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by

Copyright

Dave Alan Miller

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2007

The Dissertation Committee for Dave Alan Miller Certifies that this is the approved
version of the following dissertation:

Improved Oral Absorption of Poorly Water-Soluble Drugs by

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Advanced Solid Dispersion Systems

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Committee:

James W. McGinity, Co-Supervisor

Robert O. Williams III, Co-Supervisor
Roger T. Bonnecaze
Alan B. Combs
Krishnendu Roy
Robert L. Talbert

Improved Oral Absorption of Poorly Water-Soluble Drugs by

Advanced Solid Dispersion Systems

by

Dave Alan Miller, B.S.

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Dissertation

Presented to the Faculty of the Graduate School of

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The University of Texas at Austin

in Partial Fulfillment
of the Requirements
for the Degree of

Doctor of Philosophy

The University of Texas at Austin

December 2007

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UMI Number: 3291310

UMI Microform 3291310

Copyright 2008 by ProQuest Information and Learning Company.

All rights reserved. This microform edition is protected against
unauthorized copying under Title 17, United States Code.

ProQuest Information and Learning Company

300 North Zeeb Road
P.O. Box 1346
Ann Arbor, MI 48106-1346

Dedication

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To Mom, Dad, and Allison

Acknowledgements

I would foremost like to thank my parents, Mark and Janie Miller for their love
and support throughout every stage of my life. My success in life has merely been a

reflection of your success as parents. I would like to give my deepest gratitude to my

girlfriend Allison Earle for providing the love I needed to see me through the past eight

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years. You have made countless sacrifices so that I could achieve this success, and for
that I am forever grateful. I must also thank my sister and my nephew, Michelle and

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Chase Pina, for all their love and support as well as providing much needed distractions
from the daily stresses of graduate school. I would also like to thank the Earle family for
their love, encouragement, and Sunday night dinners.
To my supervising professors, Drs. James W. McGinity and Robert O. Williams
III, I would like to extend my deepest gratitude for the opportunities you have given me
over the past four years. This has truly been a life enriching experience and I owe most of
that experience to the both of you. I would like to thank Dr. Jason McConville for being a
friend and mentor during my early years in graduate school. I would like to thank Jim
DiNunzio for all of his help over the past few months which has proven essential to the
completion of this dissertation. I would like to thank Wei Yang for the countless hours
she spent helping me with my in vivo studies. I would like to sincerely thank Chris

Brough, Mike Miller, and Gershon Yaniv for their support of the TKC project and for
taking the time to seriously consider the crazy ideas of a young graduate student.
A heartfelt thank you goes out to all of my friends down in the basement, past and
present, who have all helped and supported me along the way: Shawn Kucera, Dorothea
Sauer, Caroline Dietzsch, Mamoru Fukuda, Troy Purvis, Alan Watts, Justin Tolman,
Loni Coots, Sandra Schilling, Kirk Overhoff, Jason Vaughn, Michal Matteucci, Chris
Young, Weija Zheng, and Prapasri Sinswat. Thank you to the people at PharmaForm who

helped turn a summer internship into a lifelong carrier: John Koleng, Feng Zhang, Pann
Mahaguna, Michael Crowley, Frank Sherwood, Mark Mendoza, and Chris Lively. I

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would also like to thank my mentor at Celanese, Jim Wann, for his encouraging words in
a time of despair and his guidance in helping me find a life after Celanese. I would like to

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thank the College of Pharmacy Staff for making an overworked graduate students life a
little easier: Claudia McClelland, Yolanda Abasta, Mickie Sheppard, Joyce McClendon,
Jay Hamman, Jim Baker, and Steve Littlefield.

Finally, I would like to thank my extended Miller and Standefer families for your
praise and support. To know that I am making you all proud provides me with the
inspiration I need to keep going when I am ready to quit.

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Improved Oral Absorption of Poorly Water-Soluble Drugs by

Advanced Solid Dispersion Systems
Publication No._____________

Dave Alan Miller, Ph.D.

The University of Texas at Austin, 2007

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Supervisors: James W. McGinity and Robert O. Williams III

Current high-throughput molecular screening methods have resulted in a vast

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increase in the proportion of new drugs which are poorly water-soluble. Since poor
water-solubility typically precludes efficacy of therapeutic molecules, there is a growing
need for advanced processing and formulational techniques to improve the dissolution
properties of poorly water-soluble drugs.

In Chapter 2, particle engineering and hot-melt extrusion (HME) were utilized to

produce advanced solid dispersion systems that improved the dissolution properties of a
poorly water-soluble drug, itraconazole (ITZ), in acidic media. A subsequent in vivo
study revealed a substantial absorption improvement with these formulations over
crystalline ITZ; however, a pH switch dissolution test indicated limited intestinal
absorption due to ITZ precipitation at neutral pH.
Polymeric carriers that promote supersaturation of ITZ following an acidic to
neural pH switch were investigated in Chapter 2. It was discovered that high molecular
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weight polymers with hydrogen bond donor sites are the optimal stabilizers of ITZ in
neutral pH solution. An in vivo study revealed that stabilization of supersaturated ITZ
following acidic-to-neutral pH transition resulted in substantially improved absorption.
A targeted intestinal delivery system with sustained supersaturation of ITZ in
neutral pH media was developed in Chapter 4. Carbopol 974P at two different
formulation concentrations was evaluated as a stabilizing additive to a pH-dependant,
enteric release system for ITZ. It was hypothesized that Carbopol 974P would prolong

ITZ supersaturation in the small intestine thus providing greater absorption with less
variability. An in vitro pH switch dissolution analysis proved the stabilizing effects of the

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Carbopol additive on supersaturated ITZ in neutral pH. In vivo studies demonstrated

that the Carbopol additive provided an additional mechanism for ITZ absorption that

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contributed to 5 and 3-fold improvements in absorption over the best performing solid
dispersion formulations from Chapters 2 and 3, respectively.
The final chapter introduced a novel, thermal process for the production of
amorphous solid dispersion systems, known as thermokinetic compounding (TKC). This
process was utilized to produce amorphous compositions of high-melting point drugs in
both thermally stable and temperature sensitive polymers without the need for processing
aids representing a significant advancement to solid dispersion manufacturing.

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Table of Contents
List of Tables ....................................................................................................... xiii
List of Figures ...................................................................................................... xvi
Chapter 1: Solid Dispersion Technologies: Improving Oral Drug Therapies .........1
1.1 Introduction...............................................................................................1
1.1.1 Overview of solid dispersion technologies ...................................3
1.2 Contributions of solid dispersion technologies to oral drug therapies......7
1.2.1 Treatment of cardiovascular disorders..........................................7

1.2.2 Pain management ........................................................................16

1.2.3 Cancer therapy ............................................................................23

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1.2.4 HIV treatment .............................................................................28

1.2.5 Anti-biotic treatments .................................................................34
1.2.6 Immunosuppression ....................................................................40

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1.2.7 Other drug treatments .................................................................43

1.3 Concluding Remarks...............................................................................46
1.4 References...............................................................................................50
1.5 Dissertation Objectives and Outline .......................................................60
Chapter 2: Hot-Melt Extrusion for Enhanced Delivery of Drug Particles.............64
2.1 Abstract ...................................................................................................64
2.2 Introduction.............................................................................................65
2.3 Materials and Methods............................................................................69
2.3.1 Production of ITZ-PVP and ITZ-HPMC micronized particles..70
2.3.2 Hot-melt extrusion of micronized particles ................................71
2.3.3 Differential scanning calorimetry ...............................................71
2.3.4 X-Ray diffraction ........................................................................72
2.3.5 Scanning electron microscopy ....................................................72
2.3.6 Dissolution testing .....................................................................73
2.3.7 Oral dosing of rats.......................................................................75
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2.3.8 Plasma extraction and chromatographic analysis .......................75

2.3.9 Pharmacokinetic analysis............................................................76
2.4 Results and Discussion ...........................................................................77
2.4.1 Evaluation of micronized particle properties before and after hotmelt extrusion..............................................................................77
2.4.2 Evaluation of dissolution performance at sink conditions..........81
2.4.3 Evaluation of supersaturation dissolution performance..............82
2.4.4 Evaluation of supersaturation performance with a pH change ...84
2.4.5 Evaluation of in vivo performance .............................................86
2.5 Conclusions.............................................................................................88

2.6 Acknowledgements.................................................................................88
2.7 References...............................................................................................89

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Chapter 3: Enhanced In Vivo Absorption of Itraconazole via Stabilization of

Supersaturation Following Acidic-to-Neutral pH Transition .......................96
3.1 Abstract ...................................................................................................96

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3.2 Introduction.............................................................................................97
3.3 Materials ...............................................................................................101
3.4 Methods.................................................................................................102
3.4.1 Hot-melt Extrusion (HME) .......................................................102
3.4.2 Differential Scanning Calorimetry (DSC) ................................103
3.4.3 Dissolution Testing ...................................................................103
3.4.4 In Vivo Studies .........................................................................105
3.4.5 Plasma Extraction and Chromatographic Analysis...................105
3.4.6 Pharmacokinetic Analysis.........................................................106
3.5 Results and Discussion .........................................................................107
3.5.1 Rationale for Polymer Carrier Selection...................................107
3.5.2 DSC Analysis of HME Processed ITZ-Polymer Formulations 110
3.5.2.1 Immediate Release Formulations..................................110
3.5.2.2 Enteric Release Formulations .......................................111
3.5.3 Dissolution Testing with pH Change........................................113
3.5.3.1 Immediate Release Polymers........................................113
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3.5.3.2 Enteric Release Polymers .............................................119

3.5.4 In Vivo Absorption Analysis ....................................................122
3.6 Conclusions...........................................................................................126
3.7 References.............................................................................................128
Chapter 4: Targeted Intestinal Delivery of Supersaturated Itraconazole for Improved
In Vivo Absorption .....................................................................................135
4.1 Abstract .................................................................................................135
4.2 Introduction...........................................................................................136
4.3 Materials ...............................................................................................140
4.4 Methods.................................................................................................140

4.4.1 Hot-Melt Extrusion (HME).......................................................140

4.4.2 Differential Scanning Calorimetry (DSC) ................................141
4.4.3 Energy Dispersing X-ray Spectroscopy (EDS).........................142

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4.4.4 Dissolution Testing ...................................................................142

4.4.5 In Vivo Studies .........................................................................144

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4.4.6 Plasma Extraction and Chromatographic Analysis...................144

4.4.7 Pharmacokinetic Analysis.........................................................145
4.5 Results and discussion ..........................................................................146
4.5.1 DSC Analysis of HME Processed Formulations ......................146
4.5.2 Analysis of Drug Distribution by EDS .....................................149
4.5.3 Dissolution Analysis with pH Switch .......................................150
4.5.4 In Vivo ITZ Absorption Analysis .............................................154
4.6 Conclusions...........................................................................................159
4.7 Acknowledgements...............................................................................160
4.8 References.............................................................................................161
Chapter 5: Thermokinetic Compounding: A Novel Technology for the Production of
Pharmaceutical Solid Dispersions...............................................................165
5.1 Abstract .................................................................................................165
5.2 Introduction...........................................................................................166
5.3 Materials ...............................................................................................174
5.4 Methods.................................................................................................174
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5.4.1 Thermokinetic Compounding ...................................................174

5.4.2 HPLC Analysis .........................................................................176
5.4.3 Hot-Melt Extrusion (HME).......................................................176
5.4.4 Differential Scanning Calorimetry (DSC) ................................177
5.4.5 Dissolution Testing ...................................................................178
5.5 Results and discussion ..........................................................................178
5.5.1 Analysis of Drug Degradation in TKC Processed Compositions178
5.5.2 DSC Analysis of TKC Processed Compositions with Thermally
Stable Polymers ........................................................................180
5.5.3 Dissolution Testing of TKC Processed KTZ in Methocel E50 and
Kollidon 30 .............................................................................184

5.5.4 Production of Solid Dispersion Systems by TKC with a

Thermolabile Polymeric Carrier ...............................................186

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5.6 Conclusions...........................................................................................189
5.7 Acknowledgements...............................................................................190
5.8 References.............................................................................................191

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Tables...................................................................................................................198
Figures..................................................................................................................213
Appendices...........................................................................................................249
Appendix A: Raw Data from Figures Presented in Chapter 2....................249
Appendix B: Raw Data from Figures Presented in Chapter 3 ....................253
Appendix C: Raw Data from Figures Presented in Chapter 4 ....................256
Appendix D: Raw Data from Figures Presented in Chapter 5....................258
Bibliography ........................................................................................................259
Vita .....................................................................................................................286

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List of Tables
Table 1.1: Mean Pharmacokinetic Parameters and Relative Bioavailabilities
for the Three Formulation Approaches ........................................................198
Table 1.2: Pharmacokinetic parameters of ABT-963 after oral dosing of 50 mg
ABT-963 in capsules and PEG solution in fasted dogs................................199
Table 1.3: Pharmacokinetics Data of the Solid Dispersions and Cyclodextrin

Complexes with Lonidamine (Lon) ...............................................................200

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Table 1.4: Pharmacokinetic parameters of CGP 70726 incorporated in

Eudragit L100-55 pH-sensitive particles after oral administration

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to dogs; Mean6S.E.M. (n=4) .........................................................................201

Table 1.5: Pharmacokinetic parameters (S.D.) of itraconazole and
hydroxyitraconazole after oral administration of four different
formulations in healthy humans.....................................................................202
Table 1.6: Pharmacokinetic Parameters of CyA After Oral Administration of
CyA Solid Dispersion and Sandimmun Neoral to Wistar Rats ..................203
Table 2.1: Area under the supersaturation dissolution curve values for acid,
pH change, and adjusted pH change for the micronized particle
extrudate (MPE) formulations. ......................................................................204

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Table 2.2: Pharmacokinetic parameters calculated using non-compartmental

analysis in Win-Nonlin of rats dosed with micronized particle
extrudate (MPE) compositions and crystalline ITZ.......................................205
Table 3.1: Hot-melt extrusion processing parameters for each investigated
composition....................................................................................................206
Table 3.2: Area Under Dissolution Curve (AUDC) values for the acid phase,

neutral phase and total dissolution test for each composition. Each
composition contains 33% ITZ by weight. ....................................................207

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Table 3.3: Pharmacokinetic data from the in vivo absorption study with the

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ITZ:Methocel E50 and ITZ:EUDRAGIT L100-55 HME

processed amorphous solid dispersion formulations. ....................................208
Table 4.1: Formulation summary for HME processed ITZ:EUDRAGIT L
100-55 amorphous solid dispersions with Carbopol 974P
additives .........................................................................................................209
Table 4.2: Area under the dissolution curve (AUDC) values for the acid phase,
neutral phase and total dissolution test for the EUDRAGIT L
100-55, 20% Carbopol 974P, and 40% Carbopol 974P
formulations ................................................................................................. 210

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Table 4.3: Pharmacokinetic data from the in vivo absorption study with the
20% Carbopol 974P additive formulation and the 40%
Carbopol 974P additive formulation......................................................... 211
Table 5.1: Operating parameters of the thermokinetic compounding process
for each processed batch ................................................................................212
Table A.1: Raw data presented in Figure 2.4.................................................................. 249

Table A.2: Raw data presented in Figure 2.5.................................................................. 250

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Table A.3: Raw data presented in Figure 2.6.................................................................. 251

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Table A.4: Raw data presented in Figure 2.7.................................................................. 252

Table B.1: Raw data presented in Figure 3.4.................................................................. 253
Table B.2: Raw data presented in Figure 3.5.................................................................. 254
Table B.3: Raw data presented in Figure 3.6.................................................................. 255
Table C.1: Raw data presented in Figure 4.4.................................................................. 256
Table C.2: Raw data presented in Figure 4.5.................................................................. 257
Table D.1: Raw data presented in Figure 5.5.................................................................. 258

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List of Figures
Figure 1.1: Plasma concentration vs. time curve of FNB after oral
administration of () pH-sensitive self-assemblies of PEG-bP(nBA17-co-MAA17), () Lipidil MicroR and () FNB powder

to fasted SpragueDawley rats at a dose of 7.5 mg/kg.

MeanFSEM for n =6. ..................................................................................213

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Figure 1.2: Results of the pharmacokinetic study with 18 healthy male subjects.

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Comparison of the R103757 100-mg melt extrudate tablet, the

100-mg bead capsule, and the 100mg GTS capsule under (a)
fasting and (b) fed conditions. ....................................................................214

Figure 1.3: Geometric mean ibuprofen plasma concentrations following single

oral administration of a 400-mg ibuprofen extrudate (square),
lysinate (triangle), and regular (diamond) tablet under fed (filled)

and fasted (open) conditions, respectively..................................................215

Figure 1.4: Plasma concentration of ABT-963 following oral administration of
PEG solution and capsule formulations to fasted dogs...............................216
Figure 1.5: In vitro dissolution in 0.1N HCl of (a)physical mixture containing
crystalline ritonavirPEG at 10:90, and amorphous ritonavir in
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PEG solid dispersions at concentrations of (b) 10%, (c) 20%, and

(d) 30% (w/w). Dissolution was determined by the USP I method
(50 rpm, 378C).The data for20%dispersion is an average of two
runs; others are three runs. ..........................................................................217
Figure 1.6: Mean plasma concentrationtime profiles of ritonavir after a single
oral dose to beagle dogs. Ritonavir was administered in (a) the
crystalline form or the amorphous in PEG solid dispersions at

concentrations of (b) 10%, (c) 20%, and (d) 30% (w/w)............................218

media of pH 1.2 - 6.5:

, physical mixture;

hydroxypropylmethylcellulose

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with

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Figure 1.7: Dissolution behavior of albendazole from solid dispersions in

methylcellulose
hydroxypropyl

phthalate;

methylcellulose;

and

solid
,

solid

, solid dispersion
hydroxypropyl
dispersion
dispersion

with
with

hydroxypropyl methylcellulose phthalate...................................................219

Figure 1.8: Mean plasma concentrations of albendazole sulphoxide after oral

administration of physical mixture ( , ) and solid dispersion
(

, ) to normal acidity rabbits (A) and to low acidity rabbits (B)

at a dose of 5 mg/kg. Each point represents the mean standard

error of results from five rabbits. ................................................................220

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Figure 1.9: Mean griseofulvin plasma concentration-time profile following oral

administration to rats ( S.D., n = 4). ( ) Control; ( ) Spraydried; ( ) Spraydried + Poloxamer 407. ...................................................221
Figure 1.10: Blood concentration of tacrolimus after oral administration of
SDF with HPMC to beagle dogs. ( ) SDF of tacrolimus with
HPMC; ( ) tacrolimus crystalline powders. Values are expressed
as the mean with a vertical bar showing S.E. of six animals. Each

dosage form was administered at the dose of 1mg as tacrolimus. ..............222

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Figure 1.11: Oral Bioavailability of Danazol in a Mouse Model for the SFL
Composition (Danazol:PVP-K15 1:1) (), EPAS Composition

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(Danazol:PVP-K15 1:1) (), Physical Mixture (Danazol:PVP-K15

1:1) (*), and Commercially Available Danazol (). .................................223

Figure 2.1: DSC thermograms of (a) ITZ-HPMC micronized particles (b) ITZPVP micronized particles (c) ITZ-HPMC micronized particle
extrudates, (d) ITZ-PVP micronized particle extrudates (e)
extrudate formulation with bulk crystalline ITZ (f) bulk
crystalline ITZ (g) poloxamer 407:PEO (7:3) placebo extrudate.
The samples were heated from 20 to 200 C in open aluminum
pans at a heating rate of 10 C/min under nitrogen purge...........................224
Figure 2.2: X-ray diffraction patterns of (a) poloxamer 407:PEO (7:3) placebo
extrudate (b) extrudate formulation with crystalline ITZ (c) ITZxviii

HPMC micronized particle extrudates (d) ITZ-PVP micronized

particle extrudates (e) bulk crystalline ITZ (f) ITZ-PVP
micronized particles and (g) ITZ-HPMC micronized particles.
The arrows indicate peaks due to crystalline ITZ present in the
extrudate formulation containing crystalline ITZ. ......................................225
Figure 2.3: SEM images of (a) ITZ-HPMC micronized particles (b) a typical
cross section of the ITZ-HPMC micronized particle extrudates (c)

ITZ-PVP micronized particles (d) close-up view of a typical ITZPVP micronized particle within the polymer matrix of the

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extrudate......................................................................................................226

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Figure 2.4: Dissolution testing at sink conditions of the micronized particle and
micronized particle extrudate formulations and bulk crystalline
ITZ. Approximatly 5 mg of ITZ was present in each vessel (n=6).
Testing was conducted in 900 mL of 0.1N HCl at 37 C and a
paddle speed of 50 rpm. ..............................................................................227

Figure 2.5: Supersaturation dissolution testing of the ITZ-HPMC and ITZ-PVP

micronized particle extrudate formulations. Approximately 100
mg of ITZ was added to each dissolution vessel (n=6). Testing
was conducted in 900 mL of 0.1N HCl at 37 C and a paddle
speed of 50 rpm...........................................................................................228

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Figure 2.6: Supersaturation dissolution testing of the ITZ-HPMC and ITZ-PVP

micronized particle extrudate formulations by a pH change
method according to the USP 29 specifications for the Method A
enteric test. Approximately 100 mg of ITZ was added to each
dissolution vessel (n=6). Testing was conducted for 2 hours in
750 mL of 0.1N HCl followed by pH adjustment with 250 mL of
0.2M sodium phosphate tribasic at 37 C and a paddle speed of 50

rpm. .............................................................................................................229
Figure 2.7: Plasma ITZ concentration versus time from oral dosing of the ITZ-

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HPMC micronized particle extrudate, ITZ-PVP micronized

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particle extrudate, and bulk crystalline ITZ. The dosing was done
by oral gavage in the amount of 30 mg/kg per subject (n=3). ....................230

Figure 3.1: DSC analysis of: (a) HME processed ITZ:Methocel E5 (1:2), (b)
HME processed ITZ:Methocel E50 (1:2), (c) HME processed
ITZ:Kollidon 90 (1:2), (d) HME processed ITZ:Kollidon 12
(1:2), (e) ITZ:Kollidon 90 (1:2) physical mixture, (f)
ITZ:Methocel E50 (1:2) physical mixture, and (g) crystalline
ITZ. .............................................................................................................231
Figure 3.2: DSC analysis of: (a) EUDRAGIT L 100-55 powder, (b) glassy
ITZ, (c) placebo (HME processed EUDRAGIT L 100-55 with
20% TEC based on polymer mass), (d) HME processed
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ITZ:[EUDRAGIT L100-55 w/ 20% TEC] (1:2), and (e) physical

mixture of ITZ:[EUDRAGIT L100-55 w/ 20% TEC] (1:2)....................232
Figure 3.3: DSC analysis of: (a) HP-55 powder, (b) HP-55S powder, (c)
placebo (HME processed HP-55S w/ 20% TEC based on dry
polymer mass), (d) glassy ITZ, (e) HME processed ITZ:[HP-55
w/ 20% TEC] (1:2), (f) HME processed ITZ:[HP-55S w/ 20%
TEC] (1:2), and (g) physical mixture of ITZ:[HP-55S w/ 20%

Supersaturation dissolution testing of the ITZ-IR polymer HME

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Figure 3.4:

TEC] (1:2)...................................................................................................233

processed compositions by pH modulation method. Each

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dissolution vessel (n = 3) contained 180 mg of the formulation (60

mg ITZ equivalent) corresponding to 20 times the saturation
solubility of ITZ in the acid phase. Testing was conducted for 2 hr

in 750 mL of 0.1 N HCl followed by pH adjustment 6.8 0.5

with 250 mL of 0.2 M tribasic sodium phosphate solution. .......................234

Figure 3.5: Supersaturation dissolution testing of the ITZ-enteric polymer

HME processed compositions by pH modulation method. Each
dissolution vessel (n = 3) contained 180 mg of the formulation (60
mg ITZ equivalent) corresponding to 20 times the saturation
solubility of ITZ in the acid phase. Testing was conducted for 2 hr

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in 750 mL of 0.1 N HCl followed by pH adjustment 6.8 0.5

with 250 mL of 0.2 M tribasic sodium phosphate solution. ......................235
Figure 3.6: Plasma ITZ concentration versus time from oral dosing of (A)
HME processed ITZ:Methocel E50 (1:2) and (B) HME
processed ITZ:[EUDRAGIT L 100-55 w/ 20% TEC] (1:2). The
dose was administered by oral gavage in the amount of 30 mg

ITZ/kg per subject (n = 4)...........................................................................236

Figure 4.1: DSC analysis of: (a) HME processed active 20% Carbopol 974P

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additive formulation (b) HME processed placebo 20% Carbopol

974P additive formulation (c) EUDRAGIT L 100-55 powder (d)

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Carbopol 974P powder (e) amorphous ITZ (f) physical mixture

of the active 20% Carbopol 974P additive formulation...........................237

Figure 4.2: DSC analysis of: (a) HME processed active 40% Carbopol 974P
additive formulation (b) HME processed placebo 40% Carbopol
974P additive formulation (c) EUDRAGIT L 100-55 powder (d)
Carbopol 974P powder (e) amorphous ITZ (f) physical mixture
of the active 20% Carbopol 974P additive formulation...........................238
Figure 4.3: EDS Mapping of ITZ:EUDRAGIT L 100-55 (1:2) (Top) and 40%
Carbopol 974P additive (Bottom) formulations.

Red = Cl,

Green = N, Yellow = Overlap of Cl and N. Note that nitrogen

shown in EDS images outside of the sample are due to small
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amounts of nitrogen adsorbed on the copper film. (Color images

available online.).........................................................................................239
Figure 4.4: Supersaturation dissolution testing of the 20% Carbopol 974P
additive formulation, the 40% Carbopol 974P additive
formulation, as well as an all EUDRAGT L 100-55 carrier
system by pH switch method. Each dissolution vessel contained
180 mg of the formulation (60 mg ITZ equivalent) corresponding

to 20 times the saturation solubility of ITZ in the acid phase.

Testing was conducted for 2 hr in 750 mL of 0.1 N HCl followed

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by pH adjustment to 6.8 0.5 with 250 mL of 0.2 M tribasic

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sodium phosphate solution..........................................................................240

Figure 4.5: Plasma ITZ concentration versus time from oral dosing of (A) 20%
Carbopol 974P additive formulation and (B) 40% Carbopol
974P additive formulation. The doses were administered by oral
gavage in the amount of 30 mg TZ/kg body weight per subject in

rats (n = 4)...................................................................................................241

Figure 5.1: HPLC analysis of ACM:EUDRAGIT L 100-55 (1:2) TKC

processed material as compared to an ACM standard injection. ................242
Figure 5.2: HPLC analysis of KTZ:Kollidon 30 (1:2) TKC processed
material in comparison to a KTZ standard injection and the
Kollidon 30 polymer alone. .....................................................................243
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