CONTENTS
Page
Acknowledgement ........................................................................................................... iv
Abstract ................................................................................................................................. vi
List of Tables .................................................................................................................... xiv
List of Figures .................................................................................................................. xvi
CHAPTER 1
1.0 GENERAL INTRODUCTION ............................................................................. 1
1.1 OBJECTIVE .............................................................................. -2
1.2 CELLULOSE ........................................................................................................... 3
1.2.1 Production of a-cellulose from plant sources ......................................................... 4
1.2.2 Modification of Cellulose ....................................................................................... 6
1.2.3 Sourcing for microcrystalline Cellulose ................................................................ 8
1.2.3.1 Sorghum bicolour ........................................................................................ 9
1.2.3.2 Andropogon gayanus ................................................................................ 10
1.3 COMPRESSED TABLETS .................................................................................. 10
Methods of Tableting ............................................................................................ 13
Wet granulation ........................................................................................ 15
Dry granulation ......................................................................................... 15
Direct Compression Tableting .................................................................. 16
DIRECT COMPRESSION EXCIPIENT ............................................................. 18
Classification of Direct Compression Excepients ................................................. 18
Development of Direct Compression Excipient ............................................... 19 !' .I.... : . Microcrystalline Cellulose(MCC) ........... : ......................................................... 21
FACTORS IN FORMULATION DEVELOPMENT .......................................... 25
Compressibility .................................................................................................... 26
Fluidity ................................................................................................................. 28 . . Lubrication .......................... .... ........................................................... 29
PHARMACEUTICAL POWDERS ..................................................................... 30
Particle Size and Size Distribution ........................................................................ 31
Determination of Particle Size ............................................................................. 31
Particle Morphology ............................................................................................... 33
Particle Shape and Surface Area ............................................................................ 35
Derived Properties of powders .............................................................................. 36
1.6.5.1 Porosity ........................... ............................................................... 37
1.6.5.2 Density ....................................................................................................... 38
(i) True density .............................................................................................. 39
(ii) Bulk density ............................................................................................... 39
1.6.6 Flow of Powder ......................... .................................................................. 4 1
1.6.7 Water uptake ...................................................................................................... 43
1.6.7.1 Hydration Capacity ............ .................................................................. 43
1.6.7.2 Contact angle ........................................................................................... 44
1.6.7.3 Equilibrium Moisture Content .................................................................. 45
1.6.8 Swelling ............................................................................................................. 45
1.7 COMPRESSION AND COMPACTION ............................................................ 48
1.7.1 Particle Rearrangement (Transitional Re-Packing) .............................................. 50
1.7.2 Deformation at points of Contact .......................................................................... 51
1.7.3 Fragmentation ......................................................................................................... 52
1.7.4 Plasto-Elasticity and Brittle - Fracture Index ........................................................ 54
1.7.5 Bonding .................................................................................................................. 56
1.7.5.1 Mechanical Bonding ................................................................................. 57
1.7.5.2 Intermolecular Forces of Attraction .......................................................... 58 . . 1.7.5.3 Liquid Surface Film ................................................................................... 58
1.7.5.4 Bonding Propensity ................................................................................... 59
1.7.6 Densification Behaviour of Powders ..................................................................... 59
1.7.6.1 Pressure - Volume Relationship ................................................................ 60
1.7.6.2 Heckel EquationIAnalysis ......................... ............... ................................. 60
1.7.6.3 Kawakitas Equation ............. ............................................................. 65
EVALUATION OF TABLETSTRENGTH ........................................................ 66
Crushing Strength .................................................................................................. 66
Tensile Strength ...................................................................................................... 67
Indentation Hardness ...................... ................................................................ 68
Reworking Potential ..................... .............................................................. 69
Work of Failure ............................. .............................................................. 70 . , .. .-
DIRECT COMPRESSION FORMULATIONS .................................................. 71
Dilution Capacity ................................................................................................... 72
Paracetamol ............................... ...................................................................... 73
Ascorbic acid ............................ .................................................................. 75
Metronidazole ......................................................................................................... 76
CHAPTER 2
2.0 EXPERIMENTAL ................................................................................................. 79
2.1 IDENTIFICATION OF PLANTS .................................................... 79
2.2 MATERIALS ....................................................................................................... 79
2.3 METHODS ............................................................................................................. 80
2.3.1 Preliminary Experiments in the Production of a -Cellulose ............................ .... 80
2.3.1.1 Effect of particle Size Fraction of Standing Material ............................. 80
2.3.1.2 Effect of Reagent type ............................................................................... 81
2.3.1 Control of Processing Conditions .......................................................................... 81
2.3.1.1 Digestion/Delignification .......................................................................... 81
2.3.1.2 Removal of hemicelluloses (Maceration) ................................................. 82
2.3.1.3 Bleaching of a-Cellulose .......................... ......................................... 83
2.3.3 Extraction of a-Cellulose From Sorghum and Andropogon ............................... 84
2.3.4 Production of Microcrystalline Cellulose ......................................................... 85
2.3.5 Physicochemical Properties of SOMCC and AMCC ................................ 86 . . 2.3.6 Acute toxicity test ................................................................................................... 86
2.3.7 Powder properties ................................................................................................... 87
2.3.7.1 Particle Size Distribution .......................................................................... 87
2.3.7.2 Particle morphology .................................................................................. 88
2.3.7.3 Bulk Density .............................................................................................. 88
2.3.7.4 True density ................................... .... ...................................................... 89
2.3.7.5 Porosity, Compressibility Index and Angle Repose ................................ 89
2.3.8 Hydration Capacity ......................................................................................... 90
2.3.9 Swelling Capacity ................................................................................................... ..... ? ......... v2 . 91
2.3.10 Compactability aiia ablet tin^ proberties ........................................................... 92
2.3.10.1 Preliminary Experiment ......................................... .................................. 92
2.3.10.2 Compactability of SOMCC and AMCC ................................................. 95
2.3.1 1 Spectroscopic analysis .......................................................................................... 97
2.3.1 1.1 SOMCC and AMCC ................................................................................ 97
2.3.1 1.2 ~cetamino~hen, .~scorbic.acid, and Metronidazole ................................ 97
2.3.1 1.3 Drug-Excipient compatibility Tests ........................................................ 97
2.3.12 Direct Compression Formulations ...................................................................... 98
2.3.12.1 Preparation of Acetaminophen Tablets ............................ .. ................ 98
2.3.12.2 Preparation of Ascorbic acid Tablets ...................................................... 98
2.3.12.3 Preparation of Metronidazole Tablets ................................................. 100
2.3.1 3 Evaluation of tablet properties ............................................................................. 100
2.3.13.1 Weight Variation .................................................................................. 101
2.3.13.2 Tablet Dimensions and Density .............................................................. 101
2.3.13.3 Tablet Strength ........................................................................................ 102
2.3.14 Reworking potential ......................................................................................... 103
2.3.15 Friability tests ................................................................................................. 103
2.3.16 Disintegration tests ............................................................................................. 104
2.3.17 Dissolution testing ........................................................................................... 104
2.3.18 Effect of storage on drug content ......................................................................... 105
CHAPTER 3
RESULTS AND DISCUSSION ................................................................. 107
IDENTIFICATION OF PLANTS ................................................... 107
EXTRACTION OF a-CELLULOSE ................................................................. 107
Digestion and Delignification ............................................................................. 107
Effect of particle size fractions .......................................................... 107
Effect of Reagent type ......................................................................... 108
Effect of time and temperature ............................................................. 108
Effect of concentration of sodium hydroxide ......................................... 111
Removal of hemicellulose by maceration .......................................................... 111
Bleaching of a-Cellulose ..................................................................................... 112
Effect ofpH ............................................................................................ 114
Extraction of Cellulose from sorghum and Andropogon plants ........................ 114
Processing Conditions ....................................................................................... 114
Yield of cellulose grades ..................................................................................... 116
Physicochemical properties of SC, AC, SOMCC and AMCC ......................... 116
Organoleptic properties ....................................................................................... 116
Compendia1 tests on the cellulose grades ..................................................... 118
Acute Toxicity test ....... :: .~.:':..!:.r ... ....i........ .......................................................... 118
Powder Properties ............................................................................................ 120 ... Particle size and size Distribution ........................................................................ 120
Particle Morphology ............................................................................................. 122
Infrared Spectra of SOMCC and AMCC ....................................................... 122
Densities .............................................; ............................................................ 122 ....... Flowability ......................................................................................................... 128
Hydration Capacity .............................................................................................. 131
Swelling Capacity ................................................................................................ 131
Preliminary evaluation of cellulose grades ........................................................ 135
Effect as filler-binder ..................... .............................................................. 135
Effect as disintegrant ...................................................................................... 138
Compression and Compaction Characteristics of SOMCC and AMCC ........... 141
3.8.1 Effect of particle size on compressibility of the polymers .......... 14 1
3.8.2 Compressibility profiles of SOMCC, AMCC and Avicel PH 10 1 .................... 144
3.8.3 Consolidation behaviours of SOMCC and AMCC ........................................... 146
3.8.4 Reworking potential ........................... .. ........................................................... 151
3.8.5 Dilution Capacity of SOMCC or AMCC ...................... .................................. 153
3.8.5.1 Acetaminophen Compacts .................................................................... 154
3.8.5.2 Ascorbic acid Compacts ................... .. .............................................. 160
3.8.5.3 Metronidazole Compacts ........................................................................ 166
3.9 Drug - Excipient compatibility tests with SOMCC or AMCC .......................... 169
3.10 Formulations ................ .................................................................................. 171
3.10.1 Acetaminophen tablets ......................................................................................... 171
3.10.2 Ascorbic acid tablets ........................... .. ...................................................... 177
3.10.3 Metronidazole tablets ........................................................................................... 179
3.10.4 Uniformity of weight, thickness and diameter .................................................... 188
3.10.5.1 Effect of aging on the drug content ................................................................. 188
CHAPTER 4
4.0 SUMMARY AND CONCLUSION ................................................................... 191
REFERENCES ............................................................................................................. 197
APPENDIX ............................. .................................................................................... 214
