Dr. Sandra Klein, Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University Frankfurt

1. Design and Calibration of aDissolution Test EquipmentTraining Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System. Kyiv, Ukraine, June 25 - 27 2007 Dr. Sandra Klein, Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University Frankfurt

2. Dosage forms to be tested • immediate release dosage forms • powders, granules / beads, tablets, capsules • controlled release dosage forms • powders, granules / beads, tablets, capsules • transdermal systems • implants

3. Official Dissolution Monographs • United States Pharmacopeia • USP XXX (30) • European Pharmacopoeia • Ph. Eur. 5th Edition, Supplement 5.3 • British Pharmacopoeia • BP 2007 • Japanese Pharmacopoeia • JP XIV (14) • http://jpdb.nihs.go.jp/jp14e/contents.html

4. Official dissolution apparatus • USP 30 classification • Rotating Basket (Ph.Eur./BP/JP) • Paddle (Ph.Eur./BP/JP) • Reciprocating Cylinder (Ph.Eur.) • Flow Through Cell (Ph.Eur./BP/JP) • Paddle Over Disk (Ph.Eur.) • Rotating Cylinder (Ph.Eur.) • Reciprocating Holder

5. Which type of dissolution apparatus ? • Depends on intention • Quality control • examining batch homogeneity • examining batch to batch conformity • examining stability • Research & Development • examining drug release behavior of preformulations • in vitro simulation of the gastrointestinal passage • IVIVC

6. Apparatus 1 - Basket • Useful for • capsules • beads • delayed release / entericcoated dosage forms • floating dosage forms • surfactants in media • Standard volume • 900/1000 ml • 1, 2, 4 liter vessels

7. Apparatus 1 - Basket • Advantages • breadth of experience(more than 200 monographs) • full pH change during the test • can be easily automated which is important for routine investigations

8. Apparatus 1 - Basket • Disadvantages • disintegration-dissolution interaction • hydrodynamic „dead zone“ under the basketdegassing is particularly important • limited volume  sink conditions for poorly soluble drugs ?

9. Apparatus 1 - Basket

10. Apparatus 2 - Paddle • Useful for • tablets • capsules • beads • delayed release / entericcoated dosage forms • Standard volume • 900/1000 ml • Method of first choice !!!

11. Apparatus 2 - Paddle • Advantages • easy to use • robust • can be easily adapted to apparatus 5 • long experience • pH change possible • can be easily automated which is important for routine investigations

12. Apparatus 2 - Paddle • Disadvantages • pH/media change is often difficult • limited volume  sink conditions for poorly soluble drugs ? • hydrodynamics are complex, they vary with site of the dosage form in the vessel (sticking,floating) and therefore may significantly affect drug dissolution • „coning“ • sinkers for floating dosage forms

13. Sinker types • JP/ USP / Ph. Eur. 5.3 Sinker • „a small loose piece of nonreactive material such as • not more than a few turns of wire helix may be attached • to dosage units that would otherwise float …“ • „…. other validated sinker devices may be used“

14. Coning

15. Apparatus 2 - Paddle

16. Apparatus 3 – Reciprocating cylinder • Useful for • tablets • beads • controlled release formulations • Standard volume • 200-250 ml per station

17. Apparatus 3 – Reciprocating cylinder • Advantages • easy to change the pH • pH-profiles • hydrodynamics can be directly influenced by varying the dip rate • Disadvantages • small volume (max. 250 ml) • little experience • limited data

18. Apparatus 3 – Reciprocating cylinder

19. Apparatus 4 – Flow-Through Cell • Useful for • low solubility drugs • microparticulates • implants • suppositories • controlled release formulations • Variations • open system • closed system

20. Cell types Tablets 12 mm Tablets 22,6 mm Powders / Granules Implants Suppositories / Soft gelatine capsules

21. Apparatus 4 – Flow-Through Cell • Advantages • easy to change media pH • pH-profile possible • sink conditions • different modesa) open systemb) closed system • Disadvantages • Deaeration necessary • high volumes of media • labor intensive

22. Apparatus 4 – Flow-Through Cell

23. Apparatus 5 – Paddle over disk • Useful for • transdermal patches • Standard volume • 900 ml

24. Apparatus 5 – Paddle over disk • Advantages • standard equipment (paddle) can be used, only add a stainless steel disk assembly • Disadvantages • disk assembly restricts patch size

25. Apparatus 6 – Rotating cylinder USP apparatus 7 – Reciprocating holder most probably will be removed from the USP !!!

26. Summary • Immediate release dosage forms: •  apparatus 1 or 2 (preferably 2) • Controlled release dosage forms: •  apparatus 1 or 2 using different media for QC apparatus 3 or 4 for R&D purposes • Beside the selection of an adequate dissolution apparatus, adequate test conditions are crucial for all purposes !

27. Qualification of Dissolution Systems

28. Calibration • Why ? • to confirm suitability of the equipment and proper operation of the apparatus • How ? • mechanical calibration (verification of physical parameters) • chemical calibration („Apparatus Suitability Test“ – USP) • When ? • before using new test equipment • after relocation or major maintenance • at regular intervals („every 6 months“)

29. Factors that may affect reliability of the test • Proper alignment/geometry of dissolution apparatus • dimensions of vessels, paddles, baskets, cylinders • height, centering and wobble • Proper conditions during dissolution test • temperature • agitation speed • degassing • sampling (sampling zone, timing, filtration, dilution) • vibration • Proper validation of analytical method • specified in USP Chapter <1225>

30. Mechanical calibration • Verification of physical parameters specified in the pharmacopoeia: USP apparatus 1 and 2

31. Mechanical calibration - Parameters • Height – Vertical Position of the Paddle or Basket • the vertical position of paddle or basket affects the hydrodynamics condition in the vessel • each paddle or basket should be individually adjusted to the compendial distance • in the pharmacopoeia, a distance of 2.5 + 0.2 cm is specified • different kinds of height gauges can be usedto align or check* this parameter *

32. Mechanical calibration - Parameters • Rotational Speed – Stirring Rate • input variable that affects the hydrodynamics • changes in the rotational speed result in a changing liquid-solid interface between the solvent and the dosage form • the rotational speed can be checked by using adigital tachometer* • the compendia specify a rotational speed tolerance of + 4 % *

33. Mechanical calibration - Parameters • Shaft Wobble – Eccentricity of Stirring Device • assumed to alter the pattern of fluid movement in both paddle and basket apparatus and therefore may influence the dissolution rate • can be measured with a micrometer* • measured is the sum of distance between both sides (180°) of the axis of rotation *

34. Mechanical calibration - Parameters • Centering (Vessel / Shaft) • the axis of the rotating shaft must coincide at allpoints with the axis of the vessel to within + 1 mm • “the shaft has to positioned so that is axis is not more than 2^mm at any point from the vertical axis of the vessel and rotates smoothly without significant wobble” *

35. Mechanical calibration • Measurement tools • all mechanical tools used forcalibration should be certifiedto assure their reliability • the results of mechanical calibration have to be documented

36. Apparatus suitability test (USP) • if all parts ( apparatus, geometry, test conditions, analytical method) are within compliance – why perform an apparatus suitability test? • the apparatus suitability is to check for parameters that can not be conveniently measured (vibration, vessel cleanliness, medium degassing ...) and also to provide an overall check of the system

37. Apparatus suitability test (USP) • first established in 1978 • routine test in most pharmaceutical laboratories • calibration at regular intervals (every 6 months) • standard calibrator substances according USP chapter <711> • only the method(s) to be used have to be calibrated ! • if six units are tested – all have to pass

38. Apparatus suitability test (USP) • Standard calibrators according to USP chapter <711> • Apparatus I, II and V: • disintegrating type • USP Prednisone Tablets • nondisintegrating type • USP Salicylic acid Tablets • Apparatus III: • USP Chlorpheniramine Maleate Extended-Release Tablets

39. Information supplied with calibrators http:/www.usp.org/referenceStandards/useAndstorage/calibrators.html

40. Apparatus suitability test (USP) • USP Prednisone Tablets RS – current lot P0E203 • (10 mg nominal prednisone content per tablet) • disintegrating type • paddle and basket, 50 rpm • 500 ml deaerated water, 37°C • quantity of prednisone released after 30 minutes is determined • specified ranges Lot P0E203: Apparatus 1: 47-82 % Apparatus 2: 37-70 %

41. Apparatus suitability test (USP) • USP Salicylic acid Tablets RS – current lot Q0D200 • (300 mg nominal salicylic acid content per tablet) • nondisintegrating type • paddle and basket, 100 rpm • 900 ml deaerated phosphate buffer, 37°C • quantity of salicylic acid, released after 30 minutes is determined • specified ranges Lot Q0D200: Apparatus 1: 23-30 % Apparatus 2: 17-25 %

42. Apparatus suitability test (USP) • Controversies regarding the current test • the variability in the intrinsic performance of the USP calibrator tablets is so great that it exceeds the variability in intrinsic performance of modern test dissolution assemblies • this variability becomes obvious in both vessel-to-vessel variability and inter-laboratory variability of results for a given lot of calibrators

43. Troubleshooting • Calibrator Tablets: • always check the incoming tablets ! • right lot of calibrators ? • are the tablets broken, fused or severely chipped ? • particularly salicylic acid tablets are often subject to sublimation ( dust on the tablets and the inner surface of the container) • use correct storage conditions ! • take the tablets out of the original container immediately before test !

44. Troubleshooting • Standard / Standard solution: • USP Standard used ? • drying procedure conducted ? • standard solution prepared on day of test ? • standard solution filtered in the same manner as sample ? • amount of alcohol used in the standard < 5% ?

45. Troubleshooting • Vibration • vibration produces unwanted variation in dissolution data and mostly results in an increased dissolution rate • internal vibration may be caused e.g. from frayed drive belts • external vibration may be caused by e.g. magnetic stirrers, centrifuges, vacuum pumps, old fridges, nearby construction, ... • inability to properly measure vibration levels at various points within an apparatus is the main reason why calibrator tablets were originally developed

46. Troubleshooting Vibration effects – case example: Effect of vibration levels of the dissolution apparatus on the dissolution rate of enteric coated granules of Cefalexin. The vertical dotted line indicates 0.05 m/s2. Kaniwa N. et al. (1998) Int J Pharm, 175, 119-129 „Low vibration“: < 0.05 m/s2 „High vibration“: > 0.05 m/s2

47. Troubleshooting • Vibration: • dissolution equipment placed planar ? • drive chain or belt free of tension and/or dirt ? • torn parts replaced ? • correctly functioning gear plates ? • individual spindles are not surging ? • bench/table stable ? • no sources of vibration nearby ?

48. Troubleshooting • Dissolution medium: • correctly degassed ? • correct amount used (900/500 ml) ? • correct amount dosed (weight/volume) ? • dosing procedure gentle (resaturation/spillage) ? • buffer correct (pH + 0.05 units, buffer salts, molarity) ? • correct temperature during test (32°C / 37°C + 0.5°C)? • evaporation during test negligible ?

49. Troubleshooting • Importance of degassing: • insufficient degassing may result in decreased dissolution rates of several drugs • e.g. prednisone tablets but also a range of poorly soluble drugs are very sensitive to the amount of dissolved gases in the dissolution medium • the degassing procedure should therefore be efficient and reproducible for every test

50. Troubleshooting • Deaeration method USP • heat the dissolution medium to about 41°C • vacuum filter through a 0.45-µm-porosity membrane into a flask, stirring with a magnetic stirrer • continue to draw a vacuum and stir for an additional 5 min • gently transfer the medium directly into the vessel • rotating the apparatus 2 shafts to speed equilibration to 37°C is discouraged!!! • use medium promptly after equilibration