Practical Application of Supercritical Fluid Chromatography for Pharmaceutical Research and Development provides a valuable “go-to reference for many difficult-to-solve challenges using pertinent chromatographic theory, first-hand case studies, and examples provided from academic and industry experts. This text also enables professors teaching an analytical instrumental course to introduce and instruct students about one of the most sustainable and powerful separation methods currently available. While the text has broad applicability across industrial sectors, it focuses primarily on application in the pharmaceutical industry. The book is designed to allow readers to align current HPLC/UHPLC capabilities with SFC as an orthogonal tool for project specific methods in the pharmaceutical industry. It highlights where SFC falls on the spectrum of useful chromatographic tools for routine and challenging separative methods.
Experienced HPLC users who are interested in developing knowledge in orthogonal separation techniques, as well as newcomers to the field of separation science, will find this text particularly useful. Chapters address where SFC may fit the analytical needs of the pharmaceutical industry and alert the readers as to where the technique will not fit. Readers will gain an understanding of how and where SFC may be applied and adapted more routinely across the pharmaceutical industry as a ‘green’ way of undertaking separation opportunities and challenges. Areas within the pharmaceutical industry include early drug discovery, process chemistry, and late stage development and manufacturing.
Author(s): Michael B. Hicks, Paul D. Ferguson
Series: Separation Science and Technology, 14
Publisher: Academic Press
Year: 2022
Language: English
Pages: 431
City: London
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
Back Cover
