_K63-Carrageenan [Kappa-Carrageenan] micropellets [Elektronische Ressource] : production and dissolution behavior / / vorgelegt von Angelina Yoo

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κ-Carrageenan Micropellets: Production and Dissolution Behavior INAUGURAL - DISSERTATION zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf vorgelegt von Angelina Yoo aus Hamburg Düsseldorf, Dezember 2008 Aus dem Institut für Pharmazeutische Technologie und Biopharmazie der Heinrich-Heine-Universität Düsseldorf Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf Referent: Prof. Dr. Peter Kleinebudde Koreferent: Prof. Dr. Jörg Breitkreutz Tag der mündlichen Prüfung: 10.12.2008 IITable of content Table of content........................................................................................................................ III List of abbreviations.............................................................................................................. VIII 1 Introduction....................................................................................................................... 1 1.1 Multiple unit dosage forms ......................................................................................... 1 1.2 Micropellets.. 1 1.2.1 Definition............................................................................................................. 1 1.2.2 Sprinkle capsule........................
Publié le : jeudi 1 janvier 2009
Lecture(s) : 27
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Source : DOCSERV.UNI-DUESSELDORF.DE/SERVLETS/DERIVATESERVLET/DERIVATE-10594/PROMOTION%20%28A%20YOO%29.PDF
Nombre de pages : 141
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κ-Carrageenan Micropellets:
Production and Dissolution Behavior





INAUGURAL - DISSERTATION

zur
Erlangung des Doktorgrades der
Mathematisch-Naturwissenschaftlichen Fakultät der
Heinrich-Heine-Universität Düsseldorf



vorgelegt von

Angelina Yoo
aus Hamburg




Düsseldorf, Dezember 2008 Aus dem Institut für Pharmazeutische Technologie und Biopharmazie
der Heinrich-Heine-Universität Düsseldorf






















Gedruckt mit der Genehmigung der
Mathematisch-Naturwissenschaftlichen Fakultät der
Heinrich-Heine-Universität Düsseldorf




Referent: Prof. Dr. Peter Kleinebudde
Koreferent: Prof. Dr. Jörg Breitkreutz

Tag der mündlichen Prüfung: 10.12.2008
IITable of content

Table of content........................................................................................................................ III
List of abbreviations.............................................................................................................. VIII
1 Introduction....................................................................................................................... 1
1.1 Multiple unit dosage forms ......................................................................................... 1
1.2 Micropellets.. 1
1.2.1 Definition............................................................................................................. 1
1.2.2 Sprinkle capsule................................................................................................... 2
1.2.3 Dose sipping technology ..................................................................................... 2
1.3 Pelletization aids......................................................................................................... 3
1.3.1 Definition 3
1.3.2 Microcrystalline Cellulose................................................................................... 3
1.3.3 κ-Carrageenan...................................................................................................... 4
2 Micropellets production techniques .................................................................................. 6
2.1 Introduction................................................................................................................. 6
2.2 Extrusion..................................................................................................................... 6
2.3 Spheronization............................................................................................................. 7
2.4 Drying.......................................................................................................................... 7
3 Dissolution behavior......................................................................................................... 8
3.1 Introduction.. 8
3.2 Matrix dissolution....................................................................................................... 8
3.2.1 Definition 8
3.2.2 Diffusion-controlled dissolution.......................................................................... 8
3.3 Evaluation by Korsmeyer and Peppas......................................................................... 9
4 Aims of this work............................................................................................................ 11
5 Results and Discussion.................................................................................................... 12
5.1 Optimization of spheronizer conditions .................................................................... 12
5.1.1 Introduction and objective................................................................................. 12
5.1.2 Production.......................................................................................................... 12
5.1.3 Evaluation parameters....................................................................................... 13
5.1.3.1 Introduction................................................................................................ 13
5.1.3.2 Moisture content......................................................................................... 13
5.1.3.3 Shape 13
5.1.3.4 Size and size distribution............................................................................ 13
5.1.3.5 Yield........................................................................................................... 14
5.1.4 Design of Experiments - Quality of the Model ................................................. 14
5.1.5 Spheronization of 500µm extrudates – CCC-design......................................... 14

III5.1.6 Comparison between two spheronizers ............................................................. 19
5.1.7 Adaptation of the additional spheronizer process variables .............................. 23
5.1.8 Summary............................................................................................................ 25
5.2 Micropellets containing spironolactone as API ........................................................ 26
5.2.1 Introduction and objective................................................................................. 26
5.2.2 Evaluation parameters....................................................................................... 26
5.2.2.1 Introduction................................................................................................ 26
5.2.2.2 Drug release 26
5.2.2.3 Similarity of the dissolution profiles.......................................................... 26
5.2.2.4 Mechanical stability................................................................................... 27
5.2.3 Choice of filler................................................................................................... 27
5.2.3.1 Introduction 27
5.2.3.2 Tricalcium phosphate................................................................................. 27
5.2.3.3 Lactose monohydrate 29
5.2.4 Extrusion/ spheronization using tricalcium phosphate as filler......................... 29
5.2.4.1 Production and characterization................................................................. 29
5.2.4.2 Dissolution behavior.................................................................................. 31
Introduction and objective.................................................................... 31
Fast dissolving media ........................................................................... 32
Chloride salts with different cations..................................................... 35
Combined media................................................................................... 47
FeSSIF medium.................................................................................... 47
Milk medium ........................................................................................ 50
5.2.4.3 Summary.................................................................................................... 53
5.2.5 Extrusion/ spheronization using dicalcium phosphate as filler ......................... 53
5.2.5.1 Introduction and objective.......................................................................... 53
5.2.5.2 Production and characterization................................................................. 54
5.2.5.3 Dissolution behavior.................................................................................. 54
5.2.5.4 Summary.................................................................................................... 56
5.2.6 Extrusion/ spheronization using lactose monohydrate as filler......................... 56
5.2.6.1 Introduction and objective 56
5.2.6.2 Production and characterization 57
5.2.6.3 Dissolution behavior 58
5.2.6.4 Summary.................................................................................................... 61
5.2.7 Extrusion/ spheronization using calcium lactate as filler .................................. 61
5.2.7.1 Introduction and objective.......................................................................... 61
5.2.7.2 Production and characterization................................................................. 61
5.2.7.3 Dissolution behavior.................................................................................. 62
5.2.7.4 Summary 63

IV5.2.8 Extrusion/ spheronization using MCC as pelletization aid ............................... 63
5.2.8.1 Introduction and objective.......................................................................... 63
5.2.8.2 Production and characterization................................................................. 63
5.2.8.3 Dissolution behavior.................................................................................. 64
5.2.8.4 Summary.................................................................................................... 67
5.3 Micropellets containing different APIs ..................................................................... 68
5.3.1 Choice of model substances as API................................................................... 68
5.3.1.1 Specification............................................................................................... 68
5.3.1.2 Spironolactone............................................................................................ 68
5.3.1.3 Griseofulvin................................................................................................ 68
5.3.1.4 Itraconazole 69
5.3.2 Extrusion/ spheronization of theophylline monohydrate................................... 69
5.3.2.1 Introduction and objective.......................................................................... 69
5.3.2.2 Production and characterization................................................................. 70
5.3.2.3 Dissolution behavior.................................................................................. 71
5.3.2.4 Summary.................................................................................................... 76
5.3.3 Extrusion/ spheronization of hydrochlorothiazide ............................................ 76
5.3.3.1 Introduction and objective 76
5.3.3.2 Production and characterization 76
5.3.3.3 Dissolution behavior.................................................................................. 77
5.3.3.4 Summary 81
5.3.4 Extrusion/ spheronization of griseofulvin ......................................................... 81
5.3.4.1 Introduction and objective.......................................................................... 81
5.3.4.2 Production and characterization................................................................. 82
5.3.4.3 Dissolution behavior 82
5.3.4.4 Summary.................................................................................................... 85
5.3.5 Extrusion/ spheronization of itraconazole ......................................................... 86
5.3.5.1 Introduction and objective 86
5.3.5.2 Production and characterization................................................................. 86
5.3.5.3 Dissolution behavior.................................................................................. 86
5.3.5.4 Summary 87
5.3.6 Overview of the standard formulations in 0.1 M calcium chloride solution..... 88
5.3.6.1 Comparison of the standard formulations containing different fillers ....... 88
5.3.6.2 Comparison of the standard formulations containing different APIs ........ 89
5.3.6.3 Summary.................................................................................................... 91
5.4 Different types of κ-carrageenan............................................................................... 92
5.4.1 Introduction and objective................................................................................. 92
5.4.2 Evaluation of different types of κ-carrageenan ................................................. 92
5.4.2.1 Concentration of counter-ions.................................................................... 92
V5.4.2.2 Rheological behavior of different κ-carrageenans ..................................... 93
5.4.2.3 Rheological behavior of κ-carrageenan in different dissolution media ..... 95
5.4.3 Summary............................................................................................................ 96
6 Summary......................................................................................................................... 97
7 Zusammenfassung der Arbeit.......................................................................................... 99
8 Experimental part.......................................................................................................... 101
8.1 Materials.................................................................................................................. 101
8.1.1 Carrageenan..................................................................................................... 101
8.1.2 API................................................................................................................... 101
8.1.3 Filler................................................................................................................. 102
8.1.4 Other Substances............................................................................................. 103
8.2 Methods 104
8.2.1 Pellet production.............................................................................................. 104
8.2.1.1 Blending of raw materials ........................................................................ 104
8.2.1.2 Extrusion.................................................................................................. 104
8.2.1.3 Spheronization.......................................................................................... 104
8.2.1.4 Drying....................................................................................................... 105
8.2.2 Determination of evaluation parameter ........................................................... 105
8.2.2.1 Moisture content....................................................................................... 105
8.2.2.2 Yield......................................................................................................... 105
8.2.2.3 Pellet shape, size and distribution ............................................................ 105
8.2.2.4 Mechanical stability................................................................................. 106
8.2.2.5 Statistical evaluation parameter of the DOE ............................................ 106
8.2.2.6 Drug release.............................................................................................. 108
8.2.2.7 High performance liquid chromatography ............................................... 108
8.2.2.8 Preparation of biorelevant media ............................................................. 109
8.2.2.9 Similarity of dissolution profiles.............................................................. 112
8.2.3 Analytical methods.......................................................................................... 113
8.2.3.1 Scanning electron microscopy ................................................................. 113
8.2.3.2 Differential scanning calorimetry 113
8.2.3.3 Karl-Fischer titration................................................................................ 114
8.2.3.4 Laser light diffraction............................................................................... 114
8.2.3.5 Imaging of wet micropellets..................................................................... 114
8.2.3.6 Inductively coupled plasma optical emission spectrometry..................... 115
8.2.3.7 Complexometric titration......................................................................... 115
8.2.3.8 Rheological analysis................................................................................. 115
8.2.3.9 Ring shear cell tester 116
8.2.3.10 Helium pycnometry.................................................................................. 117
8.2.3.11 Bulk density.............................................................................................. 117
VI8.2.3.12 pH measurements..................................................................................... 117
8.2.3.13 X-ray diffraction....................................................................................... 117
9 References..................................................................................................................... 118
10 Acknowledgement......................................................................................................... 131

VIIList of abbreviations

Abbreviation meaning
Abs absorption value
Amoxi amoxicillin trihydrate
ANOVA analysis of variance
API active pharmaceutical ingredient
ar aspect ratio
BCS Biopharmaceutics Classification Scheme
ι-Carr ι-carrageenan (iota)
κ κ-carrageenan (kappa)
λ-Carr λ-carrageenan (lambda)
CCC central composite circumscribed design
CIAA Confederation of the Food and Drink Industries in the EU
®C13-03 tricalcium phosphate (Tri-Cafos PF)
®C53-06 CP 30 )
C92-14 dicalcium phosphate (Di-Cafos)
d dimensionless diameter d
d equivalent diameter eq
DAB Deutsches Arzneibuch
DOE design of experiments
DSC differential scanning calorimetry
DST dose sipping technology
FCC Food chemicals codex
FDA US Food and Drug Administration
FeSSIF Fed State Simulating Intestinal Fluid
ffc flowability function
f similarity factor 2
GDA Guideline daily amount
GIT gastrointestinal tract
®GL200 lactose monohydrate (GranuLac200 )
GRAS generally recognized as safe
GsF griseofulvin
h hours
HCl hydrochloric acid
HCT hydrochlorothiazide
HPLC high performance liquid chromatography
ICP-OES inductively coupled plasma optical emission spectrometry
VIIIICZ itraconazole
inl inlet air pressure
IQR interquartile range
IVIVC in vitro in vivo correlation
L-HPC low substituted hydroxypropylcellulose
loa loading of the spheronizer
-1M mol ⋅l
mc moisture content (of extrudates)
MCC microcrystalline cellulose
MUDF multiple unit dosage form
NaCl sodium chloride
NaOH sodium hydroxide
ndr normalized drug release
p p-value of statistic (lack of fit)
p.a. pro analysis
Ph.Eur. Pharmacopoeia Europaea
Q single charge point
2Q Predictibility
REM scanning electron microscopy
rpm round per minute
2R adjusted coefficient of determination adj
SD standard deviation
spd spheronization speed
SpL spironolactone
SUDF single unit dosage form
SUPAC-MR scale-up and post-approval changes-modified release
temp temperature of the spheronizer wall
ThP theophylline monohydrate
tim residence time
USP United States Pharmacopoeia
x mean
x median 50

IX

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