3. mckelvery presentation
Post on 30-May-2018
221 Views
Preview:
TRANSCRIPT
-
8/9/2019 3. McKelvery Presentation
1/51
Solid Dispersions
New Approaches and Technologies in Oral Drug DeliveryControlled Release Society; Rutgers, NJ
02 June 2009
Craig A. McKelvey
Merck & Co., Inc.
-
8/9/2019 3. McKelvery Presentation
2/51
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
-
8/9/2019 3. McKelvery Presentation
3/51
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)
-
8/9/2019 3. McKelvery Presentation
4/51
Practically no marketed drugs with less than 10 g/ml solubility in 70sor 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
1000 pints+ 125 full stomachs
* 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) +Image with permission of Sam Calagione,Dogfish Head Brewing Company, Milton, DE
Oral Delivery of Insoluble Drugs: Motivation
for New Approaches
-
8/9/2019 3. McKelvery Presentation
5/51
Practically no marketed drugs with less than 10 g/ml solubility in 70sor 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
1000 pints+ 125 full stomachs
* 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)
Oral Delivery of Insoluble Drugs: Motivation
for New Approaches
+Image with permission of Sam Calagione,Dogfish Head Brewing Company, Milton, DE
Not a generally accepted delivery vehicle
-
8/9/2019 3. McKelvery Presentation
6/51
Conventional Oral Deliverya Simplistic View
Disintegration Solubilization Precipitation
Absorption
-
8/9/2019 3. McKelvery Presentation
7/51
Disintegration Solubilization Precipitation
Absorption
pH?
Food?Native Surfactant?
Dilution?
Fluid Dynamics?
Conventional Oral Deliverya Simplistic View
-
8/9/2019 3. McKelvery Presentation
8/51
Disintegration Solubilization Precipitation
Absorption
pH?
Food?Native Surfactant?
Dilution?
Fluid Dynamics?
Conventional Oral Deliverya Simplistic View
Formulation Toolbox:Increase dissolution rate (improve wetting, disintegration time, surface area)
Increase dissolution extent (supersaturation)
-
8/9/2019 3. McKelvery Presentation
9/51
Conventional Oral Deliverya Simplistic View
Energy
Xtal + water
solution
For a mathematical treatment, see Jain andYalkowsky, J Pharm Sci (2001) 90:2, 234-252
-
8/9/2019 3. McKelvery Presentation
10/51
Conventional Oral Deliverya Simplistic View
Energy
Formulation Toolbox:
Make water a more desirable place for drug
- micellization- microemulsions
Xtal + water
solution
For a mathematical treatment, see Jain andYalkowsky, J Pharm Sci (2001) 90:2, 234-252
-
8/9/2019 3. McKelvery Presentation
11/51
Conventional Oral Deliverya Simplistic View
Energy
Formulation Toolbox:
Make water a more desirable place for drug
- micellization- microemulsions
Make the drug solid phase less desirable- neat amorphous
- dissolved
Xtal + water
solution
For a mathematical treatment, see Jain andYalkowsky, J Pharm Sci (2001) 90:2, 234-252
-
8/9/2019 3. McKelvery Presentation
12/51
Conventional Oral Deliverya Simplistic View
Energy
Formulation Toolbox:
Make water a more desirable place for drug
- micellization- microemulsions
Make the drug solid phase less desirable- neat amorphous
- dissolved
Xtal + water
solution
For a mathematical treatment, see Jain andYalkowsky, J Pharm Sci (2001) 90:2, 234-252
This option inherently introduces physical stability riskas more stable state is known to exist
-
8/9/2019 3. McKelvery Presentation
13/51
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
-
8/9/2019 3. McKelvery Presentation
14/51
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
-
8/9/2019 3. McKelvery Presentation
15/51
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
-
8/9/2019 3. McKelvery Presentation
16/51
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)
-
8/9/2019 3. McKelvery Presentation
17/51
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
-
8/9/2019 3. McKelvery Presentation
18/51
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
-
8/9/2019 3. McKelvery Presentation
19/51
GibbsFreeEne
rgy
0 21
for fixed T and P
Amorphousapparent Solubility
PolymerAPI
Solid Dispersions Performance and Risk
unstable
amorphous-
amorphous equilibrium
-
8/9/2019 3. McKelvery Presentation
20/51
GibbsFreeEne
rgy
0 21
for fixed T and P
Amorphousapparent Solubility
1
Solubility PolymerAPI
Solid Dispersions Performance and Risk
unstable
amorphous-
amorphous equilibrium
crystal-amorphous
equilibrium
-
8/9/2019 3. McKelvery Presentation
21/51
Solid Dispersions Performance and Risk
liquid
sc liquid
crystal
glass
TMTG
Volume
orEnthalpy
-
8/9/2019 3. McKelvery Presentation
22/51
Solid Dispersions Performance and Risk
liquid
sc liquid
crystal
glass (history 1)
TMTG
glass (history 2)
Volume
orEnthalpy
-
8/9/2019 3. McKelvery Presentation
23/51
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
-
8/9/2019 3. McKelvery Presentation
24/51
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
-
8/9/2019 3. McKelvery Presentation
25/51
-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
-
8/9/2019 3. McKelvery Presentation
26/51
-4
-2
0
2
HeatFlow(W/g)
0 50 100 150 200 250 300
Temperature (C)Exo Down Universal V3.8B TA Instruments
50% Compound E/ 50% PVP-PVAc Copolymer (10oC/min; 5 cycles)
Example Screening Approach for Miscibility
-
8/9/2019 3. McKelvery Presentation
27/51
-4
-2
0
2
HeatFlow(W/g)
0 50 100 150 200 250 300
Temperature (C)Exo Down Universal V3.8B TA Instruments
70% Compound E/ 30% PVP-PVAc Copolymer (10oC/min; 5 cycles)
Example Screening Approach for Miscibility
-
8/9/2019 3. McKelvery Presentation
28/51
Drug solubilized
in polymer
Drug particles
dispersed in
polymer
Drug-excipient
granules or
paste
Extrudate Composition
Potential Extrusion-Based Routes to Pharmaceutical Products
-
8/9/2019 3. McKelvery Presentation
29/51
Drug solubilized
in polymer
Drug particles
dispersed in
polymer
Drug-excipient
granules or
paste
Extrudate Composition
Potential Extrusion-Based Routes to Pharmaceutical Products
Polymeric films Injection molding Cylinders/Strands
Extrudate Macrostructure
-
8/9/2019 3. McKelvery Presentation
30/51
Drug solubilized
in polymer
Drug particles
dispersed in
polymer
Drug-excipient
granules or
paste
Extrudate Composition
Potential Extrusion-Based Routes to Pharmaceutical Products
Polymeric films Injection molding Cylinders/Strands
Extrudate Macrostructure
Congealing
Encapsulation
Pelletization/Spheronization/Spray
Compaction
Taste
masked/modified
release pellets
Compaction
Post Extrusion Processing
CuttingCalenderingMulti-
laminate
-
8/9/2019 3. McKelvery Presentation
31/51
Drug solubilized
in polymer
Drug particles
dispersed in
polymer
Drug-excipient
granules or
paste
Extrudate Composition
Potential Extrusion-Based Routes to Pharmaceutical Products
Polymeric films Injection molding Cylinders/Strands
Extrudate Macrostructure
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
-
8/9/2019 3. McKelvery Presentation
32/51
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
-
8/9/2019 3. McKelvery Presentation
33/51
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
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
V l f
-
8/9/2019 3. McKelvery Presentation
34/51
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
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
Die: Physically
shape extrudate
(e.g., rods, sheets, tubes)
Graphic courtesy Leistritz
-
8/9/2019 3. McKelvery Presentation
35/51
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
-
8/9/2019 3. McKelvery Presentation
36/51
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
-
8/9/2019 3. McKelvery Presentation
37/51
PressureTransducer
Feeder
Feed ThroatRaman + tNIRportsDie
Extrusion: Intermediate Scale
(16 mm ThermoPrism)
-
8/9/2019 3. McKelvery Presentation
38/51
Extruder: An Inside Look
Material Feed
KneadingPaddles
Die End
-
8/9/2019 3. McKelvery Presentation
39/51
Feed Stream #1Process Model
Feed Stream #2Process Model
Feed Stream #3Process 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
-
8/9/2019 3. McKelvery Presentation
40/51
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
-
8/9/2019 3. McKelvery Presentation
41/51
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
-
8/9/2019 3. McKelvery Presentation
42/51
Spray drying equipment
Niro SD Micro
Image with permission of GEAPharma Systems-Niro Inc.
-
8/9/2019 3. McKelvery Presentation
43/51
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
Quality Testing: Dissolution
-
8/9/2019 3. McKelvery Presentation
44/51
Quality Testing: Dissolution
(Compound E; in capsule)
-
8/9/2019 3. McKelvery Presentation
45/51
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
-
8/9/2019 3. McKelvery Presentation
46/51
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)
e.g., Moser et al., American PharmaceuticalReview (2008), 11(6), 68-73
Plasma
Concentration
Time
-
8/9/2019 3. McKelvery Presentation
47/51
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
e.g., Moser et al., American PharmaceuticalReview (2008), 11(6), 68-73
Plasma
Concentration
Time
-
8/9/2019 3. McKelvery Presentation
48/51
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
-
8/9/2019 3. McKelvery Presentation
49/51
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)
Milling orAtomization
Solution/Suspension
Spray Drying(solvent out)
Use any process thatreliably produces thedesired phase state forthe application
PlasmaConce
ntration
Time
-
8/9/2019 3. McKelvery Presentation
50/51
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)
Milling orAtomization
Solution/Suspension
Spray Drying(solvent out)
Use any process thatreliably produces thedesired phase state forthe application
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
-
8/9/2019 3. McKelvery Presentation
51/51
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
top related