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Characterization of Impurities and Degradants Using Mass Spectrometry [Kõva köide]

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Characterization of Impurities and Degradants Using Mass SpectrometrySuurem pilt
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The book highlights the current practices and future trends in structural characterization of impurities and degradants. It begins with an overview of mass spectrometry techniques as related to the analysis of impurities and degradants, followed by studies involving characterization of process related impurities (including potential genotoxic impurities), and excipient related impurities in formulated products.  Both general practitioners in pharmaceutical research and specialists in analytical chemistry field will benefit from this book that will detail step-by-step approaches and new strategies to solve challenging problems related to pharmaceutical research.

Arvustused

"It will be valuable for scientists working in industrial, academic, and healthcare-related fields who use mass spectrometry to investigate impurities and degradants." (Doody's, 16 September 2011)  

Preface xv
Contributors xvii
Acronyms xix
Part I Methodology
1 Introduction to Mass Spectrometry
3(56)
Scott A. Smith
Ruth Waddell Smith
Yu Xia
Zheng Ouyang
1.1 History
3(6)
1.1.1 Atomic Physics
4(3)
1.1.2 Early Applications
7(1)
1.1.3 Organic Structural Analysis
7(1)
1.1.4 The Biological Mass Spectrometry Revolution
8(1)
1.2 Ionization Methods
9(1)
1.3 Mass Spectrometer Types
10(18)
1.3.1 Magnetic Sector Mass Spectrometers
10(4)
1.3.2 Quadrupole Mass Filter and Quadrupole Ion Trap Mass Spectrometers
14(5)
1.3.3 Time-of-Flight Mass Spectrometers
19(3)
1.3.4 Fourier Transform Ion Cyclotron Resonance Mass Spectrometers
22(3)
1.3.5 Orbitrap Mass Spectrometers
25(3)
1.4 Tandem Mass Spectrometry
28(7)
1.4.1 Ion Isolation
29(1)
1.4.2 Ion-Molecule Collisions and Collision-Induced Dissociation
30(2)
1.4.3 Electron Capture Dissociation and Electron Transfer Dissociation
32(3)
1.5 Separation Techniques Coupled to Mass Spectrometry
35(13)
1.5.1 Gas Chromatography-Mass Spectrometry
35(2)
1.5.2 Liquid Chromatography-Mass Spectrometry
37(5)
1.5.3 Capillary Electrophoresis-Mass Spectrometry
42(3)
1.5.4 Ion Mobility Spectrometry-Mass Spectrometry
45(3)
1.6 Prospects for Mass Spectrometry
48(3)
References
51(8)
2 LC Method Development and Strategies
59(22)
Gang Xue
Yining Zhao
2.1 Introduction
59(1)
2.2 Column, pH, and Solvent Screening
60(9)
2.2.1 Resolution: Goal of Separation
60(1)
2.2.2 Screening: Systematic Approach to Seeking Selectivity
60(7)
2.2.3 Screening Instrumentation and Controlling Software
67(2)
2.3 Gradient and Temperature Optimization
69(1)
2.4 Orthogonal Screening
70(6)
2.4.1 Method Orthogonality
71(1)
2.4.2 Selection of Orthogonal Methods
72(2)
2.4.3 Impurity Orthogonal Screening
74(2)
2.5 High-Efficiency Separation
76(2)
2.6 Conclusions
78(1)
References
78(3)
3 Rapid Analysis of Drug-Related Substances using Desorption Electrospray Ionization and Direct Analysis in Real Time Ionization Mass Spectrometry
81(28)
Hao Chen
Jiwen Li
3.1 Introduction
81(2)
3.2 Ionization Apparatus, Mechanisms, and General Performance
83(4)
3.2.1 Desorption Electrospray Ionization (DESI)
83(2)
3.2.2 Direct Analysis in Real Time (DART)
85(2)
3.3 Drug Analysis in Biological Matrices using DESI and DART
87(5)
3.3.1 DESI Application
88(1)
3.3.2 DART Application
89(3)
3.4 High-Throughput Analysis
92(2)
3.5 Chemical Imaging and Profiling
94(7)
3.6 Future Perspectives
101(1)
References
101(8)
4 Orbitrap High-Resolution Applications
109(26)
Rohert J. Strife
4.1 Historical Anecdote
109(1)
4.2 General Description of Orbitrap Operating Principles
110(2)
4.3 The Orbitrap is a "Fourier Transform" Device
112(1)
4.4 Performing Experiments in Trapping Devices
113(2)
4.4.1 "Raw" HPLC Data Look Like Infusion Data
114(1)
4.4.2 How Much Mass Resolution Should Be Used During HPLC
114(1)
4.5 Determining Elemental Compositions of "Unknowns" Using an Orbitrap
115(2)
4.6 Orbitrap Figures of Merit in Mass Measurement
117(4)
4.6.1 Accuracy
117(1)
4.6.2 Precision
118(1)
4.6.3 Discussion
118(3)
4.7 HPLC Orbitrap MS: Accurate Mass Demonstration and Differentiation of Small Molecule Formulas Very Proximate in Mass/Charge Ratio Space
121(1)
4.8 Determination of Trace Contaminant Compositions by Simple Screening HPLC-MS and Infusion Orbitrap MS
122(2)
4.9 Determining Substructures: Orbitrap Tandem Mass Spectrometry (MSn)
124(3)
4.10 Multianalyzer (Hybridized) System: The Linear Ion Trap/Orbitrap for MS/MS and Higher-Order MSn, n > 2
127(2)
4.11 Mass Mapping to Discover Impurities
129(2)
4.12 The Current Practice of Orbitrap Mass Spectrometry
131(1)
4.13 Conclusion
132(1)
References
132(3)
5 Structural Characterization of Impurities and Degradation Products in Pharmaceuticals Using High-Resolution LC-MS and Online Hydrogen/Deuterium Exchange Mass Spectrometry
135(48)
Guodong Chen
Birendra N. Pramanik
5.1 Introduction
135(2)
5.2 Characterization of Impurities
137(18)
5.2.1 Mometasone Furoate
137(15)
5.2.2 Enol Tautomer Impurity in Hepatitis C Virus (HCV) Protease Inhibitor
152(3)
5.3 Characterization of Degradation Products
155(21)
5.3.1 Everninomicin
156(8)
5.3.2 Posaconazole
164(12)
5.4 Conclusions
176(1)
References
177(6)
6 Isotope Patten Recognition on Molecular Formula Determination for Structural Identification of Impurities
183(32)
Ming Gu
6.1 Introduction
183(1)
6.2 Three Basic Approaches to Isotope Pattern Recognition
184(6)
6.2.1 With Centriod Data
185(2)
6.2.2 With Profile Data without Peak Shape Calibration
187(2)
6.2.3 With Profile Data with Peak Shape Calibration
189(1)
6.3 The Importance of Lineshape Calibration
190(4)
6.3.1 Lineshape Calibration Using Standards
191(2)
6.3.2 Lineshape Self-Calibration
193(1)
6.4 Spectral Accuracy
194(1)
6.5 Formula Determination with Quadrupole MS
194(9)
6.5.1 Impurity Identification with LC-MS
195(5)
6.5.2 Impurity Identification with GC-MS
200(1)
6.5.3 Pros and Cons of Determination of Elemental Decomposition (DEC) with Quadrupole MS
201(2)
6.6 Formula Determination with High-Resolution MS
203(5)
6.7 Conclusions and Future Directions
208(1)
References
208(7)
Part II Application
7 Practical Application of Very High-Pressure Liquid Chromatography Across the Pharmaceutical Development-Manufacturing Continuum
215(16)
Brent Kleintop
Qinggang Wang
7.1 Introduction
215(2)
7.2 Theory and Benefits of VHPLC
217(3)
7.3 VHPLC Method Development
220(6)
7.3.1 Adapting Existing HPLC Methods to VHPLC
220(4)
7.3.2 Developing New VHPLC Methods
224(2)
7.4 Other Practical Considerations
226(1)
7.5 VHPLC Method Validation
227(2)
7.6 Summary
229(1)
References
229(2)
8 Impurity Identification for Drug Substances
231(20)
David W. Berberich
Tao Jiang
Joseph McClurg
Frank Moser
R. Randy Wilhelm
8.1 Introduction
231(1)
8.2 Case Studies
232(17)
8.2.1 Identification of Impurities in Each Synthetic Step of Drug Substance during Process Development
232(5)
8.2.2 Impurity ID by LC/MS during Exploratory Chemistry: Evaluation of New Raw Materials
237(6)
8.2.3 Impurity Identification during Accelerated Stability Studies
243(6)
8.3 Conclusions
249(1)
References
250(1)
9 Impurity Identification in Process Chemistry by Mass Spectrometry
251(28)
David Q. Liu
Mingjiang Sun
Lianming Wu
9.1 Introduction
251(1)
9.2 Experimentation
252(2)
9.2.1 Liquid Chromatography Conditions
252(1)
9.2.2 LC-MS Systems
253(1)
9.2.3 GC-MS System
253(1)
9.2.4 Accurate Mass
253(1)
9.2.5 Online H/D Exchange LC-MS
254(1)
9.3 Applications
254(21)
9.3.1 Identification of Reaction Byproducts by Data-Dependent LC/MSn
254(3)
9.3.2 Online H/D Exchange Aids Structural Elucidation of Process Impurities
257(3)
9.3.3 LC-MS for Chemical Reaction Impurity Fate Mapping
260(2)
9.3.4 GC-MS for Impurity Profiling of Small-Molecule Starting Materials
262(3)
9.3.5 Identification of a Process Impurity that Impacts Downstream Formulation
265(2)
9.3.6 Differential Fragmentation between Sodiated and Protonated Molecules as a Means of Structural Elucidation
267(8)
9.4 Concluding Remarks
275(1)
Acknowledgments
275(1)
References
276(3)
10 Structure Elucidation of Pharmaceutical Impurities and Degradants in Drug Formulation Development
279(58)
Changkang Pan
Frances Liu
Michael Motto
10.1 Importance of Drug Degradation Studies in Drug Development
279(2)
10.2 Drug Degradation Studies in Formulation Development
281(3)
10.2.1 Drug Substance-Excipient Interaction
281(1)
10.2.2 Small Unknown Peaks (~,0.1%) (Low-Dose Drugs < 1 mg per Dose)
282(1)
10.2.3 "Busy" LC Chromatogram with Multiple Peaks (Combination Drug Products)
282(1)
10.2.4 Modification of Non-MS-Compatible LC Methods
282(1)
10.2.5 Uncontrollable Multiple Chemical Reactions in Stability Samples
283(1)
10.2.6 Separation Interference and Contamination Induced by Excipients
283(1)
10.2.7 Peak Isolation and NMR Confirmation for Late-Phase Projects
284(1)
10.3 Complexity of Impurity Identification in Drug Development
284(11)
10.3.1 Drug Substance (DS) Degradation
284(1)
10.3.2 DS Excipient Interaction
285(2)
10.3.3 DS-Residual Solvent Interaction
287(1)
10.3.4 DS-Solvent Impurity Interaction
287(2)
10.3.5 Metal Ion-Catalyzed Reaction
289(1)
10.3.6 DS-Excipient Impurity Interaction
289(2)
10.3.7 DS-Salt Interaction
291(1)
10.3.8 DS-Preservative Interaction
291(1)
10.3.9 Preservative-Excipient Interaction
292(1)
10.3.10 Excipient Degradation
292(1)
10.3.11 Leachables and Extractables
293(2)
10.4 Strategy for Structure Elucidation of Unknowns
295(5)
10.4.1 Non-MS-Compatible Method versus MS-Compatible Method
295(3)
10.4.2 Selection of Ionization Mode (ESI or APCI, Positive or Negative)
298(1)
10.4.3 Multiple Approaches for Structure Elucidation
298(1)
10.4.4 Structure Confirmation
299(1)
10.5 Hyphenated Analytical Techniques Used in Drug Development
300(7)
10.5.1 LC-MS/MS for Fragmentation Pathways
302(1)
10.5.2 High-Resolution MS for Chemical Formula/Elemental Composition
302(2)
10.5.3 SEC/CLND or HPLC/CLND: Nitrogen-Specific Detection
304(1)
10.5.4 GC-MS with EI-CI Combination
305(1)
10.5.5 Headspace GC-MS: Volatile Compounds
305(1)
10.5.6 NMR and LC-NMR
306(1)
10.5.7 TD-GC/MS: Chemical Reactions Attributing to Weight Loss in TGA
307(1)
10.6 Case Studies
307(19)
10.6.1 LC-MS, GC-MS, and LC-NMR Studies of a Drug Degradation Product
307(1)
10.6.1.1 LC-MS Analysis
308(1)
10.6.1.2 GC-MS Analysis
308(1)
10.6.1.3 LC-NMR Analysis
308(5)
10.6.2 Strategy for Identification of Leachables in Packaged Liquid Formulation
313(3)
10.6.3 Characterization of Methionine Oxidation in Parathyroid Hormone Formulation
316(1)
10.6.3.1 Oxidation, Isolation, and Digestion of PTH1-34
316(1)
10.6.3.2 Mass Assignment of PTH 1-34 Oxidized Variants
317(1)
10.6.3.3 Mass Assignment of CNBr Digested Peptide Fragments
318(1)
10.6.3.4 LC-MS/MS Studies of Ion Fragments from Oxidized Peptides
322(4)
Acknowledgment
326(1)
References
326(11)
11 Investigation of Degradation Products and Extractables in Developing Topical OTC (Over the Counter) and NCE (New Chemical Entity) Consumer Healthcare Medication Products
337(54)
Fa Zhang
11.1 Introduction
337(1)
11.2 Oxidatively Induced Coupling of Miconazole Nitrate with Butylated Hydroxytoluene in a Topical Ointment
338(9)
11.2.1 HPLC-MS Screening
339(2)
11.2.2 Organic Synthesis
341(3)
11.2.3 Degradation Mechanism
344(3)
11.3 Extractables from Rubber Closures of a Prefilled Semisolid Drug Applicator
347(5)
11.3.1 Isolation of the Extractables
348(1)
11.3.2 Structural Identification of Extractables 5 and 6
348(1)
11.3.3 Structural Identification of Extractables 7 and 8
349(2)
11.3.4 Structural Identification of Extractable 9
351(1)
11.4 New Degradation Products and Pathways of Vitamin D and Its Analogs
352(31)
11.4.1 Thermal Isomerization of Vitamin D3 in DMSO
355(1)
11.4.2 Autoxidation of Isotachysterol
356(1)
11.4.2.1 Mechanism of Isotachysterol Autoxidation
362(2)
11.4.3 Thermal Degradation of Ecalcidene
364(4)
11.4.4 Acid-Induced Degradation of Ecalcidene
368(2)
11.4.5 Iodine-Induced Degradation of Ecalcidene
370(1)
11.4.5.1 cis/trans-Isomerization of Ecalcidene
371(1)
11.4.5.2 cis/trans-Isomerization of Previtamin D3-Type Isomer 24
372(4)
11.5 Reductive Degradation of a 1,2,4-Thiadiazolium Derivative
376(6)
11.6 Conclusions
382(1)
References
383(8)
12 Characterization of Impurities and Degradants in Protein Therapeutics by Mass Spectrometry
391(36)
Li Tao
Michael Ackerman
Wei Wu
Peiran Liu
Reb Russell
12.1 Introduction to Therapeutic Proteins
391(1)
12.2 Recent Advances in Mass Spectrometry
392(1)
12.3 Impurities
393(2)
12.3.1 Endotoxin
394(1)
12.3.2 Residual DNA
394(1)
12.3.3 Residual HCP
395(1)
12.4 Degradation Products
395(18)
12.4.1 Chemical Degradation
396(1)
12.4.1.1 Deamidation/Isomerization
396(1)
12.4.1.2 Protein Fragmentation
400(1)
12.4.1.3 Oxidation
401(3)
12.4.2 Variants Caused by Posttranslational Modification
404(1)
12.4.2.1 Case Study: Characterization of S-Thiolation on Secreted Proteins from E. coli
406(1)
12.4.2.2 TM307
408(1)
12.4.2.3 TM485
408(1)
12.4.2.4 TM358 and TM687
410(3)
12.5 Conclusions
413(1)
References
413(14)
13 Identification and Quantification of Degradants and Impurities in Antibodies
427(23)
David M. Hambly
Himanshu S. Gadgil
13.1 Introduction to Antibodies and Protein Drugs
427(4)
13.1.1 Antibody Classification and Subtypes
427(1)
13.1.2 Antibody Structure
428(1)
13.1.3 Antibody-Domain Structure
429(1)
13.1.4 Recombinant Antibody Production
429(1)
13.1.5 Methods for Characterizing Antibody Degradation and Impurity
430(1)
13.2 Overview of Degradations and Impurities in Protein Drugs and Antibodies
431(4)
13.2.1 Chemical Degradations and Impurities
431(1)
13.2.1.1 Methionine Oxidation
431(1)
13.2.1.2 Disulfide Bonds or Reduced Cysteine
432(1)
13.2.1.3 Deamidation of Asparagine and Glutamine
432(1)
13.2.1.4 Isomerization of Aspartic Acid and Glutamic Acid
433(1)
13.2.1.5 Amide Backbone Hydrolysis Reactions
433(1)
13.2.1.6 Glycation of Lysine Residues
433(1)
13.2.1.7 C-Terminal Lysine Variants
434(1)
13.2.1.8 Carbohydrate Variants
434(1)
13.3 Methods Used to Identify and Quantitate Degradations and Impurities
435(15)
13.3.1 Whole-Protein Mass Analysis Methods
435(1)
13.3.1.1 Carbohydrate Variation
435(1)
13.3.1.2 Detection of Lysine C-terminal Variants and Glycated Lysine
437(1)
13.3.1.3 Detection of Disulfide Bond Variants in IgG2 Antibodies
437(1)
13.3.2 Methods for Evaluating the Mass of Protein Fragments
438(1)
13.3.2.1 Limited Digestion Method for Antibodies
438(1)
13.3.2.2 Limited and Reduced Method for Antibodies
440(1)
13.3.2.3 Reduced Protein Mass Analysis
441(2)
13.3.3 Methods for Evaluating Peptides for Impurities and Degradations
443(1)
13.3.3.1 Reduced and Alkylated Peptide Mapping
443(7)
13.4 Conclusions
450(1)
Appendix 450(3)
References 453(8)
Index 461
BIRENDRA N. PRAMANIK is a Distinguished Fellow at Merck Research Laboratories, where he directs spectroscopy programs covering mass spectrometry and NMR efforts. He was previously a distinguished fellow at Schering-Plough Research Institute. He received his PhD in organic chemistry under the late Professor Ajay K. Bose from Stevens Institute of Technology in 1977. MIKE S. LEE is President of Milestone Development Services, a provider of consulting services specializing in pharmaceutical analysis and accelerated drug discovery and development strategies in Newtown, Pennsylvania. He previously directed program research at Bristol-Myers Squibb, Pharmaceutical Research Institute in New Brunswick, New Jersey.

GUODONG CHEN is Principal Scientist in Bioanalytical and Discovery Analytical Sciences at Bristol-Myers Squibb in Princeton, New Jersey. He heads a mass spectrometry group in support of drug discovery as well as development programs in small molecule pharmaceuticals and biologics. He received his PhD in analytical chemistry from Purdue University under the direction of Professor R. Graham Cooks.