xvi LIST OF TABLES S.NO Title of the Table Page No 2.1 Composition of zolmitriptan formulations Powder flow properties and angle of repose 58

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1 xvi LIST OF TABLES S.NO Title of the Table Page No CHAPTER Composition of zolmitriptan formulations Powder flow properties and angle of repose Uniformity of weight Calibration curve of zolmitriptan in 0.1N HCl Calibration curve of zolmitriptan in mixture of buffer and acetronitrile (90%:10%) Zolmitriptan method validation parameters Powder flow properties of the zolmitriptan formulations Evaluation tests of sublingual tablets of zolmitriptan Evaluation tests of sublingual tablets of zolmitriptan Evaluation tests of sublingual tablets of zolmitriptan In vitro release profile of the zolmitriptan formulations Effect of storage of formulation F9 at 40±2⁰C/ 75±5% RH 83 CHAPTER Information for zolmitriptan sublingual tablet Information for zolmitriptan IV injection Study design for rabbit pharmacokinetic study 89

2 xvii 3.4 Preparation of calibration curve stock dilutions Preparation of spiking solution dilutions K 2EDTA rabbit plasma for calibration curve standards Quality Control samples preparation Preparation of quality control stock dilutions Preparation of quality control spiking solutions Detection parameters Standard curve concentrations (ng/ml) precision and accuracy In study-validation quality control samples (ng/ml) Individual animal serum concentration (ng/ml) of zolmitriptan following sublingual administration (5mg/tablet) Individual animal serum concentration (ng/ml) of zolmitriptan following intravenous administration (5mg/kg) Body weights of individual and dose volume of zolmitriptan sublingual tablet and IV administration given to New Zealand rabbits 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 Mean serum concentration (ng/ml) of zolmitriptan following sublingual administration (5mg/tablet) Pooled concentration (ng/ml) versus time data for zolmitriptan

3 xviii following intravenous administration (5mg/kg) Mean serum concentration (ng/ml) of zolmitriptan following intravenous administration (5mg/kg) Pharmacokinetic parameters of zolmitriptan sublingual tablets In rabbits following administration of optimised zolmitriptan sublingual tablets (F9) and intravenous administration 112 CHAPTER Composition of the rizatriptan sublingual formulations Powder flow properties and angle of repose Uniformity of weight Standard graph of rizatriptan in water at 282nm Calibration curve of rizatriptan benzoate in mixture of buffer (ph3.5) and acetonitrile (80:20) Rizatriptan benzoate method validation parameters Powder flow properties of the rizatriptan benzoate formulations Evaluation tests of sublingual tablets rizatriptan Evaluation tests of sublingual tablets rizatriptan Evaluation tests of sublingual tablets rizatriptan In vitro drug release profiles of the rizatriptan benzoate tablet formulations Effect of storage of formulation F9 at 40±2⁰C/75±5% RH 151

4 xix CHAPTER Information for rizatriptan sublingual tablets Information for rizatriptan oral tablets Study design for rabbit pharmacokinetic study Preparation of calibration stock dilutions Dilutions of spiking solution K 2EDTA Rabbit plasma for CC standards Quality Control (QC) samples preparation Preparation of quality control stock dilutions Preparation of quality control spiking solutions Detection parameters Calibration curve concentrations (ng/ml) accuracy and Precision In study-validation quality control samples (ng/ml) Individual animal serum concentration (ng/ml) of rizatriptan following sublingual administration (10mg/tablet) Individual animal serum concentrations (ng/ml) of rizatriptan following oral administration (10 mg/tablet) Individual body weight and dose volume of rizatriptan sublingual tablet and oral administration given to New Zealand rabbits 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

5 xx 5.17 Mean serum concentration (ng/ml) of rizatriptan following sublingual administration (10mg/tablet) Pooled concentration (ng/ml) versus time data for rizatriptan following oral tablet administration (10mg/tablet) Mean serum concentration (ng/ml) of rizatriptan following oral administration (10mg/tablet) Pharmacokinetic parameters of rizatriptan sublingual tablets in rabbits following administration of optimised rizatriptan sublingual tablets (F9) and oral rizatriptan marketed tablets (10mg/tablet) 180

6 xxi LIST OF FIGURES S.NO Title of the Figures Page No CHAPTER Calibration curve of zolmitriptan in 0.1N HCl Typical chromatogram of zolmitriptan Calibration curve of zolmitriptan in mixture of buffer and acetronitrile (90%:10%) Comparison of dissolution of F1, F2 and F3 zolmitriptan formulations containing 2%, 4% and 6% of sodium starch glycollate Comparison of dissolution of F4, F5and F6 zolmitriptan formulations containing 2%, 4% and 6% of croscarmellose sodium Comparison of dissolution of F7, F8 and F9 zolmitriptan formulations containing 2%, 4% and 6% of crospovidone Scanning Electron Microscope images of a) zolmitriptan standard b) zolmitriptan sublingual tablets DSC thermo grams of a) placebo (tablet) b) physical mixture without drug c) Physical mixture with drug d) sublingual zolmitriptan tablets e) zolmitriptan standard Powder X-ray diffraction studies of a) zolmitriptan sublingual tablets b) zolmitriptan physical mixture with drug c) zolmitriptan standard. 80

7 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 Calibration curve of zolmitriptan Chromatograms of rabbit blank plasma and rabbit blank plasma with internal standard Study sample chromatograms of zolmitriptan along with internal standard Plasma concentration time curve of zolmitriptan sublingual tablets and intravenous (zolmitriptan standard) administration Mean serum concentrations (ng/ml) of zolmitriptan across the time points following sublingual administration (5mg/tablet) Mean serum log concentrations of zolmitriptan across the time points following sublingual administration(5mg/kg) Mean serum concentrations (ng/ml) of zolmitriptan across the time points following intravenous administration (5mg/kg) Mean serum Log concentrations of zolmitriptan across the time points following intravenous administration (5mg/kg) 114

8 xxiii CHAPTER Standard graph of rizatriptan in water at 282nm Typical chromatogram of rizatriptan benzoate in mixture of buffer (3.5) and acetonitrile Calibration curve of rizatriptan benzoate in mix. buffer (ph3.5) and acetronitrile (80:20) Comparison of dissolution of F1, F2 and F3 rizatriptan formulations containing 2%, 4% and 6% of sodium starch glycollate Comparison of dissolution of F4, F5and F6 rizatriptan formulations containing 2%, 4% and 6% of croscarmellose sodium Comparison of dissolution of F7, F8 and F9 rizatriptan formulations containing 2%, 4% and 6% of crospovidone Scanning Electron Microscope images of a) Rizatriptan standard b) Rizatriptan sublingual tablets DSC thermo grams of a) placebo (tablet) b) Rizatriptan Physical mixture with drug c) Sublingual Rizatriptan tablets d) Rizatriptan standard Powder X-ray diffraction patterns of a) Rizatriptan sublingual tablets b) Rizatriptan physical mixture with drug c) Rizatriptan standard 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

9 xxiv CHAPTER Calibration curve of rizatriptan Chromatograms of blank plasma and blank plasma of rabbit with internal standard Study sample chromatograms of rizatriptan along with internal standard The plasma concentration time curve of rizatriptan sublingual tablets and oral (marketed formulation) administration Mean serum concentrations (ng/ml) of rizatriptan across the time points following sublingual administration (10 mg/tablet) Mean serum log concentrations of rizatriptan across the time points following sublingual administration (10 mg/tablet) Mean serum concentrations (ng/ml) of rizatriptan across the time points following oral administration (10mg/tablet) Mean serum log concentrations of rizatriptan across the time points following oral administration (10 mg/tablet) 185

10 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

11 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,

12 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

13 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, TV0351N Centrifuge Heraeus, Deep Freezer (-20⁰C) Carrier, E Vertex Mixer IKA, MS3 23 Animal Weighing Balance Sartorius, SIWADCP 24 Biosafety Cabinet Lanconco Corporation, Pipettes Fischer scientific, FJ Pipettes Fischer Scientific, FK Animal Weighing Balance Sartorius, MSA225S-100-DA 28 Stability Chamber Thermo Lab, USA