BASF ExactFair Crowley For Print

Developing Better
Treatments for
Poorly Soluble
Compounds with
OptiMeltTM HME
Kieran Crowley PhD
Catalent Pharma Solutions
Somerset NJ
USA
Catalyst + Talent. Our name combines these ideas.

From drug and biologic development to delivery technologies to
supply solutions, we are the catalyst for your success. Whether you
are looking for a single, tailored solution or multiple answers
throughout your products lifecycle, we can improve the total value
of your treatmentsfrom discovery to market and beyond.
Catalent. More products. Better treatments. Reliably supplied.
CONFIDENTIAL for CATALENT
WHY CATALENT? Unrivaled experience, deepest expertise, and

a track record of market success on a global scale.
We serve 49 of the top 50 pharmaceutical and
36 of the top 50 biotech companies
We operate 20+ global sites across 100+ markets
We create expert solutions from over 1,000 scientists
We support 40% of recent new U.S. drug approvals
We manufacture or package 100 billion units annually
We are the industry leader in drug delivery technology
We use a multi-faceted approach to solve bioavailability
and patient adherence challenges
We provide end-to-end biologics technologies, from
gene expression to fill/finish
Presentation Overview
1. Introduction to Drug Delivery Technologies
2. The Amorphous State and Solid Dispersions
3. Hot Melt Extrusion (HME) & OptiMeltTM
4. HME Formulation Case Studies
5. Summary Comments Capturing Value with HME
Catalent Somerset, New Jersey USA
Somerset Pharmaceutical
Development Center
Softgel
MRT Oral
Solids
MRT
Zydis
We provide Drug Delivery Solutions from a wide

range of Drug Delivery Technology Platforms
Bioavailability enhancement represents the biggest

challenge in oral drug delivery
What is your biggest challenge in oral drug
delivery/formulation development?
N=12
Other
2
It can be quite resource intensive to develop

formulations for poorly-soluble drugs. The
problem is most severe when the molecule
has both low solubility and high-dose
Exe. Director, Pharmaceutical R&D
10
Bioavailability
enhancement
We are seeing more poorly soluble drugs in

early phase development. Most of the
compounds I have right now are poorly
soluble
VP, Pharmaceutical Development
Historically, our infrastructure is based on

conventional technologies. We dont have
enough capacity and capability in new
technologies that address bioavailability
issues
Director, Formulation Development
SOURCE: Mckinsey & Company Customer interviews
Drug Delivery Technology Platform What attributes are needed to capture full value?
An effective solution delivers drug
precisely, reproducibly & safely
Fully integrated solution
equipment, materials, human
resource from End-to-End
Compliant solution equipment,
controls, scientific knowledge are
current & approvable
Exclusive solution / Freedom to Operate
IP or technical barriers to competition,
Operational solution acceptable

unit dose cost
Technology Platform Attributes Hot Melt Extrusion

Critical Attributes
OptiMeltTM
An effective solution
HME dispersions achieve a specific

solubility increase in vivo & utilize
GRAS excipients
HME is a continuous process suited for

scale-up, and finished dosage forms
may be made using conventional
equipment
Compliant solution
Numerous oral products and devices

have been filed with regulatory
agencies
Exclusive solution
HME technology requires significant

know-how to commercialize. The drug
delivery profile may be patentable
Operational solution
Proven in pharma & other industries as

a robust process readily integrated into
a manufacturing operation
HME Technology Platform OptiMeltTM

GMP Bench to Pilot to Commercial scale, with global capabilities
Schorndorf, Germany and Somerset, New Jersey
Broadest selection of downstream processing technologies, colocated with OptiMeltTM hot melt extrusion
Integrated solutions provider, with over 75 years of industry
experience
Development, formulation, scale-up, manufacturing, packaging
Formulation acceleration and optimization with open CatalentBASF bioavailability alliance
Broad range of excipients designed specifically to enhance solubility,

particularly with hot melt extrusion
Non-exclusive arrangement to increase development efficiency and deliver

better treatments for your molecules
88
Solubility Enhancement Strategies / Technologies
Neat API
Size-Reduced
High-Energy
Solid
Liquid API
Disintegrants,
Surfactants
Micron Nano
scale
scale
Amorphous,
Softgels, SEDDS,
liq.fill caps, etc.
Solid Dispersion
Dissolution
Crystalline
API
present
Crystalline
API
absent
Solid Dispersion Products Melt approach

common
Product
Company
Technology
Matrix Excipient
Afeditab (nifedipine)
Elan
Melt (granulation)
Poloxamer/PVP
Certican (everolimus)
Novartis
Solvent (SDD)
HPMC
Cesamet (nabilone)
Valeant
Solvent (granulation)
PVP
Fenoglide (fenofibrate)
LifeCycle Ph.
Melt (spray)
PEG
Gris-Peg (griseofulvin)
Pedinol
Melt (tablet)
PEG
Ibuprofen
Soliqs
Melt (HME)
Various
Intelence (etravirine)
Tibotec
Solvent (SDD)
HPMC
Isoptin SRE-240 (verapamil)
Soliqs
Melt (HME)
Various
Norvir (ritonavir)
Abbott
Melt (liquid fill cap)
PEG-glyceride
Kaletra (lopinavir/ritonavir)
Abbott-Soliqs
Melt (HME)
PVP/PVA
LCP-Tacro (tacrolimus)
LifeCycle Ph.
Melt (granulation)
HPMC
Rezulin (troglitazone)*
Pfizer
Melt (HME)
PVP
Sporanox (itraconazole)
Janssen
Solvent (layering)
HPMC
* Withdrawn from market

10
The Amorphous State

&
Solid Dispersions
11
Amorphous State Structure
Hexagonal Close Packing

fraction of voids = 0.26
Random Close Packing

fraction of voids > 0.36
DATA SOURCES: Jalali, J. Chem. Phys. 120 (2004) 1138; Bates, et al. Pharm.Res. 23 (2006) 2333
12
Amorphous State Thermodynamics

Enthalpy
Liquid
Supercooled
Liquid
Amorphous
(glass)
Crystal
Temp.
Tg
Tm
Higher Energy State of Amorphous phase is shown relative

to Crystalline phase
13
Amorphous State Thermal Analysis

10000
5000
Power (uW)
Tg
Tc
Tm
0
-5000
-10000
-15000
Endothermic
-20000
20
40
60
80
100
120
140
160
180
Temperature ( C)
Differential Scanning Calorimetry of Amorphous

Indomethacin API
14
Amorphous State Properties

The Amorphous State of a Poorly Soluble API can generate
enhanced dissolution and bioavailability due to increased
apparent solubility
The Amorphous State is a thermodynamically unstable relative
to the crystalline state, which must be considered when
developing a viable drug product
The Amorphous State is formed by quenching from a melt
(e.g. extrusion, granulation, capsule filling) or by controlled
precipitation (rotary evaporation, spray drying, freeze drying)
15
Amorphous State Materials Characterization

Critical Properties
Analytical Tools
Absence of crystal lattice

(no 3D structure)
X-ray Diffraction (XRD)

Differential Scanning Calorimetry (DSC)
Polarized Light Microscopy
Molecular conformation /
mobility
Relaxation times (SSNMR, rheology)
Moisture absorption
Dynamic Vapor Sorption (DVS)
Increased apparent
solubility
Kinetic solubility studies
Spectroscopy (Raman, SSNMR)
(e.g. dissolution, supersaturation)
16
Amorphous State Stability

1
Model glass-former:
Tg ~ 45oC
Weight Fraction Crystallized
Indomethacin (IMC)
0.9
40 C
30 C
20 C
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
100
200
300
Time (days)
Critical relationship between Glass Transition Temp (Tg)

and storage temperature
SOURCE: Andronis and Zografi, J. Non-Cryst. Solids 271 (2000) p236
17
Amorphous State Stability

Crystallization kinetics for different particle sizes of
amorphous IMC at 30 oC
Percent crystallinity
100
80
0-40 m
60
75-150 m
40
250-425 m
600-710 m
20
0
0
20
40
60
80
100
Time (days)
SOURCE: Crowley and Zografi, Pharm. Res. 20 (2003) p1417
18
Amorphous State Stabilization

Amorphous State Stabilization is directed at preventing the
initiation and/or reducing the rate of crystal nucleation and
growth
Regulatory Agencies will demand to see good control and
understanding of this property
Available strategies:
Avoid Tg reduction (e.g. moisture protection)
Elevate Tg significantly above room temperature
Chemical interactions (H-bonding, complexation)
Anti-nucleation methods (additives, surface modification)
19
Principles of Solid Dispersions

Solid Dispersions are intimate mixtures of two (or more)
components that typically have a high degree of miscibility.
Poorly Soluble Drug Dispersions can achieve enhanced solubility
by creating a physically stable and processable non-crystalline
form.
Crystalline active
+ polymer
Solid Dispersion
Tablets
HME
Precipitate
methods
20
GRAPHIC SOURCE: Modified from BASF Pharma Ingredients & Services
20
Solid Dispersions Control of Tg

Stabilization of Amorphous IMC using poly(vinylpyrrolidone)
by increasing Tg in a molecular dispersion
Cl
200
180
CH3
160
140
CH3O
Tg ( C)
120
100
CH2COOH
Indomethacin
80
60
40
20
N
0
0
20
40
60
80
100
PVP content (%w/w)
C
H
CH2
PVP
SOURCE: Yoshioka et al. J. Pharm. Sci. 84 (1995) p983
21
Solid Dispersions Drug-Polymer Interactions

Amorphous IMC containing 5% PVP has greatly increased
physical stability stored at 30 oC storage for 100 days
Percent crystallized
100
pure IMC
5% PVP
80
60
40
20
0
0
50
100
Time (days)
IMC-PVP H-bonding reduces crystal nucleation and growth

SOURCE: Matsumoto and Zografi, Pharm. Res. 16 (1999) p1722
22
Hot Melt Extrusion

&
OptiMeltTM
23
Hot Melt Extrusion The Basics

Twin-screw extruders with varying screw
design / rotation achieve intimate mixing
of drug and excipient
Shear forces drive co-melting of drug and
excipient
Cooled mixture is a Solid Dispersion
preferably containing amorphous (noncrystalline) drug
Process opportunities
Liquid drugs
Potent drugs
Labile drugs (solvent or moisture
sensitive)
24
Hot-Melt Extrusion
HME Twin Screw Extruder Equipment Variables

polymer
Feeder configuration
Processing zone configuration
Die size / number
Main feed
Feed
motor
Liquid injection
Vent
API
Liquid injection
Die
Drive motor
and
gearbox
Side stuffer
Forward Elements
Distributive
Mixing
Dispersive
Mixing
Conveying
Zoning
Feeding/ Compressing
30 degree
90 degree
25
HME - Process Variables and Outputs

Feed rate input
polymer
API
Screw speed input

Barrel temperature
inputs
Main feed
Feed
motor
Drive motor
and
gearbox
Die
Material temp,
Pressure, PAT
Barrel temperature
outputs
Screw
speed
Torque
26
HME Downstream Extrudate Processing

A wide range of finished dosage forms can be generated
1. Upstream
Feeder I
Feeder II
2. Compounding Extrusion
Granulator
Extruder
3. Downstream Pellets, Granules, Calendering, Inj molding
SOURCE: BASF Pharma Ingredients & Services
27
HME Process Advantages

Twin-screw design delivers excellent co-mixing of components
Solvent free
Process is well-controlled and scalable
Good materials handling/ containment
Extrudate downstream processing is flexible
Feasibility trials are easy to design and predictive
28
HME Development OptiMeltTM Feasibility Plan

Request for
Proposal
Technical
analysis / IP
Miscibility study
Accelerated
stability study
Formulation
concept
HME process simulation
Stability
prediction
HME small scale

trials
GLP / GMP
batches
Downstream
dosage form trials
Scale-up
29
29
HME Feasibility Assessments

Miscibility may be assessed by predictive or small-scale
experimental techniques
DSC of binary mixtures to identify single Tg
Hot stage microscopy to observe phase melting/dissolution at
different temperatures
Film casting of binary mixtures from common solvent visual
examination for crystal formation
A significant benefit of HME is that proof-of-concept evaluations

may be performed at small-scale, quickly and with minimal API
30
HME Feasibility Assessments

The following API information directs formulation strategy:
API Tg if available or otherwise estimate
(Tg / Tm [Kelvin] Ratio ~0.7 based on fragility theory )
API chemical stability at increased temperature
API availability for H-bonding
Poorly Soluble Model Drugs:
Tg / Tm (oC)
Solubility at pH7 (g/mL)
Fenofibrate
Indomethacin
Itraconazole
-20 / 80
45 / 155
59 / 166
~1
~1
31
Hot Melt Extrusion

Formulation
Case Studies
32
HME Process Design of Experiments
fill rate
input
temperature
drug load
high
screw speed
Using 2 model drugs (fenofibrate, itraconazole) and 2 carriers

(Soluplus, Kollidon VA 64)
to identify a knowledge space for HME processing
low
output
operating states
high
low
drug load
30%
10%
torque
temperature
140C
130C
pressure
fill rate
400 g/h
200 g/h
screw speed
200 rpm
100 rpm
residence time
trial
drug load
temperature
screw speed
fill rate
high
high
high
high
low
high
high
high
high
low
high
low
high
low
low
high
high
high
low
low
low
high
high
low
low
high
low
high
low
low
low
low
center point
center point
center point
center point
SOURCE: Catalent Pharma Solutions Schornforf site
33
HME Process Design of Experiments

Surface Plot of Torque(Nm) vs FEED_SP(g/h); Temperature(C)
10
T or que( Nm)
8
6
400
4
300
170
70
FEED_SP ( g/h)
180
T emper atur e( C )
19
90
200
Worksheet: HotMelt_Basics_Experimentations; 12/06/2012; Luc Burgard; Catalent
SOURCE: Catalent Pharma Solutions Schorndorf site
34
Drug-Polymer Extrusion
20% Fenofibrate Kollidon VA64 dispersion extrusion prepared
Equipment: Leistritz ZSE-18
Temperature Zones
(oC)
Scale: 12 Kg
Z8
Z7
Z6
Z5
Z4
Z3
Z2
Z1
120
140
140
140
140
140
120
80
XRD & DSC Results indicate Molecular Dispersion (Tg 61oC)
XRPD Comparison of Fenofibrate, VA-64 and 20% Feno HM Extrudate
Sample: 12JM-120E grnd extrudate18May12

Size: 4.3000 mg
Method: Feno HME Temp Cycling 3
Comment: Catalent Pharma Solutions, INS-J0946
20% Fenofibrate in VA64 extrudate CPS Ops 18May2012
800
DSC
File: C:...\Preformulation\2012\ZDSC0917.001
Operator: Vitez
Run Date: 21-May-2012 16:58
Instrument: DSC Q1000 V9.9 Build 303
0.0
700
600
-0.2
500
Heat Flow (W/g)
Lin (Counts)
VA64 99405616KO
400
300
-0.4
61.14C(I)
-0.6
200
Fenofibrate 22110, #0910791

100
-0.8
0
2
10
20
30
2-Theta - Scale
Fenofibrate 22110, #0910791 - File: XRD4604.raw - Type: 2Th/Th locked - Start: 2.000 - End: 40.000 - Step: 0.050 - Step time: 1. s - Temp.: 24 C - Time Started: 9 s - 2-Theta: 2.000 - Theta: 1.00
Operations: Import
VA64 99405616KO - File: XRD4563.raw - Type: 2Th/Th locked - Start: 2.000 - End: 40.000 - Step: 0.050 - Step time: 1. s - Temp.: 23 C - Time Started: 9 s - 2-Theta: 2.000 - Theta: 1.000 - Chi: 0.
Operations: Y Scale Add 100 | Y Scale Add 100 | Y Scale Add 100 | Y Scale Add 100 | Import
20% Fenofibrate in VA64 extrudate CPS Ops 18May2012 - File: XRD4646.raw - Type: 2Th/Th locked - Start: 2.000 - End: 40.000 - Step: 0.050 - Step time: 1. s - Temp.: 24 C - Time Started: 15 s - 2
Operations: Y Scale Add 100 | Y Scale Add 100 | Y Scale Add 100 | Y Scale Add 100 | Y Scale Add 100 | Y Scale Add 100 | Import
-1.0
-10
40
Exo Up
SOURCE: Catalent Pharma Solutions Somerset site
90
Temperature (C)
140
190
Universal V4.5A TA Instruments
35
Polymer Extrudate Processing Milling DOE

Fitz-mill Process DOE performed using Kollidon VA64
Goal: to identify processing knowledge space for extrudate
Surface Plot of Carr Index (%)
Surface Plot of Product Temperature (C)
24
26.5
P r oduct T emp ( C ) 26.0
20
C ar r Index ( % )
25.5
7500
16
25.0
7500
5000
0.009
2500
0.006
0.003
Scr een Size ( inches)
Worksheet: Worksheet 1; 5/21/2012
5000
12
M ill Speed ( r pm)
M ill Speed ( r pm)
2500
0.009
0.006
0.003
Scr een Size ( inches)
Worksheet: Worksheet 1; 5/21/2012
Outcome: Milling gave good yield with minimal Temp increase & acceptable
Carrs Index. Particle size remained granular (>200 micron)
SOURCE: Catalent Pharma Solutions Somerset site
36
HME Process DOE and Solubility Studies

HME Equipment
Extruder
Materials
RONDOL 10 mm TS Extruder
- barrel length 40 L/D
- 8 barrel heating zones
- output 25 400 g per hour
APIs
- Itraconazole
- Fenofibrate
polymers
- Soluplus
- Kollidon VA 64
Analytical Methods
Dissolution
Sotax AT7 Type 2 apparatus (paddle)

700 ml; 0.08 N HCL; 50 rpm
on-line sampling,
sequence: 5 minutes
HPLC/UV detection at 286 nm
37
Fenofibrate-Soluplus Solubility Enhancement

Solubility
FENOFIBRATE + SOLUPLUS
extrudate Fenofibrate:Soluplus 10%
Solubility [mg/l]
125,0
extrudate Fenofibrat:Soluplus 30%

powder mix Fenofibrat+Soluplus 30+70
100,0
suspensions - tested at pH ~ 1
75,0
50,0
solubility
[mg/L]
enhancement
<1
1.8
111
101
./.
>2
>100
>100
fenofibrate
physical mixture
10+90 extrudate
30+70 extrudate
25,0
0,0
0
20
40
60
80
100
120
Time [minutes]
38
Fenofibrate Kollidon Solubility Enhancement

Solubility
FENOFIBRATE + KOLLIDON VA 64
extrudate Fenofibrate:KollidonVA 64 10%
Solubility [mg/l]
125,00
extrudate Fenofibrate:Kollidon VA 64 30%

powder mix Fenofibrat+Kollidon VA 64
100,00
suspensions - tested at pH ~ 1
75,00
solubility enhancement
[mg/L]
50,00
fenofibrate
physical mixture
10+90 extrudate
30+70 extrudate
25,00
0,00
0
25
50
75
Time [minutes]
<1
0.1
104
109
./.
~
>100
>100
100
39
Itraconazole Kollidon Solubility Enhancement

Solubility
ITRACONAZOLE + KOLLIDON VA 64
extrudate Itraconazole+Kollidon VA 64 10+90
extrudate Itraconazole+Kollidon VA 64 30+70
powder mix Itraconazole+Kollidon VA 64
Solubility [mg/l]
125,00
100,00
suspension - tested at pH ~ 1
solubility
[mg/L]
75,00
50,00
Itraconazole
physical mixture
10+90 extrudate
30+70 extrudate
25,00
0,00
0
25
50
75
<1
8.1
114
124
enhancement
./.
>8
>114
>124
100
Time [minutes]
40
Drug Release from Soluplus Extrudates

USP II, 50 rpm, 700 mL 0.1 N HCl, cut extrudates, 100 mg API (n=3)
100
drug release [%]
90
80
70
15% itraconazole in Soluplus
60
50
40
30
20
10
0
0
30
60
90
120
t [min]
Very high drug loads (~50%) are possible without affecting the
release profiles in a negative way
41
Stability of Solid Dispersion

(3 month 40oC/75%RH)
USP II, 50 rpm, 700 mL 0.1 N HCl, granulated extrudates with 100 mg itraconazole, (n=3)
Drug release [%]

100
80
60
- after production
- after storage
40
20
0
0
20
40
60
80
100
120
Time [min]
After accelerated storage conditions dissolution rates are

still comparable
42
In vivo Performance of Solid Dispersion

Itraconazole 10 mg / kg bw, beagle dogs (n=5) fasted state
blood concentration [ng/mL]
450
400
350
solid solution
300
physical mixture
crystalline itraconazole
250
200
150
100
50
0
0
10
15
20
t [h]
Massively increased bioavailability of itraconazole from Soluplus

extrudates compared to physical mixture and crystalline API
43
Summary
Comments
44
HME: Journey from Rotavap to Viable Technology

Platform
1971. Pharmaceutical Applications of Solid Dispersion Systems.
J. Pharm. Sci. Vol. 60 p1281. Chiou & Riegelman
1997. Characteristics and significance of amorphous solids in

pharmaceutical systems. J. Pharm. Sci. Vol. 86 p1. Hancock & Zografi
1999. Solid dispersions of poorly water-soluble drugs: Early
promises, subsequent problems, and recent breakthroughs.
J. Pharm. Sci. Vol. 88 p1058. Serajuddin
2012. Assessing the Performance of Amorphous Dispersions.

J. Pharm. Sci. Vol. 101 p1355 Newman et al.
45
HME: Capturing Value in the future

Relative to crystalline references, Amorphous Solid
Dispersions improve bioavailability in 82%
HME provides the platform to realize this potential and

capture the full value of your API
Source: Newman et al. Journal of Pharmaceutical Sciences, Vol. 101, No. 4, April 2012
46
Future of OptiMeltTM Platform Technology

Critical Attributes
OptiMeltTM
An effective solution
Expertise in selecting formulations that

maximize solubility enhancement
potential of Solid Dispersions
Parallel R&D effort on downstream

processing (e.g. milling, compression,
calendering)
Compliant solution
Leverages Catalents strong audit

record. Working with reliable
equipment and raw materials suppliers
Exclusive solution
Optimized HME formulations may yield

IP for customers. Opportunities to
combine with Catalent proprietary
platforms
Operational solution
Fully integrated with other

manufacturing, analytical and
packaging services
47
In Summary
OptiMeltTM: A Viable Platform Technology
An effective solution delivers drug
precisely, reproducibly & safely
equipment, materials, human
resource from End-to-End
Compliant solution equipment,
controls, scientific knowledge are
current & approvable
Exclusive solution / Freedom to Operate
IP or technical barriers to competition,
Operational solution acceptable

unit dose cost
48
acknowledgements.
Somerset team, CATALENT PHARMA SOLUTIONS
Schorndorf team, CATALENT PHARMA SOLUTIONS
Dr. Andreas Gryczke, BASF Pharma Ingredients & Services
Prof. George Zografi, University of Wisconsin-Madison
49
discover more.
CATALENT PHARMA SOLUTIONS
14 SCHOOLHOUSE ROAD
SOMERSET, NJ 08873
+ 1 866 720 3148
www.catalent.com

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Developing Better

Catalyst + Talent. Our name combines these ideas.

CONFIDENTIAL for CATALENT

WHY CATALENT? Unrivaled experience, deepest expertise, and

CONFIDENTIAL for CATALENT

Catalent Somerset, New Jersey USA

We provide Drug Delivery Solutions from a wide

Bioavailability enhancement represents the biggest

It can be quite resource intensive to develop

CONFIDENTIAL for CATALENT

We are seeing more poorly soluble drugs in

Historically, our infrastructure is based on

SOURCE: Mckinsey & Company Customer interviews

Operational solution acceptable

Technology Platform Attributes Hot Melt Extrusion

HME dispersions achieve a specific

Fully integrated solution

HME is a continuous process suited for

Numerous oral products and devices

HME technology requires significant

Proven in pharma & other industries as

CONFIDENTIAL for CATALENT

HME Technology Platform OptiMeltTM

Schorndorf, Germany and Somerset, New Jersey

Development, formulation, scale-up, manufacturing, packaging

Formulation acceleration and optimization with open CatalentBASF bioavailability alliance

Broad range of excipients designed specifically to enhance solubility,

Non-exclusive arrangement to increase development efficiency and deliver

CONFIDENTIAL for CATALENT

Solubility Enhancement Strategies / Technologies

CONFIDENTIAL for CATALENT

Solid Dispersion Products Melt approach

Isoptin SRE-240 (verapamil)

Melt (liquid fill cap)

* Withdrawn from market

The Amorphous State

CONFIDENTIAL for CATALENT

Amorphous State Structure

Hexagonal Close Packing

Random Close Packing

Amorphous State Thermodynamics

Higher Energy State of Amorphous phase is shown relative

Amorphous State Thermal Analysis

Differential Scanning Calorimetry of Amorphous

Amorphous State Properties

CONFIDENTIAL for CATALENT

Amorphous State Materials Characterization

Absence of crystal lattice

X-ray Diffraction (XRD)

Relaxation times (SSNMR, rheology)

Dynamic Vapor Sorption (DVS)

Kinetic solubility studies

CONFIDENTIAL for CATALENT

Spectroscopy (Raman, SSNMR)

(e.g. dissolution, supersaturation)

Amorphous State Stability

Weight Fraction Crystallized

Critical relationship between Glass Transition Temp (Tg)

SOURCE: Andronis and Zografi, J. Non-Cryst. Solids 271 (2000) p236

Amorphous State Stability

CONFIDENTIAL for CATALENT

SOURCE: Crowley and Zografi, Pharm. Res. 20 (2003) p1417

Amorphous State Stabilization