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1
Terahertz pulsed imaging and spectroscopy for biomedical and pharmaceutical applications

Type: Object | Advantage: None | Novelty: New | ConceptID: Obj1

Terahertz (THz) radiation lies between the infrared and microwave regions of the electromagnetic spectrum.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac1

Advances in THz technology have opened up many opportunities in this scientifically and technologically important spectroscopic region.

Type: Motivation | Advantage: None | Novelty: None | ConceptID: Mot1

The THz frequency range excites large amplitude vibrational modes of molecules as well as probing the weak interactions between them.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac2

Here we describe two techniques that utilize THz radiation, terahertz pulsed imaging (TPI) and terahertz pulsed spectroscopy (TPS).

Type: Object | Advantage: None | Novelty: New | ConceptID: Obj2

Both have a variety of possible applications in biomedical imaging and pharmaceutical science.

Type: Motivation | Advantage: None | Novelty: None | ConceptID: Mot2

TPI, a non-invasive imaging technique, has been used to image epithelial cancer ex vivo and recently in vivo.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res1

The diseased tissue showed a change in absorption compared to normal tissue, which was confirmed by histology.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res2

To understand the origins of the differences seen between diseased and normal tissue we have developed a TPS system.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res3

TPS has also been used to study solids of interest in the pharmaceutical industry.

Type: Goal | Advantage: None | Novelty: None | ConceptID: Goa1

One particularly interesting example is ranitidine hydrochloride, which is used in treatment of stomach ulcers.

Type: Object | Advantage: None | Novelty: New | ConceptID: Obj3

Crystalline ranitidine has two polymorphic forms known as form 1 and form 2.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac3

These polymorphs have the same chemical formula but different crystalline structure that give rise to different physiochemical properties of the material.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac4

Using TPS it is possible to rapidly distinguish between the two polymorphic forms.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res4

Introduction

Terahertz (THz) radiation is at the interface between infrared light and microwaves.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac5

The THz gap, typically defined as the frequency range, 0.1 to 10 THz was a previously unexplored region of the electromagnetic spectrum, owing to a lack of suitable sources and detectors.^1,2

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac6

Advances over the last ten years in laser and semiconductor technology have opened up many opportunities in this scientifically and technologically important spectroscopic region.

Type: Motivation | Advantage: None | Novelty: None | ConceptID: Mot3

Radiation in this frequency range is of particular interest as it excites the intermolecular interactions, such as the librational and vibrational modes as well as probing the weak interactions between molecules.³

Type: Motivation | Advantage: None | Novelty: None | ConceptID: Mot4

Here we describe two systems and example applications that utilize this frequency range.

Type: Object | Advantage: None | Novelty: New | ConceptID: Obj4

Terahertz pulsed imaging (TPI) is a non-invasive, coherent, reflection imaging modality that explores this frequency region and has a current useable range of 0.1 to 3 THz, corresponding to a wavelength range of 3 mm to 100 µm.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res5

These wavelengths are significantly larger than the scattering structures in tissue, and scattering using TPI should therefore be considerably reduced compared to techniques using near infrared or visible radiation.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac7

The current lateral and axial resolutions attainable with our system at 3 THz are 200 µm and 20 µm respectively, making it a viable imaging modality.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res6

As TPI is a coherent, time gated, low noise technique, both phase and amplitude information can be obtained, from which the absorption and refractive index of a medium can be determined.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res7

TPI is a time-domain technique therefore depth information can readily be extracted.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res8

Broadband detection allows for the acquisition of information over a wide spectral range at THz frequencies.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res9

Terahertz pulsed spectroscopy (TPS) is similar to TPI but uses a transmission rather than reflection geometry, thus, is more suited to looking at the absorption spectra of liquid and solid samples.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res10

Basal cell carcinoma and terahertz pulsed imaging

Epithelial cancers account for 85% of all cancers.⁴

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac8

One type, basal cell carcinoma (BCC) is the most common form of cancer worldwide in white populations.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac9

In the UK the incidence rate has increased by 50% over the last 10 years,⁵ and has a reported annual incidence of around one million in the US.⁶

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac10

The diagnosis of BCC is based on visual assessment and possibly a biopsy.⁷

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac11

Well-defined, solid, cystic and superficial BCCs, and tumours of less than 20 mm in diameter are surgically excised.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac12

A minimum margin of 4 mm is required to completely excise the tumour in over 95% of cases.⁸

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac13

Ill-defined tumours may extend 15 mm or more beyond the clinical edge.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac13

In these cases Mohs' micrographic surgery (MMS) is the best technique as it allows review of all the margins and same-day closure of defects.⁹

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac14

A study was conducted to determine whether TPI could differentiate between BCC and normal tissue and to test whether it can help with outlining tumour margins prior to surgery.

Type: Goal | Advantage: None | Novelty: None | ConceptID: Goa2

Materials and methods – BCC and TPI

TPI system

A portable THz imager, TPI Scan (TeraView Ltd, UK), was used for ex vivo and in vivo measurements performed on samples and patients at Addenbrooke's Hospital, Cambridge, UK.

Type: Method | Advantage: None | Novelty: New | ConceptID: Met1

The TPI system used reflection geometry, as shown in Fig. 1.

Type: Method | Advantage: None | Novelty: New | ConceptID: Met2

Optical excitation was achieved using an ultrafast fiber laser (Femtolite, IMRA America Inc.) emitting 180 fs pulses centered at a wavelength of 780 nm, with a 48 MHz repetition rate and an average power of 25 mW.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met3

A beamsplitter separated the laser light into two beams, an excitation beam and a detection beam.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met3

Generation of the THz pulses was achieved by optical excitation of a gallium arsenide emitter.¹⁰

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met3

The THz pulses were collimated and focused onto the top surface of a z-cut quartz window by a pair of off-axis parabolic (OAP) mirrors.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met3

The sample under investigation is placed onto the quartz window, as indicated in Fig. 1.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met4

The angle of reflection was 30 degrees to the normal.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met4

The THz pulses reflected from the tissue were re-collimated using another pair of OAP mirrors and focused onto a bow-tie photoconductive receiver on which the detection beam is also focused.

Type: Method | Advantage: None | Novelty: New | ConceptID: Met5

The system gave a usable frequency range of 0.1 to 3 THz with an average power of approximately 100 nW.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res11

By sweeping the optical delay through the entire THz pulse at a rate of 15 Hz, the time-domain THz waveforms were obtained.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met6

The entire THz optics indicated by the dashed box (Fig. 1), and hence the THz beam, were raster-scanned in the x–y plane over a defined area.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met7

A THz waveform is acquired at each x–y point.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met8

To remove any system response, the raw THz waveform of the tissue at each pixel was divided by a reference waveform in the frequency-domain and a numerical bandpass filter applied to remove high and low frequency noise.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met9

The time resolution was approximately 200 fs which is limited by the laser pulse; assuming a refractive index of two in skin tissue in the THz frequency range, an axial resolution of approximately 20 µm close to the skin surface can be achieved.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met9

The signal-to-noise ratio was approximately 5000∶1.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res12

The time-domain waveform provided information to a depth on the order of 1 mm into the skin samples.²

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac15

The incident energy is over 1000 times lower than the maximum permissible exposure at similar frequencies (EN 60825-1, 1994).¹¹

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac16

Cultured keratinocytes irradiated for longer times have shown no adverse change;¹² therefore we assume the skin samples are unaffected by the THz radiation.

Type: Model | Advantage: None | Novelty: None | ConceptID: Mod1

Tissue preparation

Excised skin tissue was obtained from the Department of Dermatology at Addenbrooke's Hospital, Cambridge, UK.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met10

Appropriate consent was obtained for the study; all patient material was anonymised.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met11

A sample typically consisted of a piece of suspected BCC with a margin of normal tissue surrounding it.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met12

Prior to imaging, excess fluid was removed from the skin samples using surgical gauze.

Type: Experiment | Advantage: None | Novelty: None | ConceptID: Exp1

The quartz window was covered with a transparent sterile dressing (Tegaderm™, 3M Healthcare, Germany).

Type: Experiment | Advantage: None | Novelty: None | ConceptID: Exp2

This prevented contamination of the quartz window.

Type: Experiment | Advantage: None | Novelty: None | ConceptID: Exp3

The skin sample was placed in direct contact with the covered quartz window (diameter 38 mm, thickness 2 mm), with the top surface of the skin facing the incident THz radiation.

Type: Experiment | Advantage: None | Novelty: None | ConceptID: Exp4

No immersion medium was used between the quartz window and the tissue, and air gaps were minimized.

Type: Experiment | Advantage: None | Novelty: None | ConceptID: Exp5

After imaging the tissue was photographed and placed in formalin and submitted for routine histology.

Type: Experiment | Advantage: None | Novelty: None | ConceptID: Exp6

Data analysis

The TPI images were generated using an analysis technique called time post pulse (TPP), where TPP = E(t)/E(min).

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met13

TPP normalizes the THz pulse, E(t), at a time t, by the minimum peak value, E(min).

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met14

This analysis technique allows for the direct comparison of the relative change of THz waveforms and can differentiate between diseased and normal tissue.¹³

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac17

An example is given in Fig. 2.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs1

As the THz pulse propagates through an absorptive medium, such as skin tissue, it broadens in time.²

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac18

The TPI images in Fig. 3 were produced by plotting the TPP value at a particular time, t, at each pixel over the area scanned.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs2

Typically, t was chosen to provide the best contrast between the diseased and normal tissue.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met15

A suture placed on the edge of the BCC allowed orientation of the histology sections and acted as a reference point for both the visible and THz images.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met16

The histology cross-section was taken from the suture location through the centre of the tumour.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met17

Results – BCC and TPI

Fig. 3 shows a comparison between the visible images, THz images and histology.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs2

Fig. 3a shows a clinical photograph of a male patient with a featureless, primary, clinically ill-defined BCC on the forehead.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs3

The black outline approximately represents the tissue removed and imaged.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs4

The resulting THz image of the excised tissue is shown in Fig. 3b.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs5

The false colour THz image shows a strong contrast between the diseased tissue shown as red ‘hot spots’ and the surrounding normal tissue which shows a more uniform green/yellow colour throughout.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs6

The X marks the location of the suture and the dotted black line indicates the axis of the vertical histology section.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met18

The histology (Fig. 3c) shows a nodular BCC, and the suture is indicated on the left with an ‘X’.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs7

Nodules of tumour are indicated with an ‘*’.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met19

These nodules of tumour in the histology correlate well with location of areas of contrast in the THz image.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res13

Fig. 3d shows a clinical photograph of a bland looking lesion on the right temple of a female patient.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs8

The black outline approximately represents the tissue removed and imaged.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs9

The resulting THz image of the excised tissue is shown in Fig. 3e and the histology in Fig. 3f.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs10

This histology in Fig. 3f shows a sclerotic basal cell carcinoma which extends over the region between the two asterisks which corresponds to the area of contrast seen on the THz image.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs11

Discussion – BCC and TPI

The study describes the application of TPI for imaging BCC ex vivo over a region of the electromagnetic spectrum not previously investigated.

Type: Object | Advantage: None | Novelty: New | ConceptID: Obj5

The BCCs showed an increase in absorption of THz compared to normal tissue.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs12

The level of contrast observed in the THz images was sufficient to identify tumour margins when compared to histology.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res14

However, the source of this contrast is still under investigation.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res15

Simple diatomic polar molecules, for example water, readily absorb THz radiation.¹⁴

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac19

Water has a strong broadband absorption around 5.4 THz, arising from the stretching of the hydrogen bond between molecules, the tail of which extends to the lower frequencies, with significant absorption in the operating range of our TPI system.^3,15

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac20

Increased water content in malignant tissues has been observed in many different tumour types, and is often used as a marker for malignancy.^16–18

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac21

The change in absorption in diseased regions that gives rise to contrast in TPI images might be attributed to a change in the intermolecular vibrational modes of water molecules with other functional groups.

Type: Hypothesis | Advantage: None | Novelty: None | ConceptID: Hyp1

Introduction to terahertz pulsed spectroscopy (TPS)

To understand the nature of the contrast mechanism observed in TPI images (for example in Figs. 3b and 3e), it is necessary to understand the spectroscopy of materials in the THz region.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met19

To this end we have constructed a THz spectrometer.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res16

Terahertz pulsed spectroscopy (TPS) is a quick and easy-to-use technique and has recently been applied to a range of materials.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac22

Walther et al¹⁹. have used the technique to study a range of saccharides.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac23

They observe a series of distinct absorption lines which originate from the lowest intermolecular vibrational modes.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac24

However, when the sugars are melted to form an amorphous state, the sharp features observed in the crystalline form disappear to give a broad, featureless absorption spectrum.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac25

100

This is because the long-scale intermolecular interactions (or phonon modes) have been broken down leading to random orientation of the molecules.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac26

101

The same group also report on some anomalous behaviour in the peak positions of the phonon vibrations when the sample is cooled to 5 K. Because there is considerable lack of theoretical understanding of weak non-covalent forces assigning and understanding the source of these vibrational features is not possible.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac27

102

However, several groups are beginning to use density functional theory (DFT) to predict and try to understand THz spectra.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac28

103

For example, Shen et al²⁰. have used DFT to try to explain the THz absorption spectra of purine and adenine.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac29

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The use of the theory is still at an early stage but with more groups using THz technology a deeper understanding of the meaning of the spectra will be obtained.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac30

105

A molecule that has been well studied and is believed to be of great importance to TPI is water.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac31

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Water is a good example of a molecule that undergoes intermolecular interaction, more commonly known, as hydrogen bonding.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac32

107

Water molecules can form up to four hydrogen bonds forming a tetrahedral structure.²¹

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac33

108

In low frequency Raman spectroscopy some investigators have reported observation of an absorption band at 1.8 THz.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac34

109

The origin of this band is believed to be due to a hydrogen bond bending motion, because of the selection rules this band is not observed in the THz absorption spectrum.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac35

110

There is another strong hydrogen bonding transitions at 5.4 THz due to a hydrogen-bonding stretching mode.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac36

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A broad featureless absorption spectrum of water has been reported by Ronne and Keiding.²¹

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac37

112

The broad spectrum is believed to be due to the superposition of a continuum of water active rotational and translational modes.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac38

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The sensitivity of TPS leads us to investigate the possibility of distinguishing between polymorphs.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac39

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Walther et al¹⁹. has reported that it is possible to distinguish between different isomers of hydroxybenzoic acid.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac40

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This is a result of isomers having different crystalline structures arising from the different packing density due to functional groups being in different positions within the parent molecule.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac41

116

However, it is not obvious that the same would be true for polymorphs.

Type: Hypothesis | Advantage: None | Novelty: None | ConceptID: Hyp2

117

Taday et al²². have reported for the first time that it is possible to discriminate between the polymorphs of ranitidine HCl.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac42

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We report here the temperature dependent spectrum of the two polymorphs which should aid in the assignment of the features observed.

Type: Object | Advantage: None | Novelty: New | ConceptID: Obj6

Polymorphs

119

Many materials of pharmaceutical interest can exist in more than one solid form.²³

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac43

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These different forms have different crystalline structures which can lead to different physiochemical properties of a material.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac44

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These different crystalline structures are known as polymorphs.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac45

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The formation of different polymorphs can be controlled during crystallization by solvent used, cooling rate and the degree of super saturation of the solution.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac46

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Once in the crystalline form the polymorphic state can change by incorrect storage or during tablet preparation.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac47

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Ranitidine hydrochloride (HCl) is used in treatment of duodenal-gastric ulceration and Zollinger–Ellison syndrome.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac48

125

Ranitidine HCl exists in two polymorphic forms.²⁴

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac49

126

Form 1 is obtained by crystallizing from an ethanolic solution after the addition of ethyl acetate,²⁵ while form 2 is obtained from a solution of isopropanol–HCl.²⁶

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac50

127

The two forms have equal solubilities and there is no difference in bioavailability.^27,28

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac51

128

The molecular structure of ranitidine HCl is shown in Fig. 4.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac52

Materials and methods – Polymorph detection and TPS

129

Ranitidine HCl forms 1 and 2 were obtained from Neuland Laboratories Limited and were used without any further purification.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met20

130

The drugs were lightly crushed and mixed with polyethylene (PE) powder at a percentage weight of 25%.

Type: Experiment | Advantage: None | Novelty: None | ConceptID: Exp7

131

The mixture was compressed into discs of thickness about 1 mm with a compression of about 2 tons.

Type: Experiment | Advantage: None | Novelty: None | ConceptID: Exp8

132

It is possible to convert one polymorphic into the other by compressing a tablet.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac53

133

To check that this did not occur with ranitidine HCl, a series of polyethylene disc mixtures were prepared at different compressions between 1 to 2 tons.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met21

134

The THz spectra of these disc showed that there was no interconversion between the two polymorphic states.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res17

135

The sample was placed in a helium-cooled cryostat and held at temperatures as low as 4 K. It should be noted, however, that at this stage of the development the temperature at the sample position has not been accurately determined.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met22

136

All temperatures stated in this report are recorded at the heat exchanger of the cryostat.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met23

TPS system

137

The apparatus employed for TPS is similar to that used for TPI but uses a transmission rather than reflection geometry and is described in .^{ref. 22}

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met24

138

Briefly the laser used in these experiments was a Ti:Sapphire laser (Vitesse, Coherent Inc), that produces 90 fs near-bandwidth limited pulses.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met25

139

A schematic of the experimental setup is shown in Fig. 5(a).

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met26

140

The laser beam is split into two.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met27

141

One beam is used to generate the THz-radiation; the other beam is used as a probe to detect the THz-radiation using electro-optic sampling (EOS),²⁹ a typical waveform is shown in Fig. 5(b).

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met28

142

By changing the delay and monitoring the change to the probe beam on a pair of balanced photodiodes, a THz waveform is obtained.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met29

143

The waveform is obtained in the time-domain and a fast-Fourier transform (FFT) can be performed to convert the refractive index, n, to obtain spectral information shown in Fig. 5(c).

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met30

144

The useful bandwidth of the waveform to the frequency domain to obtain spectral information shown in Fig. 5(c).

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs13

145

The useful bandwidth of detection is from about 300 GHz to about 3 THz (10–100 cm^–1).

Type: Result | Advantage: None | Novelty: None | ConceptID: Res18

146

The range of the temporal scan determines the spectral resolution of a system.

Type: Model | Advantage: None | Novelty: None | ConceptID: Mod2

147

A resolution of the order 2.5 GHz (0.08 cm^–1) can be achieved with our system.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res19

148

The THz-field transmitted through a sample is attenuated by dispersion and absorption.

Type: Model | Advantage: None | Novelty: None | ConceptID: Mod3

149

The ratio of the electric field strength before, E_s(ω), and after transmission, E_r(ω), is given by where d is the thickness of the sample, ω the frequency of the radiation, c the speed of light in vacuo and T[n(ω)] are the reflection losses at the sample surface.

Type: Model | Advantage: None | Novelty: None | ConceptID: Mod4

150

Both the refractive index n(ω) and the absorption coefficient α(ω) can be determined from the ratios of the measured THz-fields.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res20

151

We report here only the absorption coefficient α(ω) of the material.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res21

Results and discussion

152

Fig. 6 shows the THz absorption spectra for forms 1 and 2 of ranitidine HCl for three different temperatures, 5 K, 150 K and 300 K. The data are fitted to a series of Lorentzian lineshape functions.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs14

153

From the room temperature spectra (300 K) one can see there are major differences between the two polymorphs.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs15

154

The spectra recorded at different temperatures may allow us to understand which features are due to intermolecular interactions (or phonon modes) and which are due to intramolecular vibrations.

Type: Method | Advantage: None | Novelty: New | ConceptID: Met31

155

At this stage of the research there has been no normal mode or DFT calculation on ranitidine HCl, so assignment of the transitions observed in the spectra is not possible.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met32

156

A detailed assignment of the vibrational modes in the THz region is a challenging task.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res22

157

We limited ourselves to a description of the spectra observed.

Type: Method | Advantage: None | Novelty: New | ConceptID: Met33

158

In the temperature dependent spectra of form 1 of ranitidine HCl, the feature seen at 2.54 THz (84.7 cm^–1) in the 300 K spectrum disappears in the 150 K and 5 K spectra.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs16

159

This could be explained by the fact that the vibrational potential for this particular hydrogen bond stretch is anharmonic and as the temperature increases the bond softens causing a red shift in the peak position.

Type: Hypothesis | Advantage: None | Novelty: None | ConceptID: Hyp3

160

However, the feature at 2.75 THz (91.7 cm¹) is not affected by temperature change and thus hides the 2.54 THz feature.

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs17

161

Again, the 2.75 THz feature could be a hydrogen bond with a harmonic potential or an intramolecular vibration which is not affected by temperature change.

Type: Hypothesis | Advantage: None | Novelty: None | ConceptID: Hyp4

162

Another interesting feature in the form 1 spectra is the considerable change in intensity in the peak at 1.78 THz (59.3 cm^–1).

Type: Observation | Advantage: None | Novelty: None | ConceptID: Obs18

163

At the moment without good theoretical background it is difficult to understand.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res23

164

But, we speculate that there are competing modes within this peak and as one mode dominates the other we observe a variation in intensity.

Type: Hypothesis | Advantage: None | Novelty: None | ConceptID: Hyp5

165

The spectrum of form 2 of ranitidine HCl is considerably different from that of form 1 which is in good agreement with the data obtained in .^{ref. 22}

Type: Result | Advantage: None | Novelty: None | ConceptID: Res24

166

This remains true for all temperatures which were measured in these experiments, so over the range 5–300 K there is no phase change between the polymorphs.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res25

167

It is noted that form 2 appears to be more temperature sensitive than form 1, with most of the major peaks red-shifting with increase of temperature.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res26

168

It is clear from our work and others that a greater theoretical understanding is required.

Type: Conclusion | Advantage: None | Novelty: None | ConceptID: Con1

Conclusions

169

Over the past year results emerging from new applications of terahertz technologies have grown considerably.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac54

170

Here we have presented two examples.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res27

171

It has been shown that TPS is a technique that can provide information about the physical state of a pharmaceutical active ingredient during the processing and storage of a tablet formulation.

Type: Conclusion | Advantage: None | Novelty: None | ConceptID: Con2

172

Moreover, there is scope for further development of this technique for these and other applications.

Type: Conclusion | Advantage: None | Novelty: None | ConceptID: Con2

173

Advanced data processing methods such as chemometrics will facilitate a greater understanding of solid dose formulations.

Type: Conclusion | Advantage: None | Novelty: None | ConceptID: Con3

174

TPS has been used in the investigation of the crystalline structure of materials.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res28

175

This is of considerable interest to the pharmaceutical industry where the lack of identification of polymorphs could lead to loss of patent protection (e.g. GSK Paxil™/Seroxal™) or if found during manufacture the company could be penalised by their national regulator.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac55

176

The technique has a fast data acquisition rate; currently raw data waveforms can be obtained in less than 100 ms, and it is envisaged that further developments will reduce this to less than 100 µs.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res29

177

This will open opportunities for incorporation of the technology into a high throughput polymorph screening system.

Type: Conclusion | Advantage: None | Novelty: None | ConceptID: Con4

178

TPI has been used to image epithelial cancer ex vivo.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res30

179

The diseased tissue showed a change in absorption compared to normal tissue, which correlated well with regions of tumour seen in histology.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res31

180

This suggests that TPI may have potential as a tool to identify boundaries of tumours.

Type: Conclusion | Advantage: None | Novelty: None | ConceptID: Con5

181

These measurements are now being conducted in vivo and will be published at a later date.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res32

182

Also, TPS measurements are being performed on malignant and healthy tissue to determine sources of contrast and spectral features which may allow diagnosis of many conditions.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res33

183

The origin of this useful and interesting spectral behaviour in polymorphs as well as that of water and biomolecules which contribute to the contrast in TPI images of tissue are now being explored and are an important area of scientific investigation.

Type: Conclusion | Advantage: None | Novelty: None | ConceptID: Con6

184

TPI is one amongst several imaging techniques that are being evaluated as diagnostic tools for skin lesions and tumour margin assessment.

Type: Conclusion | Advantage: None | Novelty: None | ConceptID: Con6

185

TPI may prove advantageous in distinguishing type, lateral spread and depth of tumours.

Type: Conclusion | Advantage: None | Novelty: None | ConceptID: Con7