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Challenges in the Analysis of Spray Dried Formulations: Dissolution Dr Adele Patterson Senior Research Investigator II Bristol-Myers Squibb 8 th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

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Page 1: Challenges in the Analysis of Spray Dried Formulations ...fplreflib.findlay.co.uk/images/pdf/Adele-Patterson-BMS.pdfpH 1.0 SLS pH 4.5 SLS pH 6.0 SLS pH 6.8 SLS pH 1.0 Tween pH 4.5

Challenges in the Analysis of Spray Dried Formulations: Dissolution

Dr Adele PattersonSenior Research Investigator II

Bristol-Myers Squibb

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

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Acknowledgements

Ana FerreiraClare Rawlinson-Malone

Zoe Gault

Other BMS colleagues in DPST and ABD at Moreton UK and New Brunswick USA

28th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

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Outline

• What is driving the interest in amorphous materials in the pharmaceutical industry?

• Polymer Selection

• Understanding dissolution behaviour of amorphous materials

Advantages

Mechanistic Understanding – Why & How?

• Development of in-vitro dissolution methods

Challenges / Limitations

What can we change?

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

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Why Are We Interested?

Solid

Cs

0x

x

Solid

Cs

0x

x

Solid

Cs

0x

x

Biopharmaceutic Classification Systema

a Amidon, Lennernas et al. (1995) Pharmaceutical Research b L. Benet et al, (2006) Bulletin Technique Gattefosse . .

HIGH LOW

Co-crystals

35-70% of APIs b

Class II

Amorphous

Size reduce

Salt or Solvate

Colloid systemsSolid Dispersions

Wetting and

Porosity

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Dissolution of Amorphous Dispersion:“Spring and Parachute” model

Guzmán et al, J. Pharm.Sci. 2007, 96(10) 2686-27025

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POLYMER SELECTION

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How Do You Select a Polymer?

• Primary Function = Maintain Physical Stability of the API

• Dissolution Rate / Sustainment

Solubility Considerations

Water Uptake

Interactions with API

Chemical Stability

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

Target Material Profile (TMP)

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What Are the ASD Critical Parameters?

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

TMPBackbone

Functional Groups

Substitution

Mol Weight Dist ASD

Powder Properties

Drug Loading in

ASD

ASD Loading in

Tablet

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MECHANISTIC UNDERSTANDING

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In vivo performance model

Free drug

Particles dissolve

kdis(must be

rapid) kabs

Bile-salt micelles

Colloids

Drug Species

Intestinalbilayer

Crystalline drug

Rapid absorption

:.:.

:.:. :.:.:.:.

:.:.:. :.:.

:. :.:.:.:.:.:.:.

:.:.

:. :.:.:.:.:.:.:.

:.:.

:. :.:.:.:.:.:.:.

:.:.

:. :.:.:.:.:.:.:.

:.:.

:. :.:.:.:.:.:.:.:.

:.:. :.:.:.:.

:.:.:.

Granules

Particles

10

Rapiddisintegration

is critical

Bioperformanceis function of dispersion

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

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SDD dissolution mechanistic models

11

Seconds Polymer Gel

Drug Nanostructures

Dry SDD Particle

Minutes

Polymer Chains

Minutes to Hours

Dispersion Hydrates Resulting in nano-scale

Phase Separation

Dispersion hydrates with limited phase separation. As drug

diffuses from particle boundary layer, polymer becomes soluble.

SDD particles erodes. Drug diffuses from particle into solution.

kdiff

Hypothesis: 1.Dissolution fast most of the time: k relatively size and loading independent. 2.Situation is better for nanoaggregateformation.

Hypothesis: 1.Dissolution is a function of loading and particle size (surface area)2.Situation is worst for nanoaggregateformation3.Sink and non-sink dissolution behavior may be very different.

Drug with low solubility in hydrated polymer

Drug with high solubility in hydrated polymer

Seconds Polymer Gel

Drug Nanostructures

Dry SDD Particle

Minutes

Polymer Chains

Minutes to Hours

Dispersion Hydrates Resulting in nano-scale

Phase Separation

Dispersion hydrates with limited phase separation. As drug

diffuses from particle boundary layer, polymer becomes soluble.

SDD particles erodes. Drug diffuses from particle into solution.

kdiff

Hypothesis: 1.Dissolution fast most of the time: k relatively size and loading independent. 2.Situation is better for nanoaggregateformation.

Hypothesis: 1.Dissolution is a function of loading and particle size (surface area)2.Situation is worst for nanoaggregateformation3.Sink and non-sink dissolution behavior may be very different.

Drug with low solubility in hydrated polymer

Drug with high solubility in hydrated polymer

Chapter 9 in Amorphous Solid Dispersions – Theory and Practice, Eds. Navnit Shah et al., Springer 2014

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Dissolution Methods

12BMS Confidential & Proprietary

Dissolution Methods

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

Research methods

Non Sink

Low Volume

Powder

Complex Media

Specialist Equipment

QC Release methods

Sink

≥ 500 mLs

Tablets

USP Media

USP Equipment

Formulation Development

Sink

≥ 500 mLs

Tablet

Wide Range of

Media

USP Equipment

Build Mechanistic Understanding

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Support for SDD UnderstandingDissolution Methodology - Sink Method

SDD syringe dissn method – rate of dissolution – Media: 2% NaTc/POPC in PBS pH 5.8 Dose: 75µg API/ml

138th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

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14

Support for SDD UnderstandingDissolution Methodology – non sink methods

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

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Chord Length (μm)

Co

un

ts

Fibre Optics

Sapphire Window

Rotating Optics

Beam Splitter

Focussed Beam Reflectance Measurement

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

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Dry SDD particleParticle erosion rate-limiting step

Drug Y - UV

Drug Y - FBRM

Colloidal nano speciesrate-limiting step

Drug X - UV

Drug X - FBRM

Drug YDrug ADrug B Drug ZDrug X

?

Drug C

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

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Dissolution Methods

17BMS Confidential & Proprietary 8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

Research methods

Non Sink

Low Volume

Powder

Complex Media

Specialist Equipment

QC Release methods

Sink

≥ 500 mLs

Tablets

USP Media

USP Equipment

Formulation Development

Sink

≥ 500 mLs

Tablet

Wide Range of

Media

USP Equipment

Monitor Product Performance against Specification

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Dissolution Methods

18BMS Confidential & Proprietary 8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

Research methods

Non Sink

Low Volume

Powder

Complex Media

Specialist Equipment

QC Release methods

Sink

≥ 500 mLs

Tablets

USP Media

USP Equipment

Formulation Development

Sink or Non Sink

≥ 500 mLs

Tablet

Wide Range of

Media

USP Equipment

Identify & Discriminate for Critical

Performance Parameter

(CPP)

Evidence of Recrystallization

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METHOD DEVELOPMENT

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Method Development

• Physical Parameters

Apparatus

Rotation Speed

Media Volume

Detection Method

• Media Selection

pH

Buffer Ionic strength

Surfactant Class / Concentration

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

Affect Sink Conditions for your API and the

Polymer

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Media Ranking: Sink Solubility of SDD

Dissolution

Media

Sink

Solubility

pH 1.0

pH 4.5

pH 6.0 > 0.25 mg / mL

pH 6.8 > 0.10 mg / mL

pH 1.0 CTAB < 0.10 mg / mL

pH 4.5 CTAB

pH 6.0 CTAB

pH 6.8 CTAB

pH 1.0 SLS

pH 4.5 SLS

pH 6.0 SLS

pH 6.8 SLS

pH 1.0 Tween

pH 4.5 Tween

pH 6.0 Tween

pH 6.8 Tween

pH 1.0 CHAPS

pH 4.5 CHAPS

pH 6.0 CHAPS

pH 6.8 CHAPS

0 2 4 6 80

20

40

60

80

100

120

0

2

4

6

8

10

12

Pol

ymer

Sol

ubili

ty (

% D

isso

lved

)

pH

AP

I Sol

ubili

ty (

mg/

mL)

pH Dependant Solubility of SDD Components

API Polymer

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Media Ranking: Sink Solubility of SDD

Dissolution

Media

Sink

Solubility

pH 1.0

pH 4.5

pH 6.0 > 0.25 mg / mL

pH 6.8 > 0.10 mg / mL

pH 1.0 CTAB < 0.10 mg / mL

pH 4.5 CTAB

pH 6.0 CTAB

pH 6.8 CTAB

pH 1.0 SLS

pH 4.5 SLS

pH 6.0 SLS

pH 6.8 SLS

pH 1.0 Tween

pH 4.5 Tween

pH 6.0 Tween

pH 6.8 Tween

pH 1.0 CHAPS

pH 4.5 CHAPS

pH 6.0 CHAPS

pH 6.8 CHAPS

0 2 4 6 80

20

40

60

80

100

120

0

2

4

6

8

10

12

Pol

ymer

Sol

ubili

ty (

% D

isso

lved

)

pH

AP

I Sol

ubili

ty (

mg/

mL)

pH Dependant Solubility of SDD Components

API Polymer

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Media Ranking: Sink Solubility of SDD

AU

-0.010

0.000

0.010

0.020

0.030

0.040

0.050

0.060

0.070

0.080

0.090

Minutes0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 2.00 2.20 2.40 2.60 2.80 3.00 3.20 3.40 3.60 3.80 4.00 4.20 4.40

pH 4.5 Tween pH 6.8 SLS

pH 1.0 no surfpH 6.0 CTAB

Dissolution

Media

Sink

Solubility

HPLC Peak

Shape

pH 1.0

pH 4.5

pH 6.0

pH 6.8

pH 1.0 CTAB

pH 4.5 CTAB

pH 6.0 CTAB

pH 6.8 CTAB

pH 1.0 SLS

pH 4.5 SLS

pH 6.0 SLS

pH 6.8 SLS

pH 1.0 Tween

pH 4.5 Tween

pH 6.0 Tween

pH 6.8 Tween

pH 1.0 CHAPS

pH 4.5 CHAPS

pH 6.0 CHAPS

pH 6.8 CHAPS

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Media Ranking: Sink Solubility of SDD

CTAB

Dissolution

Media

Sink

Solubility

HPLC Peak

Shape

Solution

Appearance

Media

Ranking

pH 1.0

pH 4.5

pH 6.0

pH 6.8

pH 1.0 CTAB

pH 4.5 CTAB

pH 6.0 CTAB

pH 6.8 CTAB

pH 1.0 SLS

pH 4.5 SLS

pH 6.0 SLS

pH 6.8 SLS

pH 1.0 Tween

pH 4.5 Tween

pH 6.0 Tween

pH 6.8 Tween

pH 1.0 CHAPS

pH 4.5 CHAPS

pH 6.0 CHAPS

pH 6.8 CHAPS

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0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100 120

% D

isso

lved

Mins

1 % Brij PSD2 1 % CTAB PSD2

1 % SDS PSD2 1 % CHAPS PSD2

Non-ionisable drug / ~ 50% Ionised polymer / Variable surfactant

Dissolution: Effect of Surfactant Class

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80

Dis

so (

%)

Time (mins)

HCl & SDS -1% HCl & CTAB -1%

+vely drug / Un-Ionised polymer / Charged surfactant

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Dissolution: Effect of Media pH

-10

10

30

50

70

90

110

0 10 20 30 40 50 60 70 80

Dis

so (

%)

Time (mins)

HCl & SDS -1% pH 6.0 & SDS -1%

0

20

40

60

80

100

120

0 20 40 60 80 100 120 140

% D

isso

lved

(%

)

Time (mins)

pH 5.25 pH 5.4

pH 5.5 pH 5.6

pH 5.7 pH 5.8

Ionisable drug / Ionisable polymer / -velyCharged surfactant

Non-ionisable drug / ionisable polymer / non-ionisable surfactant

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27

0

20

40

60

80

100

120

0 10 20 30 45 60 90 120

% D

isso

lved

Time (Mins)

pH 5.25 pH 5.4pH 5.5 pH 5.6pH 5.7 pH 5.8

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

Dissolution: Effect of Surfactant Grade

0

20

40

60

80

100

120

0 20 40 60 80 100 120 140

% D

isso

lved

(%

)

Time (mins)

pH 5.25 pH 5.4

pH 5.5 pH 5.6

pH 5.7 pH 5.8

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0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100 120

% D

isso

lved

(%

)

Time (mins)

Effect of Surfactant Concentration on Dissolution

0% Brij 0.05% Brij 0.10% Brij

0.15% Brij 0.20% Brij 0.40% Brij

0.60% Brij 0.80% Brij 1.00% Brij

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

Dissolution: Effect of Surfactant Concentration

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-4.5

-4

-3.5

-3

-2.5

-2

-1.5

0 1 2 3 4 5 6 7 8 9 10

Lo

g k

ob

s(h

-1)

pH

The log kobs-pH profile for degradation at 40C.

• API / Polymer Trace level impurities Chemical structure Intermolecular interactions

• Water Free / bound in polymer Uptake

• Amorphous materials are inherently less stable

Chemical Stability

29

O

OR

OR

CH2OR1

O

OR2

OR

CH2OR

O

n

O

R1 = -H R2 = -COCH3

-CH3 -COCH2CH2COOH-CH2CH(CH3)OH

HPMC-AS

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

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• API / Polymer Trace level impurities Chemical structure Intermolecular interactions

• Water Free / bound in polymer Uptake

• Amorphous materials are inherently less stable

Chemical Stability

30

Inc in Degradant after 3 wks

SDI with HPMC-AS Grade

L M H

40/75 (Open) 0.7 0.5 0.4

50/75 (Open) 2.6 2.0 1.3

Acetyl Levels 5 - 9% 7 - 11% 10 - 14%

Succinyl Levels 14 - 18% 10 - 14% 4 - 8%

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

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• API / Polymer Trace level impurities Chemical structure Intermolecular interactions

• Water Free / bound in polymer Uptake

• Amorphous materials are inherently less stable

Chemical Stability

31

Patterson et al. (2015) Int J of Pharmaceutics 478, 348-360

𝑙𝑛𝑘 = 𝑙𝑛𝐴 −𝐸𝑎𝑅𝑇

+ 𝐵 %𝑅𝐻 + 𝐶 %𝑆𝐴

R2 = 0.9905, RMSEC = 0.0161

𝑙𝑛𝑘 = 𝑙𝑛𝐴 −𝐸𝑎𝑅𝑇

+ 𝐵 %𝑅𝐻

R2 = 0.9827, RMSEC = 0.0290

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

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Summary

Knowledge / Understanding

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

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Thank you for your attention

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

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8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

Backup Slides

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Particle erosion model of SDD dissolution

35

Relative impact of SDD powder properties vs polymer chemistry

25% drug 75% HPMCAS

Central composite design 16 SDD lots + 6 re-sprays + 4 confirmation lots Total = 26 lots

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

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0 2 4 6 8 10 12 14 16 18 200

20

40

60

80

100

120

140

Time (min)

% D

isso

lved

(pH

5.8

) -

corr

ecte

d fo

r po

tenc

y an

d st

artin

g do

se v

aria

tion

Run 1Run 2

Run 3

Run 4

Run 5Run 6

Run 7

Run 8Run 9

Run 10

Run 11Run 12

Run 13

Run 14

Run 15Run 16

Confirmation 13

Confirmation 14Confirmation 9

Confirmation 5

Respray 1Respray 5

Respray 14

Respray 9

Respray 13Respray 6

Sink conditions: 300µg/ml SDD in pH 5.8 PBS with 2% bile salts

SDD in-vitro dissolution

36

First order model used to determine dissolution rate

)1( kteQQ

with Q ∞ = 100 % 0 10 20 30 40 50 60 70 80 90 1000

50

100

Dissolution @ pH 5.8

Dis

solu

tion

pred

icte

d by

mod

el

R2 = 0.993

Run 1

0 2 4 6 8 10 12 14 16 18 200

50

100

Time (min)

% D

isso

lved

(pH

5.8

)

Run 1

Data

Unweighted fit95% Confidence Limits

0 10 20 30 40 50 60 70 80 90 1000

50

100

Dissolution @ pH 5.8

Dis

solu

tion

pred

icte

d by

mod

elR2 = 0.993

Run 1

0 2 4 6 8 10 12 14 16 18 200

50

100

Time (min)

% D

isso

lved

(pH

5.8

)

Run 1

Data

Unweighted fit95% Confidence Limits

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

Page 37: Challenges in the Analysis of Spray Dried Formulations ...fplreflib.findlay.co.uk/images/pdf/Adele-Patterson-BMS.pdfpH 1.0 SLS pH 4.5 SLS pH 6.0 SLS pH 6.8 SLS pH 1.0 Tween pH 4.5

Relative impact of powder properties and polymer:Interactive effects

37Succinoyl content Bulk Vol Particle Size (D90)

Succinylcontent

Bulk Vol

Particle SIze

2-way: Dissn rate is more sensitive to bulk vol (and to a lesser extent particle size) at high succinoyl content3-way: None observed

Succinoylcontent B

ulk Vol

Particle S

ize (D90)

Page 38: Challenges in the Analysis of Spray Dried Formulations ...fplreflib.findlay.co.uk/images/pdf/Adele-Patterson-BMS.pdfpH 1.0 SLS pH 4.5 SLS pH 6.0 SLS pH 6.8 SLS pH 1.0 Tween pH 4.5

Target Product Profile

388th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

Page 39: Challenges in the Analysis of Spray Dried Formulations ...fplreflib.findlay.co.uk/images/pdf/Adele-Patterson-BMS.pdfpH 1.0 SLS pH 4.5 SLS pH 6.0 SLS pH 6.8 SLS pH 1.0 Tween pH 4.5

0

20

40

60

80

100

120

140

160

180

200

0 50 100 150 200 250

Time (min)

Co

nc

en

tra

tio

n (

ug

/mL

)

0

20

40

60

80

100

120

140

160

180

200

0 50 100 150 200 250

Co

ncen

trati

on (u

g/m

L)

Time (min)

0

20

40

60

80

100

120

140

160

180

200

0 50 100 150 200 250

Co

ncen

trati

on (u

g/m

L)

Time (min)

ML H

0

50

100

150

200

0 30 60 90 120

[Dru

g] (µ

g/m

L)

Time (min)

40%A HPMCAS SDD

25%A HPMCAS SDD

40%A PVPVA SDD

25%A PVPVA SDD

40% API:HPMC-AS SDD

25% API:HPMC-AS SDD

40% API:PVP-VA SDD25% API:PVP-VA SDD

Effect of Formulation Choices on Dissolution of Amorphous Dispersion:

39

Not just fast dissolution

Sustainment in solution

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

Page 40: Challenges in the Analysis of Spray Dried Formulations ...fplreflib.findlay.co.uk/images/pdf/Adele-Patterson-BMS.pdfpH 1.0 SLS pH 4.5 SLS pH 6.0 SLS pH 6.8 SLS pH 1.0 Tween pH 4.5

BRI Test Ref: BREC0249-041

G

Add 1.8 mL MFDS

Allow to StandUndisturbedat 37°C

CA

E

Sample 50 µLDilute Into250 µL Organic Solvent

MicrocentrifugeTube ContainingDispersion

B

F

Cap + Resuspendon Vortex for~30 Seconds

Cap + ContinuouslyMix on Vortex for60 Seconds

D

Centrifuge at13,000 RPM for1 Minute or 80,000 RPMfor 20 min (Free Drug)

Repeat Steps C-G for Sampling of Timepoints

* After 90 minutes, the supernatant was completely removed & replaced with fresh MFDS

Support for SDD UnderstandingDissolution Methodology – non sink methods

8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017

[AP

I]