Crystal form of neuroactive steroid derivative and application thereof

Abstract

The invention provides a crystal form of a neuroactive steroid derivative and application thereof, and belongs to the technical field of medicines. The crystal form of the neuroactive steroid derivative (with the structure as shown in the formula I) provided by the invention is radiated by Cu-K alpha, and characteristic diffraction peaks of an X-ray powder diffraction pattern expressed by a 2 theta angle comprise 11.450 + / -0.200 degrees, 15.724 + / -0.200 degrees, 19.040 + / -0.200 degrees, 22.955 + / -0.200 degrees and 24.975 + / -0.200 degrees. The crystal form provided by the invention has the advantages of good fluidity, no electrostatic phenomenon, high stability and almost no hygroscopicity, and can stably exist under the conditions of high temperature, high humidity and illumination; the compound has a relatively strong positive regulation effect on a GABAA receptor, has relatively good pharmacokinetic properties and oral absorption rate, and can be applied to preparation of oral and other dosage form medicines for efficiently resisting diseases such as postpartum depression. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a crystal form of a neuroactive steroid derivative and application thereof. Background Art

[0002] Allopregnanolone is an endogenous neuroactive steroid (NASs) synthesized from progesterone in the brain. NASs mainly bind to γ-aminobutyric acid type A receptors (GABA A NASs can act as synaptic and extrasynaptic GABA receptors to rapidly affect neuronal excitability. A Positive allosteric modulators (PAMs) of the receptor activate and enhance phasic and tonic currents, respectively, ultimately enhancing GABA A Receptor-mediated tonic inhibitory current. Allopregnanolone differs from other NASs in that, in addition to activating GABA receptors containing both α and β subunits, A Receptors that also regulate GABA containing gamma and delta subunits A Receptor.

[0003] Brexanolone is an endogenous neuroactive steroid with a CAS registration number of 516-54-1. On March 19, 2019, the U.S. FDA approved brexanolone (trade name Zulresso) injection for the treatment of postpartum depression in adult women. This is the first drug specifically for postpartum depression (PPD) and can enhance the expression of recombinant GABA A The current mediated by GABA in mammalian cells with receptors. However, the administration of brexanolone is continuous intravenous infusion for more than 60 hours. During the two and a half days of brexanolone infusion, medical staff must be on site to continuously monitor the patient, which is inconvenient to use.

[0004] The neuroactive steroid derivative having the structure shown in Formula I is the 3-hydroxy nitrate of brenoside, which maintains GABA A It has high oral bioavailability based on receptor activity and can avoid the inconvenience caused to patients by long-term intravenous drip.

[0005]

[0006] However, the neuroactive steroid derivatives having the structure shown in Formula I in the prior art have poor fluidity, which brings inconvenience to the weighing, transportation and use of the product. Summary of the invention

[0007] The object of the present invention is to provide a crystalline form of a neuroactive steroid derivative and its application. The crystalline form of the neuroactive steroid derivative provided by the present invention has good fluidity, making the weighing, transportation and use of the product more convenient.

[0008] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0009] The present invention provides a crystalline form of a neuroactive steroid derivative, wherein Cu-Kα radiation is used, and characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in 2θ angles include 11.450±0.200°, 15.724±0.200°, 19.040±0.200°, 22.955±0.200° and 24.975±0.200°;

[0010] The neuroactive steroid derivative has a structure shown in Formula I:

[0011]

[0012] Preferably, the characteristic diffraction peaks also include 7.843±0.200°, 9.643±0.200°, 12.338±0.200°, 13.384±0.200°, 14.210±0.200°, 15.032±0.200°, 16.498±0.200°, 17.148±0.200°, 17. 802±0.200°, 18.739±0.200°, 19.313±0.200°, 19.726±0.200°, 20.276±0.200°, 22.464±0.200°, 23.558±0.200°, 25.897±0.200°, 26.445±0.200°, 26.9 14±0.200°、27.202±0.200°、27.964±0.200°、28.781±0.200°、29.102±0.200°、29.451±0.200°、29.760±0.200°、31.706±0.200°、32.133±0.200°、32.61 6±0.200°, 32.922±0.200°, 33.952±0.200°, 34.662±0.200°, 36.355±0.200°, 36.778±0.200°, 37.511±0.200°, 38.559±0.200° and 39.073±0.200°.

[0013] Preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.843±0.200°, 11.450±0.200°, 15.724±0.200°, 18.739±0.200°, 19.040±0.200°, 19.726±0.200°, 22.955±0.200° and 24.975±0.200°.

[0014] Preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.843±0.200°, 11.450±0.200°, 13.384±0.200°, 15.724±0.200°, 16.498±0.200°, 17.148±0.200°, 18.739±0.200°, 19.040±0.200°, 19.726±0.200°, 20.276±0.200°, 22.955±0.200°, 23.558±0.200°, 24.975±0.200°, 28.781±0.200° and 29.102±0.200°.

[0015] Preferably, the differential scanning calorimetry spectrum of the crystalline form of the neuroactive steroid derivative has an endothermic peak at 139.9°C±3°C; the differential scanning calorimetry spectrum of the crystalline form of the neuroactive steroid derivative has an onset value of the endothermic peak at 138.5°C±3°C.

[0016] Preferably, the thermogravimetric analysis spectrum of the crystal form of the neuroactive steroid derivative shows a weight loss of ±0.5% at 159.4°C±3°C.

[0017] Preferably, the crystal form of the neuroactive steroid derivative is an orthorhombic system, the space group is P212121; the unit cell parameters are: α=90°,β=90°,γ=90°;the unit cell volume is Z=4.

[0018] Preferably, the particle size D90 of the crystal form of the neuroactive steroid derivative is 240-530 μm, D50 is 105-270 μm, and D10 is 20-65 μm.

[0019] The present invention provides the use of the crystal form of the neuroactive steroid derivative described in the above technical solution in the preparation of drugs for treating mood disorders, mental diseases, neurodegenerative diseases or neuropathic pain.

[0020] Preferably, the mood disorder includes generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder, premenstrual dysphoric disorder, major depression or postpartum depression; the psychiatric disease includes epilepsy, convulsions or insomnia; the neurodegenerative disease includes Alzheimer's disease, Parkinson's disease, multiple sclerosis or Niemann-Pick type C disease; the neuropathic pain includes menstrual and postmenopausal migraine, diabetic peripheral neuropathy, chemotherapy pain or sciatica.

[0021] The present invention provides a crystalline form (denoted as A crystalline form) of a neuroactive steroid derivative (having a structure shown in Formula I, denoted as Formula I compound), using Cu-Kα radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in 2θ angles include 11.450±0.200°, 15.724±0.200°, 19.040±0.200°, 22.955±0.200° and 24.975±0.200°. Compared with the amorphous form of the Formula I compound, the A crystalline form of the Formula I compound of the present invention has a smaller repose angle and Carr index, indicating that the A crystalline form of the Formula I compound of the present invention has good fluidity, making the weighing, transportation and use of the product more convenient, such as effectively shortening the mixing time with the auxiliary materials.

[0022] In addition, the crystal form A of the compound of formula I provided by the present invention has no static electricity, high stability, almost no hygroscopicity, can be stably present under high temperature, high humidity and light conditions, and no obvious degradation occurs, which meets the requirements of storage and subsequent processing and production, and avoids the risk of crystal transformation during storage and processing, which leads to changes in the quality of the drug preparation and further leads to clinical effectiveness problems. The crystal form A of the compound of formula I provided by the present invention has no effect on GABA A The receptor has a strong positive regulatory effect, and has good pharmacokinetic (PK) properties and oral absorption rate, and can be used to prepare highly effective oral dosage drugs for diseases such as postpartum depression. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 is the amorphous X-ray powder diffraction (XRPD) pattern of the compound of formula I in the comparative example of the present invention;

[0024] Figure 2 The XRPD pattern of the crystal form A of the compound of formula I in the embodiment of the present invention;

[0025] Figure 3 The differential scanning calorimetry (DSC) spectrum of the crystal form A of the compound of formula I in the embodiment of the present invention;

[0026] Figure 4 Thermogravimetric analysis (TGA) spectrum of Form A of the compound of Formula I in the embodiment of the present invention;

[0027] Figure 5 is a particle size distribution diagram of the crystal form A of the compound of formula I in the embodiment of the present invention;

[0028] Figure 6 The dynamic vapor sorption analysis (DVS) spectrum of the crystal form A of the compound of formula I in the embodiment of the present invention;

[0029] Figure 7 is a three-dimensional structural ellipsoid diagram of the compound of formula I;

[0030] Figure 8 The A crystal form of the compound of formula I in the embodiment of the present invention and the effect of allopregnanolone on GABA A Comparison chart of half-maximal effect concentration of receptors;

[0031] Fig. 9 The average plasma drug concentration-time curves of male and female SD rats after single oral administration of 10 mg / kg, 30 mg / kg and 100 mg / kg of Form A of the compound of Formula I in the test example of the present invention. DETAILED DESCRIPTION

[0032] The present invention provides a crystalline form of a neuroactive steroid derivative, wherein Cu-Kα radiation is used, and characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in 2θ angles include 11.450±0.200°, 15.724±0.200°, 19.040±0.200°, 22.955±0.200° and 24.975±0.200°;

[0033] The neuroactive steroid derivative has a structure shown in Formula I:

[0034]

[0035] In an embodiment of the present invention, the characteristic diffraction peaks may also include 7.843±0.200°, 9.643±0.200°, 12.338±0.200°, 13.384±0.200°, 14.210±0.200°, 15.032±0.200°, 16.498±0.200°, 17.148±0.20 0°、17.802±0.200°、18.739±0.200°、19.313±0.200°、19.726±0.200°、20.276±0.200°、22.464±0.200°、23.558±0.200°、25.897±0.200°、26.445±0.200°、 26.914±0.200°, 27.202±0.200°, 27.964±0.200°, 28.781±0.200°, 29.102±0.200°, 29.451±0.200°, 29.760±0.200°, 31.706±0.200°, 32.133±0.200°, 32. One or more of 616±0.200°, 32.922±0.200°, 33.952±0.200°, 34.662±0.200°, 36.355±0.200°, 36.778±0.200°, 37.511±0.200°, 38.559±0.200° and 39.073±0.200°.

[0036] In an embodiment of the present invention, the crystal form of the neuroactive steroid derivative uses Cu-Kα radiation, and the obtained X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.843±0.200°, 11.450±0.200°, 15.724±0.200°, 18.739±0.200°, 19.040±0.200°, 19.726±0.200°, 22.955±0.200° and 24.975±0.200°.

[0037] In an embodiment of the present invention, the crystal form of the neuroactive steroid derivative is irradiated with Cu-Kα, and the obtained X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.843±0.200°, 11.450±0.200°, 13.384±0.200°, 15.724±0.200°, 16.498±0.200°, 17.148 ±0.200°, 18.739±0.200°, 19.040±0.200°, 19.726±0.200°, 20.276±0.200°, 22.955±0.200°, 23.558±0.200°, 24.975±0.200°, 28.781±0.200° and 29.102±0.200°.

[0038] In an embodiment of the present invention, the crystal form of the neuroactive steroid derivative is irradiated with Cu-Kα, and the obtained X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.843±0.200°, 11.450±0.200°, 13.384±0.200°, 14.210±0.200°, 15.724±0.200°, 16.498±0.200°, 17.148 ±0.200°, 18.739±0.200°, 19.040±0.200°, 19.313±0.200°, 19.726±0.200°, 22.955±0.200°, 23.558±0.200°, 24.975±0.200°, 29.102±0.200°, 36.355±0.200° and 37.511±0.200°.

[0039] In an embodiment of the present invention, the crystal form of the neuroactive steroid derivative is irradiated with Cu-Kα, and the obtained X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.843±0.200°, 11.450±0.200°, 13.384±0.200°, 14.210±0.200°, 15.724±0.200°, 16.498±0.200°, 17.148±0.200°, 18.739 ±0.200°, 19.040±0.200°, 19.313±0.200°, 19.726±0.200°, 20.276±0.200°, 22.955±0.200°, 23.558±0.200°, 24.975±0.200°, 28.781±0.200°, 29.102±0.200°, 36.355±0.200° and 37.511±0.200°.

[0040] In an embodiment of the present invention, the crystal form of the neuroactive steroid derivative is irradiated with Cu-Kα, and the obtained X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.843±0.200°, 9.643±0.200°, 11.450±0.200°, 12.338±0.200°, 13.384±0.200°, 14.210±0.200°, 15.032±0.200° °, 15.724±0.200°, 16.498±0.200°, 17.148±0.200°, 17.802±0.200°, 18.739±0.200°, 19.040±0.200°, 19.313±0.200°, 19.726±0.200°, 20.276±0.200°, 22.464±0.200°, 22.955±0.200° , 23.558±0.200°, 24.975±0.200°, 25.897±0.200°, 26.445±0.200°, 26.914±0.200°, 27.202±0.200°, 27.964±0.200°, 28.781±0.200°, 29.102±0.200°, 29.451±0.200°, 29.760±0.200°, 31.706±0.200°, 32.133±0.200°, 32.616±0.200°, 32.922±0.200°, 33.952±0.200°, 34.662±0.200°, 36.355±0.200°, 36.778±0.200°, 37.511±0.200°, 38.559±0.200° and 39.073±0.200°.

[0041] In an embodiment of the present invention, the crystal form of the neuroactive steroid derivative is irradiated with Cu-Kα, and the obtained X-ray powder diffraction pattern is as follows: Figure 2 As shown, the error is within ±0.20°. Figure 2 The corresponding analytical data are shown in Table 1.

[0042] Table 1 XRPD spectrum analysis data of Form A of the compound of Formula I

[0043]

[0044]

[0045] In an embodiment of the present invention, the differential scanning calorimetry spectrum of the crystal form of the neuroactive steroid derivative specifically has an endothermic peak at 139.9°C±3°C; the differential scanning calorimetry spectrum of the crystal form of the neuroactive steroid derivative specifically has an onset value of the endothermic peak at 138.5°C±3°C. In an embodiment of the present invention, the differential scanning calorimetry spectrum of the crystal form of the neuroactive steroid derivative is as follows: Figure 3 As shown (unless otherwise specified, the exothermic peak of the DSC spectrum is facing upward), wherein the starting temperature is 40.0°C, the heating rate is 10.00°C / min, the holding temperature is 170.0°C, and the holding time is 0 min; the endothermic peak is at 139.93°C, the extrapolated starting point is at 138.52°C, and the extrapolated end point is at 142.49°C; the heat is -72.03 J / g.

[0046] In an embodiment of the present invention, the thermogravimetric analysis spectrum of the crystal form of the neuroactive steroid derivative shows a weight loss of ±0.5% at 159.4°C±3°C, for example, specifically -0.1%. In an embodiment of the present invention, the thermogravimetric analysis spectrum of the crystal form of the neuroactive steroid derivative is as follows: Figure 4 As shown, the heating rate is 10.00℃ / min, the holding temperature is 300.0℃, and the holding time is 0min; the starting time is 7.62min, and the temperature is 90.00℃; the end time is 14.62min, and the temperature is 160.00℃; the midpoint time is 0.00min, and the temperature is 0.00℃; the extrapolated starting temperature is 90.08℃, and the extrapolated end temperature is 159.39℃; and the weight loss is -0.100%.

[0047] In an embodiment of the present invention, the crystal form of the neuroactive steroid derivative is specifically an orthorhombic system, the space group is specifically P212121; the unit cell parameters are specifically: α=90°,β=90°,γ=90°;the specific unit cell volume is Z = 4. In the present invention, the relevant crystal data of the crystal form of the neuroactive steroid derivative is shown in Table 5 of the test example, the atomic coordinates and equivalent isotropic shift parameters are shown in Table 6 of the test example, the bond length is shown in Table 7 of the test example, the bond angle is shown in Table 8 of the test example, and the torsion angle is shown in Table 9 of the test example, which will not be repeated here.

[0048] In an embodiment of the present invention, the particle size D90 of the crystal form of the neuroactive steroid derivative is 240-530 μm, D50 is 105-270 μm, and D10 is 20-65 μm; specifically, the particle size D90 of the crystal form of the neuroactive steroid derivative is 240-380 μm, D50 is 105-180 μm, and D10 is 20-45 μm.

[0049] In the embodiments of the present invention, the angle of repose of the crystal form of the neuroactive steroid derivative is specifically 39.2, and the Carr index is specifically 14, indicating that it has good fluidity.

[0050] The present invention provides a method for preparing the crystal form of the neuroactive steroid derivative described in the above technical solution, comprising the following steps:

[0051] Mixing a neuroactive steroid derivative having a structure shown in Formula I with an organic solvent, heating and dissolving the mixture to obtain a solution;

[0052] The dissolved liquid is cooled to 0-10°C at a rate of 18-22°C / h, kept warm for crystallization, and subjected to solid-liquid separation and solid drying to obtain the crystal form of the neuroactive steroid derivative.

[0053] In the present invention, unless otherwise specified, the raw materials and reagents used are commercially available products well known to those skilled in the art or are prepared by methods well known to those skilled in the art; the organic solvents used are directly commercially available products and can be used without further purification.

[0054] The present invention mixes a neuroactive steroid derivative having a structure shown in Formula I (i.e., a compound of Formula I) with an organic solvent, heats and dissolves the mixture to obtain a solution. As an embodiment of the present invention, the organic solvent may include anhydrous ethanol, ethyl acetate, acetone, n-heptane, methyl tert-butyl ether or dimethyl sulfoxide, and may specifically be anhydrous ethanol. As an embodiment of the present invention, the amount ratio of the compound of Formula I to the organic solvent may be 98 g: 0.8 to 1.2 L, and may specifically be 98 g: 0.9 to 1 L. As an embodiment of the present invention, the temperature for heating and dissolving may be 50 to 110° C., and may specifically be selected according to the type of organic solvent. For example, when the organic solvent is anhydrous ethanol, the temperature for heating and dissolving may be 75 to 85° C., and may specifically be 78 to 80° C.; when the organic solvents are ethyl acetate, acetone, n-heptane, methyl tert-butyl ether and dimethyl sulfoxide, the temperatures for heating and dissolving may be 70 to 80° C., 50 to 60° C., 90 to 100° C., 50 to 60° C. and 100 to 110° C., respectively. The heating and dissolving of the present invention can be carried out under stirring conditions; after the heating and dissolving, stirring can be continued for 25 to 35 minutes (specifically 28 to 30 minutes) to obtain a dissolved solution.

[0055] After obtaining the dissolved solution, the present invention cools the dissolved solution to 0-10°C at a rate of 18-22°C / h, keeps the temperature for crystallization, and obtains the crystal form of the neuroactive steroid derivative through solid-liquid separation and solid drying. In the present invention, the cooling rate during the cooling and crystallization process is 18-22°C / h, specifically 19-20°C / h; the present invention stops cooling when the temperature is cooled to 0-10°C (specifically 3-5°C), keeps the temperature for crystallization, and obtains the crystal form of the neuroactive steroid derivative (i.e., the A crystal form of the compound of formula I) through solid-liquid separation and solid drying. As an embodiment of the present invention, the crystallization time can be 25-35min, specifically 28-30min; the crystallization can be carried out under stirring conditions. As an embodiment of the present invention, the solid-liquid separation method can be filtration. As an embodiment of the present invention, the solid drying can be vacuum drying the solid obtained by solid-liquid separation; the vacuum degree of the vacuum drying can be -0.07 to -0.08 MPa, specifically -0.075 to -0.078 MPa; the temperature can be 45 to 55°C, specifically 48 to 50°C; the time can be 8 to 12 hours, specifically 9 to 10 hours. The A crystal form of the compound of formula I of the present invention is specifically a white crystalline powder.

[0056] The present invention provides the use of the crystal form of the neuroactive steroid derivative described in the above technical solution or the crystal form of the neuroactive steroid derivative prepared by the preparation method described in the above technical solution in the preparation of drugs for mood disorders, mental illnesses, neurodegenerative diseases or neuropathic pain. As an embodiment of the present invention, the mood disorder may include generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder, premenstrual dysphoria, major depression or postpartum depression; the mental illness may include epilepsy, convulsions or insomnia; the neurodegenerative disease may include Alzheimer's disease, Parkinson's disease, multiple sclerosis or Niemann-Pick type C disease; the neuropathic pain may include menstrual and postmenopausal migraine, diabetic peripheral neuropathy, chemotherapy pain or sciatica.

[0057] In the present invention, the drug specifically includes an active ingredient and a pharmaceutically acceptable carrier, and the active ingredient is a crystal form of the neuroactive steroid derivative described in the above technical solution. As an embodiment of the present invention, the pharmaceutically acceptable carrier can be a solid carrier or a liquid carrier; the solid carrier includes but is not limited to cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, saccharin sodium, sucrose, dextrin, talc, starch, pectin, gelatin, tragacanth gum, gum arabic, sodium alginate, parabens, methylcellulose, sodium carboxymethylcellulose, low melting point wax and cocoa butter; the liquid carrier includes but is not limited to water, ethanol, polyols (such as one or more of glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils (such as one or more of peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glyceride, agar, pyrogen-free water, isotonic saline and Ringer's solution.

[0058] In the present invention, the dosage form of the drug may include tablets, lozenges, lozenges, suspensions (such as aqueous suspensions or oily suspensions), dispersible powders, dispersible granules, emulsions, hard capsules, soft capsules, syrups, elixirs, solutions, sprays, aerosols or dry powder preparations, nasal drops or nasal sprays; the administration of the drug may include oral, intrapulmonary, intranasal or transdermal administration.

[0059] The A crystal form of the compound of formula I provided by the present invention can be used as synaptic and extrasynaptic GABA A Positive allosteric modulators (PAMs) of the receptor activate and enhance phasic and tonic currents, respectively, ultimately enhancing GABA A Receptor-mediated tonic inhibitory current. The A crystal form of the compound of formula I of the present invention has good pharmacokinetic (PK) properties and oral absorption rate, and can be used to treat diseases such as postpartum depression. The A crystal form of the compound of formula I of the present invention is stable, almost non-hygroscopic, and is less affected by light and heat. It is not easy to absorb moisture and deteriorate during the preparation process, and the drug storage period is longer.

[0060] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0061] Some of the test methods involved in the following test examples of the present invention are as follows:

[0062] 1. X-ray powder diffraction (XRPD) method

[0063] Instrument model: Empyrean X-ray diffractometer;

[0064] Test method: About 10-20 mg of sample is used for XRPD detection;

[0065] XRPD testing parameters include:

[0066] Light pipe: Cu, Kα,

[0067] Light tube voltage: 45kV;

[0068] Light tube current: 40mA;

[0069] Divergence slit: 1 / 8°;

[0070] Detector slit: 7.5mm;

[0071] Anti-scatter slit: 1 / 4°;

[0072] Scanning range: 3-40°;

[0073] Step length: 0.0263°;

[0074] Scan time: 46.665s.

[0075] 2. Differential Scanning Calorimeter (DSC) method

[0076] Instrument model: DSC-60Plus Shimadzu differential scanning calorimeter;

[0077] Test method: Take a sample (2-5 mg) and place it in a covered aluminum crucible. Test it under the protection of 50 mL / min dry nitrogen. The method is: heat up from 40°C to the set test temperature at a heating rate of 10°C / min.

[0078] 3. Thermogravimetric analysis (TGA) method

[0079] Instrument model: TGA-50M Shimadzu thermogravimetric analyzer;

[0080] Test method: Take a sample (2-5 mg) and place it in an alumina crucible. Test it under the protection of 50 mL / min dry nitrogen. The method is: room temperature to 350°C, and the heating rate is 10°C / min.

[0081] 4. Dynamic Vapor Sorption (DVS) method

[0082] Instrument model: Quantachrome dynamic vapor adsorption instrument;

[0083] Test method: Take a sample (10-15 mg) and place it in the DVS sample tray for testing;

[0084] DVS test parameters include:

[0085] Temperature: 25℃;

[0086] Balance: dm / dt = 0.002% / min (minimum: 10min, maximum: 180min);

[0087] Drying: Drying at 0% RH for 120 min;

[0088] RH(%) test level:

[0089] 10% (0%RH~90%RH, 90%RH~0%RH);

[0090] 5% (90%RH~95%RH, 95%RH~90%RH);

[0091] RH (%) test step range: 0% ~ 95%;

[0092] The classification of moisture absorption evaluation is shown in Table 2:

[0093] Table 2 Classification of moisture absorption evaluation

[0094]

[0095]

[0096] Note: ΔW% indicates the weight gain of the test sample at 25±1℃ and 80±2%RH.

[0097] 5. X-ray single crystal diffraction method

[0098] Instrument model: Single crystal X-ray diffractometer Rigaku OxfordDiffractionXtaLAB Synergy-S;

[0099] Test method: Directly carry out using the samples provided;

[0100] Detector: HyPix-6000HE area detector;

[0101] Cryogenic system: Oxford Cryostream 800;

[0102] Light source: Cu: 50W;

[0103] The distance from the crystal to the detector: d = 35 mm;

[0104] Light tube voltage: 50kV;

[0105] Light tube current: 1mA.

[0106] Comparative Example 1: Preparation of amorphous sample of compound of formula I

[0107] Add dichloromethane (DCM, 42mL) to a 250mL three-necked flask, add allopregnanolone (2.0g) under stirring, then lower the temperature of the resulting mixture to -10°C, start to drop acetic anhydride (Ac2O, 18mL); after the dropwise addition is completed, add concentrated nitric acid (4mL, concentration is 63-65wt%) to the system while maintaining -10°C. After the dropwise addition is completed, react for 3h under stirring at -10°C; after the reaction is complete, wash the reaction solution with purified water, saturated sodium bicarbonate aqueous solution and purified water in turn, concentrate under reduced pressure to obtain a crude product, separate by column chromatography (the eluent used is ethyl acetate and petroleum ether, the volume ratio of ethyl acetate and petroleum ether is 1:10), and obtain an amorphous sample of the compound of formula I (1.9g, yield 83.2%), an off-white solid.

[0108] The amorphous XRPD pattern of the compound of formula I is as follows: Figure 1 shown.

[0109] Example 1: Preparation of Form A of the Compound of Formula I

[0110]

[0111] Dichloromethane (DCM, 5.0L) was added to the reaction kettle, and allopregnanolone (490g) was added under stirring. Then, the temperature of the obtained mixture was lowered to 5±5°C, and acetic anhydride (Ac2O, 1.27kg) was added dropwise. After the addition was completed, concentrated nitric acid (780g, concentration was 63-65wt%) was added dropwise to the system. During the addition, the temperature of the system was controlled at 5±5°C. After the addition was completed, the reaction was carried out under stirring for 1.0±0.5h. After the reaction, the obtained product system was washed with purified water, saturated sodium bicarbonate aqueous solution and purified water in sequence, and concentrated under reduced pressure to obtain a crude product 1 of the compound of formula I.

[0112] Anhydrous ethanol (5.0 L) was added to the reaction kettle, and the crude compound of formula I 1 (568 g) was added under stirring. The temperature was raised to 80±5°C and stirring was continued for 30 min; then the temperature was lowered to 5±5°C and filtered, and the filter cake was vacuum dried at -0.075 MPa and 50±5°C for 10±2 h to obtain the crude compound of formula I 2.

[0113] Anhydrous ethanol (1.0 L) was added to the reactor, and the crude product 2 (98 g) of the compound of formula I was added to the reactor under stirring. The temperature was raised to 80±5°C, and all the solids were dissolved. Stirring was continued for 30 min. Then, the temperature was lowered to 5±5°C at a cooling rate of 20°C / h, and stirring was continued for 30 min. The mixture was filtered, and the filter cake was vacuum dried at -0.075 MPa and 50±5°C for 10±2 h to obtain Form A of the compound of formula I (85 g, yield 77.6%) as a white crystalline powder.

[0114] 1 H NMR (400MHz, CDCl3): δ5.23-5.17(m,1H),2.53(t,J=9.0Hz,1H),2.15(d,J=9.7Hz,1H),2.11(s,3H),2.00(dt,J=11.8,3.2Hz,1H),1.97-1.89(m,1 H),1.78(dd,J=14.1,3.3Hz,1H),1.70-1.53(m,7H),1.50-1.35(m,3H),1 .30-1.13(m,6H),0.95(dd,J=12.1,4.8Hz,1H),0.81(m,4H),0.61(s,3H).

[0115] MS: 364.30[M+H] + .

[0116] The XRPD pattern of Form A of the compound of Formula I is as follows: Figure 2 As shown, the DSC spectrum is Figure 3 As shown, the TGA spectrum is Figure 4 shown.

[0117] Figure 5 The particle size distribution diagram of the A crystal form of the compound of formula I (dry method test) shows that the particle size D90 is 377 μm, D50 is 176 μm, and D10 is 41.1 μm.

[0118] The crystal form A of the compound of formula I used in the following test examples were all prepared by the method of Example 1, and the amorphous samples of the compound of formula I were all prepared by the method of Comparative Example 1.

[0119] Test Example 1: Mechanical stability test of crystal form A of the compound of formula I

[0120] This test example carried out a mechanical stability test on the A crystal form of the compound of formula I, and the results are shown in Table 3. It can be seen that the crystal form of the compound of formula I did not change under the mechanical conditions shown in Table 3.

[0121] Table 3 Mechanical stability test results of Form A of the compound of Formula I

[0122] Serial number Mechanical conditions Crystal form 1 Grind in mortar for 30 minutes A crystal form 2 Crushing in mechanical crusher for 30 minutes A crystal form 3 Tablet pressing machine A crystal form

[0123] Test Example 2: Hygroscopicity Analysis of Crystal Form A of Compound of Formula I

[0124] This test example conducts dynamic vapor adsorption analysis on the A crystal form of the compound of formula I, and its DVS spectrum is as follows Figure 6 As shown, it can be seen that the crystal form A of the compound of formula I described in the present invention is almost non-hygroscopic.

[0125] Test Example 3: Solid Stability Test of Crystal Form A of Compound of Formula I

[0126] According to the "Guidelines for Stability Testing of APIs and Preparations" (Chinese Pharmacopoeia 2020 Edition Part IV General Principles 9001), the A crystal form of the compound of formula I prepared in Example 1 was investigated under high temperature (60°C, exposed), high humidity (25°C / 92.5%RH, exposed) and strong light (white light illumination 5500Lx, ultraviolet light illumination 95μW / cm 2 , exposed) conditions, as follows:

[0127] Weigh 15 mg of the A crystal form of the compound of formula I, place it at the bottom of a glass sample bottle, and spread it into a thin layer. The sample placed under high temperature and high humidity conditions is sealed with aluminum foil, and several small holes are punched in the aluminum foil to ensure that the sample can fully contact with the ambient air. The sample placed under strong light conditions is sealed with a threaded bottle cap. The samples placed under different conditions were sampled and tested (XRPD) on the 5th day, 10th day, and 1 month, and the test results were compared with the initial test results on day 0. The experimental results are shown in Table 4. It can be seen that the A crystal form of the compound of formula I has good crystal stability under high temperature, high humidity and strong light conditions.

[0128] Table 4 Solid stability test results of Form A of the compound of Formula I

[0129]

[0130] Test Example 4: X-ray single crystal diffraction analysis of Form A of the compound of Formula I

[0131] This test example conducts X-ray single crystal diffraction detection and analysis on the A crystal form of the compound of formula I. According to the X-ray single crystal diffraction detection and analysis, the product prepared in Example 1 contains one molecule of the compound of formula I in one unit cell. The detected crystal is a colorless block (0.20×0.05×0.05mm 3 ), belongs to the orthorhombic system P212121 space group. Unit cell parameters α=90°, β=90°, γ=90°, Z = 4. Calculated density Dc = 1.248 g / cm 3, the number of electrons in the unit cell F(000) = 792.0, the linear absorption coefficient of the unit cell μ(Cu Kα) = 0.682 mm -1 , the diffraction experiment temperature is T = 150.00 (10) K. The specific crystal data are shown in Table 5. The stereo configuration of each chiral center of this product is confirmed by single crystal diffraction to be 3R, 5S, 8R, 9S, 10S, 13S, 14S, 17S. The molecular structure ellipsoid diagram of the compound of formula I of this product is shown in Figure 7 The atomic coordinates and equivalent isotropic shift parameters are shown in Table 6, the bond lengths are shown in Table 7, the bond angles are shown in Table 8, and the torsion angles are shown in Table 9.

[0132] Table 5 Crystal data of single crystal of compound of formula I

[0133]

[0134]

[0135] Table 6 Atomic coordinates of single crystal of compound of formula I (×10 4 ) and the equivalent isotropic shift parameter

[0136]

[0137]

[0138] Table 7 Bond lengths of single crystals of compounds of formula I

[0139]

[0140] Table 8 Bond angles of single crystals of compounds of formula I

[0141]

[0142]

[0143] Table 9 Torsion angle of single crystal of compound of formula I

[0144]

[0145]

[0146] Test Example 5: Powder Properties of Crystal Form A of Compound of Formula I

[0147] Weigh 50 g of each of the amorphous sample of the compound of formula I and the crystal form A sample of the compound of formula I, respectively, and measure the angle of repose using a repose angle tester; use a tap density tester to measure the bulk density and tap density, and then calculate the Carr index. The specific results are shown in Table 10 and Table 11. It can be seen that the repose angle of the crystal form A of the compound of formula I prepared by the present invention is smaller than that of the amorphous sample, and the Carr index is smaller than that of the amorphous sample, indicating that the crystal form A of the compound of formula I prepared by the present invention has better fluidity than the amorphous form.

[0148] Table 10 Angle of repose of amorphous form and crystal form A of compound of formula I

[0149] Serial number Amorphous / ° A crystal form / ° 1 47.2 39.0 2 47.1 39.0 3 47.4 39.5 average value 47.2 39.2

[0150] Table 11 Carr index of amorphous form and crystal form A of compound of formula I

[0151]

[0152] Test Example 6: Analysis of electrostatic phenomena of crystal form A of the compound of formula I

[0153] Fold the weighing paper in half along the diagonal and place it on the balance pan, weigh 1g of the amorphous sample of the compound of formula I and the crystal form A sample of the compound of formula I, pick up the weighing paper containing the above samples and gently squeeze it in your hand, and then transfer it to the beaker. The amorphous sample of the compound of formula I is fluffy and can be easily squeezed into a cake shape, and there is obvious residue on the weighing paper; the crystal form A sample of the compound of formula I is loose, and there is no cake phenomenon after squeezing, and there is no residue on the weighing paper after transfer. It can be seen that compared with the amorphous sample of the compound of formula I, the crystal form A sample of the compound of formula I is

[0154] The type has no obvious static electricity phenomenon, is easier to transfer, and has better fluidity.

[0155] Test Example 7: GABA of the A-form of the compound of Formula I A Receptor positive regulatory activity assay

[0156] 1. Experimental methods:

[0157] Experiments using transiently expressed GABA A The HEK293 cell line expressing the α4β3δ receptor was used to study the effect of this product (i.e., the A-form sample of the compound of formula I) on GABA A The half-maximal effect concentration (EC 50 ) values. The experiment used a manual patch clamp system HEKAEPC 10 signal amplifier and digital conversion system for whole-cell current recording of GABA A The chloride ion current of the channel was measured under normal room temperature.

[0158] The GABA after each concentration of GABA and the mixture of 3μM of this product A The peak current of α4β3δ receptor was normalized with the current of the mixture of saturated GABA and 3 μM of this product as a control. 化合物 / Peak current 对照 ), and for each concentration ratio the mean, standard deviation, and standard error were calculated.

[0159] Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)×HillSlope))

[0160] The EC of this product was calculated using the above equation 50 The dose-dependent effect was fitted nonlinearly, where EC 50 is the half-maximal effect concentration. EC 50 The calculation and curve fitting were completed using GraphPad Prism software.

[0161] While keeping the experimental scheme and experimental parameters unchanged, the above experiment was repeated with allopregnanolone instead of this product, and the EC of allopregnanolone was calculated by the above equation. 50 The dose-dependent effect was fitted nonlinearly, where EC 50 is the half-maximal effect concentration. EC 50 The calculation and curve fitting were completed using GraphPad Prism software.

[0162] 2. Experimental results:

[0163] Figure 8 A crystal form of the compound of formula I and allopregnanolone to GABA A The half-maximal effect concentration (EC 50 ) comparison diagram, in which compound 1 represents the A crystal form of the compound of formula I, and the relevant data are shown in Table 12. The results show that the A crystal form of the compound of formula I of the present invention has an effect on GABA A The half-maximal effect concentration (EC 50 ) value is 10.514nM, allopregnanolone to GABA A The half-maximal effect concentration (EC 50 ) value is 8.328nM, indicating that this product has an effect on GABA A The receptor has a strong positive regulatory effect, and its activity is close to that of allopregnanolone.

[0164] Table 12 Effects of Form A of the compound of formula I and allopregnanolone on GABA A Half maximal effect concentration of receptor

[0165] project Crystal form A of the compound of formula I (3 μM) Allopregnanolone (3 μM) HillSlope 0.5627 0.2059 <![CDATA[EC 50 ]]> 10.514 8.328

[0166] Test Example 8: Pharmacokinetic study of single intravenous injection and oral administration of Form A of the compound of Formula I to male and female SD rats and repeated oral administration for 7 days

[0167] 1. Experimental purpose: To evaluate the pharmacokinetic behavior of Form A of the compound of formula I after single intravenous injection and oral administration, to examine the bioavailability after oral administration, and to compare the difference between males and females, and to examine whether there is accumulation or induction in rats after 7 consecutive days of oral administration.

[0168] 2. Experimental drugs:

[0169] Preparation of intravenous injection:

[0170] The solvent was a 30% (w / v) aqueous solution of sulfobutyl-β-cyclodextrin (SBE-β-CD) and was prepared according to the following procedure:

[0171] a. Add about 50% volume of purified water to a suitable container and heat to 80-90°C.

[0172] b. When the water temperature reaches the specified value range, turn off the heater and slowly add the required amount of sulfobutyl-β-cyclodextrin into the above container while stirring continuously.

[0173] c. Continue stirring until the temperature drops to room temperature and the solution is visually clear.

[0174] d. Add an appropriate amount of Form A of the compound of formula I to the above solution, and adjust the solution to the final volume with an appropriate amount of pure water.

[0175] e. Continue stirring and ultrasonic mixing at 40°C until a homogeneous, clear solution is formed.

[0176] f. Filter the above solution through a 0.22 μm microporous filter membrane for sterilization and store at room temperature for later use.

[0177] Preparation of oral administration preparations:

[0178] The solvent was sesame oil and was prepared according to the following procedure:

[0179] 1. Weigh an appropriate amount of the test sample into a suitable container and slowly add an appropriate volume of solvent into the container.

[0180] 2. Keep stirring until the preparation is visually uniform.

[0181] 3. Make up the volume to the final volume with the solvent and continue stirring until the preparation is visually uniform.

[0182] Store the prepared preparation in a refrigerator at 2-8°C away from light and use on the same day.

[0183] 3. Research methods and experimental design:

[0184] After the animals (as shown in Table 13) arrive at the animal facility, they will be acclimatized for at least 3 days. At the end of the acclimatization period, a veterinarian or designated personnel will check the health status of the animals to assess whether the animals are suitable for experimental research.

[0185] Table 13 Information about experimental animals

[0186] Species Rat strain SD source Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. Number of Genders 30 rats (15 males and 15 females) Age at the start of the experiment 7-10 weeks old Body weight at the start of the experiment 200-400g (male); 150-300g (female)

[0187] Before the first administration, the animals were divided into 5 groups according to their body weight. The experimental design is summarized in Table 14.

[0188] Table 14 Experimental design of intravenous injection and oral administration of Form A of the compound of Formula I

[0189]

[0190]

[0191] On the first day of the experiment, the animals in group 1 were given a single injection of the drug through the tail vein; the animals in groups 2, 3 and 4 were given a single oral administration of the drug, with a dosage volume of 5 mL / kg; the animals in group 5 were given the drug by oral administration once a day for 7 consecutive days. The animals were weighed before administration, and the dosage volume was calculated based on the body weight.

[0192] 4. Sample collection:

[0193] After each preparation was prepared, two intravenous injection (iv) solutions (upper and bottom layers) and three oral gavage solutions (upper, middle and bottom layers) were collected and analyzed by HPLC-UV to investigate the accuracy of the preparation concentration.

[0194] The sample collection schedule is shown in Table 15.

[0195] Table 15 Sample collection schedule for intravenous injection and oral gavage

[0196]

[0197] Whole blood samples were collected by jugular vein puncture (or other appropriate blood collection sites) at the specified time (about 0.16 mL for Group 1, Group 2, Group 3 and Group 4; about 0.08 mL before administration on the 3rd, 4th, 5th and 6th days of Group 5, and about 0.17 mL before administration on the 7th day and 0.25h, 0.75h, 1.5h, 4h, 6h, 8h, 10h, 12h, 14h, 24h, 36h, 48h after administration), and the actual blood collection time was recorded in the test record. The acceptable error of the collection time point is ±1min within 1h of administration, and ±5% of the theoretical time for other time points.

[0198] All blood samples were transferred to commercial tubes containing K2-EDTA and placed on wet ice. Within 60 min after blood collection, they were centrifuged at 3200×g for 10 min at approximately 4°C, and the supernatant plasma was aspirated, quickly placed in dry ice, and then stored at -60°C or lower for LC-MS / MS analysis.

[0199] 5. Sample analysis and result discussion:

[0200] The concentration of this product in plasma was determined using a validated high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0201] The retention time of compounds and internal standards, chromatogram acquisition and chromatogram integration were processed using the software Analyst (Applied Biosystems), and the statistics of the data were processed using the software Watson LIMS (Thermo Fisher Scientific) or Analyst (SCIEX). The concentration of analytes in the samples was expressed in ng / mL, with 3 significant figures retained, and all values ​​expressed in percentages (such as % deviation and % coefficient of variation, etc.) were retained to one decimal place.

[0202] Table 16 shows the results of intravenous injection and oral gavage. Fig. 9 The average plasma drug concentration-time curves of male and female SD rats after single oral administration of 10 mg / kg, 30 mg / kg and 100 mg / kg of Form A of the compound of Formula I.

[0203] Table 16 Results of intravenous injection and oral gavage

[0204]

[0205]

[0206] Note: a : Bioavailability by AUC 0-last and theoretical dose calculation; --: Not applicable.

[0207] The above results show that after a single intravenous injection of 3 mg / kg of this product in male and female SD rats, the plasma clearance (Cl) was 72.7 mL / min / kg and 38.8 mL / min / kg, respectively, and the steady-state apparent distribution volume (Vd ss ) were 23.0 L / kg and 12.5 L / kg, respectively, and the elimination half-life (T 1 / 2 ) were 13.0h and 10.8h respectively; the area under the plasma concentration-time curve from 0 to the last quantifiable time point (AUC 0-last ) values ​​were 641ng·h / mL and 1220ng·h / mL respectively.

[0208] After a single oral administration of 10mg / kg, 30mg / kg and 100mg / kg of this product to male SD rats, the peak concentration (C max ) were 280ng / mL, 920ng / mL and 1650ng / mL, respectively, and the peak time (T max ) appeared at 5.33h, 4.67h and 4.67h after administration, respectively. AUC 0-last The bioavailability of the drug in the 10 mg / kg oral administration group was 58.0%.

[0209] After a single oral administration of 10mg / kg, 30mg / kg and 100mg / kg of this product to female SD rats, the peak concentration (C max ) were 261ng / mL, 1270ng / mL and 2840ng / mL, respectively, and the peak time (T max ) appeared at 8.00h, 6.67h and 6.67h after administration, respectively. AUC 0-last The bioavailability of the drug in the 10 mg / kg oral administration group was 40.8%.

[0210] The systemic exposure of this product (AUC 0-last ) Except for the 100 mg / kg oral gavage group, there was a gender difference in systemic exposure (AUC 0-last and C0 / C max )There was no significant gender difference.

[0211] As the oral dose increased from 10 mg / kg to 100 mg / kg, the systemic exposure (AUC 0-last With C max ) increases in the same proportion as the dosage.

[0212] After oral administration of 30 mg / kg of this product once a day for 7 consecutive days, the systemic exposure (AUC 0-last With C max ) remained basically unchanged, with no significant accumulation; while the systemic exposure in male SD rats (AUC 0-last With C max ) accumulation, AUC 0-last With C max The accumulation index (day 7 / day 1) was 2.18 and 2.36, respectively.

[0213] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A crystalline form of a neuroactive steroid derivative, wherein the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation include 11.450±0.200°, 15.724±0.200°, 19.040±0.200°, 22.955±0.200° and 24.975±0.200°; The neuroactive steroid derivative has a structure shown in Formula I:

2. The crystalline form of the neuroactive steroid derivative according to claim 1, characterized in that: The characteristic diffraction peaks also include 7.843±0.200°, 9.643±0.200°, 12.338±0.200°, 13.384±0.200°, 14.210±0.200°, 15.032±0.200°, 16.498±0.200°, 17.148±0.200°, 17.802 ±0.200°, 18.739±0.200°, 19.313±0.200°, 19.726±0.200°, 20.276±0.200°, 22.464±0.200°, 23.558±0.200°, 25.897±0.200°, 26.445±0.200°, 26.914 ±0.200°、27.202±0.200°、27.964±0.200°、28.781±0.200°、29.102±0.200°、29.451±0.200°、29.760±0.200°、31.706±0.200°、32.133±0.200°、32.616 ±0.200°, 32.922±0.200°, 33.952±0.200°, 34.662±0.200°, 36.355±0.200°, 36.778±0.200°, 37.511±0.200°, 38.559±0.200° and 39.073±0.200°.

3. The crystalline form of the neuroactive steroid derivative according to claim 1 or 2, characterized in that: The X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.843±0.200°, 11.450±0.200°, 15.724±0.200°, 18.739±0.200°, 19.040±0.200°, 19.726±0.200°, 22.955±0.200° and 24.975±0.200°.

4. The crystalline form of the neuroactive steroid derivative according to claim 1 or 2, characterized in that: The X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.843±0.200°, 11.450±0.200°, 13.384±0.200°, 15.724±0.200°, 16.498±0.200°, 17.148±0.200°, 18.739±0.200°, 19.040±0.200°, 19.726±0.200°, 20.276±0.200°, 22.955±0.200°, 23.558±0.200°, 24.975±0.200°, 28.781±0.200° and 29.102±0.200°.

5. The crystalline form of the neuroactive steroid derivative according to claim 1 or 2, characterized in that: The differential scanning calorimetry spectrum of the crystal form of the neuroactive steroid derivative has an endothermic peak at 139.9°C±3°C; the differential scanning calorimetry spectrum of the crystal form of the neuroactive steroid derivative has an onset value of the endothermic peak at 138.5°C±3°C.

6. The crystalline form of the neuroactive steroid derivative according to claim 1 or 2, characterized in that: The thermogravimetric analysis spectrum of the crystal form of the neuroactive steroid derivative shows a weight loss of ±0.5% at 159.4°C±3°C.

7. The crystalline form of the neuroactive steroid derivative according to claim 1 or 2, characterized in that: The crystal form of the neuroactive steroid derivative is an orthorhombic system, the space group is P212121; the unit cell parameters are: α=90°,β=90°,γ=90°;the unit cell volume is Z=4.

8. The crystalline form of the neuroactive steroid derivative according to claim 1 or 2, characterized in that: The particle size D90 of the crystal form of the neuroactive steroid derivative is 240-530 μm, D50 is 105-270 μm, and D10 is 20-65 μm.

9. Use of the crystalline form of the neuroactive steroid derivative according to any one of claims 1 to 8 in the preparation of a drug for treating mood disorders, mental illnesses, neurodegenerative diseases or neuropathic pain.

10. The use according to claim 9, characterized in that: The emotional disorders include generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder, premenstrual dysphoric disorder, major depression or postpartum depression; the psychiatric diseases include epilepsy, convulsions or insomnia; the neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis or Niemann-Pick type C disease; the neuropathic pain includes menstrual and postmenopausal migraine, diabetic peripheral neuropathy, chemotherapy pain or sciatica.

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