3. McKelvery Presentation

8/9/2019 3. McKelvery Presentation

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Solid Dispersions

New Approaches and Technologies in Oral Drug DeliveryControlled Release Society; Rutgers, NJ

02 June 2009

Craig A. McKelvey

Merck & Co., Inc.


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Today

Solid dispersions: motivation and definition

Solid dispersion preparation Performance and risk

Screening drugs and excipients

Extrusion

Spray drying

Applications and Performance In vitro Preclinical


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Oral Delivery of Insoluble Drugs: Motivation

for New Approaches Practically no marketed drugs with less than 10 g/ml solubility in 70s

or 80s (0.01-0.1 mg/mL was considered low)*

Industry-wide increase in insoluble drug candidates**

Solubilities of 0.1 g/mL not uncommon

500,000 mL water to dissolve 50 mg dose

* Recent Advances in the Application of Solid Dispersions for Poorly Water-Soluble Drugs, 2004 AAPS andSimonelli Conference, A.T.M. Serajuddin (Novartis)** For example Cambridge Health Institute Issue 15:1, Adapting to Change in Technology and Markets,

Christopher A. Lipinski (Pfizer)


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Practically no marketed drugs with less than 10 g/ml solubility in 70sor 80s (0.01-0.1 mg/mL was considered low)*




1000 pints+ 125 full stomachs


Christopher A. Lipinski (Pfizer) +Image with permission of Sam Calagione,Dogfish Head Brewing Company, Milton, DE


for New Approaches


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Practically no marketed drugs with less than 10 g/ml solubility in 70sor 80s (0.01-0.1 mg/mL was considered low)*




1000 pints+ 125 full stomachs


Christopher A. Lipinski (Pfizer)


for New Approaches

+Image with permission of Sam Calagione,Dogfish Head Brewing Company, Milton, DE

Not a generally accepted delivery vehicle


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Conventional Oral Deliverya Simplistic View

Disintegration Solubilization Precipitation

Absorption


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Absorption

pH?

Food?Native Surfactant?

Dilution?

Fluid Dynamics?



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Absorption

pH?

Food?Native Surfactant?

Dilution?

Fluid Dynamics?


Formulation Toolbox:Increase dissolution rate (improve wetting, disintegration time, surface area)

Increase dissolution extent (supersaturation)


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Energy

Xtal + water

solution

For a mathematical treatment, see Jain andYalkowsky, J Pharm Sci (2001) 90:2, 234-252


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Energy

Formulation Toolbox:

Make water a more desirable place for drug

- micellization- microemulsions

Xtal + water

solution



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Energy




Make the drug solid phase less desirable- neat amorphous

- dissolved

Xtal + water

solution



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Energy




Make the drug solid phase less desirable- neat amorphous

- dissolved

Xtal + water

solution


This option inherently introduces physical stability riskas more stable state is known to exist


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Solid Dispersion: Definition

Common jargon Solid solutions Amorphous formulations

Physically stabilized High energy state

Todays presentation: focused on solid solutionsof API,polymer(s), and/or compatabilizers


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Solid Dispersions: Products

US Patent5,663,015

Spray dry ontosubstrate

1996J&JSporanox

Bloch et al.,Pharm Acta

Helv, 62, 1987

ProcessUnknown

1985Eli LillyCesamet

Spray Drying

Extrusion

Extrusion

Melt process;exact processunknown

Technology

Kaur et al., JPharm Sci, 69,1980

1975Pedinal PharmInc.

GrisPEG

Jan 2005Arden House

1997PfizerRezulin

31 Oct 2005

Press Release

2005

(sNDA)

AbbottKaletra

24 June 2005Press Release

Ph IIIPfizerTorcetrapib

ReferenceYear

Approved

CompanyProduct


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Today Solid dispersions: motivation and definition



Extrusion

Spray drying

Applications and Performance In vitro

Preclinical


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Solid Solution Preparation Most processes to make solid solutions involve the formation of a

true solution followed by quenching

Cooling

Solvent removal

Other processes include mechanical activation, precipitationtechniques, etc.

Ingredient

feed

Extrusion

(heat in)Cooling Milling

Solution

Spray Drying

(solvent out) Densification

Compaction/

Encapsulation

These routes can be used for clinical manufacture, other analagousprocesses can be used for screening (e.g. batch solvent casting)


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Solid Solution Preparation Process should result in homogeneous glass

Notion that one process is universally superior suspect

Processes can be interchangeable

Impact of inhomogeneity likely dramatic

Sample history will lead to different relaxation states

Quench rate, mechanical stress, conditioning

May impact kinetics of physical stability


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GibbsFreeEne

rgy

0 21

for fixed T and P

PolymerAPI

Solid Dispersions Performance and Risk

Polymer selection defines this curve Process does not define this curve


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GibbsFreeEne

rgy

0 21

for fixed T and P

Amorphousapparent Solubility

PolymerAPI


unstable

amorphous-

amorphous equilibrium


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GibbsFreeEne

rgy

0 21

for fixed T and P

Amorphousapparent Solubility

1

Solubility PolymerAPI


unstable

amorphous-

amorphous equilibrium

crystal-amorphous

equilibrium


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liquid

sc liquid

crystal

glass

TMTG

Volume

orEnthalpy


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liquid

sc liquid

crystal

glass (history 1)

TMTG

glass (history 2)

Volume

orEnthalpy


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Screening

Monomers or liquid oligomer surrogates of polymers1

High throughput solvent casting2,3

Cyclical DSC of blends or manually solvent cast4

1. Breitenbach et al., US Patent 6599931; 20032. A. Shanbhag et al., IJP (2008), 351, 209-2183. V. Barillaro et al., J Combinatorial Chemistry (2008), 10:5, 637-6434. Mura et al., International Journal of Pharmaceutics (1995), 119, 71-79


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Screening

Monomers or liquid oligomer surrogates of polymers1

High throughput solvent casting2,3

Cyclical DSC of blends or manually solvent cast4

1. Breitenbach et al., US Patent 6599931; 20032. A. Shanbhag et al., IJP (2008), 351, 209-2183. V. Barillaro et al., J Combinatorial Chemistry (2008), 10:5, 637-6434. Mura et al., International Journal of Pharmaceutics (1995), 119, 71-79


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-4

-2

0

2

HeatFlow(W/g)

0 50 100 150 200 250 300

Temperature (C)Exo Down Universal V3.8B TA Instruments

PVP-PVAc Copolymer (10oC/min; 5 cycles)

Example Screening Approach for Miscibility


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-4

-2

0

2

HeatFlow(W/g)

0 50 100 150 200 250 300


50% Compound E/ 50% PVP-PVAc Copolymer (10oC/min; 5 cycles)



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-4

-2

0

2

HeatFlow(W/g)

0 50 100 150 200 250 300


70% Compound E/ 30% PVP-PVAc Copolymer (10oC/min; 5 cycles)



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Drug solubilized

in polymer

Drug particles

dispersed in

polymer

Drug-excipient

granules or

paste

Extrudate Composition

Potential Extrusion-Based Routes to Pharmaceutical Products


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Drug solubilized

in polymer

Drug particles

dispersed in

polymer

Drug-excipient

granules or

paste



Polymeric films Injection molding Cylinders/Strands

Extrudate Macrostructure


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Drug solubilized

in polymer

Drug particles

dispersed in

polymer

Drug-excipient

granules or

paste





Congealing

Encapsulation

Pelletization/Spheronization/Spray

Compaction

Taste

masked/modified

release pellets

Compaction

Post Extrusion Processing

CuttingCalenderingMulti-

laminate


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Drug solubilized

in polymer

Drug particles

dispersed in

polymer

Drug-excipient

granules or

paste





Congealing

Encapsulation

Pelletization/Spheronization/Spray

Compaction

Taste

masked/modified

release pellets

Compaction

Post Extrusion Processing

CuttingCalenderingMulti-

laminate

Traditional

Tablets

Capsules and

Performance CapsulesPerformance

Tablets

Tablet-like

dosage forms

Fast dissolve strips/

Transdermal

Oral Dosage Forms=> Transdermal, ocular, sub-cutaneous inserts, biomedical devices, implants possible


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Selected Examples Highlighting

Processing Flexibility

Screw and Barrel Modularity: Feed, vacuum, mixing,

heating/cooling, and compression locations/duration can be easily

modified to suit applicationGraphic courtesy Leistritz


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Dry Feed: Could be combined

or separate loss in weight or

volumetric

Wet/Dry Feed: Can pump slurries

or solutions or stuff solid powders

of actives and excipients





modified to suit applicationGraphic courtesy Leistritz

V l f


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Dry Feed: Could be combined

or separate loss in weight or

volumetric

Vacuum: removal of

residual solvents/water

Wet/Dry Feed: Can pump slurries

or solutions or stuff solid powders

of actives and excipients





modified to suit application

Die: Physically

shape extrudate

(e.g., rods, sheets, tubes)

Graphic courtesy Leistritz


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Screws and Barrels are Modular

Flanged barrels, electricallyheated and liquid cooled

Screws are assembled onhigh torque splined shafts

=> Provides process flexibility from a single instrument

Pictures courtesy Leistritz


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Extrusion: Small Scale Recirculating extruders

Moderate amount of API

Generally conical screw design with no aggressive mixing

Some models have capability to estimate viscosity

Manual operation (slow)

Pharmalab mixer (5-10 g batch size)

Image with permission from ThermoFisher Scientific


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PressureTransducer

Feeder

Feed ThroatRaman + tNIRportsDie

Extrusion: Intermediate Scale

(16 mm ThermoPrism)


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Extruder: An Inside Look

Material Feed

KneadingPaddles

Die End


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Feed Stream #1Process Model



Real time massfeeder flow ratedata at t=t0

Real timenumericalconvolution

Future outletcompositions att=t0+m

Predict the outlet composition one mean residence time in the future

Extruder: Predicting the Future

Slide courtesy Gregory Troup


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0

10

20

30

40

50

60

70

80

90

100

14:45:36 14:52:48 15:00:00 15:07:12 15:14:24

API Model

SURF model

POLY model

API NIR

SURF NIR

POLY NIR

Model Predictive Process Monitoring

Slide courtesy Gregory Troup

Spray Drying


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Spray Drying

Spray Dried API/VA64

Atomization

Gas

Evaporationof Solvent

Heat in

Hotterregion

Coolerregion

SprayDroplet

SpraySolution Hot

CoolProcessing Gas

Courtesy of G. Shi

Liquid feed of drug, polymer, and/or surfactants (solution or suspension)

Atomize liquid feed to generate droplets

Dry droplets to generate amorphous solid particles

Collect product by cyclone & bag filter


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Spray drying equipment

Niro SD Micro

Image with permission of GEAPharma Systems-Niro Inc.


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Today Solid dispersions: motivation and definition



Extrusion Spray drying

Applications and Performance In vitro

Preclinical

Quality Testing: Dissolution


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Quality Testing: Dissolution

(Compound E; in capsule)


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Preparing Suspensions from Solid

Dispersionsdrug dissolved to formdrug-excipient solution

drug particles (crystalline oramorphous) in excipient(s)

-or-

milling,atomization,

pellitization,etc.

particles

suspensionscompaction/encapsulation

Suspension Applications:

Ex-clinical studies (discovery, safety, etc.)Human use (powder for constitutione.g., sachet)

general use, pediatric, geriatricCoating for other dosage form routesApplications requiring metered/customized dose

e.g., Moser et al., American PharmaceuticalReview (2008), 11(6), 68-73


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Suspension Application: Impact

Plasma Concentration Profile Following OralAdministration in Male Sprague-Dawley Rats

(Compound A; n=4)

Solid dispersion-based suspension (300 mpk)

Crystalline API suspended in 20%Vitamin E TPGS (1200 mpk)


Plasma

Concentration

Time


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Suspension Application: Impact

Plasma Concentration Profile Following OralAdministration in Male Sprague-Dawley Rats

(Compound A; n=4)

Solid dispersion-based suspension (300 mpk)

Crystalline API suspended in 20%Vitamin E TPGS (1200 mpk)

4-16X750 mpk 10%

PS80

200

mpk

D

2-6X300 mpkMethocelSuspension

100mpk

C

67X100 mpkImwitor 742:PS80

100mpk

B

2-8X1200 mpk 20%Vitamin ETPGS

300mpk

A

Exposureincrease

Referenceformulation

SDsusp.

dose

Cpd

Cross-ProjectPK Data Summary


Plasma

Concentration

Time


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Suspension Application: Route FlexibilityRaw Materials

FeedExtrusion(heat in)

Milling orAtomization

Solution/Suspension

Spray Drying(solvent out)

Use any process thatreliably produces thedesired phase state forthe application


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Suspension Application: Route Flexibility

Plasma Concentration Profile Following OralAdministration of Compound A Solid Dispersion(male beagle dogs; n=6; crossover; 50 mg dose)

Raw MaterialsFeed

Extrusion(heat in)


Solution/Suspension



PlasmaConce

ntration

Time


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Suspension Application: Route Flexibility

Plasma Concentration Profile Following OralAdministration of Compound A Solid Dispersion(male beagle dogs; n=6; crossover; 50 mg dose)

Raw MaterialsFeed

Extrusion(heat in)


Solution/Suspension



Key Considerations: Particle size/density (suspension

stability) Phase state desired

Phase stability in suspension Formulation with tuneability solubility

(prevent premature solubilization) pH temperature non-aqueous vehicleP

lasmaConce

ntration

Time

A k l d t


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AcknowledgementsMichael LowingerTodd Gibson

Jeff CasselBhagwant Rege

David Pipkorn

Wei XuCurt PanzerMike RiebeAmanda Sinha

Sami Karaborni

Laman AlaniHenry Wu

Adam ProcopioMelanie MarotaBrit Rudeen

Patrick MarsacNarayan VariankavalBrett Cooper

Galen ShiKatie Kleissas

Celia CruzLuke SchenckSeth ForsterAdam Chen

Jennifer Ho

Stephen WahnJohn Higgins

Justin MoserSarah Geers

Karim Younan

Hui XuZhen Liu

Varaporn TreemaneekarnRobert Meyer

Paul Harmon

Li LiLixia CaiCindy Starbuck

Jeff KoFilippos Kesisoglou

Greg Troup

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3. McKelvery Presentation