Transcript WHO Prequalification Programme June 2007

Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
Why do Dissolution Testing?
Prof. Dr. Jennifer Dressman
Johann Wolfgang Goethe University
Frankfurt am Main, Germany
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
 What is Dissolution?
 Dissolution is the primary quality control test to
determine whether a drug product can release its
active pharmaceutical ingredient(s) in a timely
manner.
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
 What factors influence dissolution from drug
products?
– The properties of the API
– The quality and design of the drug product
– The conditions under which the test is run
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
 Properties of the API important to dissolution include
– The solubility of the API in the dissolution medium, which is
usually an aqueous buffer solution (may contain surfactants as
well)
– Whether the API is hydrophilic or hydrophobic (ease of surface
wetting)
– The particle size of the API
– Whether the API is crystalline or amorphous in the drug product
– If there are polymorphs, which polymorph is present
– If a salt form is used
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
 Properties of the drug product important to
dissolution include
– Whether the product is designed to immediately
release the API, to delay release, or to release the
drug over time.
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
 Properties of the drug product important to
dissolution include
– The composition of the drug product
(which excipients are used)
- The manufacturing parameters
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
 Dissolution test parameters important to the
results
–
–
–
–
–
–
Choice of apparatus
Choice of stirring/dip/flow rate
Choice of dissolution medium
Duration of test
Sampling method and analysis
Standardization of the method
is also important to obtaining
meaningful results.
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
API properties
Dissolution:
An interplay of three groups
of factors
WHO Prequalification Programme
Formulation
Analytics
Design
In-Vitro Drug Release
June 2007
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
Applications of Dissolution in the Pharmaceutical Industry
1. As a formulation design aid (since formulation can profoundly affect dissolution
behaviour)
2. As a quality control measure immediately after production for batch release
3. As a quality control measure to check performance during the shelf life
4. To predict performance under various dosing conditions („biorelevant“
methods)
5. To verify that the quality of a product is not adversely affected when there is a
change in excipients or manufacturing method (can sometimes be used instead of
a pharmacokinetic study)
6. To obtain approval for a multisource drug product („generic“ version of an
existing drug product) – in certain cases a pharmacokinetic study is not required.
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
1. Dissolution as an aid to formulation in the
Pharmaceutical Industry:
The dissolution of the pure API is determined. If this is too slow for the
target release rate from the API, the formulation has to be enhanced
to improve the release characteristics.
100
80
dissolved (%)
chloroquine diphosphate dissolved / % of label claim
Dissolution SGFsp
Itraconazole
60
40
Resochin Tabletten, film coated tablets
Chlorochin 250 mg Berlin-Chemie, film coated tablets
Weimerquin Tabletten, uncoated tablets
chloroquine diphosphate drug substance
20
90
80
70
60
50
40
30
20
10
0
0
30
60
90
120
150
180
210
time (min)
0
0
10
20
30
40
Chloroquine
50
time / min
WHO Prequalification Programme
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chlqphos_drug_ph68
June 2007
SD Pharmacoat 603
PM Pharmacoat 603
Sporanox (2X100mg)
SD Luviskol VA64
PM Luviskol VA64
240
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
2.&3. Dissolution as a quality control measure for batch
release, and to ensure continued quality during the shelf
life.
Here it is important to have a well-designed dissolution test that can
detect batches with poor quality without rejecting batches of
adequate quality.
The USP and, recently, the International Pharmacopeia, make
recommendations for specific drug products
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability and
Biopharmaceutics Classification
WHO Standard dissolution method for highly soluble APIs
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–
–
–
–
–
Paddle Apparatus
500 mL
SIFsp/IP Phosphate Buffer pH 6.8
75 Rpm
37 °C
Sampling at 30 min.
 Specification:
– >85 % release within 30 min.
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability and
Biopharmaceutics Classification
Widely used for:
•
Why the Paddle Apparatus?
Tablets and capsules
(can also be used for pellets,
MR dosage forms)
Advantages:
•
easy to use, robust
•
long experience
•
Many examples in USP
Disadvantages:
•
•
possibility of coning
Method of choice for
IR – dosage forms
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability and
Biopharmaceutics Classification
 Why 500 mL medium?
– Corresponds approximately to the volume of the contents in
the upper GI tract in the fasting state plus a glass of water.
 Why 75 rpm?
– Avoids coning problems in most cases
– For most drugs and drug products studied to date, if there is
no coning, the results are very similar at 50 and 100 rpm.
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability and
Biopharmaceutics Classification
Volumes in the upper GI tract after two types of meals
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability and
Biopharmaceutics Classification
 Why 37°C?
– Corresponds to the temperature of the GI fluids
– For transdermal products a lower temperature, usually 32°C
is used, since this is closer to skin temperature.
 Why a pH 6.8 Phosphate buffer?
– Corresponds to one of the three pH values stipulated by the
FDA in its biowaiver guidance
– Both the USP and IP buffers have good buffer capacity.
Nevertheless, the pH should be checked at the end of the
experiment.
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability and
Biopharmaceutics Classification
Case Example: Doxycycline hyclate
 Solubility:
– SGFsp pH 1.2
– Aq. puricata
– SIFsp pH 6.8
40.1 mg/mL
> 50.0 mg/mL
28.7 mg/mL
USP Method
Paddle Apparatus, 75 rpm
Paddle 4.5 cm above the vessel bottom
900 mL de-ionized water
30 min. for Capsules, 90 min. for
Tablets
95 %
WHO Method
Paddle Apparatus, 75 rpm
Standard paddle position
500 ml pH 6.8 phosphate buffer
>85% release in 30 min.
 Dose – 230 mg
 Permeability:
– Bioavailability:
– Cmax, p.o. admin. 2–3 h
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability and
Biopharmaceutics Classification
Comparison of dissolution results for products that
contain 230.8 mg Doxycycline hyclate
120
doxycycline dissolved / % of label claim
doxycycline dissolved / % of label claim
120
100
80
60
40
doxy 200 von ct, ct-Arzneimittel GmbH, batch B20499
Doxycyclin STADA 200 mg Filmtabletten, STADApharm GmbH, batch 5611
Azudoxat 200 mg, Azupharma GmbH & Co., batch 11608
Doxy-Diolan 200, BRAHMS Arzneimittel GmbH, batch 0011
Doxy-Wolff 200, DR. AUGUST WOLFF Arzneimittel GmbH, batch 106010
20
100
80
60
40
doxy 200 von ct, ct-Arzneimittel GmbH, batch B20499
Doxycyclin STADA 200 mg Filmtabletten, STADApharm GmbH, batch 5611
Azudoxat 200 mg, Azupharma GmbH & Co., batch 11608
Doxy-Diolan 200, BRAHMS Arzneimittel, batch 0011
Doxy-Wolff 200, DR. AUGUST WOLFF Arzneimittel, batch 106010
20
0
0
0
10
20
30
40
50
60
70
80
90
100 110 120 130
time / min
10
20
30
40
50
60
70
80
90
time / min
doxycyc_sif
doxycyc_water
WHO Method
USP Method
WHO Prequalification Programme
0
June 2007
100
Dissolution, Pharmaceutical Product Interchangeability and
Biopharmaceutics Classification
 Why a specification of 85% in 30 min?
– Corresponds to the specification stipulated by the FDA in its
biowaiver guidance
– During development of the method, it is advisable to
generate a dissolution profile (e.g. samples at 10, 20, 30, 45
and 60 mins) so that the dissolution is adequately
characterized
– For determination of bioequivalence, it must be shown that
the dissolution profile of the test product varies by less than
10% from the comparator product (usually by f2
comparison)
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability and
Biopharmaceutics Classification
WHO Standard dissolution method for highly soluble APIs
–
–
–
–
–
–
Paddle Apparatus
500 mL
SIFsp/IP Phosphate Buffer pH 6.8
75 Rpm
37 °C
Sampling at 30 min.
 Specification:
– >85 % release within 30 min.
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability and
Biopharmaceutics Classification
Dissolution tests proposed for Pharm. Int.
 Chloroquine phosphate and sulfate
 Doxycyline hyclate
doxycycline dissolved / % of label claim
100
 Ethambutol dihydrochloride
 Isoniazid
 Metronidazole
 Primaquine diphosphate
60
40
doxy 200 von ct, capsules
Doxycyclin STADA 200 mg Filmtabletten, film coated tablets
Azudoxat 200 mg, uncoated tablets
Doxy-Diolan 200 mg, film coated tablets
Doxy-Wolff 200, film coated tablets
doxycycline hyclate drug substance
20
0
 Pyrazinamide
0
10
20
30
time / min
 Rifampicin
WHO Prequalification Programme
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June 2007
40
50
60
doxycyc_drug_sif
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
However, many APIs are poorly soluble, creating
dissolution problems
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
Some dissolution test options for poorly soluble
drugs
1. Adjust the pH of the medium
2. Add a surfactant to the medium
3. Increase the volume of the dissolution medium
4. Increase the duration of the dissolution test
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
Some dissolution test options for poorly soluble
drugs: Adjust the pH of the medium
100000
61202
16011
10000
559
1000
124
Conc. (mg/l)
100
10
3,9
1,7
1
0,4
0,1
pH 1.2
pH 2
pH 3
pH 4
WHO Prequalification Programme
pH 5
pH 6.5
June 2007
pH 8
pH-dependent solubility:
weak base
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
Some dissolution test options for poorly soluble
drugs: Adjust the pH of the medium
100
% Freisetzung
80
SGF pH2
60
Acetatpuffer pH5
40
pH-dependent solubility:
weak base
20
0
0
30
60
90
120
150
Zeit (min)
WHO Prequalification Programme
June 2007
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Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
Some dissolution test options for poorly soluble drugs:
Add a surfactant to the medium
Increasing levels of sodium lauryl
sulfate (0.1-1%) increase
dissolution of danazol (left panel)
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
Some dissolution test options for poorly soluble drugs:
Increase the volume of the medium
Using the Flow-Through tester,
volumes of up to several liters can
be used.
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
4. Dissolution to predict performance under various dosing
conditions:
One question that often comes up is whether the API release is affected
by coadministration of a meal.
Danazol absorption
Danazol dissolution
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
5.&6. Dissolution to obtain (continued) approval to market
a drug product
In certain circumstances, dissolution testing can serve as a
surrogate for a bioequivalence study in humans. This is
referred to as a „biowaiver“.
One example is when a change has to be made to the
formulation or manufacture of an existing product
Another example is in the approval of a new multisource
product.
WHO Prequalification Programme
June 2007
Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
 What is Dissolution?
 Dissolution is an important tool in the development of
new drug products, crucial to quality assurance for
existing products and can be a key tool in the
approval of new multisource drug products.
WHO Prequalification Programme
June 2007
„Must have“ Literature
 „Handbook of Dissolution Testing 3. Auflage“
Roy Hanson & Vivian Gray
Published by Dissolution Technologies (2005)
www.dissolutiontechnologies.com
 „Pharmaceutical Dissolution Testing“
Edited by J. Dressman & J. Krämer
Published by Taylor and Francis
www.taylorandfrancis.com
 General Chapter on Dissolution Testing (United States Pharmacopeia)
WHO Prequalification Programme
June 2007