Crystal form of 20 (S)-protopanoxadiol, preparation method and application thereof

Abstract

The invention relates to the field of medicines, in particular to a crystal form A and a crystal form B of 20 (S)-protopanoxadiol as well as a preparation method and application of the crystal form A and the crystal form B. The crystal form A and the crystal form B provided by the invention are different from the existing known 20 (S)-protopanoxadiol crystal form, have distinct contours, can be perfectly reproduced, and have good characteristics in bulk density, fluidity and stability and in treatment of diseases such as depression resistance, anxiety resistance, cognitive disorder resistance, tumor resistance or cardiovascular resistance; the method has a wide application prospect in drug development of 20 (S)-protopanoxadiol.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a crystal form, a preparation method and application of 20(S)-protopanaxadiol. Background Art

[0002] 20(S)-Protopanaxdiol (20(S)-PPD) is a plant ingredient with many pharmacological functions, such as inhibiting cancer cell growth, anti-depression, anti-anxiety, anti-cognitive impairment, and anti-cardiovascular disease. Its molecular formula is C 30 H 52 O3, the structural formula is:

[0003]

[0004] At present, there are few studies on the crystal forms of 20(S)-protopanaxadiol. Patent Publication No. CN115991729A discloses two crystal forms of 20(S)-protopanaxadiol, which are obtained by heating and dissolving in acetone and acetonitrile and then cooling and crystallizing. Compared with the amorphous powder of 20(S)-protopanaxadiol from conventional sources, they have higher density and higher purity due to the regular crystal structure.

[0005] In addition, existing studies have also disclosed some preparation methods of 20(S)-protopanaxadiol. Most of these preparation methods use plant (ginseng, Panax notoginseng, red ginseng, American ginseng, Gynostemma pentaphyllum) saponins as raw materials, obtain 20(S)-protopanaxadiol through hydrolysis and other technologies, and then use alcohol as the main elution solvent system to separate and purify it by column chromatography technology, and finally obtain white powder 20(S)-protopanaxadiol. However, the above-mentioned 20(S)-protopanaxadiol crystal form and the 20(S)-protopanaxadiol product (including amorphous crystals of 20(S)-protopanaxadiol) obtained by conventional preparation methods still have the disadvantages of low bulk density and poor stability.

[0006] In view of this, the present invention is proposed. Summary of the invention

[0007] The present invention provides a new crystal form of 20(S)-protopanaxadiol, a preparation method and application thereof. The details are as follows:

[0008] In a first aspect, the present invention provides a crystalline form A of 20(S)-protopanaxadiol.

[0009] In the present invention, the X-ray powder diffraction pattern of the crystalline form A expressed as a diffraction angle of 2θ±0.2° shows characteristic diffraction peaks at least at 6.5°, 4.2° and 15.7°.

[0010] Preferably, the X-ray powder diffraction pattern of the crystalline form A represented by a diffraction angle of 2θ±0.2° is at least:

[0011] (1) at least one of 17.1°, 18.6°, and 13.1° shows a characteristic diffraction peak; and / or

[0012] (2) At least one of 17.9°, 10.6°, and 20.7° shows a characteristic diffraction peak.

[0013] In a preferred embodiment, the X-ray powder diffraction pattern of the crystalline form A represented by a diffraction angle of 2θ±0.2° shows characteristic diffraction peaks at least at 6.5°, 4.2°, 15.7°, 17.1°, 18.6°, 13.1°, 17.9°, 10.6°, and 20.7°.

[0014] In a further preferred embodiment, the crystalline form A of 20(S)-protopanaxadiol of the present invention has substantially Figure 1 Powder X-ray diffraction pattern shown.

[0015] The crystal form A is represented by the spectral line position (Bragg angle 2θ, expressed in degrees), relative intensity (%) and interplanar spacing d, and its data are basically as shown in Table 1:

[0016] Table 1

[0017] Diffraction angle 2θ d value Relative Strength % 4.2 21.2 82.3 6.5 13.5 100.0 10.6 8.4 18.0 13.1 6.7 27.9 15.7 5.6 41.1 17.1 5.2 31.2 17.9 5.0 21.3 18.6 4.8 30.8 20.7 4.3 9.1

[0018] In the present invention, the melting point of the crystalline form A is 219-221°C.

[0019] When differential scanning calorimetry analysis is performed, Form A has an endothermic signal when heated to around 133°C, an exothermic signal when heated to around 175°C, and begins to melt when heated to around 220°C. The DSC graph is shown in Figure 2 shown.

[0020] The 20(S)-protopanaxadiol crystal form A provided by the present invention has a clear outline and can be perfectly reproduced. It has the characteristics of high bulk density and strong fluidity, and especially exhibits superior properties in terms of mechanical stability and solid-state stability. It exhibits higher solubility in FaSSIF (artificial intestinal fluid in the fasting state), and has broad application prospects in the drug development of 20(S)-protopanaxadiol.

[0021] In a second aspect, the present invention provides a method for preparing the crystalline form A.

[0022] In the present invention, the preparation method of the crystal form A comprises: dissolving the crude 20(S)-protopanaxadiol in a positive solvent to obtain a 20(S)-protopanaxadiol solution, adding an anti-solvent to the 20(S)-protopanaxadiol solution until a colloid is formed, and subjecting the colloid to at least one temperature cycle.

[0023] Among them, the crude 20(S)-protopanaxadiol described in the present invention is an existing known compound, which can be obtained through various channels.

[0024] In an optional embodiment of the present invention, the crude 20(S)-protopanaxadiol can be selected from the "protopanaxadiol" prepared by the preparation method described in the invention patent with patent publication number CN1252082C (method for preparing protopanaxadiol and protopanaxadiol); or, selected from the "crystal form A" described in the invention patent with patent publication number CN115991729A (20(S)-protopanaxadiol crystal form A, crystal form B and preparation method thereof). After detection and characterization, the crystal form of the above-mentioned "protopanaxadiol" and the "crystal form A" in CN115991729A is the "crystal form D" described in the present invention.

[0025] In a more specific embodiment provided by the present invention, the crude 20(S)-protopanaxadiol is preferably prepared by the method provided in Example 3 of the invention patent publication number CN1252082C (Preparation method of protopanaxadiol and protopanaxantriol).

[0026] The preparation method of the crystal form A of the present invention first dissolves the crude 20(S)-protopanaxadiol in a positive solvent to obtain a 20(S)-protopanaxadiol solution.

[0027] The positive solvent may be a solvent known to dissolve 20(S)-protopanaxadiol well, preferably at least one of methyl isobutyl ketone, anisole or chloroform, and more preferably methyl isobutyl ketone.

[0028] In order to further control the dissolution state of the solute, the dosage ratio of the crude 20(S)-protopanaxadiol to the positive solvent is preferably 10-30 mg: 0.5-1.0 mL, and more preferably 18-22 mg: 0.6-0.8 mL.

[0029] In the preparation method provided by the present invention, after obtaining the 20(S)-protopanaxadiol solution, it is preferred to further filter the 20(S)-protopanaxadiol solution using a filter membrane with a pore size of 0.4-0.5 μm.

[0030] In the present invention, the above-mentioned filtration operation can not only achieve conventional impurity removal, but also effectively eliminate the influence of impurities on the formation of the microstructure of the crystal during the subsequent crystallization process of gas-liquid permeation, thereby promoting the smoother precipitation of crystal form A from the crude 20(S)-protopanaxadiol solution.

[0031] The pore size of the filter membrane of the present invention is preferably 0.44-0.46 μm, more preferably 0.45 μm.

[0032] The present invention does not particularly limit the material of the filter membrane, and any conventional commercial source in the art can be used.

[0033] In a more specific embodiment provided by the present invention, the filter membrane is selected from a polytetrafluoroethylene filter membrane.

[0034] In the preparation method provided by the present invention, the obtained 20(S)-protopanaxadiol solution is preferably stirred to obtain a clear solution. Preferably, the stirring speed is 500-2000 r / min, and more preferably 1000 r / min.

[0035] Furthermore, in the present invention, an anti-solvent is added dropwise to the 20(S)-protopanaxadiol solution until a jelly is formed; and then the jelly is subjected to at least one temperature cycle.

[0036] The anti-solvent may be a solvent that is unfavorable to 20(S)-protopanaxadiol, and is preferably at least one of n-heptane, n-hexane or n-pentane, and more preferably n-heptane.

[0037] In the present invention, the ratio of the amount of the anti-solvent to the amount of the positive solvent is preferably 5 mL: 0.5-1.0 mL, more preferably 5 mL: 0.6-0.8 mL, to better promote the formation of crystals.

[0038] In the preparation method provided by the present invention, temperature control is one of the key factors for the formation of high-quality crystals. The dissolution state of 20(S)-protopanaxadiol in the positive solvent and anti-solvent of the present invention will be affected by temperature to a certain extent. Appropriate temperature control is very beneficial to the crystal growth and crystallization of 20(S)-protopanaxadiol.

[0039] Preferably, the temperature cycle includes: heating the colloid to 45-55°C, keeping the temperature constant for 1-3 hours, cooling to 4-6°C at a rate of 0.05-1°C / min, and growing the crystal at the constant temperature for 1-3 hours. Preferably, the heating is: uniformly heating to 45-55°C within 10-40 minutes; the cooling rate is preferably 0.1-0.5°C / min.

[0040] In a more preferred embodiment provided by the present invention, the temperature cycle includes: heating the colloid to 50°C within 0.3-0.5 hours, maintaining the temperature for 2 hours, then reducing the temperature to 5°C at a rate of 0.1-0.5°C / min, and maintaining the temperature for 2 hours.

[0041] The preparation method provided by the present invention preferably stirs the colloid except for the constant temperature crystal growing stage while subjecting the colloid to temperature cycling (i.e., heating, constant temperature of heating to 45-55°C and cooling are all carried out under stirring); preferably, the stirring speed is 800-1200r / min; more preferably 1000r / min.

[0042] The present invention does not particularly limit the specific operation mode of stirring in each step, and conventional stirring operations in the art, such as magnetic stirring, etc., can be used.

[0043] In the present invention, the number of cycles of the temperature cycle is preferably 2-4. After the temperature cycle is completed, the precipitated solid crystal form A can be obtained.

[0044] In the present invention, the precipitated solid crystal form A is preferably filtered and dried. The filtering and drying steps can be carried out by conventional methods in the art, and the present invention is not particularly limited thereto.

[0045] As the best embodiment of the present invention, the preparation method preferably comprises the following steps:

[0046] About 20 mass units of 20(S)-protopanaxadiol crude solid were weighed and placed in a glass bottle, and 0.6 volume units of methyl isobutyl ketone were added to dissolve the 20(S)-protopanaxadiol crude solid. The sample solution was filtered into a new glass bottle using a polytetrafluoroethylene filter with a pore size of 0.45 microns, and then magnetically stirred (at a speed of about 1000 revolutions per minute) to obtain a clear solution, and 5 volume units of n-heptane were added dropwise thereto to obtain a colloidal sample, and the sample was transferred to a temperature cycle condition for crystal growth and crystallization.

[0047] In the preparation method of the present invention, unless otherwise specified, when the mass unit is mg, the corresponding volume unit is mL.

[0048] The temperature cycle conditions are as follows:

[0049] First cycle: uniformly raise the temperature to 50°C over 0.3 hours and maintain the temperature at 50°C for 2 hours; reduce the temperature to 5°C at a rate of 0.5°C / min and maintain the temperature at 5°C for 2 hours.

[0050] Second cycle: the temperature was raised to 50°C at a constant rate over 0.4 hours and maintained at 50°C for 2 hours; the temperature was lowered to 5°C at a rate of 0.3°C / min and maintained at 5°C for 2 hours.

[0051] The third cycle: the temperature was raised to 50°C at a constant rate over 0.5 hours and maintained at 50°C for 2 hours; the temperature was lowered to 5°C at a rate of 0.1°C / min and maintained at 5°C for 2 hours.

[0052] In the above three cycles, except for the crystal growth at a constant temperature of 5°C for 2 hours, the other cycles were carried out under magnetic stirring.

[0053] After a total of 3 cycles, solid precipitated, and the obtained solid was separated by centrifugation to obtain Form A.

[0054] The preparation method provided by the present invention can perfectly reproduce the 20(S)-protopanaxadiol crystal form A, and the product quality is stable and reliable, which plays an important role in the subsequent development and application of the 20(S)-protopanaxadiol crystal form A.

[0055] The crude 20(S)-protopanaxadiol obtained in Example 3 of the invention patent of announcement number CN1252082C (method for preparing protopanaxadiol and protopanaxadiol) has a powder X-ray diffraction pattern as shown in Figure 3 .

[0056] Depend on Figure 3 It can be seen that the X-ray powder diffraction pattern of the crude 20(S)-protopanaxadiol expressed at a diffraction angle of 2θ±0.2° shows characteristic diffraction peaks at 5.0°, 5.8°, 12.6°, 17.5°, 7.3°, 17.0°, 10.0°, 16.6°, and 15.3°.

[0057] It is expressed by the spectral line position (Bragg angle 2θ, expressed in degrees), relative intensity (%) and interplanar spacing d. Figure 3 The data of the crude 20(S)-protopanaxadiol are basically as shown in Table 2:

[0058] Table 2

[0059]

[0060]

[0061] The crude 20(S)-protopanaxadiol has a melting point of 215-217°C.

[0062] When differential scanning calorimetry analysis was performed, the crude 20(S)-protopanaxadiol had an endothermic signal when heated to about 50°C, an exothermic signal when heated to about 159°C, and began to melt when heated to about 216°C. The DSC graph is shown in the attached figure. Figure 4 shown.

[0063] The crude 20(S)-protopanaxadiol can also be represented by crystal form D in the present invention. The powder X-ray powder diffraction pattern (i.e. Figure 3 ), DSC diagram (i.e. Figure 4 ) and other information and the powder X-ray diffraction pattern of the 20(S)-protopanaxadiol crystal form A claimed in the present invention (i.e. Figure 1 ), DSC diagram (i.e. Figure 2) and other information, it can be seen that the crystal form A obtained in the present invention is different from the currently known 20(S)-protopanaxadiol crystal form.

[0064] In a third aspect, the present invention provides another crystalline form B of 20(S)-protopanaxadiol.

[0065] In the present invention, the X-ray powder diffraction pattern of the crystalline form B expressed at a diffraction angle of 2θ±0.2° shows characteristic diffraction peaks at least at 7.5°, 14.4° and 15.4°.

[0066] Preferably, the X-ray powder diffraction pattern of the crystalline form B represented by a diffraction angle of 2θ±0.2° is at least:

[0067] (1) at least one of 4.6°, 3.8° and 16.9° shows a characteristic diffraction peak; and / or

[0068] (2) At least one of 18.1°, 6.7°, and 13.1° shows a characteristic diffraction peak.

[0069] In a preferred embodiment, the X-ray powder diffraction pattern of the crystalline form B represented by a diffraction angle of 2θ±0.2° shows characteristic diffraction peaks at least at 7.5°, 14.4°, 15.4°, 4.6°, 3.8°, 16.9°, 18.1°, 6.7°, and 13.1°.

[0070] In a further preferred embodiment, the crystalline form B of 20(S)-protopanaxadiol of the present invention has substantially Figure 5 Powder X-ray diffraction pattern shown.

[0071] The crystal form B is represented by the spectral line position (Bragg angle 2θ, expressed in degrees), relative intensity (%) and interplanar spacing d, and its data are basically as shown in Table 3:

[0072] Table 3

[0073] Diffraction angle 2θ d value Relative Strength % 3.8 23.2 63.5 4.6 19.0 68.1 6.7 13.2 56.0 7.5 11.7 100.0 13.1 6.8 46.0 14.4 6.1 78.9 15.4 5.8 69.0 16.9 5.2 60.9 18.1 4.9 60.0

[0074] In the present invention, the melting point of the crystalline form B is 218-220°C.

[0075] When differential scanning calorimetry analysis was performed, Form B began to melt when heated to around 219°C. Its DSC graph is shown in the attached figure. Figure 6 shown.

[0076] The 20(S)-protopanaxadiol crystal form B provided by the present invention has a clear outline and can be perfectly reproduced, and has the characteristics of high bulk density, strong fluidity and good solid-state stability.

[0077] In a fourth aspect, the present invention provides a method for preparing the crystalline form B.

[0078] In the present invention, the preparation method of the crystal form B comprises: first heating the crude 20(S)-protopanaxadiol to 160-180°C and maintaining it for 2-5 minutes; then cooling it to 25-35°C to obtain the crystal form B.

[0079] Among them, the crude 20(S)-protopanaxadiol is also an existing known compound (crystalline form D). In a more specific embodiment provided by the present invention, the crude 20(S)-protopanaxadiol is prepared by the method provided in Example 3 of the invention patent announcement No. CN1252082C (Preparation method of protopanaxadiol and protopanaxantriol).

[0080] In the method for preparing Form B of the present invention, the heating is preferably carried out in an inert gas environment, wherein the inert gas is preferably N2.

[0081] In the present invention, the heating rate is preferably 8-15°C / min, more preferably 10-12°C / min. The cooling rate is preferably 25-35°C / min, more preferably 30°C / min.

[0082] As the best embodiment of the present invention, the preparation method preferably comprises the following steps:

[0083] The crude solid of 20(S)-protopanaxadiol was placed in a DSC aluminum pan, and under nitrogen purge, the temperature was increased to 170°C at a heating rate of 10-15°C / min, maintained at a constant temperature for 3 minutes, and then cooled to 30°C at a cooling rate of 30°C / min to collect the solid.

[0084] The X-ray powder diffraction pattern of the crude 20(S)-protopanaxadiol powder (i.e. Figure 3 ), DSC diagram (i.e. Figure 4 ) and other information and the powder X-ray diffraction pattern of the 20(S)-protopanaxadiol crystal form B claimed in the present invention (i.e. Figure 5 ), DSC diagram (i.e. Figure 6 ) and other information, it can be seen that the crystal form B obtained in the present invention is different from the currently known 20(S)-protopanaxadiol crystal form.

[0085] In a fifth aspect, the present invention also provides a pharmaceutical composition containing the above-mentioned 20(S)-protopanaxadiol crystal form A or crystal form B, and the specific pharmaceutical composition includes but is not limited to powder injection, tablets, capsules, microspheres, self-microemulsion compositions, dry suspensions, lyophilized powders or infusions, etc.

[0086] The composition of the present invention may further contain pharmaceutically acceptable excipients; more preferably, the pharmaceutically acceptable excipients include at least one of a carrier, a diluent and an excipient. For example, when the composition is a lyophilized powder, the pharmaceutically acceptable carrier may be an excipient; when the composition is a tablet, the pharmaceutically acceptable carrier may be a disintegrant, an excipient, etc.

[0087] The 20(S)-protopanaxadiol crystal form A or crystal form B of the present invention has the same chemical formula structure as the crude 20(S)-protopanaxadiol (only the crystal form is different), and it also shows ideal therapeutic effects in anti-depression, anti-anxiety, anti-cognitive disorder, anti-tumor or anti-cardiovascular disease.

[0088] Since the 20(S)-protopanaxadiol crystal form A or crystal form B obtained in the present invention has ideal physical and chemical properties, those skilled in the art can foresee that after preparing it into various pharmaceutical preparations, the stability and efficacy of the pharmaceutical preparations can be further improved, and the determination of the specific dosage form and its prescription is within the control of those skilled in the art.

[0089] In addition, the present invention further claims to protect any of the following applications of the above-mentioned 20(S)-protopanaxadiol crystal form A or crystal form B:

[0090] (1) For the preparation of antidepressant, antianxiety, anti-cognitive disorder, anti-tumor or anti-cardiovascular disease drugs;

[0091] (2) Used for anti-depression, anti-anxiety, anti-cognitive disorder, anti-tumor or anti-cardiovascular disease.

[0092] The 20(S)-protopanaxadiol crystal form A or crystal form B of the present invention exhibits medicinal activity comparable to that of the crude 20(S)-protopanaxadiol or the 20(S)-protopanaxadiol disclosed in the prior art in terms of anti-depression, anti-anxiety, anti-cognitive disorder, anti-tumor and anti-cardiovascular disease, with no significant difference. In addition, the 20(S)-protopanaxadiol crystal form A or crystal form B of the present invention exhibits better bulk density, fluidity and stability, and has advantages in the drug development of 20(S)-protopanaxadiol.

[0093] Beneficial effects:

[0094] The present invention provides new 20(S)-protopanaxadiol crystal form A and crystal form B, and provides corresponding preparation methods and applications. The new crystal form provided by the present invention has a clear outline, can be perfectly reproduced, and exhibits good properties in terms of bulk density, fluidity and stability, and has broad application prospects in the drug development of 20(S)-protopanaxadiol. The preparation method provided by the present invention is simple and easy to operate, and is conducive to popularization and application. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] Figure 1 This is the X-ray powder diffraction pattern of the 20(S)-protopanaxadiol crystal form A of the present invention.

[0096] Figure 2 This is a differential scanning calorimetry analysis diagram of 20(S)-protopanaxadiol crystal form A of the present invention.

[0097] Figure 3 The X-ray powder diffraction pattern of the crude 20(S)-protopanaxadiol (crystalline form D) used in the present invention.

[0098] Figure 4 This is a differential scanning calorimetry analysis diagram of the crude 20(S)-protopanaxadiol (crystalline form D) used in the present invention.

[0099] Figure 5 This is the X-ray powder diffraction pattern of the 20(S)-protopanaxadiol crystal form B of the present invention.

[0100] Figure 6 This is a differential scanning calorimetry analysis diagram of 20(S)-protopanaxadiol crystal form B of the present invention.

[0101] Figure 7 This is a dynamic moisture adsorption diagram of the 20(S)-protopanaxadiol crystal form A of the present invention.

[0102] Figure 8 This is a dynamic moisture adsorption diagram of 20(S)-protopanaxadiol crystal form B of the present invention.

[0103] Fig. 9 This is a dynamic water adsorption diagram of the crude 20(S)-protopanaxadiol (crystalline form D) used in the present invention.

[0104] Fig.10 This is the PLM diagram of the 20(S)-protopanaxadiol crystal form A of the present invention.

[0105] Fig.11 This is the PLM diagram of 20(S)-protopanaxadiol crystal form B of the present invention.

[0106] Fig.12 This is the PLM diagram of the crude 20(S)-protopanaxadiol (crystalline form D) used in the present invention. DETAILED DESCRIPTION

[0107] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. Obviously, the described embodiments are only a part of the present invention, rather than all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by those skilled in the art without making creative work, all belong to the scope of protection of the present invention.

[0108] The abbreviations used in the present invention are explained as follows:

[0109] XRPD: X-ray powder diffraction

[0110] DSC: Differential Scanning Calorimetry

[0111] TGA: Thermogravimetric analysis

[0112] DVS: Dynamic Water Sorption

[0113] The X-ray powder diffraction pattern of the present invention is collected on a PANalytical Empyrean or X'Pert3 X-ray powder diffractometer. The method parameters of the X-ray powder diffraction of the present invention are as follows:

[0114] X-ray source: Cu, Kα

[0115] 1.54060; 1.54439

[0116] Kα2 / Kα1 intensity ratio: 0.50

[0117] Voltage: 45 kV

[0118] Current: 40 milliamperes (mA)

[0119] Scanning range: from 3.0 to 40.0 degrees

[0120] The differential scanning calorimetry (DSC) diagram of the present invention was collected on a TA Discovery 2500. The method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:

[0121] Scan rate: 10℃ / min

[0122] Shielding gas: N2

[0123] The thermogravimetric analysis (TGA) graph of the present invention was collected on a TA Discovery 5500. The method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:

[0124] Scan rate: 10℃ / min

[0125] Shielding gas: N2

[0126] The high performance liquid chromatography (HPLC) purity data in the present invention is collected from the Thermo Fisher Vanquish Core, and the detector used is a diode array detector (DAD). The HPLC method parameters for testing purity described in the present invention are as follows:

[0127] 1. Chromatographic column: Xselect CSH C18, 150×4.6mm, 3.5μm

[0128] 2. Mobile phase:

[0129] A: water

[0130] B: Acetonitrile

[0131] The elution gradient is as follows:

[0132] Time (min) B(％) 0.0 80 16.0 80

[0133] 3. Flow rate: 1.0mL / min

[0134] 4. Injection volume: 5μL

[0135] 5. Detection wavelength: 203nm

[0136] 6. Column temperature: 40℃

[0137] 7. Injector temperature: room temperature

[0138] 8. Diluent: acetonitrile

[0139] Unless otherwise specified, the following examples were all operated at room temperature.

[0140] Example 1

[0141] Preparation of crude 20(S)-protopanaxadiol:

[0142] The crude product of 20(S)-protopanaxadiol was prepared by the method of Example 3 of the invention patent 200410018038.8 (method for preparing protopanaxadiol and protopanaxadiol).

[0143] Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crude 20(S)-protopanaxadiol is shown in Figure 3 .

[0144] It is expressed by the spectral line position (Bragg angle 2θ, expressed in degrees), relative intensity (%) and interplanar spacing d. Figure 3 The crude product of 20(S)-protopanaxadiol is shown in Table 2.

[0145] When differential scanning calorimetry analysis was performed, the crude 20(S)-protopanaxadiol had an endothermic signal when heated to about 50°C, an exothermic signal when heated to about 159°C, and began to melt when heated to about 216°C. The DSC graph is shown in FIG. Figure 4 .

[0146] Example 2

[0147] Preparation of 20(S)-protopanaxadiol Crystalline Form A:

[0148] The crude 20(S)-protopanaxadiol prepared in Example 1 was used as a raw material, and about 20 mg of the crude solid 20(S)-protopanaxadiol was weighed and placed in a 20 ml glass vial, and 0.6 ml of methyl isobutyl ketone was added to dissolve the crude solid 20(S)-protopanaxadiol. The sample solution was filtered into a new 20 ml glass vial using a polytetrafluoroethylene filter with a pore size of 0.45 μm, and then magnetically stirred (at a speed of about 1000 rpm) to obtain a clear solution, and 5 ml of n-heptane was added dropwise thereto to obtain a colloidal sample, and the sample was transferred to a crystal growing under temperature cycling conditions (except for the constant temperature crystal growing stage, all others were carried out under magnetic stirring, and the speed of magnetic stirring was about 1000 rpm).

[0149] The temperature cycle conditions are as follows:

[0150] First cycle: uniformly raise the temperature to 50°C over 0.3 hours and maintain the temperature at 50°C for 2 hours; reduce the temperature to 5°C at a rate of 0.5°C / min and maintain the temperature at 5°C for 2 hours.

[0151] Second cycle: the temperature was raised to 50°C at a constant rate over 0.4 hours and maintained at 50°C for 2 hours; the temperature was lowered to 5°C at a rate of 0.3°C / min and maintained at 5°C for 2 hours.

[0152] The third cycle: the temperature was raised to 50°C at a constant rate over 0.5 hours and maintained at 50°C for 2 hours; the temperature was lowered to 5°C at a rate of 0.1°C / min and maintained at 5°C for 2 hours.

[0153] After a total of 3 cycles, solid precipitated, and the obtained solid was separated by centrifugation to obtain Form A.

[0154] Using Cu-Kα radiation, the X-ray powder diffraction pattern of the 20(S)-protopanaxadiol crystal form A is shown in Figure 1 .

[0155] The 20(S)-protopanaxadiol crystal form A is represented by the spectral line position (Bragg angle 2θ, expressed in degrees), relative intensity (%) and interplanar spacing d, and the data are shown in Table 1.

[0156] When differential scanning calorimetry analysis is performed, Form A has an endothermic signal when heated to around 133°C, an exothermic signal when heated to around 175°C, and begins to melt when heated to around 220°C. The DSC graph is shown in Figure 2 .

[0157] Example 3

[0158] Preparation of 20(S)-protopanaxadiol Crystalline Form A:

[0159] The crude 20(S)-protopanaxadiol prepared in Example 1 was used as a raw material, and about 19.8 mg of the crude 20(S)-protopanaxadiol solid was weighed and placed in a 20 ml glass vial, and 0.8 ml of anisole was added to dissolve the crude 20(S)-protopanaxadiol solid. The sample solution was filtered into a new 20 ml glass vial using a polytetrafluoroethylene filter with a pore size of 0.45 μm, and then magnetically stirred (at a speed of about 1000 rpm) to obtain a clear solution, and 5 ml of n-pentane was added dropwise thereto to obtain a colloidal sample, and the sample was transferred to a crystal growing under temperature cycling conditions (except for the constant temperature crystal growing stage, all others were carried out under magnetic stirring, and the speed of magnetic stirring was about 1000 rpm).

[0160] The temperature cycle program is as follows:

[0161] First cycle: uniformly raise the temperature to 50°C over 0.3 hours and maintain the temperature at 50°C for 2.5 hours; reduce the temperature to 5°C at a rate of 0.5°C / min and maintain the temperature at 5°C for 2.5 hours.

[0162] Second cycle: the temperature was raised to 50°C at a constant rate over 0.4 hours and maintained at 50°C for 2.5 hours; the temperature was lowered to 5°C at a rate of 0.3°C / min and maintained at 5°C for 2.5 hours.

[0163] The third cycle: the temperature was raised to 50°C at a constant rate over 0.5 hours and maintained at 50°C for 2.5 hours; the temperature was lowered to 5°C at a rate of 0.1°C / min and maintained at 5°C for 2.5 hours.

[0164] After a total of 3 cycles, solid was precipitated, and the solid crystals obtained by centrifugation were tested to be Form A.

[0165] Example 4

[0166] Preparation of 20(S)-protopanaxadiol Crystalline Form A:

[0167] The crude 20(S)-protopanaxadiol prepared in Example 1 was used as a raw material, and about 19.8 mg of the crude 20(S)-protopanaxadiol solid was weighed and placed in a 20 ml glass vial, and 0.8 ml of chloroform was added to dissolve the crude 20(S)-protopanaxadiol solid. The sample solution was filtered into a new 20 ml glass vial using a polytetrafluoroethylene filter with a pore size of 0.45 μm, and then magnetically stirred (at a speed of about 1000 rpm) to obtain a clear solution, and 5 ml of n-hexane was added dropwise thereto to obtain a colloidal sample, and the sample was transferred to a crystal growing under temperature cycling conditions (except for the constant temperature crystal growing stage, all others were carried out under magnetic stirring, and the speed of magnetic stirring was about 1000 rpm).

[0168] The temperature cycle program is as follows:

[0169] First cycle: uniformly raise the temperature to 50°C over 0.3 hours and maintain the temperature at 50°C for 1.5 hours; reduce the temperature to 5°C at a rate of 0.5°C / min and maintain the temperature at 5°C for 1.5 hours.

[0170] Second cycle: the temperature was raised to 50°C at a constant rate over 0.4 hours and maintained at 50°C for 1.5 hours; the temperature was lowered to 5°C at a rate of 0.3°C / min and maintained at 5°C for 1.5 hours.

[0171] The third cycle: the temperature was raised to 50°C at a constant rate over 0.5 hours and maintained at 50°C for 1.5 hours; the temperature was lowered to 5°C at a rate of 0.1°C / min and maintained at 5°C for 1.5 hours.

[0172] After a total of 3 cycles, solid was precipitated, and the solid crystals obtained by centrifugation were tested to be Form A.

[0173] Example 5

[0174] Preparation of 20(S)-protopanaxadiol Crystal Form B:

[0175] The crude 20(S)-protopanaxadiol prepared in Example 1 was used as a raw material, and about 15 mg of the crude 20(S)-protopanaxadiol solid was weighed and placed in a DSC aluminum pan. Under nitrogen purge conditions, the temperature was raised to 170°C at a heating rate of 10°C per minute, and then the temperature was kept constant for 3 minutes and then cooled to 30°C at a cooling rate of 30°C per minute. A total of 17 batches were set up in parallel. All solids were collected, which was Form B.

[0176] Using Cu-Kα radiation, the X-ray powder diffraction pattern of the 20(S)-protopanaxadiol crystal form B is shown in Figure 5 .

[0177] The 20(S)-protopanaxadiol crystal form B is represented by the spectral line position (Bragg angle 2θ, expressed in degrees), relative intensity (%) and interplanar spacing d, and the data are shown in Table 3.

[0178] When differential scanning calorimetry analysis was performed, Form B began to melt when heated to around 219°C, and its DSC graph was shown in Figure 6 .

[0179] Comparative Example 1

[0180] The crude 20(S)-protopanaxadiol prepared in Example 1 was used as a raw material, 19.7 mg of the crude 20(S)-protopanaxadiol was weighed and placed in a 2 ml glass vial, and 0.3 ml of tetrahydrofuran / n-heptane (volume ratio 1:1) was added to obtain a suspension. The suspension was magnetically stirred at 50°C (speed of about 1000 rpm) for about two hours, then sealed and cooled from 50°C to 5°C at a rate of 0.1°C per minute, and then kept at a constant temperature of 5°C for about one day to obtain solid crystals. After detection and characterization, the solid crystals obtained in this comparative example are crystal form D.

[0181] Comparative Example 2

[0182] The crude 20(S)-protopanaxadiol prepared in Example 1 was used as a raw material, 20.1 mg of the crude 20(S)-protopanaxadiol solid was weighed and placed in a 3 ml glass vial, and 1.0 ml of acetonitrile was added to obtain a suspension. The suspension was magnetically stirred at 50°C (speed of about 1000 rpm) for about two hours, and then sealed and cooled from 50°C to 5°C at a rate of 0.1°C per minute, and then kept at a constant temperature of 5°C for about one day to obtain solid crystals. After detection and characterization, the solid crystals obtained in this comparative example are crystal form D.

[0183] Comparative Examples 3-6

[0184] Using the crude 20(S)-protopanaxadiol prepared in Example 1 as a raw material, weigh about 20 mg of the crude 20(S)-protopanaxadiol solid and place it in a 3 ml glass vial, add a corresponding volume of solvent, seal the 3 ml glass vial with a sealing film, pierce 4 small holes in the sealing film, and place it at room temperature to evaporate until solid precipitates.

[0185] The detailed test conditions involved in the above comparative examples are shown in Table 4.

[0186] Table 4

[0187]

[0188] After testing and characterization, the solid crystals obtained in Comparative Examples 3-6 are all of Form D.

[0189] Comparative Example 7

[0190] The crude 20(S)-protopanaxadiol prepared in Example 1 was used as a raw material, and about 20 mg of the crude solid of 20(S)-protopanaxadiol was weighed and placed in a 20 ml glass vial, and 0.6 ml of methyl isobutyl ketone was added to dissolve the crude solid of 20(S)-protopanaxadiol. Subsequently, magnetic stirring (speed of about 1000 rpm) was performed to obtain a clear solution. After the solvent was naturally evaporated slowly, the solid was precipitated, and the solid obtained by centrifugation was characterized by detection. The solid crystal obtained in this comparative example was crystal form D.

[0191] Test Example 1: Moisture absorption test

[0192] In this test example, the crude 20(S)-protopanaxadiol (crystal form D) prepared in Example 1, the 20(S)-protopanaxadiol crystal form A prepared in Example 2, and the 20(S)-protopanaxadiol crystal form B prepared in Example 5 were used as test samples, and the hygroscopicity of each test sample was tested.

[0193] The dynamic moisture adsorption-desorption (DVS) curves of each sample were tested and plotted, and the experimental results are shown in Table 5. Among them, the DVS curve of the crystal form A described in Example 2 is shown in Figure 7 The DVS diagram of Form B described in Example 5 is shown in Figure 8 The DVS diagram of the crude 20(S)-protopanaxadiol described in Example 1 is shown in Fig. 9 .

[0194] Table 5

[0195] Crystalline Form A Form B Crystal form D 25℃ / 80%RH Humidity gain (%) 0.5763 0.2227 0.3863 Crystal form changes after DVS test constant constant constant

[0196] According to the definition of drug hygroscopicity in the "Chinese Pharmacopoeia 2020 Edition", the crystal form A, crystal form B and 20(S)-protopanaxadiol crude product described in the present invention are all slightly hygroscopic, and can still maintain stable properties under high humidity conditions. During the production, storage and use, they can remain stable without specific humidity control conditions, and can well meet the requirements of drug production and use.

[0197] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Guidelines for hygroscopicity testing of drugs in the 2020 edition of the Chinese Pharmacopoeia):

[0198] Deliquescent: Absorbs enough water to form a liquid

[0199] Highly hygroscopic: weight gain due to moisture absorption is no less than 15%

[0200] Hygroscopic: Weight gain due to moisture absorption is less than 15% but not less than 2%

[0201] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%

[0202] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0203] Test Example 2 Solubility Test

[0204] In this test example, the crude 20(S)-protopanaxadiol (crystal form D) prepared in Example 1, the 20(S)-protopanaxadiol crystal form A prepared in Example 2, and the 20(S)-protopanaxadiol crystal form B prepared in Example 5 were used as test samples, and the solubility of each test sample was tested.

[0205] Weigh 50 mg of each sample to be tested, and prepare suspensions with 5.0 ml of pure water, pH 1 buffer, SGF (simulated gastric juice), FaSSIF (artificial intestinal juice in fasting state), and FeSSIF (artificial intestinal juice in fed state), respectively. After balancing at 37°C for 1 hour, 2 hours, 4 hours, and 24 hours, filter to obtain clear solutions. The content of the sample in the saturated solution was determined by HPLC. The test results are shown in Table 6.

[0206] The test results show that in pure water and pH 1 buffer media, the 24-hour solubility of Form A, Form B and crude 20(S)-protopanaxadiol is small, the 24-hour solubility of Form A is 0.13-0.15 μg / mL, and the solubility of Forms B and D is less than LOQ. There is no significant difference in the solubility of Form A, Form B and crude 20(S)-protopanaxadiol (Form D) in SGF, and the solubility of Form A and crude 20(S)-protopanaxadiol (Form D) is higher than that of Form B in FaSSIF.

[0207] Table 6

[0208]

[0209] LOQ1 is: 0.1 μg / mL. LOQ2 is: 0.3 μg / mL.

[0210] Test Example 3 Bulk density and tap density test

[0211] In this test example, the crude 20(S)-protopanaxadiol (crystal form D) prepared in Example 1, the 20(S)-protopanaxadiol crystal form A prepared in Example 2, and the 20(S)-protopanaxadiol crystal form B prepared in Example 5 were used as test samples, and the bulk density and tap density of each test sample were tested respectively.

[0212] Take about 800 mg of each sample to be tested and add them to a 5 ml graduated cylinder respectively, and record the volume at this time. Tap the graduated cylinder on the table 200 times and record the volume at this time. Perform three tests in parallel. The test results are shown in Table 7.

[0213] Table 7

[0214]

[0215] Test Example 4: Angle of Repose Test

[0216] In this test example, the crude 20(S)-protopanaxadiol (crystal form D) prepared in Example 1, the 20(S)-protopanaxadiol crystal form A prepared in Example 2, and the 20(S)-protopanaxadiol crystal form B prepared in Example 5 were used as test samples, and the repose angle of each test sample was tested.

[0217] Take an appropriate amount of each sample to be tested. Take a funnel and fix it on the iron frame so that it is placed perpendicular to the table. Add the taken Form A and Form B samples into the funnel respectively, so that they form a cone after free falling, and measure the height and diameter of the cone to calculate the angle of repose. Perform three tests in parallel. The test results are shown in Table 8. The results show that Form A has a smaller angle of repose than Form B and 20 (S) - protopanaxadiol crude product, and exhibits better fluidity.

[0218] Table 8

[0219]

[0220]

[0221] Test Example 5 Contact angle test

[0222] In this test example, the crude 20(S)-protopanaxadiol (crystal form D) prepared in Example 1, the 20(S)-protopanaxadiol crystal form A prepared in Example 2, and the 20(S)-protopanaxadiol crystal form B prepared in Example 5 were used as test samples, and the contact angle of each test sample was tested.

[0223] Take appropriate amount of each sample to be tested and test the contact angle to water. Perform two tests in parallel. The test results are shown in Table 9.

[0224] Table 9

[0225] Crystal form Test 1 Test 2 Crystalline Form A 70.7°-74.0° 73.7°-78.3° Form B 78.4°-83.5° 68.1°-69.9° Crystal form D 124.8°-125.2° 129.8°-129.8°

[0226] Test Example 6 Mechanical stability test

[0227] In this test example, the crude 20(S)-protopanaxadiol (crystal form D) prepared in Example 1, the 20(S)-protopanaxadiol crystal form A prepared in Example 2, and the 20(S)-protopanaxadiol crystal form B prepared in Example 5 were used as test samples, and the mechanical stability of each test sample was tested.

[0228] Take appropriate amount of each sample to be tested, place them in an agate mortar, grind them manually for about 3 minutes, and then test the crystal form. The test results show that the crystal form A, crystal form B and crude 20(S)-protopanaxadiol are basically transformed into amorphous after grinding.

[0229] Take an appropriate amount of each sample to be tested, add it to the tablet press, and test the crystal form after tableting at a pressure of 200MPa. The test results show that crystal form A, crystal form B and crude 20(S)-protopanaxadiol did not undergo crystal form transformation after tableting, but the crystallinity of crystal form B and crude 20(S)-protopanaxadiol decreased, indicating that crystal form A is superior to crystal form B and crude 20(S)-protopanaxadiol.

[0230] Test Example 7 Thermodynamic stability test

[0231] In this test example, the crude 20(S)-protopanaxadiol (crystal form D) prepared in Example 1, the 20(S)-protopanaxadiol crystal form A prepared in Example 2, and the 20(S)-protopanaxadiol crystal form B prepared in Example 5 were used as test samples, and the thermodynamic stability of each test sample was tested.

[0232] Take an appropriate amount of Form A in a 2 ml glass vial, add 0.5 ml of the corresponding solvent, and magnetically stir at the corresponding temperature for about 5 hours to obtain a suspension, which is filtered into a new 2 ml glass vial with a polytetrafluoroethylene filter membrane with a pore size of 0.45 microns at room temperature or 50°C. Weigh about 5 mg of Form A, Form B, and 20(S)-protopanaxadiol crude product, respectively, add them to the filtered filtrate, and magnetically stir at the corresponding temperature. The test results show that the mixture of Form A, Form B, and 20(S)-protopanaxadiol crude product is stirred at room temperature and 50°C to obtain Form A, and the test results are shown in Table 10. The test results show that within the range of room temperature to 50°C, Form A is more stable than Form B and 20(S)-protopanaxadiol crude product.

[0233] Table 10

[0234]

[0235] Test Example 8 Solid State Stability Test

[0236] In this test example, the crude 20(S)-protopanaxadiol (crystal form D) prepared in Example 1, the 20(S)-protopanaxadiol crystal form A prepared in Example 2, and the 20(S)-protopanaxadiol crystal form B prepared in Example 5 were used as test samples, and the solid-state stability of each test sample was tested.

[0237] Weigh an appropriate amount of each sample to be tested, set up a stability test at 80°C for 1 day in a closed state, and at 25°C / 60%RH and 40°C / 75%RH for 1 month in an open state. The solid samples separated under different conditions were tested for crystal form by XRPD to evaluate physical stability, and HPLC to test chemical purity to evaluate chemical stability. The evaluation results are summarized in Table 11. The XRPD results showed that crystal form A, crystal form B and 20(S)-protopanaxadiol crude product did not undergo crystal form transformation under the three conditions. The HPLC results showed that the purity of 20(S)-protopanaxadiol crude product decreased slightly after being closed for 1 day at 80°C, and the chemical purity decreased slightly after being open for 1 month at 25°C / 60%RH and 40°C / 75%RH; crystal form A and crystal form B did not undergo a significant decrease in chemical purity under the three conditions, indicating that crystal form A and crystal form B have better solid-state stability.

[0238] Table 11

[0239]

[0240]

[0241] Test Example 9 Polarized Light Microscope (PLM) Test

[0242] In this test example, the crude 20(S)-protopanaxadiol (crystal form D) prepared in Example 1, the 20(S)-protopanaxadiol crystal form A prepared in Example 2, and the 20(S)-protopanaxadiol crystal form B prepared in Example 5 were used as test samples, and PLM observations were performed on each test sample.

[0243] The PLM diagram of Form A described in Example 2 is shown in Fig.10 The PLM diagram of Form B described in Example 5 is shown in Fig.11 The PLM diagram of the crude 20(S)-protopanaxadiol described in Example 1 is shown in Fig.12 .

[0244] Depend on Fig.10 , Fig.11 and Fig.12 It can be seen that: under a polarizing microscope, it was observed that Form A and Form B were mainly composed of irregular granular crystals, and Form D was mainly composed of irregular granular and needle-shaped / long plate-shaped crystals.

[0245] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made thereto based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims

1. 20(S)-Protopanaxadiol crystalline form A, characterized in that: The X-ray powder diffraction pattern of the crystalline form A expressed at a diffraction angle of 2θ±0.2° shows characteristic diffraction peaks at least at 6.5°, 4.2° and 15.7°; Preferably, the X-ray powder diffraction pattern of the crystalline form A represented by a diffraction angle of 2θ±0.2° is at least: (1) at least one of 17.1°, 18.6°, and 13.1° shows a characteristic diffraction peak; and / or (2) at least one of 17.9°, 10.6°, and 20.7° shows a characteristic diffraction peak; More preferably, the X-ray powder diffraction pattern of the crystalline form A represented by a diffraction angle of 2θ±0.2° shows characteristic diffraction peaks at least at 6.5°, 4.2°, 15.7°, 17.1°, 18.6°, 13.1°, 17.9°, 10.6°, and 20.7°.

2. The crystalline form A of 20(S)-protopanaxadiol according to claim 1, characterized in that: The melting point of the crystalline form A is 219-221°C.

3. The method for preparing the crystalline form A of 20(S)-protopanaxadiol according to claim 1 or 2, characterized in that: Dissolving crude 20(S)-protopanaxadiol in a positive solvent to obtain a 20(S)-protopanaxadiol solution, adding an antisolvent dropwise to the 20(S)-protopanaxadiol solution until a jelly is formed, and subjecting the jelly to at least one temperature cycle; The temperature cycle comprises: raising the temperature of the colloid to 45-55° C., maintaining the temperature for 1-3 hours, reducing the temperature to 4-6° C. at a rate of 0.05-1° C. / min, and maintaining the temperature for 1-3 hours; Preferably, the temperature cycle is repeated 2-4 times.

4. The preparation method according to claim 3, characterized in that: Before adding the anti-solvent, the 20(S)-protopanaxadiol solution is filtered using a filter membrane with a pore size of 0.4-0.5 μm; and / or the positive solvent is selected from at least one of methyl isobutyl ketone, anisole or chloroform; the anti-solvent is selected from at least one of n-heptane, n-hexane or n-pentane. 5.20(S)-Protopanaxadiol crystalline form B, characterized in that: The X-ray powder diffraction pattern of the crystalline form B expressed at a diffraction angle of 2θ±0.2° shows characteristic diffraction peaks at least at 7.5°, 14.4°, and 15.4°; Preferably, the X-ray powder diffraction pattern of the crystalline form B represented by a diffraction angle of 2θ±0.2° is at least: (1) at least one of 4.6°, 3.8°, and 16.9° shows a characteristic diffraction peak; and / or (2) at least one of 18.1°, 6.7°, and 13.1° shows a characteristic diffraction peak; More preferably, the X-ray powder diffraction pattern of the crystalline form B represented by a diffraction angle of 2θ±0.2° shows characteristic diffraction peaks at least at 7.5°, 14.4°, 15.4°, 4.6°, 3.8°, 16.9°, 18.1°, 6.7°, and 13.1°.

6. The crystalline form B of 20(S)-protopanaxadiol according to claim 5, characterized in that: The XRPD data of the crystalline form B are substantially as shown in Table 3; and / or, the XRPD pattern of the crystalline form B is substantially as shown in FIG5 .

7. The crystalline form B of 20(S)-protopanaxadiol according to claim 5 or 6, characterized in that: The melting point of the crystalline form B is 218-220°C.

8. The method for preparing the crystalline form B of 20(S)-protopanaxadiol according to any one of claims 5 to 7, characterized in that: The crude 20(S)-protopanaxadiol was first heated to 160-180°C and maintained for 2-5 minutes; then cooled to 25-35°C to obtain Form B; Preferably, the heating rate is 8-15°C / min; and / or the cooling rate is 25-35°C / min.

9. A pharmaceutical composition, characterized in that Contains a therapeutically effective amount of the crystalline form A according to any one of claims 1-2 or the crystalline form B according to any one of claims 5-7; preferably, the pharmaceutical composition also includes a pharmaceutically acceptable excipient.

10. Any one of the following uses of the crystalline form A according to any one of claims 1 to 2, or the crystalline form B according to any one of claims 5 to 7, or the pharmaceutical composition according to claim 9: (1) For the preparation of antidepressant, antianxiety, anti-cognitive disorder, anti-tumor or anti-cardiovascular disease drugs; (2) Used for anti-depression, anti-anxiety, anti-cognitive disorder, anti-tumor or anti-cardiovascular disease.

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