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Selorm Modzabi, Marianna A. Busch and Kenneth W. Busch Baylor University One Bear Place #97348

Selection of appropriate chiral selectors for chiral analysis by regression modeling of spectral data. Selorm Modzabi, Marianna A. Busch and Kenneth W. Busch Baylor University One Bear Place #97348 Waco, TX 76798. Need for chiral analysis*. Pharmaceutical industry Drug development

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Selorm Modzabi, Marianna A. Busch and Kenneth W. Busch Baylor University One Bear Place #97348

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  1. Selection of appropriate chiral selectors for chiral analysis by regression modeling of spectral data Selorm Modzabi, Marianna A. Busch and Kenneth W. Busch Baylor University One Bear Place #97348 Waco, TX 76798

  2. Need for chiral analysis* • Pharmaceutical industry • Drug development • Process control • Agro-chemical industry • Food and beverage industry • Fragrance industry • Basic research *Chiral Analysis, K. W.Busch & M. A. Busch Eds., Elsevier, 2006

  3. CHIRAL ANALYSIS BY REGRESSION MODELING OF SPECTRAL DATA (CARMSD) • Modern chemical instrumentation allows us to combine— • Multivariate (multi-wavelength) data collection • with • Multivariate modeling • to give a powerful combination that can extract latent information from the multivariate data that would not be possible with univariate measurements

  4. Basic Strategy of CARMSD1. Calibration Phase • Prepare a set ofcalibration samples • Same total concentration of chiral analyte • Different known enantiomeric compositions • Fixed concentration of chiral auxiliary

  5. Basic Strategy of CARMSD1. Calibration Phase • Collect spectral data on the calibration set • Perform PLS-1 regression modeling

  6. Basic Strategy of CARMSD2. Validation Phase • Prepare a new set of validation samples • Collect spectral data • Enter the spectral data into the regression model and predict the enantiomeric compositions • Compare the predicted enantiomeric compositions with the known values

  7. CARMSD • Clearly the chiral auxiliary is at the heart of the CARMSD method. • Regression modeling depends on changes in the spectral signature with enantiomeric composition of the sample. • The larger these spectral changes are, the easier it is to develop robust regression models.

  8. CARMSD • Chiral Selectors used to date • Cyclodextrins • Modified cyclodextrins • Surfactants & mixed cyclodextrins • Chiral Surfactants • Chiral Ionic Liquids

  9. Enantiomeric discrimination by transient noncovalent complex formation with cyclodextrins— An Example Enantiomeric pair CD CD Diastereomeric pair (hypothetical) Enantiomer-CD transient inclusion complexes

  10. Chiral selectors used to date Chiral analytes: amino acids, pharmaceuticals, other organics Analyte to selector (CDs, MCDs) mole ratio: = 1 : 2 RMSEP = [S (xip – xi)2/n]1/2 : xi = known mole fraction, xpi = predicted mole fraction & n = total samples predicted

  11. Problems with CDs • Limited Solubility • Extent of interaction depends on formation constant of inclusion complex • Possibility of more than one complex in solution (R—CD, CD—R—CD, etc.) • Inclusion complex formation depends on size of analyte in relation to cyclodextrin

  12. What about other possible chiral auxiliaries?

  13. Use of Chiral Amines Ion-pair formation as a means of enantiomeric discrimination Formation of quaternary ammonium salts of carboxylic acids

  14. CARMSD with a Homochiral Amine Chiral selector: (S)-1-phenylethylamine (S-PEA) Determination of enantiomeric composition of Tyrosine with (S)-phenylethylamine using UV spectroscopy Zwitterion Diastereomeric ion pairs

  15. Originalspectra Isosbestic point (343 nm) Use of (S)-1-phenylethylamine Determination of enantiomeric composition of Tyrosine (Tyr to S-PEA ratio = 1 : 1)

  16. Effect of pH on spectrum Effect of varying PEA/Tyr mol ratios at neutral pH Effect of varying PEA/Tyr mol ratios in acid solution

  17. Job’s Plot Job’s plot in neutral solution indicating 1:1 ion pair formation Job’s plot in acid solution indicating lack of ion pair formation

  18. Determination of enantiomeric composition of Tyrosine with (S)-phenylethylamine using UV spectroscopy— PLS1 Calibration Model Plots Randomly Selected Calibration Samples: 0.0500, 0.150, 0.300, 0.400, 0.500, 0.650, 0.850, 0.950

  19. Determination of enantiomeric composition of Tyrosine with (S)-phenylethylamine using UV spectroscopy— Results of CARMSD Cross validation of calibration samples: 0.0500, 0.150, 0.300, 0.400, 0.500, 0.650, 0.850, 0.950 Cross validation plot

  20. Determination of enantiomeric composition of Phenylalanine with (S)-phenylethylamine using UV spectroscopy- Results of CARMSD Cross validation of calibration samples: 0.0500, 0.100, 0.200, 0.392, 0.500, 0.527, 0.700, 0.950

  21. Determination of enantiomeric composition of Alanine with(S)-phenylethylamine using UV spectroscopy- Results of CARMSD Cross validation of calibration samples: 0.0500, 0.100, 0.250, 0.350, 0.500, 0.650, 0.750, 0.850

  22. Use of Chiral Alcohols Fischer Esterification Esterification results in the formation of true covalent diastereomers

  23. CARMSD with Homochiral (S)-(+)-1,2-propanediol Determination of enantiomeric composition of Phenylalanine with (S)-1,2-propanediol using UV spectroscopy Possible products

  24. Determination of enantiomeric composition of Phenylalanine with 1,2-propanediol using UV spectroscopy Original UV spectra (15 samples) Mean centered UV spectra (15 samples)

  25. Determination of enantiomeric composition of Phenylalanine with 1,2-propanediol using UV spectroscopy- PLS1 Calibration Model Plots Randomly selected calibration samples: 0.050, 0.150, 0.250, 0.300, 0.500, 0.750, and 0.950

  26. Determination of enantiomeric composition of Phenylalanine with 1,2-propanediol using UV spectroscopy- Results of CARMSD Randomly selected calibration samples: 0.050, 0.150, 0.250, 0.300, 0.500, 0.750, and 0.950

  27. 0.6 0.5 0.4 LEL 0.3 UEL UEL - LEL 0.2 0.1 0 Cyclodextrins Modified Chiral Surfactants Chiral Ionic Liquids Covalent/ionic Cyclodextrins Diatereomers CARMSD with noncovalent diastereomers vs. CARMSD with covalent diastereomers RMSEP figure of merit analysis of chiral discrimination strategies LEL = lower RMSEP limit and UEL = upper RMSEP limit

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