JP2011257179A - Crystal form monitoring method and crystal form monitoring device - Google Patents

Abstract

PROBLEM TO BE SOLVED: To allow for polymorphism quantitative analyses of a product mixed with a diluent or excipient and a product contained in a plastic container etc.SOLUTION: An irradiation unit 3 irradiates an analyte 1 with a pulsed terahertz wave, a detection unit 4 detects a terahertz wave passed through the analyte 1, and a computation control unit 5 acquires an absorption characteristic spectrum of the analyte 1 from the detected terahertz wave, and compares the absorption characteristic spectrum of the analyte 1 with absorption characteristic spectra of various crystal forms stored in a storage unit 51 to identify a crystal form included in the analyte 1. Further, the crystal form monitoring device can analyze a product formed into a tablet by mixing a raw material synthesized into a target crystal form with the diluent or excipient such as a filler, a bulk filler, a binder, a humidity adding agent, a disintegrant, a surface active agent, and a lubricant, and a tablet contained in the plastic container etc. without any change.

Description

  The present invention relates to a technique for monitoring a crystal form using terahertz waves.

  Polymorphism is a phenomenon in which a chemical substance takes a plurality of different crystal forms even though they have the same chemical composition. The physical and chemical properties of polymorphs depend on the crystalline form, ie the molecular arrangement. Furthermore, when a co-crystal composed of a plurality of chemical compositions is formed, it becomes possible to develop functions and physical properties that cannot be obtained with crystals composed of only a single compound. It is also known that the crystal form and properties differ depending on the mixing ratio of D-form and L-form.

  In pharmaceuticals, the in vivo dynamics change due to polymorphism, so that there are known effects such as large differences in drug efficacy (Non-Patent Documents 1 and 2). Therefore, it is important to control the polymorph in the pharmaceutical manufacturing process. In order to control polymorphism, it is important to grasp not only the chemical composition but also the crystal form. Examples of methods for analyzing the crystal form include X-ray diffraction, thermal analysis, Raman spectroscopy, and infrared spectroscopy.

  Since polymorphs are manifested by taking not only the thermodynamic most stable structure but also a metastable structure, the polymorph is characterized by being easily changed. It is important that the structure of the crystal form does not change in the manufacturing process to which various conditions are added. In pharmaceuticals, the raw material synthesized in the desired crystal form is mixed with diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc. In quality control, it is important to confirm whether the crystal form is stably held in a process such as tablet molding. Therefore, monitoring of the crystal form in each step is required not only during the synthesis of the crystal form.

Takahiro Ueno, 5 others, “Simplified Quantitative Determination of Polymorphs and Amorphous Forms of Active Drugs in Formulations Using FT-Raman Spectroscopy”, YAKUGAKU ZASSHI, Japan Pharmaceutical Association, 2005, Vol. 125, No. 10 No., p.807-814 Yoshiaki Kato, “The Latest Technology and Application of Crystalline Polymorphism: From Basics of Polymorphism to Database Information”, CMC Publishing, August 31, 2005, p.181-191 K. LIEN NGUYEN, et al., "Terahertz time-domain spectroscopy and the quantitativemonitoring of mechanochemical cocrystal formation", nature materials, 2007, vol. 6, p.206-209 Andrew V. Trask, et al., "Physical stability enhancement of theophylline via cocrystallization", International Journal of Pharmaceutics, 2006, vol. 320, p.114-123

  However, the crystal form analysis method described above directly analyzes a purified sample, and forms various pharmaceutical preparations prepared by using raw materials and diluents or excipients, or is packed in a plastic container or the like. Analyzing the prepared tablets as they are has a problem that they cannot be applied to the monitoring of crystal forms because of the large interference caused by signals from excipients and container materials.

  Regarding FT Raman spectroscopy, although there are reports of polymorphism analysis in tablet models prepared using excipients, it is still difficult to analyze tablets packed in plastic containers or the like as they are because the spectra overlap. (Nonpatent literature 1).

  On the other hand, a quantitative qualitative analysis method using an electromagnetic wave having a frequency of 0.1 to 3 THz (hereinafter referred to as “terahertz wave”), for example, terahertz time domain spectroscopy, is a technique such as hydrogen bonding which is important in the stability of molecules and crystal structures. This is useful as a method for analyzing vibration modes due to weak interactions between molecules and within molecules (Non-patent Document 3). In addition, electromagnetic waves of 0.1 to 3 THz are characterized by transmitting materials that do not transmit visible light such as plastic, paper, wood, ceramics, and security applications utilizing high transparency (for example, concealment inspection, Mail non-destructive inspection etc.) are also attracting attention.

  The present invention has been made in view of the above, and an object of the present invention is to enable quantitative qualitative analysis of polymorphs in a product mixed with a diluent or an excipient or a product packaged in a plastic container. .

  The crystal form monitoring apparatus according to the first aspect of the present invention is a crystal form monitoring method for identifying a crystal form of a specimen containing a chemical substance having a polymorph which has a plurality of different crystal forms despite having the same chemical composition. Then, irradiating the subject with a pulsed terahertz wave, detecting a terahertz wave transmitted through the subject, obtaining an absorption characteristic spectrum based on the detected terahertz wave, Comparing the acquired absorption characteristic spectrum with the normalized absorption characteristic spectrum of the crystal form stored in the storage means, and identifying the crystal form included in the subject.

  The crystal form monitoring method according to the second aspect of the present invention is a crystal form monitoring apparatus for identifying a crystal form of a specimen containing a chemical substance having a polymorphism having a plurality of different crystal forms even though they have the same chemical composition. An irradiation unit that irradiates the subject with a pulsed terahertz wave, a detection unit that detects a terahertz wave transmitted through the subject, and an acquisition that acquires an absorption characteristic spectrum based on the detected terahertz wave Means for storing the normalized absorption characteristic spectrum of the crystal form, and comparing the acquired absorption characteristic spectrum with the normalized absorption characteristic spectrum of the crystal form stored in the storage means And an identification means for identifying a crystal form included in the structure.

  ADVANTAGE OF THE INVENTION According to this invention, the polymorphic quantitative qualitative analysis in the product mixed with the diluent or the excipient | filler or the product packaged in the plastic container etc. can be enabled.

It is a functional block diagram which shows the structure of the crystal form monitoring apparatus in this Embodiment. FIG. 3 is a diagram showing an absorption characteristic spectrum of a subject in Example 1. FIG. 6 is a diagram showing an absorption characteristic spectrum of a subject in Example 2.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings.

  FIG. 1 is a functional block diagram showing a configuration of a crystal form monitoring apparatus according to the present embodiment. A crystal form monitoring apparatus 10 shown in FIG. 1 transmits a placement unit 2 for placing a chamber 11 for housing the subject 1, an irradiation unit 3 for irradiating the subject 1 with a pulsed terahertz wave, and the subject 1. The detection unit 4 that detects the terahertz wave, the absorption control spectrum of the subject 1 based on the terahertz wave detected by the detection unit 4, the calculation control unit 5 that assigns the structure of the subject 1, and the atmosphere of the subject 1 A pressure adjusting unit 6 that controls the pressure and a temperature adjusting unit 7 that controls the temperature of the subject 1 are provided.

  The subject 1 is fixed by the holder 12 in the chamber 11 so that the irradiation surface is perpendicular to the irradiation direction of the terahertz wave (vertical direction in FIG. 1). The chamber 11 includes an optical window 11a through which a terahertz wave can be transmitted at an upper portion where the terahertz wave is incident and a lower portion where the terahertz wave transmitted through the subject 1 is emitted. On the terahertz wave irradiation surface side of the subject 1, an aperture 13 having an inner diameter smaller than the irradiation surface of the subject 1 is installed. By this aperture 13, the terahertz wave that reaches the detection unit 4 is transmitted through the subject 1.

  If the subject 1 is too thin in the terahertz wave irradiating direction, the amount of the target component is reduced, so that the detection accuracy is lowered, and if it is too thick, the terahertz wave is hardly transmitted. Therefore, the thickness of the subject 1 is preferably 0.1 to 15 mm, and more preferably 0.5 to 2 mm. By setting the thickness of the subject within the above range, the detection accuracy can be improved and the terahertz wave can be transmitted with certainty. In addition, multiple reflection and interference are less likely to occur.

  The subject 1 preferably has an in-plane dimension that intersects the terahertz wave irradiation direction exceeding 1 to 3 mm. If this dimension is too small, the inner diameter of the aperture 13 is also reduced, so that the energy of the transmitted terahertz wave is weakened and the detection accuracy is lowered.

  The placement unit 2 is a stage arranged substantially horizontally, and has a size that allows the chamber 11 to be placed. In addition, you may provide the moving mechanism which moves the mounting part 2 in the in-plane direction which cross | intersects the irradiation direction of a terahertz wave, and an irradiation direction.

  The irradiation unit 3 includes a light source 8 and a pulse generator 9. The light source 8 excites an electromagnetic wave (excitation light) of 0.1 to 3 THz. Examples of the light source 8 include a pulse laser and a titanium sapphire laser that are femtosecond laser excitation light. The pulse generator 9 receives excitation light from the light source 8 and generates a pulsed terahertz wave. Examples of the pulse generator 9 include a nonlinear optical crystal, a photoconductive antenna, a semiconductor, a quantum well, and a high-temperature conductive thin film. The terahertz wave output from the irradiation unit 3 is introduced by the mirror 20 and irradiated onto the subject 1. The terahertz wave that has passed through the subject 1 reaches the detection unit 4 by the mirror 21.

  The detection unit 4 detects a terahertz wave that has passed through the subject 1. For example, a photoconductive antenna.

  The calculation control unit 5 converts the terahertz wave detected by the detection unit 4 into a frequency domain by Fourier transform to obtain an absorption characteristic spectrum. The storage unit 51 included in the calculation control unit 5 stores absorption characteristic spectra of various crystal forms normalized per unit thickness and unit concentration of the target component. The calculation control unit 5 refers to the storage unit 51 and identifies the crystal form from the absorption characteristic spectrum obtained from the terahertz wave transmitted through the subject 1. When identifying the crystal form, the entire waveform of a spectrum in a certain range in the measurement region or a plurality of characteristic absorption bands is read from the storage unit 51 and fitted to the obtained absorption characteristic spectrum. Alternatively, the absorption intensity of a specific fixed frequency may be used.

  The pressure adjustment unit 6 includes a gas pressure control valve 14 for feeding dry nitrogen or dry air, a vacuum pump 15, and a vacuum gauge 16. The pressure inside the chamber 11 can be reduced by the vacuum pump 15 through the path 15a. In addition, by sending dry nitrogen or dry air through the gas introduction pipe 14a, the atmosphere inside the chamber 11 can be replaced with a desired gas. The pressure adjustment unit 6 preferably has a performance of adjusting the pressure inside the chamber 11 to 0.1 Pa to atmospheric pressure. Moreover, it is preferable that the precision of the pressure control of the pressure adjustment part 6 has the stability of +/- 0.1-1Pa.

  The temperature adjustment unit 7 includes a refrigerant tank 17 such as liquid nitrogen, a heater 18, and a temperature sensor 19. The inside of the chamber 11 is cooled or heated by sending a refrigerant such as liquid nitrogen into the chamber 11 from the path 17 a and conducting to the heater 18 a introduced into the chamber 11. It is preferable that the temperature adjusting unit 7 has a heating / cooling performance capable of setting the temperature of the chamber 11 to −200 degrees to 100 degrees Celsius. Moreover, it is preferable that the temperature adjustment accuracy of the temperature adjustment unit 7 has a stability of ± 0.1 to 1.0 degrees Celsius.

  Next, a method for monitoring the subject 1 using the crystal form monitoring apparatus 10 will be described.

  In the monitoring process, when the light source 8 emits excitation light and the pulse generator 9 receives the excitation light, the pulse generator 9 generates a pulsed terahertz wave W1. The terahertz wave W1 is introduced by the mirror 20 and irradiated on the subject 1.

  When the subject 1 is irradiated with the terahertz wave W1, it resonates with energy of weak interaction such as hydrogen bond, van der Waals bond, π-electron interaction, electrostatic interaction and the like.

  Then, the terahertz wave W <b> 2 that has passed through the subject 1 reaches the detection unit 4 by the mirror 21.

  The detection unit 4 detects a temporal change in the electric field intensity of the terahertz wave W <b> 2 and transmits it to the calculation control unit 5 as a detection value.

  The calculation control unit 5 converts the received detection value into a function of frequency by Fourier transform, and obtains an absorption characteristic spectrum of the subject 1. Then, the crystal form of the subject 1 is identified with reference to the absorption characteristic spectrum stored in the storage unit 51. Since the resonance frequency and absorption intensity of the energy of the interaction are in accordance with the crystal form of the crystal contained in the subject 1, the crystal form can be identified from this absorption characteristic spectrum. Moreover, the calculation control part 5 quantifies content of a certain crystal form using absorption intensity. Since the thickness of the subject 1 is known, the concentration of a certain crystal form in the subject 1 is referred to by referring to the unit thickness and the absorption characteristic spectrum normalized per unit concentration of the target component stored in the accumulation unit 51. And the content can be determined. When the subject 1 includes a plurality of types of crystals, the ratio thereof can be obtained.

  Further, if necessary, the pressure adjusting unit 6 is used to reduce the pressure inside the chamber 11 to about 10 to several hundred Pa, or to replace with dry nitrogen or dry air. In general, replacement with a vacuum atmosphere or dry nitrogen or dry air reduces the influence of absorption of terahertz waves by water vapor, so that the accuracy of monitoring increases.

  Further, as necessary, the temperature controller 7 is driven by the calculation controller 5 in accordance with the temperature inside the chamber 11 detected by the temperature sensor 19 to heat or cool the inside of the chamber 11 to a predetermined temperature. In general, the lower the temperature, the sharper the absorption characteristic peak, and the higher the accuracy of monitoring. Further, if the crystal form is heated to the transition temperature, the change in the absorption spectrum accompanying the transition of the crystal form can be monitored.

  As described above, according to the present embodiment, the irradiation unit 3 irradiates the subject 1 with the pulsed terahertz wave, and the detection unit 4 detects the terahertz wave that has passed through the subject 1 to perform calculation. The control unit 5 acquires the absorption characteristic spectrum of the subject 1 from the detected terahertz wave, and compares the absorption characteristic spectrum of the subject 1 with the absorption characteristic spectra of various crystal forms stored in the storage unit 51. The crystal form contained in the specimen 1 can be identified.

  According to the present embodiment, the raw material synthesized in the target crystal form is a diluent or excipient such as a filler, a bulking agent, a binder, a moistening agent, a disintegrant, a surfactant, a lubricant, etc. Since it is possible to directly analyze a product molded into a tablet by mixing with a tablet or a tablet packaged in a plastic container or the like, it is possible to confirm whether the crystal form is stably held in each manufacturing process.

  In addition, polymorphs with strong mechanical strength, polymorphs with high stability against humidity, and polymorphs with high solubility in water have high utility as pharmaceuticals, but these properties are molecules such as hydrogen bonds. There is a big relationship with weak interactions in the molecule. According to the present invention, in the polymorph to be monitored, knowledge about the mechanical strength of the crystal and the solubility in water can be obtained by using weak interaction between molecules such as hydrogen bonds as an index.

  The crystal to be monitored by the crystal form monitoring apparatus 10 is a polymorph having a plurality of different crystal forms even though a certain chemical substance has the same chemical composition (and also handles optical isomers). It is characterized by having. The polymorph may form a co-crystal having a plurality of chemical compositions.

  Examples of co-crystals to be monitored include (a) carbamazepine and saccharin, (b) carbamazepine and nicotinamide, (c) carbamazepine and trimesic acid, (d) celecoxib and nicotinamide, (e) olanzapine and nicotinamide, (F) Celecoxib and 18-crown-6, (g) Itraconazole and succinic acid, (h) Itraconazole and fumaric acid, (i) Itraconazole and L-tartaric acid, (j) Itraconazole and L-malic acid, (k) Itraconazole HCl and tartaric acid, (l) modafinil and malonic acid, (m) modafinil and grecolic acid, (n) modafinil and maleic acid, (o) topiramate and 18-crown-6, (p) 5-fluorouracil Urea, (q) hydrochlorothiazide and nicotinic acid, (r) hydrochlorothiazide and 18-crown-6, (s) hydrochlorothiazide and piperazine, (t) acetaminophen and 4,4′-bipyridine, (u) phenytoin and pyridone, (V) aspirin and 4,4′-bipyridine, (w) ibuprofen and 4,4′-bipyridine, (x) flurbiprofen and 4,4′-bipyridine, (y) flurbiprofen and trans-1. , 2-bis (4-pyridyl) ethylene, (z) carbamazepine and p-phthalaldehyde, (aa) carbamazepine and 2,6-pyridinecarboxylic acid, (bb) carbamazepine and 5-nitroisophthalic acid, (cc) carbamazepine and 1,3,5,7-adaman Tetracarboxylic acid, (dd) carbamazepine and benzoquinone, (ee) acetaminophen and phenazine, (ff) acetaminophen and theophylline, (gg) acetaminophen and succinic acid, (hh) acetaminophen and oxalic acid, (Ii) theophylline and caffeine, (jj) theophylline and oxalic acid, (kk) theophylline and malonic acid, (ll) theophylline and maleic acid, (mm) theophylline and glutaric acid, (nn) caffeine and oxalic acid. Can be mentioned.

  Examples of polymorphs having a single composition include (A) formotidine, A type, B type, C type, (B) barbital, A type, B type, (C) indomethacin, (D) carbamazepine, I Type, type II, type III, (E) acetaminophen, type I, type II.

  The form of the subject 1 is a powder obtained by purifying the crystal, a sample obtained by molding the crystal powder, the crystal powder as a filler, a bulking agent, a binder, a moistening agent, a disintegrant, a surfactant, a lubricant, and the like. Examples include various forms prepared using a diluent or excipient.

  As a diluent for analysis using a terahertz wave, various types well known in the art can be widely used. For example, polyethylene powder and magnesium oxide powder can be used.

  Representative forms of various pharmaceutical preparations include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), etc. However, the monitoring targets of the present crystal form monitoring apparatus 10 are tablets, pills, powders, granules, capsules, and suppositories that are solid forms.

  In molding into a tablet form, various carriers well known in the art can be widely used as carriers. Examples include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and other excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin Solutions, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate , Disintegrating agents such as stearic acid monoglyceride, starch, lactose, white sugar, stearin, cacao butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium base, absorption promoters such as sodium lauryl sulfate, glycerin Moisturizing agents such as starch, starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid, purified talc, stearates, boric acid powder, a lubricant such as polyethylene glycol can be used. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets. When forming into the form of a pill, those conventionally known in this field can be widely used as the carrier. Examples include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin, ethanol, and disintegrants such as laminaran and agar. Can be used. In molding into a suppository form, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like. Capsules are usually prepared by mixing the active ingredient compound with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules and the like according to conventional methods. Furthermore, a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetening agent, etc. and other pharmaceuticals may be contained in a pharmaceutical formulation as needed.

The subject 1 may be packaged in a container partially using any material of plastic, paper, wood, or ceramics.
[Example 1]
Next, Example 1 of the present invention will be described. In addition, this invention is not limited to an Example.

  In Example 1, an analytical test was performed using the crystal form monitoring apparatus 10 shown in FIG. The crystal-type monitoring device 10 uses a vitese (100 femtosecond type, manufactured by Coherent) as a light source 8, a photoconductive antenna (manufactured by Hamamatsu Photonics) as a pulse generator 9, and a light as a detection unit 4. It was produced using a spectroscopic device (manufactured by Advanced Infrared, THz-TDS2004) equipped with a conductive antenna (manufactured by Hamamatsu Photonics).

  As the subject 1, theophylline and oxalic acid 2: 1 co-crystal, theophylline and malonic acid 1: 1 co-crystal, theophylline and maleic acid 1: 1 co-crystal were used. For reference, theophylline single crystal, oxalic acid single crystal, malonic acid single crystal, and maleic acid single crystal were used.

  Theophylline and oxalic acid 2: 1 co-crystal was synthesized by dissolving 2.047 g of theophylline and 512 mg of oxalic acid in 40 ml of chloroform and 11 ml of methanol, refluxing at 55 degrees Celsius, and then cooling the solution to room temperature. The precipitate was filtered.

  Theophylline and malonic acid 1: 1 co-crystal was synthesized by refluxing 587 g of theophylline and 339 mg of malonic acid in 40 ml of chloroform and 2 ml of methanol, and then stirring with the core prepared by grinding theophylline and malonic acid to a total volume of 15 ml. After evaporating the solvent, the resulting precipitate was filtered.

  Theophylline and maleic acid 1: 1 co-crystal were synthesized by refluxing 2.02 g of theophylline and 1.30 g of maleic acid in 65 ml of chloroform: methanol solution 6: 1, cooling with stirring, and filtering the resulting precipitate. I went there.

  The obtained co-crystal was confirmed to match the crystal form of Non-Patent Document 4 using the conventional X-ray diffraction method.

  Then, the subject 1 was irradiated with the terahertz wave W 1 using the irradiation unit 3, and the terahertz wave W 2 transmitted through the subject 1 was detected by the detection unit 4. If the subject 1 is too thin, the amount of the target component is reduced and the detection accuracy is reduced. If the subject 1 is too thick, the terahertz wave is difficult to transmit. However, in this example, such a reduction in detection accuracy did not occur. It can be determined that the thickness of the specimen 1 is appropriate.

  Further, since the in-plane dimension of the subject 1 intersecting the terahertz wave irradiation direction is 10 mm, the aperture 13 is set to 7 mm. Since the energy of the transmitted terahertz wave did not decrease, it can be determined that the sizes of the subject 1 and the aperture 13 are appropriate.

  FIG. 2 is a diagram showing an absorption characteristic spectrum of the subject 1 measured by the above method. Fig. 2 (1) shows the absorption characteristic spectrum of theophylline and oxalic acid 2: 1 co-crystal and theophylline single crystal and oxalic acid single crystal. Fig. 2 (2) shows theophylline and malonic acid 1: 1 co-crystal and theophylline single crystal. Fig. 2 (3) shows absorption characteristic spectra of theophylline and maleic acid 1: 1 co-crystal and theophylline single crystal and maleic acid single crystal.

  As indicated by reference numeral 211 in FIG. 2 (1), in theophylline and oxalic acid 2: 1 co-crystal, absorption bands resonating with intermolecular interactions were observed around 1.5 THz and 1.8 THz. As indicated by reference numeral 221 in FIG. 2 (2), theophylline and malonic acid 1: 1 co-crystal exhibited a wide absorption band resonating with the intermolecular interaction in the vicinity of 2.5 THz. As indicated by reference numeral 231 in FIG. 2 (3), in theophylline and maleic acid 1: 1 co-crystal, a wide absorption band resonating with the intermolecular interaction was observed around 2.0 THz.

  The reference theophylline single crystal (reference numerals 212, 222, 232) has two locations of 1.1 THz and 1.8 THz, the oxalic acid single crystal (reference numeral 213) is 1.3 THz, and the malonic acid single crystal (reference numeral 223) is 1. For 5 THz, maleic acid single crystal (reference numeral 233), several absorption bands resonating with intermolecular interactions were observed at frequencies higher than 2.0 THz.

  Thus, a unique THz absorption spectrum was observed for each different crystal form assigned by the X-ray diffraction method. Therefore, it is possible to analyze the crystal form in the unknown sample based on the absorption characteristic spectrum obtained by storing the absorption characteristic spectrum of the crystal form in the storage unit 51 and detecting the terahertz wave transmitted through the subject 1.

[Example 2]
Next, a second embodiment of the present invention will be described.

  The crystal form monitoring apparatus 10 used the same configuration as in Example 1.

  As the subject 1, theophylline and oxalic acid 2: 1 co-crystal synthesized in the same manner as in Example 1 were introduced, and theophylline single crystal and oxalic acid single crystal were used for reference. Each crystal powder formed into a cylindrical pellet having a thickness of 1 mm and a diameter of 10 mm was used as a first specimen. In addition, a second specimen was formed by molding this crystal powder into a cylindrical pellet having a thickness of 1 mm and a diameter of 10 mm using polyethylene powder as a diluent so as to have a concentration of 10%. The second subject was packaged in an envelope made of high-quality paper having a thickness of 0.3 mm as the third subject.

  The first to third subjects 1 were irradiated with the terahertz wave W1 using the irradiation unit 3, and the terahertz wave W2 transmitted through the subject 1 was detected by the detection unit 4. Further, the temperature control unit 7 was driven by the calculation control unit 5 in accordance with the temperature in the chamber 11 detected by the temperature sensor 19, and the chamber 11 was cooled to room temperature and -196 degrees Celsius for comparison. At -196 degrees Celsius with respect to room temperature, the intensity of the absorption characteristic peak was approximately doubled, and the half-value width was sharpened by about half.

  FIG. 3 (1) shows an absorption characteristic spectrum obtained by measuring the first specimen and a theophylline single crystal and oxalic acid single crystal for reference at -196 degrees Celsius. As indicated by reference numeral 311, in the first subject, absorption bands resonating with the intermolecular interaction were observed in the vicinity of 1.5 THz and 1.8 THz. The reference theophylline single crystal (reference numeral 312) has two absorption bands at 1.1 THz and 1.8 THz, and the oxalic acid single crystal (reference numeral 313) has an absorption band resonating with the intermolecular interaction at 1.3 THz.

  FIG. 3 (2) shows an absorption characteristic spectrum obtained by measuring the second subject at −196 degrees Celsius. As indicated by reference numeral 320, similar to the result shown in FIG. 2 (1), absorption bands thought to resonate with the intermolecular interaction were observed near 1.5 THz and 1.8 THz. Compared with the results shown in FIG. 2 (1), the absorption intensity is weak, but the transmittance is high, so that a peak shape with less noise is obtained and the accuracy is high. Therefore, it can be seen that the crystal shape does not change by mixing with the diluent, the monitoring is not hindered by the diluent, and the transmittance is increased by cooling, so that a peak shape with less noise is obtained and the accuracy is improved. It was.

  FIG. 3 (3) shows an absorption characteristic spectrum obtained by measuring the third subject at −196 degrees Celsius. As indicated by reference numeral 330, similar to the result shown in FIG. 2 (1), absorption bands thought to resonate with the intermolecular interaction were observed near 1.5 THz and 1.8 THz. Compared with the results shown in FIG. 2 (1), the background was slightly increased due to slight absorption by the paper, but the peak detection accuracy was almost unchanged. Therefore, it was found that the monitoring is not hindered by wrapping in paper, and the detection accuracy is almost the same as when not wrapping.

DESCRIPTION OF SYMBOLS 10 ... Crystal form monitoring apparatus 1 ... Subject 2 ... Mounting part 3 ... Irradiation part 4 ... Detection part 5 ... Calculation control part 51 ... Accumulation part 6 ... Pressure adjustment part 7 ... Temperature adjustment part 8 ... Light source 9 ... Pulse generator DESCRIPTION OF SYMBOLS 11 ... Chamber 11a ... Optical window 12 ... Holder 13 ... Aperture 14 ... Gas pressure control valve 14a ... Gas introduction pipe 15 ... Vacuum pump 15a ... Path | route 16 ... Vacuum gauge 17 ... Refrigerant tank 17a ... Path | route 18 ... Heater 18a ... Heater 19 ... Temperature sensor 20, 21 ... Mirror

Claims (10)

A crystal form monitoring method for identifying a crystal form of an analyte containing a chemical substance having a polymorph having a plurality of different crystal forms even though they have the same chemical composition,
Irradiating the subject with a pulsed terahertz wave;
Detecting terahertz waves transmitted through the subject;
Obtaining an absorption characteristic spectrum based on the detected terahertz wave;
Comparing the acquired absorption characteristic spectrum with the normalized absorption characteristic spectrum of the crystal form stored in the storage means to identify the crystal form contained in the specimen;
The crystal form monitoring method characterized by having.   The identifying step includes identifying the crystal form by fitting the entire waveform of the absorption characteristic spectrum read from the storage means or the characteristic absorption spectrum to one or more characteristic absorption bands. The crystal form monitoring method according to claim 1, wherein:   The crystal form monitoring method according to claim 1, wherein the specimen is packaged.   The crystal form monitoring method according to claim 1, further comprising a step of controlling a pressure of an atmosphere of the subject.   The crystal form monitoring method according to claim 1, further comprising a step of controlling a temperature of the specimen. A crystal form monitoring device for identifying a crystal form of an analyte containing a chemical substance having a polymorph having a plurality of different crystal forms even though they have the same chemical composition,
Irradiation means for irradiating the subject with pulsed terahertz waves;
Detection means for detecting terahertz waves transmitted through the subject;
Obtaining means for obtaining an absorption characteristic spectrum based on the detected terahertz wave;
Storage means for storing the normalized absorption characteristic spectrum of the crystal form;
Identifying means for comparing the acquired absorption characteristic spectrum with a normalized absorption characteristic spectrum of the crystal form stored in the storage means to identify a crystal form contained in the subject;
A crystal form monitoring device comprising:   The identification means identifies the crystal form by fitting the entire absorption characteristic spectrum waveform read from the storage means or the characteristic absorption spectrum of one or more characteristic absorption bands. The crystal form monitoring apparatus according to claim 6.   8. The crystal form monitoring apparatus according to claim 6, wherein the subject is packaged.   9. The crystal form monitoring apparatus according to claim 6, further comprising pressure adjusting means for controlling the pressure of the atmosphere of the subject.   The crystal form monitoring apparatus according to claim 6, further comprising a temperature adjusting unit that controls a temperature of the subject.

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