ABSTRACT
The concept of co-processing as a particle engineering technique has been used as a toolto improve the functionality of many existing .
This study was designed toimprove the functionality of cassava as excipient for direct compression by coprocessing with gelatin and colloidal silicon dioxide.
The of (DoE) approach was employed to the percentageratios of the primary excipients for the co-processed excipient.
Fourteen experimentalformulations containing varying proportions of the primary excipients were prepared bythe method of co-fusion and twelve tablets each weighing 400 mg each were producedfor each formulation using the Hydraulic Carver Press.
The compressed tablets werekept for 24 h in the desiccator and evaluated for tensile strength and disintegration time.
The data obtained from the tabletswere suitably analysed using the Design Expertsoftware and fittedto a special quartic model that correlated the effect of varying theproportions of the excipients in the different formulations on tablet .
Thecomposition of the co-processed excipient that produced tablets of desirablecharacteristics after optimization was found to be cassava starch (90 %), (7.5 %)and colloidal silicon dioxide (2.5 %).
The optimized co-processed excipient subsequently known as “StarGelaSil” (SGS) wasprepared in large quantities and stored in an airtight container for further studies.
Solidstate characterization was conducted on SGS todetermine its particle size, shape,distribution, surface morphology, degree of crystallinity, hygroscopicity, compatibilityetc using established analytical techniques.
TABLE OF CONTENTS
DECLARATION……………………………………………………………………………………………….iii
CERTIFICATION ……………………………………………………………………………………………..iv
DEDICATION…………………………………………………………………………………………………… v
ACKNOWLEDGEMENT………………………………………………………………………………….. vi
ABSTRACT……………………………………………………………………………………………………..vii
TABLE OF CONTENTS…………………………………………………………………………………….ix
LIST OF FIGURES ………………………………………………………………………………………….xiii
LIST OF TABLES……………………………………………………………………………………………. xv
LIST OF PLATES …………………………………………………………………………………………… xvi
LIST OF APPENDICES…………………………………………………………………………………..xvii
LIST OF ABBREVIATIONS…………………………………………………………………………..xviii
CHAPTER ONE………………………………………………………………………………………………… 1
1.0 INTRODUCTION ……………………………………………………………………………………. 1
1.1 Solid Dosage Forms………………………………………………………………………………. 1
1.2 Excipients…………………………………………………………………………………………….. 1
1.2.1 Types of excipients…………………………………………………………………………. 2
1.2.2 Functionality of an excipient ……………………………………………………………. 6
1.2.3 Powder compaction and particle bonding process……………………………….. 8
1.3 Tableting Methods ………………………………………………………………………………. 13
1.3.1 Wet granulation…………………………………………………………………………….. 13
1.3.2 Dry granulation …………………………………………………………………………….. 13
1.3.3 Direct compression ……………………………………………………………………….. 14
1.4 Co-processing……………………………………………………………………………………… 18
1.5 Statement of Research Problem …………………………………………………………….. 18
1.6 Justification for the Study …………………………………………………………………….. 20
1.7 Aim and Objectives……………………………………………………………………………… 21
1.7.1 Aim …………………………………………………………………………………………….. 21
1.7.2 Objectives ……………………………………………………………………………………. 21
1.8 Research Hypothesis……………………………………………………………………………. 22
1.8.1 Null Hypothesis (H0) …………………………………………………………………….. 22
1.8.2 Alternate Hypothesis (Ha)………………………………………………………………. 22
CHAPTER TWO……………………………………………………………………………………………… 23
2.0 LITERATURE REVIEW ………………………………………………………………………… 23
2.1 Development of novel excipients…………………………………………………………… 23
2.2 Sources of novel excipients…………………………………………………………………… 24
2.2.1 Particle engineering as a source of new excipients…………………………….. 26
2.2.2 Co-processing as a tool for developing novel excipients ……………………. 29
2.3 Role of material science in co-processing……………………………………………….. 31
2.4 Methods of Co-processing ……………………………………………………………………. 33
2.5 Advantages of co-processed excipients ………………………………………………….. 34
2.6 Co-processed excipients for direct compression………………………………………. 37
2.6.1 Lactose-based excipients ……………………………………………………………….. 38
2.6.2 Cellulose-based excipients……………………………………………………………… 45
2.7 Studies carried out on other investigational co-processed excipients………….. 47
2.8 Research output on starch-based co-processed excipients…………………………. 49
2.9 Constituent excipients for co-processing ………………………………………………… 52
2.9.1 Starch ………………………………………………………………………………………….. 52
2.9.2 Cassava starch………………………………………………………………………………. 55
2.9.3 Colloidal silicon dioxide………………………………………………………………… 57
2.9.4 Gelatin…………………………………………………………………………………………. 61
2.9.5 Ibuprofen……………………………………………………………………………………… 65
2.10 Pharmaceutical Quality by Design (QbD)/Design of Experiment (DoE) …. 68
CHAPTER THREE ………………………………………………………………………………………….. 71
3.0 MATERIALS AND METHODS………………………………………………………………. 71
3.1 Materials…………………………………………………………………………………………….. 71
3.1.1 Chemicals…………………………………………………………………………………….. 71
3.1.2 Instruments/Equipment………………………………………………………………….. 72
3.2 Methods……………………………………………………………………………………………… 74
3.2.1 Selection and optimization of the composition of the co-processed excipient using Design of Experiments (DoE) …………. 74
3.2.2 Preparation of co-processed excipient (CPE)……………………………………. 76
3.2.3 Solid-state characterization…………………………………………………………….. 76
3.2.4 Physico-mechanical properties……………………………………………………….. 79
3.2.5 Compaction Studies………………………………………………………………………. 79
3.2.6 Dilution Potential Studies………………………………………………………………. 81
3.2.7 Lubricant Sensitivity Ratio …………………………………………………………….. 82
3.2.8 Formulation Studies with Ibuprofen ………………………………………………… 82
3.2.9 Tablet Evaluation………………………………………………………………………….. 84
CHAPTER FOUR…………………………………………………………………………………………….. 87
4.0 RESULTS ……………………………………………………………………………………………… 87
4.1 Selection of an optimized composition using DoE…………………………………… 87
4.2 Solid-state Characterization ………………………………………………………………… 111
4.2.1 Optical and polarized microscopy …………………………………………………. 111
4.2.2 Hot stage microscopy (HSM) ……………………………………………………….. 118
4.2.3 Scanning Electron Microscopy (SEM)…………………………………………… 120
4.2.4 Confocal laser scanning microscopy (CLSM)…………………………………. 122
4.2.5 Differential Scanning Calorimetry (DSC)………………………………………. 124
4.2.5 Powder X-ray diffraction (PXRD)…………………………………………………. 128
4.2.6 Fourier Transform Infrared Spectroscopy (FT-IR)…………………………… 133
4.2.7 Dynamic Vapour Sorption (DVS) analysis …………………………………….. 140
4.2.8 Circular Dichroism (CD) spectroscopy ………………………………………….. 144
4.3 Physicomechanical Properties……………………………………………………………… 146
4.4 Compaction Studies …………………………………………………………………………… 148
4.5 Tablet Properties ……………………………………………………………………………….. 158
CHAPTER FIVE ……………………………………………………………………………………………. 162
5.0 DISCUSSION………………………………………………………………………………………. 162
5.1 Selection of an optimized composition using DoE…………………………………. 162
5.2 Solid state characterization …………………………………………………………………. 166
5.2.1 Optical microscopy……………………………………………………………………… 167
5.2.2 Hot stage microscopy…………………………………………………………………… 168
5.2.3 Scanning electron microscopy ………………………………………………………. 168
5.2.4 Confocal laser scanning microscopy ……………………………………………… 169
5.2.5 Circular dichroism spectroscopy …………………………………………………… 169
5.2.6 Differential scanning calorimetry ………………………………………………….. 170
5.2.7 Powder X-ray diffraction ……………………………………………………………… 171
5.2.8 Fourier transform infrared spectroscopy…………………………………………. 171
5.2.9 Dynamic vapour sorption……………………………………………………………… 173
5.3 Physicomechanical Properties……………………………………………………………… 175
5.4 Compaction Studies …………………………………………………………………………… 176
5.5 Tablet Properties ……………………………………………………………………………….. 181
CHAPTER SIX………………………………………………………………………………………………. 185
6.0 SUMMARY, CONTRIBUTION TO KNOWLEDGE, CONCLUSION AND RECOMMENDATIONS FOR FURTHER STUDY ……….. 185
6.1 Summary ………………………………………………………………………………………….. 185
6.2 Contribution to Knowledge…………………………………………………………………. 186
6.3 Conclusion………………………………………………………………………………………… 186
6.4 Recommendations for further study……………………………………………………… 186
REFERENCES ………………………………………………………………………………………………. 188
APPENDICES ……………………………………………………………………………………………….. 203
INTRODUCTION
Solid Dosage Forms
Tablets account for more than 80 % of all dosage forms in the market (Khomane andBansal, 2013)because of the following properties:
(i) They are easy to dispense,
(ii) Offer dosage accuracy,
(iii) They are amenable to mass production at a relatively cheap cost,
(iv) Tamper resistant compared to capsules, and
(v) Offer better stability to heat and moisture compared to liquid and semi-solid formulations (Jivraj et al., 2000; Pucelj, 2014).
The European Pharmacopoeia (2002) defines tablets as solid preparations eachcontaining a single dose of one or more active substances and usually obtained bycompressing uniform volumes of particles.
Tablets are intended for oral administration.Some are swallowed whole, some after being chewed, some are dissolved or dispersedin water before being administered and some are retained in the mouth where the activesubstance is liberated.
Despite the long and continuing history of the development ofnew technologies for administration of drugs, the tablet form remains the mostcommonly used dosage form (European Pharmacopoeia, 2002).
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