Crystal form of neuroactive steroid derivative and use thereof

Abstract

The present invention belongs to the technical field of medicine. Provided are a crystal form of a neuroactive steroid derivative and the use thereof. For the crystal form of the neuroactive steroid derivative (having a structure represented by formula (I)), the characteristic diffraction peaks in an X-ray powder diffraction pattern expressed as 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 crystal form has good flowability, no electrostatic phenomenon, high stability, and almost no hygroscopicity, and remains stable under high temperature, high humidity and light exposure conditions. The crystal form has a strong positive modulatory effect on a GABAA receptor, and has favorable pharmacokinetic properties and a favorable oral absorption rate. Therefore, the crystal form can be applied in the preparation of oral and other dosage forms of drugs with a high efficacy against diseases such as postpartum depression.

Description

Crystal form of a neuroactive steroid derivative and its application

[0001] This application claims priority to Chinese Patent Application No. CN202411536243.7, filed on October 31, 2024, entitled "A Crystal Form of a Neuroactive Steroid Derivative and Its Application", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This application relates to the field of pharmaceutical technology, and in particular to a crystal form of a neuroactive steroid derivative and its applications. Background Technology

[0003] Allogenein is an endogenous neuroactive steroid (NAS) synthesized in the brain from progesterone. NAS primarily interacts with γ-aminobutyric acid type A receptors (GABA). A NAS (receptor-mediated ion channel interaction) can rapidly influence neuronal excitability. NAS can act as receptors for both synaptic and extrasynaptic GABA. A Positive allosteric modulators (PAMs) of receptors activate and enhance phasic and tonic currents, respectively, ultimately enhancing GABA. A Receptor-mediated tonic inhibitory currents. Unlike other NASs, allogeneinolone can activate GABA containing both α and β subunits. A The receptor can also regulate GABA containing γ and δ subunits. A Receptors.

[0004] Brexanolone is an endogenous neuroactive steroid, CAS Registry No. 516-54-1. On March 19, 2019, the U.S. FDA approved brexanolone (brand name Zulresso) injection for the treatment of postpartum depression in adult women. This was the first drug specifically for postpartum depression (PPD) that enhances the expression of recombinant GABA. A The receptor is a GABA-mediated current in mammalian cells. However, brinolone is administered via continuous intravenous infusion for more than 60 hours. During the two and a half days of brinol infusion, medical personnel must be on-site to continuously monitor the patient, making it inconvenient to use.

[0005] The neuroactive steroid derivative having the structure shown in Formula I is a 3-hydroxynitrate of brinolone, while retaining GABA. A It has high oral bioavailability based on receptor activity, which can avoid the inconvenience to patients caused by prolonged intravenous infusion.

[0006] However, the neuroactive steroid derivatives with the structure shown in Formula I in the related technologies have poor flowability, which causes inconvenience for weighing, transporting and using the products. Summary of the Invention

[0007] The purpose of this application is to provide a crystal form of a neuroactive steroid derivative and its application. The crystal form of the neuroactive steroid derivative provided in this application has good fluidity, making the weighing, transportation and use of the product more convenient.

[0008] To achieve the above-mentioned objectives, this application provides the following technical solution:

[0009] This application provides a crystal form of a neuroactive steroid derivative. 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°.

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

[0011] Preferably, the characteristic diffraction peaks further include those with 2θ angles of 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°, and 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 0.914±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°, 32.6 One or more of the following: 16±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°.

[0012] 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°.

[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°, 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°.

[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°, 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°.

[0015] 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°, 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°

[0016] Preferably, the 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°.

[0017] Preferably, the differential scanning calorimetry spectrum of the crystal form of the neuroactive steroid derivative has an endothermic peak at 139.9℃±3℃; the starting value of the absorption peak is 138.5℃±3℃.

[0018] Preferably, the thermogravimetric analysis (TGA) spectrum of the crystal form of the neuroactive steroid derivative shows a weight loss of ±0.5% at 159.4℃±3℃.

[0019] Preferably, the neuroactive steroid derivative has an orthorhombic crystal system with space group P212121; the unit cell parameters are: α = 90°, β = 90°, γ = 90°; unit cell volume is Z = 4.

[0020] Preferably, the crystal form of the neuroactive steroid derivative has a particle size D90 of 240–530 μm, a D50 of 105–270 μm, and a D10 of 20–65 μm.

[0021] Preferably, the crystal form of the neuroactive steroid derivative has a repose angle of 39.2° and a Cartesian index of 14%.

[0022] This application 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 illnesses, neurodegenerative diseases, or neuropathic pain.

[0023] Preferably, the mood disorder includes generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder, premenstrual anxiety disorder, major depressive disorder, or postpartum depression.

[0024] Preferably, the mental illness includes epilepsy, seizures, or insomnia.

[0025] Preferably, the neurodegenerative disease includes Alzheimer's disease, Parkinson's disease, multiple sclerosis, or Niemann-Pick disease type C.

[0026] Preferably, the neuropathic pain includes menstrual and postmenopausal migraines, diabetic peripheral neuropathy, chemotherapy pain, or sciatica.

[0027] Preferably, the drug comprises an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient is a crystal form of the neuroactive steroid derivative; and the pharmaceutically acceptable carrier is a solid carrier or a liquid carrier.

[0028] Preferably, the solid carrier comprises one or more of the following: cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, astragalus gum, gum arabic, sodium alginate, parabens, methylcellulose, sodium carboxymethyl cellulose, low-melting-point wax, and cocoa butter.

[0029] Preferably, the liquid carrier comprises one or more of water, ethanol, polyol, vegetable oil, glycerol ester, agar, pyrogen-free water, isotonic saline, and Ringer's solution.

[0030] Preferably, the polyol includes one or more of glycerol, propylene glycol, and liquid polyethylene glycol; the vegetable oil includes one or more of peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil.

[0031] Preferably, the drug is administered orally, intrapulmonaryly, intranasally, or transdermally.

[0032] Preferably, the dosage form of the drug includes tablets, lozenges, lozenges, suspensions, dispersible powders, dispersible granules, emulsions, hard capsules, soft capsules, syrups, elixirs, solutions, sprays, aerosols or dry powder preparations, nasal drops or nasal sprays.

[0033] This application provides a crystal form (denoted as crystal form A) of a neuroactive steroid derivative (having the structure shown in Formula I, denoted as Compound I). Using Cu-Kα radiation, the characteristic diffraction peaks in the X-ray powder diffraction pattern, expressed at an angle of 2θ, include 11.450±0.200°, 15.724±0.200°, 19.040±0.200°, 22.955±0.200°, and 24.975±0.200°. Compared to the amorphous form of Compound I, the crystal form A of Compound I has a smaller angle of repose and Karl elliptic index, indicating that the crystal form A of Compound I has better flowability, making the weighing, transfer, and use of the product more convenient, such as effectively shortening the mixing time with excipients.

[0034] Furthermore, the A-crystal form of the compound of formula I provided in this application exhibits no electrostatic phenomena, high stability, and almost no hygroscopicity. It remains stable under high temperature, high humidity, and light conditions without significant degradation, meeting the requirements for storage and subsequent processing. This avoids the risk of crystal transformation during storage and processing, which could alter the quality of the pharmaceutical preparation and consequently affect clinical efficacy. The A-crystal form of the compound of formula I provided in this application is also effective against GABA. A The receptor has a strong positive regulatory effect and good pharmacokinetic (PK) properties and oral absorption rate, and can be used to prepare highly effective oral dosage forms of drugs for treating postpartum depression and other diseases. Attached Figure Description

[0035] Figure 1 shows the amorphous X-ray powder diffraction (XRPD) pattern of compound I in the comparative example of this application;

[0036] Figure 2 is the XRPD pattern of the A crystal form of the compound of formula I in the embodiments of this application;

[0037] Figure 3 is a differential scanning calorimetry (DSC) spectrum of crystal form A of compound I in the embodiments of this application;

[0038] Figure 4 shows the thermogravimetric analysis (TGA) spectrum of the A crystal form of the compound of formula I in the embodiments of this application;

[0039] Figure 5 is a particle size distribution diagram of the A crystal form of the compound of formula I in the embodiments of this application;

[0040] Figure 6 shows the dynamic vapor adsorption analysis (DVS) spectrum of the A crystal form of the compound of formula I in the embodiments of this application;

[0041] Figure 7 is a stereoscopic ellipsoidal diagram of the compound of formula I;

[0042] Figure 8 shows the crystal form A of compound I in the embodiments of this application and the effect of allogeneic acid on GABA. A Comparison of receptor half-maximal effector concentrations;

[0043] Figure 9 shows the mean plasma drug concentration-time curves after a single oral gavage administration of 10 mg / kg, 30 mg / kg, and 100 mg / kg of the A crystal form of compound I to male and female SD rats in the test cases of this application. Detailed Implementation

[0044] This application provides a crystal form of a neuroactive steroid derivative. 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°.

[0045] The neuroactive steroid derivative has the structure shown in Formula I:

[0046] In embodiments of this application, the characteristic diffraction peaks may further include those with 2θ angles of 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°, and 17.148±0. 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 One or more of the following: 0.616±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°.

[0047] In the embodiments of this application, the crystal form of the neuroactive steroid derivative was obtained by Cu-Kα irradiation, and the resulting X-ray powder diffraction pattern had 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°.

[0048] In the embodiments of this application, the crystal form of the neuroactive steroid derivative was determined using Cu-Kα radiation, and the resulting X-ray powder diffraction pattern exhibited 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°, and 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°.

[0049] In the embodiments of this application, the crystal form of the neuroactive steroid derivative was determined using Cu-Kα radiation, and the resulting X-ray powder diffraction pattern exhibited 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°.

[0050] In the embodiments of this application, the crystal form of the neuroactive steroid derivative was determined using Cu-Kα radiation, and the resulting X-ray powder diffraction pattern exhibited 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°.

[0051] In the embodiments of this application, the crystal form of the neuroactive steroid derivative was determined using Cu-Kα radiation, and the resulting X-ray powder diffraction pattern exhibited 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°, and 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°.

[0052] In the embodiments of this application, the crystal form of the neuroactive steroid derivative was determined using Cu-Kα radiation, and the resulting X-ray powder diffraction pattern is shown in Figure 2, with an error within ±0.20°. In this application, the analytical data corresponding to Figure 2 are shown in Table 1.

[0053] Table 1. XRPD spectrum analysis data of crystal form A of compound I.

[0054] In the embodiments of this application, the differential scanning calorimetry (DSC) spectrum of the crystal form of the neuroactive steroid derivative specifically has an endothermic peak at 139.9℃±3℃; the DSC spectrum of the crystal form of the neuroactive steroid derivative specifically has the initial value of the endothermic peak at 138.5℃±3℃. In the embodiments of this application, the DSC spectrum of the crystal form of the neuroactive steroid derivative is shown in Figure 3 (unless otherwise specified, the exothermic peak in the DSC spectrum faces upward), wherein the initial temperature is 40.0℃, the heating rate is 10.00℃ / min, the holding temperature is 170.0℃, and the holding time is 0min; the endothermic peak is at 139.93℃, the extrapolation start point is at 138.52℃, and the extrapolation end point is at 142.49℃; the heat is -72.03J / g.

[0055] In the embodiments of this application, the thermogravimetric analysis (TGA) spectrum of the crystal form of the neuroactive steroid derivative shows a weight loss of ±0.5% at 159.4℃±3℃, specifically -0.1%. In the embodiments of this application, the TGA spectrum of the crystal form of the neuroactive steroid derivative is shown in Figure 4, where the heating rate is 10.00℃ / min, the holding temperature is 300.0℃, and the holding time is 0 min; the initial point time is 7.62 min at 90.00℃; the final point time is 14.62 min at 160.00℃; the midpoint time is 0.00 min at 0.00℃; the extrapolated initial point temperature is 90.08℃, and the extrapolated final point temperature is 159.39℃; the weight loss is -0.100%.

[0056] In the embodiments of this application, the crystal form of the neuroactive steroid derivative is specifically orthorhombic, and the space group is specifically P212121; the cell parameters are specifically: α = 90°, β = 90°, γ = 90°; the specific unit cell volume is... Z = 4. In this application, the relevant crystal data of the neuroactive steroid derivative are detailed in Table 5 of the test examples, the atomic coordinates and equivalent isotropic shift parameters are detailed in Table 6 of the test examples, the bond lengths are detailed in Table 7 of the test examples, the bond angles are detailed in Table 8 of the test examples, and the torsion angles are detailed in Table 9 of the test examples, and will not be repeated here.

[0057] In the embodiments of this application, the crystal form of the neuroactive steroid derivative has a particle size D90 of 240–530 μm, a D50 of 105–270 μm, and a D10 of 20–65 μm; specifically, the crystal form of the neuroactive steroid derivative has a particle size D90 of 240–380 μm, a D50 of 105–180 μm, and a D10 of 20–45 μm.

[0058] In the embodiments of this application, the crystal form of the neuroactive steroid derivative has a repose angle of 39.2° and a Cartesian index of 14%, indicating that it has good fluidity.

[0059] This application provides a method for preparing the crystal form of the neuroactive steroid derivative described in the above technical solution, comprising the following steps:

[0060] A neuroactive steroid derivative having the structure shown in Formula I was mixed with an organic solvent and heated to dissolve, resulting in a solution.

[0061] The solution was cooled to 0-10°C at a rate of 18-22°C / h, and crystallized by maintaining the temperature. After solid-liquid separation and solid drying, the crystal form of the neuroactive steroid derivative was obtained.

[0062] Unless otherwise specified, all raw materials and reagents used in this application are commercially available products known to those skilled in the art or prepared using methods known to those skilled in the art; the organic solvents used are commercially available products and can be used without further purification.

[0063] This application involves mixing a neuroactive steroid derivative having the structure shown in Formula I (i.e., the compound of Formula I) with an organic solvent and heating it to dissolve, thereby obtaining a solution. As an embodiment of this application, the organic solvent may include anhydrous ethanol, ethyl acetate, acetone, n-heptane, methyl tert-butyl ether, or dimethyl sulfoxide, specifically anhydrous ethanol. As an embodiment of this application, the ratio of the compound of Formula I to the organic solvent may be 98g:0.8–1.2L, specifically 98g:0.9–1L. As an embodiment of this application, the heating and dissolving temperature may be 50–110°C, specifically selected according to the type of organic solvent. For example, when the organic solvent is anhydrous ethanol, the heating and dissolving temperature may be 75–85°C, specifically 78–80°C; when the organic solvents are ethyl acetate, acetone, n-heptane, methyl tert-butyl ether, and dimethyl sulfoxide, the heating and dissolving temperatures may be 70–80°C, 50–60°C, 90–100°C, 50–60°C, and 100–110°C, respectively. The heating and dissolving process described in this application can be carried out under stirring conditions; after heating and dissolving, stirring can continue for 25 to 35 minutes (specifically 28 to 30 minutes) to obtain a solution.

[0064] After obtaining the solution, this application cools the solution to 0-10°C at a rate of 18-22°C / h, maintains the temperature for crystallization, and then separates the solid and dries the solid to obtain the crystal form of the neuroactive steroid derivative. In this application, the cooling rate during the cooling and crystallization process is 18-22°C / h, specifically 19-20°C / h; the cooling is stopped when the temperature reaches 0-10°C (specifically 3-5°C), and the crystallization is maintained for crystallization. After solid-liquid separation and solid drying, the crystal form of the neuroactive steroid derivative (i.e., crystal form A of compound I) is obtained. As an embodiment of this application, the crystallization time can be 25-35 min, specifically 28-30 min; the crystallization can be carried out under stirring conditions. As an embodiment of this application, the solid-liquid separation method can be filtration. As one embodiment of this application, the solid drying can be performed by vacuum drying of the solid obtained from 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; and the time can be 8 to 12 hours, specifically 9 to 10 hours. Specifically, the A crystal form of the compound of formula I described in this application is a white crystalline powder.

[0065] This application provides the use of the crystal form of the neuroactive steroid derivative described in the above-described technical solution or the crystal form of the neuroactive steroid derivative prepared by the preparation method described in the above-described technical solution in the preparation of drugs for mood disorders, mental illnesses, neurodegenerative diseases, or neuropathic pain. As an embodiment of this application, the mood disorder may include generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder, premenstrual anxiety disorder, major depressive disorder, or postpartum depression; the mental illness may include epilepsy, seizures, or insomnia; the neurodegenerative disease may include Alzheimer's disease, Parkinson's disease, multiple sclerosis, or Niemann-Pick disease C; the neuropathic pain may include menstrual and postmenopausal migraines, diabetic peripheral neuropathy, chemotherapy pain, or sciatica.

[0066] In this application, the drug specifically includes an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient is the crystalline form of the neuroactive steroid derivative described in the above-mentioned technical solution. As an embodiment of this application, the pharmaceutically acceptable carrier can be a solid carrier or a liquid carrier; the solid carrier includes, but is not limited to, one or more of cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, astragalus gum, gum arabic, sodium alginate, parabens, methylcellulose, sodium carboxymethyl cellulose, low-melting-point waxes, and cocoa butter; the liquid carrier includes, but is not limited to, one or more of water, ethanol, polyols (e.g., one or more of glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils (e.g., one or more of peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycerides, agar, pyrogen-free water, isotonic saline, and Ringer's solution.

[0067] In this application, the dosage form of the drug may include tablets, lozenges, lozenges, suspensions (e.g., aqueous 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 route of administration of the drug may include oral, intrapulmonary, intranasal, or transdermal administration.

[0068] The A crystal form of the compound of formula I provided in this application can serve as synaptic and extrasynaptic GABA. A Positive allosteric modulators (PAMs) of receptors 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 described in this application exhibits good pharmacokinetic (PK) properties and oral absorption rate, and can be used to treat postpartum depression and other diseases. The A crystal form of the compound of formula I described in this application is stable, virtually non-hygroscopic, and minimally affected by light and heat, making it less prone to moisture absorption and deterioration during formulation, resulting in a longer drug shelf life.

[0069] The technical solutions of this application will be clearly and completely described below with reference to the embodiments therein. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this application without creative effort are within the scope of protection of this application.

[0070] The following test methods are some of the test methods involved in the test examples of this application:

[0071] 1. X-ray powder diffractometer (XRPD) method

[0072] Instrument model: Empyrean X-ray diffractometer;

[0073] Test method: Approximately 10–20 mg of sample is used for XRPD detection;

[0074] XRPD detection parameters include:

[0075] Optical tube: Cu, Kα,

[0076] Phototube voltage: 45kV;

[0077] Phototube current: 40mA;

[0078] Diverging slit: 1 / 8°;

[0079] Detector slit: 7.5mm;

[0080] Anti-scattering slit: 1 / 4°;

[0081] Scanning range: 3–40°;

[0082] Step size: 0.0263°;

[0083] Scan time: 46.665s.

[0084] 2. Differential Scanning Calorimeter (DSC) method

[0085] Instrument model: Shimadzu DSC-60Plus Differential Scanning Calorimeter;

[0086] Test method: Take a sample (2-5 mg) and place it in a covered aluminum crucible. Test under the protection of dry nitrogen at 50 mL / min. The method is as follows: heat from 40℃ to the set test temperature at a heating rate of 10℃ / min.

[0087] 3. Thermogravimetric Analysis (TGA) Method

[0088] Instrument model: TGA-50M Shimadzu thermogravimetric analyzer;

[0089] Test method: Take a sample (2-5 mg) and place it in an alumina crucible. Test it under the protection of dry nitrogen at 50 mL / min. The method is: room temperature to 350℃, heating rate is 10℃ / min.

[0090] 4. Dynamic Vapor Sorption (DVS) Method

[0091] Instrument model: Quantachrome dynamic vapor adsorption instrument;

[0092] Test method: Place the sample (10-15 mg) in the DVS sample tray for testing;

[0093] DVS test parameters include:

[0094] Temperature: 25℃;

[0095] Equilibrium: dm / dt = 0.002% / min (shortest: 10min, longest: 180min);

[0096] Drying: Dry at 0% RH for 120 min;

[0097] RH (%) test steps:

[0098] 10% (0%RH~90%RH, 90%RH~0%RH);

[0099] 5% (90%RH~95%RH, 95%RH~90%RH);

[0100] RH (%) test range: 0% to 95%;

[0101] The classification of hygroscopicity is shown in Table 2:

[0102] Table 2 Classification of Hygroscopicity Evaluation Note: ΔW% represents the moisture gain of the test sample at 25±1℃ and 80±2%RH.

[0103] 5. X-ray single crystal diffraction method

[0104] Instrument model: Rigaku Oxford Diffraction XtaLAB Synergy-S single crystal X-ray diffractometer;

[0105] Test method: The test was conducted directly using the provided sample;

[0106] Detector: HyPix-6000HE area detector;

[0107] Cryogenic system: Oxford Cryostream 800;

[0108] Light source: Cu: 50W;

[0109] Distance from crystal to detector: d = 35 mm;

[0110] Phototube voltage: 50kV;

[0111] Phototube current: 1mA.

[0112] Comparative Example 1: Amorphous sample of compound I (preparative formula)

[0113] Dichloromethane (DCM, 42 mL) was added to a 250 mL three-necked flask, and allogeneic ketone (2.0 g) was added under stirring. The temperature of the resulting mixture was then lowered to -10 °C, and acetic anhydride (Ac₂O, 18 mL) was added dropwise. After the addition was complete, concentrated nitric acid (4 mL, concentration 63–65 wt%) was added dropwise to the system while maintaining the temperature at -10 °C. After the addition was complete, the reaction was stirred at -10 °C for 3 h. After the reaction was complete, the reaction solution was washed successively with purified water, saturated sodium bicarbonate aqueous solution, and purified water. The crude product was concentrated under reduced pressure and separated by column chromatography (the eluent used was ethyl acetate and petroleum ether, with a volume ratio of 1:10) to obtain an amorphous sample of compound I (1.9 g, yield 83.2%), an off-white solid.

[0114] The amorphous XRPD spectrum of compound I is shown in Figure 1.

[0115] Example 1: Preparation of the A-type crystal form of compound I

[0116] Dichloromethane (DCM, 5.0 L) was added to the reaction vessel, and allogeneic ketone (490 g) was added under stirring. The temperature of the resulting mixture was then lowered to 5 ± 5 °C, and acetic anhydride (Ac2O, 1.27 kg) was added dropwise. After the addition was complete, concentrated nitric acid (780 g, concentration 63–65 wt%) was added dropwise to the system. The temperature of the system was controlled at 5 ± 5 °C during the addition. After the addition was complete, the reaction was carried out under stirring for 1.0 ± 0.5 h. After the reaction, the resulting product system was washed successively with purified water, saturated sodium bicarbonate aqueous solution, and purified water. After concentration under reduced pressure, crude product 1 of formula I was obtained.

[0117] Anhydrous ethanol (5.0 L) was added to the reaction vessel, and crude product 1 (568 g) of compound I was added under stirring. The temperature was raised to 80±5℃ and stirring was continued for 30 min. Then the temperature was lowered to 5±5℃ and filtered. The filter cake was vacuum dried at -0.075 MPa and 50±5℃ for 10±2 h to obtain crude product 2 of compound I.

[0118] Anhydrous ethanol (1.0 L) was added to the reaction vessel, and crude product 2 (98 g) of compound I was added to the reaction vessel under stirring. The temperature was raised to 80±5 °C, and the solid was completely 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 crystal form A of compound I (85 g, yield 77.6%), a white crystalline powder.

[0119] 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).

[0120] MS: 364.30 [M+H] + .

[0121] The XRPD spectrum of the A crystal form of compound I is shown in Figure 2, the DSC spectrum is shown in Figure 3, and the TGA spectrum is shown in Figure 4.

[0122] Figure 5 shows the particle size distribution of the A crystal form of compound I (dry method test). The results show that its particle size D90 is 377 μm, D50 is 176 μm, and D10 is 41.1 μm.

[0123] In the following test examples, the A crystal form of the Formula I compound was prepared using the method of Example 1, and the amorphous samples of the Formula I compound were prepared using the method of Comparative Example 1.

[0124] Test Example 1: Mechanical stability test of crystal form A of compound I

[0125] This test example focuses on the mechanical stability of compound A of formula I, and the results are shown in Table 3. It can be seen that the crystal form of compound I remains unchanged under the mechanical conditions shown in Table 3.

[0126] Table 3 shows the mechanical stability test results of crystal form A of compound I.

[0127] Test Example 2: Hygroscopicity Analysis of Crystal Form A of Compound I

[0128] This test example focuses on dynamic vapor adsorption analysis of the A crystal form of compound I. The DVS spectrum is shown in Figure 6. It can be seen that the A crystal form of compound I described in this application is almost non-hygroscopic.

[0129] Test Example 3: Solid stability test of crystal form A of compound I

[0130] According to the "Guidelines for Stability Testing of Active Pharmaceutical Ingredients and Preparations" (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 9001), the A crystal form of the compound of formula I prepared in Example 1 was investigated under high temperature (60°C, exposed to the elements), high humidity (25°C / 92.5% RH, exposed to the elements), and strong light (white light illuminance 5500 Lx, ultraviolet light illuminance 95 μW / cm²). 2 The stability under (exposed) conditions is as follows:

[0131] Weigh 15 mg of crystal form A of compound I and place it at the bottom of a glass sample vial, spreading it into a thin layer. For samples placed under high temperature and high humidity conditions, seal the vial opening with aluminum foil, making several small holes in the foil to ensure sufficient contact between the sample and ambient air. For samples placed under strong light conditions, seal the vial with a screw cap. Samples placed under different conditions were sampled and analyzed on day 5, day 10, and month 1 (XRPD). The results were compared with the initial results from day 0. The experimental results are shown in Table 4. This indicates that crystal form A of compound I exhibits good crystal stability under high temperature, high humidity, and strong light conditions.

[0132] Table 4 shows the solid stability test results of crystal form A of compound I.

[0133] Test Example 4: X-ray single-crystal diffraction analysis of crystal form A of compound I

[0134] This test example focuses on X-ray single-crystal diffraction analysis of crystal form A of compound I. The analysis revealed that one unit cell in the product prepared in Example 1 contains one molecule of compound I. The tested crystal was a colorless, blocky substance (0.20 × 0.05 × 0.05 mm). 3 It belongs to the orthorhombic crystal system, space group P212121. Cell parameters... α=90°, β=90°, γ=90°, Z = 4. Calculate the density Dc = 1.248 g / cm³. 3 The number of electrons in the unit cell F(000) = 792.0, and the linear absorption coefficient of the unit cell μ(Cu Kα) = 0.682 mm. -1The diffraction experiment temperature was T = 150.00(10) K. Specific crystal data are shown in Table 5. Single-crystal diffraction confirmed the stereoconfiguration of each chiral center of this product as 3R, 5S, 8R, 9S, 10S, 13S, 14S, and 17S. The molecular structure ellipsoid diagram of this compound of formula I 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.

[0135] Table 5. Crystal data of single crystals of compound I.

[0136] Table 6. Atomic coordinates of single crystals of compound I (×10⁻¹⁰) 4 and equivalent isotropic shift parameters

[0137] Table 7 Bond lengths of single crystals of compound I

[0138] Table 8 shows the bond angles of single crystals of compound I.

[0139] Table 9. Twist angles of single crystals of compound I.

[0140] Test Example 5: Powder properties of crystal form A of compound I

[0141] 50g each of the amorphous sample and the A-crystal sample of Formula I were weighed, and their angles of repose were measured using an angle of repose meter. Their bulk density and tap density were measured using a tap density meter, and their Karl elliptic index was calculated. The specific results are shown in Tables 10 and 11. It can be seen that the angle of repose of the A-crystal sample of Formula I prepared in this application is smaller than that of the amorphous sample, and the Karl elliptic index is also smaller, indicating that the A-crystal sample of Formula I prepared in this application has better flowability compared to the amorphous sample.

[0142] Table 10 Angles of repose for amorphous and A-type compounds of Formula I.

[0143] Table 11 Karl Fischer indexes for amorphous and A-type compounds of Formula I

[0144] Test Example 6: Electrostatic Analysis of Crystal Form A of Compound I

[0145] Fold weighing paper diagonally and place it on the balance pan. Weigh 1g each of the amorphous sample of compound I and the A-crystal sample of compound I. Pick up the weighing paper containing the samples and gently squeeze it in your hand, then transfer it to a beaker. The amorphous sample of compound I is fluffy and easily squeezed into a cake shape, leaving obvious residue on the weighing paper; the A-crystal sample of compound I is loose, does not form a cake shape after squeezing, and leaves no residue on the weighing paper after transfer. Therefore, compared to the amorphous sample of compound I, the A-crystal sample of compound I has no obvious electrostatic phenomenon, is easier to transfer, and has better fluidity.

[0146] Test Example 7: GABA in crystal form A of compound I A Assay of receptor positive regulatory activity

[0147] 1. Experimental Method:

[0148] The experiment used transient expression of GABA A The HEK293 cell line, containing the (α4β3δ) receptor, was used to study the effect of this product (i.e., the A crystal form sample of compound I) on GABA. A The role of (α4β3δ) receptors, testing the half-maximal effective concentration (EC50) of compounds. 50 Numerical values. Whole-cell current recordings were performed using a manual patch-clamp system (HEKAEPC 10), a signal amplifier, and a digital conversion system. A The chloride ion current in the channel was determined, and all experiments were conducted under normal room temperature conditions.

[0149] The GABA obtained by reacting each concentration of GABA with a 3μM solution of this product A The (α4β3δ) receptor current and the current of a mixture of saturated GABA and this product at 3 μM were standardized (Peak current). 化合物 / Peak current 对照 ), and calculate the mean, standard deviation, and standard error for each concentration ratio. Y = Bottom + (Top - Bottom) / (1 + 10^(LogEC) 50 -X)×HillSlope))

[0150] The EC of this product can be calculated using the above equation. 50 The values ​​were calculated, and a nonlinear fit was performed on the dose-dependent effect, where EC 50 This is the half-maximal effect concentration. EC 50 The calculations and curve fitting were performed using GraphPadPrism software.

[0151] While keeping the experimental protocol and parameters unchanged, the above experiment was repeated using allogeneic ketone instead of this product. The EC50 of allogeneic ketone was calculated using the above equation.50 The values ​​were calculated, and a nonlinear fit was performed on the dose-dependent effect, where EC 50 This is the half-maximal effect concentration. EC 50 The calculations and curve fitting were performed using GraphPadPrism software.

[0152] 2. Experimental Results:

[0153] Figure 8 shows the A crystal form of compound I and the effect of allogeneic acid on GABA. A half-maximal effect concentration of receptor (EC50) 50 The comparison diagram shows that compound 1 represents crystal form A of compound I, and the relevant data are shown in Table 12. The results show that crystal form A of compound I in this application is related to GABA. A half-maximal effect concentration of receptor (EC50) 50 The value was 10.514 nM, indicating that allogeneic ketones have a positive effect on GABA. A half-maximal effect concentration of receptor (EC50) 50 The value is 8.328 nM, indicating that this product is effective against GABA. A The receptor has a strong positive regulatory effect, and its activity is close to that of allogeneic alcoholone.

[0154] Table 12 shows the crystal form A of compound I and the effect of allogeneic ketone on GABA. A half-maximal effect concentration of receptor

[0155] Test Example 8: Pharmacokinetic Study of Compound I Crystal Form A After Single Intravenous Booster and Gavage Administration in Male and Female SD Rats and Repeated Gavage Administration for 7 Days

[0156] 1. Experimental objective: To evaluate the pharmacokinetic behavior of compound A crystal form after single intravenous injection and gavage administration, to investigate the bioavailability after gavage administration, to compare the differences between male and female rats, and to investigate whether there is accumulation or induction in rats after continuous gavage administration for 7 days.

[0157] 2. Experimental drugs:

[0158] Preparation of intravenous bolus injection formulations:

[0159] The solvent is a 30% (w / v) aqueous solution of sulfonyl-β-cyclodextrin (SBE-β-CD), and it is prepared according to the following procedure:

[0160] a. Add approximately 50% of the volume of purified water to a suitable container and heat to 80–90°C.

[0161] b. When the water temperature reaches the specified range, turn off the heater, slowly add the required amount of sulfobutyl-β-cyclodextrin to the above container while stirring continuously.

[0162] c. Continue stirring until the temperature drops to room temperature and the solution appears clear to the naked eye.

[0163] d. Add an appropriate amount of crystal form A of compound I to the above solution, and dilute the solution to the final volume with an appropriate amount of pure water.

[0164] e. Stir and sonicate continuously at 40°C until a homogeneous, clear solution is formed.

[0165] f. Filter the above solution through a 0.22 μm microporous membrane to remove bacteria, and store at room temperature for later use.

[0166] Preparation of oral administration formulations:

[0167] The solvent is sesame oil, and the mixture is prepared according to the following procedure:

[0168] 1. Weigh an appropriate amount of the test sample into a suitable container and slowly add an appropriate volume of solvent into the container.

[0169] 2. Stir continuously until the preparation appears to be homogeneous.

[0170] 3. Add solvent to bring the volume to the final volume, stirring constantly until the mixture appears to be a homogeneous formulation.

[0171] Store the prepared formulation in a refrigerator at 2–8°C, away from light, and use it on the same day.

[0172] 3. Research Methods and Experimental Design:

[0173] After arriving at the animal facility, the animals (as shown in Table 13) will undergo at least 3 days of acclimatization. At the end of the acclimatization period, a veterinarian or designated personnel will check the animals’ health status to assess whether the animals are suitable for experimental research.

[0174] Table 13 Information related to experimental animals

[0175] Before the first administration, the animals were divided into 5 groups according to their body weight. The experimental design is summarized in Table 14.

[0176] Table 14 shows the intravenous bolus and gavage administration designs for crystal form A of compound I.

[0177] On day 1 of the experiment, animals in group 1 were given a single injection via tail vein; animals in groups 2, 3, and 4 were given a single gavage dose of 5 mL / kg; animals in group 5 were given the drug once daily for 7 consecutive days via gavage. Animals were weighed before administration, and the dosage was calculated based on their body weight.

[0178] 4. Sample collection:

[0179] After each formulation was prepared, two intravenous bolus (iv) administration solutions (upper and lower layers) and three oral administration solutions (upper, middle, and lower layers) were collected. HPLC-UV was used to analyze the formulations and examine the accuracy of the formulation concentrations.

[0180] The sample collection schedule is shown in Table 15.

[0181] Table 15 Timetable for Sample Collection of Intravenous Bottom Injection and Gavage Administration

[0182] Whole blood samples were collected at specified times via jugular vein puncture (or other suitable sampling sites). Samples were collected approximately 0.16 mL for groups 1, 2, 3, and 4; approximately 0.08 mL before administration on days 3, 4, 5, and 6 of group 5; and approximately 0.17 mL before administration on day 7 and at 0.25 h, 0.75 h, 1.5 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 24 h, 36 h, and 48 h after administration. The actual blood collection time was recorded in the experimental log. The acceptable error for collection time points was ±1 min for time points within 1 hour of administration, and ±5% for other time points based on the theoretical time.

[0183] After collection, all blood samples were transferred to commercially available tubes containing K2-EDTA and placed on wet ice. Within 60 minutes of blood collection, the samples were centrifuged at 3200×g for 10 minutes at approximately 4°C. The supernatant plasma was then aspirated, placed on dry ice, and stored at -60°C or lower for LC-MS / MS analysis.

[0184] 5. Sample Analysis and Results Discussion:

[0185] The concentration of this product in plasma was determined using validated high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0186] Retention times of compounds and internal standards, chromatogram acquisition, and chromatogram integration were processed using Analyst (Applied Biosystems) software. Statistical analysis was performed using Watson LIMS (Thermo Fisher Scientific) or Analyst (SCIEX) software. Analyte concentrations in samples are expressed in ng / mL, with three significant figures retained. All percentage values ​​(e.g., % deviation and % coefficient of variation) are rounded to one decimal place.

[0187] Table 16 shows the results of intravenous bolus and gavage administration, and Figure 9 shows the mean plasma drug concentration-time curves after single gavage administration of 10 mg / kg, 30 mg / kg and 100 mg / kg of the A crystal form of compound I to male and female SD rats.

[0188] Table 16 Results of intravenous bolus and gavage administration Note: a Bioavailability is determined by AUC 0-last And theoretical dose calculation; --: Not applicable.

[0189] The results above show that after a single intravenous bolus injection of 3 mg / kg of this product into 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 volume of distribution (Vd) was [not specified]. ss The concentrations were 23.0 L / kg and 12.5 L / kg, respectively, with elimination half-lives (Ti) of 12.5 L / kg. 1 / 2 The values ​​were 13.0 h and 10.8 h, respectively; the area under the plasma concentration-time curve (AUC) from 0 point to the last quantifiable time point was... 0-last The values ​​were 641 ng·h / mL and 1220 ng·h / mL, respectively.

[0190] After a single oral administration of 10 mg / kg, 30 mg / kg, and 100 mg / kg of this product to male SD rats, the peak concentration (C0) was [not specified]. max The concentrations were 280 ng / mL, 920 ng / mL, and 1650 ng / mL, respectively, with peak times (T0) of [missing information]. max The AUC values ​​appeared at 5.33 h, 4.67 h, and 4.67 h after drug administration, respectively. 0-last The effective doses were 1240 ng·h / mL, 4160 ng·h / mL, and 9730 ng·h / mL, respectively. The bioavailability of the drug in the 10 mg / kg gavage dose group was 58.0%.

[0191] After a single oral administration of 10 mg / kg, 30 mg / kg, and 100 mg / kg of this product to female SD rats, the peak concentration (C0) was [not specified]. max The concentrations were 261 ng / mL, 1270 ng / mL, and 2840 ng / mL, respectively, with peak times (T0, T ... max The AUCs appeared at 8.00 h, 6.67 h, and 6.67 h after administration, respectively. 0-last The effective doses were 1660 ng·h / mL, 7220 ng·h / mL, and 19700 ng·h / mL, respectively. The bioavailability of the drug in the 10 mg / kg gavage dose group was 40.8%.

[0192] Systemic exposure (AUC) of this product 0-last Except for the 100 mg / kg gavage group, where there were gender differences, the systemic exposure (AUC) was the same in all other groups. 0-last and C0 / C max There was no significant gender difference.

[0193] As the oral gavage dose increased from 10 mg / kg to 100 mg / kg, the systemic exposure (AUC) in male and female SD rats was [data missing]. 0-last With C max The dosage increases in roughly the same proportion as the dose.

[0194] Following administration of 30 mg / kg of this product via gavage once daily for 7 consecutive days, the systemic exposure (AUC) in female SD rats was determined. 0-last With C max The systemic exposure (AUC) remained essentially unchanged in male SD rats, with no significant accumulation; while the systemic exposure (AUC) in male SD rats remained largely unchanged. 0-last With C max Accumulation occurs, AUC 0-last With C max The accumulation indices (day 7 / day 1) were 2.18 and 2.36, respectively.

[0195] The above description is only a preferred embodiment of this application. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of this application, and these improvements and modifications should also be considered within the scope of protection of this application.

Claims

1. A crystal form of a neuroactive steroid derivative, with characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation, including 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 the structure shown in Formula I:

2. The crystal form of the neuroactive steroid derivative according to claim 1, characterized in that, The characteristic diffraction peaks also include those with 2θ angles of 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°, and 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 One or more of the following: 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°.

3. The crystal 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 crystal 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 crystal form of the neuroactive steroid derivative according to claim 1 or 2, characterized in that, The X-ray powder diffraction pattern exhibits 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°, and 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°.

6. The crystal form of the neuroactive steroid derivative according to claim 1 or 2, characterized in that, The X-ray powder diffraction pattern exhibits 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. 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° 7. The crystal form of the neuroactive steroid derivative according to claim 1 or 2, characterized in that, The X-ray powder diffraction pattern exhibits 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°, and 16.498±0.

2. 00°, 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 0.975±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 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°.

8. The crystal form of the neuroactive steroid derivative according to claim 1 or 2, characterized in that, The differential scanning calorimetry (DSC) spectrum of the crystal form of the neuroactive steroid derivative has an endothermic peak at 139.9℃±3℃; the starting value of the absorption peak is 138.5℃±3℃.

9. The crystal form of the neuroactive steroid derivative according to claim 1 or 2, characterized in that, The thermogravimetric analysis (TGA) spectrum of the crystal form of the neuroactive steroid derivative showed a weight loss of ±0.5% at 159.4℃±3℃.

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

11. The crystal form of the neuroactive steroid derivative according to claim 1 or 2, characterized in that, The crystal forms of the neuroactive steroid derivatives have a particle size of D90 of 240–530 μm, D50 of 105–270 μm, and D10 of 20–65 μm.

12. The crystal form of the neuroactive steroid derivative according to claim 1 or 2, characterized in that, The crystal form of the neuroactive steroid derivative has a repose angle of 39.2° and a Cartesian index of 14%.

13. The use of the crystal form of the neuroactive steroid derivative according to any one of claims 1 to 12 in the preparation of a medicament for treating mood disorders, mental illnesses, neurodegenerative diseases or neuropathic pain.

14. The application according to claim 13, characterized in that, The mood disorders mentioned include generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder, premenstrual anxiety disorder, major depressive disorder, or postpartum depression.

15. The application according to claim 13, characterized in that, The mental illnesses mentioned include epilepsy, seizures, or insomnia.

16. The application according to claim 13, characterized in that, The neurodegenerative diseases mentioned include Alzheimer's disease, Parkinson's disease, multiple sclerosis, or Niemann-Pick type C disease.

17. The application according to claim 13, characterized in that, The neuropathic pain includes menstrual and postmenopausal migraines, diabetic peripheral neuropathy, chemotherapy pain, or sciatica.

18. The application according to any one of claims 13 to 17, characterized in that, The drug comprises an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient is a crystal form of the neuroactive steroid derivative; and the pharmaceutically acceptable carrier is a solid carrier or a liquid carrier.

19. The application according to claim 18, characterized in that, The solid carrier includes one or more of the following: cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, astragalus gum, gum arabic, sodium alginate, parabens, methylcellulose, sodium carboxymethyl cellulose, low-melting-point waxes, and cocoa butter.

20. The application according to claim 18, characterized in that, The liquid carrier includes one or more of the following: water, ethanol, polyol, vegetable oil, glycerol ester, agar, pyrogen-free water, isotonic saline, and Ringer's solution.

21. The application according to claim 20, characterized in that, The polyols include one or more of glycerol, propylene glycol, and liquid polyethylene glycol; the vegetable oils include one or more of peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil.

22. The application according to any one of claims 13 to 17, characterized in that, The drug can be administered orally, intrapulmonaryly, intranasally, or transdermally.

23. The application according to claim 22, characterized in that, The dosage forms of the drug include tablets, lozenges, lozenges, suspensions, dispersible powders, dispersible granules, emulsions, hard capsules, soft capsules, syrups, elixirs, solutions, sprays, aerosols or dry powder preparations, nasal drops or nasal sprays.

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