Crystal of benzimidazole compound as well as preparation method and application of crystal

Abstract

The invention relates to the field of medicinal chemistry, relates to a crystal of a benzimidazole compound as well as a preparation method and application thereof, and in particular relates to a crystal of a compound as shown in a formula (I) and a preparation method thereof. The crystal of the compound shown in the formula (I) has good stability and can be applied to preparation of drugs for treating peptic ulcer.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to the crystals and uses of benzimidazole compounds. More specifically, this invention relates to crystal form I and crystal form II of sodium salts of benzimidazole compounds, their preparation methods, and uses. Background Technology

[0002] Ilaprazole is a second-generation proton pump inhibitor, belonging to the benzimidazole class of compounds. Its chemical name is 2-[[4-methoxy-3-methyl]-2-pyridyl]meththioyl]-5-(1H-pyrrolo-1-yl)-1H-benzimidazole, also known as TY-81149. It is a novel irreversible proton pump inhibitor developed by Ilyang Pharmaceutical Co., Ltd. of South Korea. Later, it was developed and marketed in China by Livzon Pharmaceutical Group, and approved for marketing in South Korea in September 2008. Livzon Pharmaceutical Group's new, potent enteric-coated proton pump inhibitor is indicated for duodenal ulcers and reflux esophagitis. Compared with first-generation proton pump inhibitors such as omeprazole, pantoprazole, and lansoprazole, ilaprazole showed stronger and longer-lasting acid-suppressing effects than omeprazole in controlling gastric acid pH in patients with gastroesophageal reflux disease.

[0003] However, the non-salt form of proton pump inhibitors (PPIs) is unstable under high temperature and high humidity. In order to improve the stability and water solubility of PPIs, it is advisable to prepare them into alkali metal salts, such as omeprazole sodium, rabeprazole sodium, lansoprazole sodium, and pantoprazole sodium. Improving the stability of PPIs during storage and transportation is of great significance to drug research. Summary of the Invention

[0004] This application aims to provide crystal forms of benzimidazole compounds, their preparation methods, and uses, such as crystal forms of benzimidazole compound salts.

[0005] The sodium salt of benzimidazole compounds (compound of formula I) provided in this application has been found through extensive research to have good stability. For example, under conditions such as light, high temperature, high humidity and time, this crystal form is not prone to crystal transformation and is easier to store and transport than existing crystal forms.

[0006] The first aspect of the present invention provides a crystal I of a compound of formula (I):

[0007]

[0008]

[0009] A second aspect of the invention provides crystals II of compounds of formula (I) as shown above.

[0010] A third aspect of the invention provides a pharmaceutical composition comprising any one or more crystals of the invention, and one or more pharmaceutically acceptable carriers.

[0011] A fourth aspect of the invention provides the use of the crystals or pharmaceutical compositions of the invention in the preparation of a medicament for treating peptic ulcers.

[0012] The fifth aspect of the invention provides the use of the crystal or pharmaceutical composition of the invention in a medicament for treating peptic ulcers.

[0013] A sixth aspect of the invention provides a method for preventing or treating peptic ulcers, comprising administering an effective amount of the crystal or pharmaceutical composition of the invention to an individual in need.

[0014] The seventh aspect of the present invention provides a method for preparing the crystal of the present invention.

[0015] The crystals of the present invention not only exhibit excellent efficacy and low toxicity in the prevention or treatment of peptic ulcer disease, but also possess other advantages. For example, preferred crystals of the compounds of formula (I) of the present invention possess excellent physical properties (including solubility, dissolution rate, photostability, low hygroscopicity, high temperature resistance, high humidity resistance, flowability, thermal stability, etc.), maintaining their efficacy and safety even after prolonged storage. Furthermore, the preferred crystalline form of the present invention may possess superior properties in areas such as bioavailability, physical and / or chemical stability, lipid solubility, and ease of preparation. The preferred crystalline form of the present invention is more suitable and convenient for large-scale preparation and formulation, reducing irritation and improving absorption, addressing metabolic rate issues, significantly reducing toxicity, improving safety, and effectively ensuring the quality and efficacy of pharmaceutical products. Attached Figure Description

[0016] Figure 1 The image shows the XRPD pattern of crystal I of compound (I).

[0017] Figure 2 The XRPD pattern of crystal II of compound (I) is shown.

[0018] Figure 3 The image shows the Raman spectrum of crystal I of compound (I).

[0019] Figure 4 The image shows the infrared spectrum of crystal I of compound (I).

[0020] Figure 5 The image shows the DSC diagram of crystal I of compound (I).

[0021] Figure 6 The image shows the TGA diagram of crystal I of compound (I). Detailed Implementation

[0022] definition

[0023] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0024] The terms “including,” “comprising,” “having,” “containing,” or “involving,” as used herein, and their other variations thereof, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0025] As used herein, the terms “one or more” or “at least one” refer to one, two, three, four, five, six, seven, eight, nine or more.

[0026] If the number of components or parts of this invention is not previously specified, it indicates that there is no limitation on the number of times a component or part may appear (or be present). Therefore, it should be interpreted as including one or at least one, and the singular form of a component or part also includes the plural, unless the value clearly indicates a singular number.

[0027] As used herein, the terms “optional” or “optionally” mean that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0028] As used herein, the term "about" means within an acceptable standard error of a value, as would be considered by one of ordinary skill in the art, such as within a 95% confidence interval of the average or within ±10% of a specified value, or a wider range, such as ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2, or ±3. It should be understood herein that when multiple values ​​or ranges are listed, each listed value or range may be subject to the designation "about," even if only the first value or endpoint is designated as "about."

[0029] As used in this article, the term “differential scanning calorimetry (DSC) spectrum” refers to a curve recorded by a differential scanning calorimeter.

[0030] As used in this article, the term "thermogravimetric analysis (TGA) curve" refers to the curve recorded by a thermogravimetric analyzer.

[0031] As used herein, the term "substantially identical" means taking into account variations in representative peak positions and / or intensities. For example, for X-ray diffraction peaks, those skilled in the art will understand that peak positions (2θ) will show some variation, typically up to 0.1–0.2 degrees, and that the instrument used to measure diffraction will also cause some variation. Furthermore, those skilled in the art will understand that relative peak intensities will vary due to differences between instruments, as well as the degree of crystallinity, preferred orientation, the surface of the prepared sample, and other factors known to those skilled in the art, and should be considered as qualitative measurements only.

[0032] In this article, "compound (I)" and "compound of formula (I)" both refer to compounds with the following structural formula (I).

[0033]

[0034] The term "pharmaceutical composition" refers to an active ingredient that may optionally be combined with one or more pharmaceutically acceptable chemical components (e.g., but not limited to carriers and / or excipients). The active ingredient may be, for example, crystal I, crystal II of a compound of formula (I), or one or more of the compositions of the present invention.

[0035] The terms “administration” or “giving” refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral, parenteral (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), local, and rectal administration.

[0036] For pharmaceuticals or pharmacologically active agents, the term "effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition can be the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0037] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “activator” refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom. In this document, the term may refer to, for example, crystal I, crystal II of compound (I), or one or more of the compositions of the present invention.

[0038] As used herein, the term "pharmaceutically acceptable carrier" refers to carriers that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. This includes, but is not limited to, any flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers acceptable for human or animal (e.g., livestock) use. Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Further information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0039] As used herein, the term "amorphous" refers to any solid material that is not ordered in three dimensions. In some cases, amorphous solids can be characterized by known techniques, including XRPD crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. As explained below, amorphous solids produce diffuse XRPD spectra, which typically include one or two broad peaks (i.e., peaks with a basis width of about 5°2θ or greater).

[0040] As used herein, the terms “crystal form,” “crystal,” and “crystal shape” have the same meaning and can be used interchangeably in this document. They refer to any solid material exhibiting a three-dimensional arrangement, as opposed to amorphous solid materials, which produce characteristic XRPD spectra with clearly defined peaks.

[0041] As used in the text, the term "solvent compound" refers to a solvent compound formed when a substance dissolves in a solvent, and solvent molecules combine with solute molecules or ions, causing the solute to change its original state.

[0042] As used in this text, the term "hydrate" refers to a salt of the compounds provided herein, which further includes stoichiometric or nonstoichiometric amounts of water bound together by noncovalent intermolecular forces.

[0043] The term "non-covalent form" used in this article refers to weak intermolecular interactions other than covalent bonds, including but not limited to hydrogen bonds, van der Waals forces, salt bonds, hydrophobic interactions, aromatic ring stacking, π-π stacking, halogen bonds, etc.

[0044] As used in this article, the term "X-ray powder diffraction pattern (XRPD pattern)" refers to an experimentally observed diffraction pattern or parameters derived from it. XRPD patterns are typically characterized by peak position (x-axis) and / or peak intensity (y-axis).

[0045] In X-ray powder diffraction (XRPD or XRD) spectroscopy, the diffraction patterns obtained from crystalline compounds are often characteristic of a specific crystal form. The relative intensities of bands (especially at low angles) can vary due to dominant orientation effects resulting from differences in crystallization conditions, grain size, and other measurement conditions. Therefore, the relative intensities of diffraction peaks are not characteristic of the target crystal form; when determining whether a crystal form is identical to a known crystal form, attention should be paid to the relative positions of the peaks rather than their relative intensities. Furthermore, slight errors in peak positions are possible for any given crystal form, which is well known in crystallography. For example, peak positions can shift due to variations in temperature during sample analysis, sample movement, or instrument calibration; the measurement error for 2θ values ​​can sometimes be approximately ±0.2°. Therefore, this error should be taken into account when determining the structure of each crystal form. If the crystal forms of the present invention are described substantially as shown in the specified figures, the term "substantially" is also intended to cover such differences in diffraction peak positions.

[0046] In XRPD spectra, peak positions are typically represented by the 2θ angle or the interplanar distance d, with a simple conversion: d = λ / 2sinθ, where d represents the interplanar distance, λ represents the wavelength of the incident X-rays, and θ is the diffraction angle. For the same crystal form of the same compound, the peak positions in their XRPD spectra are generally similar, although the relative intensity error may be relatively large. It should also be noted that in the identification of mixtures, factors such as decreased content may cause the absence of some diffraction lines. In such cases, it is not necessary to rely on all bands observed in a high-purity sample; even a single band may be characteristic of a given crystal.

[0047] As used herein, the term "2θ" refers to the peak position in degrees, as defined in an experimental setup based on X-ray diffraction experiments, and is typically the horizontal axis unit in a diffraction pattern. If the reflection is diffracted when the incident beam forms an angle θ with a lattice plane, the experimental setup requires recording the reflected beam at a 2θ angle. It should be understood that a specific 2θ value for a particular crystal mentioned herein is intended to represent a 2θ value (in degrees) measured using the X-ray diffraction experimental conditions described herein. X-ray powder diffraction patterns can be obtained by detection under Cu-palladium irradiation conditions using an X-ray powder diffractometer (e.g., an X'Pert3 Powder diffractometer), for example, by detection using an absolute scan at room temperature.

[0048] As used herein, the term "Raman spectroscopy" refers to the signal peaks recorded by a Raman spectrometer. Raman spectroscopy can be performed using a Raman spectrometer (e.g., a Thermo Fisher Nicolet iS50 FT-Raman) at a specific laser wavelength (e.g., 1063 nm) and a specific resolution (e.g., 8 cm⁻¹). -1 The sample is obtained by focusing and scanning the sample under specific sampling gain (e.g., 1.0), moving mirror speed (e.g., 0.3165), and aperture (e.g., 50.00) parameters.

[0049] As used herein, the term "substantially identical" for X-ray diffraction peak positions means taking into account representative peak positions and intensity variations. For example, those skilled in the art will understand that peak positions (2θ) will show some variation, typically up to 0.1–0.2 degrees, and that the instruments used to measure diffraction will also show some variation. Furthermore, those skilled in the art will understand that relative peak intensities will show variations between instruments as well as variations due to degree of crystallinity, preferred orientation, the prepared sample surface, and other factors known to those skilled in the art, and should be considered as qualitative measurements only.

[0050] As used in this article, the term "room temperature" refers to 20℃±5℃.

[0051] When describing methods, components, or steps, the use of letters or numbers for identification is for distinguishing purposes only and does not imply that these methods, components, or steps must be performed in the order or sequence indicated. Those skilled in the art can reasonably adjust these arrangements. For example, "Organic Solvent I," "Organic Solvent II," and "Organic Solvent III" are used for distinguishing purposes only and do not indicate any sequential relationship; the different identifiers may refer to the same or different objects.

[0052] As used in this article, the term "minimum asymmetric unit" refers to the smallest independent part of a unit cell that, after all the space group symmetry operations, can be obtained, which is exactly the smallest part composed of all the atoms, ions, or molecules in the unit cell.

[0053] The solid form (preferably crystalline) can be separated and recovered by methods including decantation, centrifugation, evaporation, gravity filtration, vacuum filtration, or any other technique for solid separation under pressure or depressurization. The separated solids can optionally be dried. "Drying" in this invention can be carried out under forced draft or reduced pressure (preferably vacuum) at any temperature (preferably room temperature) until the residual solvent content is reduced to the limits given in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. The residual solvent content depends on the type of solvent, but does not exceed about 5000 ppm, or preferably about 4000 ppm, or more preferably about 3000 ppm. The drying can be carried out in a disc dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, rotary flash dryer, rapid dryer, etc. The drying can be carried out at temperatures below about 100°C, below about 80°C, below about 60°C, below about 50°C, below about 30°C, or any other suitable temperature, under atmospheric pressure or reduced pressure (preferably vacuum), for any desired time (e.g., about 1, 2, 3, 5, 10, 15, 20, 24 hours, or overnight) to achieve the desired results. The drying can be performed any desired number of times until the desired product quality is achieved. The dried product may optionally undergo a pulverizing operation to produce a desired particle size. Grinding or micronization can be performed before or after drying. Techniques that can be used to reduce particle size include, but are not limited to, ball milling, roller milling, hammer milling, and jet milling.

[0054] Crystals and their preparation methods

[0055] In some embodiments, the present invention relates to crystals of compounds of formula (I), wherein said compounds of formula (I) have the following structure:

[0056]

[0057] Crystal I

[0058] In some embodiments, the present invention provides a crystal I of the compound of formula (I) whose X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of about 5.6 ± 0.2°, about 10.1 ± 0.2°, about 11.20 ± 0.2°, about 11.99 ± 0.2°, and about 12.94 ± 0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of the crystal I of the compound of formula I further includes peaks at diffraction angles (2θ) of about 16.85 ± 0.2°, about 18.27 ± 0.2°, about 20.19 ± 0.2°, about 25.06 ± 0.2°, about 25.75 ± 0.2°, and about 27.40 ± 0.2°.

[0059] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal I of compound (I) includes peaks at diffraction angles (2θ) of about 5.6 ± 0.2°, about 10.1 ± 0.2°, about 11.20 ± 0.2°, about 11.99 ± 0.2°, about 12.94 ± 0.2°, about 14.45 ± 0.2°, about 15.52 ± 0.2°, about 16.23 ± 0.2°, about 16.85 ± 0.2°, about 18.27 ± 0.2°, about 20.19 ± 0.2°, about 25.06 ± 0.2°, about 25.75 ± 0.2°, and about 27.40 ± 0.2°.

[0060] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal I of compound (I) includes peaks at diffraction angles (2θ) of 5.6 ± 0.2°, 10.1 ± 0.2°, 11.20 ± 0.2°, 11.99 ± 0.2°, and 12.94 ± 0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of crystal I of compound I also includes peaks at diffraction angles (2θ) of 16.85 ± 0.2°, 18.27 ± 0.2°, 20.19 ± 0.2°, 25.06 ± 0.2°, 25.75 ± 0.2°, and 27.4 ± 0.2°.

[0061] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal I of compound (I) includes peaks at diffraction angles (2θ) of 5.6 ± 0.2°, 10.1 ± 0.2°, 11.20 ± 0.2°, 11.99 ± 0.2°, 12.94 ± 0.2°, 14.45 ± 0.2°, 15.52 ± 0.2°, 16.23 ± 0.2°, 16.85 ± 0.2°, 18.27 ± 0.2°, 20.19 ± 0.2°, 25.06 ± 0.2°, 25.75 ± 0.2°, and 27.40 ± 0.2°.

[0062] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal I of compound (I) includes a peak at the following 2θ angle:

[0063]

[0064]

[0065] In a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of crystal I of compound (I) includes the following: Figure 1 The peaks shown are at essentially the same diffraction angle (2θ).

[0066] In a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of crystal I of compound (I) is as follows: Figure 1 The results are basically the same.

[0067] In some embodiments, the Raman spectrum of crystal I of compound I further includes a value at approximately 1445 ± 2 cm⁻¹. -1 1388±2cm -1 1330±2cm -1 1278±2cm -1 1260cm -1 ±2cm -1 One or more Raman displacement characteristic peaks in the sample.

[0068] In a preferred embodiment, the Raman spectrum of crystal I of compound (I) includes approximately 3140 ± 2 cm⁻¹. -1 3102±2cm -1 3056±2cm -1 3015±2cm -1 2938±2cm -1 1616±2cm -1 1572±2cm -1 and 1498±2cm -1 cm -1 One or more Raman displacement characteristic peaks in the sample.

[0069] In a preferred embodiment, the Raman spectrum of crystal I of compound (I) includes approximately 3140 ± 2 cm⁻¹. -1 3102±2cm -1 3056±2cm -1 3015±2cm -1 2938±2cm -1 1616±2cm -1 1572±2cm -1 1498±2cm-1 1445±2cm -1 1388±2cm -1 1330±2cm -1 1278±2cm -1 1260cm -1 ±2cm -1 One or more Raman displacement characteristic peaks in the sample.

[0070] In a preferred embodiment, the Raman spectrum of crystal I of compound (I) is substantially as follows: Figure 3 As shown. In a more preferred embodiment, the Raman spectrum of crystal I of compound (I) is as follows. Figure 3 As shown.

[0071] In a preferred embodiment, the infrared spectrum of crystal I of compound (I) is substantially as follows: Figure 4 As shown. In a more preferred embodiment, the infrared spectrum of crystal I of compound (I) is as follows. Figure 4 As shown.

[0072] In a preferred embodiment, the DSC plot of crystal I of compound (I) is substantially as follows: Figure 5 As shown.

[0073] In a preferred embodiment, the DSC plot of crystal I of compound (I) is as follows: Figure 5 As shown.

[0074] In a preferred embodiment, the onset temperature of crystal I of the compound of formula (I) is about 134.2 ± 5 °C, and the peak temperature is about 147.8 ± 5 °C.

[0075] In a preferred embodiment, the TGA plot of crystal I of compound (I) is substantially as follows: Figure 6 As shown.

[0076] In a preferred embodiment, the TGA image of crystal I of compound (I) is as follows: Figure 6 As shown, there is a weight loss of approximately 8.24% at temperatures of approximately 80–130°C.

[0077] In some embodiments, crystal I of the compound of formula (I) is a solvate.

[0078] In some embodiments, crystal I of the compound of formula (I) is a hydrate; preferably, crystal I is a dihydrate.

[0079] Crystal II

[0080] In some embodiments, the present invention provides crystals II of the compound of formula (I) whose X-ray powder diffraction (XRPD) patterns include peaks at diffraction angles (2θ) of about 5.64 ± 0.2°, about 10.64 ± 0.2°, about 11.66 ± 0.2°, about 12.41 ± 0.2°, about 14.02 ± 0.2°, and about 14.89 ± 0.2°.

[0081] In some embodiments, the present invention provides crystals II of the compound of formula (I) whose X-ray powder diffraction (XRPD) patterns include peaks at diffraction angles (2θ) of 5.64 ± 0.2°, 10.64 ± 0.2°, 11.66 ± 0.2°, 12.41 ± 0.2°, 14.02 ± 0.2°, and 14.89 ± 0.2°.

[0082] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal II of the compound of formula (I) includes diffraction peaks at diffraction angles (2θ) of about 5.64 ± 0.2°, about 10.64 ± 0.2°, about 11.66 ± 0.2°, about 12.41 ± 0.2°, about 14.02 ± 0.2°, about 14.89 ± 0.2°, about 16.10 ± 0.2°, about 16.91 ± 0.2°, about 18.15 ± 0.2°, about 18.51 ± 0.2°, about 19.33 ± 0.2°, and about 19.68 ± 0.2°.

[0083] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal II of the compound of formula (I) includes diffraction peaks at diffraction angles (2θ) of 5.64±0.2°, 10.64±0.2°, 11.66±0.2°, 12.41±0.2°, 14.02±0.2°, 14.89±0.2°, 16.10±0.2°, 16.91±0.2°, 18.15±0.2°, 18.51±0.2°, 19.33±0.2°, and 19.68±0.2°.

[0084] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal II of the compound of formula (I) includes diffraction peaks at diffraction angles (2θ) of about 5.64 ± 0.2°, about 10.64 ± 0.2°, about 11.66 ± 0.2°, about 12.41 ± 0.2°, about 14.02 ± 0.2°, about 14.89 ± 0.2°, about 16.10 ± 0.2°, about 16.91 ± 0.2°, about 18.15 ± 0.2°, about 18.51 ± 0.2°, about 19.33 ± 0.2°, about 19.68 ± 0.2°, about 20.67 ± 0.2°, about 21.39 ± 0.2°, and about 22.49 ± 0.2°.

[0085] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal II of the compound of formula (I) includes diffraction peaks at diffraction angles (2θ) of 5.64±0.2°, 10.64±0.2°, 11.66±0.2°, 12.41±0.2°, 14.02±0.2°, 14.89±0.2°, 16.10±0.2°, 16.91±0.2°, 18.15±0.2°, 18.51±0.2°, 19.33±0.2°, 19.68±0.2°, 20.67±0.2°, 21.39±0.2°, and 22.49±0.2°.

[0086] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal II of the compound of formula (I) includes diffraction peaks at diffraction angles (2θ) of about 5.64 ± 0.2°, about 10.64 ± 0.2°, about 11.66 ± 0.2°, about 12.41 ± 0.2°, about 14.02 ± 0.2°, about 14.89 ± 0.2°, about 16.10 ± 0.2°, about 16.91 ± 0.2°, about 18.15 ± 0.2°, about 18.51 ± 0.2°, about 19.33 ± 0.2°, about 19.68 ± 0.2°, about 20.67 ± 0.2°, about 21.39 ± 0.2°, about 22.49 ± 0.2°, about 24.16 ± 0.2°, and about 27.27 ± 0.2°.

[0087] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal II of the compound of formula (I) includes diffraction peaks at diffraction angles (2θ) of 5.64±0.2°, 10.64±0.2°, 11.66±0.2°, 12.41±0.2°, 14.02±0.2°, 14.89±0.2°, 16.10±0.2°, 16.91±0.2°, 18.15±0.2°, 18.51±0.2°, 19.33±0.2°, 19.68±0.2°, 20.67±0.2°, 21.39±0.2°, 22.49±0.2°, 24.16±0.2°, and 27.27±0.2°.

[0088] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal II of compound (I) includes the following diffraction peaks at the 2θ angle:

[0089]

[0090] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal II of compound (I) includes... Figure 2 The peaks shown are at essentially the same diffraction angle (2θ).

[0091] In a preferred embodiment, the XRPD peak position of crystal II of compound (I) is similar to... Figure 2 The results are basically the same.

[0092] Crystal preparation methods

[0093] Another object of the present invention is to provide a method for preparing the crystal of the present invention.

[0094] In some embodiments, the present invention provides a method for preparing the above-described crystal I, the method comprising:

[0095] The compound of formula (I) is dissolved in solvent I, and an antisolvent is added to precipitate the solid, yielding crystal I.

[0096]

[0097] In a preferred embodiment, solvent I is selected from one or more of water, tetrahydrofuran, and acetonitrile.

[0098] In a preferred embodiment, the antisolvent is selected from one or more of acetonitrile, ethyl acetate, tetrahydrofuran, and isopropyl acetate; preferably, the antisolvent is selected from one or more of tetrahydrofuran, acetonitrile, and ethyl acetate.

[0099] In a preferred embodiment, solvent I is selected from tetrahydrofuran, and antisolvent is selected from ethyl acetate.

[0100] In a preferred embodiment, solvent I is selected from one or both of water and acetonitrile, and antisolvent is selected from acetonitrile.

[0101] In a preferred embodiment, solvent I is selected from dimethyl sulfoxide, and the antisolvent is selected from one or more of tetrahydrofuran and ethyl acetate. Preferably, the antisolvent is selected from a mixed solvent of tetrahydrofuran and ethyl acetate.

[0102] In a preferred embodiment, the weight-to-volume ratio (g / ml) of the compound of formula (I) to solvent I is 1:(0.5-10). In some embodiments, the weight-to-volume ratio (g / ml) of the compound of formula (I) to solvent I is 2:1, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, and 1:20.

[0103] In a preferred embodiment, the compound of formula (I) is added to a solvent and then heated to dissolve the compound of formula (I).

[0104] In a preferred embodiment, the heating temperature is 20-60°C.

[0105] In some embodiments, the present invention provides a method for preparing the above-described crystal II, the method comprising: suspending crystal I in an organic solvent II to obtain crystal II.

[0106] In a preferred embodiment, the organic solvent II is selected from ethanol.

[0107] In a preferred embodiment, the preparation method of crystal II further includes pulping and filtering steps.

[0108] In a preferred embodiment, the weight-volume ratio of the compound of formula (I) to organic solvent II is 1:(1-20) g / ml. Preferably, the weight-volume ratio of the compound of formula (I) to organic solvent II is 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19 and 1:20.

[0109] Pharmaceutical Compositions and Uses

[0110] Another object of the present invention is to provide a pharmaceutical composition comprising any one or more crystals of the present invention, and one or more pharmaceutically acceptable carriers.

[0111] Another object of the present invention is to provide the use of crystals of the compound of formula (I) of the present invention (e.g., crystal I, crystal II or any combination thereof of the compound of formula (I)) or pharmaceutical compositions in the preparation of a medicament for treating peptic ulcers.

[0112] Another object of the present invention is to provide crystals of the compound of formula (I) of the present invention (e.g., crystal I, crystal II or any combination thereof of the compound of formula (I)) or pharmaceutical compositions for the treatment of peptic ulcers.

[0113] Another object of the present invention is to provide a method for treating peptic ulcers, comprising administering to an individual in need an effective amount of a crystal of the compound of formula (I) of the present invention (e.g., crystal I, crystal II, or any combination thereof of the compound of formula (I)) or a pharmaceutical composition.

[0114] As used herein, the term "pharmaceuticalally acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with reasonable benefits / risks.

[0115] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The compositions may also contain small amounts of wetting agents, emulsifiers, or pH buffers as needed. Oral formulations may contain standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0116] The compounds of the present invention may be administered, either in pure form or as a suitable pharmaceutical composition, by any acceptable mode of administration that provides a medicament for similar use. The pharmaceutical compositions of the present invention may be prepared by combining the compounds of the present invention or salts thereof with a suitable pharmaceutically acceptable carrier.

[0117] The pharmaceutical compositions of the present invention can be manufactured using methods well known in the art, such as conventional mixing methods, etc.

[0118] Typical routes of administration of the compounds or pharmaceutical compositions of the present invention include, but are not limited to, oral, injection, intravenous, intra-arterial, rectal, transmucosal, enteric administration, or local, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0119] In a preferred embodiment, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with a pharmaceutically acceptable carrier, excipient, and / or medium well known in the art. These carriers, excipients, and media enable the compounds of the present invention to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0120] As used in this article, the term "effective amount" refers to the amount of a compound that, when administered, will alleviate one or more symptoms of the treated condition to some extent.

[0121] The dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0122] The amount of the compounds of the present invention administered will depend on the individual being treated, the severity of the condition or illness, the rate of administration, the disposal of the compounds, and the prescribing physician's judgment. Generally, the effective dose is from about 0.0001 mg to about 50 mg per kg of body weight per day, for example, from about 0.01 mg / kg / day to about 10 mg / kg / day (single or divided doses). For a 70 kg person, this would total from about 0.007 mg / day to about 3500 mg / day, for example, from about 0.7 mg / day to about 700 mg / day. In some cases, dose levels not exceeding the lower limit of the foregoing range may be sufficient, while in other cases, larger doses may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses administered throughout the day.

[0123] The content or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg.

[0124] Unless otherwise stated, as used herein, the term “treating” means to reverse, alleviate, or inhibit the progression of a disease or condition or one or more symptoms of such a disease or condition to which such term is applied, or to prevent such a disease or condition or one or more symptoms of such a disease or condition.

[0125] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0126] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation.

[0127] Example

[0128] The present invention will be further illustrated by the following embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of the present invention. Those skilled in the art can make some non-essential improvements and adjustments, which still fall within the protection scope of the present invention.

[0129] Information on the testing instruments and methods used in the experiment:

[0130] The testing conditions for X-ray powder diffraction (XRPD) are as follows:

[0131] The X'Pert3 Powder Diffractometer was used, which employs Cu-palladium irradiation, and the Absolutescan was used for detection at room temperature.

[0132] The Raman spectroscopy test conditions were as follows: Thermo Fisher Nicolet iS50 FT-Raman was used.

[0133] Thermal analysis (DSC) was performed using a TA DSC2500 differential scanning calorimeter.

[0134] Thermogravimetric analysis (TGA) test conditions: METTLER TOLEDO TGA1 was used. The liquid chromatography instrument used was an Agilent 1260 HPLC.

[0135] The HPLC experimental conditions are as follows:

[0136] Column: Agilent Extend C18, 4.6mm x 250mm, 3μm

[0137] Flow rate: 1.0-2.0 ml / min, column temperature: 25±5℃, detection wavelength: 237 nm, diluent: 0.05 M NaOH: methanol (V / V) = 60:40;

[0138] Mobile phase A: 0.01M dipotassium hydrogen phosphate; Mobile phase B: acetonitrile-water (90:10);

[0139] Gradient elution: 0-35 min, volume percentage of mobile phase A% : mobile phase B% = (85-50) : (15-50); 36-50 min, volume percentage of mobile phase A% : mobile phase B% = (10-85) : (90-15).

[0140] All solvents used in this invention are commercially available and can be used without further purification.

[0141] Example 1. Preparation of crystal I of compound (I)

[0142] Weigh 10g of compound (I) and add it to a round-bottom flask. Add 5ml of water and 30ml of acetonitrile, stir and heat to 40℃ to dissolve. After the solution is clear, add 80ml of acetonitrile dropwise, and crystals will precipitate. After the addition is complete, slowly cool to 5℃, stir for 1 hour, filter, collect the filter cake, dry at 40℃ for 4 hours, and collect the solid. Perform XRPD analysis on the solid. The obtained XRPD spectrum is shown below. Figure 1 The image shown is crystal I of compound (I) of this invention. Raman spectroscopy was performed on the solid, and the resulting Raman spectrum is shown below. Figure 3 As shown in the figure, infrared spectroscopy was performed on the solid, and the resulting infrared spectrum is as follows. Figure 4 As shown in the image.

[0143] Example 2. Preparation of crystal I of compound (I)

[0144] Weigh 10g of compound (I) and add it to a round-bottom flask. Add 50ml of tetrahydrofuran and 2.5ml of water, stir and heat to 50℃ to dissolve. After dissolving completely, cool to 25℃, add seed crystals, stir at room temperature for 30 minutes, add 50ml of ethyl acetate dropwise, stir to precipitate crystals for 2 hours, filter, collect the filter cake, dry at 40℃ for 4 hours, collect the solid, and perform XRPD analysis on the solid. The obtained XRPD spectrum is shown below. Figure 1 As shown, this is crystal I of compound (I) of the present invention. Raman spectroscopy was performed on the solid, and the resulting Raman spectrum is shown below. Figure 3 As shown in the figure, infrared spectroscopy was performed on the solid, and the resulting infrared spectrum is as follows. Figure 4 As shown in the image.

[0145] Example 3. Preparation of crystal II of compound (I)

[0146] Weigh 10g of crystal I of compound (I) and add it to a round-bottom flask. Add 100ml of ethanol, stir at room temperature for 2 hours, filter, and collect the solid. Perform XRPD analysis on the solid; the obtained XRPD spectrum is shown below. Figure 2 The image shown is crystal II of the compound of formula (I) of this invention.

[0147] Experimental Example 4. Stability test of crystal I of compound (I)

[0148] The stability of crystal I obtained in Example 1 and the known crystal III (prepared according to Example 4 of CN201210222649.9) under high temperature, high humidity, light, and time conditions were tested, and the purity was determined by high performance liquid chromatography (HPLC). The results are shown in the table below:

[0149]

[0150] The results show that crystal I is more stable than crystal III under light, high temperature, high humidity and time conditions, and the crystal of the present invention has better physical and chemical stability.

[0151] The above detailed embodiments provide a further description of the present invention. However, it should not be construed as limiting the scope of the present invention to the listed embodiments; all technical solutions implemented based on the content of the present invention fall within the scope of the present invention.

Claims

1. Crystal I of compound (I), wherein, The compound of formula (I) has the following structure: Its X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of approximately 5.6 ± 0.2°, approximately 10.1 ± 0.2°, approximately 11.20 ± 0.2°, approximately 11.99 ± 0.2°, and approximately 12.94 ± 0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of crystal I also includes peaks at diffraction angles (2θ) of approximately 16.85 ± 0.2°, approximately 18.27 ± 0.2°, approximately 20.19 ± 0.2°, approximately 25.06 ± 0.2°, approximately 25.75 ± 0.2°, and approximately 27.40 ± 0.2°.

2. Crystal I of the compound of formula (I) as claimed in claim 1, wherein the X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of about 5.6 ± 0.2°, about 10.1 ± 0.2°, about 11.20 ± 0.2°, about 11.99 ± 0.2°, about 12.94 ± 0.2°, about 14.45 ± 0.2°, about 15.52 ± 0.2°, about 16.23 ± 0.2°, about 16.85 ± 0.2°, about 18.27 ± 0.2°, about 20.19 ± 0.2°, about 25.06 ± 0.2°, about 25.75 ± 0.2°, and about 27.40 ± 0.2°.

3. Crystal I of the compound of formula (I) as described in claim 1 or 2, wherein the XRPD pattern comprises a peak at a diffraction angle (2θ) that is substantially the same as that shown in FIG1, and preferably, the XRPD peak positions are substantially the same as those shown in FIG1.

4. Crystal I of the compound of formula (I) as described in any one of claims 1-3, wherein the Raman spectrum further includes an image at approximately 1445 ± 2 cm⁻¹. -1 1388±2cm -1 1330±2cm -1 1278±2cm -1 1260cm -1 ±2cm -1 One or more Raman displacement characteristic peaks in the sample.

5. Crystal I of the compound of formula (I) as described in any one of claims 1-4, having one or more of the following characteristics: (1) The infrared spectrum of the crystal I is basically as shown in Figure 4; (2) The DSC diagram of crystal I is basically as shown in Figure 5. Preferably, the melting peak onset temperature of crystal I is about 134.2±5℃ and the melting peak temperature is about 147.8±5℃. (3) The TGA chart of the crystal I is basically as shown in Figure 6. Preferably, it has a weight loss of about 8.24% at a temperature of about 80 to 130°C. Preferably, the crystal I of the compound of formula (I) is a solvate (e.g., a hydrate), and more preferably, the crystal I of the compound of formula (I) is a dihydrate.

6. A method for preparing crystal I of the compound of formula (I) according to any one of claims 1-5, the method comprising dissolving the compound of formula (I) in solvent I, adding an antisolvent to precipitate the solid, and obtaining crystal I.

7. The preparation method according to claim 6, wherein solvent I is selected from one or more of water, acetonitrile, tetrahydrofuran, and dimethyl sulfoxide.

8. The preparation method according to any one of claims 6-7, wherein the antisolvent is selected from one or more of acetonitrile, ethyl acetate, tetrahydrofuran, and isopropyl acetate.

9. Crystal II of compound of formula (I), wherein, The compound of formula (I) has the following structure: The X-ray powder diffraction pattern of crystal II of the compound of formula (I) includes peaks at diffraction angles (2θ) of about 5.64 ± 0.2°, about 10.64 ± 0.2°, about 11.66 ± 0.2°, about 12.41 ± 0.2°, about 14.02 ± 0.2°, and about 14.89 ± 0.2°.

10. A method for preparing crystal II of the compound of formula (I) according to claim 9, the method comprising suspending crystal I in organic solvent II to obtain crystal II; preferably, the method further comprises the steps of pulping and filtering.

11. A pharmaceutical composition comprising: crystal I or crystal II of the compound of formula (I) according to any one of claims 1-5 and 9, and one or more pharmaceutically acceptable carriers.

12. Use of crystal I or crystal II of the compound of formula (I) according to any one of claims 1-5 and 9, or the pharmaceutical composition of claim 10, in the preparation of a medicament for treating peptic ulcers.

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