Charged Aerosol Detection for Liquid Chromatography and Related Separation Techniques

PAUL H. GAMACHE is Director of Research and Development at Thermo Fisher Scientific. He has more than thirty years' experience within the analytical instrument industry. His primary area of expertise is in the development of instrumentation and techniques based on liquid chromatography. He has published more than 50 articles and book chapters including the first publication describing commercial CAD technology. In 2005 he was co-awardee of an NIH Metabolomics Roadmap research grant.

• List of Contributors xviiPreface xxiAcknowledgment xxvSection 1 Fundamentals of Charged Aerosol Detection 11 Principles of Charged Aerosol Detection 3Paul H. Gamache and Stanley L. Kaufman1.1 Summary 31.2 History and Introduction to the Technology 41.3 Charged Aerosol Detection Process 91.3.1 Nebulization 91.3.2 Aerosol Conditioning 131.3.2.1 Solvent Load Reduction 131.3.2.2 Secondary Processes 131.3.2.3 Summary: Aerosol Transport 161.3.3 Evaporation 161.3.3.1 Aerosol Evaporation Process 171.3.3.2 Evaporation Rate (Re) 171.3.3.3 Dried Particle Size 191.3.3.4 Volatility and Detector Response 201.3.3.5 Particle Size Dependency 201.3.3.6 Ionizable Solutes 211.3.3.7 Background Solutes: Impurities 221.3.3.8 Summary 241.3.4 Aerosol Charging 241.3.4.1 Mechanisms 241.3.4.2 Diffusion Charging Overview 251.3.4.3 Unipolar Diffusion Charging Theory 261.3.4.4 CAD “Corona Jet” Charger Design 271.3.4.5 Corona Ion Jet and Aerosol Particle Jet 281.3.5 Summary of Aerosol Charging 291.3.6 Summary of CAD Process 291.4 CAD Response Model 311.4.1 Primary Droplet Size Distribution 321.4.2 Impactor 321.4.3 Drying and Residue Formation 331.4.3.1 Residue Particle Parameters 331.4.4 Charging of Residue Particles 331.4.5 Ion Removal 341.4.5.1 Attenuation of Particle Signal by Ion Trap 361.4.6 Signal Current 371.4.7 Signal from an Eluting Peak: Peak Shape 381.4.8 Peak Area Versus Injected Mass 391.4.9 Summary 391.5 Performance Characteristics 401.5.1 Response Curve: Shape and Dynamic Range 401.5.1.1 Semivolatile Analytes 441.5.1.2 Calibration 451.5.2 Peak Shape 481.5.3 Mass Versus Concentration Sensitivity 491.5.4 Sensitivity Limits 511.5.5 Response Uniformity 521.5.5.1 Solvent Gradient Effects 531.5.5.2 Analyte Volatility and Salt Formation 531.5.5.3 Analyte Density 541.5.5.4 Dependence of Aerosol Measurement Technique on Residue Particle Material 541.5.6 CAD Versus Formation of Gaseous Ions for MS 561.5.6.1 Pneumatically Assisted ESI 571.5.6.2 APCI 571.5.6.3 Main Differences between CAD and MS 58References 592 Charged Aerosol Detection: A Literature Review 67Ian N. Acworth and William Kopaciewicz2.1 Introduction 672.2 CAD History and Background 742.3 Application Areas 792.3.1 Carbohydrates 792.3.2 Lipids 792.3.3 Natural Products 862.3.4 Pharmaceutical and Biopharmaceutical Analysis 862.3.5 Other Application Areas 1312.4 Conclusions 131Acknowledgements 131References 1413 Practical Use of CAD: Achieving Optimal Performance 163Bruce Bailey, Marc Plante, David Thomas, Chris Crafts, and Paul H. Gamache3.1 Summary 1633.2 Introduction 1643.2.1 First‐ and Second‐Generation Instrument Designs 1653.2.2 Liquid Flow Range 1653.2.3 Excess Liquid Removal 1673.2.4 Temperature Control 1673.2.5 Aerosol Creation and Transport 1673.3 Factors Influencing CAD Performance 1683.3.1 Analyte Properties 1683.3.1.1 Formation of Aerosol Residue Particles 1683.3.1.2 Inherent Response of Downstream Aerosol Detector 1693.3.1.3 Summary of Analyte Properties 1693.3.2 Eluent Properties and Composition 1693.3.2.1 Mass Transport 1693.3.2.2 Eluent Purity 1703.3.2.3 Mobile Phase Additives 1713.3.2.4 Additional Sources of Eluent Impurities 1733.3.2.5 Column Bleed 1743.3.2.6 Basic Eluents 1743.3.2.7 System Components and Laboratory Equipment 1753.3.2.8 Summary 1763.4 System Configurations 1773.4.1 Microscale LC 1773.4.2 Post‐column Addition 1773.4.3 Multi‐detector Configurations 1783.5 Method Transfer 1803.6 Calibration and Sensitivity Limits 1823.6.1 Power Function 1853.6.2 Summary of Calibration and Sensitivity Limits 186References 1864 Aerosol‐Based Detectors in Liquid Chromatography: Approaches Toward Universal Detection and to Global Analysis 191Joseph P. Hutchinson, Greg W. Dicinoski, and Paul R. Haddad4.1 Summary 1914.2 Introduction 1924.3 Universal Detection Methods 1944.4 Factors Affecting the Response in Charged Aerosol Detection 1984.5 Gradient Compensation 2044.6 Response Models 2054.7 Green Chemistry 2064.8 Temperature Gradient Separations 2094.9 Supercritical CO 2 Separations 2104.10 Capillary Separations 2114.11 Global Analysis and Multidimensional Separations 2124.12 Conclusions 215References 216Section 2 Charged Aerosol Detection of Specific Analyte Classes 2215 Lipid Analysis with the Corona CAD 223Danielle Libong, Sylvie Héron, Alain Tchapla, and Pierre Chaminade5.1 Introduction 2235.2 Principles of Chromatographic Separation of Lipids 2275.2.1 Theory of Retention Mechanism in Reversed‐Phase Liquid Chromatography 2275.2.2 Optimizing Selectivity 2315.2.3 Note on Using pH Modifiers for Selectivity Optimization 2355.3 Application: Strategy of Lipid Separation 2355.3.1 Separation of Individual Lipid Classes 2365.3.2 Separation of Subclasses of Lipids 2405.3.2.1 Size Exclusion Chromatography 2405.3.2.2 Argentation Chromatography 2415.3.3 Separation of Congeners Belonging to Specific Classes of Lipids 2425.3.4 Behavior of Lipid Separation in Reversed‐Phase Chromatography 2465.3.5 Behavior of Lipid Separation in Reversed‐Phase Sub‐ and Supercritical Fluid Chromatography 2505.3.6 Multimodal Chromatographic Systems 2525.3.7 Identification of the Molecular Species 2525.3.7.1 Methodology for Identification of Congeners 2565.4 Literature Review: Early Use of Corona CAD in Lipid Analysis 2575.4.1 Biosciences 2575.4.2 Food Chemistry 2585.4.3 Pharmaceutical Sciences 2605.4.3.1 Emulsions 2605.4.3.2 Liposomes 2615.4.3.3 Surfactants 2625.4.3.4 Contrast Agents 2635.4.3.5 Determination of Degradation Product and Impurities 2635.5 Calibration Strategies 2645.5.1 Calibration Strategies in Quantitative Analysis of Lipids 2645.5.2 Classical Calibration (External Calibration, Normalization) 2665.5.3 Calibration in Absence of Standards 268References 2726 Inorganic and Organic Ions 289Xiaodong Liu, Christopher A. Pohl, and Ke Zhang6.1 Introduction 2896.2 Technical Considerations 2916.2.1 Instrumentation Platform 2916.2.2 Separation Column 2926.2.3 Mobile Phase 2956.2.4 CAD Parameter Setting 2976.2.5 Sensitivity 2976.2.6 Calibration Curve, Dynamic Range, Accuracy, and Precision 2986.3 Applications 3006.3.1 Pharmaceutical Counterions and Salts 3016.3.2 Bisphosphonate 3036.3.3 Phosphorylated Carbohydrates 3046.3.4 Ionic Liquids 3046.3.5 Pesticides 3056.3.6 Other Applications 3056.4 Concluding Remarks 306References 3067 Determination of Carbohydrates Using Liquid Chromatography with Charged Aerosol Detection 311Jeffrey S. Rohrer and Shinichi Kitamura7.1 Summary 3117.2 Liquid Chromatography of Carbohydrates 3127.3 Charged Aerosol Detection 3147.4 Why LC‐CAD for Carbohydrate Analysis? 3157.5 Early Applications of CAD to Carbohydrate Analysis 3167.6 Additional Applications of CAD to Carbohydrate Analysis 317References 3228 Polymers and Surfactants 327Dawen Kou, Gerald Manius, Hung Tian, and Hitesh P. Chokshi8.1 Summary 3278.2 Introduction 3288.3 Polymer Analysis 3288.4 Polyethylene Glycol 3298.4.1 PEG Reagents 3308.4.2 Low Molecular Weight PEGs 3338.4.3 PEGylated Molecules 3358.5 Surfactants 336References 3399 Application of Charged Aerosol Detection in Traditional Herbal Medicines 341Lijuan Liang, Yong Jiang, and Pengfei Tu9.1 Summary 3419.2 Introduction 3429.3 Factors that Affect the Sensitivity of CAD 3439.3.1 Mobile Phase Composition 3439.3.2 Effects of Nitrogen Gas Purity on the Sensitivity of CAD 3449.3.3 The Effect of Mobile Phase Modifiers 3449.3.4 Comparison of Flow Rate Effect on the Sensitivity of CAD 3459.4 Application of CAD in Quality Analysis of Traditional Herbal Medicines 3459.4.1 Determination of Saponins in Radix et Rhizoma Notoginseng by CAD Coupled with HPLC 3459.4.2 Determination of Ginsenosides by LC‐CAD 3469.4.3 Other Applications of CAD 3499.5 Conclusion 353References 353Section 3 Industrial Applications of Charged Aerosol Detection 35510 Charged Aerosol Detection in Pharmaceutical Analysis: An Overview 357Michael Swartz, Mark Emanuele, and Amber Awad10.1 Summary 35710.2 Introduction 35810.3 Analytical Method Development 35910.4 Analytical Method Validation 36110.5 CAD in Analytical Method Transfer 36310.6 CAD in Formulation Development and Ion Analysis 36410.7 Carbohydrate Analysis by CAD 36810.8 CAD in Stability Analyses 37110.9 Conclusion 373References 37411 Impurity Control in Topiramate with High Performance Liquid Chromatography: Validation and Comparison of the Performance of Evaporative Light Scattering Detection and Charged Aerosol Detection 379David Ilko, Robert C. Neugebauer, Sophie Brossard, Stefan Almeling, Michael Türck, and Ulrike Holzgrabe11.1 Summary 37911.2 Introduction 38011.3 Material and Methods 38211.3.1 Reagents and Material 38211.3.2 HPLC–ELSD/CAD 38211.3.3 TLC and HPTLC Limit Test for Impurity A 38311.4 Results and Discussion 38311.4.1 Method Validation: Impurity Control 38311.4.2 Method Validation: Assay 38811.4.3 TLC and HPTLC Limit Test for Impurity A 39011.5 Conclusion 390Acknowledgment 390References 39112 Applying Charged Aerosol Detection to Aminoglycosides: Development and Validation of an RP‐HPLC Method for Gentamicin and Netilmicin 393Arul Joseph and Abu Rustum12.1 Introduction 39312.1.1 Background 39412.2 Development and Validation of an RP‐HPLC Method for Gentamicin Using Charged Aerosol Detection 39512.2.1 Method Development 39512.2.1.1 Selection of Detector 39512.2.1.2 Related Substances 39512.2.1.3 Mobile Phase Composition and Column Selection 39812.2.1.4 Sample Preparation 40012.2.2 Method Validation 40212.2.2.1 Experimental 40212.2.2.2 Specificity 40312.2.2.3 Linearity 40312.2.2.4 Accuracy 40412.2.2.5 Limit of Detection and Limit of Quantitation 40512.2.2.6 Reproducibility and Precision 40612.2.2.7 Robustness 40612.2.2.8 Alternate Column Validation 40612.2.2.9 Calculation 40712.2.2.10 Chromatographic Conditions of the Final Method 40912.2.3 Discussion 40912.3 Application of Strategy to Netilmicin Sulfate 41012.3.1 Method Development 41012.3.1.1 Sample Preparation 41412.3.2 Method Validation 41512.3.2.1 Specificity 41512.3.2.2 Linearity 41512.3.2.3 Limit of Detection and Limit of Quantitation 41712.3.2.4 Robustness 41712.3.2.5 Calculation 41812.3.2.6 Chromatographic Conditions of the Final Method 41812.3.3 Discussion 41812.4 Conclusion 420Acknowledgments 420References 42013 Determination of Quaternary Ammonium Muscle Relaxants with Their Impurities in Pharmaceutical Preparations by LC‐CAD 425Agata Blazewicz, Magdalena Poplawska, Malgorzata Warowna‐Grzeskiewicz, Katarzyna Sarna, and Zbigniew Fijalek13.1 Summary 42513.2 Introduction 42613.3 Experimental 42913.3.1 Equipment and Conditions 42913.3.2 Material Studied 43013.3.3 Standard Solutions 43113.4 Results and Discussion 43113.4.1 Selection of Chromatographic Conditions 43113.4.1.1 LC‐CAD Method for Atracurium, Cisatracurium, and Mivacurium and Their Impurities 43113.4.1.2 LC‐CAD Method for Pancuronium and Its Impurities 43213.4.2 Identification of Analytes 43413.4.3 Validation of the Methods 43413.4.3.1 Linearity 43613.4.3.2 Detection and Quantitation Limits 43813.4.3.3 Precision and Accuracy 44113.4.3.4 Range 44213.4.4 Determination of Active Substances and Impurities in Pharmaceutical Preparations 44313.4.5 Stability 44313.5 Conclusion 445Acknowledgments 445References 44614 Charged Aerosol Detection of Scale Inhibiting Polymers in Oilfield Chemistry Applications 449Alan K. Thompson14.1 Summary 44914.2 Background to Scale Inhibition in Oilfields 45014.2.1 General Background 45014.2.2 Squeeze Programs 45214.2.3 Polymeric Inhibitors 45414.3 Historical Methods of Analysis 45514.4 Charged Aerosol Detection for Polymeric Scale Inhibitors 45914.4.1 Theoretical Application of CAD 45914.4.2 Practical Application of CAD 46014.4.3 Typical Validation of Methodology 46114.4.3.1 Linearity of Detection 46214.4.3.2 Precision of Injection 46314.4.3.3 Assay Accuracy and Precision 46414.4.3.4 Assay Ruggedness 46414.4.3.5 Assay Ruggedness 2: Inter‐instrument Variability 46514.4.3.6 Limit of Detection and Limit of Quantification 46614.4.3.7 Analysis of Routine Oilfield Brine Samples for Polymeric Scale Inhibitor Using HPLC‐CAD 46614.4.4 Limits of Methodology 46714.5 Conclusions and Further Work 468References 46915 Applications of Charged Aerosol Detection for Characterization of Industrial Polymers 471Paul Cools and Ton Brooijmans15.1 Introduction 47115.2 Liquid Chromatography of Polymers 47215.3 Solvents 47515.4 Quantitative Detection of Polymer Molecules 47615.4.1 Ultraviolet Detection 47615.4.2 Differential Refractive Index Detection 47615.4.3 Evaporative Detection 47715.4.4 Charged Aerosol Detection 47715.4.5 Molar Mass Dependent Detection 47815.4.6 Mass Spectrometry 47815.5 Size Exclusion Chromatography and Charged Aerosol Detection 47915.6 Gradient Polymer Elution Chromatography and CAD 48615.7 Liquid Chromatography Combined with UV, CAD, and MS Detection 49015.7.1 LC‐ESI‐TOF MS System at DSM Coating Resins 49115.8 Typical Examples of Industrial Applications Using LC‐MS‐CAD 49215.8.1 Raw Material Analysis 49315.8.2 Intermediates 49415.8.3 End Products 49515.9 Epilogue 497Acknowledgments 497References 497Index 501