WHO Prequalification Programme June 2007 Why do Dissolution Testing? Prof. Dr. Jennifer Dressman Johann Wolfgang Goethe University Frankfurt am Main, Germany.

WHO Prequalification Programme June 2007

Why do Dissolution Testing?

Prof. Dr. Jennifer Dressman

Johann Wolfgang Goethe University

Frankfurt am Main, Germany

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.




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


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




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.




Properties of the drug product important to dissolution include

– The composition of the drug product (which excipients are used)

- The manufacturing parameters




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.






Dissolution:

An interplay of three groups of factors

API properties

Analytics

In-Vitro Drug Release

Formulation

Design




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.




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.

0 10 20 30 40 50 600

20

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chlqphos_drug_ph68

Resochin Tabletten, film coated tablets Chlorochin 250 mg Berlin-Chemie, film coated tablets Weimerquin Tabletten, uncoated tablets chloroquine diphosphate drug substancec

hlo

roq

uin

e d

iph

osp

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te d

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d /

% o

f la

be

l cla

im

time / min

Dissolution SGFsp

0102030405060708090

0 30 60 90 120 150 180 210 240

time (min)

dis

solv

ed

(%

)SD Pharmacoat 603 SD Luviskol VA64PM Pharmacoat 603 PM Luviskol VA64Sporanox (2X100mg)

Chloroquine

Itraconazole




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


– 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 Standard dissolution method for highly soluble APIs


Widely used for:

• 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


Why the Paddle Apparatus?


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.



Volumes in the upper GI tract after two types of meals



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.



Case Example: Doxycycline hyclateCase Example: Doxycycline hyclateSolubility:

– SGFsp pH 1.2 40.1 mg/mL– Aq. puricata > 50.0 mg/mL– SIFsp pH 6.8 28.7 mg/mL

Dose – 230 mg

Permeability:– Bioavailability: 95 %– Cmax, p.o. admin. 2–3 h

USP MethodPaddle Apparatus, 75 rpmPaddle 4.5 cm above the vessel bottom

900 mL de-ionized water30 min. for Capsules, 90 min. for

Tablets

WHO MethodPaddle Apparatus, 75 rpmStandard paddle position

500 ml pH 6.8 phosphate buffer>85% release in 30 min.



Comparison of dissolution results for products that contain 230.8 mg Doxycycline hyclate

Comparison of dissolution results for products that contain 230.8 mg Doxycycline hyclate

USP Method WHO Method

0 10 20 30 40 50 60 70 80 90 100 110 120 1300

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doxycyc_water

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 106010do

xycy

clin

e di

ssol

ved

/ % o

f lab

el c

laim

time / min

0 10 20 30 40 50 60 70 80 90 1000

20

40

60

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100

120

doxycyc_sif

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

doxy

cycl

ine

diss

olve

d / %

of l

abel

cla

imtime / min



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)



– 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 Standard dissolution method for highly soluble APIs


Dissolution tests proposed for Pharm. Int.Dissolution tests proposed for Pharm. Int. Chloroquine phosphate and sulfate

Doxycyline hyclate

Ethambutol dihydrochloride

Isoniazid

Metronidazole

Primaquine diphosphate

Pyrazinamide

Rifampicin0 10 20 30 40 50 60

0

20

40

60

80

100

doxycyc_drug_sif

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

doxy

cycl

ine

diss

olve

d / %

of l

abel

cla

im

time / min



However, many APIs are poorly soluble, creating dissolution problems




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




Some dissolution test options for poorly soluble drugs: Adjust the pH of the medium



61202

16011

559

124

3,91,7

0,4

0,1

1

10

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1000

10000

100000

pH 1.2 pH 2 pH 3 pH 4 pH 5 pH 6.5 pH 8

Con

c. (

mg/

l) pH-dependent solubility: weak base


Some dissolution test options for poorly soluble drugs: Adjust the pH of the medium



pH-dependent solubility: weak base

0

20

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60

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100

0 30 60 90 120 150 180

Zeit (min)

% F

reis

etzu

ng SGF pH2

Acetatpuffer pH5


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)


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.




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 dissolution Danazol absorption




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.




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.


„Must have“ Literature„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 Why do Dissolution Testing? Prof. Dr. Jennifer Dressman Johann Wolfgang Goethe University Frankfurt am Main, Germany.

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