Crystalline and amorphous forms of carmixinetosylate

Abstract

The application discloses a crystal form and amorphous form of carmixin p-toluenesulfonate and a preparation method thereof, relates to the field of medicinal chemistry, and solves the problems of instability, difficulty in scale-up synthesis, and difficulty in drug preparation of carmixin in the prior art. The crystal form and amorphous form of carmixin p-toluenesulfonate disclosed by the application have the characteristics of high purity, high stability, high bioavailability, easy scale-up synthesis, industrialized production and the like, have good moisture-inducing characteristics, and are convenient to store.

Description

[0001] This application claims priority to the invention patent filed on January 3, 2023, entitled "Crystal and Amorphous Forms of Carestine p-Toluenesulfonate" with patent number CN202310000722.6, which is hereby expressly incorporated herein by reference. Technical Field

[0002] This invention relates to the field of pharmaceutical chemistry, specifically to the crystalline and amorphous forms of carestine p-toluenesulfonate, its uses, and preparation methods. Background Technology

[0003] Carebastine is the active metabolite of ebastine, a second-generation histamine H1 receptor antagonist. Neither enters the central nervous system, and it has no adverse central nervous system effects or anticholinergic effects. It also avoids the first-pass effect of ebastine in the liver, and has a faster onset of action. It can be used to treat allergic diseases such as urticaria, allergic rhinitis, eczema, dermatitis, prurigo, and pruritus. It is especially suitable for the emergency treatment of acute allergic diseases such as acute urticaria and asthma.

[0004] However, carristin has drawbacks such as light instability, difficulty in purification, difficulty in large-scale synthesis, and difficulty in drug formulation; therefore, there are currently no marketed carristin drugs. Furthermore, detailed reports on carristin salts, especially carristin p-tosylate and its crystalline and amorphous forms, have not been found. This invention aims to provide a crystalline and amorphous form of carristin p-tosylate to overcome the deficiencies of the existing technology and provide a reliable option for clinical use. Summary of the Invention

[0005] To address at least one of the technical problems existing in the prior art, this invention provides both crystalline and amorphous forms of carristin p-toluenesulfonate. The crystalline and amorphous forms of carristin p-toluenesulfonate of this invention exhibit high stability, good hygroscopicity, high bioavailability, ease of purification, suitability for scale-up production, and are beneficial for drug formulation.

[0006] On the one hand, the present invention provides a crystal form of carestine p-toluenesulfonate with the structure shown in formula (1).

[0007] Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form has diffraction peaks at the following 2θ values: 4.26±0.2°, 6.43±0.2°, 14.49±0.2°, 15.11±0.2°, and 18.95±0.2°.

[0008] Furthermore, the X-ray powder diffraction pattern of the above crystal form has diffraction peaks at the following 2θ values: 4.26±0.2°, 6.43±0.2°, 14.49±0.2°, 15.11±0.2°, 18.95±0.2°, and optionally 19.12±0.2°.

[0009] Furthermore, the X-ray powder diffraction patterns of the above-mentioned crystal form show diffraction peaks at the following 2θ values: 4.26±0.2°, 6.43±0.2°, 13.10±0.2°, 14.49±0.2°, 15.11±0.2°, 15.77±0.2°, and 18.95±0.2°.

[0010] Preferably, the X-ray powder diffraction pattern of the above-mentioned crystal form has diffraction peaks at the following 2θ values: 4.26±0.2°, 6.43±0.2°, 13.10±0.2°, 14.49±0.2°, 15.11±0.2°, 15.77±0.2°, 18.95±0.2°, and 19.12±0.2°.

[0011] Furthermore, the X-ray powder diffraction patterns of the above-mentioned crystal form show diffraction peaks at the following 2θ values: 4.26±0.2°, 6.43±0.2°, 13.10±0.2°, 14.49±0.2°, 15.11±0.2°, 15.77±0.2°, 18.95±0.2°, 19.59±0.2°, 23.49±0.2°, and 24.97±0.2°.

[0012] Preferably, the X-ray powder diffraction pattern of the above-mentioned crystal form has diffraction peaks at the following 2θ values: 4.26±0.2°, 6.43±0.2°, 13.10±0.2°, 14.49±0.2°, 15.11±0.2°, 15.77±0.2°, 18.95±0.2°, 19.12±0.2°, 19.59±0.2°, 23.49±0.2°, and 24.97±0.2°.

[0013] Furthermore, the X-ray powder diffraction patterns of the above-mentioned crystal form show diffraction peaks at the following 2θ values: 4.26±0.2°, 6.43±0.2°, 13.10±0.2°, 13.97±0.2°, 14.16±0.2°, 14.49±0.2°, 15.11±0.2°, 15.43±0.2°, 15.77±0.2°, 18.95± 0.2°, 19.12±0.2°, 19.34±0.2°, 19.59±0.2°, 23.49±0.2°, 23.87±0.2°, 24.11±0.2°, 24.97±0.2°, 25.15±0.2°, 25.73±0.2°, 26.10±0.2°, 28.98±0.2°, 29.28±0.2°.

[0014] Preferably, the X-ray powder diffraction pattern of the above-mentioned crystal form has diffraction peaks at the following 2θ values: 4.26±0.2°, 6.43±0.2°, 13.10±0.2°, 13.97±0.2°, 14.16±0.2°, 14.49±0.2°, 15.11±0.2°, 15.43±0.2°, 15.61±0.2°, 15.77±0.2°, 18 0.95±0.2°, 19.12±0.2°, 19.34±0.2°, 19.59±0.2°, 23.49±0.2°, 23.87±0.2°, 24.11±0.2°, 24.97±0.2°, 25.15±0.2°, 25.73±0.2°, 26.10±0.2°, 28.98±0.2°, 29.28±0.2°.

[0015] Furthermore, the X-ray powder diffraction patterns of the above-mentioned crystal form show diffraction peaks at the following 2θ values: 4.26±0.2°, 6.43±0.2°, 10.77±0.2°, 12.41±0.2°, 12.56±0.2°, 12.78±0.2°, 13.10±0.2°, 13.97±0.2°, 14.16±0.2°, 14.49±0.2°, 15.11±0.2°, 15.43±0.2°. 0.2°, 15.77±0.2°, 18.95±0.2°, 19.12±0.2°, 19.34±0.2°, 19.59±0.2°, 23.49±0.2°, 23.87±0.2°, 24.11±0.2°, 24.97±0.2°, 25.15±0.2°, 25.73±0.2°, 26.10±0.2°, 28.98±0.2°, 29.28±0.2°.

[0016] Preferably, the X-ray powder diffraction pattern of the above-mentioned crystal form has diffraction peaks at the following 2θ values: 4.26±0.2°, 6.43±0.2°, 10.77±0.2°, 12.41±0.2°, 12.56±0.2°, 12.78±0.2°, 13.10±0.2°, 13.97±0.2°, 14.16±0.2°, 14.49±0.2°, 15.11±0.2°, 15.43±0.2°, 15 0.61±0.2°, 15.77±0.2°, 18.95±0.2°, 19.12±0.2°, 19.34±0.2°, 19.59±0.2°, 23.49±0.2°, 23.87±0.2°, 24.11±0.2°, 24.97±0.2°, 25.15±0.2°, 25.73±0.2°, 26.10±0.2°, 28.98±0.2°, 29.28±0.2°.

[0017] Furthermore, the X-ray powder diffraction pattern of the above-mentioned crystal form exhibits characteristic peaks and their relative intensities at the following positions with a diffraction angle of 2θ:

[0018] 2θ <![CDATA[Relative intensity (I / I0)]]> 4.26±0.2° 28.8±5％ 6.43±0.2° 3.7±5％ 14.49±0.2° 65.1±5％ 15.11±0.2° 53.8±5％ 18.95±0.2° 100±5％ Optional 19.12±0.2° 67.1±5％ .

[0019] Preferably, the X-ray powder diffraction pattern of the above-mentioned crystal form has characteristic peaks and their relative intensities at diffraction angles of 20° or less:

[0020] 2θ <![CDATA[Relative intensity (I / I0)]]> 4.26±0.2° 28.8％ 6.43±0.2° 3.7％ 14.49±0.2° 65.1％ 15.11±0.2° 53.8％ 18.95±0.2° 100％ Optional 19.12±0.2° 67.1％ .

[0021] Furthermore, the X-ray powder diffraction pattern of the above-mentioned crystal form exhibits characteristic peaks and their relative intensities at the following positions with a diffraction angle of 2θ:

[0022] 2θ <![CDATA[Relative intensity (I / I0)]]> 4.26±0.2° 28.8±5％ 6.43±0.2° 3.7±5％ Optional 13.10±0.2° 16.3±5％ 14.49±0.2° 65.1±5％ 15.11±0.2° 53.8±5％ Optional 15.77±0.2° 30.9±5％ 18.95±0.2° 100±5％ Optional 19.12±0.2° 67.1±5％ Optional 19.59±0.2° 21.5±5％ Optional 23.49±0.2° 38.8±5％ Optional location 24.97±0.2° 42.8±5％ .

[0023] Preferably, the X-ray powder diffraction pattern of the above-mentioned crystal form has characteristic peaks and their relative intensities at the following positions with a diffraction angle of 2θ:

[0024] 2θ <![CDATA[Relative intensity (I / I0)]]> 4.26±0.2° 28.8％ 6.43±0.2° 3.7％ Optional 13.10±0.2° 16.3％ 14.49±0.2° 65.1％ 15.11±0.2° 53.8％ Optional 15.77±0.2° 30.9％ 18.95±0.2° 100％ Optional 19.12±0.2° 67.1％ Optional 19.59±0.2° 21.5％ Optional 23.49±0.2° 38.8％ Optional location 24.97±0.2° 42.8％ .

[0025] Furthermore, the above-mentioned crystal forms have basic properties such as Figure 1 The X-ray powder diffraction pattern shown is shown.

[0026] It is worth noting that in the X-ray powder diffraction patterns of the above-mentioned crystal forms, at the following 20 values, due to differences in detection conditions, such as the degree of powder grinding, there may be indistinct peaks, or the peaks may be swallowed up by large peaks, resulting in flat peaks or slight bulging, such as 15.61±0.2°, 19.12±0.2°, and 25.15±0.2°. It should be understood that these minor differences in peak position and peak morphology should all fall within the scope of this invention.

[0027] Furthermore, the differential scanning calorimetry spectrum of the above crystal form shows an endothermic peak at 171℃±5℃.

[0028] Preferably, the differential scanning calorimetry spectrum of the above-mentioned crystal form has an endothermic peak at 171.51℃±3℃.

[0029] More preferably, the differential scanning calorimetry spectrum of the above-mentioned crystal form has an endothermic peak at 171.51℃±1.0℃.

[0030] Furthermore, the above-mentioned crystal forms have basic properties such as Figure 2 The differential scanning calorimetry curve is shown.

[0031] Furthermore, the above-mentioned crystal form has the basic characteristics as follows: Figure 3 The thermogravimetric analysis spectrum is shown.

[0032] On the other hand, the present invention also provides an amorphous form of carestine p-toluenesulfonate with the structure shown in formula (1).

[0033]

[0034] Furthermore, the aforementioned amorphous material, when subjected to Cu-Kα radiation, exhibits diffuse peaks in its X-ray powder diffraction pattern; preferably, the aforementioned amorphous material possesses essentially the following characteristics: Figure 5 The X-ray powder diffraction pattern shown is shown.

[0035] Thirdly, the present invention provides a method for preparing any of the above-mentioned crystalline forms or any of the above-mentioned amorphous forms, comprising the following salt-forming steps: heating and stirring an appropriate amount of 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid and p-toluenesulfonic acid in an organic solvent to dissolve and react to form a salt; after the reaction is complete, cooling is performed, a solid is precipitated, and the mixture is filtered to obtain crude carestine p-toluenesulfonate.

[0036] Furthermore, the organic solvents used in the above salt formation steps include, but are not limited to, alcohols, esters, ethers, ketones, aromatic hydrocarbons, glycol derivatives, pyrrolidones, tetrahydrofurans, amides, or other types.

[0037] Further, the alcohols include C1-C6 straight-chain or branched saturated alkyl alcohols, preferably methanol, ethanol, propanol, or isopropanol; the esters include lower alkyl esters, preferably ethyl acetate, propyl acetate, or isopropyl acetate; the ethers include lower alkyl ethers, preferably methyl ether or diethyl ether; the ketones include lower alkyl ketones, preferably acetone or butanone; the aromatic hydrocarbons include benzene, toluene, xylene, or trimethylbenzene, preferably toluene; the glycol derivatives include ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, or ethylene glycol monobutyl ether, preferably ethylene glycol monomethyl ether; the pyrrolidones include N-methylpyrrolidone or N-ethylpyrrolidone; the tetrahydrofurans include tetrahydrofuran or 2-methyltetrahydrofuran; the amides include N,N-dimethylformamide or N,N-dimethylacetamide; and the other classes include dioxane, acetonitrile, dimethyl sulfoxide, or mixtures of the above organic solvents with water.

[0038] More preferably, the organic solvents mentioned above include methanol, ethanol, isopropanol, acetone, butanone, acetonitrile, ethyl acetate, isopropyl acetate, toluene, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, N-methylpyrrolidone, tertiary methyl ether, diethyl ether, dimethyl sulfoxide, or mixtures of the above organic solvents with water.

[0039] Furthermore, the aforementioned organic solvents include ethanol, butanone, acetonitrile, or isopropyl acetate.

[0040] Furthermore, the reaction temperature of the above salt formation step is 40–100°C; preferably 60–90°C.

[0041] Furthermore, the precipitation temperature of the above-mentioned salt formation step is -20 to 30°C; preferably -5 to 20°C.

[0042] Furthermore, the present invention provides a method for preparing the above-mentioned crystal form, comprising the following steps: taking crude carestine p-toluenesulfonate, adding solvent, heating and stirring, cooling to crystallize, filtering, and drying to obtain carestine p-toluenesulfonate crystals.

[0043] Furthermore, the solvents used in the above-mentioned crystal form preparation method include one or more of the following: water, alcohols, esters, ethers, ketones, aromatic hydrocarbons, glycol derivatives, pyrrolidones, tetrahydrofurans, amides, and other organic solvents.

[0044] Further, the alcohols include C1-C6 straight-chain or branched saturated alkyl alcohols, preferably methanol, ethanol, propanol, or isopropanol; the esters include lower alkyl esters, preferably ethyl acetate, propyl acetate, or isopropyl acetate; the ethers include lower alkyl ethers, preferably methyl ether or diethyl ether; the ketones include lower alkyl ketones, preferably acetone or butanone; the aromatic hydrocarbons include benzene, toluene, xylene, or trimethylbenzene, preferably toluene; the glycol derivatives include ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, or ethylene glycol monobutyl ether, preferably ethylene glycol monomethyl ether; the pyrrolidones include N-methylpyrrolidone or N-ethylpyrrolidone; the tetrahydrofurans include tetrahydrofuran or 2-methyltetrahydrofuran; the amides include N,N-dimethylformamide or N,N-dimethylacetamide; and other organic solvents include dioxane, acetonitrile, or dimethyl sulfoxide.

[0045] More preferably, the solvent used in the above-mentioned crystal form preparation method includes one or more of the following: water, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tertiary methyl ether, acetone, butanone, toluene, ethylene glycol monomethyl ether, N-methylpyrrolidone, N-ethylpyrrolidone, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, acetonitrile, and dimethyl sulfoxide.

[0046] More preferably, the solvent used in the above-mentioned crystal form preparation method includes one or two of the following: water, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, methyl ether, acetone, butanone, toluene, N-methylpyrrolidone, N-ethylpyrrolidone, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, acetonitrile, and dimethyl sulfoxide.

[0047] In particular, when using a composite solvent, a mixture of the aforementioned organic solvent and water is preferred.

[0048] Furthermore, the crystallization temperature in the above-mentioned crystal preparation method is 30–100°C; preferably 50–90°C.

[0049] Furthermore, the crystallization temperature of the above-mentioned crystal preparation method is -20 to 35°C; preferably -5 to 25°C; more preferably 0 to 20°C.

[0050] Furthermore, the above-mentioned amorphous preparation method includes the following steps: adding crude carestine p-toluenesulfonate to a solvent, heating under reflux, and after the solid is completely dissolved, filtering, and spray-drying or freeze-drying the filtrate to obtain a white solid.

[0051] Furthermore, the solvents used in the above-mentioned amorphous preparation method include one or more of the following: water, alcohols, esters, ethers, ketones, aromatic hydrocarbons, glycol derivatives, pyrrolidones, tetrahydrofurans, amides, and other organic solvents.

[0052] Further, the alcohols include C1-C6 straight-chain or branched saturated alkyl alcohols, preferably methanol, ethanol, propanol, or isopropanol; the esters include lower alkyl esters, preferably ethyl acetate, propyl acetate, or isopropyl acetate; the ethers include lower alkyl ethers, preferably methyl ether or diethyl ether; the ketones include lower alkyl ketones, preferably acetone or butanone; the aromatic hydrocarbons include benzene, toluene, xylene, or trimethylbenzene, preferably toluene; the glycol derivatives include ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, or ethylene glycol monobutyl ether, preferably ethylene glycol monomethyl ether; the pyrrolidones include N-methylpyrrolidone or N-ethylpyrrolidone; the tetrahydrofurans include tetrahydrofuran or 2-methyltetrahydrofuran; the amides include N,N-dimethylformamide or N,N-dimethylacetamide; and other organic solvents include dioxane, acetonitrile, or dimethyl sulfoxide.

[0053] More preferably, the solvent used in the above-mentioned amorphous preparation method includes one or more of the following: water, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tertiary methyl ether, acetone, butanone, toluene, ethylene glycol monomethyl ether, N-methylpyrrolidone, N-ethylpyrrolidone, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, acetonitrile, and dimethyl sulfoxide.

[0054] More preferably, the solvent used in the above-mentioned amorphous preparation method includes one or two of the following: water, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, methyl ether, acetone, butanone, toluene, N-methylpyrrolidone, N-ethylpyrrolidone, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, acetonitrile, and dimethyl sulfoxide.

[0055] In particular, when using a composite solvent, a mixture of the aforementioned organic solvent and water is preferred.

[0056] Furthermore, the reflux temperature in the above amorphous preparation method is 30–100°C; preferably 50–90°C.

[0057] Fourthly, the present invention also provides a pharmaceutical composition comprising any one of the above-mentioned carestine p-toluenesulfonate in crystalline or amorphous form, characterized in that the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0058] The term "pharmaceutically acceptable carrier" refers to a diluent, excipient, or carrier that is administered co-administered with the active ingredient 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 a reasonable benefit / risk ratio.

[0059] Fifthly, the present invention also provides the use of any of the above-mentioned carestine p-toluenesulfonate crystal or amorphous form in the preparation of a medicament for histamine H1 receptor antagonists.

[0060] Furthermore, the above uses include uses in the preparation of medicaments for the treatment and / or prevention of allergic diseases.

[0061] Furthermore, the aforementioned allergic diseases also include acute allergic diseases.

[0062] Furthermore, the aforementioned allergic diseases are selected from urticaria, allergic rhinitis, eczema, dermatitis, or pruritus; preferably, the aforementioned acute allergic diseases are selected from acute urticaria or acute allergic rhinitis.

[0063] Note: Unless otherwise stated or provided, the molar ratio of carestine to p-toluenesulfonic acid in the compound of formula (1) of this invention is 1:1; the molar ratio of the two in the corresponding crystalline and amorphous forms is also 1:1.

[0064] The solvents used in the methods for preparing crystalline and amorphous forms of the present invention include the term "the organic solvent" in "a mixture of the above-mentioned organic solvent and water," which includes, but is not limited to, all organic solvents listed in the present invention.

[0065] In this invention, the term "crude product" refers to a drug with a purity of not more than 99%, preferably not more than 98.5%.

[0066] Compared with the prior art, the present invention has the following beneficial effects:

[0067] The crystalline and amorphous forms of Carestine p-toluenesulfonate of the present invention (1) have good pharmaceutical solid form, are non-hygroscopic or slightly hygroscopic, have high purity and stability, and are easy to transport and store; (2) have simple production process, cheap and readily available materials, are easy to scale up production, have short production cycle, and are energy-saving and environmentally friendly; (3) have better pharmacokinetic properties, higher blood drug concentration, faster onset of action, longer half-life, and have the potential to treat acute allergic diseases such as acute urticaria, with stronger and longer efficacy and high safety. Attached Figure Description

[0068] Figure 1 X-ray powder diffraction (XRPD) pattern of the crystal form of carestine p-toluenesulfonate;

[0069] Figure 2 Differential scanning calorimetry (DSC) curves of the crystal form of carestine p-toluenesulfonate;

[0070] Figure 3 Thermogravimetric analysis (TGA) diagram of the crystal form of carestine p-toluenesulfonate;

[0071] Figure 4XRPD overlay images of the crystal forms of carestine p-toluenesulfonate in Examples 2-6;

[0072] Figure 5 This is the X-ray powder diffraction (XRPD) pattern of the amorphous form of carestine p-toluenesulfonate. Detailed Implementation

[0073] The present invention will be further described in detail below with reference to embodiments and test examples. The embodiments and test examples of the present invention are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Any equivalent substitutions made in the art based on the content disclosed in the present invention shall fall within the protection scope of the present invention.

[0074] The structure of the compound is determined by nuclear magnetic resonance (NMR). 1 Determined by ¹H NMR or LC-MS.

[0075] The liquid chromatography-mass spectrometry (LC-MS) system is an Agilent G6120B (compatible with an Agilent 1260 liquid chromatography system); the nuclear magnetic resonance spectrometer (… 1 H NMR) is Bruker AVANCE ~400 or Bruker AVANCE ~800, nuclear magnetic resonance (NMR) 1 ¹H NMR shifts (δ) are given in parts per million (ppm), the solvent is CDCl₃, the internal standard is tetramethylsilane (TMS), and the chemical shifts are expressed in 10⁻⁶ ppm. ～6 (ppm) is given as the unit.

[0076] In this invention, the term "room temperature" refers to a temperature between 10 and 30°C.

[0077] The ebastine used in the following examples and test cases (Comparative Example 1) was in free state, commercially available, with a purity of ≥98%; and the carestine (Comparative Example 2) was in free state, commercially available, with a purity of ≥99%.

[0078] Example 1: Preparation of crude 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid p-toluenesulfonate (Carestine p-toluenesulfonate)

[0079]

[0080] The synthesis route is as follows:

[0081] Add 500 g (0.1 mol) of 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid (carestine) and 1 L of isopropanol to a three-necked flask, heat to 60–90 °C, add 172 g (1 mol) of p-toluenesulfonic acid, stir, cool, and a white solid precipitates. Filter and dry to obtain 571 g of carestine p-toluenesulfonate, yield 85%, purity 98.05%.

[0082] ESI-MS: m / z = 500.3(M+H) + .

[0083] 1 H NMR (600MHz, CDCl3) δ: 10.01 (s, 1H), 7.80~7.83 (d, 2H), 7.74~7.76 (d, 2H), 7 .43~7.46(d,2H),7.27~7.37(m,10H),7.13~7.15(d,2H),5.44(s,1H),3.83~ 3.85(m, 1H), 3.53~3.55(m, 2H), 3.10~3.17(m, 4H), 3.00~3.05(m, 2H), 2.32( s, 3H), 2.21 ~ 2.29 (m, 2H), 2.09 ~ 2.19 (m, 2H), 2.01 ~ 2.08 (m, 2H), 1.58 (s, 6H).

[0084] Example 2: Preparation of Carestine p-toluenesulfonate crystal form

[0085] 1.5 kg of ethanol and 100 g of crude carestine p-toluenesulfonate were added at room temperature, stirred and heated to 60–80 °C, and kept at this temperature for 0.5–1.2 h. The mixture was then cooled to 5–20 °C to allow crystallization for 0.5–1.5 h. The mixture was filtered, the filter cake was washed with ethanol, dried under vacuum, and dried to obtain 83 g of crystalline carestine p-toluenesulfonate, with a yield of 83% and a purity of 99.42%.

[0086] ESI-MS: m / z = 500.3(M+H)+.

[0087] 1H NMR (600MHz, CDCl3) δ: 10.01 (s, 1H), 7.80~7.83 (d, 2H), 7.74~7.76 (d, 2H), 7 .43~7.46(d,2H),7.27~7.37(m,10H),7.13~7.15(d,2H),5.44(s,1H),3.83~ 3.85(m, 1H), 3.53~3.55(m, 2H), 3.10~3.17(m, 4H), 3.00~3.05(m, 2H), 2.32( s, 3H), 2.21 ~ 2.29 (m, 2H), 2.09 ~ 2.19 (m, 2H), 2.01 ~ 2.08 (m, 2H), 1.58 (s, 6H).

[0088] The X-ray powder diffraction, differential scanning calorimetry, and thermogravimetric analysis results of the carestin p-toluenesulfonate crystal form in this embodiment are attached. Figures 1-3 .

[0089] Example 3: Preparation of Carestine p-toluenesulfonate crystal form

[0090] Add 500 mg of methyl ethyl ketone (MEK) and 50 mg of crude carestine p-toluenesulfonate at room temperature, stir and heat to 70–80 °C, maintain the temperature and stir for 0.2–1.0 h; cool to 0–15 °C to allow crystallization for 0.2–1.2 h; filter, wash the filter cake with MEK, dry under vacuum, and dry to obtain 45 mg of crystalline carestine p-toluenesulfonate, yield 90%, purity 99.76%. Mass spectrometry, NMR, and X-ray powder diffraction were performed as in Example 2.

[0091] Example 4: Preparation of Carestine p-toluenesulfonate crystal form

[0092] 2 g of methyl ether and 100 mg of crude carestine p-toluenesulfonate were added at room temperature, stirred, and heated to 30–55 °C, and stirred for 0.2–1.0 h. The mixture was then cooled to 0–20 °C to allow crystallization for 0.2–1.5 h. The mixture was filtered, the filter cake was washed with methyl ether, dried under vacuum, and dried to obtain 95 mg of crystalline carestine p-toluenesulfonate, with a yield of 95% and a purity of 99.56%. Mass spectrometry, NMR, and X-ray powder diffraction were performed as in Example 2.

[0093] Example 5: Preparation of Carestine p-toluenesulfonate crystal form

[0094] 100 mg of isopropanol, 10 mg of water, and 100 mg of crude carestine p-toluenesulfonate were added at room temperature. The mixture was stirred and heated to 70–80 °C, and kept at this temperature for 0.2–1.0 h. The mixture was then cooled to 0–20 °C to allow crystallization for 0.2–1.5 h. The mixture was filtered, the filter cake was washed with isopropanol, dried under vacuum, and then dried to obtain 85 mg of crystalline carestine p-toluenesulfonate, with a yield of 85% and a purity of 99.86%. Mass spectrometry, nuclear magnetic resonance, and X-ray powder diffraction were performed as in Example 2.

[0095] Example 6: Preparation of Carestine p-toluenesulfonate crystal form

[0096] 16 kg of acetonitrile and 2 kg of crude carestine p-toluenesulfonate were added at room temperature, stirred, and heated to 60–80 °C, and stirred for 0.5–1.2 h. The mixture was then cooled to 5–20 °C to allow crystallization for 0.5–1.5 h. The mixture was filtered, the filter cake was washed with acetonitrile, dried under vacuum, and then dried to obtain 1.8 kg of crystalline carestine p-toluenesulfonate, with a yield of 90% and a purity of 99.66%. Mass spectrometry, NMR, and X-ray powder diffraction were performed as in Example 2.

[0097] Example 7: Preparation of Carestine p-toluenesulfonate crystal form

[0098] Add 1-2.5 kg of methanol and 100 g of crude carestine p-toluenesulfonate at room temperature, stir and heat to 40-60 °C, maintain the temperature and stir for 0.5-1.2 h; cool to 0-15 °C to allow crystallization for 0.5-1.5 h; filter, wash the filter cake with methanol, dry under vacuum, and dry to obtain 92 g of crystalline carestine p-toluenesulfonate, with a yield of 92% and a purity of 99.86%. Mass spectrometry, NMR, and X-ray powder diffraction were performed as in Example 2.

[0099] Example 8: Preparation of Carestine p-toluenesulfonate crystal form

[0100] Add 0.5–1.5 kg of tetrahydrofuran and 100 g of crude carestine p-toluenesulfonate at room temperature, stir and heat to 30–60 °C, maintain the temperature and stir for 0.5–1.2 h; cool to 0–20 °C to allow crystallization for 0.5–1.5 h; filter, wash the filter cake with tetrahydrofuran, dry under vacuum, and dry to obtain 85 g of crystalline carestine p-toluenesulfonate, yield 85%, purity 99.96%. Mass spectrometry, NMR, and X-ray powder diffraction were performed as in Example 2.

[0101] Example 9: Preparation of Carestine p-toluenesulfonate crystal form

[0102] Add 1.5–2.5 kg of dioxane and 100 g of crude carestine p-toluenesulfonate at room temperature, stir and heat to 50–80 °C, maintain the temperature and stir for 0.5–1.2 h; cool to 0–20 °C to allow crystallization for 0.5–1.5 h; filter, wash the filter cake with dioxane, dry under vacuum, and dry to obtain 89 g of crystalline carestine p-toluenesulfonate, yield 89%, purity 99.66%. Mass spectrometry, NMR, and X-ray powder diffraction were performed as in Example 2.

[0103] Example 10: Preparation of Carestine p-toluenesulfonate crystal form

[0104] Add 1.5–2.5 kg of toluene and 100 g of crude carestine p-toluenesulfonate at room temperature, stir and heat to 80–100 °C, maintain the temperature and stir for 0.2–1.5 h; cool to 0–20 °C to allow crystallization for 0.2–1.5 h; filter, wash the filter cake with toluene, dry under vacuum, and dry to obtain 92 g of crystalline carestine p-toluenesulfonate, with a yield of 92% and a purity of 99.76%. Mass spectrometry, NMR, and X-ray powder diffraction were performed as in Example 2.

[0105] Example 11: Preparation of Carestine p-toluenesulfonate crystal form

[0106] Add 1.0–2.5 kg of water and 100 g of crude carestine p-toluenesulfonate at room temperature, stir and heat to 80–100 °C, maintain the temperature and stir for 0.2–1.5 h; cool to 0–20 °C to allow crystallization for 0.2–1.5 h; filter, wash the filter cake with water, dry under vacuum, and dry to obtain 95 g of crystalline carestine p-toluenesulfonate, with a yield of 95% and a purity of 99.66%. Mass spectrometry, NMR, and X-ray powder diffraction were performed as in Example 2.

[0107] Example 12: Preparation of Carestine p-toluenesulfonate crystal form

[0108] Add 0.5–2.5 kg of dimethyl sulfoxide, 0.1–0.5 kg of water, and 100 g of crude carestine p-toluenesulfonate at room temperature. Stir and heat to 80–100 °C, maintain the temperature and stir for 0.2–1.5 h. Cool to 0–20 °C to allow crystallization for 0.2–1.5 h. Filter, wash the filter cake with water, dry under vacuum, and dry to obtain 95 g of crystalline carestine p-toluenesulfonate, with a yield of 95% and a purity of 99.86%. Mass spectrometry, NMR, and X-ray powder diffraction were performed as in Example 2.

[0109] Example 13: Preparation of Carestine p-toluenesulfonate crystal form

[0110] Add 0.5–2.5 kg of acetonitrile, 0.1–0.5 kg of methanol, and 100 g of crude carestine p-toluenesulfonate at room temperature. Stir and heat to 30–60 °C, maintain the temperature and stir for 0.2–1.5 h. Cool to 0–20 °C to allow crystallization for 0.2–1.5 h. Filter, wash the filter cake with acetonitrile, dry under vacuum, and dry to obtain 99 g of crystalline carestine p-toluenesulfonate, with a yield of 99% and a purity of 99.16%. Mass spectrometry, NMR, and X-ray powder diffraction are the same as in Example 2.

[0111] Comparison of crystal structure confirmatory data for carestine p-toluenesulfonate in Examples 2-13 showed that they all belonged to the same crystal form. The overlap of the X-ray powder diffraction patterns of the crystal forms in Examples 2-6 is shown in the appendix. Figure 4 This demonstrates that the carestine p-toluenesulfonate of the present invention has good crystal form reproducibility, is easy to prepare, and is suitable for large-scale production.

[0112] Example X: Preparation of the amorphous form of carestine p-toluenesulfonate

[0113] Take 1 kg of crude carestine p-toluenesulfonate and add it to 2–4 kg of water. Heat under reflux until the solid is completely dissolved. Filter the solution, and spray-dry or freeze-dry the filtrate to obtain a white solid. X-ray powder diffraction shows it to be amorphous. See details below. Figure 5 .

[0114] ESI-MS: m / z = 500.3(M+H)+.

[0115] 1 H NMR (600MHz, CDCl3) δ: 10.01 (s, 1H), 7.80~7.83 (d, 2H), 7.74~7.76 (d, 2H), 7 .43~7.46(d,2H),7.27~7.37(m,10H),7.13~7.15(d,2H),5.44(s,1H),3.83~ 3.85(m, 1H), 3.53~3.55(m, 2H), 3.10~3.17(m, 4H), 3.00~3.05(m, 2H), 2.32( s, 3H), 2.21 ~ 2.29 (m, 2H), 2.09 ~ 2.19 (m, 2H), 2.01 ~ 2.08 (m, 2H), 1.58 (s, 6H).

[0116] Experimental Example 1: Stability Study

[0117] 1. Test samples: Carestine (Comparative Example 2), crystalline form of Carestine p-toluenesulfonate (Example 2), amorphous form of Carestine p-toluenesulfonate (Example X).

[0118] 2. Test method: Weigh three portions each of carestine (Comparative Example 2), the crystalline form of carestine p-toluenesulfonate (Example 2), and the amorphous form of carestine p-toluenesulfonate (Example X), and place them in weighing bottles. Each group of samples was placed under high temperature (60°C), high humidity (RH 80%), and light (5000 Lux) conditions. Samples were taken for testing after 30 days.

[0119] Detection method: Accurately weigh appropriate amounts of each sample, dissolve and quantitatively dilute with acetonitrile to a solution containing approximately 0.08 mg per ml. High-performance liquid chromatography (HPLC) is used, with octadecylsilane-bonded silica gel as the stationary phase, water-acetonitrile (1:1) as the mobile phase, a detection wavelength of 256 nm, a column temperature of 35 °C, and an injection volume of 10 μL. Each sample solution is injected separately into the HPLC system, and the chromatograms are recorded. The content of carestine is calculated using the external standard method, and the impurity content is calculated using the peak area normalization method.

[0120] 3. Test Results: After 30 days of testing under the influence of high temperature, high humidity, and light, the content of Carresine (Comparative Example 2) decreased by more than 1.0% under high temperature and high humidity conditions, and by more than 10% under light conditions, with the maximum content of a single impurity exceeding 0.5%. In contrast, the crystalline (Example 2) and amorphous (Example X) forms of Carresine p-toluenesulfonate of the present invention showed a content decrease of no more than 0.1% under high temperature, high humidity, and light conditions, with the maximum content of a single impurity not exceeding 0.1%. This demonstrates that the crystalline and amorphous forms of Carresine p-toluenesulfonate of the present invention are stable and more suitable for pharmaceutical use.

[0121] Table 1. Results of the experiment on influencing factors

[0122]

[0123] Experimental Example 2: Hygroscopicity Study

[0124] 1. Test samples: Carestine (Comparative Example 2), Carestine hydrochloride (Comparative Example 3), crystalline form of Carestine p-toluenesulfonate (Example 2), and amorphous form of Carestine p-toluenesulfonate (Example X). Carestine hydrochloride was prepared according to the description in patent US6340761B1, with a purity of ≥99%.

[0125] 2. Test method: (1) Take a dry glass weighing bottle with a stopper (outer diameter of 50 mm and height of 15 mm), and place it in a suitable constant temperature desiccator (with ammonium chloride or ammonium sulfate saturated solution placed at the bottom) or artificial climate chamber (temperature set at 25℃±1℃ and relative humidity at 80%±2%) one day before the test, and accurately weigh it with the lid on (m1);

[0126] (2) Take an appropriate amount of the test sample and spread it evenly in the weighing bottle mentioned above. The thickness of the test sample is generally about 1 mm. Weigh it accurately with the cap on (m2).

[0127] (3) Leave the weighing bottle open and place it together with the bottle cap under the above constant temperature and humidity conditions for 24 hours;

[0128] (4) Close the weighing bottle cap and accurately weigh the weight (m3);

[0129] (5) Percentage gain = (m3-m2) / (m2-m1)×100%.

[0130] 3. Test Results: The hygroscopicity results are shown in the table below: The results show that the crystalline form of Carresine p-toluenesulfonate of the present invention (Example 2) has no or almost no hygroscopicity, the amorphous form of Carresine p-toluenesulfonate (Example X) has slight hygroscopicity, but the free base of Carresine (Comparative Example 2) and its hydrochloride salt (Comparative Example 3) are hygroscopic and extremely hygroscopic, respectively; this proves that the crystalline and amorphous forms of Carresine p-toluenesulfonate of the present invention have better hygroscopicity characteristics and are significantly superior to the free base or hydrochloride salt form of Carresine.

[0131] Table 2 Hygroscopicity Results

[0132] compound Weight gain percentage (%) Feature Description Comparative Example 2 6 Hygroscopic Comparative Example 3 15.9 Extremely hygroscopic Example 2 -0.1 None or almost none hygroscopic Example X 0.3 Slightly hygroscopic

[0133] According to the pharmacopoeia definition, the above results are as follows: "hygroscopic" means that the weight gain due to hygroscopic absorption is less than 15% but not less than 2%; "extremely hygroscopic" means that the weight gain due to hygroscopic absorption is not less than 15%; "no or almost no hygroscopicity" means that the weight gain due to hygroscopic absorption is less than 0.2%; "slightly hygroscopic" means that the weight gain due to hygroscopic absorption is less than 2% but not less than 0.2%.

[0134] Experimental Example 3: Pharmacokinetic Study

[0135] This study investigated the bioavailability of the crystalline and amorphous forms of carristin p-tosylate through pharmacokinetic studies.

[0136] 1. Test drugs: Ebastine (Comparative Example 1), Carristin (Comparative Example 2), the crystalline form of Carristin p-toluenesulfonate (Example 2), and the amorphous form of Carristin p-toluenesulfonate (Example X) were respectively prepared into enteric-coated capsules.

[0137] 2. Test methods:

[0138] (1) Laboratory animals

[0139] Species: Beagle;

[0140] Level: Common;

[0141] Number and sex of animals: 8, all male;

[0142] Age: All children were 1-2 years old at the time of grouping;

[0143] Weight: The weight range for grouping was 8.90-10.3 kg, with a mean of 10.0 kg.

[0144] (2) Dosage and method of administration

[0145] Dosage: Equimolar doses of carristin were administered to each group. An appropriate amount of the compound was weighed and filled into capsules. That is, each capsule contained 2.23 mg of carristin.

[0146] Table 3. Trial grouping and dosing design

[0147]

[0148] Each test substance was filled into capsules and subjected to a 2×4 crossover experiment according to the table above. The washout period was 7 days from the start of administration. Each group was given the corresponding test substance for different test periods.

[0149] All animals should be fasted overnight (more than 12 hours) before each administration, and resumed feeding 4 hours after administration. Free access to water is allowed.

[0150] (3) Plasma sample collection

[0151] Thirteen blood collection points were used: 0 hours before administration and 10, 20, 30, 45 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 8 hours, 10 hours, and 24 hours after administration.

[0152] At the set blood collection time points, about 2 mL of blood was collected from the forelimb vein and placed in an EDTA-K2 anticoagulant tube. The whole blood sample was placed at room temperature and centrifuged within 1.5 hours after collection at 3000g centrifugation force, 4C, for 10 minutes.

[0153] (4) Biological sample analysis

[0154] The concentration of carestine in plasma was determined using high-performance liquid chromatography-mass spectrometry (HPLC-MS / MS).

[0155] (5) Data acquisition and processing

[0156] Pharmacokinetic parameters for each group were calculated using WinNonlin software (version 8.3 and above) with a non-compartmental model.

[0157] 3. Experimental results: The pharmacokinetic results of carestine in the plasma of each group of beagle dogs are shown in the table below.

[0158] Table 4. Summary of Carristin pharmacokinetic parameters for each group (mean ± standard deviation)

[0159] PK parameters <![CDATA[T max (h)]]> <![CDATA[T 1 / 2 (h)]]> <![CDATA[C max (ng / mL)]]> <![CDATA[AUC 0-t (mg / mL)]]> Comparative Example 1 2.25±0.7 4.06±1.19 179±85.7 749±127 Comparative Example 2 0.82±0.52 3.74±2.02 191±51.4 840±161 Example 2 0.84±0.62 5.02±2.02 296±44.7 1160±252 Example X 0.89±0.59 4.35±2.12 262±38.9 980±261 .

[0160] As can be seen from the results in the table above, compared with the compound in Comparative Example 1, the crystal form of Example 2 and the amorphous form of Example X had different peak times (T0). max It's significantly faster, C max They increased by approximately 65% ​​and 46% respectively, AUC 0-t The half-life (T) increased by approximately 55% and 31% respectively. 1 / 2 The durations of these terms have also been extended.

[0161] Compared to the free state compound of Comparative Example 2, the crystalline form of Example 2 and the amorphous C of Example X are different. max The AUC increased by approximately 55% and 37% respectively. 0-t The half-life (T) increased by approximately 38% and 17% respectively. 1 / 2 ) and T also have been extended respectively. max Basically the same.

[0162] Example 2: C of the crystal form max and AUC 0-t Slightly higher than Example X (amorphous), T 1 / 2 It is also slightly longer.

[0163] In summary, the pharmacokinetic parameters of the crystalline form of Example 2 and the amorphous form of Example X are significantly better than those of the compounds in Comparative Example 1 and Comparative Example 2. This indicates that the crystalline and amorphous forms of the carresine paratoluene salt of the present invention can rapidly enter the body, inhibit histamine H1 receptors, and have the potential to treat patients with acute allergic diseases such as acute urticaria in clinical practice. Moreover, the efficacy is stronger and longer-lasting, and the safety is also higher.

[0164] The above embodiments are merely one of the preferred embodiments of the present invention and should not be used to limit the scope of protection of the present invention. Any modifications or refinements made to the main design concept and spirit of the present invention that are not of substantial significance, but solve the same technical problem as the present invention, should be included within the scope of protection of the present invention.

Claims

1. The crystal form of the compound shown in formula (1), ， Its features are, Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form shows diffraction peaks at the following 2θ values: 4.26±0.2°, 6.43±0.2°, 13.10±0.2°, 14.49±0.2°, 15.11±0.2°, 15.77±0.2°, 18.95±0.2°, 19.12±0.2°, 19.59±0.2°, 23.49±0.2°, and 24.97±0.2°.

2. The crystal form according to claim 1, characterized in that, The X-ray powder diffraction pattern of the crystal form has characteristic peaks and their relative intensities at the following positions with a diffraction angle of 2θ: 。 3. The crystal form according to claim 1, characterized in that, The crystal form has an X-ray powder diffraction pattern as shown in Figure 1.

4. The crystal form according to claim 1, characterized in that, The differential scanning calorimetry spectrum of the crystal form shows an endothermic peak at 171℃±5℃.

5. The crystal form according to claim 4, characterized in that, The crystal form has a differential scanning calorimetry curve as shown in Figure 2.

6. The crystal form according to claim 1, characterized in that, The crystal form has a thermogravimetric analysis spectrum as shown in Figure 3.

7. The amorphous form of the compound shown in formula (1), ， Its features are, Using Cu-Kα radiation, the amorphous X-ray powder diffraction pattern shows diffuse peaks and has a basic X-ray powder diffraction pattern as shown in Figure 5.

8. A method for preparing the crystal form according to any one of claims 1 to 6, characterized in that, The method for preparing the crystal form includes the following steps: taking crude carestine p-toluenesulfonate, adding solvent, heating and stirring, cooling to crystallize, filtering, and drying to obtain carestine p-toluenesulfonate crystals; the solvent is selected from one or two of water, methanol, ethanol, isopropanol, methyl ether, butanone, toluene, tetrahydrofuran, dioxane, acetonitrile, and dimethyl sulfoxide.

9. The method for preparing the crystal form according to claim 8, characterized in that, The solvent is selected from a mixture of isopropanol and water.

10. The method for preparing the crystal form according to claim 8, characterized in that, The cooling and crystallization temperature is -20~35℃.

11. The method for preparing the crystal form according to claim 10, characterized in that, The temperature ranges from -5 to 25°C.

12. A method for preparing the amorphous substance according to claim 7, characterized in that, The preparation method includes the following steps: adding crude carestine p-toluenesulfonate to water, heating under reflux, and filtering after the solid is completely dissolved. The filtrate is then spray-dried or freeze-dried to obtain a white solid.

13. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 6 or the amorphous form according to claim 7, characterized in that, The pharmaceutical composition also includes a pharmaceutically acceptable carrier.

14. Use of the crystalline form according to any one of claims 1 to 6 or the amorphous form according to claim 7 in the preparation of histamine H1 receptor antagonist drugs.

15. The use according to claim 14, characterized in that, The use mentioned includes its use in the preparation of medicaments for the treatment and / or prevention of allergic diseases.

16. The use according to claim 15, characterized in that, The allergic disease is selected from urticaria, allergic rhinitis, eczema, dermatitis, or pruritus.

17. The use according to claim 15, characterized in that, The allergic disease mentioned is an acute allergic disease.

18. The use according to claim 17, characterized in that, The acute allergic disease mentioned is acute urticaria or acute allergic rhinitis.

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