Design calibration en (1)

dissolution

1. Dr. Sandra Klein, 06/20071
Design and Calibration of aDesign and Calibration of a
Dissolution Test EquipmentDissolution Test Equipment
Training Workshop on Dissolution, Training Workshop on Dissolution,
Pharmaceutical Product Interchangeability Pharmaceutical Product Interchangeability
and Biopharmaceutical Classification System.and Biopharmaceutical Classification System.
Kyiv, Ukraine, June 25 - 27 2007 Kyiv, Ukraine, June 25 - 27 2007
Dr. Sandra Klein, Institute of Pharmaceutical Technology, Dr. Sandra Klein, Institute of Pharmaceutical Technology,
Johann Wolfgang Goethe University FrankfurtJohann Wolfgang Goethe University Frankfurt

2. Dr. Sandra Klein, 06/20072
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. Dr. Sandra Klein, 06/20073
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. Dr. Sandra Klein, 06/20074
Official dissolution apparatus
USP 30 classification
1.Rotating Basket (Ph.Eur./BP/JP)
2.Paddle (Ph.Eur./BP/JP)
3.Reciprocating Cylinder (Ph.Eur.)
4.Flow Through Cell (Ph.Eur./BP/JP)
5.Paddle Over Disk (Ph.Eur.)
6.Rotating Cylinder (Ph.Eur.)
7.Reciprocating Holder

5. Dr. Sandra Klein, 06/20075
Which type of dissolution apparatus ?
Depends on intention
1.Quality control
•examining batch homogeneity
•examining batch to batch conformity
•examining stability
2.Research & Development
• examining drug release behavior of preformulations
• in vitro simulation of the gastrointestinal passage
3.IVIVC

6. Dr. Sandra Klein, 06/20076
Apparatus 1 - Basket
Useful for
•capsules
•beads
•delayed release / enteric
coated dosage forms
•floating dosage forms
•surfactants in media
Standard volume
•900/1000 ml
•1, 2, 4 liter vessels

7. Dr. Sandra Klein, 06/20077
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. Dr. Sandra Klein, 06/20078
Apparatus 1 - Basket
Disadvantages
•disintegration-dissolution
interaction
•hydrodynamic „dead zone“
under the basket
degassing is particularly
important
•limited volume 
sink conditions for poorly
soluble drugs ?

9. Dr. Sandra Klein, 06/20079
Apparatus 1 - Basket

10. Dr. Sandra Klein, 06/200710
Apparatus 2 - Paddle
Useful for
•tablets
•capsules
•beads
•delayed release / enteric
coated dosage forms
Standard volume
•900/1000 ml
Method of first choice !!!

11. Dr. Sandra Klein, 06/200711
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. Dr. Sandra Klein, 06/200712
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. Dr. Sandra Klein, 06/200713
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. Dr. Sandra Klein, 06/200714
Coning

15. Dr. Sandra Klein, 06/200715
Apparatus 2 - Paddle

16. Dr. Sandra Klein, 06/200716
Apparatus 3 – Reciprocating cylinder
Useful for
•tablets
•beads
•controlled release formulations
Standard volume
•200-250 ml per station

17. Dr. Sandra Klein, 06/200717
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. Dr. Sandra Klein, 06/200718
Apparatus 3 – Reciprocating cylinder

19. Dr. Sandra Klein, 06/200719
Apparatus 4 – Flow-Through Cell
Useful for
•low solubility drugs
•microparticulates
•implants
•suppositories
•controlled release formulations
Variations
•open system
•closed system

20. Dr. Sandra Klein, 06/200720
Cell types

Tablets 12 mm Tablets 22,6 mm Powders / Granules Implants Suppositories /
Soft gelatine capsules

21. Dr. Sandra Klein, 06/200721
Apparatus 4 – Flow-Through Cell
Advantages
•easy to change media pH
•pH-profile possible
•sink conditions
•different modes
a) open system
b) closed system
Disadvantages
•Deaeration necessary
•high volumes of media
•labor intensive

22. Dr. Sandra Klein, 06/200722
Apparatus 4 – Flow-Through Cell

23. Dr. Sandra Klein, 06/200723
Apparatus 5 – Paddle over disk
Useful for
•transdermal patches
Standard volume
•900 ml

24. Dr. Sandra Klein, 06/200724
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. Dr. Sandra Klein, 06/200725
Apparatus 6 – Rotating cylinder
USP apparatus 7 – Reciprocating holder
most probably will be
removed from the USP !!!

26. Dr. Sandra Klein, 06/200726
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. Dr. Sandra Klein, 06/200727
Qualification of Dissolution Systems
Prednisone
y = 0,0432x - 0,0039
0
0,5
1
1,5
2
2,5
3
0 102030405060
Concentration [mg/L]
A
b
s
o
r
p
t
i
o
n

@

2
4
2

n
m

28. Dr. Sandra Klein, 06/200728
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. Dr. Sandra Klein, 06/200729
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. Dr. Sandra Klein, 06/200730
Mechanical calibration
•Verification of physical parameters specified in the
pharmacopoeia: USP apparatus 1 and 2
Calibration parameter Current USP tolerance Point of measuring
Height 25 + 2 mm paddle/basket bottom
Basket wobble + 1 mm as runout bottom of basket
Rotational speed + 4 % not applicable
Vessel/shaft centering + 2 mm from center line center line
Vessel temperature 37 + 0.5 °C not applicable
Bath levelness level base plate
Shaft/paddle wobble + 1 mm as runout above top of paddle
Paddle/basket dimensions see USP see USP
Vessel dimensions see USP see USP

31. Dr. Sandra Klein, 06/200731
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 used
to align or check* this parameter
*

32. Dr. Sandra Klein, 06/200732
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 a
digital tachometer*
–the compendia specify a rotational speed
tolerance of + 4 %
*

33. Dr. Sandra Klein, 06/200733
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. Dr. Sandra Klein, 06/200734
Mechanical calibration - Parameters
Centering (Vessel / Shaft)
–the axis of the rotating shaft must coincide at all
points 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. Dr. Sandra Klein, 06/200735
Mechanical calibration
Measurement tools

•all mechanical tools used for
calibration should be certified
to assure their reliability
•the results of mechanical
calibration have to be documented

36. Dr. Sandra Klein, 06/200736
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. Dr. Sandra Klein, 06/200737
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. Dr. Sandra Klein, 06/200738
Apparatus suitability test (USP)
Standard calibrators according to USP chapter <711>
Apparatus I, II and V:
1.disintegrating type
– USP Prednisone Tablets
1.nondisintegrating type
– USP Salicylic acid Tablets
Apparatus III:
•USP Chlorpheniramine Maleate Extended-Release Tablets

39. Dr. Sandra Klein, 06/200739
Information supplied with calibrators
http:/www.usp.org/referenceStandards/useAndstorage/calibrators.html

40. Dr. Sandra Klein, 06/200740
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. Dr. Sandra Klein, 06/200741
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. Dr. Sandra Klein, 06/200742
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. Dr. Sandra Klein, 06/200743
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 !
Troubleshooting

44. Dr. Sandra Klein, 06/200744
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% ?
Troubleshooting

45. Dr. Sandra Klein, 06/200745
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
Troubleshooting

46. Dr. Sandra Klein, 06/200746
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/s
2
.
Kaniwa N. et al. (1998)
Int J Pharm, 175, 119-129
„Low vibration“: < 0.05 m/s
2
„High vibration“: > 0.05 m/s
2
Troubleshooting

47. Dr. Sandra Klein, 06/200747
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 ?
Troubleshooting

48. Dr. Sandra Klein, 06/200748
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 ?
Troubleshooting

49. Dr. Sandra Klein, 06/200749
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
Troubleshooting

50. Dr. Sandra Klein, 06/200750
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
Troubleshooting

51. Dr. Sandra Klein, 06/200751
Alternative deaeration methods
•the USP states that „other validated deaeration techniques for
removal of dissolved gases may be used“
•other techniques include:
®heating
®sonication
®vacuum
®helium sparging (expensive)
Troubleshooting

52. Dr. Sandra Klein, 06/200752
Sampling
•take each sample at the correct time point
 sampling time points (+ 2%)
•use a single glass syringe for each vessel
•sample from the right location within the vessel
 between media surface and top of the
paddle blade
 n.l.t. 10 mm from vessel wall
Troubleshooting

53. Dr. Sandra Klein, 06/200753
Sampling
•always use a suitable filter  check filter adsorption
•check the clearity of the filtered sample
•filter the sample immediately after sampling
•for automated sampling also check the tubings
Troubleshooting

54. Dr. Sandra Klein, 06/200754
Physical conditions of the apparatus
•vessels scrupulously clean ?
•vessel surface smooth and curvature appropriate ?
Apparatus 1
•the conditions of the baskets, particularly of their clips is critical
•check all baskets for corrosion and blocked meshes before using
them
•align the air holes to prevent air cushions emerging during the test
Troubleshooting

55. Dr. Sandra Klein, 06/200755
Advantages
•high throughput of samples
•minimizes analyst-to-analyst variability in sampling and filtration
•reduces the average costs per analysis
•very promising for QC purposes
(Semi) Automation

56. Dr. Sandra Klein, 06/200756
•automated mixing of water
and concentrate
•preheating of medium
•deaeration
(vacuum and stirring)
•media can be dispensed
directly into the vessel
Media preparation

57. Dr. Sandra Klein, 06/200757
Offline system

58. Dr. Sandra Klein, 06/200758
Online system

59. Dr. Sandra Klein, 06/200759
On- / Offline system

60. Dr. Sandra Klein, 06/200760
HPLC - online system

61. Dr. Sandra Klein, 06/200761
•always validate automated methods, including analytical and
sampling methods
•validation should be performed using manual analysis,
withdrawing samples at the same times and comparing to the
automated results:
®not highly variable dissolution results: two concurrent
runs
®highly variable dissolution results: simultaneous
sampling
•pay attention to automated dilution and filtering processes
Automation

62. Dr. Sandra Klein, 06/200762
•FIP Guidelines for dissolution testing of solid oral products.
Dissolution Technologies 4:5-14 (1997).

•SM Diebold, JB Dressman. Dissolved oxygen as a measure for de- and re-aeration of aqueous
media for dissolution testing.
Dissolution Technologies 5: 13-16 (1998).
•S Qureshi. Calibration – the USP dissolution apparatus suitability test.
Drug Inf. J. 30, 1055-1061 (1996).
•N Kaniwa et al. Collaborative study on the development of a standard for evaluation of vibration
levels for dissolution apparatus.
Int. J. Pharm. 175: 119-129 (1998).
•VA Gray, CK, Brown, JB Dressman, LJ Leeson. A new general information chapter on
dissolution.
Pharmacopoeial Forum 27 (6) [Nov.-Dec. 2001]
•W Brown. General information <1092> The dissolution procedure: development and validation
Pharmacopoeial Forum 30 (1) [Jan.-Feb. 2004]

Of general interest:
•Dissolution Technologies: http://www.dissolutiontech.com
Suggested reading

63. Dr. Sandra Klein, 06/200763
Dr. Sandra Klein
Johann Wolfgang Goethe University
Institute of Pharmaceutical Technology
9 Max von Laue Street
Frankfurt, 60438, Germany
e-mail: [email protected]