GENOTOXIC IMPURITY ANALYSIS IN PHARMACEUTICALS
simply by
Matthew Austin texas Janson
A Thesis Presented to the FACULTY OF THE GRADUATE STUDENT SCHOOL COLLEGE OR UNIVERSITY OF SOUTHERN CALIFORNIA In Incomplete Fulfillment with the Requirements pertaining to the Degree LEARN OF TECHNOLOGY (PHARMACEUTICAL SCIENCE) December 2009
Copyright 2009
Matthew Austin Janson
Acknowledgements
The following persons are being recognized for their efforts in this thesis: Dr . Wei-Chiang Shen for his position as panel head and then for his invaluable guidance through the process of writing this thesis. Dr . Curtis Okamoto and Dr . Clay-based Wang intended for serving for the thesis panel. Dr . Philip Zhou and Dr . Sophie Wang for scientific discussion and overview of this thesis.
ii
Desk of Material
Acknowledgements List of Figures List of Abbreviations Subjective Introduction: Genotoxicity Genotoxicity in Pharmaceutics Genotoxic Impurity Examination and Control Regulatory Elements Analytical Methods to Monitor Genotoxic Impurities Part 1: Analytical Challenges and Techniques Sample Handling Concerns Selectivity by Matrix Additional Separation Techniques Sensitivity Approach Validation and QC Transfer Chapter two: Analytical Approach Details Hydrazines Aldehydes Nitro Compounds Arylamines Chapter a few: Conclusion Referrals Appendix A: Analytical Technique Details
ii iv ni viii you 2 5 11 17 19 20 21 3 25 twenty-eight 30 31 37 45 49 53 58 62
iii
Set of Figures
Physique 1: Genotoxic Impurity Decision Tree Number 2: Decision Tree for GTI (Genotoxic Impurity) Screening Strategy Determine 3: Scaled TTC: Attentiveness vs . Daily Dose Number 4: Useful Groups Associated with Genotoxic Harmful particles and Their Conceivable Transformations/Reactions Determine 5: Decision Tree for choosing an Appropriate Metal detector (" Chrom” = Chromophore and " Sens” sama dengan Sensitivity) Figure 6: Acetone Azine inside the LOQ (0. 1 ppm) and 1 ppm Levels. Black Find is Bare Figure six: Effect of Numerous Alcohols in HILIC Mobile Phase to separate your lives Hydrazines (1 = 1, 2-dimethylhydrazine, two = one particular, 1-dimethylhydrazine, 3 = methyl hydrazine and 4 = hydrazine) Number 8: Derivatization Reaction of Formic Acid and Formaldehyde with Acidified Alcoholic beverages Figure on the lookout for: HPLC/UV Chromatograms of Derivatized Aldehydes (1 = chemical, 2 sama dengan acetaldehyde, 3 = propanal, 4 = butanal, a few = pentanal and 6th = hexanal) in the Presence of Common Excipients (A = Aldehyde Standard without Excipients, N = Hydroxymethyl Cellulose and C sama dengan Hypromellose) Figure 10: GC/MS Method a couple of Chromatograms of Derivatized Aldehydes (1 sama dengan formaldehyde-PFBHA, two = PFBHA, 3 and 4 sama dengan acetaldehyde-PFBHA) inside the Presence of Common Excipients (A = Hypromellose, W = Hydroxylpropyl Cellulose and C = PFBHA Blank)
6 on the lookout for
14 18
26
thirty-three
35
39
41
43
iv
List of Figures: Continued
Figure 11: Comparison of HPLC (top) and UPLC (bottom) Stability-indicating Strategies. Impurities My spouse and i and 2 (8nitro-6-methoxyquinoline) are very well Resolved in the Drug Substance, Primaquine Determine 12: Schematic Showing Spiking Studies of Impurity 3 at Several Stages in the Synthesis with the API (GW786034)
47
51
v
Set of Abbreviations
ADI: Acceptable Daily Intake ALARP: As Low as Realistically Possible API: Active Pharmaceutical Ingredient CAD: Charged Suspension Detector VOTRE: Capillary Electrophoresis CLND: Chemiluminescent Nitrogen Detector DEREK: Deductive Estimation of Risk from Existing Understanding ECD: Electron Capture Metal detector ELSD: Evaporative Light Spreading Detector FID: Flame Ionizing Detector GC: Gas Chromatography GTI: Genotoxic Impurity HILIC: Hydrophilic Discussion Liquid Chromatography IC: Ion Chromatography LOD: Limit of Detection LOQ: Limit of Quantitation MCASE: Multi-computer Automatic Structure Analysis MNC: 1-methyl-4-nitro-3-propylpyrazole-5-carboxamide MNP: 1-methyl-4-nitro-3-propylpyrazole-5-carboxylic acid MS: Mass Spectrometry
vi
List of Abbreviations: Continuing
NMP: N-methylpyrrolidone PDE: Permitted Daily Exposure PFBHA: O-2, 3, four, 5, 6-(pentaflurorbenzyl)...
References: Unces. Y. Yuabova, et ing., Genotoxic impurities: A quantitative approach. Record of The liquid Chromatography & Related Solutions, 2008. 31(15): p. 2318-2
32.
L. Zhao, S. Chu and X. Xu: Optimization of non-equilibrium liquid-phase microextraction for the dedication of nitrobenzenes in aqueous samples simply by gas chromatography-electron capture diagnosis. Analytical Savoir, 2004. 20: p. 663-666.
