Design calibration en (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 InterchangeabilityPharmaceutical Product Interchangeability
and Biopharmaceutical Classification System.and Biopharmaceutical Classification System.
Kyiv, Ukraine, June 25 - 27 2007Kyiv, 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

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

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

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

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

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

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

Disadvantages
• disintegration-dissolution
interaction
• hydrodynamic „dead zone“
under the basket
degassing is particularly
important
• limited volume 
sink conditions for poorly
soluble drugs ?

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

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

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

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“

Coning

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

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

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

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

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

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

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

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

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 !

Qualification of Dissolution Systems
Prednisone
y = 0,0432x - 0,0039
0
0,5
1
1,5
2
2,5
3
0 10 20 30 40 50 60
Concentration [mg/L]
Absorption@242nm

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“)

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>

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

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 *

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 %
*

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
*

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”
*

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

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

• 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

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

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

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 %

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 %

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

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

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

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

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
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 ?
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 ?
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
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
Troubleshooting

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

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

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

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

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

• automated mixing of water
and concentrate
• preheating of medium
• deaeration
(vacuum and stirring)
• media can be dispensed
directly into the vessel
Media preparation

Offline system

Online system

On- / Offline system

HPLC - online system

• 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

• 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

Dr. Sandra Klein
Johann Wolfgang Goethe University
Institute of Pharmaceutical Technology
9 Max von Laue Street
Frankfurt, 60438, Germany
e-mail: Sandra.Klein@em.uni-frankfurt.de

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