Dissolution

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

1. DISSOLUTION Presented by: Muhammed Fahad

2. DISSOLUTION Definition : Dissolution is a process in which a solid substance solubilizes in a given solvent i.e. mass transfer from the solid surface to the liquid phase. Dissolution is the rate determining step for hydrophobic, poorly aqueous soluble drugs. E.g. Griseofulvin , spironolactone 2 DISSOLUTION

3. DISSOLUTION 3

4. Why dissolution studies? To show that the release of drug from the tablet is close to 100%. To show that the rate of drug release is uniform batch to batch. And to show that release is equivalent to those batches proven to be bioavailable and clinically effective. DISSOLUTION 4

5. Mechanism of Dissolution Diffusion layer model Danckwert’s model Interfacial barrier model 5 DISSOLUTION

6. Dissolution mechanisms 2 steps: Interfacial reaction  cause liberation of solid particles into boundary layer (C s ). Migration of solute from boundary layer into bulk of solution (C) by diffusion & convection . Overall rate of dissolution depends on the slowest step. Usually Step (2) is the RDS. 6 DISSOLUTION

7. Fick’s law: or where k = rate constant DISSOLUTION 7

8. 1. Diffusion Layer Model Also called ‘film theory’. Formation of a thin film at the interface, called as stagnant layer. 2 steps are involved: Interaction of solvent with drug surface to form a saturated drug layer , called stagnant layer. Diffusion of drug molecules from stagnant layer into bulk of the system. 8 DISSOLUTION

9. Diagram Representing Diffusion through the Stagnant Layer 9 DISSOLUTION

10. Noyes- Whitney’s equation: dC / dt = dissolution rate of the drug, k = dissolution rate constant, C s = concentration of drug in the stagnant layer, and C b = concentration of drug in the bulk of the solution at time t 10 DISSOLUTION

11. Modified Noyes-Whitney’s equation: Where, D = diffusion coefficient ( diffusivity ) of the drug A = surface area of the dissolving solid K w /o = water/oil partition coefficient of the drug. V = volume of dissolution medium h = thickness of the stagnant layer (C s – C b )= concentration gradient for diffusion of drug. 11 DISSOLUTION

12. 12 DISSOLUTION

13. 2. Danckwert’s Model Also called “ Penetration or Surface Renewal Theory ”. 13 DISSOLUTION

14. m = mass of solid dissolved, and γ = rate of surface renewal (or the interfacial tension) 14 DISSOLUTION

15. 3. Interfacial Barrier Model Drug dissolution is a function of solubility rather than diffusion. Intermediate concentration exist at the interface as a result of solvation . Dissolution rate per unit area, G is given by, where Ki = effective interfacial transport constant . 15 DISSOLUTION

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. of particles. M = initial mass of powder M = mass of powder dissolved in time, t k = cube root dissolution rate constant DISSOLUTION 16

17. Particulate Dissolution Used to study influence of particle size & surface area on dissolution. Here, surface area is not made constant. Weighed powder introduced in dissolution medium  agitated by propeller. Rate of dissolution increases with decrease in particle size. Effective and absolute surface area. 17 DISSOLUTION

18. PROCESS OF DISSOLUTION States of matter: Solid, liquid & gaseous states. Dissolution involves relocation of a solute molecule from an environment where it is surrounded by other identical molecules, into a cavity in a liquid. 18 DISSOLUTION

19. Energy changes: For spontaneous reactions, ΔG must be – ve . ‘G’ is a measure of the energy available to a system to perform work. ΔG = ΔH – TΔS Where ΔH = change in enthalpy of the system ΔS = change in entropy of the system T = temperature ΔS is usually positive for spontaneous reactions. 19 DISSOLUTION

20. Intrinsic Dissolution rate Rate which is independent of rate of agitation, area of solute available, etc. Intrinsic Dissolution Rate (IDR) : rate of mass transfer per area of dissolving surface. It is independent of boundary layer thickness and volume of slolvent . DISSOLUTION 20

21. Thus, IDR = k 1 C s IDR measures the intrinsic properties of the drug only as a function of the dissolution medium, e.g. its pH, ionic strength, counter ions, etc.) DISSOLUTION 21

22. Measurement of dissolution rates Apparatus Classification in USP: Apparatus 1 (rotating basket) Apparatus 2 (paddle assembly) Apparatus 3 (reciprocating cylinder) Apparatus 4 (flow-through cell) Apparatus 5 (paddle over disk) Apparatus 6 (cylinder) Apparatus 7 (reciprocating holder) DISSOLUTION 22

23. Apparatus Classification in European Pharmacopoeia for different dosage forms DISSOLUTION 23

24. Problems associated with development of dissolution tests: Need to have a manageable volume of dissolution medium. Development of less-soluble drugs. Insufficient analytical sensitivity for low-dose drugs. DISSOLUTION 24

25. According to USP: A drug product is considered rapidly dissolving when no less than 85% of the labeled amount of the drug substance dissolves within 30 minutes, using USP Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a volume of 900 ml or less in each of the following media: (1) 0.1 N HCl or Simulated Gastric Fluid USP without enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer. DISSOLUTION 25

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 permeability DISSOLUTION 26

27. Measurement of dissolution rates Beaker method : Developed by Levy and Hayes . Consist of 400 ml beaker with 250 ml dissolution medium. Medium is agitated by a 3-bladed polyethylene stirrer of 50 mm diameter. Stirrer is immersed to a depth of 27 mm into the dissolution medium and rotated at 60 rpm. DISSOLUTION 27

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 shaft connected to a motor. Immersed in a flask maintained at 37 C ± 0.5 C. Samples are withdrawn at regular intervals. DISSOLUTION 28

29. DISSOLUTION 29

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 poorly soluble drugs is limited. DISSOLUTION 30

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. 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. DISSOLUTION 33

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 changes during a run & full automation. Dips per minute ( dpm ) is used. Inner reciprocating tubes & outer tubes. DISSOLUTION 34

35. DISSOLUTION 35 Reciprocating Cylinder

36. Use: Especially useful in the case of chewable tablets. Studies show that 5 dpm in Apparatus 3 is equivalent to 50 rpm in Apparatus 2. So higher dpm can achieve rigorous movts . similar to chewing—not possible by Apparatus 2. Used for solutions requiring pH/buffer changes like enteric-coated/extended-release drugs. DISSOLUTION 36

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 stream of dissolution media  flow from bottom to top. DISSOLUTION 37

38. Agitation is achieved by pulsating movement of piston. 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. DISSOLUTION 39 Flow-Through Cell

40. Qualification & Validation of the Apparatus 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 be monitored periodically. Use of USP calibrator tablets for App. 1 & 2 (to be performed not less than twice a year) DISSOLUTION 40

41. Factors Affecting Dissolution Surface area & undissolved solid Surface area α dissolution. Coherent masses may reduce total surface area available  overcome by using wetting agent. Presence of pores. E.g. dissolution of phenacetin (hydrophobic) is enhanced by adding diluent gelatin (hydrophilic) during granulation. DISSOLUTION 41

42. Addition of Tween 80 to dissolution medium (0.1 N HCl ) for phenacetin increased the dissolution rate by increasing effective surface area. DISSOLUTION 42

43. Solubility of solid in dissolution medium Temp. of dissolution medium pH of the medium Solubility of the drug in dissolution medium Presence of cosolvents DISSOLUTION 43

44. Concentration of solute in solution Should simulate sink conditions present in GI tract. Larger volume of dissolution medium helps to maintain ‘C’ negligible compared to ‘C s ’. Removal of dissolved solute from dissolution medium enhances rate of dissolution. Eg . Adsorption onto another substance Partition to another immiscible liquid Removal of solute by dialysis Cont. replacement of dissolution medium DISSOLUTION 44

45. Dissolution rate constant Depend 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 medium DISSOLUTION 45

46. Disintegration & Deaggregation Disintegration and subsequent deaggregation may also be RDS for dissolution. E.g. coated dosage forms After disintegration, larger aggregates need to deaggregate to yield fine particles. DISSOLUTION 46

47. Effect of manufacturing processes Addition of lubricants E.g.: 325-mg salicylic acid dissolved rapidly in 0.1 N HCl when SLS was added to it. Dissolution rate decreases with addition of hydrophobic lubricants like Mg. stearate . Most effective lubricants are hydrophobic  act by particle coating  hence mfg. process is imp. DISSOLUTION 47

48. Addition of disintegrating agents like starch  swell & enhance dissolution. Compression force Increase in compression force may decrease or increase dissolution rate. DISSOLUTION 48

49. Recent developments in dissolution testing Use of more biorelevant media— FaSSIF & FeSSIF media. FaSSIF —Fasted State Simulated Intestinal Fluid FeSSIF —Fed State Simulated Intestinal Fluid Advantages: Provide physicochemical properties similar to human GIT. DISSOLUTION 49

50. DISSOLUTION 50

51. REFERENCE 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. 202 Leon Lachman , Herbert. A. Lieberman, The Theory and Practice of Industrial Pharmacy , 3 rd edition, Varghese Publishing House, Bombay, 1991, pp. 301-303 Brahmankar . D. M. , Sunil Jaiswal . B, Biopharmaceutics and Pharmacokinetics—A Treatise , 1 st edition, Vallabh Prakashan , New Delhi, 2006, pp. 19-25 Alfred Martin , James Swarbrick , Physical Pharmacy , 3 rd edition, Varghese Publishing House, Bombay, 1991, pp. 408-412 DISSOLUTION 51

52. DISSOLUTION 52