xvi LIST OF TABLES S.NO Title of the Table Page No CHAPTER 2 2.1 Composition of zolmitriptan formulations 55 2.2 Powder flow properties and angle of repose 58 2.3 Uniformity of weight 59 2.4 Calibration curve of zolmitriptan in 0.1N HCl 65 2.5 Calibration curve of zolmitriptan in mixture of buffer and acetronitrile (90%:10%) 67 2.6 Zolmitriptan method validation parameters 68 2.7 Powder flow properties of the zolmitriptan formulations 69 2.8 Evaluation tests of sublingual tablets of zolmitriptan 70 2.9 Evaluation tests of sublingual tablets of zolmitriptan 71 2.10 Evaluation tests of sublingual tablets of zolmitriptan 73 2.11 In vitro release profile of the zolmitriptan formulations 74 2.12 Effect of storage of formulation F9 at 40±2⁰C/ 75±5% RH 83 CHAPTER-3 3.1 Information for zolmitriptan sublingual tablet 85 3.2 Information for zolmitriptan IV injection 85 3.3 Study design for rabbit pharmacokinetic study 89
xvii 3.4 Preparation of calibration curve stock dilutions 92 3.5 Preparation of spiking solution dilutions 92 3.6 K 2EDTA rabbit plasma for calibration curve standards 93 3.7 Quality Control samples preparation 94 3.8 Preparation of quality control stock dilutions 94 3.9 Preparation of quality control spiking solutions 95 3.10 Detection parameters 98 3.11 Standard curve concentrations (ng/ml) precision and accuracy 102 3.12 In study-validation quality control samples (ng/ml) 103 3.13 Individual animal serum concentration (ng/ml) of zolmitriptan following sublingual administration (5mg/tablet) 104 3.14 Individual animal serum concentration (ng/ml) of zolmitriptan following intravenous administration (5mg/kg) 105 3.15 Body weights of individual and dose volume of zolmitriptan sublingual tablet and IV administration given to New Zealand rabbits 106 3.16 Pooled concentration (ng/ml) versus time data for zolmitriptan following sublingual tablet administration to New Zealand rabbits at the dose of 5mg of tablet per each rabbit 107 3.17 Mean serum concentration (ng/ml) of zolmitriptan following sublingual administration (5mg/tablet) 108 3.18 Pooled concentration (ng/ml) versus time data for zolmitriptan
xviii following intravenous administration (5mg/kg) 109 3.19 Mean serum concentration (ng/ml) of zolmitriptan following intravenous administration (5mg/kg) 110 3.20 Pharmacokinetic parameters of zolmitriptan sublingual tablets In rabbits following administration of optimised zolmitriptan sublingual tablets (F9) and intravenous administration 112 CHAPTER-4 4.1 Composition of the rizatriptan sublingual formulations. 122 4.2 Powder flow properties and angle of repose 125 4.3 Uniformity of weight 127 4.4 Standard graph of rizatriptan in water at 282nm 133 4.5 Calibration curve of rizatriptan benzoate in mixture of buffer (ph3.5) and acetonitrile (80:20) 135 4.6 Rizatriptan benzoate method validation parameters 136 4.7 Powder flow properties of the rizatriptan benzoate formulations 138 4.8 Evaluation tests of sublingual tablets rizatriptan 139 4.9 Evaluation tests of sublingual tablets rizatriptan 140 4.10 Evaluation tests of sublingual tablets rizatriptan. 142 4.11 In vitro drug release profiles of the rizatriptan benzoate tablet formulations 143 4.12 Effect of storage of formulation F9 at 40±2⁰C/75±5% RH 151
xix CHAPTER-5 5.1 Information for rizatriptan sublingual tablets 153 5.2 Information for rizatriptan oral tablets 153 5.3 Study design for rabbit pharmacokinetic study 157 5.4 Preparation of calibration stock dilutions 160 5.5 Dilutions of spiking solution 160 5.6 K 2EDTA Rabbit plasma for CC standards 161 5.7 Quality Control (QC) samples preparation 162 5.8 Preparation of quality control stock dilutions 162 5.9 Preparation of quality control spiking solutions 164 5.10 Detection parameters 167 5.11 Calibration curve concentrations (ng/ml) accuracy and Precision 170 5.12 In study-validation quality control samples (ng/ml) 171 5.13 Individual animal serum concentration (ng/ml) of rizatriptan following sublingual administration (10mg/tablet) 172 5.14 Individual animal serum concentrations (ng/ml) of rizatriptan following oral administration (10 mg/tablet) 173 5.15 Individual body weight and dose volume of rizatriptan sublingual tablet and oral administration given to New Zealand rabbits. 174 5.16 Pooled concentration (ng/ml) versus time data for rizatriptan following sublingual tablet administration to New Zealand rabbits at the dose of 10 mg of tablet per each rabbit 175
xx 5.17 Mean serum concentration (ng/ml) of rizatriptan following sublingual administration (10mg/tablet) 176 5.18 Pooled concentration (ng/ml) versus time data for rizatriptan following oral tablet administration (10mg/tablet) 177 5.19 Mean serum concentration (ng/ml) of rizatriptan following oral administration (10mg/tablet) 178 5.20 Pharmacokinetic parameters of rizatriptan sublingual tablets in rabbits following administration of optimised rizatriptan sublingual tablets (F9) and oral rizatriptan marketed tablets (10mg/tablet) 180
xxi LIST OF FIGURES S.NO Title of the Figures Page No CHAPTER -2 2.1 Calibration curve of zolmitriptan in 0.1N HCl 65 2.2 Typical chromatogram of zolmitriptan 66 2.3 Calibration curve of zolmitriptan in mixture of buffer and acetronitrile (90%:10%) 67 2.4 Comparison of dissolution of F1, F2 and F3 zolmitriptan formulations containing 2%, 4% and 6% of sodium starch glycollate 75 2.5 Comparison of dissolution of F4, F5and F6 zolmitriptan formulations containing 2%, 4% and 6% of croscarmellose sodium. 76 2.6 Comparison of dissolution of F7, F8 and F9 zolmitriptan formulations containing 2%, 4% and 6% of crospovidone. 77 2.7 Scanning Electron Microscope images of a) zolmitriptan standard b) zolmitriptan sublingual tablets 78 2.8 DSC thermo grams of a) placebo (tablet) b) physical mixture without drug c) Physical mixture with drug d) sublingual zolmitriptan tablets e) zolmitriptan standard. 79 2.9 Powder X-ray diffraction studies of a) zolmitriptan sublingual tablets b) zolmitriptan physical mixture with drug c) zolmitriptan standard. 80
xxii 2.10 FTIR spectra of a) placebo b) physical mixture without drug c) physical mixture with drug d) zolmitriptan standard e) sublingual zolmitriptan tablets. 82 CHAPTER-3 3.1 Calibration curve of zolmitriptan 99 3.2 Chromatograms of rabbit blank plasma and rabbit blank plasma with internal standard. 100 3.3 Study sample chromatograms of zolmitriptan along with internal standard. 101 3.4 Plasma concentration time curve of zolmitriptan sublingual tablets and intravenous (zolmitriptan standard) administration. 112 3.5 Mean serum concentrations (ng/ml) of zolmitriptan across the time points following sublingual administration (5mg/tablet). 113 3.6 Mean serum log concentrations of zolmitriptan across the time points following sublingual administration(5mg/kg) 113 3.7 Mean serum concentrations (ng/ml) of zolmitriptan across the time points following intravenous administration (5mg/kg) 114 3.8 Mean serum Log concentrations of zolmitriptan across the time points following intravenous administration (5mg/kg) 114
xxiii CHAPTER-4 4.1 Standard graph of rizatriptan in water at 282nm 133 4.2 Typical chromatogram of rizatriptan benzoate in mixture of buffer (3.5) and acetonitrile 134 4.3 Calibration curve of rizatriptan benzoate in mix. buffer (ph3.5) and acetronitrile (80:20) 135 4.4 Comparison of dissolution of F1, F2 and F3 rizatriptan formulations containing 2%, 4% and 6% of sodium starch glycollate 144 4.5 Comparison of dissolution of F4, F5and F6 rizatriptan formulations containing 2%, 4% and 6% of croscarmellose sodium. 145 4.6 Comparison of dissolution of F7, F8 and F9 rizatriptan formulations containing 2%, 4% and 6% of crospovidone. 146 4.7 Scanning Electron Microscope images of a) Rizatriptan standard b) Rizatriptan sublingual tablets. 147 4.8 DSC thermo grams of a) placebo (tablet) b) Rizatriptan Physical mixture with drug c) Sublingual Rizatriptan tablets d) Rizatriptan standard. 148 4.9 Powder X-ray diffraction patterns of a) Rizatriptan sublingual tablets b) Rizatriptan physical mixture with drug c) Rizatriptan standard. 149 4.10 FT-IR spectra of a) placebo (tablet) b) Physical mixture without drug c) Physical mixture with drug d) Rizatriptan standard e) Sublingual Rizatriptan tablets. 150
xxiv CHAPTER-5 5.1 Calibration curve of rizatriptan 168 5.2 Chromatograms of blank plasma and blank plasma of rabbit with internal standard. 169 5.3 Study sample chromatograms of rizatriptan along with internal standard. 169 5.4 The plasma concentration time curve of rizatriptan sublingual tablets and oral (marketed formulation) administration. 181 5.5 Mean serum concentrations (ng/ml) of rizatriptan across the time points following sublingual administration (10 mg/tablet) 182 5.6 Mean serum log concentrations of rizatriptan across the time points following sublingual administration (10 mg/tablet) 183 5.7 Mean serum concentrations (ng/ml) of rizatriptan across the time points following oral administration (10mg/tablet) 184 5.8 Mean serum log concentrations of rizatriptan across the time points following oral administration (10 mg/tablet) 185
xxv LIST OF MATERIALS S.NO Drugs and Chemicals Source 1 Zolmitriptan A gift sample from Suven Pharma Limited, Hyderabad, India 2 Rizatriptan Benzoate A gift sample from Natco Pharma Limited, Hyderabad, 3 Sodium starch Cheminova Remedies, Hyderabad, Glycolate 4 Croscarmellose Cheminova Remedies, Hyderabad, Sodium 5 Crospovidone Cheminova Remedies, Hyderabad, 6 Avicel ph102 Cheminova Remedies, Hyderabad, 7 Mannitol Cheminova Remedies, Hyderabad, 8 Aspartame Cheminova Remedies, Hyderabad, 9 Magnesium stearate Cheminova Remedies, Hyderabad, 10 Hydrochloric acid SD Fine Chemicals, 11 Acetonitrile HPLC Qualigens, 12 Sodium dihydrogen SD Fine Chemicals, orthophosphate monohydrate
xxvi 13 Orthophosphoric SD Fine Chemicals, acid 14 Triethylamine SD Fine Chemicals, 15 potassium SD Fine Chemicals, dihydrogen orthophosphate 16 Formic acid SD Fine Chemicals, 17 Methanol HPLC Qualigens, 18 Diethyl ether SD Fine Chemicals, 19 Dichloromethane Qualigens, 20 HPLC Water SD Fine Chemicals,
xxvii LIST OF EQUIPMENT S.NO Name of the equipment Manufacturer 1 Tablet Punching Machine Mini Press-11MT, Rimek, 2 Vernier Callipers Mututoyo, Japan. 3 Tap Density Tester Electrolab ETD-1020, USA. 4 Hardness Tester Tab machines, 5 Friabilator Electro lab, 6 Disintegration Tester Lab India, ED-2AL, 7 Dissolution Test Apparatus Lab India, DS 14000, 8 UV-Visible Schimadzu, UV1601, Japan. Spectrophotometer 9 High Performance Liquid HPLC, Agilent 1100 series, USA Chromatography 10 Scanning Electron JEOL 5400, Japan. Microscopy 11 Differential Scanning DSC 6, Perkin Elmer, USA. Calorimeter 12 X-Ray Powder Diffractometer XRD x pert PRO MPD Panalytical, USA. 13 FT-IR Spectrophotometer Perkin Elmer Spectrum one Series, USA. 14 Centrifuge Thermo Scientific X3R, USA
xxviii 15 LC-MS/MS system Perkin Elmer PE 200 series and containing HPLC mass Spectrophotometer, API, 2000, USA. 16 Multi Tube Vortexer VWR (VX-2500) 17 Electronic Balance Shimadzu, BL 220H. 18 Electronic Balance Mettler-Toledo (XS 205) 19 Turbo Evaporator Zymark, TV0351N12082 20 Centrifuge Heraeus, 40564869 21 Deep Freezer (-20⁰C) Carrier, 5.00057E+15 22 Vertex Mixer IKA, MS3 23 Animal Weighing Balance Sartorius, SIWADCP 24 Biosafety Cabinet Lanconco Corporation, 3413 25 Pipettes Fischer scientific, FJ10269 26 Pipettes Fischer Scientific, FK08755 27 Animal Weighing Balance Sartorius, MSA225S-100-DA 28 Stability Chamber Thermo Lab, USA