Crystal forms of sodium salt of polycyclic carbamoylpyridone derivative, and preparation method therefor and use thereof

Abstract

Provided in the present invention are crystal forms of the sodium salt of an HIV-1 integrase inhibitor molecule. Specifically, provided in the invention are crystal form A and crystal form B of the sodium salt of a compound as shown in formula I. The crystal forms of the present invention can be used for preventing and / or treating diseases related to HIV infections and selectively inhibiting the activity of HIV integrase.

Description

Sodium salt crystal form of polycyclic aminoformyl pyridone derivative, preparation method and application thereof Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a sodium salt crystal form of a polycyclic aminoformyl pyridone derivative, a preparation method thereof, and an application thereof. Background Art

[0002] HIV remains a chronic infection, and the number of HIV-infected individuals is increasing annually. Host cells do not contain proteins structurally similar to HIV-1 integrase, so inhibiting HIV-1 integrase activity does not affect the normal function of host cells. Integrase inhibitors block HIV replication by inhibiting the strand transfer reaction, and are therefore also called integrase strand transfer inhibitors. An observational study in the United States, published in J Acquir Immune Defic Syndr 2020;84:396–399, showed that compared with alternative medications, people who used integrase inhibitor-based antiretroviral therapy had a 21% lower risk of serious cardiovascular events. Because of their excellent antiviral efficacy, high barrier to resistance, and safety, they have become a core drug in current antiretroviral treatment and are recommended as the preferred option in international HIV treatment guidelines.

[0003] In recent years, with the continuous deepening of research on the structure of integrase and its inhibitors, more and more highly effective and low-toxic integrase inhibitors have emerged. However, drug-resistant strains of integrase inhibitors (Y143C, Q148H and N155H, etc.) have appeared one after another, and the problem of viral resistance has not been solved. It is particularly important to develop highly effective, low-toxic and resistant integrase inhibitors.

[0004] Therefore, it is of great significance to develop an integrase inhibitor that is highly stable and easy to develop into a drug.

[0005] Summary of the Invention

[0006] One object of the present invention is to provide a sodium salt crystal form A and a sodium salt crystal form B of an HIV integrase inhibitor molecule having a structure of formula I with high stability.

[0007] Another object of the present invention is to provide a preparation method and application of the sodium salt crystal form A of the compound of formula I, and a preparation method and application of the sodium salt crystal form B of the compound of formula I.

[0008] In the first aspect of the present invention, a sodium salt crystalline form of a compound of formula I is provided.

[0009] The sodium salt crystalline form of the compound of formula I is sodium salt crystalline form A, and the sodium salt crystalline form A has the following X-ray powder diffraction characteristic peaks (2θ angle): 15.587°±0.2°, 9.107°±0.2°, 24.121°±0.2°, 7.806°±0.2°, 20.828°±0.2°; or

[0010] The sodium salt crystalline form of the compound of formula I is sodium salt crystalline form B, and the sodium salt crystalline form B has the following X-ray powder diffraction characteristic peaks (2θ angle): 15.384°±0.2°, 25.98°±0.2°, 19.097°±0.2°, 8.673°±0.2°, and 21.609°±0.2°.

[0011] In another preferred embodiment, the X-ray powder diffraction pattern of the sodium salt form A further includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 27.738°±0.2°, 22.198°±0.2°, 18.226°±0.2°, 26.147°±0.2°, 18.622°±0.2°, 23.448°±0.2°; or

[0012] The X-ray powder diffraction pattern of the sodium salt form B also includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 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°.

[0013] In another preferred embodiment, the sodium salt form A further has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 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°, 23.712°±0.2°; or

[0014] The sodium salt form B also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 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°.

[0015] In another preferred embodiment, the sodium salt form A has an X-ray powder diffraction characteristic peak (2θ angle) selected from the following group: 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°, 29.763°±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

[0016] The sodium salt form B has an X-ray powder diffraction characteristic peak (2θ angle) selected from the following group: 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°.

[0017] In another preferred embodiment, the thermogravimetric analysis (TGA) spectrum of the sodium salt crystal form A produces weight loss in the range of 100°C to 380°C, and the weight loss ratio is 0.2% to 2.0%; the differential scanning calorimetry diagram of the sodium salt crystal form A has an absorption peak at 385°C to 395°C.

[0018] In another preferred embodiment, the thermogravimetric analysis (TGA) spectrum of the sodium salt crystal form B produces weight loss in the range of 100°C to 368°C, and the weight loss ratio is 1.0% to 3.0%; the differential scanning calorimetry diagram of the sodium salt crystal form B has an absorption peak at 385°C to 390°C.

[0019] In another preferred embodiment, the sodium salt crystal form A further has one or more of the following characteristics (1)-(4):

[0020] (1) the sodium salt form A has XRPD data substantially as shown in Table 1; and / or

[0021] (2) the sodium salt form A has an XRPD pattern substantially as shown in FIG1 ; and / or

[0022] (3) the sodium salt crystalline form A has a DSC&TGA spectrum substantially as shown in FIG2 ; and / or

[0023] (4) The sodium salt crystal form A has a DVS spectrum basically as shown in Figure 11.

[0024] In the second aspect of the present invention, a method for preparing the crystal form described in the first aspect of the present invention is provided, wherein the crystal form is a sodium salt crystal form, and the preparation method comprises the steps of:

[0025] The compound of formula I is added to an organic solvent or an aqueous organic solvent, sodium hydroxide is added for reaction, and crystallization is performed to obtain a sodium salt crystal form.

[0026] In another preferred embodiment, the sodium hydroxide is added in the form of sodium hydroxide aqueous solution or sodium hydroxide solid.

[0027] In another preferred embodiment, the reaction time is 8-30 hours.

[0028] In another preferred embodiment, the crystallization time is 2-8 hours, preferably 3-6 hours.

[0029] In another preferred embodiment, the crystallization is selected from room temperature crystallization, cooling crystallization, solvent evaporation crystallization, seed crystallization, or a combination thereof.

[0030] In another preferred embodiment, the cooling crystallization refers to crystallization at -5-25°C.

[0031] In another preferred embodiment, the method further comprises the steps of: filtering and drying after crystallization to obtain a sodium salt crystal form.

[0032] In another preferred embodiment, the crystal form is sodium salt crystal form B, and its preparation method comprises the steps of:

[0033] The compound of formula I is added to an organic solvent, sodium hydroxide is added within 1-30 minutes, the reaction is stirred and crystallized for 5-30 minutes, the crystals are filtered, and the crystals are dried to obtain the sodium salt form B of the compound of formula I or a mixture containing a small amount of sodium salt form A.

[0034] In another preferred embodiment, the crystallization is selected from room temperature crystallization, cooling crystallization, solvent evaporation crystallization, seed crystallization, or a combination thereof.

[0035] In another preferred embodiment, the cooling crystallization refers to crystallization at -5-25°C.

[0036] In another preferred embodiment, the molar ratio of the compound of formula I to sodium hydroxide is 1:(1-2).

[0037] In another preferred embodiment, the mass volume (g / ml) ratio of the compound of formula I to the organic solvent is 1:(20-40).

[0038] In another preferred embodiment, the sodium hydroxide is added in the form of sodium hydroxide solution.

[0039] In another preferred embodiment, the sodium hydroxide is added in the form of solid sodium hydroxide.

[0040] In another preferred embodiment, the cooling refers to cooling at a rate of 10 to 20°C / h.

[0041] In another preferred embodiment, the temperature is lowered to room temperature.

[0042] In another preferred embodiment, the organic solvent is selected from the following group: C1-C6 alcohol solvents, C1-C6 cyanide solvents, C1-C20 sulfone solvents, C1-C20 amide solvents, C1-C6 halogenated alkane solvents, C1-C6 alkane solvents, C6-C10 aromatic hydrocarbon solvents, C2-C6 ester solvents, C1-C6 ketone solvents, C1-C6 ether solvents, or a combination thereof; preferably, it is a C1-C6 alcohol solvent.

[0043] In another preferred embodiment, the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, toluene, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, methyl tert-butyl ether, n-heptane, or a combination thereof; preferably, ethanol.

[0044] In a third aspect of the present invention, a pharmaceutical composition is provided, comprising (a) the sodium salt crystalline form as described in the first aspect of the present invention as an active ingredient; and (b) a pharmaceutically acceptable carrier.

[0045] In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the following group: powder, capsule, granule, tablet, pill, cream, orally disintegrating film, suspension or injection.

[0046] In the fourth aspect of the present invention, there is provided the use of the crystal form described in the first aspect of the present invention or the pharmaceutical composition described in the third aspect of the present invention for preparing a drug or preparation for preventing and / or treating diseases caused by HIV infection.

[0047] In another preferred embodiment, the dosage form of the preparation is selected from the following group: powder, capsule, granule, tablet, pill, cream, orally disintegrating film, suspension or injection.

[0048] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] FIG1 is an X-ray powder diffraction pattern of sodium salt form A in Example 1;

[0050] FIG2 is a DSC&TGA spectrum of sodium salt form A in Example 1;

[0051] FIG3 is an X-ray powder diffraction pattern of sodium salt Form B in Example 2;

[0052] FIG4 is a DSC&TGA spectrum of sodium salt form B in Example 2;

[0053] FIG5 is an X-ray powder diffraction pattern of the sodium salt Form A prepared in Example 3;

[0054] FIG6 is an HPLC spectrum of the enlarged preparation of sodium salt Form A in Example 3;

[0055] FIG7 is an ee value spectrum of the enlarged preparation of sodium salt form A in Example 3;

[0056] FIG8 is an XRPD pattern of sodium salt Form A after 5 days under stability conditions in Example 6;

[0057] FIG9 is an XRPD pattern of sodium salt Form A after 10 days under stability conditions in Example 6;

[0058] FIG10 is a comparison of XRPD images of sodium salt Form A in Example 7 before and after DVS testing;

[0059] Figure 11 is a DVS spectrum of sodium salt Form A in Example 7;

[0060] FIG12 is an XRPD pattern of sodium salt Form A after high pressure testing in Example 8;

[0061] Figure 13 is an XRPD comparison diagram of sodium salt form A after simulated granulation test in Example 9. DETAILED DESCRIPTION

[0062] After extensive and in-depth research, the inventors have developed a sodium salt crystalline form of an HIV integrase inhibitor. This sodium salt crystalline form exhibits advantages in stability, solubility, hygroscopicity, mechanical stability, tableting stability, flowability, process development, formulation development, and powder processing performance. In particular, sodium salt Form A exhibits significant advantages in stability. Based on these findings, the inventors completed the present invention.

[0063] the term

[0064] Unless otherwise specified herein, each abbreviation has the common meaning understood by those skilled in the art.

[0065] As used herein, unless otherwise specified, the method of adding a solvent or solution is direct pouring or adding at a uniform speed.

[0066] As used herein, when used in reference to a specific recited value, the term "about" means that the value may vary by no more than 1% from the recited 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.).

[0067] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0068] As used herein, the term "room temperature" generally refers to 4-30°C, preferably 20±5°C.

[0069] As used herein, the method of "slowly adding" includes, but is not limited to, adding dropwise, adding slowly along the wall of the container, etc.

[0070] Compounds of formula I

[0071] As used herein, the term "compound of formula I" refers to a compound of the formula:

[0072] The above compound was first reported in patent CN202111336306 of Jiangsu Aidi Pharmaceutical Co., Ltd. and was prepared by the method in this document. Herein, unless otherwise specified, the term "raw material of the compound of Formula I" refers to the compound of Formula I. In the examples, API and the compound of Formula I are used interchangeably.

[0073] Pharmaceutical composition containing sodium salt crystalline form of compound of formula I and administration method

[0074] Because the crystalline form of the present invention is a highly stable sodium salt crystalline form of an HIV-1 integrase inhibitor molecule having the structure of the compound of Formula I, the sodium salt crystalline form of the present invention and a pharmaceutical composition containing the sodium salt crystalline form of the present invention as a main active ingredient can be used to prevent and / or treat diseases caused by HIV infection.

[0075] The sodium salt crystal forms include sodium salt crystal form A and sodium salt crystal form B.

[0076] The pharmaceutical composition of the present invention comprises a safe and effective amount of the polymorph of the present invention and a pharmaceutically acceptable excipient or carrier.

[0077] Here, a "safe and effective amount" refers to an amount of the compound (or polymorph) sufficient to significantly improve the condition without causing serious side effects. Typically, a pharmaceutical composition contains 1-2000 mg of the polymorph of the present invention per dose, more preferably 10-200 mg per dose. Preferably, "one dose" is one capsule or tablet.

[0078] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0079] There is no particular limitation on the administration of the polymorph or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0080] 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 inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, microcrystalline cellulose, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose; (e) solubilizing agents, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0081] Solid dosage forms such as tablets, drupes, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a certain portion of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If desired, the active ingredient can also be microencapsulated with one or more of the above-mentioned excipients.

[0082] 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 an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0083] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0084] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0085] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0086] Dosage forms of the polymorphs of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0087] The polymorphs of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0088] When using a pharmaceutical composition, a safe and effective amount of the polymorph of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 10 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0089] The pharmaceutical composition provided by the present invention preferably contains an active ingredient in an amount of 1-99% by weight, preferably comprising 65% to 99% by weight of the compound of formula I as the active ingredient, with the remainder being a pharmaceutically acceptable carrier, diluent, solution, or saline 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 apparatus for injection or infusion.

[0090] The various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The dosage unit of the formulation contains 1 mg to 700 mg of a crystalline form or salt form of the compound of formula I. Preferably, the dosage unit of the formulation contains 25 mg to 300 mg of the compound of formula I.

[0091] The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, and can be administered via the oral, nasal, dermal, pulmonary, or gastrointestinal routes. Oral administration is most preferred. The most preferred daily dose is 50-1400 mg / kg body weight taken as a single dose, or 25-700 mg / kg body weight taken in divided doses. Regardless of the route of administration, the optimal individual dose will depend on the specific treatment being used. Typically, a low dose is started and gradually increased until the most suitable dose is found.

[0092] In the present invention, unless otherwise specified, the drying method used is a conventional drying method in the art. For example, in the embodiments of the present invention, drying refers to vacuum drying or atmospheric pressure drying in a conventional drying oven. Generally, the drying time is 0.1 to 50 hours or 1 to 30 hours.

[0093] Compared with the prior art, the main advantages of the present invention include:

[0094] (a) The crystal form of the present invention has high stability, low hygroscopicity, and high bioavailability, which is beneficial for its pharmaceutical processing and use in pharmaceutical compositions.

[0095] (b) The crystalline form of the present invention can be used as an active ingredient to prevent and treat diseases caused by AIDS infection.

[0096] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0097] 1. Experimental Materials

[0098] The raw material of the compound of formula I in the examples of the present invention is the free solid prepared with reference to Example 1 of Eddie Patent CN202111336306, and the other reagents are commercially available industrial grade or analytical grade reagents.

[0099] 2. Test methods

[0100] Example 1: Preparation of sodium salt form A

[0101] 1. Solid-liquid suspension equilibrium experiment at 25°C

[0102] Approximately 30 mg of the compound of Formula I was weighed into each vial, and approximately 1 mL of each solvent listed in Table 1 was added to form a suspension. Approximately 0.5 mL of an ethanolic solution of sodium hydroxide (1.1 eq.) was slowly added to the solution, and magnetic stirring was performed at 25 ± 0.1°C for 24 h. The sample state was observed during the test to ensure that the vortex state was maintained. If any solution became clear, additional solid was added. The entire suspension was filtered and centrifuged to obtain a solid. The residual solvent on the surface was removed by purging with nitrogen or vacuum drying. The X-ray powder analysis was performed, as shown in Figure 1, and the results are shown in Table 2 below. The DSC and TGA spectra are shown in Figure 2.

[0103] Table 1 Solid-liquid suspension equilibrium experiment at 25℃

[0104] Table 2 XRD characteristic peaks of sodium salt crystal form A

[0105] 2. Solid-liquid suspension equilibrium experiment at 50°C

[0106] Approximately 30 mg of the compound of Formula I was weighed into each vial, and approximately 1 mL of the solvents listed in Table 3 below was added to prepare a suspension. To the solution, approximately 0.5 mL of an ethanolic solution of sodium hydroxide (1.1 eq.) was slowly added. The reaction solution was stirred and heated to 50°C. After stirring for 2 h, the temperature was cooled with stirring to crystallize (cooling rate 10°C / h). After cooling to 25°C, stirring and crystallizing were continued for 5 h. The solid was separated to obtain the sodium salt of the compound of Formula I, Form A.

[0107] Table 3 Solid-liquid suspension equilibrium experiment at 50℃

[0108] Example 2: Preparation of sodium salt form B

[0109] Approximately 100 mg of the compound of Formula I was weighed and added with approximately 0.5 mL of ethanol to form a suspension. Approximately 0.5 mL of a 2.0 eq. sodium hydroxide solution in ethanol was slowly added to the suspension over 1-30 minutes. The mixture was stirred at room temperature for approximately 5-10 minutes. The solid was separated to obtain the sodium salt of the compound of Formula I, Form B. X-ray powder analysis is shown in Figure 3 , and the results are shown in Table 4 below. Its DSC and TGA spectra are shown in Figure 4 .

[0110] Table 4 XRD characteristic peaks of sodium salt form B

[0111] Example 3: Scale-up experiment of sodium salt crystal form A

[0112] Add 52.6 kg of anhydrous ethanol, 6.6 kg of purified water and 2.445 kg of compound of formula I to reactor R1, start stirring, heat to 68-78 ° C, stir until dissolved, filter through a precision filter into reactor R2 in the clean area, continue to heat to 68-78 ° C, and stir until dissolved.

[0113] Separately, a solution of 0.295 kg of sodium hydroxide and 1.61 kg of purified water was prepared and filtered through a precision filter into the dropping tank of reactor R2 in the clean area. After adding 60 g of sodium salt crystal form A seed crystals to reactor R2, the temperature was controlled at 68-78 ° C and the sodium hydroxide solution was slowly added dropwise. After the addition was completed, the mixture was stirred and reacted for 22 hours. The reaction solution was slowly cooled to 10-15 ° C, and stirring and crystallization were continued for 3 hours. The mixture was centrifuged and the wet product was washed with ethanol. The wet product was placed in a dryer, the dryer jacket temperature was controlled at 45-55 ° C, and 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 residual 492 ppm). The X-ray powder test diagram is shown in Figure 5, the HPLC spectrum is shown in Figure 6, and the ee value spectrum is shown in Figure 7.

[0114] Example 4: Physicochemical properties of sodium salt form A and form B

[0115] The sodium salt crystal forms A and B prepared in Example 1 and Example 2, respectively, were tested by DSC, TGA and HPLC. The data results are shown in Table 5 below.

[0116] Table 5 Physicochemical properties of sodium salt form A and form B

[0117] Both sodium salt crystal forms have high melting points, good hygroscopicity and solid-state stability, and have good crystallinity.

[0118] Example 5: Solubility Test

[0119] 5-50 mg of the compound of Formula I and sodium salt Form A were suspended in 2-10 mL of solvent in a glass bottle, respectively. The suspension was stirred and suspended at 25° C. for 48 h. The suspension was then filtered and the concentration of the saturated solution was measured by HPLC to calculate the solubility. The results are shown in Table 6.

[0120] Table 6

[0121] The results showed that at 25°C, the solubility of sodium salt form A in water was significantly higher than that of the compound of formula I.

[0122] Example 6: Factors affecting sodium salt crystal form A

[0123] 70 mg of sodium salt Form A samples were accurately weighed and placed in glass Petri dishes. The dishes were then 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). Testing was performed regularly on the 5th and 10th days. The samples were analyzed using XRPD and HPLC, as shown in Figures 8 and 9. Color changes were also observed, with the results shown in Table 7.

[0124] Table 7 Experimental study on factors affecting sodium salt crystal form A

[0125] The above results show that the properties of sodium salt form A do not change under high temperature, high humidity and light conditions, the HPLC purity changes slightly, and the XRPD does not change, indicating that sodium salt form A exhibits good physicochemical stability.

[0126] Example 7: Hygroscopicity of Sodium Salt Form A

[0127] 20 mg of sodium salt Form A sample was weighed and subjected to DVS testing. The sample after DVS testing was then tested by XRPD. The results are shown in Table 8 below.

[0128] Table 8 Sodium salt DVS test results

[0129] As shown in Figures 10 and 11, the results of two DVS tests of sodium salt crystal form A show that the weight gain of sodium salt crystal form A at relative humidity RH80% is 0.69%, indicating that crystal form A has low hygroscopicity. The crystal form of the sample before and after the DVS test did not change, indicating that crystal form A has high moisture stability.

[0130] Example 8: High-pressure property test of sodium salt crystal form A

[0131] Approximately 300 mg of sodium salt Form A was weighed and placed on a 13 mm diameter hydraulic platen. High-pressure testing was performed using a manual hydraulic platen press at a hydraulic pressure of 10 MPa for 5 minutes. XRPD analysis of the resulting solid was performed, as shown in Figure 12. After the high-pressure test, the sodium salt Form A remained unchanged.

[0132] Example 9: Simulated granulation test of sodium salt crystal form A

[0133] Ethanol was added dropwise to the sodium salt Form A sample until the solid was fully wetted, and then ground. The resulting solid and a sample without ethanol were subjected to XRPD analysis, as shown in Figure 13. The results show that the sodium salt Form A did not undergo crystalline form change after ethanol wetting and grinding, indicating that the sodium salt Form A has granulation stability.

[0134] Example 10: Pharmacokinetic Study

[0135] Sodium salt crystalline form A, sodium salt crystalline form B and compound of formula I (0.5% HPMC / 0.1% Tween-80 suspension) were orally administered to male SD rats (dose 5 mg / kg, dosing volume 10 mL / kg, n=3). 50 μL of blood samples were collected by jugular vein puncture before administration and at each time point 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours after administration, placed in a centrifuge tube containing anticoagulant (EDTA-K2), inverted upside down to mix, placed on crushed ice, and centrifuged at 4°C, 3500 rpm for 10 minutes within 2 hours. Plasma was placed in corresponding labeled EP tubes and transferred to a -80°C ultra-low temperature freezer for storage until analysis and detection. Before analysis, the plasma in the EP tube was thawed at room temperature and vortexed to mix, and 10 μL of the sample was used for LC-MS-MS to determine the concentration of compound of formula I in the plasma. WinNonlin 8.1 was used to calculate and summarize the blood drug concentration data and pharmacokinetic parameters, see Table 9.

[0136] Table 9 Pharmacokinetic parameter results

[0137] The above results show that compared with sodium salt crystal form B and compound of formula I, the sodium salt crystal form A of the present application was orally administered to rats, and the C of compound of formula I in plasma was max The AUC and AUC values ​​are higher, indicating that the plasma exposure of the compound of formula I of sodium salt form A is higher under the same administration conditions, suggesting that sodium salt form A may have better bioabsorption.

[0138] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A sodium salt crystalline form of a compound of formula I, characterized in that: The sodium salt crystalline form of the compound of formula I is sodium salt crystalline form A, and the sodium salt crystalline form A has the following X-ray powder diffraction characteristic peaks (2θ angle): 15.587°±0.2°, 9.107°±0.2°, 24.121°±0.2°, 7.806°±0.2°, 20.828°±0.2°; or The sodium salt crystalline form of the compound of formula I is sodium salt crystalline form B, and the sodium salt crystalline form B has the following X-ray powder diffraction characteristic peaks (2θ angle): 15.384°±0.2°, 25.98°±0.2°, 19.097°±0.2°, 8.673°±0.2°, and 21.609°±0.2°.

2. The crystal form according to claim 1, characterized in that The X-ray powder diffraction pattern of the sodium salt form A also includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 27.738°±0.2°, 22.198°±0.2°, 18.226°±0.2°, 26.147°±0.2°, 18.622°±0.2°, 23.448°±0.2°; or The X-ray powder diffraction pattern of the sodium salt form B also includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 21.115°±0.2°, 18.606°±0.2°, 27.442°±0.2°, 27.18°±0.2°, 17.468°±0.2°, 18.098°±0.2°.

3. The crystal form according to claim 2, characterized in that The sodium salt form A also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 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°, 23.712°±0.2°; or The sodium salt form B also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 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°.

4. The crystal form according to claim 3, characterized in that The sodium salt form A has an X-ray powder diffraction characteristic peak (2θ angle) selected from the following group: 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°, 29.763°±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 form B has an X-ray powder diffraction characteristic peak (2θ angle) selected from the following group: 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°.

5. The crystal form according to claim 1, characterized in that The thermogravimetric analysis (TGA) spectrum of the sodium salt crystal form A produces weight loss 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 diagram of the sodium salt crystal form A has an absorption peak at 385°C to 395°C.

6. The crystal form according to claim 1, characterized in that The sodium salt crystal form A also has one or more of the following characteristics (1)-(4): (1) the sodium salt form A has XRPD data substantially as shown in Table 1; and / or (2) the sodium salt form A has an XRPD spectrum substantially as shown in FIG1 ; and / or (3) the sodium salt crystalline form A has a DSC&TGA spectrum substantially as shown in FIG2; and / or (4) The sodium salt crystal form A has a DVS spectrum basically as shown in Figure 11.

7. A method for preparing the crystal form according to claim 1, characterized in that: Includes steps: The compound of formula I is added to an organic solvent or an aqueous organic solvent, sodium hydroxide is added to react, and crystallization is performed to obtain a sodium salt crystal form.

8. The preparation method according to claim 7, characterized in that: The organic solvent is selected from the following group: C1-C6 alcohol solvents, C1-C6 cyanide solvents, C1-C20 sulfone solvents, C1-C20 amide solvents, C1-C6 halogenated alkane solvents, C1-C6 alkane solvents, C6-C10 aromatic solvents, C2-C6 ester solvents, C1-C6 ketone solvents, C1-C6 ether solvents, or a combination thereof; preferably, it is a C1-C6 alcohol solvent.

9. A pharmaceutical composition, characterized in that Contains (a) the sodium salt crystal form according to claim 1 as an active ingredient; and (b) a pharmaceutically acceptable carrier.

10. Use of the crystal form according to claim 1 or the pharmaceutical composition according to claim 9, characterized in that: Used for preparing a medicine or preparation, wherein the medicine or preparation is used for preventing and / or treating diseases caused by HIV infection.

Images