A compound crystal form and its preparation, composition and use

Abstract

The present invention discloses a crystalline form C of a compound, which exhibits excellent stability under high temperature, high humidity, and light conditions, making it suitable for storage and transportation as a principle drug. During the process of manufacturing, methanol residue can be well controlled, meeting drugability requirements.

Description

Technical Field

[0001] The present invention relates to the medical field, and in particular to a compound crystal form and its preparation, composition and use. Background Art

[0002] Sepsis is a common, critical illness in ICUs, with a high mortality rate. Globally, there is no recognized effective treatment for sepsis, and clinical treatment primarily relies on symptomatic supportive care. Sepsis is a medical challenge that urgently needs to be addressed. Patent CN201880080079.X discloses a polyanionic cellobioside sulfate compound that demonstrates promising therapeutic effects against a variety of conditions, including sepsis. The compound has entered clinical research, demonstrating promising development potential.

[0003] According to the literature (Probst, Katrin C. SYNTHESIS AND CONFORMATIONAL INVESTIGATION OF SULFATED CARBOHYDRATES[1][J]. Cheminform, 2001, 20(7-8): 549-560.) and the methods described in patents CN201880080079.X and WO2019113646A1, the amorphous form of the compound can be obtained, but it has disadvantages such as low purity and poor stability. Summary of the Invention

[0004] In view of the above problems existing in the prior art, the present invention provides a technical solution to the above problems.

[0005] The first aspect of the present invention provides a crystalline form C of β-O-methyl-D-cellobiose heptasulfate sodium salt, which has characteristic diffraction peaks of 20.80±0.2°, 23.38±0.2°, and 23.64±0.2° in an X-ray powder diffraction pattern expressed in 2θ using Cu-Ka radiation.

[0006] In a second aspect of the present invention, a method for preparing Form C is provided, comprising the following steps: adding the compound β-O-methyl-D-cellobiose heptasulfate sodium salt to a solvent X, stirring, and separating the solid to obtain Form C; wherein the solvent X is a mixture of a first solvent and a second solvent; the first solvent is water, and the second solvent is 1,4-dioxane.

[0007] The third aspect of the present invention provides a raw material drug, which comprises the crystal form C described in the present application.

[0008] The fourth aspect of the present invention provides a composition comprising the crystalline form C described herein and one or more pharmaceutically acceptable excipients.

[0009] In a fifth aspect of the present invention, provided is the use of the crystal form C, the API, or the composition described herein in the preparation of an extracellular histone inhibitor.

[0010] In a sixth aspect of the present invention, provided is the use of the Form C, the API, or the composition described herein in the preparation of a drug for treating or preventing diseases or conditions mediated by extracellular histones.

[0011] In the seventh aspect of the present invention, provided is the use of the crystalline form C, the raw material drug, or the composition described in the present application in the preparation of a medicament for treating or preventing the following diseases, wherein the diseases are selected from: inflammation, severe pneumonia, sepsis, systemic inflammatory response syndrome, acute pancreatitis, acute kidney injury, acute lung injury, acute liver injury, acute respiratory distress syndrome, ischemia-reperfusion injury, atherosclerosis, deep vein thrombosis, ischemic injury, ischemic stroke, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis, ulcerative colitis, Crohn's disease and rheumatoid arthritis.

[0012] The positive progress effect of the present invention is:

[0013] (1) Compared with other crystalline forms and amorphous forms, Form C exhibits excellent stability under high temperature, high humidity and light conditions, making it suitable for the preparation, storage and transportation of raw materials. Compared with the amorphous form, which requires low temperature and dry storage and transportation, Form C can relax the storage and transportation temperature restrictions on raw materials, making it more convenient, economical and energy-saving.

[0014] (2) Compared with the amorphous and crystalline form B, which have poor brittleness, easy cracking, unstable tablet weight difference, slow dissolution rate and low dissolution rate during dry granulation and tableting, crystalline form C has better tableting effect, advantages in dissolution rate and dissolution rate, and is more suitable for preparation of preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 H of the compound prepared in Example 1 1 NMR spectrum

[0016] Figure 2 X-ray powder diffraction pattern (XPRD) of the compound prepared in Example 1

[0017] Figure 3 H of Form C 1 NMR spectrum.

[0018] Figure 4 X-ray powder diffraction pattern (XPRD) of Form C.

[0019] Figure 5 Thermogravimetric analysis (TGA-DTG) spectrum of Form C.

[0020] Figure 6 Differential scanning calorimetry (DSC) spectrum of Form C.

[0021] Figure 7 X-ray powder diffraction pattern (XPRD) of Form B.

[0022] Figure 8 Thermogravimetric analysis (TGA-DTG) spectrum of Form B.

[0023] Figure 9 Differential scanning calorimetry (DSC) spectrum of Form B.

[0024] Figure 10 H of Form B 1 NMR spectrum. DETAILED DESCRIPTION

[0025] In a specific embodiment, the crystalline form C uses Cu-Ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed as 2θ values ​​also include any one or more of 10.98±0.2°, 11.82±0.2°, 13.04±0.2°, 21.86±0.2°, 24.88±0.2°, 27.60±0.2°, and 30.10±0.2°.

[0026] In a specific embodiment, the crystalline form C uses Cu-Ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed as 2θ values ​​further include any one or more of 5.78±0.2°, 16.30±0.2°, 18.62±0.2°, 19.50±0.2°, 19.84±0.2°, 22.78±0.2°, and 25.38±0.2°.

[0027] Specifically, the crystalline form C uses Cu-Ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in 2θ values ​​further include any one or more of 10.14±0.2°, 11.38±0.2°, 14.82±0.2°, 16.94±0.2°, 24.20±0.2°, 28.00±0.2°, 28.74±0.2°, 31.86±0.2°, and 32.58±0.2°.

[0028] Specifically, the crystal form C uses Cu-Ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in 2θ values ​​further include 4.80±0.2°, 8.10±0.2°, 9.62±0.2°, 13.44±0.2°, 13.88±0.2°, 14.48±0.2°, 15.88±0.2°, 17.46±0.2°, 17.86±0.2°, 19.02±0.2°, 21.28±0.2°, 22.30±0.2°, 25.82±0.2°, 26.18±0.2°, 26.50±0.2° °, 27.02±0.2°, 28.46±0.2°, 29.36±0.2°, 30.66±0.2°, 31.24±0.2°, 33.04±0.2°, 33.38±0.2°, 33.82±0.2°, 34.66±0.2°, 35.14±0.2°, 35.98±0.2°, 36.50±0.2°, 36.76±0.2°, 37.22±0.2°, 37.60±0.2°, 38.10±0.2°, 38.74±0.2°, and 39.54±0.2°.

[0029] In a specific embodiment, the crystal form C uses Cu-Ka radiation, and the X-ray powder diffraction pattern expressed in 2θ values ​​is as follows Figure 4 shown.

[0030] In one embodiment, the total weight loss of Form C during thermogravimetric analysis is less than 16% (specifically, 15.42%) when heated to 150±2°C. Specifically, the DTG curve of Form C has an endothermic peak at (specifically, 70°C to 150°C), and the total TGA weight loss is 15.42%.

[0031] In one embodiment, the thermogravimetric analysis spectrum of Form C is as follows Figure 5 shown.

[0032] In a specific embodiment, the differential scanning calorimetry spectrum of Form C has an endothermic peak at 110.25±2°C and an exothermic peak at 199.41±2°C (indicating that Form C may degrade). Specifically, the differential scanning calorimetry spectrum of Form C has an endothermic peak in the range of 63.18±2°C to 149.20±2°C, with a peak height at 110.25±2°C. The differential scanning calorimetry spectrum of Form C has an exothermic peak in the range of 150.37±2°C to 203.46±2°C, with a peak height at 199.41±2°C.

[0033] In a specific embodiment, the differential scanning calorimetry spectrum of Form C is as follows Figure 6 shown.

[0034] In a specific embodiment, the crystalline form C described herein is a hydrate crystalline form.

[0035] In a specific embodiment, in the method for preparing Form C, the volume ratio of the first solvent to the second solvent may be 1:9 to 1:11 (e.g., 1:9.5, 1:10, 1:10.5).

[0036] In a specific embodiment, the preparation of the crystalline form C can be carried out at 10-60°C, further at 10-50°C, and further at room temperature.

[0037] As used in this application, the term "active pharmaceutical ingredient" refers to a raw material pharmaceutical (especially the effective ingredient in the preparation, also known as the active ingredient) or synthetic intermediate used for the further preparation or production of various preparations. It is a substance prepared by chemical synthesis or biotechnology and is in the form of powder, crystals, etc. for medicinal use, but cannot be directly taken by subjects.

[0038] In a specific embodiment, the weight percentage of the crystalline form C as described above in the present application in the raw material drug (β-O-methyl-D-cellobiose heptasulfate sodium salt raw material drug) is 80.0% to 100%, and can further be 90.0% to 100%, for example, 90.0%, 91.0%, 92.0%, 93.0%, 94.0%, 95.0%, 96.0%, 97.0%, 98.0%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or 100%. In addition to the crystalline form C, the raw material drug may also include an amorphous form of the compound, other crystalline forms, water, or other substances such as impurities or solvent residues within the range allowed by the quality standard.

[0039] In a specific embodiment, the weight percentage of the crystalline form C described in the present application in the composition is 1%-99.9%. For example, the weight percentage of the crystalline form of the compound described in the present application in the composition is 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% , 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.2%, 99.8%, 99.9%.

[0040] In a specific embodiment, the composition described herein is a stable pharmaceutical composition.

[0041] In a specific embodiment, the present application provides a composition comprising the drug substance and one or more pharmaceutically acceptable excipients.

[0042] As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered active ingredient (e.g., Form C of the compound described herein or the drug substance). Specifically, the pharmaceutically acceptable excipient includes, but is not limited to, diluents, fillers, disintegrants, wetting agents, lubricants, pH adjusters, buffers, colorants, flavorings, preservatives, or other conventional additives.

[0043] In a specific embodiment, the composition further comprises a buffer. Specifically, the buffer includes, but is not limited to, a phosphate buffer (e.g., a disodium hydrogen phosphate and sodium dihydrogen phosphate buffer system), a citrate buffer system (e.g., a sodium citrate / citric acid buffer system), or an acetate buffer (e.g., a sodium acetate / acetic acid buffer system).

[0044] The pharmaceutically acceptable excipients used with the crystalline Form C described herein to form a pharmaceutical composition may depend on the intended method of administering the pharmaceutical composition.

[0045] The crystalline form C (or the drug substance) described herein may have systemic and / or local activity. To this end, it can be administered in a suitable manner, such as orally, parenterally, pulmonary, nasal, sublingually, lingually, buccally, rectally, vaginally, dermal, transdermal, conjunctival, or otically, or as an implant or stent. For these routes of administration, the crystalline form of the compound described herein can be administered in a suitable dosage form.

[0046] Specifically, for oral administration, the crystalline form C described herein (or the drug substance) can be formulated into dosage forms known in the art that are delivered quickly and / or in a slow manner, such as tablets, orally disintegrating tablets, wafers, lyophilized preparations, capsules (e.g., hard gelatin capsules or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

[0047] Specifically, parenteral administration can be performed by avoiding an absorption step (e.g., intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or including an absorption step (e.g., intramuscularly, subcutaneously, intradermally, transdermally or intraperitoneally). Suitable administration forms for parenteral administration are, in particular, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilized agents or sterile powders.

[0048] In a specific embodiment, the composition can be a sterile powder. Upon use, the sterile powder is formulated into an injectable solution for clinical use (e.g., the injectable powder is dissolved in water for injection, Ringer's solution, isotonic saline, glucose solution, etc. to prepare an injectable solution). Specifically, the sterile powder can further include a buffer (the buffer can effectively inhibit acid hydrolysis / degradation of the compound after the sterile powder is formulated into an injectable solution).

[0049] As a specific embodiment of the present invention, the crystal form C, the raw material drug, or the composition is used as an extracellular histone inhibitor in the preparation or treatment of extracellular histone-mediated diseases.

[0050] The term "extracellular histone-mediated diseases or conditions" used in this application may refer to any of the extracellular histone-mediated diseases or conditions described in patent CN201880080079.X, and this application incorporates patent CN201880080079.X as a reference.

[0051] Under normal circumstances, histones are confined to the cell nucleus, forming nucleosomes with DNA. In disease states, histones and nucleosomes are released from dying cells into the circulation. The released histones have direct toxic effects on cells and the endothelium, leading to endothelial dysfunction, cell death, tissue damage, platelet activation, induced red blood cell aggregation and lysis, microcirculatory disorders, and organ damage or dysfunction. In addition to histones released after tissue cell lysis, extracellular histones also include histones released after immune cell lysis (such as histones in neutrophil traps).

[0052] The term "extracellular histone-mediated diseases or conditions" generally refers to diseases or conditions caused by the release of histones into the circulation (extracellular histones), including but not limited to: (1) inflammation, including inflammatory diseases, hyperinflammatory response, inflammatory injury, pneumonia (including severe pneumonia); (2) acute organ damage or organ dysfunction, including but not limited to acute lung injury, acute respiratory distress syndrome, acute kidney injury, acute liver injury, acute pancreatitis; (3) systemic inflammatory response syndrome, systemic inflammatory response can be caused by infection (4) Sepsis (including septic shock), which is generally caused by infections (bacteria, viruses, fungi, parasites, prions); (5) Hemostasis or vascular occlusion (hemostasis or thrombosis caused by local coagulation mediated by extracellular histones), such as cardiovascular diseases (such as atherosclerosis), coagulation and thrombosis. (6) ischemic injury, ischemic stroke; (7) ischemic reperfusion injury; (8) autoimmune disease states and inflammatory states (e.g., inflammatory states during the pathogenesis of autoimmune diseases), including but not limited to multiple sclerosis, hyperinflammatory disease states, systemic lupus erythematosus, spondyloarthritis, ankylosing spondylitis, psoriatic arthritis, reactive arthritis, enteropathic arthritis, ulcerative colitis, Crohn's disease, irritable bowel disease, rheumatoid arthritis, juvenile rheumatoid arthritis Rheumatoid arthritis, antineutrophil cytoplasmic antibodies, related vasculitides (e.g., granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and microscopic polyangiitis), characterized by destruction and inflammation of small blood vessels, familial Mediterranean fever, amyotrophic lateral sclerosis, Sjögren's syndrome, early arthritis, viral arthritis, psoriasis, age-related organ fibrosis, idiopathic pulmonary fibrosis, juvenile diabetes mellitus (type 1), diabetes mellitus (type 2), antiphospholipid syndrome; (9) central nervous system diseases, such as Huntington's disease.

[0053] Those skilled in the art should be aware that as medicine advances, disease diagnostic standards will evolve accordingly, and standards for diseases in different countries and regions may also vary. In practice, the diseases or symptoms described in this application may have different diagnostic standards in different countries. It should be understood that all diseases and conditions related to extracellular histone release are within the scope of this application.

[0054] Unless otherwise stated, the various embodiments or embodiments of different preferences described in this application can be arbitrarily combined.

[0055] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0056] Example

[0057] Example 1 Preparation of β-O-methyl-D-cellobiose heptasulfate sodium salt

[0058] Repeat the preparation method of Example 1 of patent CN201880080079.X to prepare β-O-methyl-D-cellobiose heptasulfate sodium salt (i.e. mCBS.Na in the patent, purity 90%), H 1 NMR Figure 1 As shown, XRPD ( Figure 2 ) has no obvious characteristic peaks and is amorphous.

[0059] Example 2 Crystal Form Screening

[0060] In this example, the crystal forms B and C were obtained by screening using gas-solid diffusion, gas-liquid diffusion, slow volatilization, stirring at room temperature / 50°C, and slow cooling induction.

[0061] 2.1 Gas-solid diffusion Weigh the starting sample into a small glass vial. Place the volatile solvent into a larger glass vial. Place the small glass vial into the larger glass vial. After 10 days, perform XRPD analysis on the solid. The experimental results (Table 1-1) show that the gas-solid diffusion method only yields an amorphous form.

[0062] Table 1-1 Gas-solid diffusion test results

[0063]

[0064]

[0065] 2.2 Gas-liquid diffusionWeigh a certain amount of starting sample into a small glass vial, add the appropriate solvent, and dissolve it with shaking at room temperature to obtain a clear solution. Place the antisolvent in a large glass vial. Place the open vial into the large glass vial and securely close the lid. Leave the vial at room temperature until solid precipitates. XRPD characterize the resulting solid. The experimental results (Table 1-2) indicate that the products screened by the vapor-liquid diffusion method are all amorphous.

[0066] Table 1-2 Gas-liquid diffusion test results

[0067]

[0068] 2.3 Slow evaporation Weigh a certain amount of starting sample into a glass vial and dissolve it in the appropriate solvent. Seal the vial, poke several holes, and evaporate at 50°C. The resulting solid was analyzed by XRPD. The experimental results (Tables 1-3) indicate that the products screened by the volatilization method are all amorphous.

[0069] Table 1-3 Volatilization test results

[0070]

[0071]

[0072] 2.4 Room temperature suspension crystallization A certain amount of starting sample was weighed into a vial, the appropriate solvent was added, and the suspension was obtained by stirring at room temperature. After several days, the solid was separated by centrifugation and analyzed by XRPD. The experimental results (Tables 1-4) show that, through the room temperature stirring method, Form C was obtained in 1,4-dioxane / water and Form B in N,N-dimethylformamide / water; the amorphous form was obtained in other solvents.

[0073] Table 1-4 Room temperature suspension crystallization experiment results

[0074]

[0075] 2.5 50℃ suspension crystallization A certain amount of starting sample was weighed into a vial, the appropriate solvent was added, and a suspension was obtained by stirring at 50°C. After several days, the solid was isolated by centrifugation, dried, and analyzed by XRPD. The experimental results (Tables 1-5) show that, using the 50°C stirring method, Form C was obtained in 1,4-dioxane / water; Form B was obtained in N,N-dimethylformamide / water; and Forms obtained in other solvents remained amorphous.

[0076] Table 1-5 Results of 50℃ suspension crystallization experiment

[0077]

[0078]

[0079] Example 3 Identification of Crystal Form

[0080] X-ray powder diffraction data of the samples were collected under ambient conditions using a Bruker D8 X-ray powder diffractometer with an X-ray emitter power of 300 W. The step size was 2θ = 0.02°, the voltage was 30 kV, and the current was 10 mA. The X-ray tube used a Cu target (Kα) with a Kα2 / Kα1 intensity ratio of

[0081] Thermogravimetric analysis (TGA): TGA data were collected using a Mettler TGA2 thermogravimetric instrument. Several milligrams of sample were placed in an alumina crucible and heated from room temperature to the target temperature under nitrogen at a flow rate of 50 mL / min and a heating rate of 10°C / min.

[0082] Differential Scanning Calorimetry (DSC): Thermal data were collected using a Mettler DSC 3 differential scanning calorimeter. Several milligrams of sample were weighed into a Tzero aluminum pan, sealed with a Tzero seal lid. Heating was performed under nitrogen at a flow rate of 50 mL / min and a heating rate of 10°C / min.

[0083] H of Form C 1 NMR Figure 3 As shown, the XRPD pattern of Form C is as follows Figure 4 The specific data are shown in Table 2 below.

[0084] The TGA-DTG spectrum of Form C is as follows Figure 5 As shown; DSC spectrum as Figure 6 The DTG curve of Form C has a peak in the range of 70℃~120℃, the total weight loss of TGA is 15.42%, and the corresponding DSC curve has an endothermic peak at 110.25℃. 1 No dioxane solvent peak appears in the NMR spectrum (Form C is obtained by dioxane / water slurrying), indicating that Form C is a hydrated form.

[0085] Table 2 XRPD diffraction peak data of Form C

[0086]

[0087]

[0088]

[0089] The XRPD pattern of Form B is as follows: Figure 7 The specific data are shown in Table 3 below.

[0090] The TGA-DTG spectrum of Form B is as follows Figure 8 As shown; DSC spectrum as Figure 9 As shown, the DTG curve has no obvious characteristic peak before decomposition, and the corresponding DSC curve has no endothermic peak, indicating that Form B is anhydrous, and the total weight loss of TGA is 7.98%. 1 NMR characterization, H 1 The NMR spectrum is consistent with that of the starting compound, with a DMF solvent peak appearing in the figure (Form B is obtained by DMF / water slurrying), indicating that Form B contains DMF solvent. Combined with the DSC and TGA spectra, the TGA weight loss step is gentle and there is no obvious desolvation peak in the DSC. Therefore, Form B should contain free DMF solvent (due to the high boiling point of DMF, some of it remains in the solid during drying).

[0091] Table 3. XRPD diffraction peak data of Form B

[0092]

[0093]

[0094] Example 4 Stability Test

[0095] Experimental testing of influencing factors was conducted on the crystal form samples. The experimental details and results are shown in Table 4. It can be seen that the total impurity content of the amorphous form increased significantly at 40°C, reaching a very high level by 30 days, and the appearance also turned gray. However, it became even more unstable at 60°C, with the compound content dropping to only 43.2% after 30 days. Form B's total impurity content began to increase significantly at 40°C after 10 days, with the increase in impurities being even more pronounced at 60°C, and the solid color changed from white to gray. Under high humidity conditions, both Form B and the amorphous form transformed into Form C. Form C exhibited excellent stability under high temperature, high humidity, and light conditions, with no change in appearance.

[0096] Table 4 Stability test

[0097]

[0098]

[0099] Example 5 Preparation and Scale-up Experiment of Crystal Form

[0100] Weigh 20g of the starting sample into a glass bottle, add the corresponding solvents as shown in Table 5, and magnetically stir at room temperature. Centrifuge and isolate the solids after drying. XRPD analysis revealed that the amorphous form crystallized from 1,4-dioxane / water to Form C, with no further crystallization observed after 6 days. Form B, obtained by stirring the amorphous form in N,N-dimethylformamide / water, exhibited low crystallinity. Its preparation required N,N-dimethylformamide, which has a high boiling point and results in significant residual solvent that is difficult to remove, making it unsuitable for use as a pharmaceutical API.

[0101] Table 5

[0102]

[0103] Example 6 Dry Granulation Process

[0104] According to the formulation in Table 6, tablets were prepared using dry granulation process for Form C, Form B and amorphous form.

[0105] 1. Premixing: First, put the added API, crospovidone, microcrystalline cellulose, and colloidal silicon dioxide into a three-dimensional motion mixer and mix for 10 minutes, then add (added) magnesium stearate and mix for 2 minutes;

[0106] 2. Dry granulation: dry granulate the above materials. When granulating, select a suitable screen, adjust the roller gap, and control the feed speed.

[0107] 3. Total mixing: Weigh the externally added crospovidone and colloidal silicon dioxide, mix through a 40-mesh sieve, and then add to a three-dimensional mixer and mix at 10 rpm for 10 minutes; then add (externally added) magnesium stearate and mix at 10 rpm for 3 minutes;

[0108] 4. Tabletting: Add the granules into the hopper, open the discharge baffle, observe through the sight glass, and when the granules in the feeder are fully filled, adjust the loading amount according to the tablet weight range to make the tablet weight meet the requirements, adjust the pressure to control the average hardness of the tablets to within the target range, and select a speed of 10-14 rpm for tableting;

[0109] Table 6

[0110]

[0111] The tableting effect of crystal form C is better, without problems such as loose tablets and cracks, and the tablet weight difference can meet the requirements. The tablet dissolution rate (pH 6.8) can reach 100%, and all tablets can be dissolved within 60 minutes.

[0112] During tableting, Form B and the amorphous form exhibit poor tablet friability, prone to flakes, and tablet weights that easily exceed the ±5% target weight range. Adjustments to other formulation components have not effectively addressed this issue. In terms of dissolution rate, the dissolution rate of amorphous dry-granulated tablets is much slower than that of crystalline dry-granulated tablets, reaching only 94% (taking 120 minutes to reach 94%). Form B dissolves even more slowly than Form C, requiring nearly 120 minutes for complete dissolution.

[0113] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A compound β-O-methyl-D-cellobiose heptasulfate sodium salt crystal form C, characterized in that: Using Cu-Ka radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in 2θ include 10.98±0.2°, 11.82±0.2°, 13.04±0.2°, 20.80±0.2°, 21.86±0.2°, 23.38±0.2°, 23.64±0.2°, 24.88±0.2°, 27.60±0.2°, and 30.10±0.2°.

2. The crystalline form C according to claim 1, wherein Using Cu-Ka radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in 2θ values ​​also include any one or more of 5.78±0.2°, 16.30±0.2°, 18.62±0.2°, 19.50±0.2°, 19.84±0.2°, 22.78±0.2°, and 25.38±0.2°.

3. The crystalline form C according to claim 1, wherein Using Cu-Ka radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in 2θ values ​​also include 4.80±0.2°, 8.10±0.2°, 9.62±0.2°, 10.14±0.2°, 11.38±0.2°, 13.44±0.2°, 13.88±0.2°, 14.48±0.2°, 14.82±0.2°, 15.88±0.2°, 16.94±0.2°, 17.46±0.2°, 17.86±0.2°, 19. 02±0.2°, 21.28±0.2°, 22.30±0.2°, 24.20±0.2°, 25.82±0.2°, 26.18±0.2°, 26.50±0.2°, 27.02±0.2°, 28.00±0.2°, 28.46±0.2°, 28.74±0.2°, 29.36±0.2°, 30.66±0.2°, 31.24±0.2°, 31.86±0.2°, 32.58±0.2°, 33.04 ±0.2°, 33.38±0.2°, 33.82±0.2°, 34.66±0.2°, 35.14±0.2°, 35.98±0.2°, 36.50±0.2°, 36.76±0.2°, 37.22±0.2°, 37.60±0.2°, 38.10±0.2°, 38.74±0.2°, 39.54±0.2°, any one or more of.

4. The crystalline form C according to claim 1, characterized in that The X-ray powder diffraction pattern expressed in 2θ using Cu-Ka radiation is shown in FIG4 .

5. The crystalline form C according to claim 1, characterized in that The differential scanning calorimetry spectrum of the crystal form C has an endothermic peak at 110.25±2°C and an exothermic peak at 199.41±2°C; and / or, The thermogravimetric analysis spectrum of the crystal form C shows that the total weight loss during heating to 150±2°C is less than 16%.

6. The crystalline form C according to claim 1, characterized in that The crystal form C is a hydrate crystal form.

7. A method for preparing the crystal form C according to any one of claims 1 to 6, characterized in that: The method comprises the following steps: adding a compound β-O-methyl-D-cellobiose heptasulfate sodium salt to a solvent X, stirring, separating a solid, and obtaining a crystalline form C; wherein the solvent X is a mixture of a first solvent and a second solvent; the first solvent is water, and the second solvent is 1,4-dioxane.

8. The method for preparing Form C according to claim 7, wherein: The volume ratio of the first solvent to the second solvent is 1:9 to 1:

11.

9. A bulk drug, characterized in that: comprising the crystalline form C according to any one of claims 1 to 6, The weight percentage of the crystalline form C in the raw material drug is 80.0% to 100%.

10. A composition, characterized in that Comprising the crystalline form C according to any one of claims 1 to 6, and one or more pharmaceutically acceptable excipients.

11. The composition according to claim 10, wherein The composition is a sterile powder, and / or the pharmaceutically acceptable excipient is a buffer.

12. Use of the crystalline form C according to any one of claims 1 to 6, the API according to claim 9, or the composition according to claim 10 or 11 in the preparation of an extracellular histone inhibitor.

13. Use of the crystalline form C according to any one of claims 1 to 6, the API according to claim 9, or the composition according to claim 10 or 11 in the preparation of a medicament for treating or preventing the following diseases, wherein the diseases are selected from: sepsis, acute kidney injury, acute liver injury, ischemia-reperfusion injury, deep vein thrombosis, and multiple sclerosis.

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