Pyrroloquinoline quinone disodium salt crystal form and preparation method thereof

Abstract

The invention relates to the technical field of PQQ, in particular to a pyrroloquinoline quinine disodium salt crystal form and a preparation method thereof.The pyrroloquinoline quinine disodium salt crystal form has characteristic diffraction peaks when the diffraction angles 2 theta are 9.3 + / -0.2, 11.8 + / -0.2, 12.7 + / -0.2, 13.6 + / -0.2, 15.1 + / -0.2, 16.1 + / -0.2, 26.5 + / -0.2, 27.5 + / -0.2, 28.5 + / -0.2 and 38.1 + / -0.2 through X-ray powder diffraction analysis measured by Cu-K alpha rays, and the crystal form can be used for preparing the pyrroloquinoline quinine disodium salt crystal form. By optimizing crystallization process conditions, the pyrroloquinoline quinone disodium salt crystal form with higher thermal decomposition temperature and lower glass transition temperature is provided, and the actual application requirements are better met.

Description

Technical Field

[0001] The invention relates to the technical field of PQQ, and specifically relates to a pyrroloquinoline quinone disodium salt crystal form and a preparation method. Background Art

[0002] PQQ (pyrroloquinoline quinone) has multiple physiological functions and has broad application prospects in the food, medicine and cosmetics industries. The phenomenon that substances with the same chemical composition can crystallize into two or more crystals with different structures under different physical and chemical conditions is also called polymorphism or homogeneity. Various polymorphs have different physical properties, such as appearance, melting point, hardness, dissolution rate, chemical stability, mechanical stability, etc. For example, the Chinese patent (authorization announcement number CN105315278B) discloses pyrroloquinoline quinone A crystal form and its preparation method, which has high crystallinity, low hygroscopicity, and can form a regular crystal morphology, but the glass transition temperature of this crystal form is high and the thermal decomposition temperature is low, which limits its practical application. Summary of the invention

[0003] In order to solve the above problems, the present invention provides a pyrroloquinoline quinone disodium salt crystal form, which optimizes the crystallization process conditions to provide a pyrroloquinoline quinone disodium salt crystal form with a higher thermal decomposition temperature and a lower glass transition temperature, thereby better meeting the actual application requirements.

[0004] On the one hand, the present invention provides a pyrroloquinoline quinone disodium salt crystal form, and the pyrroloquinoline quinone disodium salt crystal form is subjected to X-ray powder diffraction analysis measured by Cu-Kα rays, and has characteristic diffraction peaks at diffraction angles 2θ of 9.3±0.2, 11.8±0.2, 12.7±0.2, 13.6±0.2, 15.1±0.2, 16.1±0.2, 26.5±0.2, 27.5±0.2, 28.5±0.2, and 38.1±0.2.

[0005] The X-ray powder diffraction of the pyrroloquinoline quinone disodium salt crystal provided by the present invention has the following characteristics: Figure 1 , Figure 2 2θ and d value data.

[0006] Furthermore, the crystallographic parameters of the pyrroloquinoline quinone disodium salt crystal form are shown in Table 1.

[0007] Table 1

[0008] Furthermore, the glass transition temperature of the pyrroloquinoline quinone disodium salt crystal is 102.60°C.

[0009] Furthermore, the thermogravimetric analysis spectrum of the pyrroloquinoline quinone disodium salt crystal showed a weight loss of 10.36% at 100-200°C and began to decompose at 368.93°C.

[0010] Furthermore, the infrared spectrum of the pyrroloquinoline quinone disodium salt crystal is at 3423 cm -1 (Carboxyl), 3285cm -1 、3240 cm -1 , 1712 cm -1 、1643 cm -1 (pyridine ring, aromatic ring), 1357 cm -1 、1326 cm -1 There are characteristic peaks at (methylene, methine).

[0011] Furthermore, in the 1H-NMR spectrum of the pyrroloquinoline quinone disodium salt crystal, 8.25 ppm and 7.18 ppm are chemical shifts of the H protons of the quinoline quinone disodium salt crystal.

[0012] Further, in the 13C-NMR spectrum of the pyrroloquinoline quinone disodium salt crystal form, 174.8ppm, 174.1ppm, 172.5ppm, 168.9ppm, 131.9ppm, 128.8ppm, 125.1ppm, 124.5ppm, 113.5ppm, and 112.3ppm are chemical shifts of the C protons of the quinoline quinone disodium salt crystal, see 13C-NMR spectrum ( Figure 8 ).

[0013] Another aspect of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, comprising the following steps: (1) Weigh the pyrroloquinoline quinone sample into a reagent bottle, add solvent and shake to dissolve; (2) Seal the mouth of the reagent bottle and leave a hole for the solvent to evaporate; (3) After standing at low temperature, pyrroloquinoline quinone disodium salt crystals are obtained.

[0014] As a preferred technical solution, the solvent is selected from at least one of acetonitrile, methanol, ethanol and water.

[0015] Preferably, the solvent is a combination of acetonitrile and water, and the mass ratio of acetonitrile to water is (5-7):1.

[0016] Preferably, the ratio of the mass of the pyrroloquinoline quinone sample to the volume of the solvent is (3-5 mg): 1 mL.

[0017] As a preferred technical solution, the step (2) specifically comprises: sealing the reagent bottle with a sealing film, and then using a toothpick to poke a hole in the film as a solvent evaporation hole.

[0018] Preferably, the puncture density is 1-2 per cm 2 .

[0019] As a preferred technical solution, the low-temperature standing temperature is 0-5°C and the time is 5-10 days.

[0020] The present invention optimizes the preparation method of the pyrroloquinoline quinone disodium salt crystal form, especially adopts acetonitrile and water as a solvent, and controls the mass ratio of acetonitrile to water to (5-7):1, so as to obtain the pyrroloquinoline quinone disodium salt crystal form with a glass transition temperature of 102.60°C and a thermal decomposition temperature of 368.93°C.

[0021] Furthermore, by optimizing the ratio of the mass of the pyrroloquinoline quinone sample to the volume of the solvent and designing the solvent volatilization port, it is ensured that the pyrroloquinoline quinone disodium salt crystal can be obtained by standing at a low temperature of 0-5°C for 5-10 days.

[0022] The preparation method provided by the invention has simple process, is easy to operate, has good reproducibility, and is suitable for large-scale industrial production.

[0023] Beneficial Effects 1. The present invention provides a pyrroloquinoline quinone disodium salt crystal form, which optimizes the crystallization process conditions to provide a pyrroloquinoline quinone disodium salt crystal form with a higher thermal decomposition temperature and a lower glass transition temperature, thereby better meeting practical application requirements.

[0024] 2. The present invention optimizes the preparation method of the pyrroloquinoline quinone disodium salt crystal, especially adopts acetonitrile and water as a solvent, and controls the mass ratio of acetonitrile and water to be (5-7):1, so as to obtain the pyrroloquinoline quinone disodium salt crystal with a glass transition temperature of 102.60°C and a thermal decomposition temperature of 368.93°C.

[0025] 3. The present invention optimizes the ratio of the mass of the pyrroloquinoline quinone sample to the volume of the solvent and cooperates with the design of the solvent volatilization port to ensure that the pyrroloquinoline quinone disodium salt crystal can be obtained by standing at a low temperature of 0-5°C for 5-10 days.

[0026] 4. The preparation method provided by the present invention has simple process, easy operation, good reproducibility, and is suitable for large-scale industrial production.

[0027] 5. The pyrroloquinoline quinone disodium salt crystal provided by the present invention can be widely used in the fields of food, cosmetics, feed, medicine and chemical analysis. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 , Figure 2 The 2θ and d value data of the X-ray powder diffraction of the pyrroloquinoline quinone disodium salt crystal form provided in Example 1 of the present invention.

[0029] Figure 3 This is the X-ray powder diffraction pattern of the pyrroloquinoline quinone disodium salt crystal form provided in Example 1 of the present invention.

[0030] Figure 4 This is a DSC test spectrum of the pyrroloquinoline quinone disodium salt crystal provided in Example 1 of the present invention.

[0031] Figure 5 This is a TGA curve diagram of the pyrroloquinoline quinone disodium salt crystal form provided in Example 1 of the present invention.

[0032] Figure 6 This is the FTIR spectrum of the pyrroloquinoline quinone disodium salt crystal provided in Example 1 of the present invention.

[0033] Figure 7 This is the 1H-NMR spectrum of the pyrroloquinoline quinone disodium salt crystal provided in Example 1 of the present invention.

[0034] Figure 8 This is the 13C-NMR spectrum of the pyrroloquinoline quinone disodium salt crystal provided in Example 1 of the present invention. DETAILED DESCRIPTION

[0035] Example 1 Embodiment 1 of the present invention provides a crystalline form of disodium salt of pyrroloquinoline quinone, and the crystalline form of disodium salt of pyrroloquinoline quinone is subjected to X-ray powder diffraction analysis measured by Cu-Kα rays, and has characteristic diffraction peaks at diffraction angles 2θ of 9.3±0.2, 11.8±0.2, 12.7±0.2, 13.6±0.2, 15.1±0.2, 16.1±0.2, 26.5±0.2, 27.5±0.2, 28.5±0.2, and 38.1±0.2.

[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 of the crystalline form of pyrroloquinoline quinone disodium salt has the following characteristics: Figure 1 , Figure 2 2θ and d value data, X-ray powder diffraction pattern see Figure 3 .

[0038] The crystallographic parameters of the pyrroloquinoline quinone disodium salt crystal form are shown in Table 1.

[0039] Table 1

[0040] The DSC 8500 differential calorimeter of PerkinElmer, USA, was used for testing, the atmosphere was nitrogen, and the heating rate was 10 degrees Celsius / minute. The glass transition temperature of the pyrroloquinoline quinone disodium salt crystal was 102.60°C, see the DSC test spectrum ( Figure 4 ).

[0041] Using a TG20F3 thermogravimetric analyzer from German NETZSCH Scientific Instruments Co., Ltd., the atmosphere was nitrogen, and the heating rate was 10 degrees / minute. The thermogravimetric analysis spectrum of the pyrroloquinoline quinone disodium salt crystal showed a weight loss of 10.36% at 100-200°C and began to decompose at 368.93°C, see the TGA curve ( Figure 5 ).

[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 pyrroloquinoline quinone disodium salt crystal is at 3423cm -1 (Carboxyl), 3285 cm -1 、3240 cm -1 , 1712 cm -1 、1643 cm -1 (pyridine ring, aromatic ring), 1357 cm -1 、1326cm -1 (methylene, methine) have characteristic peaks, see FTIR spectrum ( Figure 6 ).

[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 (number of scans): 16, DS (number of empty scans): 2). In the 1H-NMR spectrum of the pyrroloquinoline quinone disodium salt crystal form, 8.25ppm and 7.18ppm are the chemical shifts of the H protons of the quinoline quinone disodium salt crystal, see 1H-NMR spectrum ( Figure 7 ).

[0044] In the 13C-NMR spectrum of the pyrroloquinoline quinone disodium salt crystal form, 174.8ppm, 174.1ppm, 172.5ppm, 168.9ppm, 131.9ppm, 128.8ppm, 125.1ppm, 124.5ppm, 113.5ppm, and 112.3ppm are chemical shifts of the C protons of the quinoline quinone disodium salt crystal, see 13C-NMR spectrum ( Figure 8).

[0045] On the other hand, Example 1 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, comprising the following steps: (1) Weigh the pyrroloquinoline quinone sample into a reagent bottle, add solvent and shake to dissolve; (2) Seal the mouth of the reagent bottle and leave a hole for the solvent to evaporate; (3) After standing at low temperature, pyrroloquinoline quinone disodium salt crystals are obtained.

[0046] The solvent is a combination of acetonitrile and water, and the mass ratio of the acetonitrile to water is 5:1.

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

[0048] The step (2) is specifically as follows: after sealing the reagent bottle with a sealing film, use a toothpick to poke holes in the film as solvent volatilization holes. The poking density is 1 hole / cm 2 .

[0049] The temperature of the low-temperature standing is 4° C., and the time is 5 days.

[0050] Example 2 Example 2 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, 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 mass ratio of 10:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0051] Example 3 Example 3 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, 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 mass ratio of 9:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0052] Example 4 Example 4 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, 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 mass ratio of 8:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0053] Example 5 Example 5 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, 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 mass ratio of 7:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0054] Example 6 Example 6 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, 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 mass ratio of 6:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0055] Example 7 Example 7 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, 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 mass ratio of 5:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0056] Example 8 Example 8 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, 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 mass ratio of 4:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0057] Example 9 Example 9 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, 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 mass ratio of 3:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0058] Example 10 Example 10 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, 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 mass ratio of 2:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0059] Embodiment 11 Example 11 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, 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 mass ratio of 1:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0060] Example 12 Example 12 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of ethanol and water in a mass ratio of 1:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0061] Example 13 Example 13 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of ethanol and water in a mass ratio of 2:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0062] Embodiment 14 Example 14 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of ethanol and water in a mass ratio of 4:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0063] Embodiment 15 Example 15 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of ethanol and water in a mass ratio of 5:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0064] Example 16 Example 16 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of ethanol and water in a mass ratio of 6:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0065] Embodiment 17 Example 17 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of ethanol and water in a mass ratio of 7:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0066] Embodiment 18 Example 18 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of ethanol and water in a mass ratio of 8:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0067] Embodiment 19 Example 19 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of ethanol and water in a mass ratio of 9:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0068] Embodiment 20 Example 20 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of ethanol and water in a mass ratio of 10:1, the low-temperature standing temperature is 20°C, and no crystals are generated after standing for 10 days.

[0069] Embodiment 21 Example 21 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of acetonitrile and water in a mass ratio of 1:1, and no crystals are generated after standing for 10 days.

[0070] Embodiment 22 Example 22 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of acetonitrile and water in a mass ratio of 2:1, and no crystals are generated after standing for 10 days.

[0071] Embodiment 23 Example 23 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of acetonitrile and water in a mass ratio of 3:1, and no crystals are generated after standing for 10 days.

[0072] Embodiment 24 Example 24 of the present invention provides a method for preparing a crystalline form of pyrroloquinoline quinone disodium salt, and its specific implementation method is the same as that of Example 1, except that the solvent is replaced by a combination of acetonitrile and water in a mass ratio of 4:1, and no crystals are generated after standing for 10 days.

Claims

1. A pyrroloquinoline quinone disodium salt crystal form, characterized in that: The pyrroloquinoline quinone disodium salt crystal form is subjected to X-ray powder diffraction analysis measured by Cu-Kα rays, and has characteristic diffraction peaks at diffraction angles 2θ of 9.3±0.2, 11.8±0.2, 12.7±0.2, 13.6±0.2, 15.1±0.2, 16.1±0.2, 26.5±0.2, 27.5±0.2, 28.5±0.2, and 38.1±0.

2.

2. The pyrroloquinoline quinone disodium salt crystal form according to claim 1, characterized in that The glass transition temperature of the pyrroloquinoline quinone disodium salt crystal is 102.60°C.

3. The pyrroloquinoline quinone disodium salt crystal form according to claim 1, characterized in that: The thermogravimetric analysis spectrum of the pyrroloquinoline quinone disodium salt crystal shows a weight loss of 10.36% at 100-200° C. and begins to decompose at 368.93° C.

4. The pyrroloquinoline quinone disodium salt crystal form according to claim 1, characterized in that The infrared spectrum of the pyrroloquinoline quinone disodium salt crystal is at 3423 cm -1 、3285 cm -1 、3240 cm -1 , 1712 cm -1 、1643 cm -1 、1357 cm -1 、1326 cm -1 There are characteristic peaks.

5. The pyrroloquinoline quinone disodium salt crystal form according to claim 1, characterized in that: The pyrroloquinoline quinone disodium salt crystal form 1 In the H-NMR spectrum, 8.25 ppm and 7.18 ppm are chemical shifts of H protons in the quinoline quinone disodium salt crystal.

6. The pyrroloquinoline quinone disodium salt crystal form according to claim 1, characterized in that: The pyrroloquinoline quinone disodium salt crystal form 13 In the C-NMR spectrum, 174.8 ppm, 174.1 ppm, 172.5 ppm, 168.9 ppm, 131.9 ppm, 128.8 ppm, 125.1 ppm, 124.5 ppm, 113.5 ppm, and 112.3 ppm are chemical shifts of C protons in the quinoline quinone disodium salt crystal.

7. A method for preparing the pyrroloquinoline quinone disodium salt crystal according to any one of claims 1 to 6, characterized in that: Here are the steps: (1) Weigh the pyrroloquinoline quinone sample into a reagent bottle, add solvent and shake to dissolve; (2) Seal the mouth of the reagent bottle and leave a hole for the solvent to evaporate; (3) After standing at low temperature, pyrroloquinoline quinone disodium salt crystals are obtained.

8. The method for preparing the pyrroloquinoline quinone disodium salt crystal form according to claim 7, characterized in that: The solvent is selected from at least one of acetonitrile, methanol, ethanol and water.

9. The method for preparing the pyrroloquinoline quinone disodium salt crystal form according to claim 7, characterized in that: The temperature of the low-temperature standing is 0-5°C and the time is 5-10 days.

Images