qbd approach to dissolution through understanding of the release mechanisms and critical in vivo...

7/30/2019 QbD Approach to Dissolution Through Understanding of the Release Mechanisms and Critical in Vivo Parameters

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QbD Approach to Dissolution

Through Understanding of the

Release Mechanisms and Critical In

Vivo Parameters

Andreas Abend

Merck

West Point, PA



Outline

General considerations of dissolution

Formulation development

QC method

Part A: Prior knowledge/risk assessment approach

BCS based understanding of dissolution methodology in the absence of

IVIVC

Part B: IVIVC/R approach



Purpose of Dissolution testing

Guide formulation design and assess product quality The only product test that truly measures the effect of

formulation and physical properties of the API on therate of drug solubilization

The only test that can monitor if the rate of drugsolubilization is impacted by product storage conditions

It is the “best” surrogate for bio- performance if IVIVC can’tbe established

Required by many regulatory authorities for solid oral

dosage forms, transdermal patches and oral suspensions



The evolution of our understanding of the DP

characteristics from a dissolution perspective

Pre Phase 1 --- Phase 1 --- Preliminary and Final Market Image

Formulation understanding QC method

“QbD execution”

Design space experiments

QTPP

RA tools

Monitor process/ refine

SUPAC



Evolution of the method

Early development:

Disso method with bio relevant media – key in guidingformulation development in the absence of human in-vivo data:

Little value having a QC method at this stage Although required, limited value of a QC method at this stage of clinical

development

Post Prove of Concept- preliminary market formulationdevelopment:

Dissolution method gains much more importance as a “bio- performance”/ quality method:

Pivotal clinical studies (i.e. dose ranging, Phase III) Drug Product Process and components are usually defined

Exploring the Design Space and process scale-up: critical to have theright method in place

Important to ensure consistent quality (consistency in clinical trials)



Early DP development stage Dissolution Method -

General Considerations…..

Prospective method

Desired Method attributes:

Should allow ranking of potential range of drug product

formulation types (i.e. DFC, LFC, simple tablets) to maximizedrug substance exposure

Typically not sensitive of small changes within oneformulation type



Case Study 1- Formulation ranking:

Goal to identify the formulation that is likely giving maximum

exposure in Phase I Clinical trials:

• API properties:

• BCS Class II with low aqueous solubility

• 1.3ug/mL in aqueous and 7.7ug/mL in FaSSIF

• Formulation:

• Bench mark tox formulation

• Three Liquid filled capsules

• Two dry filled capsules (50mg Standard pharmaceutical ingredients

present in the formulation)

• Dissolution experiment

• Bio-relevant Medium: FaSSIF

• Non-sink condition



FaSSIF Dissolution of MK-6526

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0

110.0

0 10 20 30 40 50 60 70 80 90 1 00 110 120

time (min)

% C

l a i m

C:I:T

C:T

I:T

WG:C

WG:TPGS

SA:TPGS

LFC

DFC

Tox formulation

In-vitro dissolution and in-vivo Dog pK results

0.0

0.5

1.0

1.5

2.02.5

3.0

3.5

4.0

4.5

0 4 8 12 16 20 24

Time (hr)

C o n c ( u M )

DFC (10% Vit. E TPGS) LFC (Im:Tw)

SA Vehicle (20% Vit. E TPGS)

In-vitro dissolutionMedia FaSSIF

Apparatus USP II

Agitation 100 rpm

LFC

Tox formulation

DFC



Dissolution method development strategy – PMF

development

Usually limited human pK-data available Phase I formulation typically not the formulation going forward and

process conditions, API, excipients selection, etc. evolve

May test further formulations in Bio Comparison studies before makingfinal PMF definition

With the additional human pK-data and formulation informationopportunity to look for in-vitro and in-vivo relationship

Desired method attributes: Guide formulation selection and fine-tuning

Become more formulation specific

Predictive of in-put variables that may impact bio-performance

Builds on prior knowledge including BCS classification system



Case Study 2:

• API properties: BCS Class IV with low aqueous solubility across pH1.0-6.0

• Formulation: Tablets (doses: 100 -400 mg potency) with 25-50%drug load; Standard pharmaceutical ingredients present in theformulation. Immediate release dosage form.

• Process: Roller compaction process; API and excipients are rollercompacted. The granules are lubricated with SSF and magnesiumstearate followed by compression and film coating.

• Dissolution mechanism: Spans from fast disintegration of tablets toslow disintegration of tablets



Case Study 2: In-vitro dissolution and in-vivo

human pK results

0

1000

2000

3000

4000

50006000

7000

8000

9000

0 2 4 6 8 10 12Time (hour)

P l a s m a C o n c e n t r a t i o n

Formulation 1

Formulation 2

0

20

40

60

80

100

120

0 0.5 1 1.5 2 2.5 3

Time (hr)

% D

i s s o l v e

Formulation I

Formulation II

In-vitro dissolution

Media water

Apparatus USP II

Agitation 100 rpm



Dissolution method development strategy – Pivotal/ late

stage Clinical development

Formulation Identified, Dose(s) Identified -- Initial Quality Risk assessment

Evaluate the in-put variables on Drug Product Quality API, Excipients, Drug product manufacturing process

Identify Critical Process Parameters

Explore the process design space

Design Space: where the process works

Develop the Control Strategy

Desired Dissolution Method requirements:

Method should be sensitive to the process parameters/ in-put variablesthat may affect bio-performance

Method should be stability indicating, i.e. pick-up changes that are bio-

relevant



Closer look at dissolution testing in the context of

QbD

“Final” Formulation going into pivotal clinical studies has

been defined

CQAs have been identified

Need to ensure adequate methods are in place to control CQAs

In-vivo performance is usually always a CQA…

Dissolution testing is at this stage often the only test that probes drug

substance release



Requirements of a bio-relevant method in a QbD

context

In general methods should assure the quality of the drugproduct

Dissolution method (or surrogates) should assure consistent

bio-performance of the drug product

Should be sensitive to in-puts/ variables that have beenidentified to impact bio-performance

How can this be done?

1. Establish IVIVC (or IVIVR)

2. Use prior knowledge and appropriate risk assessment

3. A combination of both



Part A: Prior

knowledge/risk assessmentapproach



Biopharmaceutical Classification System

I

III

High solubility

High permeability

High solubility

Low permeability

IV

Low solubility

Low permeability

II

Low solubility

High permeability

Low Low

10

1.0

0.1

0.01

Volume to Dissolve Max Dose (ml)

I

III

High solubility

High permeability

High solubility

Low permeability

I

III

High solubility

High permeability

High solubility

Low permeability

IV

Low solubility

Low permeability

II

Low solubility

High permeability

High

10

1.0

0.1

0.01


A p p

a r e n t P e r m e a b i l i t y ( X 1 0 6 )

G.L. Amidon et al.



Dissolution Mechanism based on BCS

Formulateddrug

Absorbeddrug

Solubilizeddrug kd k p

k d = dissolution rate (solubility, formulation)

k p = permeability rate (API structure)

kd & kp fast - Well absorbed

BCS Class I, like dosing an oral solution

kd >> kp - permeation control BCS Class III, still like dosing an oral solution

kd << kp - dissolution controlled

BCS Class I (ER or CR), or Class II & IV (IR)




Formulated drug

or “granule”Solubilized

drug k

d

Drug Particle k

id

k dd

k dd = disintegration (cohesive properties of the formulation)

k id = solubilization of the drug (API particle size or surfacearea)

Understanding the relative importance of k dd and k id provides

a mechanistic framework to assess where dissolution tests addsvalue




k dd

>> kid

- intrinsic dissolution control

Critical attribute is API particle size or surface area

k dd

<< kid

- disintegration controlled

Cohesive properties of the formulation are important

Critical attribute is disintegration of product

k dd

~ kid

Fast release – neither cohesive properties nor physical

properties are important, Critical attribute is disintegration

Slow release - both cohesive properties and physical

properties may be important, Critical attribute is dissolution



A Design Perspective on Dissolution Testing

Specific

GeneralDissolution

Disintegration

or Erosion

Intrinsic Rateof API

Solubilization

PorosityAPI

Particle Size

API

Surface

AreaHardness

Increased

Specificity of

Quality

Attribute

“A Biopharmaceutical Classification System Approach to Dissolution: Mechanisms and Strategies” W. E. Bowen, Q. Wang,

W. P. Wuelfing, D. L. Thomas, E. Nelson, Y. Mao, B. Hill, M. Thompson, R. A. Reed In"Biopharmaceutics Applications in Drug Development " R. Krishna and Lawrence Yu, Ed.; Springer, 2008, 290.




1e-31e-21e-11e+01e+11e+21e+31e+41e+51e+61e+71e+8

Papp(x10

6 )

0.1

1

10

Merck IR Formulation BCS Experience Space

II

IV

BCS Class I

BCS Class II

BCS Class III

BCS Class IV

I

III



Disintegration Test

or capsule rupture test

Fast dissolution(<15 mins, 85%)?

CQA

Tablet disintegration

capsule rupture

Yes

Case 3

BCS Classification I/III

Immediate release Dosage Forms (N = 15)

(N = 13)



Case Study 3: BCS Class I/IIIFast release with disintegration controlled dissolution

API properties: Borderline BCS Class I/III permeability

with high aqueous solubility (>40 mg/mL) at pH 1-7.5

Formulation: tablets (doses: 25 - 200 mg) with 32% drug

load; Standard pharmaceutical ingredients present in the

formulation Process: Direct compression process; API & excipients are

blended and then lubricated with magnesium stearate and

sodium stearyl fumarate, followed by compression.

Dissolution mechanism: tablet disintegration followed by

rapid solubilization of drug particles

Critical Quality Attribute: tablet disintegration



70

80

90

100

0 15 30 45 60

Time, min

% D

i s s o l v e

pH 1.2

pH 4.5

pH 6.8

water - 50 mM NaCl

water

Dissolution in Physiological pHs

Test conditions

Media varied

Apparatus USP I

Agitation 100 rpm

Slowest profile has > 90% release in 10 minutes




Dissolution

75

80

85

90

95

100

10 15 20 25

Hardness, kP

% D

i s s o l v e d a t 1 0 m i

Disintegration

0

20

40

60

80

100

120

140

160

10 15 20 25

Hardness, kP

D i s i n t e g r a t i o n , s e

c o n

Impact of Tablet Hardness on Dissolution and Disintegration

Disintegration is the more sensitive method and serves as a

better indicator for product quality than a dissolution test




Disintegration Test



CQA


capsule rupture

Yes

Consider reformulationOr process change

No

Yes

Characterization of dissolutionmechanism

Perform Dissolution of

dosage form

and granules.

No

Case 3

Disintegration/erosion

control?

Yes

Case 4



(N = 1)

(N = 13)




Case Study 4: BCS Class I/IIIErosion Controlled Dissolution

API properties: API 1: Borderline BCS I/III permeability with high aqueous

solubility (>40 mg/mL) at pH 1-7.5; API 2: BCS III with high aqueous

solubility (~200 mg/mL) at pH 1-7.5

Formulation: Combination tablets. Standard pharmaceutical ingredients

present in the formulation

Process: Wet granulation process; Fluid-bed wet granulation of API 1 and API2. The granules are dried and blended with microcrystalline cellulose and

magnesium stearate followed by compression and film coating

Dissolution mechanism: Tablet erosion followed by rapid solubilization of

drug particles; controlled by tablet erosion

Critical Quality Attribute: tablet disintegration

Case Study 4 BCS Class I/III



Case Study 4 – BCS Class I/III

Erosion Controlled Dissolution

0

20

40

60

80

100

0 15 30 45 60

Time (min)

% R e l e a s e

Disintegration time: 30 mins



granules

Correlation of Dissolution and Disintegration

Test conditions

Media Water

Apparatus USP II

Agitation 75 rpm

y = -1.6531x + 121.7

R2

= 0.9968

70

75

80

85

90

95

15 17 19 21 23 25 27 29 31

Disintegration Time, minutes

% D

i s s o l v e d @

1 5 - m i n u t e s

Strong correlation between dissolution and disintegration

Both methods monitor critical quality attributes sufficiently

Disintegration is recommended for simplicity



Consider reformulationOr process change

Characterization of dissolutionmechanism

Perform Dissolution of

dosage form

and granules.


Disintegration/erosion

control?

Disintegration Test



CQA


capsule rupture

Yes

No

Yes

No

YesCase 3Case 4



No

Case 5

Monitor dissolution

profiles

CQA

Granule properties

or others

(N = 1)(N = 13)

(N = 1)



Case Study 5: BCS Class I

API properties: BCS Class I with high aqueous solubility (0.1

mg/mL) at pH 1-7.5. Formulation: Tablets (dose: 4 mg); Standard pharmaceutical

ingredients present in the formulation

Process: Wet granulation process; Granulated in water. The

granules were dried, blended with starch and magnesium stearatefollowed by compression

Dissolution mechanism: Fast tablet disintegration followed by

drug release from granules and rapid solubilization of drug

particles; Controlled by drug release from granules

Critical Quality Attribute: Granule particle size



Case Study 5 – BCS Class I

Dissolution Controlled by Granule Particle Size

0

20

40

6080

100

120

0 15 30 45 60 75

Time (minutes)

% R e l e a s

e

< 150 um

> 150 um

Test conditions

Media WaterApparatus USP II

Agitation 50 rpm

Overall dissolution profile is dependent on the granule size distribution

Dissolution profile is monitored for quality control



Summary of BCS Class I/III Experience

Overall Design Principle: Rapid dissolution – so like dosing an

oral solution Formulation: Tablets, Capsules or Oral Disintegrating Tablets Process: Direct compression, Wet Granulation, Roller

Compaction, Encapsulation or Freeze Drying

Dissolution mechanism: tablet or capsules disintegration followedby rapid solubilization of drug particles, i.e. k dd << k id

Critical Quality Attribute: Design for Disintegration (i.e. to makeit like dosing an oral solution)

Merck Biopharmaceutical Experience: In 3 out of 3 cases

examined, the solid oral dosage form has been bio-equivalent toan oral solution




1e-31e-21e-11e+01e+11e+21e+31e+41e+51e+61e+71e+8

0.1

1

10

Flexeril

Proscar Dexamethasone

L000124467

L000854384

Vasotec

Maxalt

MK0431

L000222628

L001169872

Pepcid

L000845704

Fosamax

BCS Class I

BCS Class II

BCS Class III

BCS Class IV

P a p p

( x 1 0

6 )

Merck BCS Class II & IV IR Formulations

III

IIIIV




1e-31e-21e-11e+01e+11e+21e+31e+41e+51e+61e+71e+8

0.1

1

10

P a p p

( x 1 0

6 )

Dissolution Media Selections

Aqueous

Surfactant

N/A

III

IIIIV

BCS Classification II/IV




Immediate Release Dosage Form

API solubilized

in formulation(LFCs, etc.)

Design Target

API remains in

solution

Disintegration Test

or capsule rupturetest

Yes

Case 6

C St d 6 BCS Cl II/IV



Case Study 6: BCS Class II/IVCapsule Rupture Controlled Dissolution

API properties: BCS Class IV with low aqueous solubilityat pH 1.0-7.0.

Formulation: Liquid Filled Capsules (LFC). Dose: 0.1 -50 mg. The drug is fully dissolved in the liquid core of theLFC

Process: API was dissolved in liquid vehicle, which is thenfiltered, and filled into hard (or soft) gelatin capsules

Dissolution mechanism: capsule disintegration followedby dispersion of liquid content

Product Design Target: API is solubilized in formulation






API solubilized


Design Target

API remains in

solution

Disintegration Test


Yes

Dissolution mechanism

characterization

Perform Dissolution of dosageform, API (different PSD)

and/or granules

No

Case 6 Consider reformulation

Or process change

k id rate limiting?

k id rate limiting?

CQA

API Particle

size, etc

YesNo

Yes

Control API particle

size, etc.

Case 7

Case Study 7: BCS Class II/IV



Case Study 7: BCS Class II/IVDrug solubilization controlled dissolution

API properties: BCS Class IV with low aqueous solubility

across pH 1.0-7.5.

Formulation: Capsules (dose: 100 mg) with 67% drug load;

Standard pharmaceutical ingredients present in the

formulation Process: API and excipients are dry blended, then

lubricated with magnesium stearate. The powder blend is

then filled in hard gelatin capsules.

Dissolution mechanism: Rupture of capsule shell followedby API dissolution. Controlled by API solubilization

Critical Quality Attribute: Physical properties of API

C S d 7 BCS Cl II/IV



0.0

20.0

40.0

60.0

80.0

100.0

0 20 40 60 80 100

Time, minutes

A v e r a g e % D

i s s o l v e d

Sieve Cut < 75 microns

Sieve Cut 180-250 microns

Sieve Cut > 355 microns


API particle size modulates dissolution

Test conditions

Media 2% Tween

Apparatus USP II

Agitation 100 rpm




Impact of API PSD on Capsule Dissolution

API PSD should be controlled and monitored






characterization


and/or granules


Consider reformulation

Or process change

API solubilized


k id rate limiting?

k id rate limiting?

CQA

API Particle

size, etc

Design Target

API remains in

solution

Disintegration Test


Yes

No

YesNo

Yes

Disintegration

or capsule rupture

limited?

No


size, etc.

Case 6

Case 7

CQA

Formulation

properties

No

Monitor dissolution

profiles

Case 8




API properties: API 1: BCS II with low solubility across pH

1-7.5; API 2: BCS Class IV with low aqueous solubilityacross pH 3.0-7.5 Formulation: Combination drugs in capsules (strength:

200/100 mg); Standard pharmaceutical ingredients presentin the formulation

Process: Roller compaction process; API’s and excipientsgranulated via roller-compaction. Granules are milled,lubricated with magnesium stearate and encapsulated in hardgelatin capsules.

Dissolution mechanism: Rapid rupture of capsule shell

followed disintegration of capsule plug and drug releasefrom granules. Controlled by plug disintegration andrelease from granules.

Critical Quality Attribute: granule density



Test conditions

Media 2% SDS

Apparatus USP II

Agitation 50 rpm

Roller Compaction Pressure vs. Dissolution in Capsules

0

20

40

60

80

100

0 15 30 45 60 75

Reference BatchClinical Batch, 18 mm Disk, Loose Plug

131-B: 60 bar Roll Pressure, Hand-filled Capsule

131-2: 90 bar Roll Pressure, Hand-filled Capsule

131-3: 120 bar Roll Pressure, Hand-filled Capsule

% D

i s s o l v e d

Time (minutes)


Monitor drug release by dissolution





characterization


and/or granules


Consider reformulation

Or process change

API solubilized


Kid rate limiting?

Kid rate limiting?

Disintegration

or capsule rupture

limited?

CQA

API Particle

size, etc

CQA

Formulation

properties

CQA

API remains in

solution

Disintegration Test


Yes

No

YesNo

Yes

No

No

Monitor dissolution

profiles


size, etc.

Case 6

Case 7Case 8

CQA


capsule rupture

Yes

Case 9





API properties: BCS Class IV with low solubility across pH

3.0-7.5. Highly soluble at gastric pH (>200 mg/mL) Formulation: Capsules (doses: 200 - 400 mg) with 65% drug

load. Standard pharmaceutical ingredients present in the

formulation

Process: Roller compaction process; API and excipients

granulated via roller-compaction. Granules are milled,

lubricated with magnesium stearate, and encapsulated in hard

gelatin capsules

Dissolution mechanism: Capsule rupture followed by rapid

release from granules. Controlled by capsule rupture Critical Quality Attribute: Capsule rupture (cross-linking)




Dissolution Profiles in 0.1N HCl

0

20

40

60

80

100

0 10 20 30 40 50Time (Minutes)

% D

i s s o l v e

Unstressed Capsules

Stressed capsules (40C/75% 48 hrs)

Granules

Test conditions

Media 0.1 N HCL

Apparatus USP II

Agitation 50 rpm

Monitor drug release by disintegration

S f CS Cl / i



Summary of BCS Class II/IV Experience

Overall Design Principle: Solubilization enhancement e.g.

LFC’s, API physical properties – reduce particle size,increase surface area – add solubilizing agents, etc.

Formulation: Capsules, Tablets, ODT’s

Process: Direct compression, Wet Granulation, Roller

Compaction, Freeze Drying, liquid filled gel caps Dissolution mechanism: varied, i.e. k id << k dd, k dd << k id ,

k dd ~ k id

Critical Quality Attribute: Disintegration, API physical

properties, dissolution

C l i



Conclusions

BCS based drug release testing leads to:

Focus on value added specifications in alignmentwith QbD principles and approaches

Removal of non-value added specifications

BCS Class I/III IR products – ability to eliminatedissolution testing and replace with disintegrationtesting

BCS Class II/IV IR products – ability to drill down tokey quality attributes and replace dissolution testingconsistent with the design of the product – somedissolution testing still adds value



Part B

IVIVC/R approach



IVIVC/IVIVR approach

IVIVC/R

Drug Product

CQA

CPP

In-vitro

Dissolution

In-vivo

human PK

Dissolution

Method

Development

Patients



IVIVC/ IVIVR

High probability for CR products Consistent with existing SUPAC guidance, this provides highest degree

of regulatory flexibility

Lower probability for IR products Disso in BCS I and III formulations often too fast

Absorption and metabolism may also make it difficult to deconvolute thedata

BCS II higher chance of achieving

Remember dissolution driven by drug solubility

BCS IV

Often no relationship between dissolution rate and pK achievable

Possible relationships between dissolution and




drug exposure in subjects – Case A

% c h

a n g e i n - v i v o

p K

- p a r a m e t e r

0

-10

% drug dissolved in-vitro time per time unit (min)

-20

Case A – no IVIVC/R

Dickinson et. al (2008) AAPS Journal 10:380-90

Dickinson (2009), Applied Biopharmaceutics and QbD for Dissolution/ Release Specification setting:Product Quality for Patient Benefit;

“C A”



“Case A”

No changes in pK-parameters observed within the tested

batches Dissolution method is sensitive to process parameters and

other in-put variables

Would suggest using % release/ time “Q” value(s) to provide process

control if required

In-put variable changes are justifiable as long as within the

above experience range

Assessment should be based on FMEAC analysis

Changes that result in disso profiles outside the experience/ spec range

likely require in-vivo justification





drug exposure in subjects – Case B

% c

h a n g e i n - v

i v o

p K - p a r a m e t e

r0

-20


-40 Case B - IVIVC

-60



“Case B”

IVIVC is achievable!

In-vitro Method can directly assess the magnitude of in-vivo

changes due to process or other in-put variable changes

As existing SUPAC already suggests, this method can be used

to justify scale-up and post – approval changes in lieu of BE

studies




pdrug exposure in subjects – Case C

% c

h a n g e i n - v

i v o

p K - p a r a m e t e r

0

-20


-40

Case C

-60



“Case C”

Suggests IVIVR or even IVIVC possible

setting the disso spec to the slowest acceptable profile.

Any result above appears to provide adequate in-vivo

performance

Any dissolution result below the proposed spec may

indicate non-acceptable change

Since IVIVC possible one can directly assess the extent of

the pK-changes



Conclusion

Part A of this presentation highlights the use of priorknowledge, QbD tools and good science to assure consistentproduct quality

Establishing IVIVC/R provides most direct link to bio-

performance Stronger link between in-vivo and in-vitro performance as compared to

using empirical approaches (F2)

Might be costly up-front investment

QbD frame-work allows for regulatory flexibility – this should be a strongincentive

But remember- achieving IVIVC/R might not always bepossible at least with the current in-vitro and in-silico toolsavailable



Acknowledgements

Bill Bowen Steve Biffar

Kim Gallagher

John Higgins

Brian Hill

Craig Ikeda

Kiki Luna

Yun Mao

Eric Nelson

Robert Reed

Denise Thomas

Mark Thompson Qingxi Wang

Conrad Winters

Pete Wuelfing



Thank you!



References

W. E. Bowen, Q. Wang, W. P. Wuelfing, D. L. Thomas, E. Nelson, Y. Mao, B. Hill, M.Thompson, R. A. Reed, “A Biopharmaceutical Classification System Approach to

Dissolution: Mechanisms and Strategies”, in Biopharmaceutics Applications in Drug

Development " by R. Krishna and Lawrence Yu (Editor); Springer, 2008, 290

P.A Dickinson, Wang Wang Lee, Paul W. Stott, Andy Townsend, John Smart, Parviz

Ghaharamani, Tracey Hammett, Linda Billet, Sheena Behn, Ryan C. Gibb, Bertil

Abrahamsson, AAPS Journal, Vol. 10, No. 2, June 2008, p.380-390 Paul Dickinson et al. (2009), Applied Biopharmaceutics and QbD for Dissolution/ Release

Specification setting: Product Quality for Patient Benefit

Amidon, G.L., H. Lennernäs, V.P. Shah, and J. R. Crison, "A theoretical basis for a

biopharmaceutics Drug Classification: The correlation of in vitro drug product dissolution and

in vivo bioavailability." Pharmaceutical Research 12 (3, March), 413-420, 1995

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