Practical Application of Supercritical Fluid Chromatography for Pharmaceutical Research and Development

Front Cover
Practical Application of Supercritical Fluid Chromatography For Pharmaceutical Research and Development
Copyright
Dedication
Contents
Contributors
Preface
	Supercritical fluids
	Historical perspectives
	SFC in the pharmaceutical industry
	Scope and relevance for this text
	References
Chapter 1: Evolution of packed column SFC as a greener analytical tool for pharmaceutical analysis
	Discovery of supercritical fluids and its relevance to analytical separation science
		The progression of analytical supercritical fluid chromatography
		Fundamentals of mobile phases
	Sustainable aspects of subcritical and supercritical chromatographic separation methods
	Analytical scale subcritical SFC
	Analytical enhanced-fluidity liquid chromatography
	Preparative and analytical scale instrument improvements
		Mobile phase pump
		Injectors and sample delivery
		Column ovens
		Detector interfaces
		Multidimensional SFC
		Preparative SFC
	Current utility and recent advancements
	Future directions
	References
Chapter 2: Application space for SFC in pharmaceutical drug discovery and development
	Introduction
	Discussion
		Historical overview of SFC applications
			1980–2000: SFC for the analysis of apolar substances and chiral drugs
			2000–2010: SFC as an alternative to RPLC for achiral applications
			2010–2014: Transition from SFC to UHPSFC
			2015–present day: SFC for highly polar compounds
	Considerations on SFC as an analytical tool in drug discovery and development
		Mobile phase composition
		Impact of the stationary phase
		Choice of injection solvent
		Hyphenation to mass spectrometer detectors
		Quantitative performance of SFC
	Conclusions and perspectives
	References
Chapter 3: Selection of SFC stationary and mobile phases
	Introduction
	Current stationary phase chemistries for SFC
		Preferred stationary phases in recent achiral pharmaceutical applications
		Preferred stationary phases in recent chiral pharmaceutical applications
		Tandem column combinations
	Flexible mobile phase composition
		Utility of cosolvents
		Additives
		Gradient elution
		Identifying an optimal mobile phase composition
		Considerations for transfer to preparative scale
	Other operating parameters: Temperature, pressure and flow rate
	Predicting retention and selectivity
	Summary
	References
Chapter 4: Measurements of drugs and metabolites in biological matrices using SFC and SFE-SFC-MS
	Introduction to drug and metabolite analysis in biological matrices using SFC and SFE-SFC-MS
		A brief history of SFC-MS for the analysis of biological matrices
		SFC-MS and SFE-SFC-MS compared to LC–MS for pharmaceutical analysis
	On-line SFE-SFC-MS method development for biological matrices
		SFE-SFC-MS instrumentation overview
		Systematic method development and workflow for SFE-SFC-MS
			Optimize MS-based detection of target analytes
			Optimize SFC-based chromatographic separation
			Optimize SFE-based on-line extraction from blank sampling matrices
			Optimize SFE-SFC-MS method for application specific matrix considerations
	Drug metabolism and pharmacokinetics (DMPK) monitoring in discovery and development
		Introduction to drug metabolism and pharmacokinetic analysis
		SFC and SFE-SFC for DMPK in discovery and development
			Analytical SFC overview and applications
			SFE-SFC-MS applications
	Discovery and dereplication of natural products
		SFC overview and applications
		SFE-SFC overview and applications
	Conclusions
	References
Chapter 5: Synthetic chemistry screening for robust analysis and purification from discovery through to development
	Introduction
	Screening strategies
		Achiral screening: Column selection
		Achiral screening: Mobile phase composition
		Achiral screening: Sample diluent
		Achiral screening: Instrumentation and methods
		Chiral screening: Overview
		Chiral screening: Instrumentation
		Chiral screening: Column selection
		Chiral screening methods
		Chiral screening: Isocratic method development
			Chiral screening: SFC and the GSK chiral screen workflow
	Practicality
		Analysis of highly polar compounds
		Experimental Polar Surface Area (EPSA) compound screening
		Array screening
	Aspects for consideration
		Compressibility of carbon dioxide
		System pressure manipulation
		Equating the average mobile phase densities in SFC
	Future refinements
	References
Chapter 6: Application of preparative SFC in the pharmaceutical industry
	Introduction to the use of preparative SFC
	Preparative SFC instrumentation and infrastructure
		Supercritical carbon dioxide as a chromatographic mobile phase
		Liquid CO2 supply infrastructure and engineering challenges
		CO2 delivery for preparative SFC
	Features and controls during preparative SFC
		Flow control
		Backpressure regulation
		Injection considerations
			Mixed stream injection
			Modifier stream injection
			Extraction injection
	Temperature control
	Detection systems
	Fraction collection
	Method development in preparative SFC
		Mobile phase considerations
		Achiral SFC stationary phases
		Chiral stationary phases (CSP) for SFC
	Preparative SFC applications: Case studies within AstraZeneca research laboratories
		A practical approach to analytical to preparative scale-up
		Overcoming solubility concerns in SFC
		Flexible solutions to compound instability
		Automated purification of crude reaction mixtures by SFC
		Efficient milligram-scale isomer separations
		Bespoke method optimization for larger multigram separations
	SFC as a sustainable chromatographic technique
	Conclusions
	References
Chapter 7: Method development approaches for small-molecule analytes
	Introduction
	Method development ``prework´´
		What is the purpose of the method and what are suitable performance indicators?
		What is the development strategy?
		Understand the analytes
	Screening tool utilization to identify optimal SFC parameters
		Instrumentation for method development
		Chromatographic column selection
			Stationary phase technology and kinetic performance
			Influence of instrumentation on the choice of column dimensions
			Choice of the stationary phase chemistry
		Mobile phase selection
			Organic modifier selection
			Mobile phase additive selection
		Method optimization
			Sample dissolution solvent
			Additive concentration
			Gradient program, temperature and backpressure
			Experimental design and in silico retention modeling
	Method validation
	Continuous method performance verification
	Summary
	Acknowledgments
	References
Chapter 8: Application of SFC for the characterization of formulated drug products
	Introduction
	Drug formulations
		Solid-oral dosage forms
			Tablets
			Capsules
		Liquid and semisolid formulations
			Semisolid formulations
			Novel drug formulations
	Sample preparation procedures
		Analyte properties and sample diluent selection
	Water and organic solvents as sample diluents in SFC for APIs and solid-oral dosage forms
		Impact of water in the sample diluent on peak shape for tablets and capsules
		Creams and emulsions
		Filtration
	Alternative approaches to solubilize analytes in SFC compatible solvents
		Liquid-liquid extraction
		Solid-phase extraction
		Supercritical fluid extraction
	Characterization of polymer excipients
		Characterization of polyethylene glycol
		Characterization of Tween 20 and Tween 80
		Characterization of polyoxyethylene alkyl ethers
		Sodium stearyl fumarate
	Conclusions
	Acknowledgments
	Appendix: Constituents of formulated drugs discussed in chapter
	References
Chapter 9: Expanding the boundaries of SFC: Analysis of biomolecules
	Historical problems analyzing polar molecules via SFC
		Early problems using SFC for analysis of polar molecules
		Deciphering the role of polar modifiers in SFC
		Deciphering the role of polar additives in SFC
		Early attempts to analyze biomolecules by SFC
		Realization that SFC does not need to be ``supercritical´´
	Role of water in modern SFC
		Early use of water in SFC
		Improving chromatographic efficiency
		Increasing solubility of other additives
		Improving ionization efficiency in mass spectrometry
		Use of water in preparative purifications
		Inducing changes in retention mechanisms
	Enhanced-fluidity liquid chromatography
		Early history of EFLC
		Modern EFLC–Expansion to biomolecules of increasing polarity
		Modern EFLC–Expansion to biomolecules of increasing molecular weight
		Expansion of EFLC
		Moving toward ``unified chromatography´´
	Applications of SFC to biomolecules
		Lipids
		Carbohydrates
		Amino acids
		Peptides and proteins
		Nucleic acid building blocks
	Concluding remarks
	References
Chapter 10: Different detectors used with SFC
	Introduction to detectors used with modern SFC
	Generic detectors used with SFC
		Flame ionization detector
		UV–Vis detector
		Aerosol-based detectors
			Evaporative light-scattering detector
			Charged aerosol detector
			Condensation nucleation light-scattering detector
			Considerations during method development using aerosol detectors
			Applications
	Coupling SFC to mass spectrometric detectors
		Practicalities of hyphenation
		Selection and impact of the mass analyzer
	Conclusions
	Acknowledgment
	References
Chapter 11: SFC in GMP testing and quality control of medicinal drug products
	Introduction
	Current use of SFC in pharmaceutical development
		Why do regulatory submission methods still not utilize SFC?
		Examples of validated and registered SFC methods
	Transfer of methods to manufacturing QC facilities
		Case study: TT of early stage SFC methods between sites
		Method transfers between different instrument types
		Case study: Inter-laboratory studies demonstrating SFC as an alternative to HPLC for compendial methods
		Instrument qualification
	Future requirements toward regulatory acceptance of SFC methods
		Column classification
		Pharmacopeial updates
		Establishing the technique within development functions
		Preparation for investment in SFC in manufacturing QC
	Conclusions
	Acknowledgments
	References
Chapter 12: Best practices and instrumental troubleshooting for successful SFC methods
	Introduction
	System configuration
	Best practice for system setup
	System performance checks
		Dwell test
		System suitability test check
		ABPR trace
		System pressure trace
	Cylinder issues
	Instrument troubleshooting and errors
		Pumping issues
		ABPR issues
		Low pressure
		High pressure
		Poor mobile phase mixing
		UV detector issues
		Detector flow cell
		Atmospheric detector issues (ELSD, CAD, MS)
	Eluent effects
		Solvent modifier effects
		Needle wash solvents
		Sample diluent effects
	Chromatographic troubleshooting
		Variable retention time
		Loss of analyte retention
	Optimization of detector sensitivity
		Flow rate effects on chromatographic noise levels
	Conclusions
	References
Chapter 13: The state-of-the-art and future perspectives for SFC
	Introduction
	Reflection on previous chapters
	Theoretical performance of SFC
	Influence of new column particle technologies and instrument design on SFC performance
	Considerations for future instrument application and design
		Future directions with SFC column selectivity and efficiency
	Method development, performance and prediction aspects
		In-silico retention modeling and prediction
	Method scaling
	Future directions and applications of SFC
		Biomolecule characterization
		Plasticizers, extractable and leachable
		Nitrosamines, mutagenic impurities
	Sustainable instrument design
		Instrument power consumption and potential for miniaturization
		Future SFC instrumental capability
	Conclusions
	Acknowledgments
	References
List of abbreviations
Index
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