Design and Calibration of A Dissolution Test Equipment

Dr.
Sandra Klein, 06/2007

1
Design and Calibration of a
Dissolution Test Equipment

Training Workshop on Dissolution,
Pharmaceutical Product Interchangeability
and Biopharmaceutical Classification System.
Kyiv, Ukraine, J une 25 - 27 2007
Dr. Sandra Klein, Institute of Pharmaceutical Technology,
Johann Wolfgang Goethe University Frankfurt
Dr. Sandra Klein, 06/2007
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

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
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
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
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
Disadvantages
disintegration-dissolution
interaction

hydrodynamic dead zone
under the basket

degassing is particularly
important

limited volume
sink conditions for poorly
soluble drugs ?

9
10
Apparatus 2 - Paddle
Useful for
tablets
capsules
beads
delayed release / enteric
coated dosage forms

Standard volume
900/1000 ml

Method of first choice !!!

11
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
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
16
Apparatus 3 Reciprocating cylinder
Useful for
tablets
beads
controlled release formulations

Standard volume
200-250 ml per station

17
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
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
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
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
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]
A
b
s
o
r
p
t
i
o
n

@

2
4
2

n
m
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

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
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
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
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
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
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
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
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
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

39
Information supplied with calibrators

http:/www.usp.org/referenceStandards/useAndstorage/calibrators.html
40
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, 37C

quantity of prednisone released after 30 minutes is determined

specified ranges Lot P0E203: Apparatus 1: 47-82 %
Apparatus 2: 37-70 %

41
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, 37C

quantity of salicylic acid, released after 30 minutes is determined

specified ranges Lot Q0D200: Apparatus 1: 23-30 %
Apparatus 2: 17-25 %

42
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
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
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
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
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
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
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
49
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
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
51
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
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
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
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
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

automated mixing of water
and concentrate

preheating of medium

deaeration
(vacuum and stirring)

media can be dispensed
directly into the vessel
Media preparation
57
Offline system
58
Online system
59

On- / Offline system
60

HPLC - online system
61
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

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
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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