WO2020104011A1 - Procédé et dispositif de classification d'un échantillon au moyen d'une spectroscopie térahertz - Google Patents

Procédé et dispositif de classification d'un échantillon au moyen d'une spectroscopie térahertz

Info

Publication number
WO2020104011A1
WO2020104011A1 PCT/EP2018/081812 EP2018081812W WO2020104011A1 WO 2020104011 A1 WO2020104011 A1 WO 2020104011A1 EP 2018081812 W EP2018081812 W EP 2018081812W WO 2020104011 A1 WO2020104011 A1 WO 2020104011A1
Authority
WO
WIPO (PCT)
Prior art keywords
sample
terahertz
tds
spectrum
radiation
Prior art date
Application number
PCT/EP2018/081812
Other languages
German (de)
English (en)
Inventor
Andrea QUINTEL
Nils Ivar ØYO
Kaspar Samuel WIDMER CANTZ
Andreas Marius DUBLER
Original Assignee
Tera Group Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tera Group Ag filed Critical Tera Group Ag
Priority to CH000527/2021A priority Critical patent/CH716952B9/de
Priority to PCT/EP2018/081812 priority patent/WO2020104011A1/fr
Publication of WO2020104011A1 publication Critical patent/WO2020104011A1/fr

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
    • G01N21/3581—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using far infrared light; using Terahertz radiation
    • G01N21/3586—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using far infrared light; using Terahertz radiation by Terahertz time domain spectroscopy [THz-TDS]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/84—Systems specially adapted for particular applications
    • G01N21/88—Investigating the presence of flaws or contamination
    • G01N21/95—Investigating the presence of flaws or contamination characterised by the material or shape of the object to be examined
    • G01N21/9508—Capsules; Tablets

Definitions

  • the invention relates to a method for examining a sample by means of a sample scanner according to the preamble of independent claim 1.
  • Spectroscopy is a group of physical methods that divide radiation according to a specific property such as wavelength, energy or mass. The intensity distribution that occurs is called the spectrum.
  • Countless methods are known in analytics to determine the most diverse properties of samples using spectroscopy.
  • methods of atomic spectroscopy are known, in which
  • Atomic spectroscopy here includes spectroscopic methods based on emission, absorption or
  • Fluorescence processes in atoms decrease and are used to determine chemical elements. There are also methods
  • Molecular spectroscopy is known in which measurements of the properties of individual molecules, especially the valence electron energy levels and the molecular vibrations and rotations are carried out.
  • Other methods of spectroscopy known in the prior art include solid-state spectroscopy, in which measurements of the properties of entire solid bodies (such as crystals) are carried out, impedance spectroscopy (dielectric spectroscopy) and laser spectroscopy.
  • Terahertz spectroscopy also called submillimeter wave, far infrared or far IR spectroscopy, also examines the interaction of matter Electromagnetic waves in the terahertz range (terahertz radiation)
  • a submillimeter wave / terahertz wave is an electromagnetic wave and lies in the electromagnetic spectrum between the infrared radiation and the microwave radiation. The classification of terahertz radiation in
  • the low energy of the THz radiation stimulates, among other things, bonds with heavy binding partners, for example low-frequency ones
  • Binding partners react primarily with small binding energies.
  • Hydrogen bonds in water and generally dipole-dipole bonds show a high degree of interaction. For example, it is possible to distinguish water of hydration from free water molecules. In contrast, metals reflect electromagnetic radiation. Non-polar materials such as paper, many plastics, textiles or ceramics appear almost completely transparent to terahertz radiation.
  • the terahertz radiation covers a relatively large frequency range between preferably 0.1 and 20 THz (3 - 660 cm -1 ). It is able to excite low-frequency modes and is therefore also sensitive to rotations of gaseous molecules and to collective vibrations of molecules with large mass and weak bonds, such as weak intermolecular ones
  • THz spectroscopy has a wide range of applications in chemistry, biology, pharmaceutical research, physics and engineering and enables that
  • THz radiation stimulates collective vibrations in crystalline samples and is therefore sensitive to intra- and intermolecular interactions
  • crystalline substances In the so-called fingerprint area of the electromagnetic spectrum, crystalline substances have a substance-specific terahertz spectrum with predominantly discrete absorption bands. Terahertz spectroscopy is also sensitive to the dynamics of
  • Hydrogen bridge networks because the rearrangements of the hydrogen bridges take place in the picosecond range.
  • THz time domain spectroscopy THz time domain spectroscopy
  • THz-TDS frequency-dependent refractive index of a sample.
  • the general principle of THz-TDS is the coherent emission and detection of THz radiation.
  • Crystal structures e.g. a chiral and a racemic crystal can be distinguished from each other on the basis of their THz spectra.
  • a typical THz time domain transmission spectrometer is made up of an exciter (e.g. femtosecond laser), an optical system (e.g.
  • THz radiation is generated by directing the exciter (e.g. laser) onto a suitable emitter (crystals, semiconductors, ).
  • a suitable emitter crystals, semiconductors, .
  • pulsed THz radiation is usually generated by optical rectification.
  • the optical system can consist, for example, of optical parabolic mirrors that focus the THz radiation onto the sample.
  • heterogeneous or foreign substances ie foreign atoms / substances in relation to drugs, other drug components or substances or, in the worst case, chemicals or other substances than drugs can be mixed in.
  • a person performs a visual inspection to detect differences in drugs based on their color or shape, thereby preventing the penetration of other types of drugs or chemical components or substances other than the desired components of the drugs.
  • Inspection devices have also been used in recent years to process the image data obtained by an image input unit such as a CCD camera to sort the drugs according to the difference in features such as shape, area or color.
  • Counterfeits can contain the right active ingredient, but in too high or too low a dose or in contaminated form. However, it can also be dangerous if there is not the slightest trace of the expected active ingredients. In many cases, counterfeit medicines contain, for example, ground brick or flour, and in rare cases also toxins such as
  • Insecticides or rat poison According to the World Health Organization, there are WFIO worldwide ten percent of counterfeit drugs, up to 30 percent in developing countries.
  • the pharmaceutical companies work closely with each other and with the customs authorities and use open and concealed, counterfeiting signs that make it difficult.
  • holograms, color-changing ink or iridescent surfaces are used.
  • pharmaceutical companies are increasingly relying on traceability technologies such as serial numbers, combined with a 2-D data matrix. It is intended to create the prerequisites for the seamless tracking of medicinal products and for an authenticity check of each individual pack. Specifically, the pharmacist checks an identification code for each medication before passing the medication on to the patient.
  • Medicinal products will often only be provided with a first opening protection (e.g. seal) and are scanned by scanning the packaging code in the pharmacy or authenticity checked upon delivery. Specifically, the pharmacist checks an identification code for each medication before passing the medication on to the patient. Medicines receive serial numbers for each package, which are stored in a protected database. This method also has the serious disadvantage that contamination and counterfeiting cannot be detected if there is a corresponding one
  • Packaging is used.
  • Sorting devices are also known for sorting drugs according to the difference in the result of the near infrared light spectral analysis reflected by the drugs using the spectrometer.
  • this device is limited in application and cannot be used in the case where the surface has the same composition as a corresponding tablet.
  • the result of the latest research has the possibility to measure the
  • terahertz - time domain spectrometry e.g. B. using light from the Terahertz region.
  • terahertz TDS terahertz radiation is directed onto a sample, and the terahertz waveform passing through the sample is measured by a temporal analysis, and the resulting waveform is represented by a Fourier transformation.
  • EP 2 042 855 A1 describes a sample analysis device comprising a terahertz radiation generating unit which generates light rays from terahertz radiation; an optical system that guides the terahertz radiation generated by the terahertz radiation generating unit to a sample as an object to be inspected; a detection unit that detects terahertz output radiation transmitted through or reflected by the sample; and a determination unit that determines a spectrum from the electrical signal detected by the detection unit and based on the determined spectrum and another predetermined spectrum
  • Fingerprint spectrum determines whether the sample contains foreign substances based on a component that is unique to the sample. From the used
  • the object of the invention is therefore a reliable method for
  • a method is to be provided in order to reliably determine counterfeits and / or impurities in a sample. The task is accomplished through procedures with the characteristics of independent
  • the sample scanner here comprises at least one terahertz source for generating a terahertz primary radiation, a detection unit for detecting terahertz secondary radiation originating from the sample, and an analysis module for generating one
  • the method according to the invention for classifying the sample comprises the following steps.
  • the terahertz primary radiation is generated by means of the terahertz source.
  • the terahertz primary radiation is directed onto the sample so that the terahertz primary radiation generated by the terahertz source is applied to the sample.
  • An interaction of the sample with the terahertz primary radiation produces a terahertz secondary radiation. This terahertz secondary radiation originating from the sample is measured using the
  • Detection unit detected as a sample TDS.
  • a sample spectrum is generated from the sample TDS using the analysis module.
  • the sample TDS is developed according to a suitable functional system. Now that the sample TDS and sample spectrum are available, a comparison can be made between the sample and a corresponding reference sample. In the comparison, a TDS deviation of the sample TDS of the sample from a reference TDS of a reference sample is determined. In addition, a spectrum deviation of the sample spectrum of the sample from one
  • Sample spectrum respectively compared with the reference TDS and the reference spectrum of the reference sample can be based on the TDS deviation and the A deviation in the spectrum can be determined.
  • the sample is classified accordingly by this assessment variable. The classification is therefore made using a combination, or a combined one
  • comparison relates to the comparison between the sample spectrum of the sample with the reference spectrum of the reference sample and / or to the comparison between the sample TDS of the sample with the reference TDS of the reference sample.
  • a spectrum is to be understood as the distribution function of an energy, frequency or mass.
  • the particular finding of the present invention is that not only the spectrum is used for the analysis of the sample, but also the TDS in addition. It has been found that certain information can be better determined from the TDS and thus the deviation from the reference sample can be better determined if both TDS (sample and reference) and spectrum (sample and reference) are used.
  • the time domain (TD) is the analysis of mathematical
  • a time domain graph shows how a signal changes over time
  • a frequency domain graph shows how much of the signal lies within a certain frequency band over a frequency range.
  • the terahertz primary radiation is preferably pulsed
  • These terahertz pulses preferably consist of only one or two cycles of electromagnetic oscillation. They can then be measured coherently, i.e. time-resolved, using electro-optical methods.
  • the underlying principle of a photoconductive antenna as an emitter for terahertz waves is to use the short optical pulse to trigger a transient current flow which serves as the source current of a radiated terahertz pulse. This requires a photoconductive (semiconductor) material in which the
  • Photons of the laser radiation can excite free charge carriers.
  • Laser pulses in the visible frequency range are preferably used to generate terahertz radiation.
  • Crystals can partially convert red laser light (with a wavelength of 780 nanometers) into violet light with twice the frequency (and half the wavelength).
  • the terahertz (radiation) source thus preferably comprises a laser and an emitter, the laser exciting the emitter, which then emits the
  • the optical system can also include a beam splitter and a shift table.
  • the beam of the laser is divided into two partial beams by the beam splitter, one of the two partial beams being delayed by the beam splitter and is led to the detector.
  • the laser can therefore be divided into a first and a second partial beam, the first partial beam being directed onto the sample for generating the terahertz primary radiation and the second partial beam being directed to the detector.
  • the interactions of the sample with the terahertz primary radiation can, among other things, excite bonds, for example low-frequency ones
  • the terahertz secondary radiation originating from the sample is therefore that
  • photoconductive antennas can also be used. In contrast to the emitter antennas for generating the terahertz primary radiation, no DC voltage is applied here, but rather a current sensor is preferably connected. If an optical laser pulse hits the photoconductive gap, charge carriers are briefly generated, which increase the conductivity of the antenna. If the terahertz pulse / the terahertz secondary radiation arrives at the antenna at the same time, the electrical terahertz field accelerates the optically excited ones
  • sample spectrum is generated from the sample TDS means that the sample TDS is developed according to the suitable functional system, that is to say preferably according to a complete orthogonal functional system. Development according to a suitable function system is preferably carried out by a Fourier transformation. Development is of course stopped after a sufficient number of terms.
  • the TDS (sample, reference) is a signal of the time domain and can be represented as a combination of periodic functions.
  • the transformation i.e. development according to a suitable functional system
  • the TDS is thus carried out by developing the TDS as a combination of sine and cosine functions.
  • information about overall amplitude is obtained, among other things. If there are digitized signal values in the time domain, these can be evaluated directly using a discrete Fourier transform (DFT).
  • DFT discrete Fourier transform
  • the Fourier transform is preferably carried out using an algorithm for fast Fourier transform (FFT). It allows efficient calculation of the discrete Fourier transform (DFT). It can be used to break down a digital signal into its frequency components and then analyze them.
  • FFT fast Fourier transform
  • the TDS deviation and the spectrum deviation make one
  • TDS and spectra are compared. This comparison can be done, inter alia, on fleas of the peaks, position of the peaks, integral of the peaks, course of TDS / spectra,
  • the material to be examined is designated as a sample.
  • This material can be a chemical substance, tissue sample, or other mixture of gases, gaseous (such as a car exhaust gas sample, an odor sample), liquid (such as drinking water samples, urine samples), solid (such as a rock sample) or a mixture of different physical states (e.g. a moist soil sample).
  • gaseous such as a car exhaust gas sample, an odor sample
  • liquid such as drinking water samples, urine samples
  • solid such as a rock sample
  • a mixture of different physical states e.g. a moist soil sample.
  • the sample preferably comprises an analyte and a matrix.
  • the analyte or analytes are the substances contained in a sample about which a chemical analysis is mainly intended to make a statement, i.e. H. which are relevant for the sample.
  • a chemical analysis is mainly intended to make a statement, i.e. H. which are relevant for the sample.
  • one of the analytes would be the active ingredient.
  • the matrix refers to those components of a sample that are not decisive for the use and / or effect of the sample.
  • the matrix according to the present invention can be found under
  • the matrix also has specific characteristics which can be identified in the TDS and spectra and can thus be used for the comparison.
  • the sample spectrum is preferably a sample frequency spectrum and the reference spectrum is a reference frequency spectrum.
  • Frequency spectrum is generally the electromagnetic spectrum, in which the illuminance is considered as a function of the radiation frequency.
  • the statement is to be visualized or output in such a way that even a “non-specialist” can determine whether a “correct” sample, counterfeit or contamination is present. This is achieved in that the sample is classified on the basis of the reference sample without manual evaluation being necessary, since the “evaluation”, that is, the classification of the sample takes place automatically.
  • the sample can therefore be almost arbitrary, there only needs to be a corresponding reference sample for classification.
  • the method can additionally include a creation step in which a reference is created.
  • One or more reference samples or multiple reference samples can be measured here in order to obtain corresponding TDS and spectra for comparison.
  • the sample can therefore include medication or food or minerals or a liquid.
  • the method according to the invention is based on the comparison of the sample with a reference sample, wherein data of the reference sample are preferably stored in a database.
  • the sample to be examined can be excited by an equally short laser pulse. The change in the transmission of the terahertz pulse can then measured depending on the time that has elapsed since the excitation.
  • the sample can be classified using a TDS tolerance range assigned to the TDS deviation and / or a spectrum tolerance range assigned to the spectrum deviation.
  • the range of tolerance and TDS tolerance range can also be generated by measuring several «same», ie similar references. The standard deviations in the spectra and TDS can then be used to determine an adequate spectrum tolerance range and TDS tolerance range.
  • the tolerance range can be defined, among other things, by an envelope of the TDS and the spectrum, as a standard deviation from certain variables, e.g. Integrals, absorption coefficient, refractive index, derivatives, smoothing functions. Square deviations can also be used. With the tolerance range, it is also possible to determine parts of the TDS / spectra in which larger / smaller deviations are permitted.
  • the reference spectrum of the reference is preferably ascertained whether the sample is a heterogeneous sample, a foreign substance or a foreign matrix or a foreign analyte.
  • composition (same main components) is carried out.
  • Reference samples of the group can then be, among other things, reference samples with the same main components but with different impurities and / or packaging and / or in different aging stages.
  • the degree of aging (or degree of oxidation) can be one
  • Drug active be determined. It is also possible, for example, to find out whether water of hydration or free water molecules are present in the sample.
  • the sample is compared with an entire database of reference samples (ie sample TDS and sample spectrum), the database being stored in the analysis module
  • a classification is made regarding the degree of agreement of the sample with the reference sample.
  • a match quantification of the sample can be carried out by outputting (e.g. a percentage) how far the sample matches the reference. It can also be simply output whether the sample is equivalent to the reference sample, whether there are impurities, whether the sample is a fake, how far the sample has aged / oxidized, whether there is water of hydration and much more.
  • the quantification can be carried out based on the tolerance range.
  • the sample preferably comprises at least one matrix and at least one analyte.
  • the conglomerate of matrix and analyte is classified here, since matrix fractions and analyte fractions usually do not differ significantly in TDS and spectrum can be.
  • the terahertz TDS and terahertz spectra are clear and individual for almost every sample. However, it is not necessarily possible to use individual peaks directly on ingredients
  • sample TDS and sample spectrum sample TDS and sample spectrum
  • reference TDS and reference spectrum reference sample
  • the terahertz TDS and terahertz spectrum contain a combination of physical and chemical properties.
  • physical properties such as solubility
  • the matrix of the sample can include all possible components.
  • the matrix can contain a filler, binder, disintegrant (disintegrant), an adjuvant, a blister, in particular a polymer and / or
  • Blisters often consist of the so-called push-through blister - a molded plastic with troughs for the individual tablets - and a push-through Closure made of aluminum foil, which is called blister film or lidding film. This enables capsules and tablets to be packaged hygienically clean and protected.
  • the plastic can be made of polyethylene, polypropylene, among others.
  • Polyvinyl chloride or polyethylene terephthalate exist.
  • Fillers ensure that the tablet receives the necessary size / mass.
  • Starches corn, potato and wheat starch
  • lactose are mostly used.
  • Binders ensure cohesion in granules and next to that
  • Dry binders such as B. MCC (microcrystalline cellulose) or starch and in wet binder / adhesives for granulation such as. B. starch paste, cellulose ether, Kollidon and gelatin.
  • Disintegrants improve the compression into durable tablets (improve particle adhesion) and the subsequent disintegration of the tablets in the gastrointestinal tract.
  • the analyte can be, inter alia, a medicament, active substance or a drug.
  • auxiliary substances can, among other things, control the targeted release of active ingredients and / or transport active ingredients specifically to their place of action.
  • auxiliary substances ensure that a medicinal product has a sufficient shelf life.
  • the matrix could consist of the packaging (usually cardboard) with packing slip, blister and filling material, while the analyte is the active ingredient. If the sample is in the packaging with a corresponding identification code (or identification feature), the
  • Identification code can be read out to identify the sample before.
  • the suitable reference TDS and reference spectra for carrying out the method according to the invention can be selected by the preliminary identification.
  • Identification code on the targeted medication are read out in order to identify the sample before and after performing the method according to the invention to classify whether the sample (i.e. the targeted medication) contains the correct medication for a patient.
  • the terahertz source can generate the light rays of the terahertz primary radiation as converging light rays and the optical system can converge the light rays onto the sample.
  • the terahertz source can generate the light rays of the terahertz primary radiation as parallel light rays and the optical system can guide the parallel light rays to the sample.
  • the optical system can refer to an optical system, in particular a lens for focusing the terahertz light beams. Also and or in addition, a further part of the optical system can be present which guides the laser beams to generate the terahertz radiation
  • the classification of the sample can in particular also be based on a
  • sample TDS and reference TDS Pattern recognition between sample TDS and reference TDS, and a pattern recognition between sample spectrum and reference spectrum.
  • sample TDS and reference TDS are compared and compared the sample spectrum and reference spectrum, for example by
  • Peak positions and curve shape are compared.
  • a signal may possibly be obtained in which the real and imaginary part of the signal can be readjusted. This process is called phase correction.
  • the phase correction can be used to better resolve signals.
  • the phase correction can be carried out, in particular automatically, in such a way that superimposed signals dissolve better.
  • negative signals can also be generated by the phase correction in order to be able to compare the peaks more easily, for example via pattern recognition.
  • phase correction according to the invention is therefore rather an expedient phase shift in order to be able to carry out a simpler classification using the spectra and TDS.
  • the comparison of the sample TDS and the sample spectrum with a reference TDS and the reference spectrum can be carried out using an average sample TDS and an average sample spectrum.
  • the averaged sample TDS and the averaged sample spectrum are obtained if several measurements are carried out on the same sample, the sample can also be measured in different orientations to the radiation source (terahertz source), or a large number of similar samples can be measured. That would be the case, for example, if you miss a whole row of tablets in a blister. Information would be given, for example, over a whole series of tablets.
  • Terahertz primary radiation can also be directed through a variety of samples. Using a blister as an example, the terahertz primary radiation would thus be directed through several tablets, in particular through a whole series of tablets.
  • the sample For the measurement of the sample, the sample can be predetermined
  • Direction are moved by a conveyor unit, e.g. change the orientation or measure another part of the sample (e.g. moving to the next tablet).
  • the structure of the sample can also be determined by the method according to the invention. This not only means that the chemical structure of the molecules is determined (which is usually the case with the ingredients), but also the crystal structure and also the structure / shape of the solid can be determined.
  • the structure / shape of the solid relate here inter alia to the size of tablets, grain size, whether a powder is present and other shape and structure properties.
  • a Laplace transform can also be used, which is very similar to the Fourier transform.
  • the terahertz primary radiation is preferably a radiation pulse
  • the length of a Terahertz radiation pulse is approximately 1 picosecond, i.e. 10 12 seconds.
  • Such radiation pulses are preferably generated by a
  • Femtosecond laser (or via frequency doubling) generated.
  • part of the optical power of a femtosecond laser can be directed onto an emitter antenna (for generating the primary radiation), while a second part is split off from the laser radiation via a beam splitter and via a
  • Delay unit is directed to the detector (antenna).
  • the delay unit is, for example, a motorized one
  • the detection in the method according to the invention can also take place via an interferrogram. It can therefore use a superposition or interference of waves to determine the quantities to be measured.
  • the sample scanner can comprise an optical system with which the terahertz primary radiation generated by the terahertz radiation source is guided to the sample.
  • the optical system can thus be designed as a lens, which focuses the terahertz radiation accordingly.
  • Polyethylene lenses are used to collimate and focus the THz radiation.
  • the terahertz secondary radiation can be a reflected and / or a
  • Transmitted terahertz secondary radiation which is reflected or transmitted by the sample.
  • measurements can preferably be taken in reflection for pills or capsules packed in polymer blister with aluminum foil as a cover and in transmission for in polymer bottles or - Glass bottles packed in bulk pills / capsules or medical
  • the aluminum foil serves as a mirror for the terahertz radiation. This is reflected to a significant extent by the aluminum foil.
  • the above-mentioned averaged sample TDS and averaged sample spectra also have the advantage that the inequalities in the reflection caused by corrugated aluminum foil are averaged out by inequalities.
  • Photoconductive antennas with an electro-optical structure are also known.
  • Organic crystals are also known as detectors / terahertz radiation emitter material.
  • Thin semiconductor wafers (with polar NLO) can also be used.
  • microwave antennas in the range of 50-500 GHz, ZnTE semiconductor wafers in the range of 1 -3 THz, organic crystals in the range of 3-10 Thz and thin semiconductor wafers in the range of 10-150 THz can be used.
  • the terahertz source preferably consists of a femtosecond laser, which is focused on a suitable terhertz radiation generator / emitter in order to generate the terahertz primary radiation.
  • Sample scanner a terahertz source for generating terahertz primary radiation, a detection unit for detecting terahertz secondary radiation originating from the sample, and an analysis module for
  • the sample scanner can additionally comprise an output module for outputting the classification of the sample.
  • This output module can be
  • Sample scanners can be carried out using appropriate software.
  • the analysis module can be designed, inter alia, as a PC or CPU.
  • the analysis module can also be integrated in the detector or connected to it.
  • the method according to the invention can thus be implemented in a software-implemented manner.
  • the sample scanner according to the invention can comprise a laser which is part of the terahertz source.
  • the laser can be a femtosecond laser.
  • the sample scanner can also include an optical system and the optical system can be a radiation splitter comprise, which can split a laser beam of the laser into a first partial beam and a second partial beam.
  • a sample frequency spectrum of the phase is preferably compared with a sample frequency spectrum of the phase and / or a sample frequency spectrum of the amplitude with a sample frequency spectrum of the amplitude.
  • the assessment size preferably the tolerance range, can be used to determine whether and to what extent the sample and reference sample match.
  • a degree of correspondence can be displayed by the output module, or simply whether the sample and reference sample match or not, it can be output with which reference sample the sample matches. In addition, it can optionally be output whether and which impurities are present, or whether the sample has aged or oxidized.
  • Sample frequency spectrum of the phase and / or a sample frequency spectrum of the amplitude are preferably obtained from the
  • Comparison of the amplitudes between zero TDS (zero measurement TDS) and sample TDS is a measure of the transmission.
  • there is a variable in the time difference between the two pulses that is directly proportional to the sample thickness.
  • the refractive index of the sample can be determined. This refractive index is another variable that is suitable for comparison with the reference sample.
  • the absorption coefficient can be determined from the sample frequency spectrum of the amplitude and the zero Determine the frequency spectrum of the amplitude.
  • the absorption coefficient is also another variable, which is suitable for comparison with the reference sample.
  • Fig. 1 is a schematic representation of a sample scanner
  • Fig. 2 is a schematic representation of a TDS
  • Fig. 3 is a schematic representation of a terahertz frequency spectrum, the amplitude
  • Fig. 4 is a schematic representation of a terahertz frequency spectrum, the phase
  • Fig. 1 shows a schematic representation of an inventive
  • Sample scanner 1 This shows the setup for a reflection terahertz time domain spectroscopy.
  • the sample scanner 1 in this case comprises the femtosecond laser 21, which belongs to the radiation source.
  • the laser beam 5 generated by the femtosecond laser 21 is by a
  • Beam splitter 41 of the optical system is divided into a first partial beam 52 and a second partial beam 53.
  • the second sub-beam 53 is the Mirror device 42 delayed by a predeterminable time. This is realized by the slider V1 of the mirror device 42.
  • the first partial beam 42 is guided through the optical system onto the terahertz emitter 22.
  • the terahertz primary radiation P is generated which strikes the sample 3.
  • the terahertz secondary radiation S originating from the sample 3 is detected by the detector 23.
  • a DC voltage bias 62 is at the terahertz emitter 22
  • An operational amplifier 63 is connected to the detector 23.
  • Operational amplifier 63 is a DC coupled electronic amplifier with a very high gain.
  • Sample 3 is designed as a medication packaging and comprises 4 layers of blisters.
  • the blisters consist of a back cover film
  • Aluminum which serves as a mirror for THz radiation and a polymer layer.
  • a series of tablets is preferably scanned. Then sample TDS and sample spectra are averaged over this row of tablets in order to compensate for the undesired scatter of the terahertz radiation due to the not completely flat aluminum foil.
  • the scanning of the row of tablets is realized in particular via the shifter V2, which shifts the entire sample 3 relative to the radiated terahertz primary radiation P.
  • the terahertz radiation in the form of the secondary beam S and primary beam P penetrate the cardboard packaging and the plastic blister without any noteworthy attenuation, since cardboard and non-polar plastics are almost transparent to terahertz radiation.
  • FIG. 2 shows a schematic representation of a TDS, in particular a sample and reference TDS.
  • TDS signal Various information can be obtained from the TDS signal.
  • a direct and simple characterization of the sample can be carried out by comparison with the reference sample. This can be done by, among other things, comparing the amplitudes between reference and sample TDS.
  • the time difference of the peaks can also be compared in order to compare the sample peaks and reference peaks.
  • Fig. 3 shows a schematic representation of a first
  • the first includes
  • Fig. 4 is a schematic representation of the second terahertz frequency spectrum.
  • the second terahertz frequency spectrum comprises the phase.
  • the sample TDS is mixed with the
  • a sample frequency spectrum of the phase with a sample frequency spectrum of the phase and / or a sample frequency spectrum can be used to compare the sample spectrum with the reference spectrum the amplitude can be compared with a sample frequency spectrum of the amplitude.
  • the assessment size preferably the tolerance range, can be used to determine whether and to what extent the sample and reference sample match.
  • the zero measurement corresponds to the measurement taken in an empty sample scanner.
  • the terahertz radiation penetrates the sample instead of an air gap and is delayed by the increased optical path.
  • losses occur due to reflection at the interfaces and through absorption.
  • the pulse of the sample measurement is both delayed and weakened compared to the reference measurement. While the comparison of the amplitudes between zero TDS (TDS of zero measurement) and sample TDS is a measure of the transmission, there is a quantity in the time difference between the two pulses that is directly proportional to the sample thickness.
  • TDS of zero measurement the terahertz radiation
  • sample TDS is a measure of the transmission
  • the sample frequency spectrum of the phase and the zero frequency spectrum of the phase can be used to determine the refractive index of the sample.
  • Refractive index is another parameter that is suitable for comparison with the reference sample.
  • the absorption coefficient can be determined from the sample frequency spectrum of the amplitude and the zero frequency spectrum of the amplitude.
  • the absorption coefficient is also another variable, which is suitable for comparison with the reference sample.

Abstract

L'invention concerne un procédé de classification d'un échantillon (3) au moyen d'un scanner (1) d'échantillon. Le scanner d'échantillon comprend une source térahertz (21, 22) destinée à produire un rayonnement primaire (P) térahertz, une unité de détection (23) pour la détection d'un rayonnement secondaire (S) térahertz provenant de l'échantillon, et un module d'analyse pour la production d'un spectre d'échantillon. Le procédé selon l'invention comprend les étapes suivantes : la production du rayonnement primaire térahertz au moyen de la source térahertz ; la soumission de l'échantillon à l'effet du rayonnement primaire térahertz produit par la source térahertz ; la détection d'une spectroscopie dans le domaine temporel d'échantillon du rayonnement secondaire térahertz provenant de l'échantillon au moyen de l'unité de détection ; la production du spectre d'échantillon par développement de la spectroscopie dans le domaine temporel d'échantillon selon un système fonctionnel adapté, par exemple une analyse de Fourier, au moyen du module d'analyse ; la constatation d'un écart de spectroscopie dans le domaine temporel par comparaison de la spectroscopie dans le domaine temporel d'échantillon à une spectroscopie dans le domaine temporel de référence d'un échantillon de référence et la constatation d'un écart de spectre par comparaison du spectre de l'échantillon à un spectre de référence de l'échantillon de référence, la détermination d'une grandeur d'évaluation sur la base de l'écart de spectroscopie dans le domaine temporel et de l'écart de spectre ; la classification de l'échantillon sur la base de la grandeur d'évaluation.
PCT/EP2018/081812 2018-11-19 2018-11-19 Procédé et dispositif de classification d'un échantillon au moyen d'une spectroscopie térahertz WO2020104011A1 (fr)

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CH000527/2021A CH716952B9 (de) 2018-11-19 2018-11-19 Verfahren zur Klassifizierung einer Probe mittels Terahertz-Spektroskopie.
PCT/EP2018/081812 WO2020104011A1 (fr) 2018-11-19 2018-11-19 Procédé et dispositif de classification d'un échantillon au moyen d'une spectroscopie térahertz

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CN113092403A (zh) * 2021-04-12 2021-07-09 桂林电子科技大学 一种学生校服纺织品材料太赫兹光谱定性检测方法
CN113340843A (zh) * 2021-05-31 2021-09-03 苏州锐心观远太赫兹科技有限公司 基于太赫兹时域谱的无损检测方法及检测系统

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