Enteric coated mucoadhesive micropellets in rotary agglomeration process for wet spheronization [Elektronische Ressource] / Marcus Hans Knöll

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ENTERIC COATED MUCOADHESIVE MICROPELLETS IN ROTARY AGGLOMERATION PROCESS FOR WET SPHERONIZATION Dissertation zur Erlangung des Grades „Doktor der Naturwissenschaften“ am Fachbereich Chemie und Pharmazie und Geowissenschaften der Johannes Gutenberg-Universität Mainz Marcus Hans Knöll geb. in Frankfurt / Main Mainz 2006 D 77 Tag der mündlichen Prüfung: 8. Dezember 2006 To I II ACKNOWLEDGEMENTS III IV TABLE OF CONTENTS DEDICATION ……………………………………………………………………………………………………..I ACKNOWLEDGEMENTS...................................................................................................................... III TABLE OF CONTENTS..........................................................................................................................V LIST OF TABLES ..................................................................................................................................IX LIST OF FIGURES.................................................................................................................................XI ABBREVIATIONS.................................................................................................................................XV INTRODUCTION.....................................................................................

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ENTERIC COATED MUCOADHESIVE
MICROPELLETS IN ROTARY
AGGLOMERATION PROCESS FOR WET
SPHERONIZATION


Dissertation zur Erlangung des Grades
„Doktor der Naturwissenschaften“



am Fachbereich Chemie und Pharmazie und Geowissenschaften
der Johannes Gutenberg-Universität
Mainz




Marcus Hans Knöll
geb. in Frankfurt / Main




Mainz 2006














D 77




































Tag der mündlichen Prüfung: 8. Dezember 2006













To


I

II

ACKNOWLEDGEMENTS
III

IV


TABLE OF CONTENTS
DEDICATION ……………………………………………………………………………………………………..I
ACKNOWLEDGEMENTS...................................................................................................................... III
TABLE OF CONTENTS..........................................................................................................................V
LIST OF TABLES ..................................................................................................................................IX
LIST OF FIGURES.................................................................................................................................XI
ABBREVIATIONS.................................................................................................................................XV
INTRODUCTION..................................................................................................................................... 1
AIMS ....................................................................................................................................... 1
CHAPTER I BACKGROUND............................................................................................................. 3
I.1. Basis for Drug Delivery to the Gastrointestinal Tract............................................................... 3
I.1.1. Anatomy and Physiology of the Gastrointestinal Tract........................................................ 3
I.1.2. Secretions of the Mucosa of the Gastrointestinal Tract....................................................... 5
I.2. Transit of Dosage Forms.......................................................................................................... 6
I.2.1. Oesophageal Transit............................................................................................................ 6
I.2.2. Gastric Emptying of Liquid Dosage Forms .......................................................................... 6
I.2.3. Gastric Emptying of Non-Digestible Solids (Solid Dosage Forms and Drug Particles)....... 7
I.2.4. Small Intestinal Transit......................................................................................................... 7
I.2.5. Large Intestinal Transit ........................................................................................................ 8
I.2.6. Prolongation of Gastrointestinal Transit Time...................................................................... 8
I.3. Mucoadhesion.......................................................................................................................... 9
I.3.1. Mechanisms of Mucoadhesion .......................................................................................... 10
I.3.2. Mucoadhesive Polymer Types........................................................................................... 11
I.3.3. Challenges to the Concept of Mucoadhesion .................................................................... 15
I.4. Mucoadhesive Polymers........................................................................................................ 16
I.4.1. Natural Polymers................................................................................................................ 16
I.4.2. Semi-Synthetic Polymers................................................................................................... 19
I.4.3. Synthetic Polymers ............................................................................................................ 21
I.5. Granulation Processes........................................................................................................... 28
I.5.1. Binding Forces of Granules ............................................................................................... 28
I.5.2. Growth Mechanisms of the Particles ................................................................................. 29
I.5.3. Fluidized Bed Technology.................................................................................................. 30
I.5.4. Rotary Processor ............................................................................................................... 34
CHAPTER II MATERIALS AND EQUIPMENT................................................................................. 40
II.1. Materials ........................................................................................................................... 40
II.2. Equipment / Software............................................................................................................. 41
CHAPTER III METHODS................................................................................................................... 43
III.1. Manufacturing of Pellets Using the GPCG1 Rotary Processor.............................................. 43
III.1.1. Na-CMC Micropellets Production....................................................................................... 43
III.1.2. Na-Alginate Micropellets Production.................................................................................. 48
III.1.3. Chitosan Micropellets Production ...................................................................................... 50
®
III.1.4. Carbopol Micropellets Production .................................................................................... 53
III.1.5. Noveon Micropellets Production ........................................................................................ 53
III.2. Characterization of Micropellets............................................................................................. 54
III.2.1. Particle Size Distribution .................................................................................................... 54
V

III.2.2. Tapped Density.................................................................................................................. 55
III.2.3. Friability Testing................................................................................................................. 55
III.2.4. Water Content at the End of the Spraying Period.............................................................. 55
III.2.5. Drying Kinetics of the Micropellets..................................................................................... 55
III.2.6. Scanning Electron Microscopy (SEM) ............................................................................... 55
III.2.7. True Density....................................................................................................................... 55
III.2.8. Estimation of the Surface Area with the Modified Blaine Method...................................... 56
III.2.9. NMR for Acetic Acid Content in the Chitosan Micropellets................................................ 57
III.2.10. Content Uniformity of Theophyllin within Micropellets by HPLC........................................ 57
III.2.11. Statistical Analysis ............................................................................................................. 58
III.3. Enteric Coating of the Micropellets ........................................................................................ 58
III.3.1. Terminology ....................................................................................................................... 58
III.3.2. Formulation of the Spraying Suspension........................................................................... 58
III.3.3. Enteric Coating using the Mini-Glatt .................................................................................. 60
®
III.3.4. Enteric Coating using the Hüttlin Mycrolab ...................................................................... 63
III.4. Dissolution Testing................................................................................................................. 66
III.4.1. Screening of Dissolution Methods for Mucoadhesive Micropellets ................................... 66
III.4.2. Dissolution of the Developed and Manufactured Micropellets using App. 2 and App. 4... 69
III.4.3. Dynamic Hydration Properties of Excipients for Mucoadhesive Micropellets.................... 71
III.4.4. Electron Dispersive X-Ray Method for Proving the Separation of an Enteric Coating Layer
from a Mucoadhesive Matrix Layer.................................................................................... 73
III.4.5. Improving the Solubility of Lipophilic Drugs by Adjusting the Hydrophilic Lipophilic Balance
(HLB Value) of the Drug Carrier System ........................................................................... 76
CHAPTER IV RESULTS .................................................................................................................... 79
IV.1. Production of Na-CMC Micropellets in the GPCG1 Rotary Processor .................................. 79
IV.1.1. Screening of Process Parameters ..................................................................................... 79
IV.1.2. Development of Process Parameters for Na-CMC Micropellets ....................................... 81
IV.2. Na-Alginate Micropellets Production in the GPCG1 Rotary Processor ................................. 90
IV.2.1. Screening of Process Parameters ..................................................................................... 90
IV.2.2. Development of Process Parameters for Na-Alginate Micropellets................................... 93
IV.3. Production of Chitosan Micropellets in the GPCG1 Rotary Processor.................................. 96
IV.3.1. Screening of Process Parameters ..................................................................................... 96
IV.3.2. Development of Process Parameters for Chitosan Micropellets ....................................... 97
®
IV.4. Carbopol Micropellet Production in the GPCG1 Rotary Processor.................................... 101
®
IV.5. Noveon AA1 Micropellet Production in the GPCG1 Rotary Processor.............................. 103
IV.6. Comparison between Rotating Cylinder and the Bolatec Friabimat for Friability
Measurements ..................................................................................................................... 104
IV.7. Rotor Torque Measurement for Monitoring the Pelletization Process as In Process Control ...
......................................................................................................................... 105
IV.8. Measurements of Air Humidity............................................................................................. 107
IV.8.1. Differences between Inlet and Outlet Air Humidity in Relationship to Product Temperature
............................................................................................................................... 107
IV.8.2. Dependence of Outlet Air Humidity on Rotor Speed ....................................................... 108
IV.8.3. Water Content of Outlet Air.............................................................................................. 109
IV.8.4. Total Water Added at Different Inlet Air Humidities ......................................................... 110
IV.9. Drying Kinetics of the Na-CMC Micropellets........................................................................ 110
IV.10. True Density and Estimation of Surface Area of the Micropellets ....................................... 111
IV.11. Content Uniformity of the Batches ....................................................................................... 111
IV.12. Dynamic Hydration Properties of Excipients used for the Manufacture of Mucoadhesive
Micropellets ......................................................................................................................... 113
IV.13. Enteric Coating of Mucoadhesive Micropellets.................................................................... 116
?
IV.13.1. Coating of Na-CMC Micropellets with EUDRAGIT L 30 D-55 using the Mini-Glatt ....... 116
®
IV.13.2. Enteric Coating using the Hüttlin Mycrolab .................................................................... 117
IV.14. Results of the Dissolution Tests........................................................................................... 122
IV.14.1. Comparison of the Different Dissolution Apparatus............................................................. 122
IV.14.2. Dissolution of the Final Batches and Comparison of Different Agitation Rates using the
Paddle Apparatus and Flow-Through Cell....................................................................... 131
IV.14.3 Summary of the Dissolution Results................................................................................ 138
IV.15. Evaluation of the Separation of an Enteric Coating Layer from a Mucoadhesive Matrix Layer
by Electron Dispersive X-Ray .............................................................................................. 139
IV.15.1. Method X1, Evaluation of the Separation of Poured Films.............................................. 139
VI

IV.15.2. Method X2, Evaluation of Separation of Multifunctional Polymers using Coated
Micropellets...................................................................................................................... 142
IV.15.3. Summary on Separation of an Enteric Layer from the Mucoadhesive Polymer.............. 146
IV.16. Improving the Solubility of Lipophilic Drugs in Lipid Matrices.............................................. 146
IV.16.1. Correlation Between HLB and logP ................................................................................. 146
IV.16.2. Estimation of the HLB Value of Different Lipid Matrices and of Spironolactone.............. 151
IV.16.3. Determination of the Solubility of Spironolactone in Different Single Lipid Matrices ....... 151
IV.16.4. Solubility of Spironolactone in Mixtures of Lipid Matrices with Adjusted HLB ................. 161
CHAPTER V. DISCUSSION............................................................................................................. 169
V.1. The Granulation Process ..................................................................................................... 169
V.1.1. Process Variables Influencing the Morphology and Topographical Quality of Micropellets..
............................................................................................................................... 170
V.1.2. Process Variables Influencing Particle Size .................................................................... 170
V.1.3. Process Variables Influencing the Span .......................................................................... 171
V.1.4. Process Variables Influencing Tapped Density ............................................................... 171
V.1.5. Process Variables Influencing Friability ........................................................................... 172
V.1.6. Impact of Inlet Air Conditions and Drying Conditions on the Total Yield ......................... 173
V.1.7. Influence of Acetic Acid Concentration on the Formation of Chitosan Micropellets ........ 174
V.1.8. Differences Between Mucoadhesive Polymers ............................................................... 174
V.1.9. Statistical Analysis ........................................................................................................... 174
V.2. Friability and Tapped Density .............................................................................................. 174
V.3. Torque Measurements......................................................................................................... 175
V.4. Enteric Coating Process....................................................................................................... 176
V.4.1. Amount of Enteric Coating ............................................................................................... 176
®
V.4.2. Comparison between the Mini-Glatt and the Hüttlin Mycrolab ....................................... 176
V.5. Dissolution and EDX ............................................................................................................ 177
V.5.1. Influence of the Dissolution Method................................................................................. 177
V.5.2. Dissolution of the Micropellets using App.2 and 4........................................................... 177
V.6. Perspectives of the Mucoadhesive Micropellets.................................................................. 179
V.7. Improving the Solubility of Spironolactone by Adjusting the HLB Value.............................. 179
CHAPTER VI. SUMMARY ................................................................................................................ 181
CHAPTER VII. APPENDIX................................................................................................................. 183
CHAPTER VIII. REFERENCES .......................................................................................................... 207
CURRICULUM VITAE......................................................................................................................... 221

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