Salt crystal form of pyrrole sulfonamide acid inhibitor as well as preparation method and application of salt crystal form

Abstract

The invention relates to a crystal of a compound as shown in a formula I and a preparation method and application thereof. Specifically, the invention discloses a crystal of a compound shown as a formula I. The crystal form of the crystal is selected from the following groups: crystal form FormA, crystal form FormB, crystal form FormC or crystal form FormD, and n is equal to 0.1-2.0. The crystal form is good in stability, fluidity and moisture absorption resistance, and the preparation method of the crystal form is simple in process, easy to control and suitable for large-scale production. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly to a salt crystal form of a pyrrole sulfonamide type acid inhibitor, a preparation method thereof, and applications thereof. Background Art

[0002] Acid-related diseases (ARDs) are a group of diseases induced or caused by gastric acid attacks, mainly including peptic ulcer disease (PUD), gastroesophageal reflux disease (GERD), etc. In the drug treatment of these diseases, clinically, acid inhibitors are the most effective means for treating acid-related diseases. Although proton pump inhibitors (PPIs) dominate the acid inhibition field, there are problems such as slow onset, unstable acid inhibition, large individual differences in drug efficacy, and many drug interactions.

[0003] Potassium competitive acid blockers (P-CABs) competitively bind to H + / K + / K + -ATPase non-covalently (hydrogen bonds and ionic bonds), thereby inhibiting the activity of H + / K + -ATPase and having a strong and lasting effect on inhibiting gastric acid secretion. 1-[5-[4-(Cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridine-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (CN 113620930 B) is used as a potassium competitive acid blocker, and this compound exhibits characteristics such as better inhibitory effect on gastric acid secretion and reduced hepatotoxicity.

[0004] In organic compounds, many substances often have the same chemical composition and can form different crystal structures under different conditions such as temperature and solvent. Different polymorphs of substances have different lattice energies, and thus exhibit different chemical and physical properties in the solid state, including chemical stability, solubility, dissolution rate, etc. These properties can directly affect the processing and production of active pharmaceutical ingredients and preparations, and will also affect the stability, solubility, and bioavailability of active pharmaceutical ingredients and preparations. For the present invention, there is a need in the art to obtain polymorphs with excellent physical and chemical properties suitable for applications. Summary of the Invention

[0005] The purpose of the present invention is to provide a crystal form of a compound of formula I with good stability and low water content.

[0006] Another object of the present invention is to provide a method for preparing a crystal form of a compound of formula I.

[0007] In a first aspect of the present invention, there is provided a crystal of a compound of formula I,

[0008]

[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 to 2.0.

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

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

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

[0013] In another preferred embodiment, the XRPD pattern of the crystal 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°, 23.1° ± 0.2°.

[0014] In another preferred embodiment, 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°.

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

[0016] (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°;

[0017] (i2) The XRPD pattern of the crystal form Form A is substantially as Figure 1 characterized;

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

[0019] (i4) The TGA spectrum of the crystalline form Form A is basically as Figure 2 characterized;

[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 crystalline form Form A is basically as Figure 2 characterized.

[0022] In another preferred example, n = 1 for the crystalline form Form A.

[0023] In another preferred example, the XRPD spectrum 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°, 22.1° ± 0.2°.

[0024] In another preferred example, the XRPD spectrum of the crystalline form Form B includes 1 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°.

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

[0026] (j1) The XRPD spectrum of the crystalline form Form B includes 6 or more 2θ values selected from the following group: 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°, 25.9° ± 0.2°;

[0027] (j2) The XRPD spectrum of the crystalline form Form B is basically as Figure 7 characterized;

[0028] (j3) The crystalline form Form B loses 2.9% of its weight at 20 - 150 °C;

[0029] (j4) The TGA spectrum of the crystalline form Form B is basically as Figure 8 characterized;

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

[0031] (j6) The DSC pattern of polymorph Form B is substantially as Figure 8 characterized.

[0032] In another preferred example, n of polymorph Form B is 0.5.

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

[0034] In another preferred example, the XRPD pattern of polymorph Form C includes 1 or more 2θ values selected from the group consisting of: 7.1° ± 0.2°, 9.7° ± 0.2°, 15.0° ± 0.2°, 21.5° ± 0.2°, 22.9° ± 0.2°, 25.7° ± 0.2°.

[0035] In another preferred example, polymorph Form C further has one or more characteristics selected from the group consisting of:

[0036] (k1) The XRPD pattern of polymorph Form C includes 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°, 37.3° ± 0.2°;

[0037] (k2) The XRPD pattern of polymorph Form C is substantially as Figure 4 characterized;

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

[0039] (k4) The TGA pattern of polymorph Form C is substantially as Figure 5 characterized;

[0040] (k5) The peak temperature of the DSC pattern of polymorph Form C is 189.3 °C;

[0041] (k6) The DSC pattern of polymorph Form C is substantially as Figure 5 characterized.

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

[0043] In another preferred example, the XRPD pattern of the crystalline form Form D includes 2θ values of 3 or more (such as 4, 5, or 6) 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°.

[0044] In another preferred example, the XRPD pattern of the crystalline form Form D includes 2θ values of 1 or more selected from the following group: 7.6° ± 0.2°, 11.7° ± 0.2°, 19.8° ± 0.2°.

[0045] In another preferred example, in another preferred example, 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 includes 2θ values of 6 or more selected from the following group: 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°, 28.0° ± 0.2°;

[0047] (m2) The XRPD pattern of the crystalline form Form D is substantially as Figure 10 characterized;

[0048] (m3) The crystalline form Form D loses 0.9% of its weight at 20 - 140 °C;

[0049] (m4) The TGA pattern of the crystalline form Form D is substantially as Figure 11 characterized.

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

[0051] In the second aspect of the present invention, there is provided a method for preparing a crystal as described in the first aspect of the present invention, the crystal being the crystalline form Form A, and the method comprising the following steps:

[0052] (a1) Take a first substance, the first substance being 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridine-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine;

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

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

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

[0056] In another preferred example, 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.

[0057] In another preferred example, the mass ratio of the first substance to fumaric acid is 10 to 3:1, preferably 5 to 3:1, more preferably 4 to 3:1.

[0058] In another preferred example, the method further includes a post-treatment step.

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

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

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

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

[0063] In the third aspect of the present invention, there is provided a method for preparing a crystal as described in the first aspect of the present invention, wherein the crystal is crystal form Form B, and the method includes the steps of: placing Form A in a liquid-phase vial, dropping a pre-heated methyl tert-butyl ether solution, forming a suspension, then dropping pre-heated DMF, transferring to -20 °C to 30 °C for cooling, centrifuging and drying the solid to obtain crystal form Form B.

[0064] In the fourth aspect of the present invention, there is provided a method for preparing a crystal as described in the first aspect of the present invention, wherein the crystal is crystal form Form C, and the method includes any one of steps (c1) and (c2):

[0065] (c1) Mixing a first substance, which is 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, with an organic solvent and fumaric acid to obtain crystal form Form C,

[0066] Among them, the molar ratio of the first substance to fumaric acid is 1:2.5 to 4.0;

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

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

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

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

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

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

[0073] In the fifth aspect of the present invention, a method for preparing a crystal as described in the first aspect of the present invention is provided. The crystal is crystalline form Form D, and the method includes the steps of: placing the crystalline form Form C in a glass vial, adding methanol and dissolving it by ultrasound, then adding toluene, stirring, transferring it to - 20 °C to 0 °C and standing for 1 - 5 days, and removing the liquid to obtain crystalline form Form D.

[0074] The sixth aspect of the present invention provides a pharmaceutical composition, which comprises: (a) any one of the crystals described in the first aspect, 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, for preparing a potassium - ion competitive acid blocker, 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.

[0076] It should be understood that within the scope of the present invention, the above - mentioned various technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. Description of the Drawings

[0077] Figure 1 The XRPD spectrum of the crystalline form Form A of the compound of the present invention is shown.

[0078] Figure 2 Shows the TGA and DSC spectra of crystalline form Form A of the compound of the present invention.

[0079] Figure 3 Shows the NMR spectrum of crystalline form Form A of the compound of the present invention.

[0080] Figure 4 Shows the XRPD spectrum of crystalline form Form B of the compound of the present invention.

[0081] Figure 5 Shows the TGA and DSC spectra of crystalline form Form B of the compound of the present invention.

[0082] Figure 6 Shows the NMR spectrum of crystalline form Form B of the compound of the present invention.

[0083] Figure 7 Shows the XRPD spectrum of crystalline form Form C of the compound of the present invention.

[0084] Figure 8 Shows the TGA and DSC spectra of crystalline form Form C of the compound of the present invention.

[0085] Figure 9 Shows the NMR spectrum of crystalline form Form C of the compound of the present invention.

[0086] Figure 10 Shows the XRPD spectrum of crystalline form Form D of the compound of the present invention.

[0087] Figure 11 Shows the TGA spectrum of crystalline form Form D of the compound of the present invention.

[0088] Figure 12 Shows the NMR spectrum of crystalline form Form D of the compound of the present invention.

[0089] Figure 13 Shows the solid-state transformation relationship diagram of the compound of the present invention.

[0090] Figure 14 Shows the XRPD comparison diagram of different salt forms and crystalline forms of the compound of the present invention.

[0091] Figure 15 Shows the XRPD comparison diagram of fumarates with different ratios of the compound of the present invention.

[0092] Figure 16 Shows the DVS curve of crystalline form Form A of the compound of the present invention; (b) XRPD diagrams before and after DVS testing.

[0093] Figure 17 Shows the PLM image of crystalline form Form A of the compound of the present invention.

[0094] Figure 18 It shows the XRPD pattern of the stability study of crystalline form Form A of the compound of the present invention.

[0095] Figure 19 It shows the XRPD pattern of the stability study of crystalline form Form C of the compound of the present invention.

[0096] Figure 20 It shows the XRPD comparison pattern of the remaining solid after oscillating in the medium for 24 h of crystalline form Form A of the compound of the present invention.

[0097] Figure 21 It shows the NMR comparison pattern of the remaining solid after oscillating in FaSSGF for 24 h of crystalline form Form A of the compound of the present invention.

[0098] Figure 22 It shows the XRPD comparison pattern of the remaining solid after oscillating in FaSSIF and FaSSGF for 24 h of crystalline form Form A of the compound of the present invention to reproduce.

[0099] Figure 23 It shows the NMR comparison pattern of the remaining solid after oscillating in FaSSIF and FaSSGF for 24 h of crystalline form Form A of the compound of the present invention to reproduce.

[0100] Figure 24 It shows the NMR comparison pattern of the remaining solid after oscillating in FaSSIF for 24 h of crystalline form Form A of the compound of the present invention to reproduce.

[0101] Figure 25 It shows the XRPD comparison pattern of the remaining solid after oscillating in water for 2 h of crystalline form Form C of the compound of the present invention (normalized).

[0102] Figure 26 It shows the (a) DVS curve; (b) XRPD patterns before and after DVS test of crystalline form Form C of the compound of the present invention.

[0103] Figure 27 It shows the superposition comparison pattern of the thermal transformation of crystalline form Form B of the compound of the present invention.

[0104] Figure 28 It shows the XRPD comparison pattern of the remaining solid after oscillating in water for 2 h of crystalline forms Form B and Form A of the compound of the present invention.

[0105] Figure 29 It shows the (a) DVS curve; (b) XRPD patterns before and after DVS test of crystalline form Form B of the compound of the present invention. Detailed implementation mode

[0106] After long-term and in-depth research, the present inventors have provided a salt crystal form of a compound of formula I. These crystal forms have advantages in terms of stability, solubility, hygroscopicity, mechanical stability, tableting stability, fluidity, process developability, formulation research and powder processing performance, etc. In particular, crystal form Form A and crystal form Form C have significant advantages in terms of preparation process and stability, etc. Based on the above findings, the inventors have completed the present invention.

[0107]

[0108] Term

[0109] In this article, unless otherwise specified, each abbreviation has the conventional meaning understood by those skilled in the art.

[0110] As used herein, unless otherwise specified, the way of adding a solvent or solution is to directly pour it in or add it at a uniform speed, etc.

[0111] As used herein, the term "room temperature" generally refers to 4 - 30 °C, preferably 20 ± 5 °C.

[0112] As used herein, the way of "slow addition" includes, but is not limited to: dropwise addition, slow addition along the wall of the container, etc.

[0113] As used herein, the term "containing" or "including (comprising)" can be open, semi-closed and closed. In other words, the said term also includes "substantially consisting of..." or "consisting of...".

[0114] As used herein, the term "m or more 2θ values selected from the following group" means including n and any positive integer greater than n (such as m, m + 1,...), where the upper limit Nup is the number of all 2θ peaks in the group. For example, "3 or more" includes not only the positive integers 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,... up to the upper limit Nup, but also ranges such as "4 or more", "5 or more", "6 or more", etc.

[0115] As used herein, the terms "compound of formula I", "raw material", "fumarate salt of the compound of formula I", "salt of pyrrolosulfonamide acid inhibitor", "1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridine-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate", "compound of the present invention" can be used interchangeably and all refer to the compound shown in formula I, where n = 0.1 - 2.0.

[0116]

[0117] As used herein, "N-methylmethylamine fumarate" and "n" can be used interchangeably, and both refer to the number of N-methylmethylamine fumarate moieties in the compound of formula I. For example, when n = 1, it is 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridine-3-ylsulfonyl)-1H-pyrrol-3-yl]-1-methylmethylamine fumarate.

[0118] As used herein, "crystalline form FormA", "FormA", "raw material (FormA)", and "1 fumarate FormA" can be used interchangeably, and all refer to the crystalline form FormA of the compound of formula I. As used herein, "crystalline form FormB", "FormB", and "0.5 fumarate FormB" can be used interchangeably, and all refer to the crystalline form FormB of the compound of formula I. As used herein, "crystalline form FormC", "FormC", and "1.5 fumarate FormC" can be used interchangeably, and all refer to the crystalline form FormC of the compound of formula I. As used herein, "crystalline form FormD" and "FormD" can be used interchangeably, and all refer to the crystalline form FormD of the compound of formula I.

[0119] A pharmaceutical composition containing a crystalline form of the compound of formula I

[0120] Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of the compound of formula I as described in the present invention, and optionally, one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials, and / or diluents. Examples of the auxiliary materials include odorants, flavorants, sweeteners, etc.

[0121] The pharmaceutical composition provided by the present invention preferably contains an active ingredient in a weight ratio of 1-99%, and a preferred ratio is that the compound of general formula I as the active ingredient accounts for 65 wt% to 99% of the total weight, and the remaining part is a pharmaceutically acceptable carrier, diluent, or solution or salt solution. The compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, etc., and can be present in a suitable solid or liquid carrier or diluent and a suitable sterilized device for injection or infusion.

[0122] The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to the conventional preparation methods in the pharmaceutical field. The unit dosage of its formulation contains 1 mg - 700 mg of the compound of general formula I. Preferably, the unit dosage of the formulation contains 25 mg - 300 mg of the compound of general formula I.

[0123] The compounds and pharmaceutical compositions of the present invention can be clinically used in mammals, including humans and animals, and can be administered through oral, nasal, dermal, pulmonary or gastrointestinal routes, etc. The most preferred route is oral administration. The most preferred daily dose is 50 - 1400 mg / kg body weight, taken once, or 25 - 700 mg / kg body weight taken in divided doses. Regardless of the administration method, the optimal dose for an individual should be determined according to the specific treatment. Usually, it starts with a small dose and gradually increases until the most suitable dose is found.

[0124] In the present invention, unless otherwise specified, the drying method used is a conventional drying method in the art. For example, in the examples of the present invention, drying refers to vacuum drying or atmospheric drying in a conventional drying oven. Generally, drying is carried out for 0.1 - 50 h or 1 - 30 h.

[0125] The main advantages of the present invention are as follows:

[0126] (1) The compound crystals of the present invention (including crystal form Form A, crystal form Form B, crystal form Form C, crystal form Form D), compared with their amorphous solids, have high purity, good stability, good fluidity, and low hygroscopicity.

[0127] (2) The preparation method of the compound crystals of the present invention (including crystal form Form A, crystal form Form B, crystal form Form C, crystal form Form D) is simple and is more suitable for industrial production compared with the freeze-drying process (which is energy-consuming and has limited production capacity).

[0128] (3) The compound crystals of the present invention (including crystal form Form A, crystal form Form B, crystal form Form C, crystal form Form D) can be used to prepare potassium ion competitive acid blockers and drugs for the treatment of erosive esophagitis, gastric ulcer, duodenal ulcer, Helicobacter pylori eradication indications, and related diseases caused by excessive gastric acid.

[0129] The present invention will be further illustrated below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following examples are usually carried out under conventional conditions or according to the conditions recommended by the manufacturers. Unless otherwise stated, percentages and parts are calculated by weight.

[0130] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to persons skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the inventive method. The preferred methods and materials described herein are for illustrative purposes only.

[0131] General methods and reagents

[0132] The solvents used in the present invention are all of analytical grade.

[0133] All the test methods of the present invention are common methods, and the test parameters are as follows:

[0134] Nuclear magnetic resonance analysis ( 1 H NMR)

[0135] Dissolve several milligrams of solid sample in dimethyl sulfoxide-d6 solvent, and perform nuclear magnetic resonance analysis on Bruker AVANCE NEO 400 (Bruker, GER).

[0136] X-ray powder diffraction (XRPD)

[0137] Use the X-ray powder diffractometer Malvern PANalytical Aeris (Malvern Panalytical, UK) for preliminary testing. The 2θ scanning angle ranges from 3° to 45°, the scanning step is 0.02°, and the test time is 4.9 min. When testing the sample, the tube voltage and current are 40 kV and 7.5 mA respectively, and the sample disk is a zero-background sample disk. Or use the X-ray powder diffractometer Panalytical EMPYREAN (PANalytical, UK) for further characterization. The 2θ scanning angle ranges from 3° to 45°, the scanning step is 0.013°, and the total test time is 3.5 min. The test method is Cu target Kα1 ray, voltage 45 kV, current 40 mA, and the sample disk is a zero-background sample disk.

[0138] In-situ variable-temperature XRPD test

[0139] Use the X-ray powder diffractometer Malvern PANalytical Aeris (Malvern Panalytical, UK) for the test. The 2θ scanning angle ranges from 3° to 40°, the scanning step is 0.02°, and the test time is 13 min. When testing the sample, the tube voltage and current are 40 kV and 7.5 mA respectively, and the sample disk is a zero-background sample disk. The sample is placed on a BTS500 hot stage (Anton Paar, AT). Perform XRPD test at room temperature, then heat it to the selected temperature at a rate of 10 °C / min, perform XRPD test at this temperature after isothermal for 10 min, and then cool it down to room temperature and perform XRPD test again.

[0140] Thermogravimetric analysis (TGA)

[0141] The model of the thermogravimetric analyzer is TA Discovery 55 (TA, US). 2 - 5 mg of the sample was placed in a balanced 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, with a nitrogen purge rate of 60 mL / min at the sample position and 40 mL / min at the balance position.

[0142] Differential scanning calorimetry (DSC)

[0143] The model of the differential scanning calorimeter is TA Discovery 2500 (TA, US). 1 - 2 mg of the sample was accurately weighed and placed in a punctured DSC Tzero sample pan, and heated to the final temperature at a rate of 10 °C / min, with a nitrogen purge rate of 50 mL / min in the furnace.

[0144] Dynamic vapor sorption (DVS)

[0145] The dynamic vapor sorption analysis for the preliminary evaluation of hygroscopicity was determined using DVS Intrinsic Plus (SMS, UK). The test was carried out in a gradient mode with humidity changes of 50% - 95% - 50%, with a humidity change of 15% for each gradient. The end of the gradient was judged by the dm / dt method, with the end of the gradient being when dm / dt was less than 0.002% and maintained for 10 minutes, or the maximum maintenance time for each gradient was 60 min. After the test, XRPD analysis was performed on the sample to confirm whether the solid form had changed.

[0146] The dynamic vapor sorption analysis was determined using DVS Intrinsic Plus (SMS, UK). The test was carried out in a gradient mode with humidity changes of 0% - 95% - 0%. In the range of 0% to 90%, the humidity change for each gradient was 10%. The end of the gradient was judged by the dm / dt method, with the end of the gradient being when dm / dt was less than 0.002% and maintained for 10 minutes, or the maximum maintenance time for each gradient was 180 minutes. After the test, XRPD analysis was performed on the sample to confirm whether the solid form had changed.

[0147] High performance liquid chromatography (HPLC)

[0148] The model of the high performance liquid chromatography is SHIMADZU LC - 20A (Shimadzu, JP), and the test conditions are shown in Table 0 below.

[0149] Table 0 HPLC test conditions

[0150]

[0151]

[0152] Preparation of Crystal Form A in Example 1

[0153] 1.1 Synthesis Method

[0154] Add 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.) into a 100 ml single-necked flask. Stir at room temperature for 0.5 h, filter, wash with ethyl acetate (6 ml), and dry in vacuo at 50 °C for 3 h to obtain 2.25 g of a white solid with a yield of 88%.

[0155] Add 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.) into a 100 ml single-necked flask. Stir at room temperature for 1 h, filter, wash with ethanol (10 ml), and dry in vacuo at 45 °C for 5 h to obtain 1.80 g of a white solid with a yield of 78%.

[0156] Add 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.) into a 100 ml single-necked flask. Stir at room temperature for 1 h, filter, wash with ethyl acetate (10 ml), and dry in vacuo at 60 °C for 6 h to obtain 2.15 g of a white solid with a yield of 84%.

[0157] 1.2 Thermal Transformation Method

[0158] The thermal transformation was carried out using an in-situ variable-temperature X-ray powder diffractometer Malvern PANalytical Aeris (Malvern Panalytical, UK). The sample was placed on a BTS500 hot stage (Anton Paar, AT). XRPD tests were performed at room temperature, then heated to the selected temperature at a rate of 10 °C / min, isothermally maintained for 10 min, and XRPD tests were carried out at this temperature. Subsequently, the temperature was lowered to room temperature and XRPD tests were performed again. The spectral data are shown in Table 1. (Hereinafter referred to as the in-situ variable-temperature XRPD experiment)

[0159] Table 1 XRPD Table of Crystal Form A

[0160]

[0161]

[0162] Preparation of Crystal Form B in Example 2

[0163] The preparation process is shown in Table 2. Form B was successfully prepared in the scale-up preparation.

[0164] Table 2 Scale-up preparation of the target salt form

[0165]

[0166]

[0167] Table 3 is the XRPD table of crystal form Form B.

[0168] Table 3 XRPD table of crystal form Form B

[0169]

[0170]

[0171] Preparation of crystal form Form C in Example 3

[0172] 3.1 Synthesis method

[0173] Add 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) to a 100 ml single-necked flask. Stir at room temperature for 0.5 h, filter, wash with ethyl acetate (10 ml), and dry in vacuo at 45 °C for 6 h to obtain 2.41 g of a white solid with a yield of 85%.

[0174] Add 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) to a 100 ml single-necked flask. Stir at room temperature for 1 h, filter, wash with methanol (10 ml), and dry in vacuo at 50 °C for 6 h to obtain 2.47 g of a white solid with a yield of 87%.

[0175] Add 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) to a 100 ml single-necked flask. Stir at room temperature for 0.5 h, filter, wash with ethanol (10 ml), and dry in vacuo at 60 °C for 6 h to obtain 2.44 g of a white solid with a yield of 86%.

[0176] Add ethanol (20 ml) and fumaric acid (0.66 g, 1.5 eq.) to 100 ml of a single port, heat to dissolve, add 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridine-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (2.00 g), stir for 0.5 h, filter, wash with ethanol (10 ml), and dry in vacuo at 50 °C for 4 h to obtain 2.04 g of a white solid with a yield of 92%.

[0177] The XRPD data of crystalline form C are shown in Table 4.

[0178] Table 4 XRPD table of crystalline form C

[0179]

[0180]

[0181] Preparation of crystalline form D in Example 4

[0182] Weigh 19.6 mg of crystalline form C using a preparation workstation ICSW-V3 (XtalPi, CN), add 1.7 ml of methanol dropwise at room temperature to completely dissolve it, then add 15.0 ml of toluene solution and stir at room temperature for 1 h. After filtration, transfer it to -15 °C and let it stand for 1 day. After centrifuging and drying the obtained solid in vacuo at room temperature, perform XRPD testing, as shown in Table 5.

[0183] Table 5 is the XRPD table of crystalline form D.

[0184] Table 5 XRPD table of crystalline form D

[0185]

[0186] Characterization of the crystal form in Example 5

[0187] 5.1 Crystal form A

[0188] The XRPD results show that Form A is a solid with good crystallinity. The TGA results show that Form A has basically no weight loss when heated to 150 °C and may decompose above 195 °C. The DSC results show that Form A has a melting endothermic signal at about 188 °C. The NMR results show that the sample is consistent with the reference spectrum and there are no obvious organic solvent signal peaks. The PLM image shows that Form A is a massive crystal with a particle size generally less than 25 μm. In summary, Form A is a non-hydrated crystal form.

[0189] Table 6 Systematic characterization results of fumarate Form A

[0190]

[0191]

[0192] 5.2 Crystal Form B

[0193] The XRPD results show that Form B is a solid with good crystallinity. The TGA results show that Form B has a weight loss of 2.9% during heating to 150 °C and may decompose above 210 °C. The DSC results show that Form C has a broad endothermic signal corresponding to the TGA weight loss from 40 °C to 90 °C, and endothermic signals at about 147 °C and about 178 °C. The results of the thermal polymorph conversion experiment show that the XRPD of Form B did not change after heating to 100 °C, see Figure 27 ... The NMR results show that the compound structure has not changed. The signal peak of fumaric acid can be seen at 6.43 ppm, the signal peaks of DMF can be seen at 2.73 ppm and 2.89 ppm, and there is a small amount of solvent residue. According to the integration results, the ratio of the compound to fumaric acid is 1:0.5. In summary, Form B is an anhydrate.

[0194] 5.3 Crystal Form C

[0195] The XRPD results show that Form C is a solid with good crystallinity. The TGA results show that Form C has no obvious weight loss during heating to 120 °C and may decompose above 190 °C. The DSC results show that Form C has an endothermic peak of melting with decomposition at about 189 °C. The NMR results show that the structure of this sample is consistent with that provided by the customer. In summary, Form C is a crystal form without water.

[0196] 5.4 Crystal Form D

[0197] The XRPD results show that Form D is a solid with poor crystallinity. The TGA results show that Form D has a weight loss of 0.9% during heating to 140 °C and may decompose after 190 °C. The NMR results show that the integration at 6.48 ppm indicates that the free state: fumaric acid ≈ 1:1 in this sample, indicating that this sample is a 1-fumarate salt; the integration at 2.30 ppm indicates the presence of a small amount of toluene. In summary, Form D is presumably a crystal form without water with a salt formation ratio (free state: fumaric acid) of 1:1.

[0198] Table 7 Crystal Form Characterization Results

[0199]

[0200] Solid State Transformation Relationship of the Crystal Forms in Example 6

[0201] The conversion relationship of the solid state (crystal form / salt form) of the compounds of the present invention is as shown in Figure 13As shown, Form C can be transformed into Form A through high-temperature suspension; Form D will transform into Form C + Form B after being placed with a closed lid at normal temperature and normal humidity after drying.

[0202] Effect Examples

[0203] Stability of Example 7

[0204] 7.1 Method

[0205] Weigh about 20 mg of the sample and place it in a weighing bottle. Then, place it in the open at high temperature (60 °C), high humidity (25 °C / 92.5% RH), light (25 °C / 4500 Lux), and accelerated (40 °C / 75% RH) conditions. Sampling is carried out at 7 days and 15 days for XRPD characterization and HPLC testing.

[0206] 7.2 Results

[0207] The results are shown in Table 8 and Figure 18 , Figure 19 As shown. The XRPD results show that the XRPD of Form A and Form C after being placed for 15 days under high temperature, high humidity, accelerated, and light conditions is the same as that at 0 day. There is no significant change in purity under high temperature, high humidity, and accelerated conditions, the purity decreases under light conditions, and the solid appearance turns yellow.

[0208] Table 8 Results of Stability Study

[0209]

[0210]

[0211] Solubility of Example 8

[0212] 8.1 Method

[0213] 8.1.1 Evaluation of Solubility in Water

[0214] Add the sample to 4.0 mL of water, shake it at a constant temperature of 37 °C for 2 h, and then take a sample; filter the sampled solution with a 0.22 μm water-based filter membrane, appropriately dilute some samples with higher concentrations with a diluent, measure the signal peak area of the solution by HPLC, and finally calculate the concentration of the compound in the solution based on the peak area, the HPLC standard curve of the raw material, and the dilution factor. In addition, XRPD testing is carried out on the remaining solid.

[0215] 8.1.2 Solubility Test

[0216] The preparation process of the biological medium is shown in Table 9. The sample was added to the biological medium, water, 0.9% normal saline, and 5% glucose, and shaken at a constant temperature of 37°C for 24 h. Samples were taken at 0.5 h, 2 h, and 24 h respectively. The sampled solution was filtered through a 0.22 μm aqueous filter membrane. Some samples with higher concentrations were appropriately diluted with a 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 24 h supernatant was measured, and the remaining solid was tested by XRPD.

[0217] Table 9 Preparation process of the biological medium

[0218]

[0219] 8.2 Results

[0220] 8.2.1 FormA

[0221] The results showed that the solubility of FormA in the three biological media, water, normal saline, and glucose at 24 h from high to low was FaSSGF > water ≈ 0.9% normal saline ≈ 5% glucose > FeSSIF > FaSSIF. After shaking in FaSSIF for 24 h, there was a very small amount of remaining solid; after shaking in FeSSIF for 24 h, it was an oily substance. After shaking in water, 0.9% normal saline, and 5% glucose for 24 h, the crystal form of the remaining solid did not change, but the crystallinity became worse; after shaking in FaSSGF for 24 h, the XRPD of the remaining solid changed. The NMR results showed that there were shifts at 6.40 ppm and 7.67 ppm, and the peaks at 2.42 ppm and 6.47 ppm (fumaric acid) disappeared. Since the amount of the remaining solid in FaSSIF and FaSSGF was small, an appropriate amount of FormA was weighed and shaken in the FaSSIF and FaSSGF solutions for 24 h, and the obtained solid was characterized. The XRPD results showed that the remaining solid after shaking in FaSSGF for 24 h was mixed with free fumaric acid. The ion chromatography test results showed that the chloride ion content was 2.4%. The NMR results showed that the proportion of fumaric acid in the remaining solid after shaking in FaSSIF for 24 h decreased. The ion chromatography test results showed that the chloride ion content was 4.9%, and the phosphate ion content was 2.9%. Based on the above results, FormA may have dissociated in the FaSSIF and FaSSGF solutions, and some of the dissociated solids formed salts with the acidic components in the medium.

[0222] Table 10 Dynamic solubility test

[0223]

[0224] Note: "*" represents the concentration of the corresponding free state in the solution calculated according to the free state standard curve.

[0225] The results of Form B in 8.2.2 Form B show that the solubility of Form B and Form A in water for 2 hours from high to low is Form A > Form B; after shaking in water for 2 hours, the crystal forms of the remaining solids did not change.

[0226] Table 11 pH buffer and water solubility evaluation results

[0227]

[0228] Note: "*" represents the concentration of the corresponding free state in the solution calculated according to the free state standard curve.

[0229] 8.2.3 Form C

[0230] The solubility of Form C in water was evaluated. The experimental method is shown in 8.1.1, and the corresponding results are shown in Table 12.

[0231] Table 12 Water solubility evaluation results

[0232]

[0233] a Calculated value according to the HPLC standard curve of the free state

[0234] Example 9 Hygroscopicity

[0235] DVS tests were carried out on Form A and Form B, as Figure 16 、 Figure 29 shown. The results show that for Form A, at 95% RH, the adsorption weight gain is about 0.105%, at 80% RH, the adsorption weight gain is about 0.047%, at 80% RH, the desorption weight gain is about 0.050%, and at 50% RH, the desorption weight loss is about 0.026%.

[0236] Table 13 Preliminary evaluation summary table

[0237]

[0238] For Form B, at 95% RH, the adsorption weight gain is about 0.855%, at 80% RH, the adsorption weight gain is about 0.427%, at 80% RH, the desorption weight gain is about 0.435%, and at 50% RH, the desorption weight loss is about 0.221%. There was no significant change in XRPD after the DVS test for Form A and Form B.

[0239] Table 14 Preliminary evaluation summary table

[0240]

[0241] The DVS test was carried out on Form C, as Figure 26 shown. The results showed that Form C gained 0.052% in weight at 95% humidity; gained 0.017% in weight at 80% humidity during the adsorption process; and gained 0.019% in weight at 80% humidity during the desorption process. The XRPD results indicated that the crystal form of Form C did not change after the rapid DVS test.

[0242] Table 15 Preliminary Evaluation Summary Table

[0243]

[0244] Study on the Dissolution Results of the Crystal Tablets of Example 10

[0245] API tablets (conventional tableting) of Form A and Form C of the present invention, with a specification of 10 mg (calculated as the free base), were used to investigate the dissolution of the samples in pH 6.8 phosphate buffer, pH 4.5 acetate buffer, pH 1.2 hydrochloric acid solution and purified water. The data comparison is shown in Tables 16 and 17.

[0246] Table 16 Dissolution Data of 10 mg Form A Product (n = 6)

[0247]

[0248] Table 17 Dissolution Data of 10 mg Form C Product (n = 6)

[0249]

[0250] The results showed that the dissolution of the tablet products prepared from Form A and Form C was greater than 85% within 15 min in pH 6.8 phosphate buffer, pH 4.5 acetate buffer, pH 1.2 hydrochloric acid solution and purified water.

[0251] All documents mentioned in the present invention are cited herein as references, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

1. A crystal of a compound of formula I, characterized in that, The crystal form of the crystal is selected from the following group: crystal form FormA, crystal form FormB, crystal form FormC or crystal form FormD, wherein, n = 0.1 to 2.

0.

2. The crystal according to claim 1, wherein The crystal form is an anhydrate.

3. The crystal according to claim 1, characterized in that, The crystal form FormA further has one or more characteristics selected from the following group: (i1) The XRPD pattern of the crystal form FormA 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 FormA 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°, 23.1° ± 0.2°; (i3) The XRPD pattern of the crystal form FormA is substantially characterized as shown in Figure 1; (i4) The crystal form FormA has no weight loss at 20 to 150 °C; (i5) The TGA pattern of the crystal form FormA is substantially characterized as shown in Figure 2; (i6) The peak temperature of the DSC pattern of the crystal form FormA is 188.4 °C; (i7) The DSC pattern of the crystal form FormA is substantially characterized as shown in Figure 2.

4. The crystal according to claim 1, wherein The crystal form FormB further has one or more characteristics selected from the following group: (j1) The XRPD pattern of the crystal form FormB 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 FormB includes 3 or more (such as 4, 5, or 6) 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 FormB is substantially characterized as shown in Figure 4; (j4) The crystal form FormB has a weight loss of 2.9% at 20 to 150 °C; (j5) The TGA pattern of the crystal form FormB is substantially characterized as shown in Figure 5; (j6) The peak temperatures of the DSC pattern of the crystal form FormB are 57.2, 146.6, 178.4 °C; (j7) The DSC pattern of the crystal form FormB is substantially characterized as shown in Figure 5.

5. The crystal according to claim 1, wherein, The crystal form FormC further has one or more characteristics selected from the following group: (k1) The XRPD pattern of the crystalline form Form C includes 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°, 37.3° ± 0.2°; (k2) The XRPD pattern of the crystalline form Form C is substantially characterized as shown in Figure 7; (k3) The crystalline form Form C has no weight loss at 20 - 120 °C; (k4) The TGA pattern of the crystalline form Form C is substantially characterized as shown in Figure 8; (k5) The peak temperature of the DSC pattern of the crystalline form Form C is 189.3 °C; (k6) The DSC pattern of the crystalline form Form C is substantially characterized as shown in Figure 8.

6. The crystal according to claim 1, characterized in that, The crystalline form Form D further has one or more characteristics selected from the group consisting of: (m1) The XRPD pattern of the crystalline form Form D includes 6 or more 2θ values selected from the group consisting of: 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 crystalline form Form D is substantially characterized as shown in Figure 10; (m3) The crystalline form Form D has a weight loss of 0.9% at 20 - 140 °C; (m4) The TGA pattern of the crystalline form Form D is substantially characterized as shown in Figure 11.

7. A method for preparing a crystal as described in claim 1 or 3, characterized in that, The crystal is crystalline form Form A, and the method includes the following steps: (a1) Take a first substance, which is 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridine-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 fumaric acid is 1:0.5 - 1.

5.

8. The preparation method according to claim 7, wherein The organic solvent is selected from the group consisting of: ethyl acetate, methyl acetate, butyl acetate, methanol, ethanol, or a combination thereof.

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

10. The preparation method according to claim 9, wherein the organic solvent is selected from the group consisting of ethyl acetate, methyl acetate, butyl acetate, methanol, ethanol, or a combination thereof.

11. A pharmaceutical composition, characterized in that, The composition comprises: (a) any one of the crystals described in the first aspect, 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, For preparing a potassium ion competitive acid blocker, for preparing a medicament or pharmaceutical composition for treating erosive esophagitis, gastric ulcer, duodenal ulcer, Helicobacter pylori eradication indication, and related diseases caused by excessive gastric acid.

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