Apparatus 5 (paddle over disk)6. Apparatus 6 (cylinder)7. Apparatus 7 (reciprocating holder)DISSOLUTION 22
  23. 23. Apparatus Classification in European Pharmacopoeiafor different dosage formsDISSOLUTION 23
  24. 24. Problems associated with development ofdissolution tests:1. Need to have a manageable volume of dissolutionmedium.2. Development of less-soluble drugs.3. Insufficient analytical sensitivity for low-dose drugs.DISSOLUTION 24
  25. 25. According to USP:A drug product is considered rapidly dissolving when noless than 85% of the labeled amount of the drugsubstance dissolves within 30 minutes, using USPApparatus I at 100 rpm (or Apparatus II at 50 rpm) in avolume of 900 ml or less in each of the following media:(1) 0.1 N HCl or Simulated Gastric Fluid USP withoutenzymes;(2) a pH 4.5 buffer; and(3) a pH 6.8 buffer.DISSOLUTION 25
  26. 26. Biopharmaceutical Classification System• Class I: High solubility—High permeability• Class II: Low solubility—High permeability• Class III: High solubility—Low permeability• Class IV: Low solubility—Low permeabilityDISSOLUTION 26
  27. 27. Measurement of dissolution ratesBeaker method:• Developed by Levy and Hayes.• Consist of 400 ml beaker with 250 ml dissolutionmedium.• Medium is agitated by a 3-bladed polyethylenestirrer of 50 mm diameter.• Stirrer is immersed to a depth of 27 mm into thedissolution medium and rotated at 60 rpm.DISSOLUTION 27
  28. 28. Flask-stirrer method:• R.B. flask is used instead of beaker.Rotating Basket method:• USP Apparatus I• Small wire mesh basket fastened to end of shaftconnected to a motor.• Immersed in a flask maintained at 370C ± 0.50C.• Samples are withdrawn at regular intervals.DISSOLUTION 28
  29. 29. DISSOLUTION 29
  30. 30. Paddle Assembly method• USP Apparatus II• Basket in above method is replaced by paddle.• Paddle is continuous with the shaft.• Tablet is placed at the bottom of the medium.Disadvantages:• Since dissolution volume is limited, use of poorlysoluble drugs is limited.DISSOLUTION 30
  31. 31. Variables in USP Apparatus I & II• Type of dissolution medium & its volume.• Type of apparatus to be used.• Speed (rpm) of rotation.• Total time of the test.• Further assay procedures.DISSOLUTION 31
  32. 32. USP Testing methods:• 6 tablets  monograph tolerance limit, Q + 5%• If fail, 6 more tablets are used  avg. of 12 tabs ≥ Q,and none is < Q-15%.• If failed, 12 more tablets used  avg. of 24 tabs ≥ Q,and no 2 tab is < Q-15% & none is < Q-25%.• Usual tolerance in USP / NF is “not less than 75%dissolved in 45 min”.DISSOLUTION 32
  33. 33. DISSOLUTION 33
  34. 34. Reciprocating Cylinder• Proposed by Beckett & incorporated in USP in 1991.• Mainly used for dissolution testing of extended-release products.• Also used for poorly soluble drugs.• Capable of agitation and media composition changesduring a run & full automation.• Dips per minute (dpm) is used.• Inner reciprocating tubes & outer tubes.DISSOLUTION 34
  35. 35. DISSOLUTION 35Reciprocating Cylinder
  36. 36. Use:• Especially useful in the case of chewable tablets.• Studies show that 5 dpm in Apparatus 3 isequivalent to 50 rpm in Apparatus 2.• So higher dpm can achieve rigorous movts. similarto chewing—not possible by Apparatus 2.• Used for solutions requiring pH/buffer changes likeenteric-coated/extended-release drugs.DISSOLUTION 36
  37. 37. Flow-Through Cell• Introduced by Langenbucher.• Open system—offer unlimited medium supply—especially useful for poorly soluble drugs.• Also used for dissolution test of sugar-coated tabs,suppositories, soft gelatin capsules, semi-solids,granules, implants, etc.• Small volume cell is subjected to continuous streamof dissolution media  flow from bottom to top.DISSOLUTION 37
  38. 38. • Agitation is achieved by pulsating movement ofpiston.• Results obtained as fraction dissolved per unit time(due to continuous media flow).• Data is transformed to the usual cumulative amt.dissolved vs. time.Advantages:• Maintenance of sink conditions.• Minimizing downtime between tests.DISSOLUTION 38
  39. 39. DISSOLUTION 39Flow-Through Cell
  40. 40. Qualification & Validation of theApparatus• To maintain “quality by design”.• Physical & chemical calibrations—geometrical &dimensional accuracy & precision.• Vibration or undesired agitation to be avoided.• Temperature, rotation speed/flow rate, volume,sampling probe, procedures, etc. need to bemonitored periodically.• Use of USP calibrator tablets for App. 1 & 2 (to beperformed not less than twice a year)DISSOLUTION 40
  41. 41. Factors Affecting DissolutionSurface area & undissolved solid• Surface area α dissolution.• Coherent masses may reduce total surface areaavailable  overcome by using wetting agent.• Presence of pores. E.g. dissolution of phenacetin (hydrophobic) isenhanced by adding diluent gelatin (hydrophilic)during granulation.DISSOLUTION 41
  42. 42.  Addition of Tween 80 to dissolution medium(0.1 N HCl) for phenacetin increased thedissolution rate by increasing effectivesurface area.DISSOLUTION 42
  43. 43. Solubility of solid in dissolution medium Temp. of dissolution medium pH of the medium Solubility of the drug in dissolution medium Presence of cosolventsDISSOLUTION 43
  44. 44. Concentration of solute in solution• Should simulate sink conditions present in GI tract.• Larger volume of dissolution medium helps tomaintain ‘C’ negligible compared to ‘Cs’.• Removal of dissolved solute from dissolutionmedium enhances rate of dissolution. Eg. Adsorption onto another substance Partition to another immiscible liquid Removal of solute by dialysis Cont. replacement of dissolution mediumDISSOLUTION 44
  45. 45. Dissolution rate constantDepend upon Thickness of boundary layer Degree of agitation Speed of stirring Shape, size & position of stirrer Vol. of dissolution medium Shape & size of container Viscosity of dissolution mediumDISSOLUTION 45
  46. 46. Disintegration & Deaggregation• Disintegration and subsequent deaggregation mayalso be RDS for dissolution.o E.g. coated dosage forms• After disintegration, larger aggregates need todeaggregate to yield fine particles.DISSOLUTION 46
  47. 47. Effect of manufacturing processesAddition of lubricantsE.g.: 325-mg salicylic acid dissolved rapidly in 0.1 NHCl when SLS was added to it.Dissolution rate decreases with addition ofhydrophobic lubricants like Mg. stearate.• Most effective lubricants are hydrophobic  act byparticle coating  hence mfg. process is imp.DISSOLUTION 47
  48. 48. Addition of disintegrating agents like starch  swell& enhance dissolution.Compression force• Increase in compression force may decrease orincrease dissolution rate.DISSOLUTION 48
  49. 49. Recent developments in dissolution testing• Use of more biorelevant media—FaSSIF & FeSSIFmedia.• FaSSIF—Fasted State Simulated Intestinal Fluid• FeSSIF—Fed State Simulated Intestinal FluidAdvantages:• Provide physicochemical properties similar to humanGIT.DISSOLUTION 49
  50. 50. DISSOLUTION 50
  51. 51. REFERENCE1. Fonner. D. E, Banker. G. S., Granulation & Tablet Characteristics,In Pharmaceutical Dosage Forms: Tablets. Vol. 2. Edited by H.Lieberman & L. Lachman, Dekker, New York, 1982, p. 2022. Leon Lachman, Herbert. A. Lieberman, The Theory and Practiceof Industrial Pharmacy, 3rd edition, Varghese Publishing House,Bombay, 1991, pp. 301-3033. Brahmankar. D. M., Sunil Jaiswal. B, Biopharmaceutics andPharmacokinetics—A Treatise, 1st edition, Vallabh Prakashan,New Delhi, 2006, pp. 19-254. Alfred Martin, James Swarbrick, Physical Pharmacy, 3rd edition,Varghese Publishing House, Bombay, 1991, pp. 408-412DISSOLUTION 51
  52. 52. DISSOLUTION 52