Dissolution

Quality Standards for Medicines, Supplements, and Food Ingredients throughout the World

Predictive Dissolution Methods

Erika Stippler Ph.D.

2

Disclaimer

Because USP text and publications may have legal implications in the U.S. and elsewhere, their language must stand on its own. The USP shall not provide an official ex post facto interpretation to one party, thereby placing other parties without that interpretation at a possible disadvantage. The requirements shall be uniformly and equally available to all parties.

In addition, USP shall not provide an official opinion as to whether a particular article does or does not comply with compendial requirements, except as part of an established USP verification or other conformity assessment program that is conducted separately from and independent of USP's standard-setting activities.

Certain commercial equipment, instruments or materials may be identified in this presentation to specify adequately the experimental procedure. Such identification does not imply approval, endorsement, or certification by USP of a particular brand or product, nor does it imply that the equipment, instrument or material is necessarily the best available for the purpose or that any other brand or product was judged to be unsatisfactory or inadequate.

3

Topics

• Definition

• Application

• Development of predictive dissolution method

- Selection of testing conditions

• Summary

4

Bioavailability of Solid Oral Dosage Forms

release absorption

first-pass-

effect

elimination

dosage-

form

��kr

GI-

tract

��ka

blood ��ke

feces /

urine

��

feces tissue

Liberation, Absorption, Distribution, Metabolism, Excretion

5

Definition of Dissolution Rate

Dissolution rate of a drug from the solid state is defined as the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface, temperature, and solvent composition.

6

Dosage Forms Requiring Dissolution

• Tablets

• Capsules

• Suspensions

• Ointments

• Creams

• Suppositories

• Pessaries

• Transdermals

• Implants

7

Goals of a Predictive Dissolution Testing

• Predict the bioavailability – surrogate parameter of

the therapeutic efficacy

• Indicate the robustness of the dosage form – drug

product related safety

• Sensitive to variations in the manufacturing process

which have critical influence on the dosage form

performance

• Quality control tool to control the uniformity of drug

product quality

8

Factors Influencing Bioavailability

• Drug substance:

– Solubility in physiological relevant media

– Permeability

– Stability

• Biopharmaceutics Classification System

Class 1

high solubility

high permeability

Class 2

low solubility

high permeability

Class 3

high solubility

low permeability

Class 4

low solubility

low permeability

9

Factors Influencing Bioavailability

• Drug product:

– Excipients

• Presence of solubility enhancers

– Composition

• Viscosity

• Molecular weight

– Manufacturing

• Particle size

• Addition order

• Moisture

• Lubrication blend time

• Compression force

• Drying methods

• Coating

10

Method Development

• Selection of the testing conditions depends

– type of dosage form under investigation

• tablets

• suspensions

• suppositories

– release pattern of the dosage form

• immediate release or

• modified release

– physiology of the site of application

• gastrointestinal tract for solid oral dosage forms,

• skin for transdermal products

11

Method Development

• The dissolution procedure requires

– An apparatus

– A dissolution medium

– Operating conditions (rpm, temperature, sampling

schedule…)

12

Compendial Dissolution – USP

• <711> Dissolution

• <724> Drug Release

• <1092> The Dissolution Procedure: Development

and Validation

• <701> Disintegration

• <1087> Intrinsic Dissolution

• <1088> In vitro and In vivo Evaluation of Dosage

Forms

• <1090> In vivo Bioequivalence Guideline

• Monographs

13

Development of Dissolution Test

• selection of suitable dissolution apparatus

• consideration of known factors

- pH-value

- concentration of salts

- volume

- temperature

- addition of enzymes

- addition of bile salts

• approach to les well described factors

- agitation

- transit time

pH 1 – 3 fasted

pH 4.5 – 5.5 (food intake)

pH 4.9 -6.5

pH 6.5pH 6.5 - 7

pH 7.0

pH 6.6

14

Selection of Dissolution Apparatus

• Preferred apparatus for solid oral dosage forms

– Apparatus 1 (Basket)

– Apparatus 2 (Paddle)

• Commercially available

• Automation

• Well documented

15

USP Apparatus 1 - Basket

• Dosage form contained within

basket

• Dissolution should occur within

basket

• Useful for :

– Tablets

– Capsules

– Beads

– Floaters

• pH change by media exchange

16

USP Apparatus 1 - Basket

• Drug product

– Solids (mostly floating)

• Monodisperse (tablets)

• Polydisperse (encapsulated beads)

• Agitation

– Rotating stirrer

– Usual speed: 50 to 100 rpm

• Disadvantage

– Formulation may clog to 40 mesh screen

17

USP Apparatus 2 - Paddle

• Dosage form should remain at the

bottom centre of the vessel

• If disintegration occurs – dissolution

should proceed throughout the

medium

• Sinkers used for floaters

• Useful for :

– Tablets

– Capsules

– Suspensions

• pH change by media addition

18

USP Apparatus 2 - Paddle

• Drug product

– Solids (mostly non floating)



• Agitation

– Rotating stirrer

– Usual speed: 25 to 75 rpm

• Disadvantages

– Floating dosage forms require sinker

– Cone formation

– Positioning of tablet

19

Paddle/ Basket Dissolution Apparatus

• Advantages

– Widely accepted apparatus for dissolution test

– Apparatus of first choice for solid oral dosage forms

– Standardized

– Easy to operate

– Robust

– Broad experience

• Disadvantages

– Limited volume

– Simulation of the gastrointestinal transit not possible

– Hydrodynamic conditions not known

20

USP Apparatus 3 - Reciprocating Cylinder

21


• Drug products

– Solids (mostly non disintegrating)



– Originally used for extended release products, particularly

beads in capsule

• Reciprocating agitation

– Reciprocating cylinder

– Usual speed 5 to 35 rpm (reciprocations per minute)

• Disadvantages

– Disintegrating dosage forms too low results

– Surfactant cause foaming

– Small volume

22


• Advantages

– Reciprocating cylinder programmed for

dissolution in various media for various

time

– Can change the media easily

– May start at pH 1 and then pH 4.5 and

then at pH 6.8

– Attempt to mirror pH changes and

transit times in the GI tract

23

USP Apparatus 4 - Flow Through Cell

24

USP Apparatus 4 - Flow Through Cell

• Drug products– Solids

• Tablets, capsules, implants, powder, granules

– Semisolids• Suppositories, soft gelatin capsules, ointments

– Liquids• Suspensions

• Flow rates– 2 – 32 mL/min

– continuous flow rate or

– recirculate media

• Flow-through cell type– Compendial: 12 mm and 22.6 mm

– Suppositories

– Granules

25

Flow-through Cell Apparatus

• Advantages

– No limitation regarding the volume of media used for the dissolution test

– Suitable for low soluble drugs

– Gentle hydrodynamic conditions

– Simulation of the gastrointestinal transit

– Suitable for special dosage forms

•Powder and granules

• Implants

• Disadvantages

– Limited experience

– Pump precision influences the results

– Fractioned primary data lead to greater experimental error when computed to cumulative profiles

26

USP Apparatus 5 - Paddle Over Disk

27

USP Apparatus 5 - Paddle Over Disk

• Use the paddle and vessel assembly from Apparatus

2 with the addition of a stainless steel disk assembly

designed for holding the transdermal system at the

bottom of the vessel

• The temperature is maintained at 32°C ± 0.5°C

• The disk assembly holds the system flat and is

positioned such that the release surface is parallel

with the bottom of the paddle blade

• Drug Products

– Matrix transdermal patches can be cut to size of the disk

assembly

28

USP Apparatus 6 - Cylinder

29

USP Apparatus 6 - Cylinder

• Use the vessel assembly from Apparatus 1 except to

replace the basket and shaft with a stainless steel

cylinder stirring element


• The dosage unit is placed on the cylinder with release

side out

• Drug products

– Resevoir transdermal patches that can not be cut smaller

30

USP Apparatus 7 - Reciprocating

Holder

31

USP Apparatus 7 - Reciprocating

Holder

• The assembly consists of a set of volumetrically

calibrated or tared solution containers made of glass

or other suitable inert material, a motor and drive

assembly to reciprocate the system vertically


• The dosage unit is placed on the cylinder with release

side out

• Drug products

– Resevoir transdermal patches that can not be cut smaller

32

Vertical Diffusion Cell

33

Vertical Diffusion Cell


• Drug products

– Ointments and creams

– Development of transdermal patches

• Samples are periodically withdrawn from sampling

port

• Not compendial

34

Special Drug Products

• Chewing Gum Apparatus

– Apparatus intensity and frequency of shearing forces that affect drug release from a gum

• Advantages

– Good simulation of the masticatoryactivity

– Easy to use

• Disadvantages

– Apparatus not commercially available

– Limited experience

– Limited volume

E4

Slide 34

E4 Drawing of the Chewing gum apparatus insertedESS, 1/9/2008

35

Method Development

• Dissolution medium

– Sink conditions with regard to API

– Appropriate with regard to physiology

– Well characterized composition

– No organic solvents

– De-gassing if necessary

– Stable

– Environmental friendly

– ….

36

Development Of A Dissolution Method

• Time points

– Immediate-release dosage forms

• The duration of the procedure is typically 30 to 60 minutes

• USP may have a single time point specification

• FDA may require additional time points for

– Product comparability

– Product registration

– Biopharmaceutics Classification System (BCS)

• See FDA Guidance

• Drug product should release 85% or more of the active drug

substance within 15 minutes

• Single time point specification

37


• Time points

– A sufficient number of time points should be selected to

adequately characterize the ascending and plateau

phases of the dissolution curve

– IR Products

• Dissolution profiles of immediate-release products typically

show a gradual increase reaching 85% to 100% at about 30

to 45 minutes

• Dissolution time points in the range of 15, 20, 30, 45, and 60

minutes are usual for most immediate-release products.

• For rapidly dissolving products, including suspensions,

useful information may be obtained from earlier points, e.g.,

5 to 10 minutes.

38


• Time points

– Slower dissolving drugs and modified release drug

products

• Time points later than 60 minutes may be useful

• May have time points in two different media

– Delayed release or enteric drug products

– Example: Diclofenac Sodium Delayed Release Tablets

– Acid stage (0.1N HCl) for 2 hr

– Buffer stage (Phosphate buffer, pH 6.8) for 45 min.

• At least three test time points are chosen to characterize the

in vitro drug release profile

39


• Infinity Time Points

– The paddle or basket speed is increased at the end of the

run for a sustained period (typically 15 to 60 minutes),

after which time an additional sample is taken

• no requirement for 100% dissolution in the profile

– Provides data that may supplement content uniformity

data

– May provide useful information about formulation

characteristics during initial development

40

Selection of Dissolution Medium

• Reflect the pH conditions at the dissolution site

• Aqueous buffer solutions pH 1.2 – pH 6.8

– Modified-release formulations up to pH 7.5

• Addition of

– bile salts (sodium cholate, sodium taurocholate)

– surfactants (sodium lauryl sulfate, polysorbate)

– enzymes (pepsin, pancreatin)

• Solubility and stability of the drug substance in the

medium has to be evaluated

– sink-conditions are desirable

– use of aqueous-organic solvent mixture is discouraged

– purified water is not ideal

41

Selection of Volume of Dissolution Medium

• Basket/ Paddle Apparatus

– normally: 500 ml – 1000 ml

– special cases: 2 or 4 liter

– Low dose: 150 ml - 250 ml (not compendial)

• Reciprocating Cylinder Apparatus

– Up to 250 ml

• Flow-through Cell Apparatus

– Normally: 4 ml/min – 16 ml/ml

– For implants: 1.0 ml/min – 2 ml/min

– special cases: up to 50 ml/min

42

Selection of Testing Conditions

• Stirring rate

– Basket Apparatus: 100 rpm

– Paddle Apparatus: 50 rpm or 75 rpm

• Suspensions: 25 rpm

• Extended release formulations: 100 rpm

– Reciprocating Cylinder Apparatus

• 5 dips/min – 35 dips/min

• Temperature

– Orally administered drugs: 37°C

– Topical/ transdermals: 32°C

43

Sampling Time Points

• Immediate-release formulations

– Development: profiles to characterize the dissolution

pattern (e.g. 10, 15, 20, 30, 45 and 60 min)

– QC: 15 min, 30 min, up to 60 min

– Rapidly dissolving products: 5 min or 10 min

• Modified release formulations

– Delayed release formulations

• Acidic stage: 1 h or 2 h

• Buffer stage: similar to IR formulations

– Extended release formulations

• One early time point: 1 or 2 hours

• Intermediate time point: 4 or 5 hours

• Final time point e.g. 8, 12 or 24 hours

44

Selection of Dissolution Testing Conditions

• USP <1092>:

–Dissolution apparatus

• paddle/basket

–Dissolution medium

• Aqueous buffer solutions (pH 1 – pH 7.5)

• Addition of surfactants/ enzymes if necessary

–Volume of dissolution medium

• Sufficient to assure “sink-conditions” (ideally)

• Paddle/basket: 500 – 900 ml

• Flow-through cell: 4 – 16 ml/min

–Deareation of medium

–Agitation

• Paddle: 50 - 75 rpm

• Basket: 100 rpm

• Reciprocating cylinder: 25 – 35 dips/min

45

Novel/Special Dosage Forms

FIP/AAPS Guidelines for Dissolution/ In vitro Release Testing of Novel/Special Dosage Forms

46

Relevant Guidelines

• FDA

– Guidance for Industry: Dissolution Testing of Immediate

Release Solid Oral Dosage Forms, 1997

– SUPAC

– Guidance for Industry: Extended Release Solid Oral Dosage

Forms: Development, Evaluation and Application of in vitro/

in vivo Correlations, 1997

– Guidance for Industry: Bioavailability and Bioequivalence

Studies for Orally Administered Drug Products - General

Considerations, 2000

47

Relevant Guidelines

• FIP

– Guidelines to Dissolution/ in vitro Release Testing of

Novel/Special Dosage Forms, 2003

– Guidelines for Dissolution Testing of Solid Oral Products,

1997

48

USP Educational Courses

• Dissolution: Theory and Best Practices

– Overview of history, theory, and practice of dissolution testing

as required by General Chapter <711>

• Advanced Dissolution

– In-depth review of USP dissolution and drug release testing,

covering method development, analytical instrument

qualification, and method validation.

• http://www.usp.org/education/classroom.html

49

Questions?

50

Thank You!

Documents

Dissolution