Pyrrole sulfonamide antacid crystal and preparation method therefor and use thereof, and pharmaceutical composition

Abstract

The present invention relates to a pyrrole sulfonamide antacid crystal and a preparation method therefor and the use thereof, and a pharmaceutical composition. Specifically, disclosed in the present invention is a pyrrole sulfonamide antacid crystal of a compound of formula (I), and the chemical structural formula of the crystal is as represented by formula (I), wherein n=0.1 to 2.0. The crystal form has good stability, fluidity and humidity resistance; and the preparation method for the crystal form involves a simple process, is easy to control and is suitable for large-scale production.

Description

A pyrrole sulfonamide acid suppressant crystal, its preparation method and application, and pharmaceutical composition

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on January 5, 2024, with application number 202410018458.3. The entire contents of the above application are incorporated by reference into this application. Technical Field

[0002] The present invention relates to the field of pharmaceutical chemistry, and in particular to a pyrrole sulfonamide acid inhibitor crystal, a preparation method and application thereof, and a pharmaceutical composition. Background Art

[0003] Acid-related diseases (ARDs) are a group of conditions triggered or caused by gastric acid attacks, primarily including peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD). Acid-suppressing drugs are the most effective treatment for these conditions. Although proton pump inhibitors (PPIs) dominate the acid suppression market, they suffer from issues such as slow onset of action, unstable acid suppression, significant inter-individual variability in efficacy, and numerous drug interactions.

[0004] Potassium competitive acid blockers (P-CABs) are based on K + Competitiveness and H + / K + -ATPase non-covalently (hydrogen bond and ionic bond), thereby inhibiting H + / K + -ATPase activity, with a potent and long-lasting inhibitory effect on gastric acid secretion. 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (CN 113620930B), a potassium ion competitive acid blocker, exhibits superior inhibitory effects on gastric acid secretion and reduced hepatotoxicity.

[0005] Among organic compounds, many substances often have the same chemical composition but can form different crystal structures under different conditions, such as temperature and solvent. Different polymorphs of a substance have different lattice energies, and thus exhibit different chemical and physical properties in the solid state, including chemical stability, solubility, and dissolution rate. These properties can directly affect the processing and production of APIs and formulations, and can affect the stability, solubility, and bioavailability of APIs and formulations. For the present invention, there is a need in the art to obtain polymorphs with excellent physical and chemical properties suitable for application. Summary of the Invention

[0006] The object of the present invention is to provide a crystalline form of the compound of formula I with good stability and low water content.

[0007] Another object of the present invention is to provide a method for preparing a crystalline form of the compound of formula I.

[0008] In the first aspect of the present invention, there is provided a pyrrole sulfonamide acid suppressant crystal of a compound of formula I,

[0009] The crystal form of the crystal is selected from the following group: crystal form Form A, crystal form Form B, crystal form Form C or crystal form Form D, wherein n=0.1-2.0.

[0010] In another preferred embodiment, the crystal is an anhydrate.

[0011] In another preferred embodiment, n=0.1-2.0, preferably 0.5-1.5, more preferably 0.5, 1 or 1.5.

[0012] In another preferred embodiment, n=0.5, 1.0 or 1.5.

[0013] In another preferred embodiment, the XRPD pattern of the crystalline form Form A includes 3 or more (such as 4, 5, or 6) 2θ values ​​selected from the following group: 4.1°±0.2°, 8.3°±0.2°, 12.5°±0.2°, 19.6°±0.2°, 20.9°±0.2°, and 23.1°±0.2°.

[0014] In another preferred example, the XRPD spectrum of the crystalline form Form A includes one or more 2θ values ​​selected from the following group: 4.1°±0.2°, 8.3°±0.2°, 12.5°±0.2°, 20.9°±0.2°, and 23.1°±0.2°.

[0015] In another preferred embodiment, the crystalline form Form A further has one or more characteristics selected from the following group:

[0016] (i1) the XRPD pattern of the crystalline form Form A comprises 6 or more 2θ values ​​selected from the group consisting of 4.1°±0.2°, 8.3°±0.2°, 12.5°±0.2°, 16.7°±0.2°, 19.6°±0.2°, 20.9°±0.2°, 23.1°±0.2°, 25.2°±0.2°, and 26.9°±0.2°;

[0017] (i2) The XRPD pattern of the crystalline form Form A is substantially as shown in FIG1 ;

[0018] (i3) the crystal form Form A has no weight loss at 20-150°C;

[0019] (i4) The TGA spectrum of the crystalline form Form A is substantially as shown in FIG2 ;

[0020] (i5) The peak temperature of the DSC spectrum of the crystalline form Form A is 188.4°C;

[0021] (i6) The DSC spectrum of the crystal form Form A is basically represented by FIG2 .

[0022] In another preferred embodiment, n of the crystal form Form A is 1.

[0023] In another preferred embodiment, the XRPD pattern of the crystalline form Form B includes 3 or more (such as 4, 5, or 6) 2θ values ​​selected from the following group: 5.3°±0.2°, 7.5°±0.2°, 9.6°±0.2°, 14.4°±0.2°, 16.0°±0.2°, 18.7°±0.2°, and 22.1°±0.2°.

[0024] In another preferred embodiment, the XRPD pattern of the crystalline form Form B includes one or more 2θ values ​​selected from the following group: 5.3°±0.2°, 9.6°±0.2°, 14.4°±0.2°, 16.0°±0.2°, 18.7°±0.2°, and 22.1°±0.2°.

[0025] In another preferred embodiment, in another preferred embodiment, the crystalline form Form B further has one or more characteristics selected from the following group:

[0026] (j1) the XRPD pattern of the crystalline form Form B comprises 6 or more 2θ values ​​selected from the group consisting of 5.3°±0.2°, 7.5°±0.2°, 8.1°±0.2°, 8.5°±0.2°, 9.6°±0.2°, 14.4°±0.2°, 16.0°±0.2°, 18.7°±0.2°, 19.2°±0.2°, 22.1°±0.2°, 22.8°±0.2°, 24.1°±0.2°, and 25.9°±0.2°;

[0027] (j2) The XRPD pattern of the crystalline form Form B is substantially as shown in FIG7 ;

[0028] (j3) the crystal form Form B loses 2.9% weight at 20-150°C;

[0029] (j4) The TGA spectrum of the crystal form Form B is basically represented by FIG8 ;

[0030] (j5) The peak temperatures of the DSC spectrum of the crystalline form Form B are 57.2°C, 146.6°C, and 178.4°C;

[0031] (j6) The DSC spectrum of the crystal form Form B is basically represented by FIG8 .

[0032] In another preferred embodiment, n of the crystal form Form B is 0.5.

[0033] In another preferred embodiment, the XRPD pattern of the crystalline form Form C includes 3 or more (such as 4, 5, or 6) 2θ values ​​selected from the following group: 7.1°±0.2°, 9.7°±0.2°, 15.0°±0.2°, 21.5°±0.2°, 22.9°±0.2°, and 25.7°±0.2°.

[0034] In another preferred embodiment, the XRPD pattern of the crystalline form Form C includes one or more 2θ values ​​selected from the following group: 7.1°±0.2°, 9.7°±0.2°, 15.0°±0.2°, 21.5°±0.2°, 22.9°±0.2°, and 25.7°±0.2°.

[0035] In another preferred embodiment, in another preferred embodiment, the crystalline form Form C further has one or more characteristics selected from the following group:

[0036] (k1) the crystalline form Form C has an XRPD pattern comprising 6 or more 2θ values ​​selected from the group consisting of 7.1°±0.2°, 9.7°±0.2°, 15.0°±0.2°, 17.1°±0.2°, 20.1°±0.2°, 21.5°±0.2°, 22.9°±0.2°, 23.8°±0.2°, 25.7°±0.2°, 30.0°±0.2°, and 37.3°±0.2°;

[0037] (k2) The XRPD pattern of the crystalline form Form C is substantially as shown in FIG4 ;

[0038] (k3) The crystal form Form C has no weight loss at 20-120°C;

[0039] (k4) The TGA spectrum of the crystal form Form C is basically represented by FIG5 ;

[0040] (k5) The peak temperature of the DSC spectrum of the crystal form Form C is 189.3°C;

[0041] (k6) The DSC spectrum of the crystal form Form C is basically represented by FIG5 .

[0042] In another preferred embodiment, n of the crystal form Form C is 1.5.

[0043] In another preferred embodiment, the XRPD pattern of the crystalline form Form D includes 3 or more (such as 4, 5, or 6) 2θ values ​​selected from the following group: 7.6°±0.2°, 11.7°±0.2°, 19.8°±0.2°, 23.9°±0.2°, and 24.6°±0.2°.

[0044] In another preferred embodiment, the XRPD spectrum of the crystalline form Form D includes one or more 2θ values ​​selected from the following group: 7.6°±0.2°, 11.7°±0.2°, and 19.8°±0.2°.

[0045] In another preferred embodiment, in another preferred embodiment, the crystalline form Form D further has one or more characteristics selected from the following group:

[0046] (m1) the XRPD pattern of the crystalline form Form D comprises 6 or more 2θ values ​​selected from the group consisting of 7.6°±0.2°, 12.6°±0.2°, 11.7°±0.2°, 16.5°±0.2°, 19.8°±0.2°, 23.9°±0.2°, 24.6°±0.2°, and 28.0°±0.2°;

[0047] (m2) The XRPD pattern of the crystalline form Form D is substantially as shown in FIG10 ;

[0048] (m3) the crystal form Form D loses 0.9% weight at 20-140°C;

[0049] (m4) The TGA spectrum of the crystal form Form D is basically represented by Figure 11.

[0050] In another preferred embodiment, n of the crystal form Form D is 1.

[0051] The second aspect of the present invention provides a method for preparing the crystal according to the first aspect of the present invention, wherein the crystal is in the crystal form Form A, and the method comprises the following steps:

[0052] (a1) taking a first substance, wherein the first substance is 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine;

[0053] (a2) mixing the first substance with an organic solvent and fumaric acid, and crystallizing to obtain crystalline Form A.

[0054] Wherein, the molar ratio of the first substance to fumaric acid is 1:0.5-1.5.

[0055] In another preferred embodiment, the organic solvent is selected from the group consisting of any one or a combination of ethyl acetate, methyl acetate, butyl acetate, methanol and ethanol.

[0056] In another preferred embodiment, the mass ratio of the first substance to fumaric acid is 10 to 3:1, preferably 5 to 3:1, and more preferably 4 to 3:1.

[0057] In another preferred embodiment, in step (a2), the mass volume ratio of the first substance to the organic solvent is 1:5-30, preferably 1:10-25, and more preferably 1:10-20.

[0058] In another preferred embodiment, the method further comprises a post-processing step.

[0059] In another preferred embodiment, the post-processing step includes filtration, washing and drying.

[0060] In another preferred embodiment, the washing is performed using an organic solvent.

[0061] In another preferred embodiment, the drying is performed under vacuum at 40-70°C.

[0062] In another preferred embodiment, the drying time is 2 to 7 hours, preferably 3 to 6 hours.

[0063] The third aspect of the present invention provides a method for preparing the crystal according to the first aspect of the present invention, wherein the crystal is a crystalline form Form B, and the method comprises the steps of placing the Form A in a liquid phase vial, adding a preheated methyl tert-butyl ether solution dropwise to form a suspension, adding preheated DMF dropwise, transferring to -20°C to 30°C for cooling, centrifuging, and drying the solid to obtain the crystalline form Form B.

[0064] A fourth aspect of the present invention provides a method for preparing the crystal according to the first aspect of the present invention, wherein the crystal is in the crystal form Form C, and the method comprises any one of steps (c1) and (c2):

[0065] (c1) mixing the first substance with an organic solvent and fumaric acid to obtain crystalline Form C,

[0066] Wherein, the first substance is 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, and the molar ratio of the first substance to fumaric acid is 1:2.5-4.0;

[0067] (c2) mixing the crystalline Form A with an organic solvent and fumaric acid at 20-70° C. to obtain the crystalline Form C.

[0068] In another preferred embodiment, the organic solvent is selected from the group consisting of any one or a combination of ethyl acetate, methyl acetate, butyl acetate, methanol and ethanol.

[0069] In another preferred embodiment, in step (c1), the mass ratio of the first substance to fumaric acid is 3 to 0.5:1, preferably 2 to 1:1.

[0070] In another preferred embodiment, in step (c1), the mass volume ratio of the first substance to the organic solvent is 1:5-30, preferably 1:10-25, and more preferably 1:10-20.

[0071] In another preferred embodiment, in step (c2), the molar ratio of the crystalline form Form A to fumaric acid is 1:1 to 1:5, preferably 1:1 to 1:2.

[0072] In another preferred embodiment, in step (c2), the organic solvent includes methanol or ethanol.

[0073] In a fifth aspect, the present invention provides a method for preparing the crystal according to the first aspect of the present invention, wherein the crystal is a crystal form Form D, and the method comprises the steps of placing the crystal form Form C in a glass vial, adding methanol and ultrasonically dissolving it, then adding toluene, stirring, moving to -20°C to 0°C and standing for 1 to 5 days, and removing the liquid to obtain the crystal form Form D.

[0074] In a sixth aspect, the present invention provides a pharmaceutical composition comprising: (a) any one of the crystals described in Formula I above, and (b) a pharmaceutically acceptable excipient or carrier.

[0075] The seventh aspect of the present invention provides a use of any one of the crystals described in the first aspect of the present invention, wherein the crystal is used to prepare a potassium ion competitive acid blocker, which is used to prepare a medicine or pharmaceutical composition for treating erosive esophagitis, gastric ulcer, duodenal ulcer, Helicobacter pylori eradication indications, and related diseases caused by excessive gastric acid.

[0076] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0077] FIG1 shows the XRPD spectrum of the crystalline form Form A of the compound of the present invention.

[0078] FIG2 shows the TGA and DSC spectra of the crystalline form Form A of the compound of the present invention.

[0079] FIG3 shows the NMR spectrum of the crystalline form Form A of the compound of the present invention.

[0080] FIG4 shows the XRPD spectrum of the crystalline form Form B of the compound of the present invention.

[0081] FIG5 shows the TGA and DSC spectra of the crystalline form Form B of the compound of the present invention.

[0082] FIG6 shows the NMR spectrum of the crystalline form Form B of the compound of the present invention.

[0083] FIG7 shows the XRPD spectrum of the crystalline form Form C of the compound of the present invention.

[0084] FIG8 shows the TGA and DSC spectra of the crystalline form Form C of the compound of the present invention.

[0085] FIG9 shows the NMR spectrum of the crystalline form Form C of the compound of the present invention.

[0086] FIG10 shows the XRPD spectrum of the crystalline form Form D of the compound of the present invention.

[0087] FIG11 shows the TGA spectrum of the crystalline form Form D of the compound of the present invention.

[0088] FIG12 shows the NMR spectrum of the crystalline form Form D of the compound of the present invention.

[0089] FIG13 shows a solid-state transformation relationship diagram of the compounds of the present invention.

[0090] FIG14 shows the XRPD comparison diagrams of different salt forms and crystal forms of the compound of the present invention.

[0091] FIG15 shows the XRPD comparison of fumarate salts of the compounds of the present invention at different ratios.

[0092] FIG16 shows (a) DVS curve of the crystalline form Form A of the compound of the present invention; (b) XRPD patterns before and after DVS test.

[0093] FIG17 shows a PLM image of the crystalline form Form A of the compound of the present invention.

[0094] FIG18 shows the XRPD pattern of the stability study of the crystalline form Form A of the compound of the present invention.

[0095] FIG19 shows an XRPD pattern of the stability study of the crystalline form Form C of the compound of the present invention.

[0096] FIG20 shows a comparative XRPD pattern of the solid remaining in the crystalline form Form A of the compound of the present invention after shaking in a medium for 24 hours.

[0097] FIG21 shows a comparative NMR graph of the solid remaining after shaking Form A of the compound of the present invention in FaSSGF for 24 hours.

[0098] FIG22 shows a comparative XRPD pattern of the solid remaining after shaking in FaSSIF and FaSSGF for 24 hours, which reproduces the crystalline form Form A of the compound of the present invention.

[0099] FIG23 shows a comparative NMR graph of the solid remaining after shaking in FaSSIF and FaSSGF for 24 hours, reproducing the crystalline form Form A of the compound of the present invention.

[0100] FIG24 shows a comparative NMR spectrum of the solid remaining after 24 hours of FaSSIF shaking, which reproduces the crystalline form Form A of the compound of the present invention.

[0101] FIG25 shows a comparison of XRPD patterns of the solid remaining after shaking Form C of the compound of the present invention in water for 2 hours (normalized).

[0102] FIG26 shows (a) DVS curve of the crystalline form Form C of the compound of the present invention; (b) XRPD patterns before and after DVS testing.

[0103] FIG27 shows a superimposed comparison diagram of thermal transformation of the crystal form Form B of the compound of the present invention.

[0104] FIG28 shows a comparative XRPD diagram of the solid remaining after the crystalline forms Form B and Form A of the compound of the present invention were shaken in water for 2 hours.

[0105] FIG29 shows (a) DVS curve of the crystalline form Form B of the compound of the present invention; (b) XRPD patterns before and after DVS test. DETAILED DESCRIPTION

[0106] After extensive and in-depth research, the present inventors have developed a salt crystalline form of the compound of Formula I. These crystalline forms exhibit advantages in stability, solubility, hygroscopicity, mechanical stability, tableting stability, flowability, process development, formulation development, and powder processing performance. In particular, Forms A and C offer significant advantages in preparation process and stability. Based on these findings, the present invention was completed.

[0107] the term

[0108] Unless otherwise specified herein, each abbreviation has the common meaning understood by those skilled in the art.

[0109] As used herein, unless otherwise specified, the method of adding a solvent or solution is direct pouring or adding at a uniform speed.

[0110] As used herein, the term "room temperature" generally refers to 4 to 30°C, preferably 20±5°C.

[0111] As used herein, the method of "slowly adding" includes, but is not limited to, adding dropwise, adding slowly along the wall of the container, etc.

[0112] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0113] As used herein, the term "m or more 2θ values ​​selected from the following group" refers to any positive integer greater than n (e.g., m, m+1, ...), wherein the upper limit Nup is the number of all 2θ peaks in the group. For example, "3 or more" includes not only 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ..., each positive integer of the upper limit Nup, but also includes ranges such as "4 or more", "5 or more", and "6 or more".

[0114] As used herein, the terms "compound of formula I", "raw material", "fumarate salt of compound of formula I", "salt of pyrrolesulfonamide acid inhibitor", "1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate", and "compound of the present invention" are used interchangeably and refer to the compound of formula I, wherein n = 0.1 to 2.0.

[0115] As used herein, "N-methylmethylamine fumarate" and "n" are used interchangeably and refer to the number of methylmethylamine fumarate groups in the compound of Formula I. For example, n=1, which is 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-1-methylmethylamine fumarate.

[0116] As used herein, "crystalline Form A", "Form A", "raw material (Form A)", and "1 fumarate salt Form A" are used interchangeably and refer to the crystalline Form A of the compound represented by Formula I. As used herein, "crystalline Form B", "Form B", and "0.5 fumarate salt Form B" are used interchangeably and refer to the crystalline Form B of the compound represented by Formula I. As used herein, "crystalline Form C", "Form C", and "1.5 fumarate salt Form C" are used interchangeably and refer to the crystalline Form C of the compound represented by Formula I. As used herein, "crystalline Form D" and "Form D" are used interchangeably and refer to the crystalline Form D of the compound represented by Formula I.

[0117] Pharmaceutical composition containing a crystalline form of a compound of formula I

[0118] Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of the compound of Formula I according to the present invention, and optionally, one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients, and / or diluents. The excipients may include, for example, flavoring agents, fragrances, sweeteners, and the like.

[0119] The pharmaceutical composition provided by the present invention preferably contains an active ingredient in an amount of 1 to 99% by weight, preferably comprising 65 to 99% by weight of the compound of formula I as the active ingredient, with the remainder being a pharmaceutically acceptable carrier, diluent, solution, or saline solution. The compounds and pharmaceutical compositions provided by the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and may be present in a suitable solid or liquid carrier or diluent and in a suitable sterile apparatus for injection or infusion.

[0120] The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dosage of the preparation formula contains 1 mg to 700 mg of the compound of formula I, preferably, the unit dosage of the preparation formula contains 25 mg to 300 mg of the compound of formula I.

[0121] The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, and can be administered via the oral, nasal, dermal, pulmonary, or gastrointestinal routes. Oral administration is most preferred. The most preferred daily dose is 50-1400 mg / kg body weight, taken as a single dose, or 25-700 mg / kg body weight, taken in divided doses. Regardless of the route of administration, the optimal individual dose will depend on the specific treatment being used. Typically, a low dose is started and gradually increased until the optimal dose is found.

[0122] In the present invention, unless otherwise specified, the drying method used is a conventional drying method in the art. For example, in the embodiments of the present invention, drying refers to vacuum drying or atmospheric pressure drying in a conventional drying oven. Generally, the drying time is 0.1 to 50 hours or 1 to 30 hours.

[0123] The main advantages of the present invention are:

[0124] (1) Compared with their amorphous solids, the crystals of the compound of the present invention (including Form A, Form B, Form C, and Form D) have higher purity, better stability, better fluidity, and lower hygroscopicity.

[0125] (2) The preparation method of the compound crystals of the present invention (including crystal form Form A, crystal form B, crystal form C, and crystal form D) is simple and more suitable for industrial production compared with the freeze-drying process (which consumes a lot of energy and has limited production capacity).

[0126] (3) The crystals of the compound of the present invention (including crystal form Form A, crystal form Form B, crystal form C, and crystal form D) can be used to prepare potassium ion competitive acid blockers, which are used to prepare drugs for treating erosive esophagitis, gastric ulcer, duodenal ulcer, Helicobacter pylori eradication indications, and related diseases caused by excessive gastric acid.

[0127] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0128] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be used in the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0129] General methods and reagents

[0130] The solvents used in the present invention are all analytically pure.

[0131] All test methods of the present invention are general methods, and the test parameters are as follows:

[0132] NMR analysis ( 1 H NMR)

[0133] Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 solvent and subjected to nuclear magnetic resonance analysis on a Bruker AVANCE NEO 400 (Bruker, Germany).

[0134] X-ray powder diffraction (XRPD)

[0135] Preliminary testing was performed using a Malvern PANalytical Aeris X-ray powder diffractometer (Malvern Panalytical, UK), with a 2θ scan angle from 3° to 45°, a scan step size of 0.02°, and a test time of 4.9 min. The tube voltage and current for the sample were 40 kV and 7.5 mA, respectively, and the sample pan was a zero-background sample pan. Alternatively, characterization was performed again using a Panalytical EMPYREAN X-ray powder diffractometer (PANalytical, UK). The 2θ scan angle was from 3° to 45°, a scan step size of 0.013°, and a total test time of 3.5 min. The test method used Cu target Kα1 radiation, a voltage of 45 kV, a current of 40 mA, and a zero-background sample pan.

[0136] Online variable temperature XRPD testing

[0137] X-ray powder diffractometer (Malvern Panalytical Aeris, UK) was used for XRPD analysis. The 2θ scan angle ranged from 3° to 40°, with a scan step size of 0.02°, and the measurement time was 13 minutes. The tube voltage and current were 40 kV and 7.5 mA, respectively, and the sample pan was a zero-background sample pan. XRPD analysis was performed on a BTS500 hot stage (Anton Paar, AT) at room temperature. The sample was then heated at a rate of 10°C / min to the selected temperature. After a 10-minute isothermal period, XRPD analysis was performed at the same temperature. The sample was then cooled to room temperature and analyzed again.

[0138] Thermogravimetric analysis (TGA)

[0139] The thermogravimetric analyzer (TA Discovery 55, TA, US) was used. A 2-5 mg sample was placed in a equilibrated open aluminum sample pan and automatically weighed in the TGA furnace. The sample was heated to the final temperature at a rate of 10°C / min. A nitrogen purge rate of 60 mL / min was maintained at the sample and 40 mL / min at the balance.

[0140] Differential Scanning Calorimetry (DSC)

[0141] The differential scanning calorimeter was a TA Discovery 2500 (TA, US). 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10°C / min, with nitrogen purge rate of 50 mL / min.

[0142] Dynamic moisture sorption / desorption analysis (DVS)

[0143] Dynamic moisture sorption / desorption analysis for preliminary hygroscopicity assessment was performed using a DVS Intrinsic Plus (SMS, UK). The test used a gradient mode with humidity changes from 50% to 95% to 50%, with each step increasing by 15%. The gradient endpoint was determined using the dm / dt method, with a dm / dt of less than 0.002% maintained for 10 minutes, or a maximum of 60 minutes per step. After the test, the sample was analyzed by XRPD to confirm any changes in the solid form.

[0144] Dynamic moisture sorption / desorption analysis was performed using a DVS Intrinsic Plus (SMS, UK). The test used a gradient mode with humidity changes from 0% to 95% to 0%, with each gradient increasing by 10% within the range. The gradient endpoint was determined using the dm / dt method, with a dm / dt of less than 0.002% maintained for 10 minutes, or a maximum of 180 minutes per gradient. After the test, the samples were analyzed by XRPD to confirm any changes in the solid form.

[0145] High-performance liquid chromatography (HPLC)

[0146] The high performance liquid chromatography model was SHIMADZU LC-20A (Shimadzu, JP), and the test conditions were shown in Table 0 below.

[0147] Table 0 HPLC test conditions

[0148] Example 1 Preparation of Crystal Form A

[0149] 1.1 Synthesis method

[0150] To a 100 mL single port were added 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (2.00 g), ethyl acetate (30 mL), and fumaric acid (0.67 g, 1.2 eq.), and the mixture was stirred at room temperature for 0.5 h. The mixture was filtered, washed with ethyl acetate (6 mL), and dried in vacuo at 50°C for 3 h to give 2.25 g of a white solid with a yield of 88%.

[0151] To a 100 mL single port were added 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (2.00 g), ethanol (20 mL), and fumaric acid (0.50 g, 0.9 eq.), and the mixture was stirred at room temperature for 1 h. The mixture was filtered, washed with ethanol (10 mL), and dried in vacuo at 45°C for 5 h to give 1.80 g of a white solid with a yield of 78%.

[0152] To a 100 mL single port were added 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (2.00 g), ethyl acetate (40 mL), and fumaric acid (0.56 g, 1.0 eq.), and the mixture was stirred at room temperature for 1 h. The mixture was filtered, washed with ethyl acetate (10 mL), and dried in vacuo at 60°C for 6 h to give 2.15 g of a white solid with a yield of 84%.

[0153] 1.2 Thermal Transformation Method

[0154] Thermal crystallization was performed using an online variable temperature X-ray powder diffractometer, a Malvern Panalytical Aeris (Malvern Panalytical, UK). The sample was placed on a BTS500 hot stage (Anton Paar, AT) and XRPD analysis was performed at room temperature. The sample was then heated at a rate of 10°C / min to a selected temperature. After a 10-min isothermal period, XRPD analysis was performed at that temperature. The sample was then cooled to room temperature and then XRPD analysis was performed again. The chromatographic data are shown in Table 1. (Hereinafter referred to as the online variable temperature XRPD experiment)

[0155] Table 1 XRPD table of Form A

[0156] Example 2 Preparation of Crystal Form B

[0157] The preparation process is shown in Table 2. Form B was successfully prepared in the scale-up preparation.

[0158] Table 2 Scale-up preparation of target salt forms

[0159] Table 3 is the XRPD table of Form B.

[0160] Table 3 XRPD table of crystal form Form B

[0161] Example 3 Preparation of Crystal Form C

[0162] 3.1 Synthesis

[0163] To a 100 mL single port was added 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (2.00 g), ethyl acetate (40 mL), and fumaric acid (1.40 g, 2.5 eq). The mixture was stirred at room temperature for 0.5 h, filtered, washed with ethyl acetate (10 mL), and dried in vacuo at 45°C for 6 h to give 2.41 g of a white solid with a yield of 85%.

[0164] To a 100 mL single port was added 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (2.00 g), methanol (30 mL), and fumaric acid (1.68 g, 3.0 eq). The mixture was stirred at room temperature for 1 h, filtered, washed with methanol (10 mL), and dried in vacuo at 50°C for 6 h to give 2.47 g of a white solid with a yield of 87%.

[0165] To a 100 mL single port were added 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (2.00 g), ethanol (30 mL), and fumaric acid (1.96 g, 3.5 eq). The mixture was stirred at room temperature for 0.5 h, filtered, washed with ethanol (10 mL), and dried in vacuo at 60°C for 6 h to give 2.44 g of a white solid with a yield of 86%.

[0166] To a 100 ml container was added ethanol (20 mL) and fumaric acid (0.66 g, 1.5 eq.), which was heated to dissolve. 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (2.00 g) was added, and the mixture was stirred for 0.5 h. The mixture was filtered, washed with ethanol (10 mL), and dried under vacuum at 50°C for 4 h to obtain 2.04 g of a white solid with a yield of 92%.

[0167] The XRPD data of Form C are shown in Table 4.

[0168] Table 4 XRPD table of Form C

[0169] Example 4 Preparation of Crystal Form D

[0170] Using a preparative workstation ICSW-V3 (XtalPi, CN), 19.6 mg of Form C was weighed and completely dissolved by the addition of 1.7 mL of methanol at room temperature. Then, 15.0 mL of toluene solution was added dropwise and stirred at room temperature for 1 hour. After filtration, the mixture was transferred to -15°C and allowed to stand for 1 day. The resulting solid was centrifuged and dried under vacuum at room temperature before XRPD analysis, as shown in Table 5.

[0171] Table 5 is the XRPD table of crystal form Form D.

[0172] Table 5 XRPD table of crystal form Form D

[0173] Example 5 Characterization of Crystalline Form

[0174] 5.1 Crystal Form A

[0175] XRPD results showed that Form A was a well-crystalline solid. TGA results showed that Form A showed little weight loss upon heating to 150°C, but decomposition may occur above 195°C. DSC results revealed a melting endotherm at approximately 188°C. NMR results showed that the sample was consistent with the reference spectrum, with no obvious organic solvent signal peaks. PLM images revealed that Form A was blocky crystals with a particle size generally less than 25 μm. In summary, Form A is an anhydrous crystalline form.

[0176] Table 6 System characterization results of fumarate Form A

[0177] 5.2 Crystal Form B

[0178] XRPD results indicated that Form B was a well-crystalline solid. TGA results revealed a 2.9% weight loss upon heating to 150°C, with potential decomposition occurring above 210°C. DSC results revealed a broad endothermic signal in Form C between 40°C and 90°C, corresponding to the TGA weight loss, with additional endothermic signals at approximately 147°C and 178°C. Thermal crystallization experiments indicated that Form B exhibited no XRPD changes upon heating to 100°C (see Figure 27). NMR results revealed no structural changes, with a fumaric acid peak at 6.43 ppm and DMF peaks at 2.73 ppm and 2.89 ppm, indicating a small amount of residual solvent. Based on the integration results, the compound-to-fumaric acid ratio was calculated to be 1:0.5. In summary, Form B is anhydrous.

[0179] 5.3 Crystal Form C

[0180] XRPD results showed Form C to be a well-crystalline solid. TGA results revealed no significant weight loss upon heating to 120°C, but decomposition may occur above 190°C. DSC results revealed an endothermic peak at around 189°C, indicating melting and decomposition. NMR results confirmed that the sample structure was consistent with the client's provided structure. In summary, Form C is an anhydrous crystalline form.

[0181] 5.4 Crystal Form D

[0182] XRPD results indicated that Form D was a poorly crystalline solid. TGA results revealed a 0.9% weight loss upon heating to 140°C, with possible decomposition occurring after 190°C. NMR results indicated that the integral at 6.48 ppm indicated a 1:1 ratio of free form to fumaric acid, indicating that the sample was a 1-fumarate salt. The integral at 2.30 ppm indicated the presence of a small amount of toluene. In summary, Form D is suspected to be an anhydrous crystalline form with a 1:1 salt ratio (free form:fumaric acid).

[0183] Table 7 Crystal form characterization results

[0184] Example 6 Solid-state transformation relationship of crystal form

[0185] The solid state (crystal form / salt form) transformation relationship of the compound of the present invention is shown in Figure 13. Form C can be transformed into Form A by high-temperature suspension; Form D can be transformed into Form C + Form B after drying and then placed under normal temperature and humidity with the lid closed.

[0186] Effect embodiment

[0187] Example 7 Stability

[0188] 7.1 Methods

[0189] About 20 mg of sample was weighed and placed in a weighing bottle. The bottle was then exposed to high temperature (60°C), high humidity (25°C / 92.5% RH), light (25°C / 4500 Lux), and accelerated (40°C / 75% RH) conditions. Samples were taken after 7 and 15 days for XRPD characterization and HPLC testing.

[0190] 7.2 Results

[0191] The results are shown in Table 8 and Figures 18 and 19. XRPD results showed that the XRPD values ​​of Form A and Form C after 15 days of storage under high temperature, high humidity, accelerated conditions, and light exposure were consistent with those after 0 days. There was no significant change in purity under high temperature, high humidity, and accelerated conditions. However, under light exposure, the purity decreased, and the solid appearance turned yellow.

[0192] Table 8 Stability study results

[0193] Example 8 Solubility

[0194] 8.1 Methods

[0195] 8.1.1 Evaluation of Solubility in Water

[0196] The sample was added to 4.0 mL of water and shaken at 37°C for 2 hours before sampling. The sampled solution was filtered through a 0.22 μm water filter. Some samples with higher concentrations were appropriately diluted with diluent. The signal peak area of ​​the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material, and the dilution factor. In addition, XRPD analysis was performed on the remaining solid.

[0197] 8.1.2 Solubility test

[0198] The preparation process of the bio-media is shown in Table 9. The sample was added to the bio-media, water, 0.9% saline, and 5% glucose and shaken at 37°C for 24 hours. Samples were taken at 0.5, 2, and 24 hours. The sampled solutions were filtered through a 0.22 μm water filter. Some samples with higher concentrations were appropriately diluted with diluent. The signal peak area of ​​the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material, and the dilution factor. In addition, the pH value of the supernatant after 24 hours was tested, and the remaining solid was analyzed by XRPD.

[0199] Table 9 Preparation process of biological medium

[0200] 8.2 Results

[0201] 8.2.1 FormA

[0202] The results showed that the solubility of FormA in three biological media, water, saline and glucose, after 24 hours, was FaSSGF>water≈0.9% saline≈5% glucose>FeSSIF>FaSSIF. After shaking in FaSSIF for 24 hours, a very small amount of solid remained; after shaking in FeSSIF for 24 hours, it was an oily substance. After shaking in water, 0.9% saline and 5% glucose for 24 hours, the crystal form of the remaining solid did not change, and the crystallinity deteriorated; after shaking in FaSSGF for 24 hours, the XRPD of the remaining solid changed. The NMR results showed that the peaks at 6.40ppm and 7.67ppm were offset, and the peaks at 2.42ppm and 6.47ppm (fumaric acid) disappeared. Since the amount of remaining solid in FaSSIF and FaSSGF was small, an appropriate amount of FormA was weighed and shaken in FaSSIF and FaSSGF solutions for 24 hours, and the resulting solid was characterized. XRPD results showed that the remaining solid after 24 hours of shaking in FaSSGF contained free fumaric acid, and ion chromatography revealed a chloride ion content of 2.4%. NMR results showed that the proportion of fumaric acid in the remaining solid after 24 hours of shaking in FaSSIF decreased, with ion chromatography revealing a chloride ion content of 4.9% and a phosphate content of 2.9%. These results suggest that Form A may dissociate in FaSSIF and FaSSGF solutions, with some of the dissociated solid forming salts with the acidic components of the medium.

[0203] Table 10 Dynamic solubility test Note: “*” represents the concentration of the corresponding free form in the solution calculated based on the free form standard curve.

[0204] 8.2.2 The results of Form B showed that the solubility of Form B and Form A in water after 2 hours was Form A > Form B. After shaking in water for 2 hours, the remaining solid crystal form did not change.

[0205] Table 11 pH buffer and water solubility evaluation results Note: “*” represents the concentration of the corresponding free form in the solution calculated based on the free form standard curve.

[0206] 8.2.3 FormC

[0207] The solubility of Form C in water was evaluated using the experimental method described in 8.1.1. The corresponding results are shown in Table 12.

[0208] Table 12 Solubility evaluation results in water a The values ​​were calculated based on the HPLC standard curve of the free form

[0209] Example 9 Hygroscopicity

[0210] DVS tests were performed on Form A and Form B, as shown in Figures 16 and 29. The results show that Form A had an adsorption weight gain of approximately 0.105% at 95% RH, an adsorption weight gain of approximately 0.047% at 80% RH, a desorption weight gain of approximately 0.050% at 80% RH, and a desorption weight loss of approximately 0.026% at 50% RH.

[0211] Table 13 Preliminary assessment summary

[0212] Form B showed an adsorption weight gain of approximately 0.855% at 95% RH, an adsorption weight gain of approximately 0.427% at 80% RH, a desorption weight gain of approximately 0.435% at 80% RH, and a desorption weight loss of approximately 0.221% at 50% RH. XRPD patterns of Form A and Form B showed no significant changes after DVS testing.

[0213] Table 14 Preliminary assessment summary

[0214] Form C was subjected to DVS testing, as shown in Figure 26. The results show that Form C gained 0.052% weight at 95% humidity, 0.017% weight at 80% humidity during adsorption, and 0.019% weight at 80% humidity during desorption. XRPD results indicate that Form C exhibited no crystalline form change after rapid DVS testing.

[0215] Table 15 Preliminary assessment summary

[0216] Example 10: Study on the dissolution results of sample preparation tablets

[0217] API tablets (conventional tableting) were prepared using Form A and Form C, with a specification of 10 mg (calculated as free base). The dissolution rates of the samples were tested in phosphate buffer (pH = 6.8), acetate buffer (pH = 4.5), hydrochloric acid solution (pH = 1.2), and purified water, respectively. The data are compared in Tables 16 and 17:

[0218] Table 16 Dissolution data of 10 mg Form A product (n=6)

[0219] Table 17 Dissolution data of 10 mg Form C product (n=6)

[0220] Conclusion: The dissolution results of the samples prepared into tablets showed that the dissolution rates of the tablet products prepared from Form A and Form C were greater than 85% within 15 minutes in phosphate buffer (pH = 6.8), acetate buffer (pH = 4.5), hydrochloric acid solution (pH = 1.2) and purified water.

[0221] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A pyrrole sulfonamide acid suppressant crystal, characterized in that, The chemical structural formula of the crystal is shown in Formula I: Among them, n = 0.1 to 2.

0.

2. The crystal according to claim 1, wherein The crystal is an anhydrate; and / or n is 0.5 to 1.

5.

3. The crystal according to claim 1, characterized in that, The crystal has crystal form Form A, and the crystal form Form A further has one or more characteristics selected from the following groups: (i1) The XRPD pattern of the crystal form Form A includes 6 or more 2θ values selected from the following group: 4.1° ± 0.2°, 8.3° ± 0.2°, 12.5° ± 0.2°, 16.7° ± 0.2°, 19.6° ± 0.2°, 20.9° ± 0.2°, 23.1° ± 0.2°, 25.2° ± 0.2°, 26.9° ± 0.2°; (i2) The XRPD pattern of the crystal form Form A includes 3 or more 2θ values selected from the following group: 4.1° ± 0.2°, 8.3° ± 0.2°, 12.5° ± 0.2°, 19.6° ± 0.2°, 20.9° ± 0.2°, 23.1° ± 0.2°; (i3) The XRPD pattern of the crystal form Form A is characterized as shown in Figure 1; (i4) The crystal form Form A has no weight loss at 20 to 150 °C; (i5) The TGA pattern of the crystal form Form A is characterized as shown in Figure 2; (i6) The peak temperature of the DSC pattern of the crystal form Form A is 188.4 °C; (i7) The DSC pattern of the crystal form Form A is characterized as shown in Figure 2; (i8) The XRPD pattern of the crystal form Form A includes 1 or more 2θ values selected from the following group: 4.1° ± 0.2°, 8.3° ± 0.2°, 12.5° ± 0.2°, 20.9° ± 0.2°, 23.1° ± 0.2°; (i9) For the crystal form Form A, n = 1.

4. The crystal according to claim 1, wherein The crystal has crystal form Form B, and the crystal form Form B further has one or more characteristics selected from the following groups: (j1) The XRPD pattern of the crystal form Form B includes 6 or more 2θ values selected from the following group: 5.4° ± 0.2°, 7.5° ± 0.2°, 8.2° ± 0.2°, 8.5° ± 0.2°, 9.6° ± 0.2°, 14.5° ± 0.2°, 16.0° ± 0.2°, 18.7° ± 0.2°, 19.2° ± 0.2°, 22.1° ± 0.2°, 22.8° ± 0.2°, 24.1° ± 0.2°, 25.9° ± 0.2°; (j2) The XRPD pattern of the crystal form Form B includes 3 or more 2θ values selected from the following group: 5.4° ± 0.2°, 14.5° ± 0.2°, 16.0° ± 0.2°, 18.7° ± 0.2°, 22.1° ± 0.2°; (j3) The XRPD pattern of the crystal form Form B is characterized as shown in Figure 4; (j4) The crystal form Form B has a weight loss of 2.9% at 20 to 150 °C; (j5) The TGA pattern of the crystal form Form B is characterized as shown in Figure 5; (j6) The peak temperatures of the DSC pattern of the crystal form Form B are 57.2 °C, 146.6 °C, and 178.4 °C; (j7) The DSC pattern of the crystal form Form B is characterized as shown in Figure 5; (j8) The XRPD pattern of the crystal form Form B includes one or more 2θ values selected from the following group: 5.3° ± 0.2°, 9.6° ± 0.2°, 14.4° ± 0.2°, 16.0° ± 0.2°, 18.7° ± 0.2°, 22.1° ± 0.2°; (j9) For the crystal form Form B, n = 0.

5.

5. The crystal according to claim 1, wherein The crystal has the crystal form Form C, and the crystal form Form C further has one or more characteristics selected from the following group: (k1) The XRPD pattern of the crystal form Form C includes six or more 2θ values selected from the following group: 7.1° ± 0.2°, 9.7° ± 0.2°, 15.0° ± 0.2°, 17.1° ± 0.2°, 20.1° ± 0.2°, 21.5° ± 0.2°, 22.9° ± 0.2°, 23.8° ± 0.2°, 25.7° ± 0.2°, 30.0° ± 0.2°, 37.3° ± 0.2°; (k2) The XRPD pattern of the crystal form Form C is characterized as shown in Figure 7; (k3) The crystal form Form C has no weight loss at 20 - 120 °C; (k4) The TGA pattern of the crystal form Form C is characterized as shown in Figure 8; (k5) The peak temperature of the DSC pattern of the crystal form Form C is 189.3 °C; (k6) The DSC pattern of the crystal form Form C is characterized as shown in Figure 8; (k7) The XRPD pattern of the crystal form Form C includes three or more 2θ values selected from the following group: 7.1° ± 0.2°, 9.7° ± 0.2°, 15.0° ± 0.2°, 21.5° ± 0.2°, 22.9° ± 0.2°, 25.7° ± 0.2°; (k8) The XRPD pattern of the crystal form Form C includes one or more 2θ values selected from the following group: 7.1° ± 0.2°, 9.7° ± 0.2°, 15.0° ± 0.2°, 21.5° ± 0.2°, 22.9° ± 0.2°, 25.7° ± 0.2°; (k9) For the crystal form Form C, n = 1.

5.

6. The crystal according to claim 1, wherein The crystal has the crystal form Form D, and the crystal form Form D further has one or more characteristics selected from the following group: (m1) The XRPD pattern of the crystal form Form D includes six or more 2θ values selected from the following group: 7.6° ± 0.2°, 11.7° ± 0.2°, 12.6° ± 0.2°, 14.1° ± 0.2°, 16.5° ± 0.2°, 18.5° ± 0.2°, 19.8° ± 0.2°, 22.6° ± 0.2°, 23.9° ± 0.2°, 24.6° ± 0.2°, 25.5° ± 0.2°, 28.0° ± 0.2°, 28.6° ± 0.2°, 31.1° ± 0.2°; (m2) The XRPD pattern of the crystal form Form D is characterized as shown in Figure 10; (m3) The crystal form Form D has a weight loss of 0.9% at 20 - 140 °C; (m4) The TGA spectrum of the crystalline form Form D is characterized as shown in Figure 11; (m5) The XRPD spectrum of the crystalline form Form D includes 3 or more 2θ values selected from the following group: 7.6° ± 0.2°, 11.7° ± 0.2°, 19.8° ± 0.2°, 23.9° ± 0.2°, 24.6° ± 0.2°; (m6) The XRPD spectrum of the crystalline form Form D includes 1 or more 2θ values selected from the following group: 7.6° ± 0.2°, 11.7° ± 0.2°, 19.8° ± 0.2°; (m7) For the crystalline form Form D, n = 1.

7. A method for preparing the crystal according to claim 1 or 3, characterized in that, The crystal is of crystalline form Form A, and the method comprises the following steps: (a1) Take a first substance, which is 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine; (a2) Mix the first substance with an organic solvent and fumaric acid, and crystallize to obtain crystalline form Form A, wherein the molar ratio of the first substance to the fumaric acid is 1:0.5 to 1.

5.

8. The preparation method according to claim 7, wherein The organic solvent is selected from the following group: any one or a combination of ethyl acetate, methyl acetate, butyl acetate, methanol and ethanol; and / or the mass-to-volume ratio of the first substance to the organic solvent is 1:5 to 30, preferably 1:10 to 25, more preferably 1:10 to 20.

9. A method for preparing the crystal according to claim 1 or 5, characterized in that The crystal is of crystalline form Form C, and the preparation method comprises any one of steps (c1) and (c2): (c1) Mix a first substance with an organic solvent and fumaric acid to obtain crystalline form Form C, wherein the first substance is 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, and the molar ratio of the first substance to the fumaric acid is 1:2.5 to 4.0; (c2) At 20 to 70 °C, mix crystalline form Form A with an organic solvent and fumaric acid to obtain crystalline form Form C.

10. According to the preparation method described in claim 9, the organic solvent is selected from the following group: any one or a combination of ethyl acetate, methyl acetate, butyl acetate, methanol and ethanol; in the step (c1), the mass ratio of the first substance to the fumaric acid is 3 to 0.5:1, preferably 2 to 1:1; the mass-to-volume ratio of the first substance to the organic solvent is 1:5 to 30, preferably 1:10 to 25, more preferably 1:10 to 20; and / or, in the step (c2), the molar ratio of crystalline form Form A to the fumaric acid is 1:1 to 1:5, preferably 1:1 to 1:2; the organic solvent includes methanol and / or ethanol.

11. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (a) any one of the crystals of formula I described in claims 1 to 6, and (b) a pharmaceutically acceptable excipient or carrier.

12. Use of any one of the crystals according to claims 1 to 6, characterized in that, The crystal is used for preparing a potassium ion competitive acid blocker and for preparing a drug or a pharmaceutical composition for treating erosive esophagitis, gastric ulcer, duodenal ulcer, Helicobacter pylori eradication indications, and related diseases caused by excessive gastric acid.

Images