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Roller compaction of pharmaceutical ingredients [Elektronische Ressource] : on the understanding of the compaction and the use of knowledge based applications in the formulation of tablets / presented by Andrés-Miguel Miguélez-Morán

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239 pages
Dissertation submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-Carola University of Heidelberg, Germany for the degree of Doctor of Natural Sciences presented by Andrés-Miguel Miguélez-Morán, Lic. Pharm. born in Esplugues de Llobregat, Spain thOral-examination: 30 April 2009 ROLLER COMPACTION OF PHARMACEUTICAL INGREDIENTS ON THE UNDERSTANDING OF THE COMPACTION AND THE USE OF KNOWLEDGE BASED APPLICATIONS IN THE FORMULATION OF TABLETS Referees: Prof. Dr. Gert Fricker Priv. Doz. Dr. Ulrich Massing The following work has been carried out at the Dept. of Pharmaceutical Technology and Biopharmacy of the Institute of Pharmacy and Molecular Biotechnology of the University of Heidelberg (Germany), and at the School of Chemical Engineering of the University of Birmingham. First of all, I would like to thank Prof. Dr. Fricker for accepting me as a doctorate student at the institute, for allowing me to perform the major part of the experimental of this work, and for agreeing to be my supervisor and my referee. I also would like to express my thanks Dr. Massing, for kindly agreeing to be my second referee. Moreover, I would like to acknowledge Prof. Dr. Hilgenfeldt and Prof. Dr. Reichling, for being part of the committee in this viva examination.
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Dissertation

submitted to the

Combined Faculties for the Natural Sciences and for Mathematics
of the Ruperto-Carola University of Heidelberg, Germany

for the degree of

Doctor of Natural Sciences

















presented by

Andrés-Miguel Miguélez-Morán, Lic. Pharm.


born in Esplugues de Llobregat, Spain

thOral-examination: 30 April 2009













ROLLER COMPACTION OF PHARMACEUTICAL
INGREDIENTS

ON THE UNDERSTANDING OF THE COMPACTION AND THE USE OF
KNOWLEDGE BASED APPLICATIONS IN THE FORMULATION OF
TABLETS

























Referees: Prof. Dr. Gert Fricker
Priv. Doz. Dr. Ulrich Massing


The following work has been carried out at the Dept. of Pharmaceutical Technology and Biopharmacy
of the Institute of Pharmacy and Molecular Biotechnology of the University of Heidelberg (Germany),
and at the School of Chemical Engineering of the University of Birmingham.

First of all, I would like to thank Prof. Dr. Fricker for accepting me as a doctorate student at the
institute, for allowing me to perform the major part of the experimental of this work, and for agreeing
to be my supervisor and my referee. I also would like to express my thanks Dr. Massing, for kindly
agreeing to be my second referee. Moreover, I would like to acknowledge Prof. Dr. Hilgenfeldt and
Prof. Dr. Reichling, for being part of the committee in this viva examination.

I would like to thank Dr. Martin Bultmann, firstly, for opening the door and offering me the possibility
to start my project under his guidance and supervision without hesitation, and for giving me the
opportunity for conducting my PhD studies at the University of Heidelberg. I also thank him the
support and the effort that he has made at arranging the funding of my stay at the department during
the last year and a half. I appreciate enormously his encouragement and his understanding anytime that
I made a decision and the freedom of choice that he has always given to me, allowing me the
development of all projects that I had in mind, and firing my enthusiasm for the research. I would also
like to thank him for the time and patience that he has devoted to me during this time, and recently to
the correction of the work. Finally, I would like to acknowledge his advices, which have been essential
for the improvement of the thesis.

In third place I would like to express effusively gratitude to the School of Engineering at the
University of Birmingham. I am deeply grateful to Professor J.P.K. Seville for accepting me as an
occasional postgraduate student in his department and for showing me how an issue can be studied
from several points of view. Especially, I want to show my appreciation to Dr. Charley Wu, the person
who made possible an unforgettable time of work in research under his supervision. I want to express
my most sincerely thanks to him for considering my application, giving me the opportunity of joining
his group, for the blind trust that he put in me from the beginning, the high interesting projects that he
offered, the excellent supervision, the support, and the continuous advice. I also appreciate
enormously his corrections and his contributions to this thesis.

The scholarship program conducted by La Caixa in co-operation with the DAAD has funded an
important part of my stay in Germany during my PhD studies. Therefore, I would like to acknowledge
these organizations since, without their support, I had never been able to initiate my project in
Heidelberg.

I also want to thank the companies that have contributed to this work:

• The company Abbott GmbH & Co. KG that has funded my stay at the university over a year.
Also thanks to the Department of Formulation for the measurements made with the helium
pycnometre.

• The company Gerteis Maschinen + Process engineering AG lent generously the MiniPactor
device to perform part of the experiments.
• The Department of Pharma Solutions of BASF AG put at our disposal its MiniPactor device
to carry out some of the experiments.

I would also like to express my gratitude to other Schools at the University of Birmingham that made
contributions to this work. Especially to the School of Material Sciences and Metallurgy, for the
measurements with the micro-indenter, the reflection microscope, and the SEM; the School of
Chemistry, for the development of the method and the measurements made with NIR-Imaging; and the
school of Dentistry, for the determinations of density made with the helium pycnometre.

To all my colleagues and friends from both universities in recognition of the good time that I spent
with them, which has become a source of motivation and a bubble of air that has brought me many
times “back to earth” and has given a reason to what I have been doing during this time. My especial
thanks to Joerg, for providing brilliant ideas, for pushing me to go ahead, and for his contributions to
this work; to Benni, for making me feel comfortable in the department from the beginning and being
always there to listen to my moaning; to my friend in need Hendrik, for his patience and readiness to
lend a helping hand, even from the distance; to Christoph, for showing me why things must be done
well; to Sonja, Johanna, Caroline, Johannes and the rest of people from the department in Heidelberg
with whom I have shared an amazing time. From the department at the University of Birmingham, I
would like to thank Yu Guo and You Van for their kindness and the good atmosphere in the office.
Also Chian, Ourania, Ryan, and Isaac, deserve a very special mention. They have been great mates
both inside and outside the University.

I also would like to give my deepest gratitude to Aga, who surely knows already how important has
she been to me since the beginning. My work and my life in Heidelberg owe much to her. I also
appreciate the support that she, Elena and Neville have given me even during the last-minute rush.

My last words go to my family. No podría acabar este agradecimiento sin dedicarle unas líneas a la
mención de aquellas personas sin cuyo apoyo, comprensión, ánimo y calor no hubiera podido seguir
adelante: mis padres, mis hermanos, sus familias, y Bea (y familia). Por haberme rescatado varias
veces de la incertidumbre y el desánimo, por darme aliento y convencerme de lo que era correcto, por
haber estado siempre ahí para escuchar, por todo lo que habéis ayudado, por todo lo que os habéis
sacrificado y especialmente a Bea, por haberme dado soporte desde la distancia y la cercanía y por
haber esperado con tanta ilusión (o aún mayor) el resultado y el final de este trabajo. Os dedico a todos
esta tesis.



TABLE OF CONTENTS

LIST OF FIGURES................................................................................................................................................I
LIST OF TABLES................................................................................................................................................ V
ABBREVIATIONS ........................................................................................................................................... VII
SUMMARY.......................................................................................................................................................VIII
1 INTRODUCTION ...................................................................................................................................... 1
2 BACKGROUND......................................................................................................................................... 3
2.1 THE TABLET AS A DOSAGE FORM AND ITS ROLE .................................................................................... 3
2.1.1 The relevance of tablet formulation............................................................................................ 4
2.1.2 Two basic requirements for tablets: endurance and optimum API release rate......................... 5
2.1.3 Tableting process........................................................................................................................ 6
2.1.4 Material tabletability .................................................................................................................. 8
2.1.5 Material densification models and tableting parameters ........................................................... 9
2.1.6 Densification heterogeneity in tablets....................................................................................... 11
2.2 DRY GRANULATION BY ROLLER-COMPACTION: AN INTERMEDIARY PROCESS IN THE TABLET
PRODUCTION................................................................................................................................................ 12
2.2.1 Dry-granulation by roller compaction...................................................................................... 13
2.2.1.1 Feeding......................................................................................................................................................14
2.2.1.2 Compaction ...............................................................................................................................................17
2.2.1.3 Granulation................................................................................................................................................20
2.2.2 The effect of roller compaction conditions on granule properties............................................ 21
2.2.3 Applications of roller compaction in tablet production............................................................ 23
2.2.4 Focus of future research in roller compaction ......................................................................... 24
2.3 COMPUTER AIDED FORMULATION THROUGH EXPERT SYSTEMS ........................................................... 25
2.3.1 Computer aided design ............................................................................................................. 25
2.3.2 Computer aided formulation design using expert systems........................................................ 25
2.3.2.1 The sources of expertise ............................................................................................................................27
2.3.2.2 Features of a powerful ES .........................................................................................................................28
2.3.2.3 Expert system vs. system of experts ..........................................................................................................28
2.3.2.4 Applications of ES in formulation design..................................................................................................29
2.3.3 Artificial neural networks ......................................................................................................... 30
2.3.3.1 Adaptative learning: Hybrid ES-ANN.......................................................................................................32
2.3.3.2 ANN applications as tools in computer-aided formulation........................................................................33
3 GOALS OF THE THESIS....................................................................................................................... 35
4 GENERAL MATERIALS AND METHODS......................................................................................... 36
4.1 PHARMACEUTICAL INGREDIENTS ........................................................................................................ 36
4.2 OTHER SUBSTANCES ........................................................................................................................... 36
4.3 LIST OF DEVICES AND TOOLS............................................................................................................... 37
4.4 DETERMINATION OF THE TRUE DENSITY.............................................................................................. 38
4.5 MIXING ............................................................................................................................................... 38
4.6 ROLLER COMPACTION ......................................................................................................................... 39
4.6.1 Gerteis MiniPactor ................................................................................................................... 39
4.6.2 Laboratory-scale compactor..................................................................................................... 41
4.7 COMPRESSION..................................................................................................................................... 42
4.7.1 Uniaxial compaction................................................................................................................. 42
4.7.2 Tablet press............................................................................................................................... 42
4.8 DETERMINATION OF THE FLOW PROPERTIES........................................................................................ 43
4.9 CARR INDEX........................................................................................................................................ 44
4.10 DETERMINATION OF THE PARTICLE SIZE DISTRIBUTION (PSD)............................................................ 45
4.11 COMPACT TENSILE STRENGTH DETERMINATION.................................................................................. 45
4.12 DISINTEGRATION TIME........................................................................................................................ 46
4.13 DISSOLUTION TIME.............................................................................................................................. 47
5 ROLLER COMPACTION OF PHARMACEUTICAL SUBSTANCES............................................. 48
5.1 SOLID FRACTION: PRODUCT PROPERTY FOR MONITORING THE COMPACTION PROCESS. METHODS OF
DETERMINATION.......................................................................................................................................... 48
5.1.1 Introduction .............................................................................................................................. 48

5.1.1.1 Geometrical determination........................................................................................................................ 50
5.1.1.2 Buoyancy (suspension-floating technique) ............................................................................................... 50
5.1.1.3 Near infra-red spectroscopy (NIRS) ......................................................................................................... 51
5.1.1.4 Micro-indentation ..................................................................................................................................... 52
5.1.1.5 X-ray micro-computed tomography (X-ray μCT)..................................................................................... 53
5.1.1.6 Nuclear magnetic resonance imaging ....................................................................................................... 55
5.1.2 Materials and methods..............................................................................................................56
5.1.2.1 Materials ................................................................................................................................................... 56
5.1.2.2 Sample preparation ................................................................................................................................... 56
5.1.2.3 Geometrical determination of solid fraction ............................................................................................. 57
5.1.2.4 The buoyancy method............................................................................................................................... 58
5.1.2.5 NIRS ......................................................................................................................................................... 59
5.1.2.6 Micro-indentation ..................................................................................................................................... 60
5.1.2.7 X-ray μCT................................................................................................................................................. 62
5.1.2.8 NMRI........................................................................................................................................................ 63
5.1.3 Results and discussion...............................................................................................................64
5.1.3.1 NIRS prediction models calibrated with the punch and the buoyancy methods as reference.................... 64
5.1.3.2 Determination of solid fraction through X-ray μCT, micro-indentation and sectioning ........................... 67
5.1.3.3 Determination of solid fraction through NMRI......................................................................................... 69
5.1.3.4 Evaluation of the different techniques ...................................................................................................... 69
5.1.4 Conclusions...............................................................................................................................71
5.2 ROLLER COMPACTION OF PHARMACEUTICAL SUBSTANCES .................................................................72
5.2.1 The analogies and contrasts between roller and uniaxial compaction .....................................72
5.2.1.1 Introduction............................................................................................................................................... 72
5.2.1.2 Materials and methods .............................................................................................................................. 74
5.2.1.3 Results and discussion .............................................................................................................................. 74
5.2.1.4 Conclusions............................................................................................................................................... 78
5.2.2 The material behaviour during roller compaction....................................................................79
5.2.2.1 Analyzing the conveyance of material at the compaction zone through examination of patterns of
coloured MCC on ribbons......................................................................................................................... 79
5.2.2.2 The drag angle and the homogeneity of the ribbon densification.............................................................. 85
5.2.3 The effects of the roller compaction conditions on the compact characteristics.......................91
5.2.3.1 Introduction............................................................................................................................................... 91
5.2.3.2 Materials and methods .............................................................................................................................. 92
5.2.3.3 Results and discussion .............................................................................................................................. 94
5.2.3.4 Conclusions............................................................................................................................................. 104
5.3 RE-WORKABILITY OF ROLLER-COMPACTED SUBSTANCES..................................................................106
5.3.1 Introduction.............................................................................................................................106
5.3.2 Materials and methods............................................................................................................108
5.3.3 Results and discussion.............................................................................................................109
5.3.3.1 Ribbon properties.................................................................................................................................... 109
5.3.3.2 Granule morphology ............................................................................................................................... 110
5.3.3.3 Compression behaviour .......................................................................................................................... 114
5.3.3.4 Tabletability............................................................................................................................................ 117
5.3.4 Conclusions.............................................................................................................................121
6 SYSTEMATIC FORMULATION AND PREDICTIVE MODELS...................................................122
6.1 THE EFFECT OF EXTRAGRANULAR ADDITION OF COMPONENTS..........................................................123
6.1.1 Introduction.............................................................................................................................123
6.1.2 Materials and methods............................................................................................................124
6.1.3 Results and discussion.............................................................................................................125
6.1.3.1 Flowability and compressibility.............................................................................................................. 125
6.1.3.2 The effects of extragranular addition of single components ................................................................... 126
6.1.3.3 The effect of extragranular addition of two components simultaneously................................................ 129
6.1.3.4 Extragranular addition versus intragranular addition .............................................................................. 131
6.1.4 Conclusions.............................................................................................................................133
6.2 MULTICOMPONENT FORMULATIONS..................................................................................................134
6.2.1 Introduction.............................................................................................................................134
6.2.2 Materials and methods............................................................................................................134
6.2.3 Results and discussion.............................................................................................................136
6.2.3.1 Ribbon properties.................................................................................................................................... 136
6.2.3.2 Granule properties................................................................................................................................... 140
6.2.3.3 Tablet properties ..................................................................................................................................... 144
6.2.3.4 Drug release............................................................................................................................................ 148
6.2.4 Conclusions.............................................................................................................................148
6.3 PREDICTIVE MODELS WITH GRM AND ANN .....................................................................................150
6.3.1 Introduction.............................................................................................................................150