INVESTIGATION OF DISSOLUTION PERFORMANCE AND PHYSICAL
CHARACTERIZATION ON DEVELOPMENT OF SOLID DISPERSION DOSAGE FORM
AHMED BASSAM FARHAN
UNIVERSITI SAINS MALAYSIA
2020
INVESTIGATION OF DISSOLUTION PERFORMANCE AND PHYSICAL
CHARACTERIZATION ON DEVELOPMENT OF SOLID DISPERSION DOSAGE FORM
by
AHMED BASSAM FARHAN
Thesis submitted in fulfilment of the requirements for the degree of
Doctor of Philosophy
May 2020
DEDICATION
I dedicate this thesis to my wonderful parents, sister and brothers, for their perpetual moral support and emphasis on the values of education. They pushed me to pursue my dreams and supported me through it.
To my wife, who has always been supportive and present for me and given motivation and strength to me. To my children, Yara and Laith, Who by being a part of me have given me the reason to accomplish my goal.
Thank you all for your unconditional love, support and believing in me.
Ahmed Al-Rawi 7/9/2019
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ACKNOWLEDGEMENT
First of all I would like to thank Allah SWT for giving me strength and guidance in completing this task. Next, I also want to express my sincere gratitude to Prof. Dr.
Habibah Binti A. Wahab (Dean, School of Pharmaceutical Sciences, USM), Assoc.
Prof. Dr. Nurzalina Binti Abdul Karim Khan and Assoc. Prof. Dr. Nornisah Binti Mohamed (Deputy Deans, School of Pharmaceutical Sciences, USM).
I would like to convey my sincere gratitude to my supervisor Dr. Chan Siok Yee for her supervision, encouragement, advice and enormous support throughout my research. She provided me with resources, great advices; guidance, encouragement and the exceptional role she played in making this project a success.
I would like to thank my beloved parents, Bassam F. Al-Rawi and Laylia R.
Al-rawi for having faith in me, giving me encouragement and supporting me throughout this project. I would also like to express my gratitude to my siblings, Zaid, Mayssam, Bilal and my twin brother Saif for their support in completing this re earch. I co ld no ha e comple ed m PhD projec i ho heir lo e and persistent confidence in me.
To my heart, my wife, Sara Q. Mohammed, for her faith, unconditional love and supports. I owe all my achievements to her. Thanks a lot for her understanding when I am emo ional hen nder re and ne er a k why I take such a long time to complete my PhD degree.
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I also want to express my deepest gratitude to my parents in law, Qaies M.
Hassan and Jenan J. Mohammed, for supporting me throughout this research process.
Their support means so much.
I gratefully thank my fellow lab members for considering me as an important member of our big family and their continuous availability and support when I need help.
Before I conclude, I must sincerely thank Universiti Sains Malaysia (USM) for providing me all that I need to undertake my PhD studies.
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TABLE OF CONTENTS
ACKNOWLEDGEMENT ... ii
TABLE OF CONTENTS ... iv
LIST OF TABLES ... xiii
LIST OF FIGURES ... xvi
LIST OF ABBREVIATIONS AND SYMBOLS ... xxii
ABSTRAK ... xxiv
ABSTRACT ... xxvii
CHAPTER 1 INTRODUCTION AND LITERATURE REVIEW ... 1
1.1 Introduction ... 1
1.2 Solid dispersion systems ... 3
1.3 Classification of solid dispersions ... 3
1.3.1 Simple eutectic mixture ... 5
1.3.2 Solid solution ... 5
1.3.2 (a) Continuous vs. discontinuous solid solutions... 6
1.3.2 (b) Substitutional vs. interstitial solid solutions ... 6
1.3.3 Glass suspension ... 7
1.3.4 Glass solution ... 7
1.4 Amorphous form of active pharmaceutical ingredients ... 8
1.5 Glass forming ability ... 10
1.6 Carriers used in solid dispersions ... 12
1.7 Preparation of solid dispersions ... 13
1.7.1 Spray Drying ... 13
1.7.2 Fusion method (Hot-Melt method) ... 14
1.7.3 Solvent method ... 14
1.8 Advantages of solid dispersions ... 15
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1.9 Factors affecting dissolution rate of SD ... 16
1.9.1 Particle size reduction ... 17
1.9.2 Increased drug porosity ... 17
1.9.3 Polymorphs ... 18
1.9.4 Improved wettability ... 18
1.9.6 Decrease drug crystallinity... 20
1.9.7 Processing and storage conditions ... 20
1.10 Problem statement ... 21
1.11 Scope of the study ... 22
CHAPTER 2 MATERIALS AND METHODS ... 24
2.1 Introduction ... 24
2.2 Model Drugs ... 24
2.2.2 Caffeine ... 25
2.2.3 Clotrimazole ... 26
2.2.4 Etoricoxib ... 27
2.2.5 Flurbiprofen ... 28
2.2.6 Gliclazide ... 29
2.2.7 Ibuprofen ... 30
2.2.8 Ketoconazole ... 31
2.2.9 Ketoprofen ... 32
2.2.10 Paracetamol ... 33
2.2.11 Piroxicam ... 34
2.3 Carriers selected ... 35
2.3.1 Hydroxypropyl methyl cellulose ... 35
2.3.2 Mannitol ... 36
2.3.3 Polyvinyl alcohol ... 36
2.3.4 Natrosol (hydroxy ethyl cellulose) ... 37
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2.3.5 Eudragit E100 ... 38
2.3.6 Carbopol 934 ... 39
2.3.7 Polyvinyl pyrrolidone vinyl acetate 6:4 ... 39
2.4 Sample preparation ... 40
2.4.1 Spray drying ... 40
2.4.1 (a) Atomization feed ... 41
2.4.1 (b) Drying chamber ... 42
2.4.1 (c) Product collection and separation... 42
2.4.2 Quench-cooled method ... 43
2.5 Physical Characterization of solid dispersion ... 44
2.5.1 Differential Scanning Calorimetry ... 44
2.5.1 (a) Heat flux DSC ... 44
2.5.1 (b) Power compensated DSC ... 45
2.5.1 (c) Sample Size of DSC ... 45
2.5.1 (d) Purge Gas ... 46
2.5.2 X-Ray Diffractometry ... 46
2.5.2 (a) Bragg la ... 47
2.5.2 (b) Instrumentation ... 48
2.5.2 (c) Sample Preparation for X-ray analysis ... 49
2.5.2 (d) Interpretation of diffraction patterns ... 50
2.5.3 Scanning Electron Microscopy ... 50
2.5.3 (a) Sample Preparation... 51
2.5.4 ATR-FTIR ... 51
2.5.5 Thermogravimetric Analysis... 52
2.5.6 Contact angle measurement ... 53
2.5.7 Ultraviolet-Visible Absorption Spectroscopy ... 54
2.5.7 (a) Beer-Lambert Law ... 56
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2.5.8 Dissolution testing... 57
2.5.8 (a) USP Apparatus 1 (Rotating Basket Apparatus) ... 58
2.5.8 (b) USP Apparatus 2 (Paddle Apparatus) ... 59
2.5.8 (c) USP Apparatus 3 (Reciprocating Cylinder) ... 59
2.5.8 (d) USP Apparatus 4 (Flow-Through Cell) ... 60
2.5.9 Tabletting ... 61
2.5.9 (a) Tabletting Press ... 61
2.5.9 (b) Quality control of tablet ... 62
2.5.9 (c) Tablet dimensions... 63
2.5.9 (d) Weight variation ... 63
2.5.9 (e) Hardness ... 63
2.5.9 (f) Friability ... 64
2.5.9 (g) Disintegration time ... 64
2.6 Molecular dynamic simulations ... 65
2.7 Stability study ... 68
2.8 Statistical Analysis ... 69
CHAPTER 3 CHARACERIZATION AND ROLES OF CARRIERS ON DISSOLUTION PERFORMANCE OF FLURBIPROFEN lN SOILD DISPERSION SYSTEMS... 70
3.1 Introduction ... 70
3.2 Materials and methods ... 73
3.2.1 De ermina ion of Lambda ma ( max) ... 73
3.2.2 Preparation of spray dried solid dispersions ... 73
3.2.3 Physical mixture preparation ... 74
3.2.4 Characterization of solid FBP polymer dispersions ... 74
3.2.4 (a) Aqueous solubility determination ... 74
3.2.4 (b) Determination of drug content in solid dispersion samples ... 75
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3.2.4 (c) DSC scan ... 75
3.2.4 (d) XRPD scan ... 75
3.2.4 (e) ATR-FTIR spectroscopy ... 76
3.2.4 (f) SEM micrograph ... 76
3.2.5 Dissolution studies ... 77
3.3 Results and discussion ... 78
3.3.1 Aqueous solubility determination ... 78
3.3.2 Drug content measurements ... 79
3.3.3 Thermal properties of the raw materials and binary systems... 79
3.3.3 (a) Thermal properties of the raw materials... 79
3.3.3 (b) Thermal properties of the binary systems ... 83
3.3.3 (c) Comparison of experimental and theoretical Tg values ... 88
3.3.4 XRPD study ... 92
3.3.5 FTIR study ... 98
3.3.6 SEM study ... 106
3.3.7 Dissolution study... 114
3.4 Conclusions ... 118
CHAPTER 4 GLASS FORMING ABILITY OF POORLY SOLUBLE ACTIVE PHARMACEUTICAL INGREDIENTS ... 119
4.1 Introduction ... 119
4.2 Materials and methods ... 120
4.2.1 Model drugs ... 120
4.2.2 Methods ... 120
4.2.2 (a) Aqueous solubility determination ... 120
4.2.2 (b) Estimation of amorphous/ crystalline solubility ratio ... 121
4.2.2 (c) TGA studies ... 122
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4.2.2 (d) DSC thermal analysis ... 122
4.2.2 (e) Preparation of quenched-cooled APIs ... 123
4.2.2 (f) ATR FTIR spectroscopy ... 123
4.2.2 (g) Microscopy analysis ... 124
4.2.2 (h) Contact angle measurement ... 124
4.2.2 (i) Dissolution studies ... 125
4.2.2 (j) Molecular dynamic simulation ... 125
4.2.2 (k) Statistical analysis ... 126
4.3 Results and discussion ... 127
4.3.1 Comparison of solubility between the raw APIs and their corresponding Quench cooled APIs. ... 127
4.3.2 TGA studies ... 128
4.3.3 DSC studies ... 129
4.3.3 (a) Calculated API Trg values ... 131
4.3.3 (b) Percentage of amorphous solids after 24 hours... 133
4.3.4 Theoretical estimation of amorphous solubility advantages ratio of the tested APIs ... 134
4.3.5 ATR-FTIR analysis ... 136
4.3.6 Microscopy analysis of APIs and quenched-cooled materials after 24 hours ... 140
4.3.7 Contact angle measurements of APIs and QC APIs ... 144
4.3.8 Dissolution performances of the APIs and QC APIs ... 146
4.3.10 Molecular dynamic simulation... 150
4.3.11 Statistical study ... 158
4.4 Conclusion ... 159
CHAPTER 5 INVESTIGATION OF FACTORS GOVERNING THE DISSOLUTION ENHANCEMENT OF SOLID DISPERSION SYSTEM ... 161
5.1 Introduction ... 161
5.2 Materials and method ... 163
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5.2.1 Model drugs ... 163
5.2.2 Carrier: PVPVA ... 163
5.2.3 Preparation of physical mixtures and solid dispersions ... 163
5.2.4 Physical characterization... 164
5.2.4 (a) DSC ... 164
5.2.4 (b) ATR-FTIR ... 165
5.2.5 Dissolution studies ... 165
5.2.6 Statistical study ... 165
5.3 Results and discussion ... 166
5.3.1 Solid state characterization ... 166
5.3.1 (a) DSC study... 166
5.3.2 ATR-FTIR ... 167
5.3.3 Dissolution performance ... 170
5.3.4 Statistical study ... 176
5.4 Conclusion ... 180
CHAPTER 6 PHYSICAL CHARACTERIZATION ON DEVELOPMENT OF SOLID DISPERSION DOSAGE FORM ... 181
6.1 Introduction ... 181
6.2 Materials and methods ... 183
6.2.1 Preparation of solid dispersions by spray dried method ... 183
6.2.2 Determination of drug content ... 183
6.2.3 ATR-FTIR Spectroscopy ... 183
6.2.4 XRPD ... 184
6.2.5 Water content ... 184
6.2.6 Tabletting ... 184
6.2.7 Description (size, shape, color) ... 185
6.2.8 Weight variation ... 185
6.2.9 Hardness ... 186
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6.2.10 Disintegration time ... 186
6.2.11 Friability ... 187
6.2.12 In vitro release profile ... 187
6.2.13 Stability study ... 188
6.2.14 Statistical study ... 189
6.3 Results and discussion ... 189
6.3.1 Drug content determination ... 189
6.3.2 ATR-FTIR ... 191
6.3.3 XRPD ... 195
6.3.4 Water content ... 197
6.3.5 Physical characterization of tablets ... 199
6.3.5 (a) Description (size, shape, color) ... 199
6.3.5 (b) Weight variations ... 199
6.3.5 (d) Hardness ... 200
6.3.5 (e) Disintegration time ... 202
6.3.5 (f) Friability ... 203
6.3.6 Dissolution studies ... 203
6.3.6 (a) The comparison between the dissolution profiles of binary and compacted SD systems ... 203
6.3.7 (a) The comparison of dissolution profiles of SD systems after storage conditions ... 205
6.4 Conclusions ... 210
CHAPTER 7 GENERAL CONCLUSIONS AND SUGGESTIONS FOR FUTURE RESEARCH ... 211
7.1 General conclusions ... 211
7.2 Suggestions for future research ... 216
REFERENCES ... 218 APPENDICES
xii LIST OF PUBLICATION
xiii
LIST OF TABLES
Page
Table 1.1 Biopharmaceutical classification system ... 1
Table 1.2 Strategies to enhance the solubility of drugs with poor water- solubility ... 3
Table 1.3 Different categories of solid dispersion according to the physical states of the carrier matrix and API... 4
Table 1.4 List of carriers used in solid dispersions [Adapted from (Vasconcelos et al., 2016)] ... 12
Table 2.1 Physicochemical Properties of Caffeine ... 25
Table 2.2 Physicochemical Properties of Clotrimazole ... 26
Table 2.3 Physicochemical Properties of Etoricoxib ... 27
Table 2.4 Physicochemical Properties of Flurbiprofen ... 28
Table 2.5 Physicochemical Properties of Gliclazide ... 29
Table 2.6 Physicochemical Properties of Ibuprofen ... 30
Table 2.7 Psychochemical Properties of Ketoconazole ... 31
Table 2.8 Psychochemical Properties of Ketoprofen ... 32
Table 2.9 Psychochemical Properties of Paracetamol ... 33
Table 2.10 Physicochemical Properties of Piroxicam ... 34
Table 2.11 Weight Variation Limits for Tablets ... 63
Table 2.12 Codes and titles used in ICH Guidelines ... 68
Table 2.13 Long-term, accelerated stability conditions ... 69
Table 4.1 Solubility of the studied API and API QC and the percent of crystallinity ... 127
Table 4.2 Decomposition Temperature of raw materials ... 128
Table 4.3 Summary of thermal properties for the API raw materials ... 132
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Table 4.4 Amorphous percentage after 24 hours of storage ... 134 Table 4.5 Melting temperature of the crystalline APIs, melting enthalpy of
the crystalline APIs, free energy difference between the crystalline APIs and their amorphous form, experimental solubility of the crystalline APIs, solubility ratio and theoretical solubility ... 135 Table 4.6 Summary of the ATR-FTIR spectra for the raw materials and
quench-cooled materials... 137 Table 4.7 Initial release rate, DE, and improvement of DE in samples for all
drugs ... 149 Table 4.8 Differences in kinetic, potential and total energies, MSD and
gyration radius between QC APIs and their APIs formin distilled water at 310 K at 50 ns ... 157 Table 4.9 Pearson Correlation of the D.E % improvement based on the
theoretical and experimental advantages, Trg and contact angle, n=8 ... 158 Table 5.1 Parameters used in the preparation of nine drugs with PVPVA
based SD systems ... 164 Table 5.2 Extension of carbonyl group of PVPVA in solid dispersion
systems ... 170 Table 5.3 Percentage DE and improvement of DE of PM and SD API-
PVPVA ... 172 Table 5.4 Experimental amorphous advantage, Modified Trg (K),
Differences between crystal and amorphous contact angles and the correlations ... 175 Table 5.5 Pearson Correlation of the D.E % improvement based on the
theoretical and experimental advantages, mTrg and contact angle, n=9. ... 176 Table 5.6 Statistical result of independent samples test ... 177 Table 5.7 The variables used in the statistical study analysis ... 177
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Table 5.8 Statistical regression results ... 178 Table 6.1 Composition of the tablet formulated with Solid dispersion ... 185 Table 6.2 Weight Variation Limits for Tablets ... 186 Table 6.3 Stability data of drug content at room temperture. Mean ±S.D.,
N=3... 191 Table 6.4 Readings of description of PM and SDs tablets ... 199 Table 6.5 Comparison of f2 value among solid dispersion of binary and
compact products ... 204 Table 6.6 Comparison of f2 value among solid dispersion products after 0, 6
and 24 months ... 206 Table 6.7 Percentage of dissolution efficiency of PM and SD of FBP/KET
with CP and PVPVA tablets in distilled water (Mean ± SD, n = 6) ... 209
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LIST OF FIGURES
Page Figure 1.1 Solid solutions classified based on solute distribution: (A)
Substitutional crystalline solid solution; (B) Interstitial crystalline
solid solution. ... 7
Figure 1.2 Schematic overview of the kinetic and thermodynamic pathways to prepare an amorphous form from a crystalline compound. Retrieved and modified from Blaabjerg et al., 2017 ... 9
Figure 1.3 Pharmaceutical applications of solid dispersions ... 16
Figure 2.1 Chemical Structure of Caffeine ... 25
Figure 2.2 Chemical Structure of Clotrimazole... 26
Figure 2.3 Chemical Structure of Etoricoxib... 27
Figure 2.4 Chemical Structure of Flurbiprofen ... 28
Figure 2.5 Chemical Structure of Gliclazide ... 29
Figure 2.6 Chemical Structure of Ibuprofen ... 30
Figure 2.7 Chemical Structure of Ketoconazole ... 31
Figure 2.8 Chemical Structure of Ketoprofen ... 32
Figure 2.9 Chemical Structure of Paracetamol ... 33
Figure 2.10 Chemical Structure of Piroxicam ... 34
Figure 2.11 Chemical structure of HPMC ... 35
Figure 2.12 Chemical structure of Mannitol ... 36
Figure 2.13 Chemical structure of PVA. ... 37
Figure 2.14 Chemical structure of Natrosol ... 37
Figure 2.15 Chemical structure of EE 100. ... 38
Figure 2.16 Chemical structure of Carbopol ... 39
Figure 2.17 Chemical structure of PVPVA ... 40
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Figure 2.18 Schematic diagram of a typical spray drying machine ... 41
Figure 2.19 Schema ic of a e ile drop, con ac angle ( ) ... 54
Figure 2.20 Energy diagram depicting various electronic transitions ... 55
Figure 2.21 Rotating basket apparatus element (A), and paddle (B). ... 58
Figure 2.22 Reciprocating cylinder apparatus ... 60
Figure 2.23 Flow-Through cell apparatus (Yuan et al., 2017) ... 61
Figure 2.24 Tablet formation (Kalidindi et al., 2019) ... 62
Figure 3.1 DSC thermogram of FBP in the first and second heating cycles ... 80
Figure 3.2 DSC first heat cycle thermograms of HPMC, PVA, Natrosol, CP, EE100, mannitol and PVPV ... 81
Figure 3.3 DSC second heat cycle thermograms of HPMC, PVA, Natrosol, CP, EE100 and PVPVA ... 82
Figure 3.4 DSC second heat cycle thermogram of mannitol ... 82
Figure 3.5 DSC thermograms of physical mixtures in the first heat cycle of 30% FBP with HPMC, PVA, Natrosol, CP, EE100, mannitol and PVPVA ... 83
Figure 3.6 DSC thermograms of solid dispersion in the first heat cycle of 30% FBP with HPMC, PVA, Natrosol, CP, EE100, mannitol and PVPVA ... 85
Figure 3.7 DSC thermograms of solid dispersion in the second heat cycle of 30% FBP with HPMC, PVA, Natrosol, EE 100 and PVPVA ... 86
Figure 3.8 DSC thermograms of solid dispersion in the second heat cycle of 30% FBP with CP and mannitol ... 87
Figure 3.9 X-ray diffractogram of pure FBP ... 92
Figure 3.10 X-ray diffractograms of mannitol, PVA, EE100, HPMC, Natrosol, CP and PVPVA ... 93
Figure 3.11 X-ray diffractograms of the PM systems: FBP-mannitol, FBP- PVA, FBP-Natrosol, FBP-EE100, FBP-HPMC, and FBP-CP and FBP-PVPVA ... 94
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Figure 3.12 X-ray diffractograms of the SD systems: FBP-mannitol, FBP- PVA, FBP-Natrosol, FBP-EE100, FBP-HPMC, FBP-CP and FBP-PVPVA ... 95 Figure 3.13 ATR-FTIR spectrum of pure FBP ... 98 Figure 3.14 ATR-FTIR spectra of CP, PM 30% FBP CP and SD 30% FBP
CP ... 99 Figure 3.15 ATR-FTIR spectra of PVA, PM 30% FBP PVA and SD 30%
FBP PVA ... 100 Figure 3.16 ATR-FTIR spectra of pure HPMC, PM 30% FBP-HPMC and SD
30% FBP-HPMC ... 101 Figure 3.17 ATR-FTIR spectra of pure mannitol, PM 30% FBP-Mannitol and
SD 30% FBP-Mannitol ... 102 Figure 3.18 ATR-FTIR spectra of pure Natrosol, PM 30 % FBP-Natrosol and
SD 30% FBP-Natrosol ... 103 Figure 3.19 ATR-FTIR spectra of pure EE100, PM 30% FBP-EE100 and SD
30% FBP-EE100 ... 104 Figure 3.20 ATR-FTIR spectra of pure PVPVA, PM 30% FBP-PVPVA and
SD 30% FBP-PVPVA ... 105 Figure 3.21 SEM micrographs of pure FBP at (A1) 500X and (A2) 5000X
magnification ... 106 Figure 3.22 SEM micrographs at 2000X magnification: FBP-PVA PM (A1)
and SD (A2). ... 107 Figure 3.23 SEM micrographs at 2000X magnification: FBP-HPMC PM (A1)
and SD (A2). ... 108 Figure 3.24 SEM micrographs at 2000X magnification: FBP-CP PM (A1) and
SD (A2) ... 109 Figure 3.25 SEM micrographs at 2000X magnification: FBP-Mannitol PM
(A1) and SD (A2) ... 110 Figure 3.26 SEM micrographs at 2000X magnification: FBP-Natrosol PM
(A1) and SD (A2) ... 111
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Figure 3.27 SEM micrographs at 2000X magnification: FBP-PVPVA PM (A1) and SD (A2) ... 112 Figure 3.28 SEM micrographs at 2000X magnification: FBP-EE100 PM
(A1) and SD (A2) ... 113 Figure 3.29 Di ol ion profile of PM ( ) and SD ( ) of 30% of FBP-PVA,
FBP-HPMC, FBP-CP, FBP-mannitol, FBP- Natrosol, FBP- EE100 and FBP-PVPVA in distilled water (Mean ± SD, n = 6) ... 115 Figure 4.1 DSC thermograms of the first heating cycle for raw caffeine,
clotrimazole, etoricoxib, flurbiprofen, gliclazide, ibuprofen, ketoconazole, ketoprofen, paracetamol and piroxicam. ... 130 Figure 4.2 DSC thermograms of the second heating cycle for raw caffeine,
clotrimazole, etoricoxib, flurbiprofen, gliclazide, ibuprofen, ketoconazole, ketoprofen, paracetamol and piroxicam ... 131 Figure 4.3 DSC thermograms of quench-cooled clotrimazole, etoricoxib,
flurbiprofen, gliclazide, ibuprofen, ketoconazole, ketoprofen and paracetamol ... 133 Figure 4.4 API morphologies: a) PCM, b) FBP, c) Ketoprofen and d)
Piroxicam. Left i) Raw APIs and ii) quench-cooled APIs were observed at 10x magnification, except d) ii at 20x magnification ... 141 Figure 4.5 API morphologies under 10x magnification: e) Etoricoxib, f)
Gliclazide, g) Ketoconazole and h) Ibuprofen. Left: i) Raw APIs and ii) quench-cooled APIs were observed at 10x magnification, except d) ii at 20x magnification ... 142 Figure 4.6 API morphologies under 10x magnification: i) Clotrimazole and
j) Caffeine. Left i )Raw APIs and ii) Quench-cooled APIs ... 143 Figure 4.7 Differences of contact angles of APIs and QC APIs ... 145 Figure 4.8 Contact angles of CLO, ETOR, FBP, GLZ, IBU, KET, KTP,
PARA, PIRof API ( ) and amorpho form)▲( ... 146
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Figure 4.9 Di ol ion profile of API ( ) and QC ( ), CLO, ETOR, FBP, GLZ ,IBU, KET, KTP, PCM and PIX of in distilled water(Mean
± SD, n = 6). ... 148 Figure 4.10 Average energy profile of each API and API QC during heating,
equilibration and production simulation phases ... 151 Figure 4.11 Simulation process of each API and their amorphous forms in
aqueous phase at o ns and 50 ns ... 153 Figure 4.12 Simulation process of each API and their amorphous forms in
aqueous phase at o ns and 50 ns ... 154 Figure 4.13 The mass-weighted radius of gyration of the studied APIs and
their quenched-cooled forms with fluctuation as a function of time ... 155 Figure 4.14 Theoverall mean square displacement plot of the studied API and
their quenched-cooled form with fluctuation as a function of time . 156 Figure 5.1 DSC thermograms of first heating cycle of SD IBU PVPVA, SD
PCM PVPVA, SD ETOR PVPVA, SD CLO PVPVA, SD PIX PVPVA, SD GLZ PVPVA, SD KET PVPVA, SD KTP PVPVA and SD FBP PVPVA ... 166 Figure 5.2 ATR-FTIR spectra of SD 30 % CLO PVPVA, amorphous CLO
prepared by quench cooling method, pure PVPVA and b rac ion re l of SD CLO PVPVA amorpho CLO . ... 168 Figure 5.3 ATR-FTIR pec ra of b rac ion of SD API PVPVA
amorpho API of ETO, FBP, GLZ and KET ... 168 Figure 5.4 ATR-FTIR spectra of subtrac ion of SD API PVPVA
amorpho API of IBU, KTP, PCM and PIX ... 169 Figure 5.5 Di ol ion profile of PM ( ) and SD ( ), of 30% of PIX
PVPVA, PCM PVPVA, KTP PVPVA, KET PVPVA, IBU PVPVA, GLZ PVPVA, FBP PVPVA, ETOR PVPVA and CLO PVPVA in distilled water (Mean ± SD, n = 6) ... 171
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Figure 6.1 ATR-FTIR spectra of PM 30% FBP-PVPVA, SD 30% FBP- PVPVA (0 months), SD 30% FBP-PVPVA (6 months) and SD 30% FBP-PVPVA (24 months) ... 193 Figure 6.2 ATR-FTIR spectra of PM 30% FBP-CP, SD 30% FBP-CP (0
months), SD 30% FBP-CP (6 months) and SD 30% FBP-CP (24 months) ... 194 Figure 6.3 ATR-FTIR spectra of PM 30% KET-CP, SD 30% KET-CP (0
months), SD 30% KET-CP (6 months) and SD 30% KET-CP (24 months) ... 194 Figure 6.4 ATR-FTIR spectra of PM 30% KET-PVPVA, SD 30% KET-
PVPVA (0 months), SD 30% KET-PVPVA (6 months) and SD 30% KET-PVPVA (24months) ... 195 Figure 6.5 XRPD analysis of PMs and SDs of 30% KET and FBP in CP
over time ... 196 Figure 6.6 XRPD analysis of PMs and SDs of 30% KET and FBP in
PVPVA over time ... 197 Figure 6.7 Water content of PM, SD and aged SD (6 and 24 months in 75%
RH) of 30% KET-CP, 30%-FBP-CP, 30% KET-PVPVA and 30% FBP-PVPVA ... 198 Figure 6.8 The effect of direct compression force on the hardness strength of
produced PM and corresponding SDs tablets with different interval periods (n = 10) ... 201 Figure 6.9 Disintegration times of the tested SD tablets prepared by direct
compression (600 mg, 13 mm in diameter) (n = 3) ... 202 Figure 6.10 Di ol ion profile of PM ( ),SD a 0 mon h ( ), SD a 6
mon h ( ) and SD a 24 mon h ( ) and of 30% of (a) KET-CP (b) FBP-CP (c) KET-PVPVA (d) FBP-PVPVA tablets in distilled water (Mean ± SD, n = 6) ... 207
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LIST OF ABBREVIATIONS AND SYMBOLS
ANOVA Anylasis of variance
API Active Pharmaceutical Ingredients ASD Amorphous soliD dispersion
ATR-FTIR Attenuated total reflectance- Fourier tranform infrared AUC Area under the curve
Avg. Average
BCS Biopharmaceutic Classification System CAc Contact angle of crystal
CAFF Caffeine
CAqc Contact angle of quenced-cooled
CLO Clotrimazole
CP Carbopol
DE Dissolution efficiency
DSC Differential scanning calorimetry EE100 Eudragit E100
ETOR Etoricoxib f2 Similarity factor
FBP Flurbiprofen
FTIR Fourier tranform infrared GFA Glass Forming Ability
GLZ Gliclazide
HPMC Hydroxy propyl methyl cellulose
IBU Ibuprofen
J Joule
K Kelvin
KET Ketoconazole
KTP Ketoprofen
MD Molecular dynamic
min Minute
MSD Mean square displacement
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mTrg Modified reduced glass temperture
nm Nano meter
NPT National pipe taper
ns Nano second
P.E Potential energy
PCM Paracetamol
PIX Piroxicam
PM Physical mixture
ps Picosecond
PVA Polyvinyl alcohol PVP Polyvinyl pyrrilodone
PVPVA Polyvinyl pyrrilodone vinyl acetate
QC Quench-cooled
R Gas constant
Rg Radius of gyration RH Relative humidity
SD Solid dispersion
SEM Scanning electron microscope
SPSS Statistical package for the social sciences
T Temperture
T.E Total energy
Tg Glass transition temperature TGA Thermogravimetric Analysis
Tm Melting temperature
Trg Reduced glass temperture XRPD X-ray powder diffraction
G Change of free energy HF Change in heat of fusion Cp Change heat capacity
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PENYIASATAN PRESTASI PERLARUTAN DAN PENCIRIAN FIZIKAL DALAM PEMBANGVNAN BENTUK DOS SEBASAN PEPEJAL
ABSTRAK
Formulasi pepejal terampai (SD) telah menarik perhatian kerana potensinya dalam peningkatan prestasi perlarutan bahan farmaseutikal aktif (API) yang kurang larut. Walau bagaimanapun, rumusan daripada kajian yang diterbitkan menunjukkan prestasi perlarutan SD adalah tidak konsisten. Tidak ada peraturan umum dalam penalaan pemilihan pengangkut dan API untuk pelaburan yang bermanfaat untuk pembangunan perumusan pepejal terampai. Oleh itu, Objektif utama kajian ini adalah untuk mengkaji kriteria sistem pengangkut yang baik dan calon API dalam formulasi SD bagi meningkatkan prestasi perlarutan API kurang larut dan pertimbangan dalam pembangunan bentuk dos tablet SD. Bagi mencapai matlamat ini beberapa sistem SD telah disediakan secara semburan pengeringan. Kaedah digunakan untuk mencirikan sistem SD; seperti DSC, XRPD, ATR-FTIR, Imbas SEM, dan simulasi dinamik molekul (MD). Untuk mengetahui kesan pengangkut pada persembahan perlarutan pada sistem SD; flurbiprofen dipilih sebagai API model dengan tujuh pengangkut yang berbeza. Pemilihan pengangkut berdasarkan perbezaan fizikokimia mereka, iaitu; polyvinyl alcohol (PVA), hydroxyl propyl methylcellulose (HPMC), carpobol (CP), mannitol, Natrosol, Eudragit E100 (EE100) dan polyvinylpyrrolidone vinyl acetate (PVPVA). Di sini, kriteria untuk sistem pengangkut yang baik adalah berkait rapat dengan interaksi pengangkut -API dan saiz zarah yang dihasilkan ketika semburan kering. Untuk mengenal pasti kesesuaian API bagi formulasi sistem SD, sepuluh API yang berbeza dipilih dengan sifat fizikokimia yang berlainan. Bentuk amorfus setiap API telah disediakan dengan
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menggunakan kaedah yang penyejukkan kedap. Kelebihan keterlarutan amorfus dikira untuk setiap API sebagai tambahan kepada TGA, ATR-FTIR, pengukuran sudut sentuh, dan kajian. Respons API apabila tersentuh air dikaji dengan simulasi molekul (MD) dalam air sulingan. Perisian ini memberikan maklumat berguna sekecil saat nano yang dianggap sebagai parameter penting untuk API amorf. Ini kerana amorf adalah keadaan pepejal API yang sangat tidak stabil, meneliti maklumat berkaitan mobiliti melalui MD akan memberi manfaat dalam meramalkan hasil proses perlarutan. Adalah didapati bahawa, Tg dan Tm sahaja tidak boleh digunakan sebagai penunjuk tunggal untuk meramal hasil perlarutan sistem pepejal API-APIan yang larut. Sebaliknya, Trg, interaksi pengangkut API, kelebihan kelarutan amorf didapati didapati berkait rapat dengan hasil perlarutan. Walau bagaimanapun, semua faktor ini mempengaruhi secara bebas yang sukar digunakan sebagai ukuran ramalan. Dalam tesis ini, tenaga kinetik dari API dalam 50 nano detik telah didapati berkorelasi dengan baik untuk hasil perlarutan sistem SD API yang tidak larut. Akhirnya analisis regresi dengan parameter MD sebagai faktor dan kecekapan perlarutan sebagai hasil telah dilakukan. Data yang diperolehi dari MD adalah ukuran kolektif Trg serta kelebihan kelarutan amorf. parameter ini telah digunakan dengan sempurna untuk menghasilkan persamaan ramalan bagi calon API kurang larut dalam formulasi sistem SD yang berkesan. Bahagian terakhir tesis melibatkan pembangunan bentuk dos sistem SD dengan menggunakan dua calon API yang sebelum ini terbukti berkesan dalam formulasi SD, iaitu tablet flurbiprofen (FBP) dan ketoconazole (KET) dengan PVPVA dan Carbopol. Perlarutan setiap SD selepas pemadatan dilakukan dan dibandingkan dengan sistem SD-binari serbuk yang sepadan. Berdasarkan hasil perlarutan, kedua-dua sistem menunjukkan nilai F2 lebih daripada 50 yang menunjukkan tiada kesan pemadatan terhadap prestasi
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perlarutan sistem SD ini. Selain itu, kajian kestabilan dilakukan selepas keadaan pen impanan (75% RH, 30 C) dalam jangka ma a ang di e apkan (6 dan 24 bulan).
FBP dan KET dengan sistem PVPVA menunjukkan kestabilan yang lebih rendah berbanding pengangkut CP. Ini adalah disebabkan oleh kecenderungan penghabluran sistem amorfus sepenuhnya (sistem PVPVA) berbanding dengan sistem separa kristal (sistem CP). Kesimpulannya, kehadiran segelintir hablur dalam sistem SD tidak menjejaskan perlarutan SD secara dramatik. Prestasi perlarutan sistem SD adalah berkait-rapat dengan kelebihan kelarutan amorf, pengukuran sudut sentuhan dan nilai Trg yang telah iubah suai. Selain itu, kajian simulasi MD dianggap sebagai kaedah yang baik untuk ramalan awal kesesuaian API yang akan menghasilkan SD yang berkesan bagi kepentingan penjimatan masa dan kos. Pertimbangan pemadatan didapati tidak mempengaruhi perlarutan tablet system SD dari segi pembangunan bentuk dos. Untuk kestabilan, kedua-dua sistem KET & FBP menunjukkan penghabluran semula selepas kajian kestabilan. Walau bagaimanapun, hasil perlarutan didapati konsisten sehingga 24 bulan kajian kestabilan dipercepat kecuali sistem SD KET-PVPVA.
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INVESTIGATION OF DISSOLUTION PERFORMANCE AND PHYSICAL CHARACTERIZATION ON DEVELOPMENT OF SOLID
DISPERSION DOSAGE FORM
ABSTRACT
Solid dispersion (SD) formulation has attracted much attention due to its potential in enhancing dissolution performance of poorly soluble active pharmaceutical ingredients (API). However, an overview of the dissolution performance of SDs implies inconsistent degree of dissolution improvement of poorly soluble APIs in SD. Therefore, the main objective of this study is to determine the criteria of a good carrier system and drug candidate for enhanced dissolution performance of a solid dispersion system for a poorly soluble drug and dosage form consideration particularly the impact of compaction. To achieve these objectives, several SD systems were prepared in this study by spray drying and quenched cooled methods. To identify the suitability of drug to be formulated in SD systems, ten different drugs were chosen with different physicochemical properties.
Amorphous form of each drug was prepared using quenched-cooled method.
Theoretical and experimental amorphous advantages were calculated for each drug.
In addition, TGA, ATR-FTIR, contact angle measurement, MD and dissolution studies were performed. From the results, it was found that these predicating factors could not be used as a single indicator for predicting dissolution outcome of a solid dispersion system of poorly soluble drugs. The last part of the thesis involved dosage form developments of SD systems using two drug candidates that were effective in SD formulation. Dissolution performances of each SD after compaction was performed and compared with the corresponding SD- binary systems. Based on the
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dissolution results, both systems showed f2 values more than 50, which indicated negligible effects of compaction on the dissolution performance of these SD systems.
Additionally, stability studies were performed after storage conditions (75 % RH, 30
°C) in predetermined intervals (6 and 24 months) and compared with a fresh sample.
The presence of trace amount of crystallinity in SD systems did not affect dramatically its dissolution performance. Dissolution performance of SD systems was significantly related to the contact angle measurement and Tg values, MD simulation study was considered a good tool for early estimation of the suitability of drugs to be formulated by SD technique, which could save time and money.
Compaction did not to significantly influence the dosage form development of the solid dispersion system. In terms of stability, both KET & FBP system revealed recrystallized trend. However, the dissolution results were found to be consistent up to 24 months in accelerated stability study except KET-PVPVA SD system.
1
CHAPTER 1 INTRODUCTION AND LITERATURE REVIEW
1.1 Introduction
Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water (Hassan et al., 2019).
Solubility is a major challenge for formulation scientis. The Biopharmaceutics Classification System (Maheshwari et al., 2018) classifies drugs into different groups based on solubility and permeability (Table 1.1).
Table 1.1 Biopharmaceutical classification system
High solubility Low solubility
High permeability I II
Low permeability III IV
It has been estimated that over 80% of all recently developed drugs are Class II chemical entities (Marano et al., 2016). Therefore, there is a high demand for techniques that improve the solubility and enhance the dissolution rate of drug formulations.
According to Noyes-Whitney equation 1.1, the parameters that influence the dissolution rate can be tweaked to tackle the poor solubility issues of Class II drugs (Hirai et al., 2017):
2
𝒅𝑪 𝒅𝒕
𝑫𝑨
𝒅 𝑪𝒔 𝑪𝒃 (Equation 1.1)
; where
= solute dissolution rate (Kg. S-1) c = mass of dissolved material
t = time
A = surface area or interface between dissolving material and solvent D = diffusion coefficient
d = hickne of bo ndar la er of ol en a di ol ing ma erial rface Cs = mass concentration of material on the surface
Cb = mass concentration of material in solvent bulk
Based on the presented equation above, several parameters can be modified to improve the dissolution efficiency of a poorly soluble drug such as drug solubility and surface area. These are the most common modifications made to achieve a desirable dissolution performance. Several techniques have been developed over the years to overcome solubility challenges (Kimura et al., 2014), some of which are listed in Table 1.2, such as salt formation, particle size reduction, soluble prodrug formation, complexation with a surfactant, and amorphous solid dispersion. Of all the aforementioned techniques, solid dispersion (SD) stands out as the most favourable approach due to a high success rate with regard to the improvement of the dissolution performance of a Class II drug (Harmon et al., 2016).
3
Table 1.2 Strategies to enhance the solubility of drugs with poor water-solubility
1.2 Solid dispersion systems
Solid dispersion (SD) refers to the dispersion of a drug within a solid matrix, which is usually a polymer or a carrier that can impart hydrophilicity to the system (Baghel et al., 2016). SD improves solubility and dissolution profiles primarily because when a lipophilic drug is dispersed in a hydrophilic carrier, the mean particle size is reduced and wettability is improved (Ghanavati et al., 2017). Furthermore, SD can improve the solubility and dissolution performance of a poorly soluble drug by replacing the crystalline form of the drug with an amorphous one, i.e., by the formation of an amorphous solid dispersion.
1.3 Classification of solid dispersions
Solid dispersion (SD) can be classified according to the physical states of the carrier and drug as summarized in Table 1.3. Different SD terms have been coined at different time points of researching on SD. The earliest description of SD was termed as Eutectics by Chiou and Riegelman in 1976. Later, extensive research about SD have been carried out which further classified the SD systems into amorphous precipitations of a drug in a crystalline carrier, solid solutions, glass suspensions and
Chemical Modification Physical Modification
Salt formation Reduction of particle size
Formation of prodrug Solid dispersion
Complexation Solubilization
Modification of solid form
4
glass solutions. These different types of SD will be briefly introduced in the subsequent subsections.
Table 1.3 Different categories of solid dispersion according to the physical states of the carrier matrix and API.
Types of solid dispersion Matrix Drug Phases
I Eutectics C C 2
II Amorphous precipitates in crystal matrix C A 2
III Solid solutions C M -
Continuous VS. discontinuous C M 1 or 2
Substitutional VS. interstitial C M 1 or 2
IV Glass suspension A C/A 2
V Glass solution A M 1
C= Crystal, A= Amorphous, M= Molecularly dispersed
5 1.3.1 Simple eutectic mixture
A eutectic mixture is defined as a mixture of two or more components which usually do not interact to form a new chemical compound but, which at certain ratios, inhibit the crystallization process of one another resulting in a system having a lower melting point than either of the components (Sekharan et al., 2019). Eutectic mixtures, can be formed between Active Pharmaceutical Ingredients (APIs), between APIs and excipient or between excipient; thereby providing a vast scope for its applications in pharmaceutical industry. Eutectic mixture formation is usually, governed by following factors (Shaikh Siraj et al., 2019): (a) the components must be miscible in liquid state and mostly immiscible in solid state, (b) Intimate contact between eutectic forming materials is necessary for contact induced melting point depression, (c) the components should have chemical groups that can interact to form physical bonds such has intermolecular hydrogen bonding etc., (d) the molecules hich are in accordance o modified Van Hoff eq a ion can form eutectic mixtures.
1.3.2 Solid solution
The erm olid ol ion refer o a olid ol e that is dissolved in a solid solvent, rendering the two components fused together in a homogenous one-phase system. It is noteworthy that solid solutions of poorly soluble drugs and rapidly soluble carriers usually dissolve faster than their corresponding eutectic mixtures.
This disparity is due to the particle size of the drug being reduced to its minimal value in a solid solution (Chiou and Riegelman 1971). Solid solutions can be classified either as continuous or discontinuous, based on drug solubility (Singh et
6
al., 2017). Solid solutions may alternatively be classified based on solute distribution within the crystalline carrier as substitutional or interstitial.
1.3.2 (a) Continuous vs. discontinuous solid solutions
A continuous solid solution is characterized as containing components that are miscible a all proportions. Discontinuous solid solutions, on the other hand, are made up of components that have limited solubility in one another (Leuner and Dressman 2000), though that might not be the case for the entire compositional range. A continuous solid solution is only possible to achieve if it is more favourable for he componen molec le o bond i h differen chemical en i ie han o bond together. Needless to mention, such solid solutions are rare in the pharmaceutical industry because most organic molecules do not behave this way (Shaikh Siraj et al., 2019).
1.3.2 (b) Substitutional vs. interstitial solid solutions
A continuous/discontinuous solid solution can be turned into a substitutional solid solution by replacing the crystalline carrier with a solute. However, as illustrated in Figure 1.1, this process can only occur if the replacement molecules are similar in size to the substituted molecules (Bag et al., 2015). Conversely, interstitial solid solutions, which are formed strictly from discontinuous solutions, may only be ob ained if he ol e molec le are maller han he ol en molec le . Thi condition is needed for the solute molecules to be able to occupy interstitial spaces in the crystalline lattice (Weizman et al., 2013).
7
Figure 1.1 Solid solutions classified based on solute ( ) distribution: (A) Substitutional crystalline solid solution; (B) Interstitial crystalline solid solution.
1.3.3 Glass suspension
A glass suspension can either be crystalline or amorphous (Chan et al., 2015).
A crystalline glass suspension is a two-phase system comprised of drug particles that are dispersed as crystals in an amorphous polymer phase (Semjonov et al., 2017). A glass suspension can be very stable due to the drug being in the crystalline form. On the other hand, an amorphous glass suspension consists of a drug in the amorphous state dispersed in an amorphous polymer phase. Such a system may not be molecularly dispersed and can undergo rapid recrystallization (Chan et al., 2015).
1.3.4 Glass solution
A glass solution refers to a system wherein drug molecules are dispersed into an amorphous carrier at the molecular level, producing a homogenous single-phase em. The erm gla deno e abr p q enching of he mel . The di ol ion efficiency of a glass solution is typically much higher than that of lower-energy solid solutions because interactions between similar molecules in a glass solution are less
8
abundant compared with interactions between different chemical species. According to Chan (2013), a glass solution, such as citric acid-PVP, is preferable due to its great dissolution power compared with other SD systems, and its stability. However, a principal disadvantage of glass solutions is that they are more prone to recrystallization under normal storage conditions, making carrier selection more difficult.
1.4 Amorphous form of active pharmaceutical ingredients
As mentioned in the previous section, one of the criteria of categorising the SD is based on physical state of the drug. Theoretically, an amorphous solid dispersion state of drug is more soluble than its crystal counterpart. A summary from the literature search shows that amorphous is a main factor in determining dissolution improvement of most SD research. Therefore, it is crucial to understand the nature of amorphous state and relate its importance to the outcome of dissolution and ultimately bioavailability.
An amorphous state can be obtained through thermodynamic and kinetic pathways. In the thermodynamic pathway, the API is converted to a thermodynamically stable disordered state by heating or dissolving, followed by a rapid change into the amorphous state by quench cooling or solvent evaporation.
Meanwhile, the kinetic pathway requires an increase in the number of crystal defects introduced into the crystalline solid until an amorphous product is formed (Blaabjerg et al., 2017). Generally, a material needs to bypass its thermodynamic tendencies to nucleate and crystallize to become amorphous (Weber et al. 2017). In the kinetic
9
pathway, mechanical activation such as milling is important to induce crystal defects until the amorphous form is obtained (Blaabjerg et al., 2017).
Figure 1.2 Schematic overview of the kinetic and thermodynamic pathways to prepare an amorphous form from a crystalline compound. Retrieved and modified
from Blaabjerg et al., 2017
The melt quenching method is suitable for APIs that are thermally stable when exposed to a temperature slightly above their melting temperature (Genina et al., 2018). In this method, the solid material is melted using heat (above melting temperature) and rapidly cooled to obtain the amorphous form. Supercooling or supersaturation is an important processing step to form the glassy state (Sarabu et al., 2019). Thus, a sufficiently fast cooling rate is required to limit nucleation and crystal growth and ensure the formation of a satisfactory amorphous product (Blaabjerg, et al., 2017). The faster the melted material is cooled, the more disorder the molecular structure will retain. The low temperature used to solidify the molten material may affect the crystallization rate, size and hardness of the crystal (Kumar et al., 2013).
10
Thus, temperature selection at both steps is important to prevent these problems.
Degradation can be prevented by heating the mixture at a temperature slightly higher than the highest melting point of the components.
1.5 Glass forming ability
Glass-forming ability (GFA) is defined as the ease of a material to undergo amorphization. It is determined by the critical cooling rate during melt-quenching when aiming to obtain a complete amorphous form (Blaabjerg et al., 2017). Active pharmaceutical ingredients (APIs) can be classified into three GFA categories based on their behaviours observed during differential scanning calorimetry (undercooled melts). API compounds that directly crystallize in the first cooling cycle are categorized as Class I, while compounds that only crystallize in the second heating cycle fall into Class II. Stable glass formers are classified as Class III, as they remain in an amorphous state upon cooling and display a glass transition temperature in the next heating cycle (Wyttenbach and Kuentz, 2017).
Amorphous materials are recognized by their glass-transition temperature (Tg). In the 1940s, the term reduced glass transition temperature (Trg) was defined as the Tg/Tm ratio, which can be used as an indicator for predicting the GFA of APIs (Blaabjerg et al., 2016). The formula to calculate Trg is as follows (Ueda et al., 2016):
𝑻𝒓𝒈 𝑻𝒈/𝑻𝒎 Equation 1.2
Where Tg is the glass transition temperature and Tm is the melting temperature of the drug. Additionally, the Tm to Tg ratio can be a predictive measure
11
of crystallization. The higher the Tm: Tg ratio, the higher the possibility of crystallization. Thus, APIs with a high Tm and low Tg will have a higher tendency to crystallize. APIs with a high Tm tend to crystallize easily due to their high energy lattice. Meanwhile, APIs with a low Tg will have higher mobility at room temperature, meaning that the chance of crystallization is higher (Kanaujia et al., 2015). However, using Tg as predictor of GFA may not be applicable to some compounds that do not exhibit a measurable glass transition, such as fast crystallizing compounds (Class I). Thus, an attractive alternative approach to predict the GFA for these compounds is by using in silico predictors. This method is also helpful to determine the GFA when the thermodynamic categorization is not available due to thermal instability (Wyttenbach and Kuentz, 2017)
The instability of amorphous materials with high energy states causes them to recrystallize during long-term storage, during the manufacturing process or in the gastrointestinal tract after oral ingestion, which will reduce their solubility under these conditions (Ueda et al., 2016). To prevent recrystallization, the molecular mobility of an amorphous form should be minimized. This is because the amorphous form of an API is thermodynamically unstable and tends to convert into a more stable crystalline form. The mobility of amorphous molecules increases above the Tg; thus, to maintain its amorphous form, it should be stored 50°C below the Tg. It is difficult to maintain finished API products at the API amorphous form Tg, which usually varies from -20°C to 80°C. Therefore, incorporation of a carrier is relevant and convenient for maintaining amorphous form stability (Kanaujia et al., 2015).
Solid dispersion is the most common technique used to improve solubility and overcome the instability problem (Ueda et al., 2016).
12 1.6 Carriers used in solid dispersions
One of the most important steps in an SD preparation is the selection of the carrier. The properties of the carrier determine the parameters to be used during b eq en proce e . The e proper ie al o pla a role in haping he dr g relea e profile, potential drug-carrier interactions, as well as the stability of the system.
Different carrier choices can lead to different melting points, glass transition temperatures and molecular weights (Khan et al., 2015).
In general, an ideal carrier for use in an SD system is pharmacologically inert (non-toxic) with a high molecular weight (MW) and a high glass transition temperature (Tg). The carrier needs to improve the solubility of the drug; therefore, the carrier should have no nucleation capacity and low hygroscopicity, and it must not form strong complexes with drug molecules (Guan et al., 2018, Pas et al., 2018) . Table 1.4 shows examples of polymers that are used as carriers in SD systems.
Table 1.4 List of carriers used in solid dispersions [Adapted from (Vasconcelos et al., 2016)]
Chemical
Classification Potential Carriers
Acids Citric acid, phosphoric acid, tartaric acid, succinic acid.
Sugars Mannitol, lactose, sucrose, maltose, soluble starch, chitosan, sorbitol, dextrose
Polymeric material HPMC, PEG 4000, PEG 6000, cyclodextrin, ethyl cellulose, Eudragit®, methyl cellulose, xanthan gum Surfactants Tweens and spans, poloxamer, polyethylene stearate.
13 1.7 Preparation of solid dispersions
As previously mentioned, there are several ways to prepare an SD system, the most common of which are spray drying, fusion (Hot-Melt) and the solvent method.
The subsequent paragraphs outline the principles of each preparation method.
1.7.1 Spray Drying
Spray drying has evolved dramatically since it was first used in the US 140 years ago. This process is a widely used approach to produce SD systems (Patil, Chauhan et al. 2014). Spray drying operates on the principle of moisture removal through controlled heating and feeding (Patil, Chauhan et al. 2014) and is comprised of a series of steps. Briefly, a liquid (solution, suspension or emulsion) is transferred at a constant rate to be divided into small droplets in a process called atomization. The droplets are released into a hot glass chamber where they are converted to fine dried particles. Next, the particles are separated from the drying gas using a cyclone or a bag filter. Compared with other drying methods, such as melt extrusion, spray drying is considered a gentle drying process. In any spray drier, the following four distinct steps can be observed: (1) feed solution atomization into fine droplets, (2) spray contact with hot gas, (3) evaporation and (4) particle separation.
Several parameters can be adjusted prior to the spray drying process to achieve a predetermined size and shape of SD particles, as well as a desirable degree of miscibility between the drug and the carrier.
14 1.7.2 Fusion method (Hot-Melt method)
The Hot-Melt method involves a starting material that is crystalline in nature.
This technique allows for a melting form of the drug to be incorporated within a carrier to obtain a stable amorphous drug form. An API melt is prepared by heating the drug slightly above its melting point. Next, a homogenous drug-carrier mixture is produced with continuous stirring and gradual cooling (Djuris et al., 2013). Stirring is continued until the mixture is cooled to room temperature or to the temperature of the cooling water bath. The resultant product is then sieved and stored until further use. The improvement of dissolution achieved in this method depends upon the solubility of the drug within the carrier. The Hot-Melt technique is especially useful for drugs with a high melting point. The primary advantages that this technique offers is that it is solvent-free, fast and easy to perform. Thus, the Hot-Melt technique has many applications in the pharmaceutical industry (Kyeremateng et al., 2014).
1.7.3 Solvent method
An SD system can be created using a technique called the solvent method, which involves dissolving both the drug and the carrier in an organic solvent to form a clear solution. The solution is evaporated using heat alone or a combination of heat and vacuum pressure. The dried product undergoes milling and sieving to generate the required SD system (Homayouni et al., 2015), which can be stored until further use. However, the solvent method is not preferable in the pharmaceutical industry because the solvent may fail to completely evaporate during the preparation process, thereby leaving toxic residues along with the SD system (Sharma et al., 2016).
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Although certain techniques, such as DSC, TGA and DTA, can be used to ensure the complete evaporation of the solvent, the solvent method has another shortcoming;
this method is only applicable to thermostable drugs and polymers with a high melting point.
1.8 Advantages of solid dispersions
There are several advantages to SD systems (Figure 1.3), which explains the high interest in the field. In addition to enhancing dissolution performance, SD systems, such as morphine-tristearin, can be quite useful for inhibiting systemic drug metabolism by deactivating certain enzymes that are responsible for drug biotransformation (Cui et al., 2013). Such inhibition decreases the dose required to achieve a therapeutic level.
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Figure 1.3 Pharmaceutical applications of solid dispersions
1.9 Factors affecting dissolution rate of SD
The dissolution profile of a poorly soluble drug can be enhanced through SD preparation. However, it is difficult to identify the primary factor behind such dissolution improvement, as several factors are usually at play. Based on literature search, the enhanced dissolution may be attributed to particle size reduction, drug porosity enhancement, wettability improvement, drug crystallinity reduction and/or processing condition.
17 1.9.1 Particle size reduction
During the preparation process, the size of the particles of an SD system is reduced. This phenomenon is especially clear when the drug is molecularly dispersed in the carrier, and in the case of glass and solid solutions. Particle size reduction leads to an improved dissolution rate due to the increased surface area and exposure to the dissolution media. The Kelvin equation provides a mathematical interpretation of the relationship between particle size and dissolution activity (Rouquerol et al., 2013), as follows:
𝒍𝒏 𝒂ₒ𝒂) 𝟐𝒚 ⊽
𝑹𝑻𝒓 (Equation 1.3)
; where = ratio of activity increase over a decrease in a large crystal r = crystal radius
y = surface area/energy of the crystal V = molar volume
T= temperture in Kelvin
This equation clarifies how a large surface area may be responsible for improvements in the dissolution performance of an SD system. However, a small particle size may also be equally important to prevent the recrystallization of an SD system.
1.9.2 Increased drug porosity
Particles in solid dispersion have been found to have high porosity (Kaur et al., 2016). The increased porosity of solid dispersion particles hastens
18
the drug release. Increase in porosity depends on carrier properties, i.e., linear polymers result in larger and more porous particles than that of reticular particles.
1.9.3 Polymorphs
The capacity for a substance to crystallize in more than one crystalline form is polymorphism. It is possible that all crystals can crystallize in different forms or polymorphs. If the change from one polymorph to another is reversible, the process is called enantiotropy. If the system is monotropic, there is a transition point above the melting points of both polymorphs. The two polymorphs cannot be converted from one to another without undergoing a phase transition. Polymorphs can vary in melting point. Since the melting point of the solid is related to solubility, so polymorphs will have different solubilities. Generally, the difference in solubility between different polymorphs is only 2-3 folds due to relatively small differences in free energy.
1.9.4 Improved wettability
The carrier choice for an SD system can result in improved drug wettability.
For example, the dissolution performance of a piroxicam SD system was shown to be improved with the use of PVP as the carrier due to its hydrophilic nature, which causes a decrease in surface tension and increased wettability (Lust et al., 2015).
Improved wettability can indirectly lead to improved dissolution, namely, by preventing particle agglomeration and increasing the surface area of drug particles that are exposed to the dissolution media.
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According to Song (2011), felodipine low dissolution rate was markedly improved when it was incorporated into an SD system using a hydrophilic polymer.
Another study showed that the polymers PEG 6000 and HPMC increased the dissolution performance of the API, as they created a favourable microenvironment.
Essentially, these polymers positioned themselves at high concentrations around the drug molecules.
Craig (2002) notes that in an SD system, a polymer forms a layer around the formulation, in which the drug dissolves upon contact with the dissolution media prior to being released (Marano et al., 2017). Jasmine et al (2015), demonstrated that the strong hydrophilic nature of PVP K90 improves water penetration to dissolve the hydrophobic molecule gliclazide more rapidly.
20 1.9.6 Decrease drug crystallinity
As mentioned earlier, the amorphous form of a drug generally exhibits higher solubility compared with the crystalline form, even within the same SD system. This phenomenon is because an amorphous state does not necessitate energy to breakdown strong bonds, as may be the case with a crystalline lattice. However, despite being more soluble, the amorphous drug form presents a major challenge, as it lacks the stability of the crystalline form.
1.9.7 Processing and storage conditions
The highest dissolution performance of an SD system can be obtained using an amorphous form of the components. Unfortunately, amorphous particles have a high tendency to undergo a transition into crystalline forms, which may be triggered by the temperature and humidity of their surroundings. This property renders the dissolution rate of an SD system dependent on the selection of the SD technique used and storage conditions. The cooling rate used in the Hot-Melt method, for instance, can influence the efficacy of the final SD product, because extended cooling may trigger rearrangements in amorphous particles and the creation of crystal nuclei.
Similarly, the solvent method is known to cause amorphous particles to undergo conversion into the crystalline form upon contact with the solvent. Moreover, compression and pulverisation during SD preparation may prompt particles to change into a more stable crystalline form.
21 1.10 Problem statement
The dissolution enhancement of SD systems has been demonstrated in many previous studies. However, some studies showed SD that did not significantly improve dissolution. Chan et al., 2016 revealed that SD formulation had little or no effect on the dissolution rates of Ketoprofen and naproxen. This implies that not all drugs produce improved dissolution performance after formulated as SD system.
The properties of drug/ carrier or factor that lead to the improved dissolution performance of SD system is still poorly understood. These have led to lack of commercial interest in the production of SD formulations, primarily because of multiple challenges pertaining to preparation, reproducibility, formulation, upscaling and stability of the final product.
SD techniques evolve with the discovery of new surfactants and emulsifying agents that can serve as carriers. Hence, researchers are encouraged to focus on investigating new carriers with valuable properties, as well as improving on existing carriers to enable their oral and topical usage. More carrier options may increase the chances of formulating better SD dosage forms in the future. Furthermore, efforts should be directed towards improving the stability of SD systems. The identification and assessment of new excipients and additives that may retard the conversion of amorphous forms into undesirable crystalline forms are key objectives.
Crystallization of an amorphous drug is a primary factor that can influence SD physical stability. Crystallization is a process that consists of the following two stages: nuclei formation and crystal growth (Markov et al., 2016). Both stages require mobile molecules that can form crystal nuclei and attach to one another to grow. Thus, molecular mobility is a key factor in crystallization and has a direct impact on the stability of SD systems. Several studies have shown that ASD
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(amorphous solid dispersion) systems have a tendency to convert into the crystalline form and exhibit reduced dissolution performance with ageing.
Moisture and temperature are the most powerful factors that influence SD dissolution performance during storage. An early investigation of the stability of an indomethacin-PEG-6000 SD system showed a marked change in the dissolution profile and tablet colour of the system when it was stored at a temperature range of 25-41 ºC and an RH level of 71% due to the crystallization of indomethacin (Semjonov et al., 2017). The presence of active functional groups, such as carboxyl and hydroxyl moieties, in SD systems was recently shown to help reduce the risk of recrystallization upon storage (Christina et al., 2015). This phenomenon demonstrates the importance of polymer selection, as it may be a parameter that affects SD stability and the production of a completely miscible drug-carrier system.
Interestingly, stability issues may be overcome in certain cases by storing SD products at a temperature lower than their Tg values. This practice is believed to significantly lower molecular mobility and recrystallization tendencies.
1.11 Scope of the study
Many researchers have reported the advantages of SD system, especially with regard to the dissolution enhancement of BCS class II drugs. However, ASD systems appear to pose greater risk of recrystallization and agglomeration compared with physical mixtures of class II drugs and hydrophilic carriers. This risk is the primary reason why there are no more than 15 SD products available in the market (Chan et al., 2015).
