Sodium salt crystalline forms of polycyclic carbamoylpyridone derivatives, methods for preparing them, and applications.

Abstract

This invention provides sodium salt crystalline forms of HIV-1 integrase inhibitor molecules. Specifically, this invention provides sodium salt crystalline forms A and sodium salt crystalline forms B of the compound represented by formula I. The crystalline forms of this invention can be used for the prevention and / or treatment of AIDS virus infection-related diseases and selectively inhibit the activity of AIDS virus integrase.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and specifically to the sodium salt crystal form of a polycyclic carbamoylpyridone derivative, its preparation method, and applications.

Background Art

[0002] HIV is still a chronic infectious disease, and the number of HIV-infected people is increasing every year. There is no protein similar to the HIV-1 integrase structure in host cells, and even if the HIV-1 integrase activity is inhibited, it does not affect the normal functions of host cells. Integrase inhibitors block the HIV replication process by inhibiting the chain transfer reaction, so they are also called integrase strand transfer inhibitors. In the US observational study published in J Acquir Immune Defic Syndr 2020, 84:396-399, it was shown that patients using antiretroviral therapy based on integrase inhibitors had a 21% lower risk of severe cardiovascular events compared with alternative drugs. Due to its good antiviral efficacy, high drug resistance barrier, and safety, it has become a core drug in current antiviral treatment and is also recommended as the first choice in international AIDS treatment guidelines.

[0003] In recent years, as research on the integrase structure and its inhibitors has deepened, more and more highly effective and low-toxic integrase inhibitors have emerged one after another. However, due to the successive emergence of drug-resistant strains of integrase inhibitors (such as Y143C, Q148H, and N155H), the problem of viral drug resistance remains unresolved. Therefore, the development of integrase inhibitors with high efficacy, low toxicity, and drug resistance is extremely important. Therefore, developing integrase inhibitors with high stability and easy drug formation has important significance.

Summary of the Invention

Problems to be Solved by the Invention

[0004] One objective of the present invention is to provide sodium salt crystalline forms A and B of an HIV integrase inhibitor molecule having the structure of formula I, which has high stability. Another object of the present invention is to provide a method for preparing sodium salt crystal form A of the compound of formula I and its applications, and a method for preparing sodium salt crystal form B of the compound of formula I and its applications. [Means for solving the problem]

[0005] A first aspect of the present invention provides a sodium salt crystalline form of the compound of formula I, [ka] The sodium salt crystal form of the compound of formula I is sodium salt crystal form A, and the sodium salt crystal form A has X-ray powder diffraction characteristic peaks (2θ angle) of 15.587°±0.2°, 9.107°±0.2°, 24.121°±0.2°, 7.806°±0.2°, and 20.828°±0.2°, or The sodium salt crystal form of the compound of formula I is sodium salt crystal form B, and sodium salt crystal form B has X-ray powder diffraction characteristic peaks (2θ angle) of 15.384°±0.2°, 25.98°±0.2°, 19.097°±0.2°, 8.673°±0.2°, and 21.609°±0.2°.

[0006] In another preferred example, the X-ray powder diffraction pattern of the sodium salt crystal form A further includes two or more (three, four, or five) X-ray powder diffraction characteristic peaks (2θ angles) selected from the group consisting of 27.738°±0.2°, 22.198°±0.2°, 18.226°±0.2°, 26.147°±0.2°, 18.622°±0.2°, and 23.448°±0.2°, or The X-ray powder diffraction pattern of the sodium salt crystal form B further includes two or more (three, four, or five) X-ray powder diffraction characteristic peaks (2θ angles) selected from the group consisting of 21.115°±0.2°, 18.606°±0.2°, 27.442°±0.2°, 27.18°±0.2°, 17.468°±0.2°, and 18.098°±0.2°.

[0007] In another preferred example, the sodium salt crystal form A further has one or more X-ray powder diffraction characteristic peaks (2θ angles) selected from the group consisting of 16.332°±0.2°, 25.756°±0.2°, 13.420°±0.2°, 17.994°±0.2°, 12.535°±0.2°, 19.299°±0.2°, 19.729°±0.2°, 25.241°±0.2°, and 23.712°±0.2°, or The sodium salt crystal form B further has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the group consisting of 6.322°±0.2°, 30.947°±0.2°, 17.267°±0.2°, 10.769°±0.2°, 14.046°±0.2°, 29.323°±0.2°, 23.132°±0.2°, 25.18°±0.2°, and 33.5°±0.2°.

[0008] In another preferred example, the sodium salt crystal form A is 22.016°±0.2°, 19.525°±0.2°, 28.184°±0.2°, 11.069°±0.2°, 11.686°±0.2°, 30.882°±0.2°, 16.849°±0.2°, 28.907°±0.2°, 33.217°±0.2°, 21.052°±0.2°, 34.521°±0.2°, 36.875°±0.2°, 13.120°±0.2°, 14.807°±0.2°, 26.963°±0.2°, 30.262°±0.2 It has an X-ray powder diffraction characteristic peak (2θ angle) selected from the group consisting of °, 29.763°±0.2°, 31.392°±0.2°, 31.776°±0.2°, 24.425°±0.2°, 38.225°±0.2°, 22.472°±0.2°, 34.820°±0.2°, 39.689°±0.2°, 24.739°±0.2°, 37.645°±0.2°, 35.908°±0.2°, 39.401°±0.2°, 6.308°±0.2°, 35.090°±0.2°, 39.014°±0.2°, or The sodium salt crystal form B has an X-ray powder diffraction characteristic peak (2θ angle) selected from the group consisting of 37.29°±0.2°, 13.481°±0.2°, 38.788°±0.2°, 23.716°±0.2°, 22.543°±0.2°, 35.05°±0.2°, 12.328°±0.2°, 35.49°±0.2°, 30.64°±0.2°, 36.322°±0.2°, 31.99°±0.2°, 12.672°±0.2°, 29.62°±0.2°, 17.07°±0.2°, and 36.75°±0.2°.

[0009] In another preferred example, the thermogravimetric analysis (TGA) spectrum of the sodium salt crystal form A shows weight loss in the range of 100°C to 380°C, with a weight loss ratio of 0.2% to 2.0%, and the differential scanning calorimetry spectrum of the sodium salt crystal form A has an absorption peak in the range of 385°C to 395°C.

[0010] In another preferred example, the thermogravimetric analysis (TGA) spectrum of the sodium salt crystal form B shows a weight loss in the range of 100°C to 368°C, with a weight loss ratio of 1.0% to 3.0%, and the differential scanning calorimetry spectrum of the sodium salt crystal form B has an absorption peak in the range of 385°C to 390°C.

[0011] In another preferred example, the sodium salt crystal form A further has one or more of the following features (1) to (4): (1) The sodium salt crystal form A basically has XRPD data as shown in Table 1, and / or (2) The sodium salt crystal form A basically has an XRPD spectrum as shown in Figure 1, and / or (3) The sodium salt crystal form A basically has a DSC & TGA spectrum as shown in Figure 2, and / or (4) The sodium salt crystal form A basically has a DVS spectrum as shown in Figure 11.

[0012] A second aspect of the present invention provides a method for preparing the crystalline form described in the first aspect of the present invention, wherein the crystalline form is a sodium salt crystalline form, and the method for preparing the crystalline form includes the steps of adding a compound of formula I to an organic solvent or a water-containing organic solvent, adding sodium hydroxide and reacting it, and crystallizing it to obtain a sodium salt crystalline form.

[0013] In another preferred example, the sodium hydroxide is added in the form of an aqueous sodium hydroxide solution or a solid sodium hydroxide solution. In another preferred example, the reaction time is 8 to 30 hours.

[0014] In another preferred example, the crystallization time is 2 to 8 hours, preferably 3 to 6 hours. In another preferred example, the crystallization is selected from room temperature crystallization, cold crystallization, solvent evaporation crystallization, seed crystal-induced crystallization, or a combination thereof.

[0015] In another preferred example, the cooling crystallization refers to crystallization at -5 to 25°C. In another preferred example, after crystallization, it further includes the steps of filtration and drying to obtain a sodium salt crystal form.

[0016] In another preferred example, the crystal form is sodium salt crystal form B, and its preparation method is to add the compound of formula I to an organic solvent, add sodium hydroxide within 1 to 30 minutes, stir and react / crystallize for 5 to 30 minutes, crystallize, filter, and dry to obtain a mixture containing sodium salt crystal form B of the compound of formula I or a small amount of sodium salt crystal form A.

[0017] In another preferred example, the crystallization is selected from room temperature crystallization, cooling crystallization, solvent evaporation crystallization, seed crystal-induced crystallization, or a combination thereof. In another preferred example, the cooling crystallization refers to crystallization at -5 to 25°C.

[0018] In another preferred example, the molar ratio of the compound raw material of formula I to sodium hydroxide is 1:(1 to 2). In another preferred example, the mass-volume (g / ml) ratio of the compound raw material of formula I to the organic solvent is 1:(20 to 40).

[0019] In another preferred example, the sodium hydroxide is added in the form of a sodium hydroxide solution. In another preferred example, the sodium hydroxide is added in the form of solid sodium hydroxide.

[0020] In another preferred example, the cooling refers to cooling at a rate of 10 to 20°C / hour. In another preferred example, it is cooled to room temperature.

[0021] In another preferred example, the organic solvent is selected from the group consisting of C1-C6 alcohol solvents, C1-C6 cyanide solvents, C1-C20 sulfone solvents, C1-C20 amide solvents, C1-C6 haloalkane solvents, C1-C6 alkane solvents, C6-C10 aromatic hydrocarbon solvents, C2-C6 ester solvents, C1-C6 ketone solvents, C1-C6 ether solvents, or combinations thereof, and is preferably a C1-C6 alcohol solvent.

[0022] In another preferred example, the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, toluene, 1,4-dioxane, dichloromethane, trichloromethane, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, methyl t-butyl ether, n-heptane, or combinations thereof, and is preferably ethanol.

[0023] A third aspect of the present invention provides a pharmaceutical composition comprising (a) the sodium salt crystal form according to the first aspect of the present invention as an active ingredient, and (b) a pharmaceutically acceptable carrier. In another preferred example, the dosage form of the pharmaceutical composition is selected from the group consisting of powders, capsules, granules, tablets, pills, creams, orally dissolving films, suspensions or injections.

[0024] A fourth aspect of the present invention provides the use of the crystal form according to the first aspect of the present invention or the pharmaceutical composition according to the third aspect of the present invention, which is used in the preparation of a drug or a formulation, and the drug or the formulation is used for the prevention and / or treatment of AIDS virus infection-related diseases. In another preferred example, the dosage form of the formulation is selected from the group consisting of powders, capsules, granules, tablets, pills, creams, orally dissolving films, suspensions or injections.

Advantages of the Invention

[0025] It should be understood that, within the scope of the present invention, new or preferred technical solutions can be constructed by combining the above-described technical features of the present invention with the technical features specifically described below (e.g., in the examples). Due to space limitations, this will not be repeated here. [Brief explanation of the drawing]

[0026] [Figure 1] This is the X-ray powder diffraction pattern of sodium salt crystal form A in Example 1. [Figure 2] This is the DSC & TGA spectrum of sodium salt crystal form A in Example 1. [Figure 3] This is the X-ray powder diffraction pattern of sodium salt crystal form B in Example 2.

[0027] [Figure 4] This is the DSC & TGA spectrum of sodium salt crystal form B in Example 2. [Figure 5] This is the X-ray powder diffraction pattern obtained by scaling up the sodium salt crystal form A from Example 3. [Figure 6] This is the HPLC spectrum of sodium salt crystal form A prepared on a scale-up basis in Example 3.

[0028] [Figure 7] This is the ee value spectrum of sodium salt crystal form A prepared on a scale-up basis in Example 3. [Figure 8] This is the XRPD spectrum of sodium salt crystal form A after 5 days under the stability conditions in Example 6. [Figure 9] This is the XRPD spectrum of sodium salt crystal form A after 10 days under the stability conditions in Example 6.

[0029] [Figure 10] This is a comparison of XRPD values ​​of sodium salt crystal form A before and after the DVS test in Example 7. [Figure 11]This is the DVS spectrum of sodium salt crystal form A in Example 7. [Figure 12] This is the XRPD spectrum of sodium salt crystal form A after the high-pressure test in Example 8. [Figure 13] This is an XRPD comparison chart of sodium salt crystal form A after the simulated granulation test in Example 9. [Modes for carrying out the invention]

[0030] As a result of long-term, meticulous research, the inventors have provided a sodium salt crystalline form of an HIV integrase inhibitor molecule. This sodium salt crystalline form exhibits excellent properties in aspects such as stability, solubility, hygroscopicity, mechanical stability, tablet stability, flowability, processability, formulation development potential, and powder processing performance, with sodium salt crystalline form A exhibiting particularly outstanding advantages in aspects such as stability. Based on the above findings, the inventors have completed the present invention.

[0031] term In this specification, unless otherwise specified, all abbreviations have the conventional meanings understood by those skilled in the art. As used herein, unless otherwise specified, the method of adding the solvent or solution is direct pouring or uniform rate addition, etc. As used herein, when used in relation to a specifically stated value, the term “about” means that the value may vary by no more than 1% from the stated value. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0032] As used herein, the terms “contain” or “include” may be open, semi-closed, or closed. In other words, the terms also include “basically consist of” or “consist of.” As used herein, the term “room temperature” generally refers to 4 to 30°C, preferably 20 ± 5°C. As used herein, the “slow addition” method includes, but is not limited to, adding drop by drop or adding slowly along the container wall.

[0033] Compound of formula I As used herein, the term “compound of formula I” refers to a compound as shown in the following formula: [ka] The above compound was first reported in patent CN202111336306 of Jiangsu Aidea Pharmaceutical Co., Ltd., and is prepared by the method described in said literature. In this specification, unless otherwise specified, the term “starting material for compound of formula I” refers to compound of formula I, and in the examples, API and compound of formula I are used interchangeably.

[0034] Pharmaceutical composition containing the sodium salt crystalline form of compound I and method of administration The present invention provides a highly stable sodium salt crystalline form of an HIV-1 integrase inhibitor molecule having the structure of the compound of formula I. Therefore, the sodium salt crystalline form of the present invention and pharmaceutical compositions containing the sodium salt crystalline form of the present invention as a main active ingredient can be used for the prevention and / or treatment of AIDS virus infection-related diseases. The sodium salt crystal form includes sodium salt crystal form A and sodium salt crystal form B.

[0035] The pharmaceutical composition of the present invention comprises a safe and effective amount of the polycrystalline material of the present invention and a pharmaceutically acceptable excipient or carrier. Here, “safe and effective dose” refers to the amount of compound (or polycrystalline substance) sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1 to 2000 mg of the polycrystalline substance / agent of the present invention, more preferably 10 to 200 mg of the polycrystalline substance / agent of the present invention. Preferably, “one agent” is one capsule or tablet.

[0036] "Pharmacochemically acceptable carrier" refers to one or more compatible solid or liquid fillers or gels that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" means that each component of the composition can be blended with each other, with respect to the active ingredients of the present invention and among them, without significantly reducing the potency of the active ingredients. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0037] The administration method of the polycrystalline substance or pharmaceutical composition of the present invention is not particularly limited, and typical administration methods include (but are not limited to) oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

[0038] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inactive excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) fillers or compatibilizers such as microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants such as glycerin; (d) agar, calcium carbonate, potato starch, potato methionine It is mixed with components such as (e) tapioca starch or tapioca starch, alginic acid, certain complex silicates, disintegrants such as sodium carbonate, crospovidone, and croscarmellose sodium, (f) retarders such as paraffin, absorption enhancers such as quaternary amine compounds, (g) wetting agents such as cetyl alcohol and glyceryl monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also include a buffer.

[0039] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coating and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active ingredient in such compositions can be delayed in specific parts of the digestive tract. Examples of usable embedding components include polymers and waxes. If necessary, the active ingredient can form microcapsules with one or more of the above excipients.

[0040] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, sesame oil, and sesame oil, or mixtures thereof.

[0041] In addition to these inert diluents, the composition may also include auxiliary agents such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances. In addition to the active ingredient, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures thereof.

[0042] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous vectors, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof. The dosage forms of the polycrystalline compounds of the present invention used for topical administration include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable vector and any preservatives, buffers, or propellants as needed.

[0043] The polycrystalline material of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When the pharmaceutical composition is used, a safe and effective amount of the polycrystalline product of the present invention is applied to a mammal (e.g., human) in need of treatment, where the dose at the time of administration is the effective dose to be considered, and for a person weighing 60 kg, the daily dose is usually 1 to 2000 mg, preferably 10 to 500 mg. Of course, the specific dose must also take into account factors such as the route of administration and the patient's health condition, all of which are within the scope of the skills of a skilled physician.

[0044] The pharmaceutical compositions provided by the present invention preferably contain 1 to 99% by weight of an active ingredient, wherein the preferred ratio is such that the compound of general formula I as the active ingredient accounts for 65 wt% to 99 wt% of the total weight, and the remainder is a pharmaceutically acceptable carrier, diluent or solution or salt solution. The compounds and pharmaceutical compositions provided by the present invention may be in various forms such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and may be present in a suitable solid or liquid carrier or diluent and in a suitable sterile instrument used for injection or infusion. Various dosage forms of the pharmaceutical composition of the present invention can be prepared by conventional preparation methods in the field of pharmacy. The unit weight of the formulation contains 1 mg to 700 mg of the crystalline or salt crystalline form of the compound of general formula I, and preferably, the unit weight of the formulation contains 25 mg to 300 mg of the compound of general formula I.

[0045] The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, by routes of administration such as oral, nasal, dermal, pulmonary, or gastrointestinal. Oral administration is most preferred. The most preferred daily dose is a single dose of 50-1400 mg / kg body weight or multiple divided doses of 25-700 mg / kg body weight, regardless of the method of administration. The optimal dose for an individual should be determined based on the specific treatment. Typically, a small dose is started and gradually increased until an appropriate dose is found.

[0046] In the present invention, unless otherwise specified, the drying method used is a conventional drying method in the art. For example, drying in the embodiments of the present invention refers to vacuum drying or atmospheric pressure drying using a conventional drying oven. Generally, drying is performed for 0.1 to 50 hours or 1 to 30 hours.

[0047] Compared to the prior art, the main advantages of the present invention are as follows: (a) The crystalline form of the present invention has high stability, low hygroscopicity, and high bioavailability, making it beneficial for drug processing and use in pharmaceutical compositions. (b) The crystalline form of the present invention can be used as an active ingredient for the prevention and treatment of diseases caused by HIV infection.

[0048] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are used solely for illustrative purposes and do not limit the scope of the invention. In the following embodiments, experimental methods that do not specify conditions generally follow conventional conditions or conditions proposed by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0049] 1. Experimental materials In the examples of the present invention, the raw materials for the compound of formula I are free-state solids prepared with reference to Example 1 of Idea Patent CN202111336306, and the other reagents are commercially available industrial or analytical reagents.

[0050] 2. Test Method [Table A]

[0051] Example 1: Preparation of sodium salt crystal form A Solid-liquid suspension equilibrium experiment at 1.25°C Approximately 30 mg of the compound of formula I was weighed into each vial, and approximately 1 mL of the solvent listed in Table 1 below was added to each to prepare a suspension. Approximately 0.5 mL of sodium hydroxide ethanol solution (1.1 eq.) was slowly added to the suspension, and the mixture was magnetically stirred at 25 ± 0.1 °C for 24 hours. During the test process, the state of the sample was observed to ensure that the mixture maintained a vortex state, and the solid was added when it became clear. All suspensions were filtered and centrifuged to obtain the solid. Residual solvent on the surface was removed by nitrogen gas purging or vacuum drying. The X-ray powder test graph for this is shown in Figure 1, the results are shown in Table 2 below, and its DSC and TGA spectra are shown in Figure 2. Table 1. Solid-liquid suspension equilibrium experiment at 25°C [Table 1] Table 2. XRD characteristic peaks of sodium salt crystal form A. [Table 2-1] [Table 2-2]

[0052] Solid-liquid suspension equilibrium experiment at 2.50°C Approximately 30 mg of the compound of formula I is weighed into each vial, and approximately 1 mL of the solvent shown in Table 3 is added to each to prepare a suspension. Approximately 0.5 mL of sodium hydroxide ethanol solution (1.1 eq.) is slowly added to the suspension, the reaction mixture is stirred, the temperature is raised to 50°C, and the mixture is stirred for 2 hours while maintaining the temperature. Then, the mixture is stirred, cooled, and crystallized (cooling rate 10°C / h). After cooling to 25°C, the mixture is stirred and crystallized for 5 hours while maintaining the temperature, and the solid is separated to obtain the sodium salt crystal form A of the compound of formula I. Table 3. Solid-liquid suspension equilibrium experiment at 50°C [Table 3]

[0053] Example 2: Preparation of sodium salt crystal form B Approximately 100 mg of compound I was weighed, and approximately 0.5 mL of ethanol was added to each to prepare a suspension. Within 1 to 30 minutes, approximately 0.5 mL of sodium hydroxide ethanol solution (2.0 eq.) was slowly added to the suspension, and the mixture was stirred at room temperature for approximately 5 to 10 minutes. The solid was then separated to obtain the sodium salt crystalline form B of compound I. The X-ray powder test results for this are shown in Figure 3, the results are shown in Table 4 below, and the DSC and TGA spectra are shown in Figure 4. Table 4. XRD characteristic peaks of sodium salt crystal form B. [Table 4-1] [Table 4-2]

[0054] Example 3: Scale-up experiment of sodium salt crystal form A Add 52.6 kg of anhydrous ethanol, 6.6 kg of purified water, and 2.445 kg of compound I to reaction vessel R1, start stirring, raise the temperature to 68-78°C, stir until clear, pressure filter the mixture into reaction vessel R2 in the clean area using a microfilter, continue raising the temperature to 68-78°C, and stir until clear.

[0055] A solution of 0.295 kg of sodium hydroxide and 1.61 kg of purified water was prepared and pressure filtered into a dropping vessel of reaction vessel R2 in the clean area using a microfilter. After adding 60 g of seed crystals of sodium salt crystal form A to reaction vessel R2, the temperature was controlled to 68-78°C and the sodium hydroxide solution was slowly added dropwise. After the addition was complete, the mixture was stirred and reacted for 22 hours while maintaining the temperature, the reaction solution was slowly cooled to 10-15°C, stirred and crystallized for 3 hours, centrifuged, the wet product was washed with ethanol, the wet product was added to a dryer, the dryer jacket temperature was controlled to 45-55°C, and it was vacuum dried to obtain 2.54 kg of sodium salt crystal form A. (Yield 96.7%, purity 100%, ee value 100%, moisture 0.3%, ethanol residue 492 ppm). The X-ray powder test graph is shown in Figure 5, the HPLC spectrum is shown in Figure 6, and the ee value spectrum is shown in Figure 7.

[0056] Example 4: Physicochemical properties of sodium salt crystal forms A and B The sodium salt crystal forms A and B prepared in Example 1 and Example 2, respectively, were tested by DSC, TGA, and HPLC, and the data results are shown in Table 5 below. Table 5. Physicochemical properties of sodium salt crystal forms A and B [Table 5] Both sodium salt crystal forms possess higher melting points, good hygroscopic properties, and solid stability, as well as excellent crystallinity.

[0057] Example 5: Solubility Test 5 to 50 mg of the compound of formula I and sodium salt crystalline form A were suspended in 2 to 10 mL of solvent in glass vials, and after stirring and suspension at 25°C for 48 hours, the suspensions were filtered, and the concentration of the saturated solution was measured by HPLC. The solubility was then calculated, and the results are shown in Table 6. Table 6 [Table 6] The results indicate that at 25°C, sodium salt crystal form A has higher solubility in water than the compound of formula I.

[0058] Example 6: Factors affecting sodium salt crystal form A 70 mg of sodium salt crystal form A sample was accurately weighed and placed in a glass culture dish. The glass culture dishes were transferred to a constant temperature and humidity chamber with three different environments: high temperature (60°C, sealed), high relative humidity (RH: 90±5%, 25°C, open), and illumination (5000±500 Lux, open), and periodic tests were performed on days 5 and 10. The samples were detected using XRPD and HPLC, as shown in Figures 8 and 9, and the color change of the samples was observed. The results are shown in Table 7. Table 7. Experiments on factors affecting sodium salt crystal form A. [Table 7] The above results indicate that sodium salt crystal form A exhibits no change in properties under high temperature, high humidity, and light irradiation conditions, with minimal change in HPLC purity and no change in XRPD. This suggests that sodium salt crystal form A exhibits good physicochemical stability.

[0059] Example 7: Hygroscopicity of sodium salt crystal form A A 20 mg sample of sodium salt crystal form A was weighed and subjected to a DVS test. The sample after the DVS test was then tested with XRPD, and the results are shown in Table 8 below. Table 8. Results of the sodium salt DVS test. [Table 8] As shown in Figures 10 and 11, the results of two DVS tests on sodium salt crystal form A show that the weight increase of sodium salt crystal form A at a relative humidity of 80% RH was 0.69%, indicating that crystal form A has low hygroscopicity, and that the crystal form of all samples remained unchanged before and after the DVS test, indicating that crystal form A has high humidity stability.

[0060] Example 8: High-pressure property test of sodium salt crystal form A Approximately 300 mg of sodium salt crystal form A was weighed and added to a 13 mm diameter hydraulic pan. A high-pressure property test was performed using a manual hydraulic press at a hydraulic pressure of 10 MPa for 5 minutes. XRPD characterization was performed on the resulting solid, as shown in Figure 12. After the high-pressure test, sodium salt crystal form A remained unchanged.

[0061] Example 9: Simulated granulation test of sodium salt crystal form A Ethanol was added dropwise to a sample of sodium salt crystal form A until the solid was completely wet, and then the sample was polished. XRPD detection was performed on the resulting solid and on the sample without added wet ethanol, and the results are shown in Figure 13. The results show that sodium salt crystal form A, when wetted and polished with ethanol, did not undergo any change in crystal form, which indicates that sodium salt crystal form A has granulation stability.

[0062] Example 10: Pharmacokinetic study Sodium salt crystal form A, sodium salt crystal form B, and compound of formula I (0.5% HPMC / 0.1% Tween-80 suspension) were force-administered orally to male SD rats (dose 5 mg / kg, administration volume 10 mL / kg, n=3). Before administration and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours after administration, 50 μL of blood was collected by jugular vein puncture and placed in a centrifuge tube containing an anticoagulant (EDTA-K2). The contents were mixed uniformly by inverting the tube, placed on crushed ice, and centrifuged for 10 minutes at 4°C and 3500 rpm within 2 hours. The plasma was collected, placed in an EP tube with the corresponding label, and stored in a -80°C cryogenic refrigerator until analysis and detection. Before analysis, the plasma in the EP tube was thawed at room temperature, mixed uniformly by vortexing, and a 10 μL sample was taken. The concentration of compound of formula I in the plasma was measured by LC-MS-MS. Using WinNonlin 8.1, blood drug concentration data and pharmacokinetic parameters were calculated and summarized, and are shown in Table 9. Table 9. Results of pharmacokinetic parameters [Table 9] The above results show that when sodium salt crystal form A of this application was orally administered to rats, compared with sodium salt crystal form B and compound of formula I, the C of compound of formula I in plasma was max The study also showed a higher AUC value, indicating that under the same administration conditions, the plasma exposure of the compound of formula I in sodium salt crystalline form A is higher, suggesting that sodium salt crystalline form A may have superior bioabsorption.

[0063] All documents referenced in this invention are cited as references in this application, as if each document were cited individually. Furthermore, after reading the above teachings of this invention, persons skilled in the art can make various changes or modifications to the invention, and these equivalent forms are also included within the scope defined by the claims appended to this application.

Claims

1. The sodium salt crystalline form of the compound represented by formula I, 【Chemistry 1】 The sodium salt crystal form of the compound of formula I is sodium salt crystal form A, and the sodium salt crystal form A has X-ray powder diffraction characteristic peaks (2θ angle) of 15.587°±0.2°, 9.107°±0.2°, 24.121°±0.2°, 7.806°±0.2°, and 20.828°±0.2°, or The sodium salt crystal form of the compound of formula I is sodium salt crystal form B, and the sodium salt crystal form B is characterized by having X-ray powder diffraction characteristic peaks (2θ angles) of 15.384°±0.2°, 25.98°±0.2°, 19.097°±0.2°, 8.673°±0.2°, and 21.609°±0.2°.

2. The X-ray powder diffraction pattern of the sodium salt crystal form A further includes two or more (three, four, or five) X-ray powder diffraction characteristic peaks (2θ angles) selected from the group consisting of 27.738°±0.2°, 22.198°±0.2°, 18.226°±0.2°, 26.147°±0.2°, 18.622°±0.2°, and 23.448°±0.2°, or The X-ray powder diffraction pattern of the sodium salt crystal form B is further characterized by including two or more (three, four, or five) X-ray powder diffraction characteristic peaks (2θ angles) selected from the group consisting of 21.115°±0.2°, 18.606°±0.2°, 27.442°±0.2°, 27.18°±0.2°, 17.468°±0.2°, and 18.098°±0.2°. The crystal form described in claim 1.

3. The sodium salt crystal form A further has one or more X-ray powder diffraction characteristic peaks (2θ angles) selected from the group consisting of 16.332°±0.2°, 25.756°±0.2°, 13.420°±0.2°, 17.994°±0.2°, 12.535°±0.2°, 19.299°±0.2°, 19.729°±0.2°, 25.241°±0.2°, and 23.712°±0.2°, or The sodium salt crystal form B is further characterized by having one or more X-ray powder diffraction characteristic peaks (2θ angles) selected from the group consisting of 6.322°±0.2°, 30.947°±0.2°, 17.267°±0.2°, 10.769°±0.2°, 14.046°±0.2°, 29.323°±0.2°, 23.132°±0.2°, 25.18°±0.2°, and 33.5°±0.2°. The crystal form described in claim 2.

4. The sodium salt crystal form A is as follows: 22.016°±0.2°, 19.525°±0.2°, 28.184°±0.2°, 11.069°±0.2°, 11.686°±0.2°, 30.882°±0.2°, 16.849°±0.2°, 28.907°±0.2°, 33.217°±0.2°, 21.052°±0.2°, 34.521°±0.2°, 36.875°±0.2°, 13.120°±0.2°, 14.807°±0.2°, 26.963°±0.2°, 30.262°±0.2°, 29.7 It has an X-ray powder diffraction characteristic peak (2θ angle) selected from the group consisting of 63°±0.2°, 31.392°±0.2°, 31.776°±0.2°, 24.425°±0.2°, 38.225°±0.2°, 22.472°±0.2°, 34.820°±0.2°, 39.689°±0.2°, 24.739°±0.2°, 37.645°±0.2°, 35.908°±0.2°, 39.401°±0.2°, 6.308°±0.2°, 35.090°±0.2°, and 39.014°±0.2°, or The sodium salt crystal form B is characterized by having an X-ray powder diffraction characteristic peak (2θ angle) selected from the group consisting of 37.29°±0.2°, 13.481°±0.2°, 38.788°±0.2°, 23.716°±0.2°, 22.543°±0.2°, 35.05°±0.2°, 12.328°±0.2°, 35.49°±0.2°, 30.64°±0.2°, 36.322°±0.2°, 31.99°±0.2°, 12.672°±0.2°, 29.62°±0.2°, 17.07°±0.2°, and 36.75°±0.2°. The crystal form described in claim 3.

5. The thermogravimetric analysis (TGA) spectrum of the sodium salt crystal form A is characterized by a weight loss occurring in the range of 100°C to 380°C, with a weight loss ratio of 0.2% to 2.0%, or the differential scanning calorimetry spectrum of the sodium salt crystal form A is characterized by having an absorption peak in the range of 385°C to 395°C. The crystal form described in claim 1.

6. The sodium salt crystal form A further has one or more of the following characteristics (1) to (4): (1) The sodium salt crystal form A basically has XRPD data as shown in Table 1, and / or (2) The sodium salt crystal form A basically has an XRPD spectrum as shown in Figure 1, and / or (3) The sodium salt crystal form A basically has a DSC & TGA spectrum as shown in Figure 2, and / or (4) The sodium salt crystal form A is characterized in that it basically has a DVS spectrum as shown in Figure 11. The crystal form described in claim 1.

7. A method for preparing the crystalline form according to claim 1, The preparation method is characterized by comprising the step of adding a compound represented by formula I to an organic solvent or a water-containing organic solvent, adding sodium hydroxide and reacting it, and crystallizing it to obtain a sodium salt crystal form.

8. The organic solvent is selected from the group consisting of C1-C6 alcohol solvents, C1-C6 cyanide solvents, C1-C20 sulfone solvents, C1-C20 amide solvents, C1-C6 haloalkane solvents, C1-C6 alkane solvents, C6-C10 aromatic hydrocarbon solvents, C2-C6 ester solvents, C1-C6 ketone solvents, C1-C6 ether solvents, or combinations thereof, and is preferably a C1-C6 alcohol solvent. The preparation method according to claim 7.

9. A pharmaceutical composition, The pharmaceutical composition comprising (a) the sodium salt crystalline form described in claim 1 as an active ingredient, and (b) a pharmaceutically acceptable carrier.

10. Use of the crystalline form according to claim 1 or the pharmaceutical composition according to claim 9 in the preparation of a drug or formulation for the prevention and / or treatment of HIV infection-related diseases.

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