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

Predictive Dissolution Methods

Erika Stippler Ph.D.

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.

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Topics

• Definition
• Application
• Development of predictive dissolution method
- Selection of testing conditions
• Summary

Bioavailability of Solid Oral Dosage Forms

Liberation, Absorption, Distribution, Metabolism, Excretion

release absorption elimination

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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.

Dosage Forms Requiring Dissolution

• Tablets
• Capsules
• Suspensions
• Ointments
• Creams
• Suppositories
• Pessaries
• Transdermals
• Implants

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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

Factors Influencing Bioavailability

• Drug substance:
– Solubility in physiological relevant media
– Permeability
– Stability

• Biopharmaceutics Classification System

Class 1 Class 2
high solubility low solubility
high permeability high permeability

Class 3 Class 4
high solubility low solubility
low permeability low permeability8
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
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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

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Method Development

• The dissolution procedure requires

– An apparatus
– A dissolution medium
– Operating conditions (rpm, temperature, sampling
schedule…)

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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
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Development of Dissolution Test

• selection of suitable
dissolution apparatus

• consideration of known
factors pH 1 – 3 fasted
- pH-value pH 4.5 – 5.5 (food intake)
- concentration of salts
- volume pH 4.9 -6.5
- temperature pH 6.6
- addition of enzymes
- addition of bile salts

• approach to les well pH 6.5 - 7

pH 6.5
described factors
- agitation pH 7.0
- transit time

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Selection of Dissolution Apparatus

• Preferred apparatus for solid oral dosage forms

– Apparatus 1 (Basket)
– Apparatus 2 (Paddle)
• Commercially available
• Automation
• Well documented

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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

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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

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 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

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USP Apparatus 2 - Paddle

• Drug product
– Solids (mostly non floating)
• Monodisperse (tablets)
• Polydisperse (encapsulated beads)
• Agitation
– Rotating stirrer
– Usual speed: 25 to 75 rpm
• Disadvantages
– Floating dosage forms require sinker
– Cone formation
– Positioning of tablet
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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

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USP Apparatus 3 - Reciprocating Cylinder

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 USP Apparatus 3 - Reciprocating Cylinder

• Drug products
– Solids (mostly non disintegrating)
• Monodisperse (tablets)
• Polydisperse (encapsulated beads)
– 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 21

USP Apparatus 3 - Reciprocating Cylinder

• 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

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USP Apparatus 4 - Flow Through Cell

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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

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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 25

USP Apparatus 5 - Paddle Over Disk

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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
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USP Apparatus 6 - Cylinder

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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 temperature is maintained at 32°C ± 0.5°C
• The dosage unit is placed on the cylinder with release
side out
• Drug products
– Resevoir transdermal patches that can not be cut smaller

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USP Apparatus 7 - Reciprocating

Holder

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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 temperature is maintained at 32°C ± 0.5°C
• The dosage unit is placed on the cylinder with release
side out
• Drug products
– Resevoir transdermal patches that can not be cut smaller

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Vertical Diffusion Cell

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 Vertical Diffusion Cell

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

• Drug products
– Ointments and creams
– Development of transdermal patches
• Samples are periodically withdrawn from sampling
port
• Not compendial

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E4

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 masticatory
activity
– Easy to use

• Disadvantages
– Apparatus not commercially
available
– Limited experience
– Limited volume 34
Slide 34

E4 Drawing of the Chewing gum apparatus inserted

ESS, 1/9/2008
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
– ….

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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

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Development Of A Dissolution Method

• 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.
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Development Of A Dissolution Method

• 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

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Development Of A Dissolution Method

• 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

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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
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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
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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

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 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
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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
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Novel/Special Dosage Forms

FIP/AAPS Guidelines for Dissolution/ In vitro Release

Testing of Novel/Special Dosage Forms 45

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

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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

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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

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Questions?

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Thank You!

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