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ABBREVIATIONS % = percentage TGA= Thermogravimetric Analysis µg/ml = microgram/milliliter IR= Infrared Spectroscopy µm = micrometer(s) NIR/NIRS= Near infrared Spectroscopy BP = British pharmacopoeia CCD= charge-coupled device CAS = Chemical Abstracts Service KSM= Key starting material ACN= Acetonitrile M = Molarity CNS = Central Nervous System mM = Millimolar OPA= Orthophosphoric Acid Min = minute TEA= Triethylamine ml/min = milliliter/minute FDA = Food and Drug NF = National Formulary Administration RC= Related Compound KH2PO4= Potassium dihydrogen NMR = Nuclear Magnetic Resonance Orthophosphate MS= Mass spectroscopy GERD = Gastro Esophageal Reflux GC= Gas Chromatography Disease KBr= Potassium Bromide Gms/mol = grams/mole PPM/ppm= Parts per Million HCl = Hydrochloride pH = Power of Hydrogen i.d = internal diameter PO4 = phosphate JP = Japanese Pharmacopoeia q.s = quantity sufficient LC = Liquid Chromatography r = Correlation coefficient LOQ = Limit of Quantitation RP = Reverse Phase QL = Quantitation limit S/N =signal-to-noise ratio °C = degree Celsius /Centigrade v/v = volume in volume AR =Analytical (Grade) Reagent mcg =microgram AUC = Area Under Curve mg = milligram Gm = gram ml/mL = milliliter mm = millimeter IP = Indian Pharmacopoeia LOD = Limit of Detection DL = Detection limit DSC= Differential Scanning N = Theoretocal plates Nm = nano meter ODS =OctaDecyl Silane PDA= Photodiode arra Detector Calorimetry Page 6 of 305 PF = Pharmacopeial Forum Ph.Eur = European Pharmacopoeia PPIs = Proton-pump Inhibitors PUD =Peptic Ulcer Disease r2 = Linear regression RSD = Relative Standard Deviation SD = Standard Deviation UV = Ultra violet µg = microgram(s) ρ = rho OQ = Operational Qualification MQ = Maintenance Qualification HPLC = High Performance /Pressure Liquid Chromatography ICH = International Conference on Harmonization USP = United States of Pharmacopoeia IQ = Installation Qualification PQ = Performance Qualification S = Slope LED= Light emitting diode Page 7 of 305 CONTENTS No Page Chapter 1- General Introduction Introduction 1 Instrumental Analysis 1 Pharmaceutical analysis 2 Combination drug products 3 Drug –Drug chemical interactions 3 High Performance Liquid Chromatography (HPLC) 7 Ultra Performance Liquid chromatography (UPLC) 17 Polymorphism in pharmaceutical solids 19 Method development by HPLC 22 Analytical method validation 25 References 31 Chapter 2 Method Development for Related substances of Atorvastatin & Clopidogrel in combination by UPLC Introduction 33 Structure confirmation of Atorvastatin Calcium 37 Impurities of Atorvastatin 41 Structure confirmation of Clopidogrel Bisulphate 45 Impurities of Clopidogrel Bisulphate 49 Method development by UPLC 51 Method validation 79 Page 8 of 305 Conclusion 99 References 100 CHAPTER 3 Method Development and validation for related substances of Bisoprolol & Hydrochlorothiazide in combination by UPLC Introduction 102 Structure confirmation of Bisoprolol Fumarate 106 Impurities of Bisoprolol Fumarate 109 Structure confirmation of Hydrochlorothiazide 111 Impurities of Hydrochlorothiazide 114 Method development by UPLC 115 Method validation 138 Conclusion 154 References 155 Page 9 of 305 CHAPTER 4 Method Development and validation for related substances of Omeprazole by UPLC Introduction 157 Structure confirmation of Omeprazole 159 Impurities of Omeprazole 166 Method development by UPLC 169 Method validation 187 Conclusion 199 References 200 CHAPTER 5 Method Development and validation for related substances of Montelukast & Cetirizine in combination by HPLC Introduction 201 Structure confirmation of Montelukast 205 Impurities of Montelukast 209 Structure confirmation of Cetirizine Dihydrochloride 212 Impurities of Cetirizine Dihydrochloride 216 Method development by HPLC 219 Method validation 242 Conclusion 272 Page 10 of 305 References 273 CHAPTER 6 Method Development and validation for Polymorphic purity determination of Sertraline Hydrochloride by NIR Near-infrared spectroscopy 274 Sertraline Hydrochloride introduction 283 Sertraline Polymorphic purity Method by NIR 280 Conformity Index method 285 Quantitative model 286 Conclusion 293 References 294 Page 11 of 305