Читать книгу Mutagenic Impurities - Группа авторов - Страница 4

1 Chapter 2Figure 2.1 EDAC.Figure 2.2 Interrelationship between degradant classes.Figure 2.3 Potential sources of mutagenic impurities.Figure 2.4 Decision matrix when evaluating two in silico predictions.

2 Chapter 3Figure 3.1 Proposed process flow for MI risk assessment for a pharmaceutical...Figure 3.2 (P)MI purge factor decision tree for use under ICH M7.Figure 3.3 Identified (I) and reasonably predicted (RP) impurities within GW...Figure 3.4 Synthetic process to GW641597X.Figure 3.5 ¹H NMR of Stage 1a product 3.Figure 3.6 ¹H NMR of Stage 4b product crude GW641597X.Figure 3.7 Nitrosamine formation pathways from Et3N and DMF.Figure 3.8 Process map of candesartan synthesis.Figure 3.9 Breakdown of purge assignments for Et₃N in the Stage 2 workup pro...Figure 3.10 Purge calculation summary for Et₃N.Figure 3.11 Purge calculation summary for DMF.Figure 3.12 Purge calculation summary for DMA and DEA.Figure 3.14 Schematic of candesartan process highlighting the purge‐based ri...Figure 3.13 Purge calculation summary for NaNO2.

3 Chapter 4Figure 4.1 Assignment of class 1–5 based on computational models and experim...Figure 4.2 Prediction using an expert alert system.Figure 4.3 Building an expert alert knowledge base.Figure 4.4 Example of a positive prediction using an expert rule‐based syste...Figure 4.5 Example of a negative prediction using an expert rule‐based syste...Figure 4.6 Process of building a statistical‐based model.Figure 4.7 Process of making a positive prediction with a statistical‐based ...Figure 4.8 Process of making a negative prediction with a statistical‐based ...Figure 4.9 Four examples with predictions from expert rule‐based and statist...Figure 4.10 An assessment by chemical analogs.Figure 4.11 Assessing the lack of reactive potential through visual inspecti...Figure 4.12 Resolving results from different (Q)SAR result. Neg – negative, ...Figure 4.13 Summary of the risk of missing a mutagenic impurity based on an ...Figure 4.14 Two chemicals where the results are negative in both systems.Figure 4.15 An example that is positive in the two (Q)SAR methodologies.Figure 4.16 An example with conflicting (Q)SAR results.Figure 4.17 Example of a prediction where one of the methodologies is an ind...Figure 4.18 Example that includes an out‐of‐domain result.Figure 4.19 Impurities report generated for four chemicals.

4 Chapter 5Figure 5.1 Derek Nexus predictions compared with Leadscope modeller predicti...Figure 5.2 Ashby–Tennant super structure.Figure 5.3 Metabolic activation of aromatic amines/aromatic nitro compounds ...Figure 5.4 Substitution pattern analysis illustrating activating and deactiv...Figure 5.5 Examples of strong activating primary aromatic amines (fused ring...Figure 5.6 Examples of strong activating primary aromatic amines (anilines)....Figure 5.7 Example of strong deactivating primary aromatic amines (anilines)...Figure 5.8 Quindioxin and related compounds, and benzo[c][1,2,5]oxadiazole 1...

5 Chapter 6Figure 6.1 Reaction of carboxylic acid/sulfonic acid halides with DMSO.Figure 6.2 Flowchart representing the standard Ames test.Figure 6.3 Overview of a rodent Pig‐a study.Figure 6.4 Flow cytometric scoring of Pig‐a mutant phenotype erythrocy...Figure 6.5 The rodent bone marrow micronucleus test.Figure 6.6 The comet assay. Hepatocyte nuclei from rats given an oral dose o...Figure 6.7 The experimental procedure for Big Blue^® and Muta™Mouse assa...Figure 6.8 Schematic representation of three “threshold” dose–response curve...

6 Chapter 7Figure 7.1 General structure of an N‐nitrosamine.Figure 7.2 General N‐nitrosamine metabolism to reactive metabolite.Figure 7.3 Comparison of Lhasa TD₅₀s and Log P (as JPogP) [93].Figure 7.4 N‐Nitrosamine representation for potency subclassifications.

7 Chapter 8Figure 8.1 Flowchart illustrating potential mechanisms underlying genotoxic ...Figure 8.2 Schematic representation of the BMD approach for analyzing dose–r...Figure 8.3 EMS‐induced thresholded dose response in vivo.Figure 8.4 DNA adduct locations in DNA coupled to DNA repair processes invol...Figure 8.5 Benchmark dose–response modeling results for HPRT gene mutations ...Figure 8.6 Example of breakpoint dose, slope transition dose, and BMD modeli...

8 Chapter 9Figure 9.1 Example reaction scheme highlighting the fate of two mutagenic im...Figure 9.2 Comparative structures of phenoxazines.Figure 9.3 Buchwald–Hartwig coupling of an aryl bromide (3) to 4 methyl pipe...Figure 9.4 Extraction curves and equilibria for Aryl Bromide 3 and Aniline 5...Figure 9.5 Consortium PMI Purge Factor Decision Tree for use under ICH M7.Figure 9.6 Stages 4 and 5 within the second generation manufacture of atovaq...Figure 9.7 A screenshot of part of the reaction grid for common reactive int...Figure 9.8 Illustration of the reactivity matrix within Mirabilis.Figure 9.9 Example of additional supporting information displayed within Mir...Figure 9.10 Identifying the appropriate purge prediction in Mirabilis.Figure 9.11 Examples of restrictions on purge parameters for various steps w...Figure 9.12 Top: Purge table in Mirabilis report. Bottom: Predicted reactivi...Figure 9.13 Synthetic process to Camicinal (GSK962040).Figure 9.14 Synthetic process to the proposed registered starting material t...Figure 9.15 Further tentatively assigned and “non‐alerting” impurities withi...Figure 9.16 Observed degradants from Camicinal forced DS degradation and DP ...

9 Chapter 10Figure 10.1 Valsartan and N‐Nitrosodimethylamine (NDMA).Figure 10.2 Timeline of events relating to N‐Nitrosamine contamination of ph...Figure 10.3 Comparison of the nitrosation of secondary and primary amines.Figure 10.4 Comparison of new revised process, based on use of sodium azide ...Figure 10.5 Quenching of sodium azide using sodium nitrite.Figure 10.6 Generation of N‐Nitrosodiethylamine (NDEA) from Triethylam...Figure 10.7 Chronology of events from September 2019 to September 2020.Figure 10.8 Postulated reaction scheme for NDMA formation via UDMH. [22]Figure 10.9 Binary VLE diagrams (constant pressure at 1 atm). Mass fraction ...Figure 10.10 EFPIA drug substance risk assessment decision tree.Figure 10.11 Solvent recycling decision tree.Figure 10.12 Structure of FD&C Blue #2/Indigo carmine aluminum lake.Figure 10.13 F‐Stages of granule formation during wet granulation.Figure 10.14 Structure of 4‐phenylpiperidine HCl salt.Figure 10.15 Illustration of a typical structure of a lidding foil and its a...Figure 10.16 Photograph of a lidding procedure.Figure 10.17 Illustration of common downstream process options.Figure 10.18 Image of a protein showing accessible surface amino acids.Figure 10.19 Reproduced from Article 5(3) report.Figure 10.20 Reproduced from Article 5(3) report.Figure 10.21 Metabolic activation of NDMA to generate the electrophilic meth...

10 Chapter 11Figure 11.1 Structural alerts for mutagenicity.Figure 11.2 Comparison of primary and secondary amine nitrosation.Figure 11.3 Formation of dinitrogen trioxide, N₂O₃.Figure 11.4 Formation of nitrosyl chloride, ClNO.Figure 11.5 The pH initial rate profiles for the nitrosation of Et₂NH (0.001...Figure 11.6 Mechanistic scheme for the formaldehyde‐catalyzed nitrosation of...Figure 11.7 Mechanistic scheme for the nitrosation of a secondary amine by a...Figure 11.8 Mechanistic scheme for the dealkylative nitrosation of simple te...Figure 11.9 Mechanistic scheme for the formation of nitroso cyclohexyl methy...Figure 11.10 Proposed mechanistic scheme for the formation of NDMA from tetr...Figure 11.11 Proposed mechanistic scheme for the formation of NDMA from trim...Figure 11.12 Photochemical degradation of nitric acid.Figure 11.13 Equilibria between nitrogen oxides.Figure 11.14 Decomposition of nitrous acid to nitric oxide.Figure 11.15 Nitrous acid scavenging reactions of hydrazoic acid, sulfamic a...Figure 11.16 Primary mechanistic options for nitroarene reduction using a no...Figure 11.17 Concentration gradients (not to scale) associated with mass tra...Figure 11.18 Condensation chemistry impurities at the end of a nitro reducti...Figure 11.19 Mechanistic representation of ArNO₂ reduction. The * represents...Figure 11.20 Contamination of aniline with a hydroxyaniline arising from a B...Figure 11.21 Vanadium‐catalyzed disproportionation of hydroxylamine.Figure 11.22 Effect of vanadium cocatalyst on outcome of N‐cyclohexyl‐N‐meth...Figure 11.23 Effect of vanadium cocatalyst on nitro reduction used in AZD893...Figure 11.24 Concentration profiles of “HOHN‐core‐NHOH,” “HOHN‐core‐NH₂,” an...Figure 11.25 Nitro reduction during synthesis of vismodegib.Figure 11.26 Nitro reduction during synthesis of ticagrelor.Figure 11.27 Use of a sulfided platinum catalyst.Figure 11.28 Reduction of a retigabine‐like drug substance.Figure 11.29 Potential mechanistic pathways for the formation of sulfonate e...Figure 11.30 Solvolysis of sulfonate esters.Figure 11.31 Schematic representation of the instrument used for the conduct...Figure 11.32 EMS formation under anhydrous conditions and the effect of temp...Figure 11.33 EMS formation – the effect of water on conversion; including ex...Figure 11.34 Effect of added base on EMS formation.Figure 11.35 Combined plot showing the impact of both temperature and water ...Figure 11.36 IMS formation under anhydrous conditions and the effect of temp...Figure 11.37 Combined plot showing the impact of both temperature and water ...Figure 11.38 Comparison between conversions of MSA and TSA to ETS and EMS in...Figure 11.39 Comparison of data from two separate determinations of the conv...Figure 11.40 Conversion of MSA to EMS as a function of MSA concentration in ...Figure 11.41 Conversion of MSA to EMS as a function of MSA concentration in ...Figure 11.42 Manufacture of MSA.Figure 11.43 Logarithm of EMS concentration versus time at different storage...

11 Chapter 12Figure 12.1 Method selection chart for PMI/MI determination in API.Figure 12.2 Alternative method selection chart for designing methods for PMI...Figure 12.3 GC‐MS configuration: (a) GC with SSL and PTV inlet, thermal deso...Figure 12.4 Typical LC‐MS configuration, with additional LC for 2D‐LC operat...Figure 12.5 Valve systems for column selection (top) and 2D‐LC (bottom).Figure 12.6 Analysis of organohalides in API (promethazine) by SHS‐GC‐MS (SI...Figure 12.7 Analysis of organohalides in API (promethazine) by headspace‐SPM...Figure 12.8 (a) Reaction of sulfonic acid with alcohol and formation of sulf...Figure 12.9 Analysis of sulfonate esters in API (ampicillin) by derivatizati...Figure 12.10 Analysis of sulfonate esters in API (promethazine) by direct in...Figure 12.11 Analysis of N‐mustards in API (doxylamine) by derivatization – ...Figure 12.12 Analysis of Michael reaction acceptors in promethazine spiked a...Figure 12.13 Principle of capillary column back‐flush.Figure 12.14 Analysis of carbamazepine using liquid injection GC‐MS with bac...Figure 12.15 Deans switch 2D‐GC‐MS setup for the analysis of PMI/MI in API b...Figure 12.16 FID monitor detector trace from first dimension separation of t...Figure 12.17 Extracted ion chromatogram from second dimension GC‐MS analysis...Figure 12.18 Analysis of aziridines in Vitamin C spiked at 1 ppm using HILIC...Figure 12.19 RPLC‐MS analysis of non‐derivatized arylamines and aminopyridin...Figure 12.20 RPLC‐MS analysis of derivatized arylamines and aminopyridines i...Figure 12.21 Analysis of 3‐aminobenzonitrile in bupivacaine spiked at 1 ppm ...Figure 12.22 High‐throughput analysis of non‐derivatized arylamine and amino...Figure 12.23 Analysis of hydrazines in Vitamin C spiked at 1 ppm level by de...Figure 12.24 Analysis of phenylhydrazine in Penicillin V spiked at 1 ppm lev...Figure 12.25 Analysis of aldehydes by DNPH derivatization – LC‐MS, Peaks: se...Figure 12.26 TIC and EIC chromatograms for blank solvent (DMSO), spiked solv...Figure 12.27 EIC MRM chromatograms for NDMA, NDMA‐d6, NDEA, NDEA‐d10, NEIPA,...Figure 12.28 EIC chromatograms for NDMA, NDMA‐d6, NMBA, NDEA, NDEA‐d10, NEIP...Figure 12.29 Untargeted analysis of unknown impurities in metoclopramide by ...

12 Chapter 13Figure 13.1 Diagrammatic representation of how an NMR spectrum is generated....Figure 13.2 The different spin‐states of H_B causes the signal from H_A to spl...Figure 13.3 The effect of coupling on a single nucleus (a) not coupled and c...Figure 13.4 Quantitative ¹H spectra of atenolol (12.36 mg, MW 266.3 g/mol) i...Figure 13.5 The return to equilibrium magnetization is governed by the relax...Figure 13.6 Relative sensitivity of the NMR experiment as a function of magn...Figure 13.7 (a) Traditional and (b) inverse probe designs. The ¹H coil is sh...Figure 13.8 A variety of NMR tube diameters: 1, 3, 5, and 10 mm.Figure 13.9 A cryoprobe installation on 600 MHz magnet. The unit on the left...Figure 13.10 The S : N as a function of the number of scans.Figure 13.11 400 mg/ml substrate (a) FID of ¹⁹F NMR spectrum with ¹H decoupl...Figure 13.12 Relative amplitude as a function of pulse angle for a fixed rel...Figure 13.13 The effect of linewidth on sensitivity. All signals from a sing...Figure 13.14 (a) Simulated spectrum (with no noise) of a substrate signal at...Figure 13.15 ¹H spectra of H₂O (spiked with 5% D₂O for a lock) with impuriti...Figure 13.16 Example of the distortion caused by receiver overload. The form...Figure 13.17 2 mM sucrose in 90% H₂O. Without water suppression the water si...Figure 13.18 Excitation profiles for rectangular 90° pulses of (a) 10 μs, (b...Figure 13.19 (a) The selective pulse experiment overlaid with (b) a normal c...Figure 13.20 Proton spectra of 100 mg API (4) in d₆‐DMSO (a and b) duplicate...Figure 13.21 Proton spectra of 100 mg API (4) in d₆‐DMSO (a and b) companion...Figure 13.22 (a) ¹H NMR spectrum of TFNB and (b) 50 ppm spike of TFNB in 500...Figure 13.23 ¹⁹F with ¹H decoupling spectra of (a) TFNB and (b) intermediate...Figure 13.24 ¹⁹F spectrum with ¹H decoupling of intermediate (6) at approxim...Figure 13.25 (a) Selective excitation experiment on spiked sample selecting ...Figure 13.26 ¹H excitation sculpting with double gradient echo exciting the ...Figure 13.27 (a) ¹H excitation sculpting with double gradient echo of spikin...Figure 13.28 (a) ¹H NMR spectrum of PLGA copolymer highlighting resolved sig...

13 Chapter 14Figure 14.1 Critical aspects of determining potential degradation products t...Figure 14.2 Proposed process flow for assessing degradation products in the ...Figure 14.3 Illustration of criterion no. 1 in a sample chromatogram: Identi...Figure 14.4 Illustration of combining criterion no. 1 with criterion no. 2 i...Figure 14.5 The degradation pathways of Molecule A in a solid‐oral dosage fo...Figure 14.6 Oxidative stress testing of galunisertib with dilute hydrogen pe...Figure 14.7 Last step in synthesis of galunisertib involves hydrolysis of th...Figure 14.8 PEGylation of MEM‐protected Naloxone.Figure 14.9 Reaction to form AZ13336989 sulphonate ester.Figure 14.10 Degradation pathway of NKTR‐118.Figure 14.11 Degradation pathway of Selumetinib.Figure 14.12 Ames test results for Selumetinib side chain.Figure 14.13 Mechanism of formation of N‐Nitrosamines.Figure 14.14 Potential formation of NDMA inter‐ or intramolecularly within r...Figure 14.15 The proposed drug product workflow for assessing the risk of th...Figure 14.16 Pathway for N‐nitrosation of tertiary amines from nitrites (mor...