Crystal form A of fisurazan hydrochloride as well as preparation method and application of crystal form A

Abstract

The invention provides a fisurazan hydrochloride crystal A. The X-ray powder diffraction pattern of the fisurazan hydrochloride crystal A has characteristic peaks at 2theta values of 9.1 + / -0.2 degrees, 13.7 + / -0.2 degrees, 14.9 + / -0.2 degrees and 18.3 + / -0.2 degrees, and has characteristic peaks at at least one of 2theta values of 8.2 + / -0.2 degrees, 12.3 + / -0.2 degrees, 17.9 + / -0.2 degrees, 20.1 + / -0.2 degrees, 21.0 + / -0.2 degrees, 21.5 + / -0.2 degrees, 22.7 + / -0.2 degrees, 23.0 + / -0.2 degrees, 24.9 + / -0.2 degrees, 25.7 + / -0.2 degrees, 28.0 + / -0.2 degrees and 28.9 + / -0.2 degrees. The preparation method of the crystal A is simple and convenient, good in reproducibility and low in requirements on a preparation process and storage conditions; under open conditions of 25 DEG C / 60% RH, 40 DEG C / 75% RH and room temperature / 92.5% RH, good physical and chemical stability is shown, and particularly, compared with a known fisurazan hydrochloride crystal form I, the fisurazan hydrochloride crystal form I has better chemical stability; and the crystal form A is in a short rod shape of less than or equal to 100 microns (preferably 20-50 microns), and the crystal form A is not easy to agglomerate, so that industrial production is facilitated.

Description

A crystalline form A of fesulazan hydrochloride and its preparation method and use

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on September 29, 2022, with application number 202211203552.3 and invention name “A kind of crystalline form A of fesulazan hydrochloride and its preparation method”, the entire contents of which are incorporated into this application by reference. Technical Field

[0002] The present application belongs to the field of chemical medicine, and specifically relates to a crystal A of Fesulazan hydrochloride, a preparation method and use thereof. Background Art

[0003] Fexuprazan, whose chemical name is 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine, is a new potassium ion competitive acid blocker (P-CAB) and a new generation of proton pump inhibitors (PPIs) developed by Daewoong Co., Ltd. in South Korea. It can reversibly block the proton pump that secretes gastric acid and is used to treat gastroesophageal reflux disease. The Phase III clinical data of Fexuprazan, a new gastroesophageal reflux disease drug, was first announced at the 2020 Digestive Disease Week (DDW), confirming that Fexuprazan has a significant effect in inhibiting gastric acid secretion and is better than esomeprazole in relieving heartburn and other non-specific symptoms. The hydrochloride compound of this drug is shown in formula (1):

[0004] Patent WO2017164575A1 discloses a compound of formula (1), a preparation method thereof, and a pharmaceutical composition thereof, including a free base, a hydrochloride, a succinate, a tartrate, and a fumarate, and discloses its solubility and stability data.

[0005] Patent WO2017164576A1 further discloses free base crystal form, hydrochloride crystal form I and crystal form II, succinate crystal form, tartrate crystal form, fumarate crystal form I and crystal form II and their preparation methods.

[0006] It is well known that different crystalline forms of the same compound have different physical and chemical properties, which can affect the solubility of the drug and ultimately its drugability. Therefore, developing polymorphs of Fesulazan hydrochloride and finding other crystalline forms suitable for formulation development are of great significance, providing new options for the industrial production of Fesulazan hydrochloride.

[0007] Summary of the Invention

[0008] The present application provides a new crystalline form A (or crystal form A or crystalline form A) of fesulazan hydrochloride (i.e., fesulazan hydrochloride) and its preparation method and use.

[0009] In a first aspect, the present application provides a crystalline form A of fesulazan hydrochloride, whose X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.1±0.2°, 13.7±0.2°, 14.8±0.2° and 18.3±0.2°.

[0010] The present application provides a crystalline form A of fesulazan hydrochloride, which has an X-ray powder diffraction pattern having characteristic peaks at 2θ values ​​of 9.1±0.2°, 13.7±0.2°, 14.9±0.2° and 18.3±0.2°, and has a characteristic peak at at least one of 2θ values ​​of 8.2±0.2°, 12.3±0.2°, 17.9±0.2°, 20.1±0.2°, 21.0±0.2°, 21.5±0.2°, 22.7±0.2°, 23.0±0.2°, 24.9±0.2°, 25.7±0.2°, 28.0±0.2° and 28.9±0.2.

[0011] The present application provides a crystalline form A of fesulazan hydrochloride, the X-ray powder diffraction spectrum of which has characteristic peaks at 2θ values ​​of 9.1±0.2°, 13.7±0.2°, 14.9±0.2°, and 18.3±0.2°, and has peaks at 2θ values ​​of 8.2±0.2°, 12.3±0.2°, 16.9±0.2°, 17.3±0.2°, 17.6±0.2°, 17.9±0.2°, 18.9±0.2°, 19.4±0.2°, 20. At least one of 1±0.2°, 20.5±0.2°, 21.0±0.2°, 21.5±0.2°, 22.7±0.2°, 23.0±0.2°, 24.9±0.2°, 25.2±0.2°, 25.7±0.2°, 26.1±0.2°, 26.4±0.2°, 26.8±0.2°, 27.8±0.2°, 28.0±0.2°, 28.9±0.2 and 29.2±0.2° has a characteristic peak.

[0012] Furthermore, the XRPD pattern (X-ray powder diffraction pattern) of the crystalline form A of fesulazan hydrochloride described in the present application is basically consistent with Figure 1.

[0013] In some embodiments of the present application, the differential scanning calorimetry (DSC) spectrum of the crystalline form A of fesulazan hydrochloride described in the present application has an endothermic peak at 215.2°C±5°C.

[0014] Furthermore, the differential scanning calorimetry (DSC) spectrum of Form A of Fesulazan hydrochloride described in the present application is substantially consistent with FIG. 2 .

[0015] In some embodiments of the present application, the thermogravimetric analysis (TGA) of the Form A of Fesulazan hydrochloride described in the present application shows no obvious weight loss at 0-100° C., and the Form A is an anhydrous crystalline form.

[0016] Furthermore, the thermogravimetric analysis TGA spectrum of Form A of Fesulazan Hydrochloride described in the present application is basically consistent with Figure 3.

[0017] In some embodiments of the present application, the dynamic vapor sorption (DVS) spectrum of the crystalline form A of fesulazan hydrochloride described in the present application shows that the adsorbed water content of the crystalline form A under 80% RH conditions is 0.2-2%, preferably 0.2-0.5%, and is slightly hygroscopic.

[0018] In some embodiments of the present application, the dynamic vapor adsorption DVS spectrum of the crystalline form A of fesulazan hydrochloride described in the present application is substantially consistent with FIG4 .

[0019] In some embodiments of the present application, the NMR spectrum of Form A of Fesulazan Hydrochloride described in the present application is consistent with FIG5 .

[0020] In some embodiments of the present application, the polarizing light microscope (PLM) image of the crystal form A of fesulazan hydrochloride described in the present application shows that the crystal form A is in the shape of regular short rods.

[0021] In some embodiments of the present application, the particle size of the crystalline form A of fesulazan hydrochloride described in the present application is ≤100 μm, preferably 20-50 μm.

[0022] The second aspect of the present application provides a method for preparing the crystalline form A of fesulazan hydrochloride described in the first application of the present application, comprising:

[0023] (1) dissolving fesulazan hydrochloride in an alcohol solvent, and evaporating the solvent at a suitable temperature until solid precipitates to obtain Form A; or

[0024] (2) Dissolve fesulazan hydrochloride in a mixed solvent of alcohols and esters, and evaporate the solvent at a suitable temperature until solid precipitates to obtain Form A.

[0025] In some embodiments of the present application, the mass volume ratio of fisurazan hydrochloride to the alcohol solvent in (1) is (10-1) mg:1 mL, preferably (6-1) mg:1 mL.

[0026] In some embodiments of the present application, the mass volume ratio of fisurazan hydrochloride to the mixed solvent of alcohols and esters in (2) is (10-1) mg:1 mL, preferably (8-1) mg:1 mL.

[0027] In some embodiments of the present application, the volume ratio of alcohols to esters in (2) is 1:(0.5-6), preferably 1:(2-3).

[0028] In some embodiments of the present application, in (1), the alcohol solvent is selected from at least one of methanol, ethanol or isopropanol, preferably ethanol.

[0029] In some embodiments of the present application, in (2), the alcohol is selected from at least one of methanol, ethanol or isopropanol, preferably ethanol.

[0030] In some embodiments of the present application, in (2), the ester is selected from at least one of ethyl acetate, methyl acetate or isopropyl acetate, preferably ethyl acetate.

[0031] In some embodiments of the present application, in (1) or (2), the dissolution temperature is 0-100°C, preferably 20-30°C, and more preferably room temperature. The room temperature mentioned in the present application is 25°C.

[0032] In some embodiments of the present application, in (1) or (2), the suitable temperature is 20-80°C, preferably 20-45°C, and more preferably room temperature. The room temperature described in the present application is 25°C.

[0033] In some embodiments of the present application, in (1) or (2), the volatilization method is rapid volatilization, preferably rapid decompression volatilization, and more preferably vacuum decompression volatilization at room temperature. The room temperature described in the present application is 25°C.

[0034] In some embodiments of the present application, in (1) or (2), the volatilization time is 1 to 24 hours, preferably 1 to 3 hours.

[0035] The fesulazan hydrochloride crystal form A provided in the present application is a new anhydrous crystal form, which is slightly hygroscopic at 25°C; the results of a one-week accelerated temperature and humidity test show that the physical and chemical properties of the crystal form A are stable; the solubility test results show that the crystal form A prepared in the present application has a water solubility performance improved by nearly 1 times compared with the crystal form I, and its solubility in pH 4.5 acetic acid buffer solution is significantly better than that of the crystal form I, and its solubility in pH 1.2 buffer solution and pH 6.8 phosphate buffer solution is comparable to that of the crystal form I, showing good drugability.

[0036] The crystalline form A of fesulazan hydrochloride prepared in the present application has stable physical and chemical properties and high solubility. The crystalline form A obtained by its preparation method has good crystal habits and no agglomeration problem, which provides more options for the formulation development of fesulazan hydrochloride.

[0037] In a third aspect, the present application further provides a pharmaceutical composition comprising a therapeutically effective amount of Form A of Fesulazan hydrochloride and a pharmaceutically acceptable carrier. The pharmaceutical composition described herein is prepared by mixing or contacting a therapeutically effective amount of Form A of Fesulazan hydrochloride with one or more pharmaceutical excipients. The specific preparation method can be used in a manner well known in the pharmaceutical art, and the composition can be prepared into various dosage forms as needed.

[0038] The fourth aspect of the present application further provides a use of the crystalline form A described in the first aspect of the present application or the pharmaceutical composition described in the third aspect of the present application in preparing a drug;

[0039] In some embodiments of the present application, the drug is used to treat peptic ulcer or reflux esophagitis.

[0040] The fifth aspect of the present application also provides a method for treating peptic ulcer or reflux esophagitis, comprising: administering a therapeutically effective amount of the crystal form A described in the first aspect of the present application or the pharmaceutical composition described in the third aspect of the present application to a subject in need.

[0041] In the present application, "the X-ray powder diffraction pattern of the crystalline form A is consistent with Figure 1", which means that the precise position of the peak in the accompanying figure should not be interpreted as an absolute value. Because it is known to those skilled in the art that the 2θ value of the X-ray powder diffraction pattern may produce errors due to different measurement conditions (such as the equipment and instruments used) and different samples, the measurement error of the diffraction angle of the X-ray powder diffraction pattern is 5% or less. Generally, a difference of ±0.2° from a given value is considered appropriate. It should also be understood that the relative intensity of the peak may fluctuate with experimental conditions and sample preparation, such as the preferred orientation of the particles in the sample. The use of automatic or fixed divergence slits will also affect the calculation of relative intensities. The intensities shown in the XRPD curves included here are only exemplary and cannot be used as absolute comparisons.

[0042] As used herein, a therapeutically effective amount refers to an amount of a drug sufficient to affect the treatment of a disease, or at least one clinical symptom of a disease or condition, when used to treat a subject. A therapeutically effective amount can vary depending on the drug, the symptoms of the disease or condition, the severity of the symptoms of the disease or condition, and the like. Wherever possible, an appropriate dosage will be readily apparent to one skilled in the art or can be determined by routine experimentation.

[0043] The pharmaceutically acceptable carrier described herein refers to a non-toxic carrier, diluent or excipient that does not adversely affect the pharmacological activity of the crystalline form formulated therewith and is safe for use in animals.

[0044] The pharmaceutical composition comprising the crystal form of the present application can be administered orally, by nasal inhalation, rectally, parenterally, or topically. For oral administration, the pharmaceutical composition can be prepared into conventional solid dosage forms such as tablets, powders, granules, capsules, etc., or liquid dosage forms such as aqueous or oily suspensions, or other liquid dosage forms such as syrups, solutions, suspensions, etc. For parenteral administration, the pharmaceutical composition can be prepared into solutions, aqueous solutions, oily suspensions, lyophilized powder injections, etc.

[0045] Beneficial technical effects of this application:

[0046] The present application provides a new anhydrous crystalline form, namely Form A of Fesulazan Hydrochloride. The Form A of Fesulazan Hydrochloride obtained in the present application shows good physicochemical stability under the conditions of 25°C / 60%RH, 40°C / 75%RH and room temperature / 92.5%RH. In particular, it has better chemical stability than the Form I of Fesulazan Hydrochloride disclosed in patent WO2017164576A1. The chemical stability of the Form A provided in the present application is also significantly better than that of the known Form I under high temperature and high humidity conditions. It has good drugability and good physical stability under mechanical force. The good physicochemical stability can ensure that the drug will not undergo crystal transformation during production and storage and that basically no impurities are generated, thereby ensuring that the quality of the raw materials and preparations can be controlled, and reducing changes in drug quality, bioavailability, and toxic side effects caused by changes in crystal form or impurities.

[0047] The crystalline form A of fesulazan hydrochloride obtained in the present application also presents a short rod-shaped particle size of ≤100 μm (better 20-50 μm). The crystalline form A is not easy to agglomerate and has good fluidity, which is conducive to industrial production. The particle size of the crystalline form A provided in the present application is uniform and smaller, with a more uniform particle size distribution. The uniform particle size helps to reduce solvent enrichment, improve product purity, reduce product solvent residue, ensure the uniformity of the drug preparation content, and reduce the variability of in vitro dissolution. Smaller particle size helps to improve the solubility and bioavailability of the drug.

[0048] The crystalline form A of fesulazan hydrochloride obtained in the present application exhibits good solubility in pH 4.5 acetate buffer and water, which are 142.8 mg / mL and 11.1 mg / mL, respectively, which is significantly better than the known hydrochloride crystalline form I discovered so far. In particular, the solubility in water is nearly 1 times higher than that of the hydrochloride crystalline form I disclosed in patent WO2017164576A1. The crystalline form A of fesulazan hydrochloride provided in the present application has a higher solubility, which is beneficial to improving the absorption of the drug in the human body and improving the bioavailability; the higher solubility reduces the dosage of the drug while ensuring the efficacy of the drug, improves the product quality, thereby reducing the side effects of the drug and improving the safety of the drug.

[0049] At the same time, it was unexpectedly discovered that by controlling the use of alcohol solvents or organic solvents of alcohols and esters in the crystallization method of this application, and coordinating the solvent volatilization process, the new crystalline form A of the hydrochloric acid of the present application also has a high yield and high purity. The photostability and accelerated stability of the obtained new crystalline form A are also particularly significant. The hydrochloric acid of the ... BRIEF DESCRIPTION OF THE DRAWINGS

[0050] The drawings described herein are used to provide further understanding of the present application and constitute a part of the present application. The illustrative embodiments of the present application and their descriptions are used to explain the present application and do not constitute improper limitations on the present application.

[0051] FIG1 is an X-ray powder diffraction (XPRD) pattern of Form A;

[0052] FIG2 is a differential scanning calorimetry (DSC) spectrum of Form A;

[0053] FIG3 is a thermogravimetric analysis (TGA) spectrum of Form A;

[0054] FIG4 is a dynamic vapor sorption (DVS) spectrum of Form A;

[0055] Figure 5 is the H NMR spectrum of Form A ( 1 H-NMR) spectrum;

[0056] FIG6 is a polarizing light microscope (PLM) image of Form A. DETAILED DESCRIPTION

[0057] To make the objectives, technical solutions, and advantages of this application more clearly understood, the present application is further described in detail below with reference to the accompanying drawings and examples. It is apparent that the described examples are only a portion of the embodiments of this application, rather than all of them. All other embodiments obtained by those skilled in the art based on this application are within the scope of protection of this application.

[0058] Comparative Example: Preparation of Form I of Fesulazan Hydrochloride

[0059] 8.9 g of fesulazan was weighed and placed in a 100 mL eggplant-shaped flask. 10.0 mL of ethyl acetate was added and stirred at room temperature. 14 mL of hydrochloric acid solution (2.0 mL of concentrated hydrochloric acid diluted with 12.0 mL of ethyl acetate) was then added. After stirring for 2 days, the mixture was filtered and rinsed with ethyl acetate to obtain a white solid. XRPD analysis of this sample showed that the XRPD spectrum of this sample was consistent with the anhydrous crystalline Form I disclosed in patent WO2017164576A1, indicating that it was the same crystalline form.

[0060] Example 1.1: Preparation of Form A of Fesulazan Hydrochloride

[0061] 40 mg of Form I of Fesulazan hydrochloride obtained in the comparative example was weighed into a 10 mL centrifuge tube, dissolved in 2.0 mL of ethanol, and then 4.5 mL of isopropyl acetate was added. The mixture was then placed in a vacuum drying oven and evaporated at room temperature for 3 hours to obtain white crystals, namely Form A. The X-ray powder diffraction (XPRD) pattern of Form A is shown in Figure 1, the differential scanning calorimetry (DSC) pattern of Form A is shown in Figure 2, the thermogravimetric analysis (TGA) pattern of Form A is shown in Figure 3, and the nuclear magnetic resonance spectrum of Form A is shown in Figure 5. Form A is short rod-shaped crystals measuring 20 to 50 μm, free of residual inclusions. The polarizing light microscopy (PLM) image is shown in Figure 6.

[0062] Example 1.2: Preparation of Form A of Fesulazan Hydrochloride

[0063] 40 mg of Form I of the hydrochloride of Fesulazan obtained in the comparative example was placed in a 10 mL centrifuge tube, 2.0 mL of ethanol was added to dissolve it, filtered, and 6.0 mL of isopropyl acetate was added. The mixture was then transferred to a vacuum drying oven and evaporated at room temperature for 3 hours to obtain white crystals, namely Form A.

[0064] Example 2 Accelerated temperature and humidity stability test

[0065] Form A of fesulazan hydrochloride and Form I of fesulazan hydrochloride disclosed in patent WO2017164576A1 were simultaneously placed under open conditions of 25°C / 60% RH, 40°C / 75% RH, and room temperature / 92.5% RH for 1 week to observe changes in crystal form and purity. The results are summarized in Table 1:

[0066] Table 1 Accelerated temperature and humidity stability test results

[0067] The results of the accelerated temperature and humidity experiment show that the crystalline form A of the non-surazan hydrochloride of the present application is stable in physical and chemical properties under the conditions of 25°C / 60%RH, 40°C / 75%RH and room temperature / 92.5%RH exposure. In particular, compared with the non-surazan hydrochloride crystalline form I disclosed in patent WO2017164576A1, it shows lower degradation or no obvious degradation under the conditions of 25°C / 60%RH, 40°C / 75%RH and room temperature / 92.5%RH exposure, and the purity of crystalline form A is higher. The crystalline form A of the non-surazan hydrochloride has better chemical stability than the crystalline form I disclosed in patent WO2017164576A1. There was no change in the crystalline form after the one-week accelerated temperature and humidity experiment of the two crystalline forms, and the physical stability of the two crystalline forms was good.

[0068] Example 3: X-ray powder diffraction analysis of Form A of Fesulazan hydrochloride

[0069] The XPRD spectrum of Form A of Fesulazan hydrochloride was collected on a Bruker D8ADVANCE diffractometer. The X-ray powder diffraction method parameters are as follows:

[0070] X-ray reflection parameters: Cu, Kα;

[0071] Tube voltage: 40 kilovolts (kV);

[0072] Tube current: 40 milliamperes (mA);

[0073] Slits: 2# scattering slit: 1°, 3# anti-scattering slit: 1°, 4# receiving slit: 0.3mm.

[0074] Scan mode: step;

[0075] Step angle: 0.02°, sampling time: 0.2s;

[0076] Scanning range: from 3.0 to 40.0 degrees.

[0077] The diffraction results are shown in FIG1 and Table 2. The X-ray powder diffraction pattern of the crystalline form A of the hydrochloride of sulfazan has corresponding characteristic diffraction peaks at corresponding positions of 2θ values.

[0078] Table 2 2θ values ​​of X-ray powder diffraction absorption peaks of Fesulazan hydrochloride Form A

[0079] Example 4: Differential Scanning Calorimetry (DSC) of Form A of Fesulazan Hydrochloride

[0080] DSC spectra were collected on a TA Instruments Discovery DSC 250 instrument. The differential scanning calorimetry method parameters were as follows:

[0081] Heating rate: 10°C / min;

[0082] Protective gas: nitrogen.

[0083] Test method: Weigh 3-5 mg of sample into an aluminum crucible, seal it with a non-sealed lid, and load the sample onto a DSC instrument for analysis. Under nitrogen, heat the sample from room temperature to 300°C at a scan rate of 10°C / min. The results are shown in Figure 2, which shows an endothermic peak at 215.2°C ± 5°C.

[0084] Example 5: Thermogravimetric analysis (TGA) of Form A of Fesulazan hydrochloride

[0085] TGA spectra were collected on a TA Instruments Discovery TGA 55 instrument. The method parameters for thermogravimetric analysis were as follows:

[0086] Heating rate: 10°C / min;

[0087] Protective gas: nitrogen.

[0088] Testing method: A 5-10 mg sample was weighed and placed on a platinum pan, then loaded onto a TGA instrument for analysis. The sample was heated from room temperature to 300°C under nitrogen at a scan rate of 10°C / min. The results are shown in Figure 3, which shows a weight loss of 0.136% at 100°C, and sample decomposition begins at 223.7°C.

[0089] Example 6: Dynamic Vapor Sorption (DVS) Test of Form A of Fesulazan Hydrochloride

[0090] Testing method: Approximately 20 mg of sample was placed in a platinum pan, which was then placed in an Intrinsic DVS Advantage instrument. The sample was subjected to adsorption-desorption at relative humidity (RH) levels of 0% to 95% to 0%, with each step of ±10% RH. At each stage, the following equilibrium criteria were used: dm / dt < 0.002% over 5 minutes, and minimum and maximum times in each stage of 10 and 360 minutes, respectively. The DVS results are shown in Figure 4. As can be seen, Form A of Fesulazan hydrochloride exhibited a slightly hygroscopic water content of 0.391% at 80% RH.

[0091] Example 7: Solubility Test

[0092] (1) Preparation of pH 1.2 hydrochloric acid buffer solution

[0093] Weigh 0.2983 g of potassium chloride, add 20 mL of water, mix and ultrasonically dissolve to obtain a 0.2 mol / L potassium chloride aqueous solution; then measure 19.67 mL of water and 0.33 mL of concentrated hydrochloric acid, mix and ultrasonically obtain a 0.2 mol / L hydrochloric acid aqueous solution; then take 10 mL of 0.2 mol / L potassium chloride aqueous solution, 17 mL of 0.2 mol / L hydrochloric acid aqueous solution and 13 mL of water and ultrasonically mix them evenly, and finally adjust the pH to 1.2 by adding hydrochloric acid aqueous solution to obtain a hydrochloric acid buffer solution.

[0094] (2) Preparation of pH 4.5 acetate buffer solution

[0095] Weigh 2.387 g of anhydrous sodium acetate, add 20 mL of water, mix and ultrasonically dissolve to obtain a 1.45 mol / L sodium acetate aqueous solution; then weigh 0.2 mL of glacial acetic acid, add 1.55 mL of water to dilute, mix and ultrasonically dissolve to obtain a 2 mol / L acetic acid aqueous solution; then take 0.56 mL of the 2 mol / L acetic acid aqueous solution and add it to the sodium acetate aqueous solution, then add 8.25 mL of water and ultrasonically mix until uniform, and finally adjust the pH by adding the acetic acid aqueous solution to obtain an acetic acid buffer solution of pH 4.5.

[0096] (3) Preparation of pH 6.8 phosphate buffer solution

[0097] Weigh 0.5444 g of potassium dihydrogen phosphate, add 20 mL of water, mix and ultrasonically dissolve to obtain a 0.2 mol / L potassium dihydrogen phosphate aqueous solution; then measure 20 mL of water, weigh 0.16 g of sodium hydroxide, mix and ultrasonically dissolve to obtain a 0.2 mol / L sodium hydroxide aqueous solution; then, take 10 mL of the 0.2 mol / L potassium dihydrogen phosphate aqueous solution, 4.48 mL of the 0.2 mol / L sodium hydroxide aqueous solution, and 25.52 mL of water and ultrasonically mix them uniformly. Finally, adjust the pH to 6.8 by adding the sodium hydroxide aqueous solution to obtain a phosphate buffer solution.

[0098] Test method: At room temperature, the crystalline form A prepared in Example 1.1 and the anhydrous crystalline form I disclosed in patent WO2017164576A1 were tested for solubility in hydrochloric acid buffer at pH 1.2, acetate buffer at pH 4.5, phosphate buffer at pH 6.8, and pure water. 10 mg of each sample was accurately weighed and placed in a vial, 10 μL of the corresponding solvent was added thereto, shaken for 30 seconds and ultrasonically shaken for 1 minute, and the process was repeated several times. The solubility was calculated by measuring the amount of solvent used to dissolve all samples. If the sample was clearly soluble, the experimental data was recorded. If the sample was not soluble after adding 5 mL of solvent, the filtrate was taken and the content was determined by HPLC. The experimental results are shown in Table 3:

[0099] Table 3 Comparative study of equilibrium solubility

[0100] The results in Table 3 above show that the crystalline form A of the hydrochloride of chloramphenicol obtained in the present application and the crystalline form I of the hydrochloride of chloramphenicol disclosed in WO2017164576A1 have relatively higher solubility in pH 4.5 acetic acid buffer solution, which are 142.8 mg / mL and 125.0 mg / mL, respectively. The solubility of crystalline form A is better than that of crystalline form I; the solubility in pure water is 11.1 mg / mL and 5.9 mg / mL, respectively. The solubility of crystalline form A of chloramphenicol hydrochloride in pure water is increased by nearly 1 times; the solubility of crystalline form A in pH 1.2 hydrochloric acid buffer solution and pH 6.8 phosphate buffer solution is basically equivalent to that of crystalline form I, and both have good solubility.

[0101] In summary, the fesulazan hydrochloride crystalline form A obtained in the present application is a new crystalline form with a unique XRPD fingerprint spectrum that is different from the previously disclosed ones. It has stable physicochemical properties, good solubility, a simple preparation method, and good reproducibility, providing more options for the application and development of fesulazan hydrochloride pharmaceutical preparations.

[0102] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included in the scope of protection of the present application.

Claims

1. A crystalline form A of fesulazan hydrochloride, characterized in that: The X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ values ​​of 9.1±0.2°, 13.7±0.2°, 14.9±0.2° and 18.3±0.2°.

2. The crystalline form A according to claim 1, characterized in that: The X-ray powder diffraction pattern of the crystalline form A has a characteristic peak at at least one of the 2θ values ​​of 8.2±0.2°, 12.3±0.2°, 17.9±0.2°, 20.1±0.2°, 21.0±0.2°, 21.5±0.2°, 22.7±0.2°, 23.0±0.2°, 24.9±0.2°, 25.7±0.2°, 28.0±0.2° and 28.9±0.

2.

3. The crystalline form A according to claim 1 or 2, characterized in that: The X-ray powder diffraction pattern of the crystalline form A is consistent with that in FIG1 ; And / or the differential scanning calorimetry (DSC) spectrum of the crystalline form A has an endothermic peak at 215.2°C±5°C; And / or the differential scanning calorimetry DSC spectrum of the crystalline form A is consistent with Figure 2; and / or the thermogravimetric analysis (TGA) spectrum of the crystalline form A shows no obvious weight loss at 0-100° C., and the crystalline form A is an anhydrous crystalline form; And / or the thermogravimetric analysis TGA spectrum of the crystalline form A is consistent with Figure 3; and / or in the dynamic vapor sorption (DVS) spectrum of the crystalline form A, the adsorbed water content of the crystalline form A at 80% RH is 0.2% to 2%, preferably 0.2% to 0.5%; And / or the dynamic vapor adsorption DVS spectrum of the crystalline form A is consistent with Figure 4; And / or the polarizing microscope PLM image of the crystal form A shows that the crystal A is in the shape of a regular short rod.

4. The crystalline form A according to claim 3, characterized in that: The particle size of the crystal form A is ≤100 μm, preferably 20 to 50 μm.

5. The method for preparing the crystal form A according to any one of claims 1 to 4, characterized in that: include: (1) dissolving fesulazan hydrochloride in an alcohol solvent, and evaporating the solvent at a suitable temperature until solid precipitates to obtain Form A; or (2) Dissolve fesulazan hydrochloride in a mixed solvent of alcohols and esters, and evaporate the solvent at a suitable temperature until solid precipitates to obtain Form A.

6. The preparation method according to claim 5, characterized in that: The mass volume ratio of Fisurazan hydrochloride to the alcohol solvent in (1) is (10-1) mg:1 mL, preferably (6-1) mg:1 mL; and / or the mass volume ratio of the fisurazan hydrochloride to the mixed solvent of alcohols and esters in (2) is (10-1) mg:1 mL, preferably (8-1) mg:1 mL; And / or the volume ratio of alcohols to esters in (2) is 1:(0.5-6), preferably 1:(2-3).

7. The preparation method according to claim 5 or 6, characterized in that: In (1), the alcohol solvent is selected from at least one of methanol, ethanol or isopropanol, preferably ethanol; And / or in (2), the alcohol is selected from at least one of methanol, ethanol or isopropanol, preferably ethanol; the ester is selected from at least one of ethyl acetate, methyl acetate or isopropyl acetate, preferably ethyl acetate.

8. The preparation method according to claim 5 or 6, characterized in that: In the above (1) or (2), the dissolution temperature is 0 to 100°C, preferably 20 to 30°C, and more preferably room temperature.

9. The preparation method according to claim 5 or 6, characterized in that: In (1) or (2), The suitable temperature is 20-80°C, preferably 20-45°C, and more preferably room temperature; and / or the volatilization method is rapid volatilization, preferably rapid reduced pressure volatilization, more preferably room temperature vacuum reduced pressure volatilization; and / or the volatilization time is 1 to 24 hours, preferably 1 to 3 hours.

10. A pharmaceutical composition, characterized in that: Comprising the crystalline form A according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

11. Use of the crystalline form A according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 10 in the preparation of a drug; Preferably, the medicament is used to treat peptic ulcer or reflux esophagitis.

12. A method for treating peptic ulcer or reflux esophagitis, characterized in that: The method comprises: administering a therapeutically effective amount of the crystalline form A according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 10 to a subject in need thereof.

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