Sodium salt crystal form of polycyclic carbamoyl pyridinone derivatives, process for the preparation thereof and use thereof

Abstract

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

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more specifically, to the sodium salt crystal form of polycyclic carbamoylpyridinone derivatives, their preparation methods, and applications. Background Technology

[0002] HIV remains a chronic infection, and the number of people infected with HIV increases annually. No protein with a structure similar to HIV-1 integrase exists within host cells, and inhibiting HIV-1 integrase activity does not affect the normal function of host cells. Integrase inhibitors block HIV replication by inhibiting the chain transfer reaction; therefore, they are also called integrase chain transfer inhibitors. A US observational study conducted in J Acquir Immune Defic Syndr 2020;84:396–399 showed that compared with alternative drugs, people using integrase inhibitor-based antiretroviral therapy had a 21% lower risk of serious cardiovascular events. Due to its good antiviral efficacy, high resistance barrier, and safety, it has become a core drug in current antiretroviral therapy and is the first-line recommendation in international HIV treatment guidelines.

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

[0004] Therefore, developing an integrase inhibitor that is highly stable and easy to drug is of great significance. Summary of the Invention

[0005] One object of the present invention is to provide sodium salt crystal forms A and B of an HIV integrase inhibitor molecule having a highly stable structure of Formula I.

[0006] Another object of the present invention is to provide a method for preparing sodium salt crystal form A of compound I and a method for preparing sodium salt crystal form B of compound I.

[0007] In a first aspect, the present invention provides a sodium salt crystal form of a compound of formula I.

[0008]

[0009] The sodium salt crystal form of the compound of formula I is sodium salt crystal form A, and sodium salt crystal 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 crystal form of the compound of formula I is sodium salt crystal form B, and sodium salt crystal 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 crystal form A further includes two or more (three, four, or five) characteristic X-ray powder diffraction peaks (2θ angle) 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

[0012] The X-ray powder diffraction pattern of the sodium salt crystal form B also includes two or more (three, four or five) characteristic X-ray powder diffraction 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°.

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

[0014] The sodium salt crystal 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°, 33.5°±0.2°.

[0015] In another preferred embodiment, the sodium salt crystal form A has X-ray powder diffraction characteristic peaks (2θ angle) selected from the group consisting of: 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°, and 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 crystal form B has X-ray powder diffraction characteristic peaks (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°.

[0017] In another preferred embodiment, the thermogravimetric analysis (TGA) spectrum of the sodium salt crystal form A shows weight loss in the range of 100℃ to 380℃, with a weight loss ratio of 0.2% to 2.0%; the differential scanning calorimetry (DSC) spectrum of the sodium salt crystal form A shows an absorption peak at 385℃ to 395℃.

[0018] In another preferred embodiment, the thermogravimetric analysis (TGA) spectrum of the sodium salt crystal form B shows weight loss in the range of 100℃ to 368℃, with a weight loss ratio of 1.0% to 3.0%; the differential scanning calorimetry (DSC) spectrum of the sodium salt crystal form B shows an absorption peak at 385℃ to 390℃.

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

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

[0021] (2) The sodium salt crystal form A described above has the basic characteristics as follows: Figure 1 The XRPD spectrum shown; and / or

[0022] (3) The sodium salt crystal form A described above has the basic characteristics as follows: Figure 2 The DSC & TGA spectra shown; and / or

[0023] (4) The sodium salt crystal form A described above has the basic characteristics as follows: Figure 11 The DVS diagram shown.

[0024] In a 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 includes the following steps:

[0025] The compound of formula I is added to an organic solvent or an aqueous organic solvent, and sodium hydroxide is added to react and crystallize to obtain the sodium salt crystal form.

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

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

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

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

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

[0031] In another preferred embodiment, the steps include: after crystallization, filtering and drying to obtain the sodium salt crystal form.

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

[0033] Add the compound of formula I to an organic solvent, add sodium hydroxide over 1-30 minutes, stir to react and crystallize for 5-30 minutes, filter, and dry to obtain sodium salt crystal form B of compound of formula I or a mixture containing a small amount of sodium salt crystal form A.

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

[0035] In another preferred embodiment, the cooling crystallization refers to crystallization at -5 to 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-to-volume (g / ml) ratio of the compound raw material 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 a sodium hydroxide solution.

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

[0040] In another preferred embodiment, the cooling refers to cooling at a rate of 10–20 °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 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 solvents, C2-C6 ester solvents, C1-C6 ketone solvents, C1-C6 ether solvents, or combinations 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 combinations thereof; preferably ethanol.

[0044] In a third aspect of the invention, a pharmaceutical composition is provided comprising (a) a sodium salt crystal form as described in the first aspect of the 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 group consisting of powder, capsule, granule, tablet, pill, cream, oral disintegrating film, suspension or injection.

[0046] In a fourth aspect of the invention, the use of the crystal form described in the first aspect of the invention or the pharmaceutical composition described in the third aspect of the invention is provided for the preparation of a drug or formulation for the prevention and / or treatment of HIV infection.

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

[0048] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described 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 described in detail here. Attached Figure Description

[0049] Figure 1 The image shows the X-ray powder diffraction pattern of sodium salt crystal form A in Example 1.

[0050] Figure 2 The DSC & TGA spectra of sodium salt crystal form A in Example 1;

[0051] Figure 3 The X-ray powder diffraction pattern of sodium salt crystal form B in Example 2;

[0052] Figure 4 The DSC & TGA spectra of sodium salt crystal form B in Example 2;

[0053] Figure 5 This is an enlarged X-ray powder diffraction pattern of sodium salt crystal form A prepared in Example 3;

[0054] Figure 6 This is the HPLC chromatogram of sodium salt crystal form A prepared in Example 3;

[0055] Figure 7 This is an enlarged ee value spectrum of sodium salt crystal form A prepared in Example 3;

[0056] Figure 8 The image shows the XRPD pattern of sodium salt crystal form A after 5 days under the stability conditions in Example 6.

[0057] Figure 9 The image shows the XRPD pattern of sodium salt crystal form A after 10 days under the stability conditions of Example 6.

[0058] Figure 10 This is a comparison of XRPD values ​​of sodium salt crystal form A before and after DVS testing in Example 7;

[0059] Figure 11 The DVS spectrum of sodium salt crystal form A in Example 7;

[0060] Figure 12 The image shown is the XRPD image of sodium salt crystal form A after high-pressure testing in Example 8.

[0061] Figure 13This is a comparison chart of XRPD values ​​after simulated granulation test of sodium salt crystal form A in Example 9. Detailed Implementation

[0062] After long-term and in-depth research, the inventors have provided a sodium salt crystal form of an HIV integrase inhibitor molecule. This sodium salt crystal form exhibits advantages in terms of stability, solubility, hygroscopicity, mechanical stability, tableting stability, flowability, processability, formulation development, and powder processing performance. In particular, sodium salt crystal form A demonstrates significant advantages in stability. Based on these findings, the inventors completed this invention.

[0063] the term

[0064] In this document, unless otherwise specified, all abbreviations have their conventional meanings as understood by those skilled in the art.

[0065] As used in this article, unless otherwise specified, solvents or solutions are added by pouring directly or adding at a constant rate.

[0066] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated values. 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 “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

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

[0069] As used in this article, the "slow addition" method includes, but is not limited to: adding drop by drop, adding slowly along the container wall, etc.

[0070] Formula I compound

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

[0072]

[0073] The above-mentioned compound was first reported in patent CN202111336306 of Jiangsu Aidi Pharmaceutical Co., Ltd., and was prepared by the method described in that document. In this document, unless otherwise specified, the term "raw material of Formula I compound" refers to Formula I compound, and in the examples, API and Formula I compound are used interchangeably.

[0074] Pharmaceutical compositions containing sodium salt crystals of compound formula I and methods of administration

[0075] Because the crystal form of the present invention is a highly stable sodium salt crystal form of an HIV-1 integrase inhibitor molecule having the structure of Formula I, the sodium salt crystal form of the present invention, and pharmaceutical compositions containing the sodium salt crystal form of the present invention as the main active ingredient, can be used for the prevention and / or treatment of HIV infection.

[0076] The sodium salt crystal forms include sodium salt crystal form A and sodium salt crystal form B.

[0077] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the polymorph of the present invention and a pharmaceutically acceptable excipient or carrier.

[0078] The term "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, the pharmaceutical composition contains 1-2000 mg of the polymorph of the present invention per dose, more preferably, 10-200 mg of the polymorph of the present invention per dose. Preferably, "one dose" refers to one capsule or tablet.

[0079] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the ability of the components in the composition to interact with and incorporate the active ingredient of the invention without significantly reducing the efficacy of the active ingredient. 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, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0080] There are no particular limitations on the administration of the polymorphs or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0081] 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: (a) fillers or compatibilizers, such as microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, sodium carbonate, crospovidone, and crospovidone carboxymethyl cellulose; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium 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, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0082] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings 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 portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active ingredient may also be formed into microcapsules with one or more of the excipients described above.

[0083] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0084] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0085] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0086] 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.

[0087] Dosage forms of the polymorphs of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0088] The polymorphs of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0089] When using the pharmaceutical composition, a safe and effective amount of the polymorph of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage at the time of administration is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 10–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0090] The pharmaceutical compositions provided by this invention preferably contain 1-99% by weight of an active ingredient, with a preferred proportion in which the compound of general formula I constitutes 65 wt% to 99 wt% of the total weight, and the remainder being a pharmaceutically acceptable carrier, diluent, solution, or saline solution. The compounds and pharmaceutical compositions provided by this invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and can be contained in suitable solid or liquid carriers or diluents and in suitable sterile instruments for injection or infusion.

[0091] Various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to conventional pharmaceutical preparation methods. The unit volume of the formulation contains 1 mg to 700 mg of the crystalline or salt form of the compound of general formula I; preferably, the unit volume of the formulation contains 25 mg to 300 mg of the compound of general formula I.

[0092] The compounds and pharmaceutical compositions of the present invention are suitable for clinical use in mammals, including humans and animals, and can be administered via oral, nasal, skin, lung, or gastrointestinal routes. Oral administration is 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, divided into multiple doses. Regardless of the method of administration, the optimal dose for an individual should be determined based on the specific treatment. Generally, a low dose is started, and the dose is gradually increased until the most suitable dose is found.

[0093] In this invention, unless otherwise specified, the drying method used is a conventional drying method in the art. For example, in the embodiments of this invention, drying refers to vacuum drying or atmospheric pressure drying in a conventional drying oven. Generally, the drying time is 0.1–50 h or 1–30 h.

[0094] Compared with the prior art, the main advantages of the present invention include:

[0095] (a) The crystal form of the present invention has high stability, low hygroscopicity, and high bioavailability, which is beneficial to its drug processing and use in pharmaceutical compositions.

[0096] (b) The crystal form of the present invention can be used as an active ingredient to prevent and treat diseases caused by HIV infection.

[0097] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0098] 1. Experimental Materials

[0099] In this invention, the raw material of compound I is a free solid prepared according to Example 1 of patent CN202111336306 from Eddie, and the other reagents are commercially available industrial or analytical grade reagents.

[0100] 2. Testing Methods

[0101]

[0102]

[0103] Example 1: Preparation of sodium salt crystal form A

[0104] Solid-liquid suspension equilibrium experiment at 1.25℃

[0105] Weigh approximately 30 mg of compound I into each vial, and add approximately 1 mL of the solvent listed in Table 1 below to prepare a suspension. Slowly add approximately 0.5 mL of sodium hydroxide in ethanol (1.1 eq.) to this solution, and magnetically stir at 25 ± 0.1 °C for 24 h. Observe the sample state during the experiment to ensure that the mixture is maintained in a vortex state; if any dissolution occurs, add solid. Filter and centrifuge all suspensions to obtain the solid. Purge with nitrogen or vacuum dry to remove residual solvent from the surface. X-ray powder testing results are shown in the image below. Figure 1 The results are shown in Table 2 below, and their DSC and TGA spectra are shown in [Table 2]. Figure 2 .

[0106] Table 1 Solid-liquid suspension equilibrium experiment at 25℃

[0107]

[0108]

[0109] Table 2. XRD characteristic peaks of sodium salt crystal form A

[0110] 6.308 1.38％ 7.806 52.40％ 9.107 92.29％ 11.069 14.46％ 11.686 14.37％ 12.535 19.17％ 13.120 8.19％ 13.420 21.78％ 14.807 6.81％ 15.587 100.00％ 16.332 24.62％ 16.849 12.61％ 17.994 19.84％ 18.226 31.47％ 18.622 26.84％ 19.299 18.76％ 19.525 16.13％ 19.729 18.33％ 20.828 39.59％ 21.052 9.67％ 22.016 16.77％ 22.198 36.15％ 22.472 4.32％ 23.448 26.33％ 23.712 16.79％ 24.121 79.71％ 24.425 4.40％ 24.739 3.15％ 25.241 18.26％ 25.756 22.64％ 26.147 27.41％ 26.963 6.32％ 27.738 38.92％ 28.184 15.74％ 28.907 12.36％ 29.763 4.84％ 30.262 5.67％ 30.882 12.71％ 31.392 4.78％ 31.776 4.62％ 33.217 10.11％ 34.521 9.64％ 34.820 3.82％ 35.090 0.68％ 35.908 2.18％ 36.875 9.30％ 37.645 2.72％ 38.225 4.39％ 39.014 0.13％ 39.401 1.75％ 39.689 3.55％

[0111] Solid-liquid suspension equilibrium experiment at 2.50℃

[0112] Weigh approximately 30 mg of compound I into each vial, add approximately 1 mL of the solvent listed in Table 3 below to prepare a suspension, slowly add approximately 0.5 mL of sodium hydroxide in ethanol (1.1 eq.) to the suspension, stir the reaction mixture and heat it to 50 °C, keep it at this temperature and stir for 2 h, then stir and cool to allow crystals to precipitate (cooling rate 10 °C / h), and continue to keep it at this temperature and stir for 5 h to allow crystals to precipitate. The solid is then separated to obtain sodium salt crystal form A of compound I.

[0113] Table 3 Solid-liquid suspension equilibrium experiment at 50℃

[0114] MeOH Crystal form A EtOH Crystal form A IPA Crystal form A EA Crystal form A IPAc Crystal form A Acetone Crystal form A THF Crystal form A MTBE Crystal form A ACN Crystal form A Heptane Crystal form A HO2 Crystal form A DMF Crystal form A DMSO Crystal form A <![CDATA[EtOH / H2O(V / V=95 / 5)]]> Crystal form A <![CDATA[ACN / H2O(V / V=95 / 5)]]> Crystal form A

[0115] Example 2: Preparation of sodium salt crystal form B

[0116] Weigh approximately 100 mg of compound I and prepare a suspension by adding approximately 0.5 mL of ethanol. Slowly add approximately 0.5 mL of an ethanol solution of sodium hydroxide (2.0 eq.) to this suspension over 1-30 minutes. Stir at room temperature for approximately 5-10 minutes. The solid is then separated to obtain sodium salt crystal form B of compound I. X-ray powder analysis is shown below. Figure 3 The results are shown in Table 4 below, and their DSC and TGA spectra are shown in [Table 4]. Figure 4 .

[0117] Table 4. XRD characteristic peaks of sodium salt crystal form B

[0118]

[0119]

[0120] Example 3: Scale-up experiment of sodium salt crystal form A

[0121] Add 52.6 kg of anhydrous ethanol, 6.6 kg of purified water, and 2.445 kg of compound I to reactor R1, start stirring, heat to 68-78℃, stir until dissolved, filter through a precision filter into reactor R2 in the clean area, continue heating to 68-78℃, and stir until dissolved.

[0122] A solution of 0.295 kg sodium hydroxide and 1.61 kg purified water was prepared and filtered through a precision filter into the dropping vessel of reactor R2 in the clean area. 60 g of sodium salt crystal form A was added to reactor R2, and the sodium hydroxide solution was slowly added dropwise while maintaining the temperature at 68-78℃. After the addition was complete, the mixture was kept at this temperature and stirred for 22 hours. The reaction solution was then slowly cooled to 10-15℃, and stirring was continued for another 3 hours to allow crystallization. The product was centrifuged, washed with ethanol, and then placed in a desiccator. The jacket temperature of the desiccator was controlled at 45-55℃, and the product 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). Its X-ray powder diagram is shown below. Figure 5 HPLC chromatograms are shown below. Figure 6 See the ee value graph. Figure 7 .

[0123] Example 4: Physicochemical properties of sodium salt crystal forms A and B

[0124] The sodium salt crystal forms A and B prepared in Examples 1 and 2, respectively, were tested by DSC, TGA, and HPLC. The data results are shown in Table 5 below.

[0125] Table 5 Physicochemical properties of sodium salt crystal forms A and B

[0126] Crystallinity high high DSC melting point (°C) 394.96 389.32 TGA weightlessness 0.367% at 380°C 2.167% at 368°C form fine particles fine particles purity(%) 99.6％ 99.5％

[0127] Both sodium salt crystal forms have high melting points, good hygroscopic properties and solid-state stability, and also exhibit excellent crystallinity.

[0128] Example 5: Solubility Test

[0129] 5-50 mg of compound I and sodium salt crystal form A were respectively suspended in 2-10 mL of solvent in glass bottles and stirred at 25 °C for 48 h. The suspensions were then filtered, and the solubility was calculated by determining the concentration of the saturated solution using HPLC. The results are shown in Table 6.

[0130] Table 6

[0131] Formula I compound water 5.1 Sodium salt crystal form A water 500.2

[0132] The results showed that at 25℃, the solubility of sodium salt crystal form A in water was significantly higher than that of compound I.

[0133] Example 6: Factors affecting sodium salt crystal form A

[0134] Accurately weigh 70 mg of sodium salt crystal form A sample and place it in separate glass petri dishes. Transfer the petri dishes to a temperature and humidity control 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 perform periodic testing on days 5 and 10. The samples were analyzed using XRPD and HPLC. Figure 8 and Figure 9 The color changes of the samples were observed, and the results are shown in Table 7.

[0135] Table 7. Experimental Factors Affecting the Crystal Form of Sodium Salt A

[0136]

[0137]

[0138] The above results indicate that sodium salt crystal form A did not change its properties under high temperature, high humidity and light conditions, its HPLC purity changed little, and its XRPD did not change, indicating that sodium salt crystal form A exhibits good physicochemical stability.

[0139] Example 7: Hygroscopicity of sodium salt crystal form A

[0140] 20 mg of sodium salt crystal form A sample was weighed and subjected to DVS test. The sample after DVS test was then tested by XRPD. The results are shown in Table 8 below.

[0141] Table 8. Sodium Salt DVS Test Results

[0142]

[0143] like Figure 10 and 11 The results of two DVS tests on sodium salt crystal form A showed that the weight gain of sodium salt crystal form A at a relative humidity of 80% was 0.69%, indicating that crystal form A has low hygroscopicity. The crystal form of the sample did not change before and after the DVS test, indicating that crystal form A has high humidity stability.

[0144] Example 8: High-pressure property test of sodium salt crystal form A

[0145] Approximately 300 mg of sodium salt crystal form A was weighed and added to a 13 mm diameter hydraulic pan. High-pressure property testing was performed using a manual hydraulic press at 10 MPa for 5 minutes. The resulting solid was characterized by XRPD. Figure 12 After high-pressure testing, the sodium salt crystal form A did not change.

[0146] Example 9: Simulated Granulation Test of Sodium Salt Crystal Form A

[0147] Ethanol was added dropwise to the sodium salt crystal form A sample until the solid was fully wetted, and then the sample was ground. The resulting solid and the sample without added wetting ethanol were subjected to XRPD analysis, and the results are as follows: Figure 13 The results showed that sodium salt crystal form A did not undergo any crystal form change after being wetted and ground with ethanol, indicating that sodium salt crystal form A has granulation stability.

[0148] Example 10: Pharmacokinetic Study

[0149] Sodium salt form A, sodium salt form B, and compound I (0.5% HPMC / 0.1% Tween-80 suspension) were administered orally to male SD rats (dose 5 mg / kg, volume 10 mL / kg, n = 3). 50 μL blood samples were collected via jugular vein puncture at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours before and after administration. The samples were placed in centrifuge tubes containing an anticoagulant (EDTA-K2), mixed thoroughly by inverting, placed on crushed ice, and centrifuged at 4°C and 3500 rpm for 10 minutes over 2 hours. Plasma samples were then transferred to correspondingly labeled EP tubes and stored at -80°C until analysis. Before analysis, the plasma in the EP tubes was thawed at room temperature and vortexed. 10 μL of the sample was used for LC-MS-MS determination of the concentration of compound I in the plasma. The blood drug concentration data and pharmacokinetic parameters were calculated and summarized using WinNonlin 8.1, as shown in Table 9.

[0150] Table 9 Results of pharmacokinetic parameters

[0151]

[0152] The above results indicate that, compared to sodium salt crystal form B and compound I, sodium salt crystal form A of this application, when orally administered to rats, resulted in a decrease in the C content of compound I in the plasma. max The higher AUC values ​​indicate that the plasma exposure of sodium salt form A (Formula I) is higher under the same administration conditions, suggesting that sodium salt form A may have better bioavailability.

[0153] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A sodium salt crystal form of a compound of formula I, characterized in that, I The sodium salt crystal form of the compound of formula I is sodium salt crystal form A, and sodium salt crystal form A has the following characteristic X-ray powder diffraction peaks at 2θ angles: 15.587°±0.2°, 9.107°±0.2°, 24.121°±0.2°, 7.806°±0.2°, 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 the following X-ray powder diffraction characteristic peaks at 2θ angles: 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 as described in claim 1, characterized in that, The X-ray powder diffraction pattern of the sodium salt crystal form A further includes two or more characteristic X-ray powder diffraction peaks with 2θ angles 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 crystal form B also includes two or more characteristic X-ray powder diffraction peaks with 2θ angles 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°.

3. The crystal form as described in claim 1, characterized in that, The X-ray powder diffraction pattern of the sodium salt crystal form A further includes 3, 4, or 5 characteristic X-ray powder diffraction peaks with 2θ angles 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 crystal form B also includes 3, 4 or 5 characteristic X-ray powder diffraction peaks with 2θ angles 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°.

4. The crystal form as described in claim 2, characterized in that, The sodium salt crystal form A further has one or more X-ray powder diffraction characteristic peaks with a 2θ angle 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°, 23.712°±0.2°; or The sodium salt crystal form B also has one or more X-ray powder diffraction characteristic peaks with 2θ angles selected from the following groups: 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°, 33.5°±0.2°.

5. The crystal form as described in claim 4, characterized in that, The sodium salt crystal form A has X-ray powder diffraction characteristic peaks with 2θ angles selected from the group consisting of: 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°, and 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 crystal form B has X-ray powder diffraction characteristic peaks with 2θ angles 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°.

6. The crystal form as described in claim 1, characterized in that, The thermogravimetric analysis spectrum of the sodium salt crystal form A shows weight loss in the range of 100℃ to 380℃, with a weight loss ratio of 0.2% to 2.0%; or the differential scanning calorimetry spectrum of the sodium salt crystal form A shows an absorption peak at 385℃ to 395℃.

7. The crystal form as described in claim 1, characterized in that, The thermogravimetric analysis spectrum of the sodium salt crystal form B shows weight loss in the range of 100℃ to 368℃, with a weight loss ratio of 1.0% to 3.0%; the differential scanning calorimetry spectrum of the sodium salt crystal form B shows an absorption peak at 385℃ to 390℃.

8. The crystal form as described in 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 crystal form A has XRPD data as shown in Table 2; and / or (2) The sodium salt crystal form A has a basic XRPD spectrum as shown in Figure 1; and / or (3) The sodium salt crystal form A has a basic DSC & TGA spectrum as shown in Figure 2; and / or (4) The sodium salt crystal form A has a basic DVS pattern as shown in Figure 11.

9. A method for preparing the crystal form according to claim 1, characterized in that, Including the following steps: When the compound of formula I is added to an organic solvent or an aqueous organic solvent, sodium hydroxide is added to react with it, crystallization occurs, yielding the sodium salt crystal form. The organic solvent is selected from the group consisting of: C1-C6 alcohol solvents, C1-C6 cyanide solvents, C1-C20 sulfone solvents, C1-C6 haloalkane solvents, n-heptane, C2-C6 ester solvents, C1-C6 ketone solvents, and C1-C6 ether solvents.

10. A method for preparing the crystal form according to claim 1, characterized in that, Including the following steps: When the compound of formula I is added to an organic solvent or an aqueous organic solvent, sodium hydroxide is added to react with it, crystallization occurs, yielding the sodium salt crystal form. The organic solvent is selected from the group consisting of: methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, ethyl acetate, isopropyl acetate, dimethyl sulfoxide, methyl tert-butyl ether, and n-heptane.

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

12. Use of the crystal form as claimed in claim 1 or the pharmaceutical composition as claimed in claim 11, characterized in that, Used to prepare a drug or preparation for the prevention and / or treatment of HIV infection.

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