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 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


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 systemb) 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]

Ab

sorp

tio

n @

242

nm


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 usedto 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 adigital 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 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”

*


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

2. 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:heatingsonicationvacuumhelium 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 dispenseddirectly 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 validationPharmacopoeial Forum 30 (1) [Jan.-Feb. 2004]

Of general interest:

• Dissolution Technologies: http://www.dissolutiontech.com

Suggested reading


Dr. Sandra KleinJohann Wolfgang Goethe University

Institute of Pharmaceutical Technology9 Max von Laue Street

Frankfurt, 60438, Germany

e-mail: [email protected]

Design calibration en (1)

Design

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