design_calibration-EN-1.ppt

5/25/2018 design_calibration-EN-1.ppt

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Dr. Sandra Klein, 06/20071

Design and Calibration of a

Dissolution Test Equipment

Train ing Work shop on Disso lut ion,

Pharmaceutical Produ ct Interchangeabi l i ty

and Biopharmaceut ical Classi f icat ion System.Kyiv, Ukraine, June 25 - 27 2007

Dr. Sandra Klein, Institute of Pharmaceutical Technology,

Johann Wolfgang Goethe University Frankfurt


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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


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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


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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 vitrosimulation 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 routineinvestigations



Apparatus 1 - BasketDisadvantages

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 volumesink 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 3Reciprocating 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 4Flow-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


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Apparatus 4Flow-Through CellAdvantages

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


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Apparatus 4Flow-Through Cell


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Apparatus 5Paddle over disk

Useful for

transdermal patches

Standard volume

900 ml


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Apparatus 5Paddle over disk

Advantages

standard equipment

(paddle) can be used, onlyadd a stainless steel disk

assembly

Disadvantages

disk assembly restricts

patch size


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Apparatus 6Rotating cylinderUSP apparatus 7Reciprocating holder

most probably will be

removed from the USP !!!


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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 !


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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@2

42nm
http://www.erweka.com/DE/Index/Products/Dissolution_Testers/Stirrer_Type/Accessoires/images/QA_station_DT800_smaller.JPG


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CalibrationWhy ?

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)


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Factors that may affect reliability of the testProper 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


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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


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Mechanical calibration - ParametersHeightVertical 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 cmis specified

different kinds of height gauges can be used

to align or check* this parameter *


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Mechanical calibration - ParametersRotational SpeedStirring 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 %

*


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Mechanical calibration - ParametersShaft WobbleEccentricity of Stirring Device

assumed to alter the pattern of fluid movement in both paddle

and basket apparatus and therefore may influence thedissolution rate

can be measured with a micrometer*

measured is the sum of distance between bothsides (180) of the axis of rotation

*


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Mechanical calibration - ParametersCentering (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

*


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Mechanical calibrationMeasurement tools

all mechanical tools used for

calibration should be certified

to assure their reliability

the results of mechanical

calibration have to be documented


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Apparatus suitability test (USP)

if all parts ( apparatus, geometry, test conditions, analytical

method) are within compliancewhy perform an apparatus

suitability test?

the apparatus suitability is to check for parameters that can not be

conveniently measured (vibration, vessel cleanliness, mediumdegassing ...) and also to provide an overall check of the system


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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

only the method(s) to be used have to be calibrated !

if six units are testedall have to pass


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Apparatus suitability test (USP)Standard calibrators according to USP chapter

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


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Information supplied with calibrators

http:/www.usp.org/referenceStandards/useAndstorage/calibrators.html


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Apparatus suitability test (USP)USP Prednisone Tablets RS cu rrent lo t P0E203

(10 mg nominal prednisone content per tablet)

disintegrating type

paddle and basket, 50 rpm

500 ml deaerated water, 37C

quantity of prednisone released after 30 minutes is determined

specified ranges Lot P0E203: Apparatus 1: 47-82 %

Apparatus 2: 37-70 %


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Apparatus suitability test (USP)USP Salicylic acid Tablets RS cu rrent lo t Q0D200

(300 mg nominal salicylic acid content per tablet)

nondisintegrating type

paddle and basket, 100 rpm

900 ml deaerated phosphate buffer, 37C

quantity of salicylic acid, released after 30 minutes is determined

specified ranges Lot Q0D200: Apparatus 1: 23-30 %

Apparatus 2: 17-25 %


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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 lotof calibrators


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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


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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


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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


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Vibration effectscase 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


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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


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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 (32C / 37C + 0.5C)?

evaporation during test negligible ?

Troubleshooting


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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


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Deaeration method USP

heat the dissolution medium to about 41C

vacuum filter through a 0.45-m-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 37C is

discouraged!!!

use medium promptly after equilibration

Troubleshooting


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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


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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


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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


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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


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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


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automated mixing of water

and concentrate

preheating of medium

deaeration

(vacuum and stirring)

media can be dispenseddirectly into the vessel

Media preparation


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Offline system


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Online system


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On- / Offline system


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HPLC - online system


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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


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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. Calibrationthe 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 The dissolution procedure: development and validation

Pharmacopoeial Forum 30 (1) [Jan.-Feb. 2004]

Of general interest:

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

Suggested reading


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Dr. Sandra Klein

Johann Wolfgang Goethe UniversityInstitute of Pharmaceutical Technology

9 Max von Laue Street

Frankfurt, 60438, Germany

e-mail: [email protected]

Documents

design_calibration-EN-1.ppt