Solid Dispersions - NJ Center for Biomaterials Workshop/3...Solid Dispersions New Approaches and Technologies in Oral Drug Delivery Controlled Release Society; Rutgers, NJ 02 June

Solid Dispersions

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

02 June 2009 Craig A. McKelveyMerck & Co., Inc.

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

Oral Delivery of Insoluble Drugs: Motivation for New Approaches

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

• Industry-wide increase in insoluble drug candidates**• Solubilities of 0.1 μg/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 and Simonelli 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)




1000 pints+ 125 full stomachs


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





1000 pints+ 125 full stomachs



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

Not a generally accepted delivery vehicle

Conventional Oral Delivery—a Simplistic View

Disintegration Solubilization Precipitation

Absorption


Absorption

pH?

Food?Native Surfactant?

Dilution?

Fluid Dynamics?



Absorption

pH?

Food?Native Surfactant?

Dilution?

Fluid Dynamics?


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

Conventional Oral Delivery—a Simplistic ViewE

nerg

y

Xtal + water

solution

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


nerg

y

Formulation Toolbox:Make water a more desirable place for drug

- micellization- microemulsions

Xtal + water

solution



nerg

y



Make the drug solid phase less desirable- neat amorphous - dissolved

Xtal + water

solution



nerg

y



Make the drug solid phase less desirable- neat amorphous - dissolved

Xtal + water

solution


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

Solid Dispersion: Definition• Common jargon

– Solid solutions– Amorphous formulations– Physically stabilized– High energy state

• Today’s presentation: focused on solid solutions of API, polymer(s), and/or compatabilizers

Solid Dispersions: Products

US Patent 5,663,015

Spray dry onto substrate

1996J&JSporanox

Bloch et al., Pharm ActaHelv, 62, 1987

Process Unknown

1985Eli LillyCesamet

Spray Drying

Extrusion

Extrusion

Melt process; exact process unknown

Technology

Kaur et al., J Pharm Sci, 69, 1980

1975Pedinal PharmInc.

GrisPEG

Jan 2005 Arden House

1997PfizerRezulin

31 Oct 2005 Press Release

2005(sNDA)

AbbottKaletra

24 June 2005 Press Release

Ph IIIPfizerTorcetrapib

ReferenceYear Approved

CompanyProduct

Today




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, precipitation techniques, 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)

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

ΔG

ibbs

Fre

e E

nerg

y

0 21

for fixed T and P

PolymerAPI

Solid Dispersions – Performance and Risk

⇒ Polymer selection defines this curve⇒ Process does not define this curve

ΔG

ibbs

Fre

e E

nerg

y

0 21

for fixed T and P

Amorphous apparent Solubility

PolymerAPI


unstable

amorphous-amorphous equilibrium

ΔG

ibbs

Fre

e E

nerg

y

0 21

for fixed T and P

Amorphous apparent Solubility

1

Solubility PolymerAPI


unstable

amorphous-amorphous equilibrium

crystal-amorphous equilibrium


liquid

sc liquid

crystal

glass

TMTG

Vol

ume

or E

ntha

lpy


liquid

sc liquid

crystal

glass (history 1)

TMTG

glass (history 2)

Vol

ume

or E

ntha

lpy

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, 209-218 3. V. Barillaro et al., J Combinatorial Chemistry (2008), 10:5, 637-6434. Mura et al., International Journal of Pharmaceutics (1995), 119, 71-79

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, 209-218 3. V. Barillaro et al., J Combinatorial Chemistry (2008), 10:5, 637-6434. Mura et al., International Journal of Pharmaceutics (1995), 119, 71-79

-4

-2

0

2

4

Hea

t Flo

w (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

-4

-2

0

2

4

Hea

t Flo

w (W

/g)

0 50 100 150 200 250 300


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


-4

-2

0

2

4

Hea

t Flo

w (W

/g)

0 50 100 150 200 250 300


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


Drug solubilizedin polymer

Drug particlesdispersed in

polymer

Drug-excipientgranules or

pasteExtrudate Composition

Potential Extrusion-Based Routes to Pharmaceutical Products



polymer




Polymeric films Injection molding Cylinders/Strands

Extrudate Macrostructure



polymer






Congealing

Encapsulation

Pelletization/Spheronization/Spray

Compaction

Tastemasked/modified

release pelletsCompaction

Post Extrusion Processing

CuttingCalenderingMulti-

laminate



polymer






Congealing

Encapsulation

Pelletization/Spheronization/Spray

Compaction

Tastemasked/modified

release pelletsCompaction

Post Extrusion Processing

CuttingCalenderingMulti-

laminate

TraditionalTablets

Capsules andPerformance Capsules

PerformanceTablets

Tablet-likedosage forms

Fast dissolve strips/Transdermal

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

Selected Examples Highlighting Processing Flexibility

Screw and Barrel Modularity: Feed, vacuum, mixing, heating/cooling, and compression locations/duration can be easily modified to suit application

Graphic courtesy Leistritz

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




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



Die: Physically shape extrudate(e.g., rods, sheets, tubes)


Screws and Barrels are Modular

Flanged barrels, electrically heated and liquid cooled

Screws are assembled on high torque splined shafts

=> Provides process flexibility from a single instrument

Pictures courtesy Leistritz

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 Thermo Fisher Scientific

Pressure Transducer

Feeder

Feed ThroatRaman + tNIRportsDie

Extrusion: Intermediate Scale (16 mm ThermoPrism)

Extruder: An Inside Look

Material Feed

KneadingPaddles

Die End

Feed Stream #1Process Model



Real time mass feeder flow rate data at t=t0

Real time numerical convolution

Future outlet compositions at t=t0+τm

Predict the outlet composition one mean residence time in the future

Extruder: Predicting the Future

Slide courtesy Gregory Troup

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 ModelSURF modelPOLY modelAPI NIRSURF NIRPOLY NIR

Model Predictive Process Monitoring

Slide courtesy Gregory Troup

Spray Drying

Spray Dried API/VA64

AtomizationGas

Evaporation of 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

Spray drying equipment

Niro SD Micro Image with permission of GEA Pharma Systems-Niro Inc.

Today




Quality Testing: Dissolution(Compound E; in capsule)

Preparing Suspensions from Solid Dispersions

drug dissolved to form drug-excipient solution

drug particles (crystalline or amorphous) in excipient(s)-or-

milling, atomization, pellitization, etc.

particles

suspensionscompaction/encapsulation

Suspension Applications:•Ex-clinical studies (discovery, safety, etc.)•Human use (powder for constitution—e.g., sachet)

⇒ general use, pediatric, geriatric•Coating for other dosage form routes•Applications requiring metered/customized dose

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

Suspension Application: Impact

Plasma Concentration Profile Following Oral Administration 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)


Pla

sma

Con

cent

ratio

n

Time

Suspension Application: Impact

Plasma Concentration Profile Following Oral Administration 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 mpk Methocel Suspension

100 mpk

C

67X100 mpk Imwitor 742:PS 80

100 mpk

B

2-8X1200 mpk 20% Vitamin E TPGS

300 mpk

A

Exposure increase

Reference formulation

SD susp. dose

Cpd

Cross-Project PK Data Summary


Pla

sma

Con

cent

ratio

n

Time

Suspension Application: Route FlexibilityRaw Materials

FeedExtrusion(heat in)

Milling or Atomization

Solution/Suspension

Spray Drying (solvent out)

Use any process that reliably produces the desired phase state for the application

Suspension Application: Route Flexibility

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

Raw MaterialsFeed

Extrusion(heat in)


Solution/Suspension



Pla

sma

Con

cent

ratio

n

Time

Suspension Application: Route Flexibility

Plasma Concentration Profile Following Oral Administration 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

lasm

a C

once

ntra

tion

Time

AcknowledgementsMichael LowingerTodd GibsonJeff CasselBhagwant RegeDavid PipkornWei XuCurt PanzerMike RiebeAmanda SinhaSami KaraborniLaman AlaniHenry WuAdam ProcopioMelanie MarotaBrit RudeenPatrick MarsacNarayan VariankavalBrett CooperGalen ShiKatie Kleissas

Celia CruzLuke SchenckSeth ForsterAdam ChenJennifer HoStephen WahnJohn HigginsJustin MoserSarah GeersKarim YounanHui XuZhen LiuVaraporn TreemaneekarnRobert MeyerPaul HarmonLi LiLixia CaiCindy StarbuckJeff KoFilippos KesisoglouGreg Troup

Documents

Solid Dispersions - NJ Center for Biomaterials Workshop/3...Solid Dispersions New Approaches and Technologies in Oral Drug Delivery Controlled Release Society; Rutgers, NJ 02 June