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A seminar on Recent advancement in impurity profiling Presented by Sudipkumar modh 1
Agenda 2 1. Definition of ICH 2. Importance 3. History 4. Systemic approach 5.Isolation And Identification 6.Case study 7.Methodology     a)Classical approaches     b)Modern approaches 8.Conclusion
Definition of ICH (Q6A specifications) ,[object Object],“Any component of the new drug substance that is not the chemical entity defined as the new drug substance“ “Any component of the drug product which is not the chemical entity defined as the drug substance or an Excipient in the drug product.” Impurity profiling: ,[object Object]
Detection, identification/structureelucidation
Quantitative determination
Of organic and inorganic impurities and residual solvents in bulk drugs & pharmaceutical formulations3
Importance all phases of synthetic drug research and production from the gram scale preparation of new compounds  For pharmacological screening up to the scaling up procedure and finally the production of bulk drugs Differentiate between synthesis-related    impurities and degradation products 4
HISTORY of instrumental analysis Period following world war II,rapid development of pharmaceutical industry Instrumental analysis was developed with military technology Qualitative analysis was met by molecular spectroscopy but with complexity Spectroscopic method were generally complex, and there was a need of expert spectroscopist  Separations techniques came, at the end of 19th century revolution came by development of TLC  After world war II,GC developed and HPLC after two decades The fully Instrumental technique science arrived 5
Systemic approach According to ICH Q3A(R2)  6 Maximum      Reporting            Identification                           Qualification daily dose     threshold             threshold                                 threshold (g/day)             (%)
Systemic approach 7
Systemic approach ,[object Object],Purified and sample should be split into aliquots for MS,NMR, and vibrational spectroscopy Repetition of MS of sample is required  ,[object Object]
2nd determine fragmentation pathway from MS/MS data Empirical formula of HRMS is useful, if impurity is unknown and unrelated with drug  In this case, by FT-IR,FT-Raman or both, functional groups are identified Structure is eluted by MS and NMR (Homo and hetero nuclear direct and long range chemical shift correlation experiments) 8
Isolation And Identification Preparative chromatography In reversed phase chromatography good isolation can be achieved, by using stationary non polar phase and polar mobile phase with polarity modifiers, pairing ions, buffers Due to diverse nature of impurity, not only RP-HPLC , but also  ,[object Object]
Supercritical fluid chromatography
Gas chromatography
Capillary electrophoresisMay be a good choice ,[object Object],9
Isolation And Identification ,[object Object],After isolation sample may contain artifacts from the isolation process, this constituents are referred as “chemical noise” This may affect particularly to high sensitivity NMR probes(1.7 mm)  10
Isolation And Identification ,[object Object]
MSMolecular weight changes show gain or loss of some neutral species exp is CO Formation of adduct ions can be useful for preliminary identification of molecular ion Exp adduct ions like sodium,pottasium,acetonitrile at +23,+39,+43 Isotope patterns also useful like of Cl, Br  HRMS is useful for unrelated impurity MS/MS provides site of chemical modification and type of modification Not useful for detection of positional isomers ,[object Object],Besides of convectional NMR , ,[object Object]
DEPT
INEPT
2d NMR like
COSY
TOCSY
HSQC
HMBCAre used now a days 11 HSQC (Heteronuclear Single Quantum Coherence)   HMBC (Heteronuclear Multiple Bond Coherence)  Distortion less Enhancement by Polarization Transfer(DEPT) Insensitive Nuclei Enhanced by Polarization Transfer (INEPT)
Isolation And Identification ,[object Object],With advancement in 2d NMR,vibrational spectroscopy like FT-IR and FT-RAMAN is somewhat not acquired  But this types of spectroscopy is essential in functional group detection,parallely with MS and NMR Carbonyl function groups are detected efficiently in vibrational spectroscopy But it is transparent in COSY and HSQC In HMBC long correlations are observed with carbonyl moiety ,[object Object],12
Case study Isolation And Identification Characterization of an unstable process impurity in the protease inhibitor Tipranavir  Colored contaminant was being formed in final step of the synthetic process  Formed due to coupling of aniline-like derivative with pyridine being used       as acid scavenger Isolated by methanol stripping of silica gel chromatography methanol solution containing the colored impurity was bright red   half life of about 18 h in methanol and <10 min in acetone By 1.7-mm 600-MHz SMIDG probe, sample was prepared and data set consisting of a proton reference spectrum, TOCSY, HSQC, and 10-Hz optimized HMBC spectra was acquired 13 SMIDG=sub micro-inverse-detection gradient
Characterization of an unstable process impurity in the protease inhibitor Tipranavir Case study Isolation And Identification drug Formed colored impurity 14 Starting material
in addition to the resonances normally observed for the drug, showed three new well-resolved signals,  ,[object Object]
 7.82(t)
 6.27(t)The doublet (8.25) and one of the triplets (6.27 ppm) , twice the intensity of  triplet (7.82 ppm), which had an integrated intensity corresponding to  half of that of a one proton signal in the drug molecule. Conclusion: impurity contained two molecules of drug and that the new resonances were present in a ratio of 2 : 2 : 1 The TOCSY spectrum confirmed the coupling of the new resonances in the aromatic region Isolation And Identification Case study Characterization of an unstable process impurity in the protease inhibitor Tipranavir 15
A HRMS spectrum gave exact mass of 848.47287Da  (less the ionizing proton) corresponding to the molecular weight of two of the aniline precursor molecules and a C5H5 fragment consistent with the integration of the new aromatic resonances in  proton spectrum. GHSQC data established the following direct proton– carbon correlation: 8.25/152.7, 7.82/125.8, and 6.27/106.2 ppm  HMBC correlations linked at 8.25/152.7 ppm resonant pair to  aromatic quaternary carbon bearing  aniline group resonating at 142.6 ppm.  other correlations were internal to five-carbon fragment Isolation And Identification Case study Characterization of an unstable process impurity in the protease inhibitor Tipranavir 16
Isolation And Identification HSQC spectrum Case study Characterization of an unstable process impurity in the protease inhibitor Tipranavir 17
Isolation And Identification HMBC spectrum Case study Characterization of an unstable process impurity in the protease inhibitor Tipranavir 18
Isolation And Identification ,[object Object],Included increase in intensity of the band at 1636 cm–1 suggesting increased double bond 1547 cm–1 consistent with C=N stretching that is not present in Tipranavir 1170 cm–1 region of C–O stretching and C–OH bending that can be accounted for by the dimeric nature of the impurity of Tipranavir The five carbon fragment linking the two aniline moieties arose from the pyridine ring coming apart during the reaction Case study Characterization of an unstable process impurity in the protease inhibitor Tipranavir 19
Methodology ,[object Object]
separation and determination of impurities with known structure
Isolation of the impurity and off-line structure elucidation
Modern approach
Using on-line hyphenated separation/spectroscopic methods20
Classical approach Methodology…. separation and determination of impurities with known structure HPLC TLC ,[object Object]
Capillary Electrophoresis
 Electrophoresis-related Chromatographic    Techniques Methods not Requiring Separation  ,[object Object],21
HPLC HPLC is often used with UV Chemometric methods used for separation optimisation but also for improving quantitative analysis Dimension 150-250 x 4.0-4.6 mm RP-stationary phase with particle size of 3.5-5.0 μm  Rt in range of 10-20 min Ultra-performance liquid chromatography (UPLC) uses short and narrow-bore columns with small particle size packing Exp  Impurities of primaquine phosphate  dimensions of the column were 50 x 2.1mm   C18 silica packing and 1.7 μm separation was achieved within 2 minutes Classical approach…. 22

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Recent advancement in impurity profiling

  • 1. A seminar on Recent advancement in impurity profiling Presented by Sudipkumar modh 1
  • 2. Agenda 2 1. Definition of ICH 2. Importance 3. History 4. Systemic approach 5.Isolation And Identification 6.Case study 7.Methodology a)Classical approaches b)Modern approaches 8.Conclusion
  • 3.
  • 6. Of organic and inorganic impurities and residual solvents in bulk drugs & pharmaceutical formulations3
  • 7. Importance all phases of synthetic drug research and production from the gram scale preparation of new compounds For pharmacological screening up to the scaling up procedure and finally the production of bulk drugs Differentiate between synthesis-related impurities and degradation products 4
  • 8. HISTORY of instrumental analysis Period following world war II,rapid development of pharmaceutical industry Instrumental analysis was developed with military technology Qualitative analysis was met by molecular spectroscopy but with complexity Spectroscopic method were generally complex, and there was a need of expert spectroscopist Separations techniques came, at the end of 19th century revolution came by development of TLC After world war II,GC developed and HPLC after two decades The fully Instrumental technique science arrived 5
  • 9. Systemic approach According to ICH Q3A(R2) 6 Maximum Reporting Identification Qualification daily dose threshold threshold threshold (g/day) (%)
  • 11.
  • 12. 2nd determine fragmentation pathway from MS/MS data Empirical formula of HRMS is useful, if impurity is unknown and unrelated with drug In this case, by FT-IR,FT-Raman or both, functional groups are identified Structure is eluted by MS and NMR (Homo and hetero nuclear direct and long range chemical shift correlation experiments) 8
  • 13.
  • 16.
  • 17.
  • 18.
  • 19.
  • 20. DEPT
  • 21. INEPT
  • 23. COSY
  • 24. TOCSY
  • 25. HSQC
  • 26. HMBCAre used now a days 11 HSQC (Heteronuclear Single Quantum Coherence) HMBC (Heteronuclear Multiple Bond Coherence) Distortion less Enhancement by Polarization Transfer(DEPT) Insensitive Nuclei Enhanced by Polarization Transfer (INEPT)
  • 27.
  • 28. Case study Isolation And Identification Characterization of an unstable process impurity in the protease inhibitor Tipranavir Colored contaminant was being formed in final step of the synthetic process Formed due to coupling of aniline-like derivative with pyridine being used as acid scavenger Isolated by methanol stripping of silica gel chromatography methanol solution containing the colored impurity was bright red half life of about 18 h in methanol and <10 min in acetone By 1.7-mm 600-MHz SMIDG probe, sample was prepared and data set consisting of a proton reference spectrum, TOCSY, HSQC, and 10-Hz optimized HMBC spectra was acquired 13 SMIDG=sub micro-inverse-detection gradient
  • 29. Characterization of an unstable process impurity in the protease inhibitor Tipranavir Case study Isolation And Identification drug Formed colored impurity 14 Starting material
  • 30.
  • 32. 6.27(t)The doublet (8.25) and one of the triplets (6.27 ppm) , twice the intensity of triplet (7.82 ppm), which had an integrated intensity corresponding to half of that of a one proton signal in the drug molecule. Conclusion: impurity contained two molecules of drug and that the new resonances were present in a ratio of 2 : 2 : 1 The TOCSY spectrum confirmed the coupling of the new resonances in the aromatic region Isolation And Identification Case study Characterization of an unstable process impurity in the protease inhibitor Tipranavir 15
  • 33. A HRMS spectrum gave exact mass of 848.47287Da (less the ionizing proton) corresponding to the molecular weight of two of the aniline precursor molecules and a C5H5 fragment consistent with the integration of the new aromatic resonances in proton spectrum. GHSQC data established the following direct proton– carbon correlation: 8.25/152.7, 7.82/125.8, and 6.27/106.2 ppm HMBC correlations linked at 8.25/152.7 ppm resonant pair to aromatic quaternary carbon bearing aniline group resonating at 142.6 ppm. other correlations were internal to five-carbon fragment Isolation And Identification Case study Characterization of an unstable process impurity in the protease inhibitor Tipranavir 16
  • 34. Isolation And Identification HSQC spectrum Case study Characterization of an unstable process impurity in the protease inhibitor Tipranavir 17
  • 35. Isolation And Identification HMBC spectrum Case study Characterization of an unstable process impurity in the protease inhibitor Tipranavir 18
  • 36.
  • 37.
  • 38. separation and determination of impurities with known structure
  • 39. Isolation of the impurity and off-line structure elucidation
  • 41. Using on-line hyphenated separation/spectroscopic methods20
  • 42.
  • 44.
  • 45. HPLC HPLC is often used with UV Chemometric methods used for separation optimisation but also for improving quantitative analysis Dimension 150-250 x 4.0-4.6 mm RP-stationary phase with particle size of 3.5-5.0 μm Rt in range of 10-20 min Ultra-performance liquid chromatography (UPLC) uses short and narrow-bore columns with small particle size packing Exp Impurities of primaquine phosphate dimensions of the column were 50 x 2.1mm C18 silica packing and 1.7 μm separation was achieved within 2 minutes Classical approach…. 22
  • 46. A new development in RP-HPLC is the introduction of oil-in-water emulsion into the mobile phase This method, named micro emulsion liquid chromatography (MELC) special application in field of impurity profiling by HPLC is high-speed counter-current chromatography (HSCCC) (semi)preparative Analysis by HPLC-DAD to determine relative purities of each fraction in course of the preparative isolation of drugs from e.g. medicinal plant matrices 23 HPLC Classical approach….
  • 47.
  • 48.
  • 49.
  • 50. An example is the polarographic and UV methods
  • 51. Exp Determination of benzophenone impurity in phenytoin impurities
  • 52. and low concentration of phenytoin do not allow direct use of UV spectrophotometry in drug impurity profiling
  • 54. Used in drug degradation studies where the relative concentration of the degradants is in per cent range
  • 55. Exp Determination of omeprazole sulphone in omeprazole
  • 56. monitoring of the photo degradation of amlodipine to it pyridine degradation product 26
  • 57.
  • 64.
  • 71.
  • 72.
  • 73.
  • 75. UV diode array detector
  • 76. HP-MSD modelD mass spectrometer
  • 78. six-position Cheminert valve is inserted on “D” line of quaternary pump to extend mobile phase selection
  • 79. Both column switcher and valve are connected through contact closures
  • 80.
  • 81. 33 Modern approach COMET instrumentation fully automated Comprehensive Orthogonal Method Evaluation Technology (COMET)
  • 83. 35
  • 84. 36
  • 85. 37 Modern approach COMET instrumentation
  • 86.
  • 89. wide ionisation capabilitiesAnise oil as starting material for the synthesis of 4-methoxy amphetamine was screened by GC-MS for impurities 38 Modern approach GC-MS
  • 90. TLC-MS Separated spots on the plate could be subjected to direct matrix-assisted-laser-desorption ionization Time-of-flight mass spectrometry (TLC-MALDI TOF -MS) no need to remove the spots from plate Only wetting spot with methanol required to transfer the analyte from inside the silica gel to the surface thus enhancing the MALDI-TOF-MS signal 39 Modern approach TLC-MS MEOH TLC PLATE
  • 91. 40 Modern approach Approaches for detection MS
  • 92. majority of applications are from the fields of metabolite and natural product analyses stopped flow HPLC-NMR technique (together with HPLC-MS) in identifying impurities in acarbose 41 Modern approach LC-NMR
  • 93. conclusion Impurity profiling is very important in the field of pharmaceutical analysis Unidentified and potentially toxic impurities are health hazards and in order to increase safety, impurity should be identified That’s all!!! 42
  • 94. references Analysis of drug impurities Edited by Richard J. smith and michael L .Webb Blackwell publishing ICH guidelines Handbook of modern pharmaceutical analysis by satinder ahuja and stephan scypinski Volume III of SEPARATION SCIENCE AND TECHNOLOGY Recent Advances in the Impurity Profiling of Drugs Dorottya Bartos and Sándor Görög* Current Pharmaceutical Analysis, 2008, 4, 215-230 Characterization of a trace by‐product of the synthesis of the protease inhibitor tipranavir GE Martin, RH Robins, FW Crow… - Journal of …, 1999 - Wiley Online Library http://www.biolab.dk/sidevisning.asp?ID=674 www.wikipedia.org http://www.welsch.com/e/index.php5 http://www.thefullwiki.org/Gas_chromatography-mass_spectrometry Automated peak tracking for comprehensive impurity profiling in orthogonal liquid chromatographic separation using mass spectrometric detection Gang Xue∗, Anne D. Bendick Journal of Chromatography A, 1050 (2004) 159–171 43
  • 95. 44