Molecular Structure and Dynamics in the Solid State - Terahertz Spectroscopy of Pharmaceuticals

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1 Molecular Structure and Dynamics in the Solid State - Terahertz Spectroscopy of Pharmaceuticals J Axel Zeitler Department of Chemical Engineering University of Cambridge jaz22@cam.ac.uk The Heidelberg PAT Conference 2007 The FDAs " Desired State" and the Pivotal Role of Spectroscopy J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

2 Outline 1 Terahertz Radiation Properties Traditional Far-Infrared Spectroscopy Terahertz Time-Domain Spectrscopy 2 PAT Applications for Terahertz Spectroscopy Identification of Solid State Modifications Solid Dosage Forms Quantitative Terahertz Spectroscopy Mechanism and Kinetics of Phase Transitions Relaxation and Crystallisation of Amorphous Materials Phase Transitions in Solid Dosage Forms 3 Future Challanges and Outlook Assignment of Vibrational Modes Quantum Cascade Lasers 4 Summary J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

3 Terahertz Radiation Outline 1 Terahertz Radiation Properties Traditional Far-Infrared Spectroscopy Terahertz Time-Domain Spectrscopy 2 PAT Applications for Terahertz Spectroscopy Identification of Solid State Modifications Solid Dosage Forms Quantitative Terahertz Spectroscopy Mechanism and Kinetics of Phase Transitions Relaxation and Crystallisation of Amorphous Materials Phase Transitions in Solid Dosage Forms 3 Future Challanges and Outlook Assignment of Vibrational Modes Quantum Cascade Lasers 4 Summary J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

4 Terahertz Radiation What is Terahertz Radiation? Properties W a v e n u m b e r [c m -1 ] 1 E F re q u e n c y [T H z ] W a v e le n g th [µm ] E n e rg y [m e V ] R a d io M ic ro w a v e T e ra h e rtz In fra re d V IS U V fa r m id n e a r Terahertz radiation frequency regime adjacent to optical and electronic techniques J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

5 Terahertz Radiation What is Terahertz Radiation? Properties J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

6 Terahertz Radiation Properties Inter- vs. intramolecular vibrations Terahertz Mid Infrared Intramolecular modes Intermolecular modes J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

7 Terahertz Radiation Properties THz Radiation Characteristics 2 to 133 cm 1 / 60 GHz to 4 THz, µw output power intrinsically safe Probes vibrational modes that extend across large domains of the lattice in organic molecular crystals Most polymeric materials are (semi-)transparent in this frequency range Ultrashort pulsed radiation readily available Coherent detection scheme using detectors operating at room temperature Measurement of the electric field rather than just its amplitude J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

8 Terahertz Radiation Traditional Far-Infrared Spectroscopy Terahertz pulse F re q u e n c y [T H z ] In te n s ity K K W a v e n u m b e r [c m -1 ] Limitations Very low intensity below 500 cm 1 Difficulties to distinguish thermal background from signal Cryogens needed to cool the detectors Radiation intensity from a blackbody radiation source J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

9 Terahertz Radiation Terahertz Time-Domain Spectrscopy Generation of Terahertz Pulses Pulsed coherent radiation from femtosecond switched photoconductive antennas V bias GaAs substrate J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

10 Terahertz Radiation Terahertz Time-Domain Spectrscopy Generation of Terahertz Pulses Pulsed coherent radiation from femtosecond switched photoconductive antennas V bias GaAs substrate J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

11 Terahertz Radiation Terahertz Time-Domain Spectrscopy Generation of Terahertz Pulses Pulsed coherent radiation from femtosecond switched photoconductive antennas V bias GaAs substrate J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

12 Terahertz Radiation Terahertz Time-Domain Spectrscopy Generation of Terahertz Pulses Pulsed coherent radiation from femtosecond switched photoconductive antennas V bias GaAs substrate J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

13 Terahertz Radiation Terahertz Time-Domain Spectrscopy Generation of Terahertz Pulses Pulsed coherent radiation from femtosecond switched photoconductive antennas V bias GaAs substrate J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

14 Terahertz Radiation Terahertz Time-Domain Spectrscopy Generation of Terahertz Pulses Pulsed coherent radiation from femtosecond switched photoconductive antennas V bias GaAs substrate J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

15 Terahertz Radiation Terahertz Time-Domain Spectrscopy Generation of Terahertz Pulses Pulsed coherent radiation from femtosecond switched photoconductive antennas V bias GaAs substrate J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

16 Terahertz Radiation Terahertz Time-Domain Spectrscopy Generation of Terahertz Pulses Pulsed coherent radiation from femtosecond switched photoconductive antennas V bias GaAs substrate J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

17 Terahertz Radiation THz-TDS setup in our lab Terahertz Time-Domain Spectrscopy J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

18 Terahertz Radiation THz-TDS setup in our lab Terahertz Time-Domain Spectrscopy J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

19 Terahertz pulse Terahertz Radiation Terahertz Time-Domain Spectrscopy averaged time domain waveform 8 wet air THz electric field / a.u time / s x Time-domain signal of the terahertz pulse from a LT-GaAs device surface emission detected by electro-optical sampling ( 0.5 mm ZnTe crystal) J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

20 Terahertz Radiation Terahertz Time-Domain Spectrscopy Photoconductive Antenna Bandwidth wet air power spectrum, time domain cut after 49 ps wavenumber / cm wet air 10 2 power frequency / Hz x Power spectrum of the pulse FFT J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

21 Terahertz Radiation Commercial THz-TDS setup Terahertz Time-Domain Spectrscopy Commercial turn-key alternative (TeraView Ltd) J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

22 PAT Applications for Terahertz Spectroscopy Outline 1 Terahertz Radiation Properties Traditional Far-Infrared Spectroscopy Terahertz Time-Domain Spectrscopy 2 PAT Applications for Terahertz Spectroscopy Identification of Solid State Modifications Solid Dosage Forms Quantitative Terahertz Spectroscopy Mechanism and Kinetics of Phase Transitions Relaxation and Crystallisation of Amorphous Materials Phase Transitions in Solid Dosage Forms 3 Future Challanges and Outlook Assignment of Vibrational Modes Quantum Cascade Lasers 4 Summary J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

form I Carbamazepine form III J Axel Zeitler (University of

23 PAT Applications for Terahertz Spectroscopy Polymorphism Crystal Structure Identification of Solid State Modifications Carbamazepine form I Carbamazepine form III J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

24 Polymorphs PAT Applications for Terahertz Spectroscopy Identification of Solid State Modifications A b s o rb a n c e (d e c a d ic ) A b s o rb a n c e (d e c a d ic ) F o rm I F o rm III W a v e n u m b e r [c m Carbamazepine F o rm II F o rm I -1 ] W a v e n u m b e r [c m Enalapril maleate -1 ] D e c a d ic a b s o rb a n c e / a.u F o rm I F o rm II F o rm III F o rm IV F o rm V w a v e n u m b e r / c m Sulfathizole C. J. Strachan et al., Chem. Phys. Lett. 390, 20 (2004); J. A. Zeitler et al., J. Pharm. Sci. 95, 2486 (2006). -1 J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

25 PAT Applications for Terahertz Spectroscopy Identification of Solid State Modifications Hydrates R e fra c tiv e in d e x A b s o rb a n c e αl H αl -H 2 0 A R e fra c tiv e in d e x A b s o rb a n c e fo rm I fo rm III d ih y d ra te B W a v e n u m b e r [c m -1 ] W a v e n u m b e r [c m -1 ] R e fra c tiv e in d e x A b s o rb a n c e fo rm I m o n o h y d ra te C R e fra c tiv e in d e x A b s o rb a n c e a n h y d ra te m o n o h y d ra te D W a v e n u m b e r [c m -1 ] W a v e n u m b e r [c m -1 ] A) Lactose, B) carbamazepine, C) piroxicam and D) theophylline J. A. Zeitler et al., Int. J. Pharm. 334, 78 (2007). J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

26 Cocrystals PAT Applications for Terahertz Spectroscopy Identification of Solid State Modifications The cocrystal constituents phenazine (blue), mesaconic acid (green) and the cocrystal (phen) (mes) K. L. Nguyen et al., Nat Mater 6, 206 (2007). J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

27 PAT Applications for Terahertz Spectroscopy Solid Dosage Forms Commercial Tablets * * a b s o rb a n c e (d e c a d ic ) * a b s o rb a n c e (d e c a d ic ) * w a v e n u m b e r / c m w a v e n u m b e r / c m -1 Tablets containing 200 mg CBZ Tablets containing 400 mg CBZ J. A. Zeitler, T. Rades, and P. F. Taday, in THz Spectroscopy: principles and applications, edited by S. L. Dexheimer (Taylor & Francis, New York, 2007 in press), pp J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

28 PAT Applications for Terahertz Spectroscopy Polymorphic Mixtures Quantitative Terahertz Spectroscopy A b s o rb a n c e (d e c a d ic ) P I 0 % % P III P I 2 0 % 8 0 % P III P I 4 0 % 6 0 % P III P I 6 0 % 4 0 % P III P I 8 0 % 2 0 % P III P I % 0 % P III W a v e n u m b e r [c m -1 ] P re d ic te d c o n c e n tra tio n [% (m /m )] % C o n fid e n c e In te rv a l 9 5 % P re d ic tio n In te rv a l P L S re g re s s io n 1 fa c to r, 1 s t d e riv a tiv e L O D % L O Q % A c tu a l c o n c e n tra tio n [% (m /m )] C. J. Strachan et al., J. Pharm. Sci. 94, 837 (2005). Physical mixture of carbamazepine form I and III J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

29 PAT Applications for Terahertz Spectroscopy Quantitative Terahertz Spectroscopy Detection of Crystalline Materials a b s o rb a n c e (d e c a d ic ) w a v e n u m b e r / c m -1 a b s o rb a n c e (d e c a d ic ) la c to s e c o n te n t p e r p e lle t / w t% Absorption feature of lactose α-monohydrate for pellets containing a 0 to 5 mg sample material Linear fit of the absorbance reading against the amount of lactose α-monohydrate J. A. Zeitler, T. Rades, and P. F. Taday, in THz Spectroscopy: principles and applications, edited by S. L. Dexheimer (Taylor & Francis, New York, 2007 in press), pp J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

30 PAT Applications for Terahertz Spectroscopy Mechanism and Kinetics of Phase Transitions Polymorph Conversion - in situ Spectra 2.5 A b s o rb a n c e (d e c a d ic ) W a v e n u m b e r [c m -1 ] J. A. Zeitler et al., Thermochim. Acta 436, 71 (2005). Conversion of carbamazepine form III to I at 433 K J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

31 PAT Applications for Terahertz Spectroscopy Polymorph Conversion - Kinetics Mechanism and Kinetics of Phase Transitions Kinetics of solid state conversion (carbamazepine form III to I at 433 K) Mechanism was found to occur via the gas phase J. A. Zeitler et al., ChemPhysChem 8, 1924 (2007). J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

32 PAT Applications for Terahertz Spectroscopy Relaxation and Crystallisation of Amorphous Materials Relaxation and Crystallisation of Amorphous Materials A b s o rb a n c e (d e c a d ic ) W a v e n u m b e r [c m K -1 ] A b s o rb a n c e (d e c a d ic ) W a v e n u m b e r [c m K -1 ] A b s o rb a n c e (d e c a d ic ) W a v e n u m b e r [c m K -1 ] A b s o rb a n c e (d e c a d ic ) W a v e n u m b e r [c m K -1 ] J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

33 PAT Applications for Terahertz Spectroscopy Change in Absorbance Relaxation and Crystallisation of Amorphous Materials 2.0 g la s s y s ta te T g ru b b e ry s ta te c ry s ta llis a tio n fo rm III p h a s e tra n s itio n fo rm I N o rm a lis e d a b s o rb a n c e (d e c a d ic ) fe a tu re 1 fe a tu re 2 fe a tu re 3 fe a tu re 4 fe a tu re 5 fe a tu re T e m p e ra tu re [K ] J. A. Zeitler et al., J. Pharm. Sci. 96, 2703 (2007). J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

34 PAT Applications for Terahertz Spectroscopy Phase Transitions in Solid Dosage Forms Direct Compressed Tablet Constituents a b s o rb a n c e (d e c a d ic ) w a v e n u m b e r / c m Spectrum of lactose α-monohydrate (red), carbamazepine form III (green) and form I (blue) -1 a b s o rb a n c e (d e c a d ic ) I w a v e n u m b e r / c m Terahertz spectrum of the tablet Roman numbers refer to spectral features of the lactose α-monohydrate and Arabic numbers refer to spectral features of carbamazepine form III II J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

35 PAT Applications for Terahertz Spectroscopy Phase Transitions in Solid Dosage Forms Direct Compressed Tablet Phase Transition K K te m p e ra tu re / K K K K a b s o rb a n c e (d e c a d ic ) w a v e n u m b e r / c m I 1 2 II 3 Contour plot of the transmission terahertz spectra acquired during heating of a 200 mg carbamazepine tablet J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

36 Future Challanges and Outlook Outline 1 Terahertz Radiation Properties Traditional Far-Infrared Spectroscopy Terahertz Time-Domain Spectrscopy 2 PAT Applications for Terahertz Spectroscopy Identification of Solid State Modifications Solid Dosage Forms Quantitative Terahertz Spectroscopy Mechanism and Kinetics of Phase Transitions Relaxation and Crystallisation of Amorphous Materials Phase Transitions in Solid Dosage Forms 3 Future Challanges and Outlook Assignment of Vibrational Modes Quantum Cascade Lasers 4 Summary J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

37 Future Challanges and Outlook Intermolecular Interactions Assignment of Vibrational Modes Possible rigid molecule distortions and descriptors of the carbamazepine dimers J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

38 Future Challanges and Outlook Tentative Assignments in CBZ Assignment of Vibrational Modes Bu: dimer oop bend Au: dimer asymmetric stretch intensity Au: dimer oop bend Au: dimer oop twist Bu: dimer oop twist Au: dimer oop bend Au: dimer oop twist Bu: dimer oop twist Bu: dimer asymmetric stretch dimer stretching + internal molecular modes dimer twisting + internal molecular modes (ring twisting) frequency (cm -1 ) Calculations were performed using a computationally cheap force-field approach G. M. Day et al., J. Phys. Chem. B 110, 447 (2006). J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

Future Challanges and Outlook Assignment of Vibrational Modes Tentative Assignments in Cocrystals Distortion of the hydrogen-bonded chain leading to an absorption peak at 1.2 THz.

39 Future Challanges and Outlook Assignment of Vibrational Modes Tentative Assignments in Cocrystals Distortion of the hydrogen-bonded chain leading to an absorption peak at 1.2 THz. The feature is a combination of wagging motions of the components in each chain (the chains propagate parallel to the crystallographic 110 direction) K. L. Nguyen et al., Nat Mater 6, 206 (2007). J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

40 Future Challanges and Outlook Assignment of Vibrational Modes Alternative Approaches CRYSTAL CASTEP VASP CHARMM... and many more J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

41 Future Challanges and Outlook Intersubband Transitions Quantum Cascade Lasers In contrast to a normal semiconductor laser the photons are emitted from transitions within the conduction band Schematic courtesy of B.S. Williams, 2005 J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

Zeitler (University of Cambridge) Experimental setup

42 Future Challanges and Outlook Quantum Cascade Lasers Quantum Cascade Laser (QCL) Device QCL mounted on copper block J Axel Zeitler (University of Cambridge) Experimental setup Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

43 Future Challanges and Outlook Polystyrene Phantom Quantum Cascade Lasers Polystyrene phantom in the shape a clown s head K. L. Nguyen et al., Opt. Express 14, 2123 (2006). J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

44 Future Challanges and Outlook Polystyrene Phantom Quantum Cascade Lasers K. L. Nguyen et al., Opt. Express 14, 2123 (2006). Some views of the reconstructed 3D image J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

45 Future Challanges and Outlook Quantum Cascade Lasers THz QCL imaging Advantages High power source (up to 50 mw) Microbolometer arrays are possible Uncomplicated optics setup Array detectors possible Current Limitations Optimum operation temperature at 4-10 K (max. 150 K) Lack of readily available optics at THz frequencies (lenses, filter) Very immature waveguide technology Limited range of operating frequencies J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

46 Summary Outline 1 Terahertz Radiation Properties Traditional Far-Infrared Spectroscopy Terahertz Time-Domain Spectrscopy 2 PAT Applications for Terahertz Spectroscopy Identification of Solid State Modifications Solid Dosage Forms Quantitative Terahertz Spectroscopy Mechanism and Kinetics of Phase Transitions Relaxation and Crystallisation of Amorphous Materials Phase Transitions in Solid Dosage Forms 3 Future Challanges and Outlook Assignment of Vibrational Modes Quantum Cascade Lasers 4 Summary J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

47 Summary Advantages of Terahertz Spectroscopy Highlights Spectral signature represents unique fingerprint that directly originates from the molecular interaction in the crystal lattice (hydrogen bonding, phonon modes) No artefacts due to preferred orientation Very fast technique, time resolved measurements are possible Many experiments can be performed in transmission (large sampling volume) Detection of the signal with room temperature detectors FT-IR and Raman sampling accessories such as ATR can be readily used J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

48 Summary Current Limitations Major challanges No diffuse reflectance sampling possible to date Limited bandwidth and power Cost and maintenance of fs lasers Signal processing can be tricky due to echo pulses and multiple reflections Limited understanding of the vibrational modes at THz frequencies J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

49 Acknowledgments Acknowledgments Department of Chemical Engineering, University of Cambridge: Prof Lynn Gladden and Edward Parrott University of Otago, NZ: Prof Thomas Rades and Louise Ho (Pharmacy), A/Prof Keith Gordon (Chemistry) Applications and Spectroscopy Group, TeraView Ltd: Dr Philip Taday, Dr Yaochun Shen (now University of Liverpool) Semiconductor Physics Group, University of Cambridge: Prof Sir Michael Pepper EPSRC for funding J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

50 For Further Reading New literature in the field from I Our group: J.A. Zeitler et al., Terahertz pulsed spectroscopy and imaging in the pharmaceutical setting a review, J. Pharm. Pharmacol., 2007, 59, K.L. Nguyen et al., Terahertz time-domain spectroscopy and the quantitative monitoring of mechanochemical cocrystal formation, Nat. Mater., 2007, 6, J.A. Zeitler et al., Drug Hydrate Systems and Dehydration Processes Studied by Terahertz Pulsed Spectroscopy, Int. J. Pharm., 2007, 334, J.A. Zeitler et al., Solid-state transition mechanism in carbamazepine polymorphs by time-resolved terahertz spectroscopy, ChemPhysChem, 2007, 8, J.A. Zeitler et al., Relaxation and crystallization of amorphous carbamazepine studied by terahertz pulsed spectroscopy, J. Pharm. Sci., 2007, 96, J.A. Zeitler et al., Analysis of coating structures and interfaces in solid oral dosage forms by three dimensional terahertz pulsed imaging, J. Pharm. Sci., 2007, 96, L. Ho et al., Analysis of sustained-release tablet film coats using terahertz pulsed imaging, J. Control. Rel., 2007, 119, J. Obradovic et al., The use of THz time-domain reflection measurements to investigate solvent diffusion in polymers, Polymer, 2007, 48, J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

51 For Further Reading New literature in the field from 2007 II Other groups: H.B Liu et al., Characterization of anhydrous and hydrated pharmaceutical materials with THz time-domain spectroscopy, J. Pharm. Sci., 2007, 96, (X.C. Zhang s group, US) J.A. Spencer et al., Delayed release tablet dissolution related to coating thickness by terahertz pulsed image mapping, J. Pharm. Sci., 2007, in press, doi: /jps (FDA and TeraView) H. Wu et al., Process analytical technology (PAT): Effects of instrumental and compositional variables on terahertz spectral data quality to characterize pharmaceutical materials and tablets, 2007, Int. J. Pharm., 343, (FDA and NIST) H. Wu et al., Process analytical technology (PAT): quantification approaches in terahertz spectroscopy for pharmaceutical application, 2007, J. Pharm. Sci., in press, doi: /jps (FDA and NIST) J Axel Zeitler (University of Cambridge) Terahertz Spectroscopy of Pharmaceuticals Heidelberg PAT / 42

Applications of Terahertz Radiation (T-ray) Yao-Chang Lee, National Synchrotron Research Radiation Center

Applications of Terahertz Radiation (T-ray) Yao-Chang Lee, yclee@nsrrc.org.tw National Synchrotron Research Radiation Center Outline Terahertz radiation (THz) or T-ray The Interaction between T-ray and