Importance and Modeling of

Hydrodynamic Effects in Dissolution and

Absorption In Vivo vs. In Vitro

FY 2016 Generic Drug Research

FDA Public Hearing

20 May 2016

1

James G. Brasseur, Ph.D.Research Professor, Aerospace Engineering Sciences

University of Colorado BoulderEmeritus/Adjunct Professor of Mechanical Engineering, Bioengineering and Mathematics

Pennsylvania State University

Intestinal vs. In Vitro Hydrodynamics

2

MACRO: Mixing at the

Lumen ScaleMICRO: Mixing and

Absorption at MucosaIntestinal Hydrodynamics:

Transport, Mixing,

Absorption

Intestinal vs. In Vitro Hydrodynamics

Videofluoroscopy of dog intestine

by H. J. Ehrlein(http://www.wzw.tum.de/humanbiology/

)

Peristaltic Contractions

(propagating waves)

(axial transport)

3

Segmental Contractions

(standing waves)

(radial mixing)

Lumen-Scale Motility in the Intestines

- Fed State -

Segmental Contractions

Peristaltic Contractions

1.92 cm

0 cm

time (s)

x (cm)

Lumen Diameter D(x,t)

1.92 cm

0 cm

time (s)

x (cm)Lumen Diameter D(x,t)

4

c ~ 1-3 mm/s

T ~ 2-4 s

(also humans)

c

T

T

In Vivo Hydrodynamics for

Drug Dissolution

5

Modeling Hydrodynamic Influences on

Dissolution Rate

6

Rj

effective

container

boundary

r

,c jV

Vj

CS

effective container

surrounding particle j

1j confinemen hydrodt ynamicsSh

,[ ( )]

( )( )

S b j

m m

j

j

j

dR tSh t

dt

C C tD

R t

Hydrodynamic Enhancements

to Dissolution:

1/ Convection

2/ Flow Shear

In vivo vs. In vitro?

Hydrodynamics, In Vivo vs. In Vitro:

Convection (Slip)

a εparticle path

mD

u

( )e

uR

R

Slip Velocity

"Reynolds Number"

Slip Velocity

"Peclet Number"u

( u)Pe

m

R

D

particle path

Ruf

up

u

7

particle path

slip velocity

Hydrodynamic Particle Parameters

for Dissolution Rate

A Previously Unappreciated Hydrodynamic Effect

on Dissolution Rate: Fluid Shear

a εparticle path

mD

2

ReS

SR

2

*m

SRS

D

Shear Reynolds Number

Shear Peclet Number

u

( u)Re

R

Slip Velocity Reynolds Number

Slip Velocity Peclet Numberu

( u)Pe

m

R

D

slope = Shear-rate

S = duf/dn

particle path

uf

n

Ru

fup

u8

Hydrodynamic Particle Parameters

for Dissolution Rate

Shear Rate: In Vitro USP II vs. In Vivo Intestine

Distribution of shear rates within

the media at 50 and 100 rpm

*J. Kukura, J. Baxter, and F. Muzzio,

Int. J. Pharm., 279 (2004) 9-17; from

Computational Fluid Dynamics

USP II, Computer Simulation*

9

GUT,

Computer Simulation**

S (s-1)

P(s

)

0 2 4 6 8 100

0.2

0.4

0.6

0.8

/ a = 0.1

/ a = 0.25

/ a = 0.5

S (s-1)

P(s

)0 2 4 6 8 10

0

0.2

0.4

0.6

0.8

/ a = 0.1

/ a = 0.25

/ a = 0.5

segmentationperistalsis

**Wang & Brasseur

Shear Parameters with Shear:

Intestine vs. USP II

Intestine USP II

Re S < 0.0007

- 0.003ReS < 0.25 - 0.5

S* < 10 - 25 S* < 250 - 500

for D< 100 m

particle path

uf

n

S*

P

0 10 20 30 40 500

0.05

0.1

0.15

0.2

/ a = 0.1

/ a = 0.25

/ a = 0.5

D = 100 m

segmentation

10

Shear Reynolds

Number

Shear Peclet

Number

Enhances

Dissolution

Rate (next)

for Felodipine

2

ReS

SR

2

*m

SRS

D

The Influence of Hydrodynamic Shear

on Dissolution

11

S*

Sh

0 100 200 300 400 5001

2

3

4

5

6

7

in vivo

in vitro

2

Shear Peclet Number: *m

SRS

D

2

Shear Reynolds number: ReS

SR

- Shear increases dissolution rate in intestine:

- Enhancement is 2-3 times larger in the

USP II device compared to the intestine

( ) ( )mS b eff

b

DC C t R t

V bdC

Sh(t)dt

( ) /m S b

D C C R

surface fluxSh

Why Hydrodynamic Shear Enhances

Dissolution Rate

12

S* = 0 S* = 1 S* = 10

S*

Sh

0 100 200 300 400 5001

2

3

4

5

6

7

2

*m

SRS

D

( ) /m S b

D C C R

surface fluxSh

Validation with Coutte Cell In Vitro Shear Experiments:

(Deanna Mudie, Greg Amidon)

13

3

4

7 2

4

0

92.73 cm /mole

3149 385

2.92 10 1

8.47 10 /

417 / / 1.08

/ 3.15 10 1

/

m

m

m

tot tot S

tot m C

S

S

D cm s

C g ml C C

C V V

C M g ml

C

Benzoic Acid

, 1 2 3: 26 , 50 , 71

RPM Shear Rate (S)

0.5 0.532 / ( relevent)

10 10.6 / ( relevent)

100

106 / ( r

avg

in vivo

in vivo

i

R R m R m R m

s

s

n vitrs o

3 Initial Particle Distributions

3 Rotation Rates

elevent)

RPM (Rv,avg)0

S* for

(Rv,avg)0

S* for

(Rmax)0

0.5 26 mm 4.19 20

10 50 mm 312 700

10 71 mm 627 1100

100 50 mm 3121 7000

100 71 mm 6270 11000

Validation of the

"Hierarchical Polydisperse Mathematical Model"

14

1 confinemenj sheartSh ,[ ( )]

( )( )

S b j

m m

j

j

j

dR tSh t

dt

C C tD

R t

S* = 4.19, R1

S* = 312, R2

S* = 627, R3

S* = 3120, R2

S* = 6267, R3

t / diss

Cb

/C

S

0 0.1 0.2 0.3 0.40

0.2

0.4

0.6

0.8

1

2

Shear Peclet Number

*m

SRS

D

Effect of Shear on Diffusion Layer Thickness

Commonly used in Mathematical Models

15

Effect of Hydrodynamic Shear (and convection)

on diffusion layer thickness :

1. reduce the thickness of the diffusion layer

2. reduce more at larger particle sizes

USP II

intestine

,[ ]m

j

S b j

m

j CdR

dt

CD

Hydrodynamic Influences are

Important to Drug Release and

Distinctions between In Vivo and In Vitro

Dissolution Dynamics,

and therefore need to be understood,

characterized and properly incorporated

into mathematical and in vitro modeling.

Conclusion

16