Sample measurement device and sample measurement method

Abstract

In the present invention, an irradiation unit scans an excitation light irradiation position along a line 32 that does not pass through the same position a plurality of times in a measurement range 31 on a sample 30, across a period in which a measurement unit acquires a single Raman spectrum. In a case in which there are a plurality of scan lines 321-32N, each respective scan line 32n does not make a plurality of passes through the same position on the sample 30. Even among the plurality of scan lines 321-32N, a plurality of passes are not made through the same position. Also, there is no mutual overlap among a plurality of excitation light irradiation regions 331-33N. A sample measurement device and a sample measurement method with which it is possible to easily perform a quantitative analysis by Raman spectroscopy in a measurement range on a sample is realized thereby.

Description

Sample measurement device and sample measurement method

[0001] The present disclosure relates to a sample measurement device and a sample measurement method for analyzing a sample by Raman spectroscopy.

[0002] When a sample is irradiated with light, the Raman effect causes the sample to produce Raman scattered light with a wavelength different from that of the irradiated light. The relationship between the difference in wavenumber between this Raman scattered light and the irradiated light and the intensity of the Raman scattered light (Raman spectrum) depends on the molecular structure, crystalline structure, components, etc. of the sample. Raman spectroscopy can analyze the sample based on this Raman spectrum.

[0003] In one example of a sample measurement device for analyzing a sample by Raman spectroscopy, a monochromatic laser beam output from a laser light source is irradiated onto the sample as excitation light, and the spectrum of Raman scattered light generated in the sample in response to this excitation light irradiation is measured using a spectrometer. A focusing optical system is provided between the laser light source and the sample to focus and irradiate the excitation light onto a limited irradiation area on the sample.

[0004] An imaging optical system is installed between the sample and the spectrometer to establish an optically conjugate relationship between the excitation light irradiation position on the sample and the spectrometer slit (the slit that passes the Raman scattered light). The width of the spectrometer slit is several micrometers to several tens of micrometers. The diameter of the excitation light irradiation area on the sample is at most several tens of micrometers. This allows the sample to be analyzed with high spatial resolution.

[0005] Using a sample measurement device with this configuration, it is possible to perform sample analysis known as mapping. In this analysis technique, multiple excitation light irradiation positions are set on the sample, and Raman spectra are acquired for limited excitation light irradiation regions surrounding each excitation light irradiation position, creating a map of the Raman spectrum on the sample. This allows the localization and distribution of specific substances in the sample to be analyzed. This mapping analysis technique can be particularly useful when analyzing the distribution of medicinal ingredients in solid mixture samples, such as solid dosage forms.

[0006] However, when analyzing a heterogeneous solid sample, the mapping analysis method cannot determine which component (e.g., whether it is due to a medicinal ingredient, other excipients, or a mixture of these) the Raman spectrum obtained for each excitation light irradiation position is due to, making it difficult to quantify the components in the solid sample or analyze the component ratios.

[0007] In the sample measurement technique described in Patent Document 1, the excitation light irradiation position is scanned over a certain measurement range on the sample, and one Raman spectrum is acquired based on the Raman scattered light generated over the scanning period.

[0008] Compared to measuring the spectrum of Raman scattered light generated in a limited excitation light irradiation region (diameter of several tens of μm) around one excitation light irradiation position on a sample, the sample measurement technique described in Patent Document 1 can obtain an integrated value or average value of the spectrum of Raman scattered light generated over a period of scanning the excitation light irradiation position over a wider measurement range. Therefore, with this technique, it is considered possible to quantify components and analyze component ratios in the measurement range of a solid sample, even when analyzing a heterogeneous solid sample, for example.

[0009] U.S. Patent Application Publication No. 2012 / 0162642

[0010] However, in the sample measurement technique described in Patent Document 1, the excitation light irradiation position is scanned along a line of a complex shape in the measurement range on the sample, so that the excitation light may be irradiated multiple times at some positions within the measurement range, while the excitation light may not be irradiated at other positions within the measurement range, and the length of time the excitation light is irradiated may vary depending on the position within the measurement range. As a result, when analyzing, for example, a heterogeneous solid sample, the obtained Raman spectrum does not represent the average amount of components in the measurement range, making quantitative analysis difficult.

[0011] An object of the present invention is to provide a sample measurement device and a sample measurement method that can easily perform quantitative analysis by Raman spectroscopy in a measurement range on a sample.

[0012] An embodiment of the present invention is a sample measurement device for analyzing a sample by Raman spectroscopy, and includes an irradiation unit that irradiates the sample with excitation light output from a light source, and a measurement unit that receives Raman scattered light generated by the sample in response to the irradiation with the excitation light to acquire a Raman spectrum, wherein the irradiation unit scans the excitation light irradiation position along a line that does not pass through the same position on the sample multiple times over the period of time that the measurement unit acquires one Raman spectrum.

[0013] An embodiment of the present invention is a sample measurement method for analyzing a sample by Raman spectroscopy, the sample measurement method including an irradiation step of irradiating the sample with excitation light output from a light source, and a measurement step of receiving Raman scattered light generated by the sample in response to the irradiation with the excitation light to acquire a Raman spectrum, wherein in the irradiation step, the excitation light irradiation position on the sample is scanned along a line that does not pass through the same position on the sample multiple times over a period of time during which one Raman spectrum is acquired in the measurement step.

[0014] According to the embodiment of the present invention, quantitative analysis by Raman spectroscopy can be easily performed in a measurement range on a sample.

[0015] FIG. 1 is a diagram illustrating the configuration of sample measurement device 1. FIG. 2 is a diagram illustrating the configuration of sample measurement device 2. FIG. 3 is a diagram illustrating scanning of the excitation light irradiation position on sample 30 by the irradiation unit. FIG. 4 is a diagram illustrating scanning of the excitation light irradiation position on sample 30 by the irradiation unit. FIG. 5 is a diagram illustrating scanning of the excitation light irradiation position on sample 30 by the irradiation unit. FIG. 6 is a diagram illustrating Raman spectra acquired for tablet samples with acetaminophen contents of 0% and 1.5% in Example 1. FIG. 7 is a diagram illustrating the spectrum after standardization processing was performed on the Raman spectrum of FIG. 6 in Example 1. FIG. 8 is a diagram illustrating a calibration curve obtained based on training data in Example 1. FIG. 9 is a diagram illustrating Raman spectra acquired when scanning the excitation light irradiation position along one scan line for one tablet sample with an acetaminophen content of 1.5% in Example 1. FIG. 10 is a diagram illustrating loading spectra obtained by performing principal component analysis in Example 1. FIG. 11 is a diagram illustrating average Raman spectra acquired for tablet samples with coating agent ratios of 0.5% and 10% in Example 2. FIG. 12 is a diagram showing a calibration curve obtained based on the learning data in Example 2.

[0016] Hereinafter, embodiments of the sample measurement device and sample measurement method will be described in detail with reference to the accompanying drawings. Note that the same elements in the description of the drawings will be given the same reference numerals, and duplicated explanations will be omitted. The present invention is not limited to these examples.

[0017] 1 is a diagram showing the configuration of a sample measurement device 1. The sample measurement device 1 includes a light source 11, a dichroic mirror 12, a lens 13, a filter 14, a lens 15, a spectroscope 16, an analysis unit 17, and a stage 21. The sample measurement device 1 analyzes a sample 30 placed on the stage 21 by Raman spectroscopy.

[0018] The light source 11 outputs excitation light to be irradiated onto the sample 30. The light source 11 is preferably a laser light source. The dichroic mirror 12 is optically connected to the light source 11 and reflects the excitation light output from the light source 11 toward the sample 30. The dichroic mirror 12 also transmits Raman scattered light generated in the sample 30 and reaching the sample 30 to a filter 14.

[0019] The lens 13 is provided on the optical path between the dichroic mirror 12 and the sample 30. The lens 13 focuses and irradiates the excitation light that has arrived from the dichroic mirror 12 onto the sample 30. The lens 13 also inputs Raman scattered light generated in the sample 30 in response to irradiation with the excitation light, and outputs the Raman scattered light to the dichroic mirror 12.

[0020] The filter 14 is optically connected to the dichroic mirror 12, and receives light that has arrived from the sample 30 via the lens 13 and the dichroic mirror 12. Of the received light, the filter 14 selectively blocks reflected or scattered excitation light, and selectively transmits Raman scattered light to the lens 15. The filter 14 may be a notch filter.

[0021] The lens 15 is optically connected to the filter 14 and inputs the Raman scattered light that has passed through the filter 14, focuses the Raman scattered light, and inputs it to the slit 16a of the spectrometer 16. The spectrometer 16 includes the slit 16a, a spectroscopic element, and a light-receiving element array. The spectrometer 16 disperses the Raman scattered light that has passed through the slit 16a using the spectroscopic element, receives the dispersed light of each wavelength component using the light-receiving element array, and detects the light intensity of each wavelength component. The spectrometer 16 outputs an electrical signal representing the light intensity of each detected wavelength component to the analysis unit 17. This electrical signal represents the spectrum of the Raman scattered light.

[0022] The analysis unit 17 is electrically connected to the spectrometer 16 and receives the electrical signal output from the spectrometer 16. The analysis unit 17 acquires a Raman spectrum based on the received electrical signal. The analysis unit 17 then analyzes the sample 30 based on the Raman spectrum. The analysis unit 17 may be a computer.

[0023] The stage 21 can place the sample 30 thereon and move the sample 30 in a direction perpendicular to the optical axis of the lens 13. This movement makes it possible to scan the excitation light irradiation position on the sample 30.

[0024] The optical system of excitation light, which travels from light source 11 through dichroic mirror 12 and lens 13 to sample 30, constitutes a focusing optical system for focusing and irradiating the excitation light output from light source 11 onto a limited irradiation area on sample 30. The optical system of Raman scattered light, which travels from sample 30 through lens 13, dichroic mirror 12, filter 14, and lens 15 to slit 16a of spectrometer 16, constitutes an imaging optical system for establishing an optically conjugate positional relationship between the excitation light irradiation position on sample 30 and the position of slit 16a.

[0025] The light source 11, the dichroic mirror 12, the lens 13, and the stage 21 constitute an irradiation unit that irradiates the excitation light onto the sample 30 and scans the excitation light irradiation position. The lens 13, the dichroic mirror 12, the filter 14, the lens 15, the spectroscope 16, and the analysis unit 17 constitute a measurement unit that receives the Raman scattered light and acquires a Raman spectrum.

[0026] 2 is a diagram showing the configuration of the sample measurement device 2. The sample measurement device 2 includes a light source 11, a dichroic mirror 12, a lens 13, a filter 14, a lens 15, a spectroscope 16, an analysis unit 17, a stage 21, and a scanning unit 22. The sample measurement device 2 analyzes a sample 30 placed on the stage 21 by Raman spectroscopy.

[0027] 2 differs from the configuration of the sample measurement device 1 shown in Fig. 1 in that it further includes a scanning unit 22. The stage 21 of the sample measurement device 2 does not need to move the sample 30 in a direction perpendicular to the optical axis of the lens 13.

[0028] The scanning unit 22 is provided on the optical path between the dichroic mirror 12 and the lens 13. The scanning unit 22 receives the excitation light that has arrived from the dichroic mirror 12 and outputs the excitation light to the lens 13. The scanning unit 22 can change the light output direction when outputting the excitation light to the lens 13. By changing the light output direction, the excitation light irradiation position on the sample 30 can be scanned. The scanning unit 22 can include, for example, a galvanometer mirror or a polygon mirror.

[0029] The optical system of excitation light, which travels from light source 11 through dichroic mirror 12, scanning unit 22, and lens 13 to sample 30, constitutes a focusing optical system for focusing and irradiating the excitation light output from light source 11 onto a limited irradiation area on sample 30. The optical system of Raman scattered light, which travels from sample 30 through lens 13, scanning unit 22, dichroic mirror 12, filter 14, and lens 15 to slit 16a of spectrometer 16, constitutes an imaging optical system for establishing an optically conjugate positional relationship between the excitation light irradiation position on sample 30 and the position of slit 16a.

[0030] The light source 11, the dichroic mirror 12, the scanning unit 22, and the lens 13 constitute an irradiation unit that irradiates the excitation light onto the sample 30 and scans the excitation light irradiation position. The lens 13, the scanning unit 22, the dichroic mirror 12, the filter 14, the lens 15, the spectroscope 16, and the analyzing unit 17 constitute a measurement unit that receives the Raman scattered light and acquires a Raman spectrum.

[0031] In both sample measurement device 1 (FIG. 1) and sample measurement device 2 (FIG. 2), the scanning of the excitation light irradiation position on sample 30 by the irradiation unit and the acquisition of the Raman spectrum by the measurement unit are performed in association with each other.

[0032] That is, over the period in which the measurement unit acquires one Raman spectrum, the irradiation unit scans the excitation light irradiation position along a line that does not pass through the same position on the sample 30 more than once. In other words, over a certain period of time, the irradiation unit scans the excitation light irradiation position along a line that does not pass through the same position on the sample 30 more than once, while the measurement unit acquires one Raman spectrum. This makes it easy to perform quantitative analysis by Raman spectroscopy in the measurement range on the sample 30.

[0033] The phrase "the scanning line does not pass through the same position on the sample 30 multiple times" means not only that the scanning line does not cross itself at a certain position, but also that a certain range of the scanning line does not overlap with another certain range. The excitation light irradiation position may be scanned along the scanning line only once or multiple times.

[0034] Furthermore, the measurement unit acquiring one Raman spectrum over a certain period of time does not only mean acquiring one Raman spectrum by continuously exposing the light receiving element array of the spectroscope 16 to light over that period of time, but also means acquiring one Raman spectrum by dividing that period into multiple partial periods and calculating the sum of the spectra detected by the light receiving element array in each partial period of time.

[0035] The sample measurement method of this embodiment is a method for analyzing a sample 30 by Raman spectroscopy, and can be performed using a sample measurement apparatus 1 (FIG. 1) or a sample measurement apparatus 2 (FIG. 2). The sample measurement method of this embodiment includes an irradiation step and a measurement step.

[0036] The irradiation step is a process performed by the irradiation unit of the sample measurement devices 1 and 2, in which excitation light output from light source 11 is irradiated onto sample 30. The measurement step is a process performed by the measurement unit of the sample measurement devices 1 and 2, in which Raman scattered light generated in sample 30 in response to the irradiation of excitation light is received to obtain a Raman spectrum. In the irradiation step, the excitation light irradiation position is scanned along a line that does not pass the same position on sample 30 multiple times over the period in which one Raman spectrum is obtained in the measurement step. The processes of the irradiation step and the measurement step are each performed during a common period.

[0037] 3 to 5 are diagrams for explaining scanning of the excitation light irradiation position on the sample 30 by the irradiation unit.

[0038] FIG. 3 shows a measurement range 31 on a sample 30, in which N scanning lines 32 １ ~32 Ｎ Each scanning line 32 when the excitation light irradiation position is scanned along each ｎ The excitation light irradiation area 33 around ｎ are indicated by hatching. N may be 1 or an integer of 2 or more. n is an integer of 1 or more and N or less. In this example, each excitation light irradiation region 33 ｎ One Raman spectrum can be acquired for each

[0039] N scan lines 32 １ ~32 Ｎ When scanning the excitation light irradiation position along each scan line in order, for example, the excitation light irradiation position may be scanned to the right along the odd-numbered scan lines, and the excitation light irradiation position may be scanned to the left along the even-numbered scan lines. ｎ－１ From the end of scanning to the next scanning line 32 ｎ When the scanning starts, the moving distance can be shortened and the time required for the movement can be shortened.

[0040] The measurement range 31 is the range on the sample 30 to be analyzed by Raman scattering spectroscopy. The excitation light irradiation position is the peak intensity position of the excitation light focused and irradiated onto the sample 30 by the lens 13. If there are multiple peak intensity positions, any of these peak intensity positions may be considered to be the excitation light irradiation position. Furthermore, if there is no clear peak intensity position, a range with an intensity close to the peak intensity (for example, an intensity of 90% or more of the peak intensity) may be considered to be the excitation light irradiation position.

[0041] Excitation light irradiation area 33 ｎ is scan line 32 ｎ This is the region that is irradiated with excitation light when the excitation light irradiation position is scanned along the line, and is a region where Raman scattered light can be generated significantly by the irradiation with excitation light.

[0042] FIG. 4 shows N scan lines 32１ ~32 Ｎ Any two adjacent scan lines 32 ｎ－１ , 32 ｎ The surrounding excitation light irradiation area 33 ｎ－１ , 33 ｎ is shown by hatching, and also shows the excitation light irradiation intensity distribution in the direction perpendicular to the scanning line. As shown in this figure, the excitation light irradiation area 33 ｎ is scan line 32 ｎ The peak intensity P of the excitation light ０ A certain percentage of the strength P １ The region may be irradiated with excitation light having an intensity equal to or greater than the predetermined ratio (P １ / P ０ ) may be, for example, 1 / 2 or 1 / e, or may be some other value.

[0043] 5 shows a case where one scanning line 32 is bent within a measurement range 31. As shown in this figure, the single scanning line 32 is repeatedly bent, so that an excitation light irradiation region 33 (hatched region) can occupy a wide portion of the measurement range 31 when the excitation light irradiation position is scanned along the single scanning line 32. In this example, one Raman spectrum can be acquired for the measurement range 31.

[0044] The shape and number of the scanning lines are arbitrary, and accordingly, the shape and number of the excitation light irradiation regions are also arbitrary. However, it is preferable that the scanning lines are linear. By making the scanning lines linear, it becomes easier to scan the excitation light irradiation position by the stage 21 or the scanning unit 22.

[0045] Also, as shown in FIG. 3, a plurality of scan lines 32 １ ~32 Ｎ In this case, each scan line 32 ｎ By making the shape of the line, a plurality of excitation light irradiation regions 33 are formed in the measurement range 31. １ ~33 Ｎ In addition, the excitation light irradiation area 33 can be easily arranged in parallel in a wide portion of the measurement range 31. ｎ In addition, each scanning line 32ｎ It is preferable to scan the excitation light irradiation position at a constant speed along the line . This allows for highly quantitative analysis by Raman spectroscopy.

[0046] As shown in FIG. 3, a plurality of scan lines 32 １ ~32 Ｎ In this case, each scan line 32 ｎ It is preferable that the scanning lines 32 do not pass over the same position on the sample 30 multiple times. １ ~32 Ｎ It is preferable that the same position or the same area is not passed through multiple times between the excitation light irradiation areas 33. １ ~33 Ｎ It is preferable that there is no overlap between the

[0047] When analyzing the sample 30 based on the Raman spectrum, the analysis unit 17 preferably performs a standardization process on the Raman spectrum and then analyzes the sample 30 based on the processed Raman spectrum. The standardization process is a process of converting the data into data with a mean value of 0 and a standard deviation of 1 by dividing the deviation of the data from the mean value by the standard deviation.

[0048] The analysis unit 17 may also extract features of the Raman spectrum by machine learning and analyze the sample 30 based on these features. The features refer to components in the sample found from the Raman spectrum (some of multiple components or a single component) or spectral components separated by calculation (for example, the signal and noise shown in FIG. 10 are each features).

[0049] Next, Examples 1 and 2 will be described. In both Examples 1 and 2, a sample measurement device 1 having the configuration shown in Fig. 1 was used, and the excitation light irradiation position on the sample was scanned with each scanning line being linear as shown in Fig. 3. A laser diode outputting laser light with a wavelength of 785 nm was used as the light source 11 as the excitation light. A 5x objective lens was used as the lens 13. A spectroscope equipped with a cooled CCD detector was used as the spectroscope 16. The beam diameter (full width at half maximum) of the excitation light on the sample was 25 µm.

[0050] In Example 1, tablet samples containing acetaminophen and a fixed proportion of corn starch and lactose as excipients were prepared as samples to be analyzed. Four acetaminophen concentrations were prepared: 0, 0.5, 1.0, and 1.5% (w / w). Ten tablet samples were prepared for each concentration. Each tablet sample had a diameter of approximately 8 mm.

[0051] In the central 4.5 mm square rectangular measurement area of ​​an 8 mm diameter, 180 linear scan lines of constant length (approximately 4.5 mm) were set in parallel at a constant pitch (25 μm). The excitation light irradiation position was scanned along each scan line at a constant speed (4.5 mm / sec). One Raman spectrum was acquired for each scan line. In other words, 180 Raman spectra were acquired for each tablet sample. The power of the excitation light at the sample was 7 mW.

[0052] 6 shows Raman spectra obtained for tablet samples containing 0% and 1.5% acetaminophen in Example 1. Each Raman spectrum shown in this figure is the average of 180 Raman spectra obtained for a single tablet sample.

[0053] As shown in this figure, the intensity of the Raman scattered light differs depending on the acetaminophen content. However, because the shape of one Raman spectrum multiplied by a constant is close to that of the other, it is difficult to determine whether the difference in the shape of the Raman spectra is due to the difference in acetaminophen content or to fluctuations in the excitation light intensity.

[0054] 7 shows the Raman spectrum after standardization of the Raman spectrum of FIG. 6 in Example 1. As shown in this figure, the Raman spectrum after standardization has approximately the same shape overall regardless of the acetaminophen content, but the peak intensity increases as the acetaminophen content increases. Therefore, the acetaminophen content can be measured based on the peak intensities in the Raman spectrum after standardization.

[0055] Calibration of the acetaminophen content was performed using partial least squares regression (PLS). In this calibration, for each of the four acetaminophen content levels, the standardized Raman spectra of five of the ten tablet samples were used as training data, and the standardized Raman spectra of the remaining five tablet samples were used as evaluation data.

[0056] FIG. 8 shows a calibration curve obtained based on the training data in Example 1. The horizontal axis represents the actual acetaminophen content, and the vertical axis represents the PLS-predicted content. The correlation coefficient for the evaluation data was 0.9952, and the least squares error was 0.055. A good correlation was observed between the actual acetaminophen content and the PLS-predicted content.

[0057] It is also possible to perform feature extraction by multivariate analysis using the 180 Raman spectra acquired for each tablet sample. Here, principal component analysis was performed as the multivariate analysis.

[0058] 9 shows Raman spectra obtained by scanning the excitation light irradiation position along one scan line for one tablet sample with an acetaminophen content of 1.5% in Example 1. 180 such Raman spectra were obtained for each tablet sample. Principal component analysis was performed on the 180 Raman spectra.

[0059] 10 is a diagram showing the loading spectrum obtained by performing principal component analysis in Example 1. From the eigenvector, the proportion of the first principal component was 98.8%. The second and subsequent principal components were determined to be mostly noise.

[0060] In Example 2, tablet samples were prepared as samples to be analyzed by coating plain tablets of the same size as in Example 1. The coating liquid was prepared by adding hypromellose, polyethylene glycol (molecular weight approximately 6000), talc, and Food Yellow No. 5 to purified water in fixed proportions.

[0061] The coating solution was applied to the uncoated tablets using a ventilated tablet coating device (manufactured by Freund Corporation). By controlling the amount of coating solution applied to the uncoated tablets, the coating agent content ratio to the uncoated tablet in the tablet sample after drying and solidification was varied within the range of 0 to 10.0% (w / w). The power of the excitation light in the sample was 12.4 mW.

[0062] Raman spectra were obtained for five tablet samples for each coating ratio. Figure 11 shows the average Raman spectra obtained for the tablet samples with coating ratios of 0.5% and 10% in Example 2. As shown in this figure, the intensity of the Raman scattered light varies with the coating ratio.

[0063] Calibration was performed using PLS for the coating agent ratio. In this calibration, for each coating agent ratio, the Raman spectra of three of the five tablet samples were used as training data, and the Raman spectra of the other two tablet samples were used as evaluation data. Tablet samples prepared using the same formulation were dissolved in water and the coating amount was quantified by absorptiometry, and the value obtained was used as the true value of the coating amount.

[0064] FIG. 12 shows the calibration curve obtained based on the training data in Example 2. The horizontal axis represents the true coating amount, and the vertical axis represents the PLS predicted amount. The correlation coefficient for the evaluation data was 0.9954, and the least squares error was 0.2579. A good correlation was observed between the true coating amount and the PLS predicted rate.

[0065] According to this embodiment, quantitative analysis by Raman spectroscopy can be easily performed in a measurement range on a sample. By scanning the excitation light irradiation position along a line that does not pass through the same position on the sample multiple times over the period of acquiring one Raman spectrum, quantitative analysis can be performed in a wide measurement range.

[0066] By providing multiple excitation light irradiation regions within the measurement range, it is possible to extract features using principal component analysis, etc. Furthermore, by providing multiple excitation light irradiation regions within the measurement range, rapid foreign matter inspection is possible for homogeneous samples.

[0067] In recent years, regulatory authorities in various countries have been promoting the establishment of a manufacturing method known as continuous production, which connects multiple manufacturing processes, with the primary goal of eliminating human error and improving product safety. This requires the automation of inspection processes, and the technology used for inspection and monitoring is known as PAT (Process Analytical Technology).

[0068] In pharmaceutical manufacturing processes, chemical quantity measurements are often required, such as monitoring content, the end point of mixing, moisture content, and coating amount. Spectroscopic measurement is effective for such inline / online chemical measurements, and Raman spectroscopy is considered a promising PAT tool for use in chemical measurements. The sample measurement device or sample measurement method of this embodiment can be effectively used in such situations.

[0069] The sample measurement device and sample measurement method are not limited to the above-described embodiment and configuration example, and various modifications are possible.

[0070] The sample measurement device according to the above embodiment is a sample measurement device that analyzes a sample using Raman spectroscopy, and includes an irradiation unit that irradiates the sample with excitation light output from a light source, and a measurement unit that receives Raman scattered light generated in the sample in response to the irradiation with the excitation light to acquire a Raman spectrum, and the irradiation unit scans the excitation light irradiation position along a line that does not pass through the same position on the sample multiple times over the period in which the measurement unit acquires one Raman spectrum.

[0071] In the above sample measurement device, the irradiation unit may be configured to scan the excitation light irradiation position along a linear line, or may be configured to scan the excitation light irradiation position along the line at a constant speed.

[0072] In the above-mentioned sample measurement device, the irradiation unit may be configured to scan the excitation light irradiation position along multiple lines, each of which does not pass through the same position on the sample multiple times, and the measurement unit may be configured to acquire one Raman spectrum for each of the multiple lines.

[0073] In the above sample measurement device, the irradiation unit may be configured to scan the excitation light irradiation position so as not to pass through the same position on the sample during scanning of the excitation light irradiation position along each of a plurality of lines on the sample. Also, the irradiation unit may be configured to scan the excitation light irradiation position so that the excitation light irradiation regions on the sample do not overlap each other during scanning of the excitation light irradiation position along each of a plurality of lines on the sample.

[0074] In the above sample measurement device, the measurement unit may be configured to perform a standardization process on the Raman spectrum and analyze the sample based on the processed Raman spectrum. Also, the measurement unit may be configured to extract feature quantities from the Raman spectrum and analyze the sample based on the feature quantities.

[0075] The sample measurement method according to the above embodiment is a sample measurement method for analyzing a sample by Raman spectroscopy, and includes an irradiation step of irradiating the sample with excitation light output from a light source, and a measurement step of receiving Raman scattered light generated in the sample in response to the irradiation with the excitation light to obtain a Raman spectrum, wherein in the irradiation step, the excitation light irradiation position is scanned along a line that does not pass through the same position on the sample multiple times over the period of time during which one Raman spectrum is obtained in the measurement step.

[0076] In the above sample measurement method, the irradiation step may be configured to scan the excitation light irradiation position along a linear line, or the irradiation step may be configured to scan the excitation light irradiation position along the line at a constant speed.

[0077] In the above-described sample measurement method, in the irradiation step, the excitation light irradiation position may be scanned along a plurality of lines, each of which does not pass through the same position on the sample more than once, and in the measurement step, one Raman spectrum may be acquired for each of the plurality of lines.

[0078] In the above sample measurement method, the irradiation step may be configured to scan the excitation light irradiation position so as not to pass through the same position on the sample during scanning of the excitation light irradiation position along each of a plurality of lines on the sample, or to scan the excitation light irradiation position so as not to overlap excitation light irradiation regions on the sample during scanning of the excitation light irradiation position along each of a plurality of lines on the sample.

[0079] In the sample measurement method, the measurement step may be configured to perform a standardization process on the Raman spectrum and analyze the sample based on the standardized Raman spectrum. Also, the measurement step may be configured to extract a feature value from the Raman spectrum and analyze the sample based on the feature value.

[0080] INDUSTRIAL APPLICABILITY The present invention can be used as a sample measurement device and a sample measurement method that can easily perform quantitative analysis by Raman spectroscopy in a measurement range on a sample.

[0081] 1, 2... sample measurement device, 11... light source, 12... dichroic mirror, 13... lens, 14... filter, 15... lens, 16... spectroscope, 17... analysis unit, 21... stage, 22... scanning unit, 30... sample, 31... measurement range, 32... scanning line, 33... excitation light irradiation area

Claims

1. A sample measurement device for analyzing a sample by Raman spectroscopy, comprising: an irradiation unit that irradiates the sample with excitation light output from a light source; and a measurement unit that receives Raman scattered light generated in the sample in response to the irradiation with the excitation light and acquires a Raman spectrum, wherein the irradiation unit scans the excitation light irradiation position along a line that does not pass through the same position on the sample more than once over the period in which the measurement unit acquires one Raman spectrum.

2. The sample measurement device according to claim 1, wherein the irradiation unit scans the excitation light irradiation position along the linear line.

3. A sample measurement device according to claim 1 or 2, wherein the irradiation unit scans the excitation light irradiation position along the line at a constant speed.

4. A sample measurement device according to any one of claims 1 to 3, wherein the irradiation unit scans the excitation light irradiation position along a plurality of lines, each of which does not pass through the same position on the sample more than once, and the measurement unit acquires one Raman spectrum for each of the plurality of lines.

5. A sample measurement device as described in claim 4, wherein the irradiation unit scans the excitation light irradiation position so as not to pass through the same position on the sample during scanning of the excitation light irradiation position along each of the multiple lines on the sample.

6. A sample measurement device as described in claim 5, wherein the irradiation unit scans the excitation light irradiation position so that excitation light irradiation areas on the sample do not overlap with each other during scanning of the excitation light irradiation position along each of the multiple lines on the sample.

7. A sample measurement device according to any one of claims 1 to 6, wherein the measurement unit performs a standardization process on the Raman spectrum and analyzes the sample based on the Raman spectrum after the standardization process.

8. The sample measurement device according to any one of claims 1 to 7, wherein the measurement unit extracts a feature quantity from the Raman spectrum and analyzes the sample based on this feature quantity.

9. A sample measurement method for analyzing a sample by Raman spectroscopy, comprising: an irradiation step of irradiating the sample with excitation light output from a light source; and a measurement step of receiving Raman scattered light generated in the sample in response to the irradiation with the excitation light to obtain a Raman spectrum, wherein in the irradiation step, the excitation light irradiation position is scanned along a line that does not pass through the same position on the sample more than once over the period of time during which one Raman spectrum is obtained in the measurement step.

10. A sample measurement method according to claim 9, wherein in the irradiation step, the excitation light irradiation position is scanned along the linear line.

11. A sample measurement method according to claim 9 or 10, wherein in the irradiation step, the excitation light irradiation position is scanned at a constant speed along the line.

12. A sample measurement method according to any one of claims 9 to 11, wherein in the irradiation step, the excitation light irradiation position is scanned along a plurality of lines, each of which does not pass through the same position on the sample more than once, and in the measurement step, one Raman spectrum is obtained for each of the plurality of lines.

13. A sample measurement method as described in claim 12, wherein in the irradiation step, the excitation light irradiation position is scanned so as not to pass through the same position on the sample during scanning of the excitation light irradiation position along each of the multiple lines on the sample.

14. A sample measurement method as described in claim 13, wherein in the irradiation step, the excitation light irradiation position is scanned so that the excitation light irradiation areas on the sample do not overlap with each other during scanning of the excitation light irradiation position along each of the multiple lines on the sample.

15. A sample measurement method according to any one of claims 9 to 14, wherein in the measurement step, a standardization process is performed on the Raman spectrum, and the sample is analyzed based on the Raman spectrum after the standardization process.

16. A sample measurement method according to any one of claims 9 to 15, wherein in the measurement step, a feature quantity of the Raman spectrum is extracted, and the sample is analyzed based on this feature quantity.

Images