Glucurolactone crystal form and preparation method thereof

Abstract

The invention relates to the technical field of glucurolactone, in particular to a glucurolactone crystal form and a preparation method thereof.The glucurolactone crystal form has characteristic diffraction peaks when the diffraction angles 2 theta are 17.68 + / -0.02, 18.22 + / -0.02, 18.52 + / -0.02, 19.33 + / -0.02, 21.77 + / -0.02, 26.40 + / -0.02, 26.97 + / -0.02, 29.00 + / -0.02, 29.55 + / -0.02, 31.77 + / -0.02, 36.26 + / -0.02, 37.83 + / -0.02, 38.90 + / -0.02, 39.26 + / -0.02, 40.07 + / -0.02 and 41.12 + / -0.02 through X-ray powder diffraction analysis measured by Cu-K alpha rays, and the glucurolactone crystal form can be used for By optimizing crystallization process conditions, the glucurolactone crystal form with larger particles and better crystal structure is provided, and the actual application requirements are better met.

Description

Technical Field

[0001] The invention relates to the technical field of glucuronolactone, in particular to a glucuronolactone crystal form and a preparation method thereof. Background Art

[0002] Glucuronolactone, abbreviated as glucuronolactone, commonly known as liver tylosin, is widely used in medicine, health products, food and feed industries. At present, glucuronolactone is mainly synthesized by nitric acid oxidation method using starch as raw material, but the obtained glucuronolactone crystal particles are small and easy to agglomerate, and further treatment is required to improve fluidity, stability and compressibility. For example, a Chinese patent application (publication number CN106309378A) discloses a glucuronolactone granule and a preparation method thereof, which requires the addition of adhesives and wetting agents to make the provided products meet the production of subsequent health foods and tablets, but it increases the application cost and is not practical enough. Summary of the invention

[0003] In order to solve the above problems, the present invention provides a glucuron lactone crystal form, which provides a glucuron lactone crystal form with larger particles and better crystal structure by optimizing the crystallization process conditions, overcomes the problem that the existing glucuron lactone crystal particles are easy to agglomerate, and further improves the melting point of glucuron lactone, so as to better meet the actual application needs.

[0004] On the one hand, the present invention provides a glucuron-lactone crystal form, and the glucuron-lactone crystal form has characteristic diffraction peaks at diffraction angles 2θ of 17.68±0.02, 18.22±0.02, 18.52±0.02, 19.33±0.02, 21.77±0.02, 26.40±0.02, 26.97±0.02, 29.00±0.02, 29.55±0.02, 31.77±0.02, 36.26±0.02, 37.83±0.02, 38.90±0.02, 39.26±0.02, 40.07±0.02, and 41.12±0.02 according to X-ray powder diffraction analysis measured by Cu-Kα rays.

[0005] The X-ray powder diffraction pattern of the glucuron-lactone crystal form provided by the present invention can be found in Figure 1 .

[0006] Furthermore, the crystallographic parameters of the glucuronolactone crystal form are shown in Table 1.

[0007] Table 1

[0008] Furthermore, the melting point of the glucuron-lactone crystal is 180.88°C.

[0009] Furthermore, the thermal gravimetric temperature of the glucuron-lactone crystal is 311.36°C.

[0010] Furthermore, the infrared spectrum of the glucuron-lactone crystal is at 3504 cm -1 、3437 cm -1 (ester group, aldehyde group), 2976 cm -1 (methylene), 1758 cm -1 (carbon-oxygen bond), 1353-1000 cm -1 There are characteristic peaks at (methylene, methine).

[0011] Furthermore, the glucuron-lactone crystal form 1 The H-NMR spectrum has characteristic peaks at 5.39 ppm, 4.96 ppm, 4.66 ppm, and 4.28 ppm.

[0012] Furthermore, the glucuron-lactone crystalline form 13 The C-NMR spectrum has characteristic peaks at 177.5 ppm, 102.8 ppm, 83.8 ppm, 77.6 ppm, 76.8 ppm, and 69.1 ppm.

[0013] Another aspect of the present invention provides a method for preparing a glucuron lactone crystal form, the steps of which are as follows: dissolving a glucuron lactone sample in a solvent, controlling the temperature and humidity, and allowing the solvent to stand without sealing to obtain the glucuron lactone crystal form.

[0014] As a preferred technical solution, the solvent includes at least methanol and water.

[0015] Preferably, the mass ratio of methanol to water is (100-180):1, preferably (100-150):1, further preferably (100-120):1, and most preferably 100:1.

[0016] As a preferred technical solution, the ratio of the mass of the glucuronolactone sample to the volume of the solvent is (1-10) mg: (1-5) mL, preferably (3-5) mg: 1 mL.

[0017] As a preferred technical solution, the temperature is 10-30°C, preferably 20-30°C, most preferably 25°C.

[0018] As a preferred technical solution, the humidity is 10-50%, preferably 10-30%, and most preferably 20%.

[0019] As a preferred technical solution, the standing time is 3-10 days, most preferably 5 days.

[0020] The present invention optimizes the preparation method of glucuron lactone crystals, especially adopts methanol and water as solvents, and controls the mass ratio of methanol to water to (100-120):1. The obtained glucuron lactone crystals have larger particles, a higher melting point, and are not easy to decompose or agglomerate. However, when other solvents are used or the mass ratio of methanol to water is not within the range, the glucuron lactone crystals cannot be obtained.

[0021] Furthermore, by optimizing the ratio of the mass of the glucuron lactone sample to the volume of the solvent and combining it with a non-sealed static design, it is ensured that the glucuron lactone crystal form can be obtained by statically standing for 3-10 days at 20-30°C and a humidity of 10-30%.

[0022] The preparation method provided by the present invention does not require complicated processing steps, is easy to operate, does not require the addition of additional additives, can stably obtain the target crystal form, greatly reduces production energy consumption and production costs, and is easy to promote and apply.

[0023] The glucuronolactone crystal form provided by the invention has high crystallinity, good stability and low hygroscopicity, and is suitable for a wider range of application fields.

[0024] Beneficial Effects 1. The present invention provides a glucuron lactone crystal form, which provides a glucuron lactone crystal form with larger particles and better crystal structure by optimizing the crystallization process conditions, overcomes the problem that the existing glucuron lactone crystal particles are easy to agglomerate, and further improves the melting point of glucuron lactone, so as to better meet the actual application needs.

[0025] 2. The present invention optimizes the preparation method of glucuron lactone crystals, especially adopts methanol and water as solvents, and controls the mass ratio of methanol to water to (100-120):1. The obtained glucuron lactone crystals have larger particles, a higher melting point, and are not easy to decompose or agglomerate.

[0026] 3. The present invention optimizes the ratio of the mass of the glucuron lactone sample to the volume of the solvent and cooperates with a non-sealed static design to ensure that the glucuron lactone crystal form can be obtained by standing for 3-10 days at 20-30°C and a humidity of 10-30%.

[0027] 4. The preparation method provided by the present invention does not require complicated processing steps, is easy to operate, does not require the addition of additional additives, can stably obtain the target crystal form, greatly reduces production energy consumption and production costs, and is easy to promote and apply.

[0028] 5. The glucuron-lactone crystal form provided by the present invention has high crystallinity, good stability, low hygroscopicity, and is suitable for a wider range of applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1This is the X-ray powder diffraction pattern of the glucuronolactone crystal form provided in Example 1 of the present invention.

[0030] Figure 2 This is the DSC test spectrum of the glucuronolactone crystal form provided in Example 1 of the present invention.

[0031] Figure 3 This is a TGA curve diagram of the glucuronolactone crystal form provided in Example 1 of the present invention.

[0032] Figure 4 This is the FTIR spectrum of the glucuronolactone crystal form provided in Example 1 of the present invention.

[0033] Figure 5 The glucuronide crystalline form provided in Example 1 of the present invention 1 H-NMR spectrum.

[0034] Figure 6 The glucuronide crystalline form provided in Example 1 of the present invention 13 C-NMR spectrum. DETAILED DESCRIPTION

[0035] Example 1 Embodiment 1 of the present invention provides a glucuronide crystalline form on the one hand, and the glucuronide crystalline form is subjected to X-ray powder diffraction analysis measured by Cu-Kα rays, and has characteristic diffraction peaks at diffraction angles 2θ of 17.68±0.02, 18.22±0.02, 18.52±0.02, 19.33±0.02, 21.77±0.02, 26.40±0.02, 26.97±0.02, 29.00±0.02, 29.55±0.02, 31.77±0.02, 36.26±0.02, 37.83±0.02, 38.90±0.02, 39.26±0.02, 40.07±0.02, and 41.12±0.02.

[0036] The X-ray powder diffraction analysis was performed using a Bruker D8advance diffractometer from Bruker Instruments GmbH, Germany, using a Cu-K ray voltage of 40 kV, a current of 40 mA, a step size of 0.02 degrees, and each step taking 0.1 seconds.

[0037] The X-ray powder diffraction pattern of glucuronolactone crystal form can be found in Figure 1 .

[0038] The crystallographic parameters of the glucuronolactone crystal form are shown in Table 1.

[0039] Table 1

[0040] The DSC 8500 differential calorimeter of PerkinElmer, USA, was used for the test. The atmosphere was nitrogen and the heating rate was 10 degrees Celsius / minute. The melting point of the glucuronolactone crystal form was 180.88°C. See the DSC test spectrum ( Figure 2 ).

[0041] Thermogravimetric analyzer TG20F3 of NETZSCH Scientific Instruments Co., Ltd. of Germany was used, the atmosphere was nitrogen, and the heating rate was 10 degrees / minute. The thermal weight loss temperature of the glucuron-lactone crystal was 311.36°C, see the TGA curve ( Figure 3 ).

[0042] Nicolet-Magna FT-IR 750 infrared spectrometer from Nicolet Corporation of the United States was used for detection at 25±2℃, with a detection range of 4000-350cm -1 Wave number, the infrared spectrum of the glucuron-lactone crystal form is at 3504, 3437 cm -1 (ester group, aldehyde group), 2976 cm -1 (methylene), 1758 cm -1 (carbon-oxygen bond), 1353-1000 cm -1 (methylene, methine) have characteristic peaks, see FTIR spectrum ( Figure 4 ).

[0043] Bruker AVANCE III HD 400M NMR was used for detection (H spectrum pulse sequence: zg30, TD (data point): 65K, RG (gain): 32, D1 (relaxation time): 10s, SW (spectrum width): 20ppm, O1p (spectrum width center): 6.175ppm, NS (scan number): 16, DS (dry scan number): 2); The glucuronolactone crystal form 1 1 The H-NMR spectrum has characteristic peaks at 5.39 ppm, 4.96 ppm, 4.66 ppm, and 4.28 ppm, see 1 1 H-NMR spectrum ( Figure 5 ).

[0044] The glucuronolactone crystal form 13 The C-NMR spectrum has characteristic peaks at 177.5 ppm, 102.8 ppm, 83.8 ppm, 77.6 ppm, 76.8 ppm, and 69.1 ppm, see 13 C-NMR spectrum ( Figure 6 ).

[0045] On the other hand, Example 1 of the present invention provides a method for preparing a glucuron lactone crystal form, the steps of which are as follows: adding a glucuron lactone sample into a reagent bottle, adding a solvent to shake and dissolve, controlling the temperature and humidity, and allowing to stand without sealing to obtain the glucuron lactone crystal form.

[0046] The solvent is a combination of methanol and water, and the mass ratio of the methanol to water is 100:1.

[0047] The ratio of the mass of the glucuronolactone sample to the volume of the solvent is 4 mg:1 mL.

[0048] The glucuronolactone sample comes from Zhucheng Haotian Pharmaceutical Co., Ltd.

[0049] The non-sealed static state specifically includes: sealing the reagent bottle with a sealing film, and then using a toothpick to pierce holes in the film to achieve non-sealing, with a piercing density of 2 holes / cm 2 .

[0050] The temperature is 25° C., the humidity is 20%, and the standing time is 5 days.

[0051] Example 2 Example 2 of the present invention provides a method for preparing a glucuronolactone crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with methanol, and no crystals are generated after standing for 5 days.

[0052] Example 3 Example 3 of the present invention provides a method for preparing a glucuronolactone crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with ethyl acetate, and no crystals are generated after standing for 5 days.

[0053] Example 4 Example 4 of the present invention provides a method for preparing a glucuronolactone crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with acetone, and no crystals are generated after standing for 5 days.

[0054] Example 5 Example 5 of the present invention provides a method for preparing a glucuronolactone crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with acetonitrile, and no crystals are generated after standing for 5 days.

[0055] Example 6 Example 6 of the present invention provides a method for preparing a glucuronolactone crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with ethanol, and no crystals are generated after standing for 5 days.

[0056] Example 7 Example 7 of the present invention provides a method for preparing a glucuronolactone crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with water, and no crystals are generated after standing for 5 days.

[0057] Example 8 Example 8 of the present invention provides a method for preparing a glucuronide crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with a combination of methanol and chloroform in a volume ratio of 199:1, and no crystals are generated after standing for 5 days.

[0058] Example 9 Example 9 of the present invention provides a method for preparing a glucuronolactone crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with a combination of methanol and chloroform in a volume ratio of 99:1, and no crystals are generated after standing for 5 days.

[0059] Example 10 Example 10 of the present invention provides a method for preparing a glucuronolactone crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with a combination of methanol and chloroform in a volume ratio of 49:1, and no crystals are generated after standing for 5 days.

[0060] Embodiment 11 Example 11 of the present invention provides a method for preparing a glucuronide crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with a combination of methanol and chloroform in a volume ratio of 19:1, and no crystals are generated after standing for 5 days.

[0061] Example 12 Example 12 of the present invention provides a method for preparing a glucuronide crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with a combination of methanol and chloroform in a volume ratio of 4:1, and no crystals are generated after standing for 5 days.

[0062] Example 13 Example 13 of the present invention provides a method for preparing a glucuronide crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with a combination of methanol and chloroform in a volume ratio of 2:1, and no crystals are generated after standing for 5 days.

[0063] Embodiment 14 Example 14 of the present invention provides a method for preparing a glucuronide crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with a combination of methanol and chloroform in a volume ratio of 1:1, and no crystals are generated after standing for 5 days.

[0064] Embodiment 15 Example 15 of the present invention provides a method for preparing a glucuronolactone crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of methanol and chloroform in a volume ratio of 1:2, and no crystals are generated after standing for 5 days.

[0065] Example 16 Example 16 of the present invention provides a method for preparing a glucuronide crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with a combination of methanol and chloroform in a volume ratio of 1:4, and no crystals are generated after standing for 5 days.

[0066] Embodiment 17 Example 17 of the present invention provides a method for preparing a glucuronide crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with a combination of methanol and chloroform in a volume ratio of 1:9, and no crystals are generated after standing for 5 days.

[0067] Embodiment 18 Example 18 of the present invention provides a method for preparing a glucuronide crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with a combination of methanol and water in a volume ratio of 199:1, and no crystals are generated after standing for 5 days.

[0068] Embodiment 19 Example 19 of the present invention provides a method for preparing a glucuronide crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with a combination of methanol and water in a volume ratio of 99:1, and no crystals are generated after standing for 5 days.

[0069] Embodiment 20 Example 20 of the present invention provides a method for preparing a glucuronide crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with a combination of methanol and water in a volume ratio of 49:1, and no crystals are generated after standing for 5 days.

[0070] Embodiment 21 Example 21 of the present invention provides a method for preparing a glucuronide crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with a combination of methanol and water in a volume ratio of 19:1, and no crystals are generated after standing for 5 days.

[0071] Embodiment 22 Example 22 of the present invention provides a method for preparing a glucuronide crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with a combination of methanol and water in a volume ratio of 4:1, and no crystals are generated after standing for 5 days.

[0072] Embodiment 23 Example 23 of the present invention provides a method for preparing a glucuronide crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of methanol and water in a volume ratio of 2:1, and no crystals are generated after standing for 5 days.

[0073] Embodiment 24 Example 24 of the present invention provides a method for preparing a glucuronide crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced with a combination of methanol and water in a volume ratio of 1:1, and no crystals are generated after standing for 5 days.

[0074] Embodiment 25 Example 25 of the present invention provides a method for preparing a glucuronide crystal form, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of methanol and water in a volume ratio of 1:2, and no crystals are generated after standing for 5 days.

Claims

1. A glucuronolactone crystal form, characterized in that: The X-ray powder diffraction analysis of the glucuron-lactone crystal form measured by Cu-Kα rays showed characteristic diffraction peaks at diffraction angles 2θ of 17.68±0.02, 18.22±0.02, 18.52±0.02, 19.33±0.02, 21.77±0.02, 26.40±0.02, 26.97±0.02, 29.00±0.02, 29.55±0.02, 31.77±0.02, 36.26±0.02, 37.83±0.02, 38.90±0.02, 39.26±0.02, 40.07±0.02, and 41.12±0.

02.

2. The glucuronolactone crystalline form according to claim 1, characterized in that: The melting point of the glucuronolactone crystal is 180.88°C.

3. The glucuronolactone crystalline form according to claim 1, characterized in that: The thermal weight loss temperature of the glucuronolactone crystal form is 311.36°C.

4. The glucuronolactone crystalline form according to claim 1, characterized in that: The infrared spectrum of the glucuron-lactone crystal is at 3504 cm -1 、3437 cm -1 , 2976 cm -1 、1758 cm -1 , 1353-1000 cm -1 There are characteristic peaks.

5. The glucuronolactone crystalline form according to claim 1, characterized in that: The glucuronolactone crystal form 1 The H-NMR spectrum has characteristic peaks at 5.39 ppm, 4.96 ppm, 4.66 ppm, and 4.28 ppm.

6. The glucuronolactone crystalline form according to claim 1, characterized in that: The glucuronolactone crystal form 13 The C-NMR spectrum has characteristic peaks at 177.5 ppm, 102.8 ppm, 83.8 ppm, 77.6 ppm, 76.8 ppm, and 69.1 ppm.

7. A method for preparing the glucuronolactone crystal form according to any one of claims 1 to 6, characterized in that: The steps are as follows: dissolving the glucuron lactone sample in a solvent, controlling the temperature and humidity, and allowing to stand without sealing to obtain the glucuron lactone crystal form.

8. The method for preparing the glucuronolactone crystal form according to claim 7, characterized in that: The solvent includes at least methanol and water, and the mass ratio of methanol to water is (100-180):

1.

9. The method for preparing the glucuronolactone crystal form according to claim 7, characterized in that: The ratio of the mass of the glucuronolactone sample to the volume of the solvent is (1-10) mg: (1-5) mL.

10. The method for preparing the glucuronolactone crystal form according to claim 7, characterized in that: The temperature is 10-30° C., the humidity is 10-50%, and the standing time is 3-10 days.

Images