Experiment

Polarization Terahertz Spectroscopy Application to Theophylline Anhydrous Single Crystal for Vibrational Mode Assignment

7

Purpose Summary A single crystal of theophylline anhydrite, large and thin enough

for wide range THz transmittance spectroscopy could be successfully fabricatedby Temperature Difference Method (TDM) in aqueous solution.

Wide range polarization spectroscopy at low temperature was shown to be useful to assign vibration modes with the aid of DFT calculation.

Sample preparation Results and discussion

0 10 20 30 40

Theophylline anhydrous

Inte

nsity

(a.u

.)

(deg)

grown crystal

XRD - 2 measurement

Pna21

P21/c

Theophylline monohydrate

P21/n

5.0 mm

1.0 Grown single crystal

Orthorhombic Pna21a=24.612,b=3.8302,c=8.5010

(110) reflection

0 1 2 3 4 5

0

1

2

3

parallel to

Frequency (THz)

Abs

orba

nce

Theophylline anhydrous single crystal70 K

1.060

0

30

60

90

1.797

2.0842.788

4.070

5.112

1.212 1.761 2.853 3.9134.390

single crystal

70 KSmoothing 50GHz

1 2 3 4 5

1

2

0Frequency (THz)

Abs

orba

nce

Theophylline

0.85

1.06

1.231.47

1.79

2.092.79

10 wt% PE pellet

2.87

3.96

powder

70 K

Pole Figure measurementto (110) reflection

Powder XRD measurement of crushed crystal

1/T

lnc

hydrate

anhydrous

0.0029

71

@1013 hPa

Temperature Difference

Crystal growth from aqueous solution

low temperature hydrous

high temperature anhydrous

Single crystal growth of Theophylline anhydrous for THz transmittance spectroscopy

8278

cooler

crystalcell

heat sinkpeltiercooler stirre

r

pump

saturated aqueous solution

82

78

heater

Air flow

air flow

CW GaP THz Spectrometer

Dryairpurged

Nb TES bolometer

MotorizedLinearStage

Chopper

LockinAmp

MotorizedRotaryStage

Collimater

DFB:Distributed FeedbacklaserECLD:modehopfree

ExternalCavityLaserDiodeYbFA:YbdopedFiberAmplifier

Collimater

Cryostat

YbFA

DFB

2channelFrequencyMeter

YbFA

ECLD

Powerfeedback

Powerfeedback

Frequencyfeedback

Frequencyfeedback

Nb TES: Nb SuperconductingTransitionEdgeSensor

CalculationDFT (Density Functional Theory) calculation with periodic boundary condition

Software package CRYSTAL09

B3LYP/6-31G(d,p) level

Fixed cell parameter

Y. Ebisuzaki, P. Boyle and J. Smith, Acta Cryst. (1997). C53, 777-779.

Geometry optimization start from crystal structure

defined by X-ray diffraction at room temperature

GaP

Frequency Absorption Direction(THz) (a.u.)

0.85

1.06 0.348

1.21 0.026

1.47

1.761 0.179

1.797

2.084 0.056

2.788 0.099

2.853 0.042

3.913 0.496

4.070 0.971

4.390

5.112 0.162

0 1 2 3 4 5

0

1

Frequency (THz)

Abso

rban

ce

102030405060

Inte

nsity

(km

/mol

)

B3LYP / 6-31G(d,p)Fixcell

DFT Calculation

Frequency Intensity Direction(THz) (km/mol)

0.696 0.80 0.737 0.99 0.796 1.18 1.212 4.74 1.235 3.65 1.344 1.80 1.723 2.84 1.726 0.14 1.955 19.64 2.160 0.04 2.190 0.14 2.663 2.50 3.477 0.10 3.562 1.34 3.616 0.68 3.993 18.13 4.049 20.46 4.170 58.02 4.419 4.83 4.604 3.23 4.777 1.02 4.793 5.71 4.958 3.04 5.058 5.55 5.063 10.55 5.462 17.39 5.466 9.37 5.469 0.59

Measurement

0.796 THz Theophyllineanhydrous

C7H8N4O2

drug for respiratory diseases

C7H8N4O2H2O

Theophylline monohydrate

DFT calculation

Polarization dependent spectra for anhydrous single crystalat low temperature

Direct comparison

Single crystal growth of Theophylline anhydrous Polarization THz spectroscopy of Theophylline anhydrous crystal

at low temperature Comparison absorption frequencies and intensities

between measurements and calculations

for THz vibrational mode assignment to obtain basic data to apply THz spectra

to pharmaceutical Product Quality Control

H2O

Supply a system (hardware and software)

Please find each vibration mode in PC (animation file)

Frequency range

Frequency accuracy &resolution

Power stability

Improvement of CW GaP THz Spectrometer

Wide range and high resolution CW THz spectrometer combined with GaP THz signal generator and mechanically cooled bolometer

Motivation

CW GaP THz Spectrometer

Dry airpurged

Nb TES bolometer

MotorizedLinearStage

Chopper

Lock-inAmp.

MotorizedRotary Stage

Collimator

DFB : Distributed - Feedback laser

ECLD: mode-hop free External Cavity Laser Diode

YbFA: Yb doped Fiber Amplifier Cryostat

DFB

2 channelFrequency Meter

YbFAECLD

Powerfeedback

Powerfeedback

Frequency feedback

Nb TES: Nb SuperconductingTransition Edge Sensor

GaP

Next Step

Lens

Collimator

Frequency feedback

YbFA

THz wave

Nb TES bolometer

0 1 2 3 4 5 6

4K Silicon bolometer QMC Nb TES bolometer

Frequency (THz)

Out

put p

ower

(re

lativ

e va

lue)

T.Sasaki

Frequency range

Signal generator

Spectrometer

Frequency resolution

Feedback control of pump beams

at seed laser

Power stability

Feedback control of pump beams

at fiber amplifier

Easy operation, Maintenancefree

Parts for optical communication

Small size, Portable

Optical fiber coupling

1000

1

GaP crystal

THzwave3 = 1 - 2

2

IRlaserbeams

DifferenceFrequencyGeneration(DFG)

Ga

P

1.95 THz

GaPFiber Amp.Powerfeedback

Fiber Laser

Modehop-free ECDL

IR lens

25W

5W

0 2 4 610-4

10-3

10-2

10-1

1

10

Frequency (THz)

THz

outp

ut (a

.u.)

IR laser beam power: 5 W x 25W (not purged)

noise floor

> 4.5 orders

3W x 3W (purged by dry air)

~ 3 order

CW GaP THz Signal Generator

GaP

THz

DFB : Distributed FeedBack laser

ECLD: External CavityLaser Diode

FA : Fiber Amplifier

DFB

ECLD

FA

FA

Mirror

Polarizer

- Global helium shortage - Price rise

Using a cryostat with a tank storing liquid helium

- Refill Liq. He every 30 hours

Problem

2.7738 2.774 2.7742

3.4 Pa 70 600 1.8k

Frequency (THz)

THz

pow

er (a

.u.)

100MHz

2.773985 THz2.773977 THzNASA JPL

measurement

Summary

combining with a CW THz SG as a light source and a bolometer detector cooled by a mechanical cooler

1 2 3 4 5 6

1

2

0

Theophylline anhydrous plate (thickness ~ 100 m)

Frequency (THz)

Abs

orba

nce

300 K

70 K

An example ofTHz absorption measurement

Theophyllineanhydrous

Pharmaceutical drugfor respiratory diseases

System optical responsivity

System RMS output noise at 80 Hz

System optical NEP at 80 Hz

QMC instruments QNbB/PTC

THz power spectraof CW GaP THz SG

measured byQMC Nb TES bolometerand4 K silicon bolometer

168 kV/W

430 /

2.6 /

CW GaP THz Spectrometer

High accuracyHigh resolutionWide dynamic rangeHigh stability Long lifetime (durability)Easy maintenanceLow equipment costLow running cost

The spectrometer is now working as non-stop system

Next targetdevelop practical industrial applications

Applying high power fiber laserin order to power up THz output

Observation of THz wave output by an oscilloscope

Chopper

THz wave

THz wave output with high power fiber laser

(HPC)

(TPAH)

+H2O,

TPAH+HPC(10:3)

+H2O,

or

50/70

or

50/70

(TPMH)

(TPMH)

1 2 3 4 5

1

2

3

4

0Frequency (THz)

Abso

rban

ce

In situ

XRD(RINT Ultima , Rigaku)CuK: 1050: 0.02

MIR (FT/IR-6300, JASCO)

: 4000-400 cm-1Scan number: 256: 2 cm-1: ATR

NIR (MPA FT-NIR, Bruker)

: 12500-4000 cm-1

Scan number: 32: 2 cm-1:

NIR

Nd:YAGLaser

Cr: Forsterite(signal)

Cr: Forsterite(pump)

GaP e

e

WP CP

RT-DTGS

1064nm

1240-1280nm

1240nm

HM

WP: /2 CP : HM:

(GaP THz Spectrometer, ): Cr:Forsterite : DTGS :0.6 6.1 THz :15GHz:

H2O

HPC

HPC

NIHS

60min

+

120min

TPTPMH0min15min60min120min240min1200min

2.0THz

TPAHTPMH0min15min60min120min240min1200min

NIR7050

4270 cm-1C-Hv(CH) + (CH)

C-H-CH3

C-H-CH3

[N-CH3]

1383cm12887cm1

CH3C-H

C-N

in situ

HPC

HPC

Theophylline monohydrate

X

CH3

2

H2O

ex. 100 m

THz

2211

VLSIULSI

PHCAP

1ppt(10-12)

()()()

C=/W (C: pn: W: )

411

(PHCAP) Deep Level Transient Spectroscopy (DLTS) Isothermal Capacitance Transient Spectroscopy (ICTS)

(PL)

PHCAP

QMC Instruments Ltd.

QNbB/Dry

THz

CW GaP THz Spectrometer

Dry airpurged

Nb TES bolometer

MotorizedLinearStage

Chopper

Lock-inAmp.

MotorizedRotary Stage

Collimator

DFB : Distributed - Feedback laser

ECLD: mode-hop free External Cavity Laser Diode

YbFA: Yb doped Fiber Amplifier Cryostat

DFB

2 channelFrequency Meter

YbFA

ECLD

Powerfeedback

Powerfeedback

Frequency feedback

Nb TES: Nb SuperconductingTransition Edge Sensor

GaPLens

Collimator

Frequency feedback

YbFA

THz wave

Nb TES bolometer

System optical responsivity

System RMS output noise at 80 Hz

System optical NEP at 80 Hz

QMC instruments QNbB/PTC

168 kV/W

430 /

2.6 /

THz

DFG

THz

CW

S/N

1.000000 THz

0.1 7.5 THz

J. Nishizawa, Y. Okuno, K. Suto, T. Sato, and S. Yamakoshi 1974 Solid State Commun. 14 889.J. Nishizawa, Y. Okuno 1975 IEEE Trans. Electron Devices ED-22 716.

GaP

,

Time

Tem

pera

ture

Time

Tem

pera

ture

P

GPG T

TPP TG:

TP:

PG:

PP:

eV01.1exp1067.4Torr

B

6GaP Tk

P