A mosapride organic acid crystal

Abstract

The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to mosapride organic acid crystals and a preparation method thereof. The organic acid in the mosapride organic acid crystals provided by the present invention is selected from oxalic acid or gallic acid. The mosapride organic acid crystals provided by the present invention have high solubility and good light stability, which helps to improve bioavailability and has important value for the optimization and development of mosapride preparations.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a mosapride organic acid crystal and a preparation method thereof. Background Art

[0002] Mosapride, with the trade name Gasmotin@ and the chemical name of (+ / -)-4-amino-5-chloro-2-ethoxy-N-[(4-fluorobenzyl)-morpholin-2-ylmethyl]benzamide citrate cocrystal dihydrate, is sold under a brand name and is applicable to gastrointestinal symptoms related to chronic gastritis (heartburn, nausea / vomiting). Mosapride stimulates the serotonin 5-HT4 receptor in the gastrointestinal nerve plexus, which increases the release of acetylcholine, thereby enhancing gastrointestinal motility and gastric emptying. It is currently approved for the treatment of gastrointestinal symptoms related to chronic gastritis, including heartburn, nausea, vomiting, and gastroesophageal reflux disease (GERD). Mosapride is also in Phase II clinical trials for the treatment of gastrointestinal dumping syndrome or post-gastrectomy syndrome. Other clinical studies have been initiated using mosapride for the treatment of constipation in patients with Parkinson's disease; treating patients with type 2 diabetes to improve insulin action; treating patients with gastroparesis; and treating patients with opiate-induced respiratory depression.

[0003] Currently, there are few reports on the crystal forms of mosapride. The crystal forms disclosed in the prior art include the mosapride ethanol solvate reported in Patent JP2011225491A, the mosapride monohydrate crystal form reported in Patent KR20090044694A, and the citric acid dihydrate reported in Patent WO2011107903A1, which have low solubility in a hydrochloric acid solution with a pH of 1.0, and often encounter problems of low dissolution or even unqualified dissolution in the actual production of mosapride citrate oral solid preparations.

[0004] Regarding the study on the stability of mosapride, "Determination of the Stability of Mosapride Citrate by HPLC" in Clinical Rational Drug Use, Vol. 8, No. 8A, August 2015, reported that there was no obvious degradation of mosapride solid after 10 days under 4500 Lx light, and the main peak decreased by about 10.0% under high temperature for 3 h and oxidation for 5 h, but the specific impurity structures were not disclosed.

[0005] Patent CN111505154A discloses a method for detecting five key impurities in mosapride citrate and its preparations. The specific structures of the five impurities are:

[0006]

[0007] ​

[0008] Among them, impurity A is an intermediate in the synthesis of mosapride and also a degradation product, which is produced by the hydrolysis of mosapride; impurity B is the defluorinated product of mosapride and is a by-product generated during the synthesis of the active pharmaceutical ingredient mosapride; impurity C is a degradation product of mosapride, which is produced under heating or light or acidic conditions; impurity D is the condensation product of mosapride and citric acid, which is produced under heating conditions; impurity E is the oxidation product of mosapride, which is produced under light or oxidation conditions. SUMMARY OF THE INVENTION

[0009] In view of the above disadvantages, the present invention provides a mosapride organic acid crystal with high stability, which provides a better basis for the application of mosapride drugs, so as to more efficiently exert the medicinal value of mosapride.

[0010] The content of the present invention is as follows:

[0011] A mosapride organic acid crystal, wherein the mosapride organic acid crystal is formed by mosapride and an organic acid, and among them, the organic acid is selected from one of oxalic acid or gallic acid.

[0012] Mosapride oxalate:

[0013] In one embodiment, the present invention relates to a mosapride oxalate, wherein the molar ratio of mosapride to oxalic acid is 1:1.

[0014] Preferably, the mosapride oxalate can be characterized by having one or more of the following physical characteristics:

[0015] (a) Having X-ray diffraction peaks at 2θ including 6.22±0.2°, 7.16±0.2°, 18.39±0.2°, 20.45±0.2°, 24.45±0.2°, 25.92±0.2°, 27.65±0.2°; preferably, having X-ray diffraction peaks at 2θ including 6.22±0.2°, 7.16±0.2°, 7.56±0.2°, 9.26±0.2°, 14.43±0.2°, 17.51±0.2°, 18.39±0.2°, 20.45±0.2°, 22.97±0.2°, 24.45±0.2°, 25.17±0.2°, 25.92±0.2°, 27.65±0.2°; more preferably, having an X-ray powder diffraction pattern as shown in Figure 1 ;

[0016] (b) Having crystallographic parameters: monoclinic system, space group P21 / c; unit cell parameters: α = 90°, β = 95.346(3)°, γ = 90°, unit cell volume of the unit cell structure;

[0017] (c) The DSC detection spectrum has endothermic peaks in two temperature ranges of 115.59 - 137.36 °C and 166.88 - 273.72 °C respectively, and their peak values are 130.66 °C and 226.78 °C respectively.

[0018] Mosapride gallic acid cocrystal methanol monohydrate:

[0019] In one embodiment, the present invention relates to a mosapride gallic acid crystal, specifically mosapride gallic acid cocrystal methanol monohydrate, wherein the molar ratio of mosapride, gallic acid, methanol, and water is 2:1:1:1.

[0020] Mosapride gallic acid cocrystal methanol monohydrate can be characterized by one or more of the following physical characteristics:

[0021] (a) Having X-ray diffraction peaks at 2θ including 3.02 ± 0.2°, 6.09 ± 0.2°, 8.80 ± 0.2°, 10.37 ± 0.2°, 21.54 ± 0.2°; preferably, having X-ray diffraction peaks at 2θ including 3.02 ± 0.2°, 5.75 ± 0.2°, 6.09 ± 0.2°, 8.80 ± 0.2°, 10.37 ± 0.2°, 13.69 ± 0.2°, 15.34 ± 0.2°, 19.69 ± 0.2°, 21.08 ± 0.2°, 21.54 ± 0.2°, 22.25 ± 0.2°, 23.58 ± 0.2°, 24.36 ± 0.2°, 24.68 ± 0.2°, 25.08 ± 0.2°, 26.83 ± 0.2°, 28.70 ± 0.2°; further preferably, having an X-ray powder diffraction pattern as shown in Figure 5 ;

[0022] (b) Having crystallographic parameters: triclinic system, space group P-1; unit cell parameters are: α = 98.3146(9)°, β = 91.1971(9)°, γ = 99.6521(9)°, unit cell volume ;

[0023] (c) The DSC detection spectrum has an endothermic peak with a temperature range of 164.54 - 223.35 °C and a peak value of 175.15 °C.

[0024] Preparation and characterization of mosapride organic acid crystal:

[0025] Mosapride can be obtained commercially or prepared according to the synthetic methods disclosed in the prior art.

[0026] The methods for preparing mosapride organic acid crystals are described in Examples 1 to 10. Among them, Examples 1 to 5 describe the preparation method of mosapride oxalate, and Examples 6 to 10 describe the preparation method of mosapride gallic acid cocrystal methanol monohydrate.

[0027] A variety of tests were carried out to physically characterize mosapride organic acid crystals, including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The method for testing the solubility of mosapride organic acid crystals is described in Verification Example 1, and the method for testing the stability of mosapride organic acid crystals is described in Verification Example 2.

[0028] Mosapride oxalate:

[0029] Mosapride oxalate can be prepared by crystallization using a variety of solvents used in the polymorph screening process and under various crystallization conditions (e.g., fast and slow evaporation, cooling of saturated solutions, grinding method, addition of solvents and antisolvents). Examples 1 to 5 summarize a method for preparing mosapride oxalate, which specifically includes the following process: Mosapride and oxalic acid are placed in an organic solvent, heated and dissolved. After the solution becomes clear, the temperature is lowered for crystallization, and then filtered and dried to obtain mosapride oxalate.

[0030] Preferably, the organic solvent is selected from at least two of methanol, acetone, isopropanol, and tetrahydrofuran; more preferably, it is a mixed solution of methanol and tetrahydrofuran.

[0031] Preferably, the molar ratio of mosapride to oxalic acid is 1:0.9 to 1.2; more preferably, it is 1:1.05 to 1.15.

[0032] Preferably, the temperature for heating and dissolving is 60 to 80 °C.

[0033] Preferably, the mass-volume ratio of mosapride to the organic solvent in the system is 20 to 35:1, where the mass is in mg and the volume is in mL.

[0034] Preferably, the temperature for controlled-temperature crystallization is 5 to 15 °C, more preferably 6 to 8 °C.

[0035] Preferably, the crystallization time is 6 to 9 hours.

[0036] Preferably, the drying temperature is 60 to 80 °C, and the drying time is 10 to 13 hours.

[0037] The following further details the preparation method of mosapride oxalate in the present invention:

[0038] Mosapride and oxalic acid with a molar ratio of 1:1.05 were dissolved in a mixed solvent of methanol and tetrahydrofuran, heated to 60 °C, the compound was dissolved, filtered after the reaction was completed, the filtrate was allowed to stand, and crystallization was carried out at a controlled temperature of 6 - 8 °C, filtered, the filter cake was rinsed with methanol, and dried under vacuum at 70 °C to obtain mosapride oxalate.

[0039] Figure 1 The characteristic XRPD spectrum (Cu-Kα, ) of mosapride oxalate is shown, and the main X-ray diffractions as 2θ and their relative intensities are summarized in Table 1.

[0040] Table 1 Characteristic XRPD peaks of mosapride oxalate (Cu-Kα)

[0041]

[0042]

[0043]

[0044] The set of the above XRPD peak positions or a subset thereof can be used to identify mosapride oxalate.

[0045] Figure 4 is the DSC / TGA diagram of mosapride oxalate. The DSC detection spectrum shows that mosapride oxalate has endothermic peaks in two temperature ranges, 115.59 - 137.36 °C and 166.88 - 273.72 °C, and their peak values are 130.66 °C and 226.78 °C respectively.

[0046] Mosapride gallic acid cocrystal methanol monohydrate:

[0047] Mosapride gallic acid cocrystal methanol monohydrate can be prepared by crystallization using various solvents and under various crystallization conditions (e.g., fast and slow evaporation, cooling of saturated solutions, grinding method, addition of solvents and anti-solvents) used in the polymorph screening process. Examples 6 - 10 summarize a method for preparing mosapride gallic acid cocrystal methanol monohydrate, which specifically includes the following process: Mosapride and gallic acid were placed in an organic solvent, heated to dissolve, after the solution was clarified, the temperature was lowered for crystallization, and then filtered and dried.

[0048] Preferably, the organic solvent is a mixed solvent of methanol, water and / or organic solvent A. Further preferably, the volume fraction of methanol in the organic solvent is 20 - 50%, and the volume fraction of water in the organic solvent is 50 - 80%.

[0049] Further preferably, the organic solvent is methanol and water. More preferably, the volume fraction of methanol in the organic solvent is 50%, and the volume fraction of water is 50%.

[0050] Preferably, the organic solvent A is selected from one of acetone and ethanol.

[0051] Preferably, the molar ratio of mosapride to gallic acid in the feed is 1:0.45 - 0.65, more preferably 1:0.5 - 0.6.

[0052] Preferably, the temperature for heating during dissolution is 60 - 80 °C.

[0053] Preferably, the mass - volume ratio of mosapride to the organic solvent in the system is 20 - 35:1, where the mass is in mg and the volume is in mL.

[0054] Preferably, the temperature for temperature - controlled crystallization is 5 - 15 °C, more preferably 8 - 10 °C.

[0055] Preferably, the crystallization time is 10 - 13 hours.

[0056] Preferably, the drying temperature is 60 - 80 °C and the drying time is 12 - 15 hours.

[0057] The following process further details the preparation process of the mosapride - gallic acid cocrystal methanol monohydrate of the present invention:

[0058] Mosapride and gallic acid with a molar ratio of 1:0.55 are dissolved in a mixed solvent of methanol and water with a volume ratio of 1:1, heated to 75 °C, the compound is dissolved, filtered after the reaction is completed, the filtrate is allowed to stand, crystallized at a temperature - controlled 8 - 10 °C, filtered, the filter cake is rinsed with methanol, and dried under vacuum at 70 °C to obtain mosapride - gallic acid cocrystal methanol monohydrate.

[0059] Figure 5 Shows the characteristic XRPD spectrum (Cu - Kα, ) of mosapride - gallic acid cocrystal methanol monohydrate. The main X - ray diffractions and their relative intensities expressed as 2θ are summarized in Table 2.

[0060] Table 2 Characteristic XRPD peaks of mosapride - gallic acid cocrystal methanol monohydrate (CuKα)

[0061]

[0062]

[0063] The set of the above - mentioned XRPD peak positions or a subset thereof can be used to identify mosapride - gallic acid cocrystal methanol monohydrate.

[0064] Figure 8It is the DSC / TGA diagram of mosapride gallic acid cocrystal methanol monohydrate. The DSC detection spectrum shows an endothermic peak with a temperature range of 164.54 - 223.35 °C and a peak value of 175.15 °C.

[0065] Confirmation of the crystal structure of mosapride organic acid:

[0066] The mosapride organic acid crystal provided by the present invention is subjected to X-ray single crystal diffraction test analysis. The X-ray single crystal diffraction instrument and test conditions involved in the present invention are: Rigaku XtaLAB Synergy X-ray single crystal diffractometer, test temperature 293(2)K, using Cu-Kα radiation, collecting data by ω scan mode and performing Lp correction. The structure is solved by the direct method, and all non-hydrogen atoms are found by the difference Fourier method. The hydrogen atoms on all carbons and nitrogens are obtained by theoretical hydrogenation, and the structure is refined by the least squares method.

[0067] The crystallographic data obtained by testing and analyzing the mosapride oxalate prepared by the present invention are shown in Table 3. Its crystallographic parameters are monoclinic system, space group P21 / c; the unit cell parameters are: α = 90°, β = 95.346(3)°, γ = 90°, unit cell volume

[0068] Table 3 Main crystallographic data of mosapride oxalate

[0069]

[0070]

[0071] The ORTEP diagram of the mosapride oxalate prepared by the present invention shows that one molecule of mosapride combines with one molecule of oxalic acid, as Figure 2 shown; the hydrogen bond diagram of mosapride oxalate shows that mosapride and oxalic acid are connected into a three-dimensional structure through intermolecular hydrogen bonds, as Figure 3 shown.

[0072] The crystallographic data obtained by testing and analyzing the mosapride gallic acid cocrystal methanol monohydrate prepared by the present invention are shown in Table 4. Its crystallographic parameters are: triclinic system, space group P-1; the unit cell parameters are: α = 98.3146(9)°, β = 91.1971(9)°, γ = 99.6521(9)°, unit cell volume

[0073] Table 4 Main crystallographic data of mosapride gallic acid cocrystal methanol monohydrate

[0074]

[0075]

[0076] The ORTEP diagram of mosapride gallate methanol monohydrate prepared by the present invention shows that two molecules of mosapride combine with one molecule of gallic acid, one molecule of methanol and one molecule of water, as Figure 6 shown; the hydrogen bond diagram of mosapride gallate methanol monohydrate shows that mosapride and gallic acid are connected into a three-dimensional structure through intermolecular hydrogen bonds, as Figure 7 shown.

[0077] The mosapride organic acid crystals prepared by the method of the present invention have the following advantages compared with the currently reported mosapride crystal forms:

[0078] (1) High solubility. The solubility of mosapride oxalate in water and phosphate buffer at pH 6.8 can reach 0.96 mg / mL and 0.98 mg / mL respectively, while mosapride citrate dihydrate is almost insoluble in water and phosphate buffer at pH 6.8.

[0079] (2) Good stability. Mosapride oxalate has good photo-stability, and after the photo-stability experiment, the purity hardly decreases. Description of the Drawings

[0080] Figure 1 : X-ray powder diffraction pattern of mosapride oxalate;

[0081] Figure 2 : ORTEP diagram of mosapride oxalate;

[0082] Figure 3 : Hydrogen bond diagram of mosapride oxalate;

[0083] Figure 4 : DSC / TGA diagram of mosapride oxalate,

[0084] Figure 5 : X-ray powder diffraction pattern of mosapride gallate methanol monohydrate;

[0085] Figure 6 : ORTEP diagram of mosapride gallate methanol monohydrate;

[0086] Figure 7 : Hydrogen bond diagram of mosapride gallate methanol monohydrate;

[0087] Figure 8 : DSC / TGA diagram of mosapride gallate methanol monohydrate. Detailed Description of the Invention

[0088] The present invention will be further described below through specific embodiments. It should be correctly understood that the embodiments of the present invention are only used to illustrate the present invention, rather than limiting the present invention. Therefore, any simple improvement to the present invention under the premise of the method of the present invention falls within the scope of protection of the present invention.

[0089] Preparation of mosapride oxalate:

[0090] Example 1

[0091] Dissolve 2.5 g of mosapride and 0.59 g of oxalic acid in 100 mL of a mixed solvent (50 mL of methanol + 50 mL of tetrahydrofuran), heat to 60 °C, after dissolution, filter, control the temperature at 6 - 8 °C for crystallization for 8.5 hours, filter, wash the filter cake with methanol, and dry the filter cake at 70 °C for 12 h to obtain 2.85 g of mosapride oxalate. The yield is 94.2%, and the purity is 99.96%.

[0092] Example 2

[0093] Dissolve 2.5 g of mosapride and 0.53 g of oxalic acid in 80 mL of a mixed solvent (50 mL of methanol + 30 mL of acetone), heat to 60 °C, after dissolution, filter, control the temperature at 5 - 7 °C for crystallization for 6 hours, filter, wash the filter cake with methanol, and dry the filter cake at 70 °C for 11 h to obtain 2.80 g of mosapride oxalate. The yield is 92.8%, and the purity is 99.93%.

[0094] Example 3

[0095] Dissolve 2.5 g of mosapride and 0.61 g of oxalic acid in 125 mL of a mixed solvent (45 mL of methanol + 80 mL of isopropanol), heat to 80 °C, after dissolution, filter, control the temperature at 8 - 10 °C for crystallization for 9 hours, filter, wash the filter cake with methanol, and dry the filter cake at 80 °C for 13 h to obtain 2.79 g of mosapride oxalate. The yield is 92.3%, and the purity is 99.90%.

[0096] Example 4

[0097] Dissolve 2.5 g of mosapride and 0.48 g of oxalic acid in 70 mL of a mixed solvent (35 mL of acetone + 35 mL of isopropanol), heat to 82 °C, after dissolution, filter, control the temperature at 13 - 15 °C for crystallization for 15 hours, filter, wash the filter cake with ethanol, and dry the filter cake at 60 °C for 11 h to obtain 2.65 g of mosapride oxalate. The yield is 87.6%, and the purity is 98.91%.

[0098] Example 5

[0099] Dissolve 2.5 g of mosapride and 0.70 g of oxalic acid in 135 mL of a mixed solvent (100 mL of methanol + 35 mL of acetone), heat to 50 °C, after dissolution, filter, control the temperature at -2 to 0 °C for crystallization for 5 hours, filter, wash the filter cake with methanol, and dry the filter cake at 70 °C for 10 h to obtain 2.49 g of mosapride oxalate. The yield is 82.6%, and the purity is 99.21%.

[0100] Preparation of mosapride gallic acid cocrystal methanol monohydrate:

[0101] Example 6

[0102] Dissolve 5.0 g of mosapride and 1.1 g of gallic acid in 170 mL of a mixed solvent (85 mL of methanol + 85 mL of water), heat to 75 °C, after dissolution, filter, control the temperature at 10 to 12 °C for crystallization for 11 hours, filter, wash the filter cake with methanol, and dry the filter cake at 70 °C for 13 h to obtain 5.78 g of mosapride gallic acid cocrystal methanol monohydrate. The yield is 92.11%, and the purity is 99.92%.

[0103] Example 7

[0104] Dissolve 5.0 g of mosapride and 1.2 g of gallic acid in 142 mL of a mixed solvent (42 mL of methanol + 100 mL of water), heat to 70 °C, after dissolution, filter, control the temperature at 5 to 7 °C for crystallization for 10 hours, filter, wash the filter cake with methanol, and dry the filter cake at 60 °C for 15 h to obtain 5.71 g of mosapride gallic acid cocrystal methanol monohydrate. The yield is 91.02%, and the purity is 99.89%.

[0105] Example 8

[0106] Dissolve 5.0 g of mosapride and 1.0 g of gallic acid in 250 mL of a mixed solvent (50 mL of methanol + 200 mL of water), heat to 80 °C, after dissolution, filter, control the temperature at 12 to 15 °C for crystallization for 13 hours, filter, wash the filter cake with methanol, and dry the filter cake at 80 °C for 12 h to obtain 5.72 g of mosapride gallic acid cocrystal methanol monohydrate. The yield is 91.16%, and the purity is 99.87%.

[0107] Example 9

[0108] Dissolve 5.0 g of mosapride and 0.90 g of gallic acid in 150 mL of a mixed solvent (30 mL of methanol + 45 mL of acetone + 75 mL of water), heat to 60 °C, after dissolution, filter, control the temperature at -2 to 0 °C for crystallization for 15 hours, filter, wash the filter cake with methanol, and dry the filter cake at 70 °C for 13 h to obtain 5.42 g of mosapride gallic acid cocrystal methanol monohydrate. The yield is 86.21%, and the purity is 99.13%.

[0109] Example 10

[0110] Dissolve 5.0 g of mosapride and 1.3 g of gallic acid in 280 mL of a mixed solvent (150 mL of methanol + 86 mL of water + 44 mL of ethanol), heat to 82 °C, after dissolution, filter, control the temperature at 18 - 20 °C for crystallization for 20 hours, filter, wash the filter cake with methanol, and dry the filter cake at 70 °C for 13 h to obtain 5.62 g of mosapride gallic acid cocrystal methanol monohydrate. The yield is 89.40% and the purity is 98.91%.

[0111] Verification Example 1, Solubility Test

[0112] Refer to the method in the pharmacopoeia. To save materials, scale down the dosage in the same proportion. Prepare phosphate buffer solution with pH = 6.8, hydrochloric acid solution with pH = 1.0 and water respectively. Take appropriate amounts of mosapride oxalate, mosapride gallic acid cocrystal methanol monohydrate, and mosapride citrate dihydrate prepared according to the method disclosed in WO2011107903A1 and put them into stoppered test tubes containing phosphate buffer solution with pH = 6.8, hydrochloric acid solution with pH = 1.0 and water respectively. Place the samples in a water bath thermostatic oscillator, equilibrate at 37 °C and 200 r / min for 24 h, take samples, filter through a 0.45 μm microporous filter membrane, take the subsequent filtrate, dilute it with water to the linear range, use the aqueous solution as the blank solution, and measure the absorbance at a wavelength of 274 nm until the absorbance no longer changes. The test results are shown in Table 5.

[0113] Table 5 Solubility of Mosapride Organic Acid Crystals

[0114]

[0115] The solubilities of mosapride oxalate and mosapride gallic acid cocrystal methanol monohydrate prepared in the examples of the present invention are much higher than that of mosapride citrate dihydrate.

[0116] Verification Example 2, Photo-stability Test of Mosapride Organic Acid Crystals

[0117] Take appropriate amounts (about 10 mg of mosapride) of mosapride oxalate, mosapride gallic acid cocrystal methanol monohydrate and mosapride citrate dihydrate prepared according to the method disclosed in WO2011107903A1 and place them in open clean containers respectively, and test their stability under light (4500 Lx ± 500 Lx). Take samples for detection at the end of day 0, day 5 and day 10. The results are shown in Table 6.

[0118] The specific method for stability investigation can refer to the method in Appendix XIX C of the second part of Chinese Pharmacopoeia 2015 edition; for purity detection, HPLC method can be used, which can refer to the method in Appendix VD of the second part of Chinese Pharmacopoeia 2015 edition.

[0119] Table 6 Results of stability test of solid under light illumination (4500Lx ± 500Lx)

[0120]

[0121]

[0122] Note: / indicates not detected

[0123] As can be seen from Table 6, the purity of mosapride oxalate hardly changed after the light illumination test. After the light illumination test of mosapride gallate co-crystal methanol monohydrate, the contents of photosensitive impurity C and photosensitive impurity E increased. After the light illumination test of mosapride citrate dihydrate, the purity decreased, especially the content of photosensitive impurity E increased significantly.

Claims

1. A mosapride organic acid crystal, characterized in that, The mosapride organic acid crystal is one of mosapride oxalate or mosapride gallic acid cocrystal methanol monohydrate; The mosapride organic acid crystal is mosapride oxalate. Using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at 6.22±0.2°, 7.16±0.2°, 18.39±0.2°, 20.45±0.2°, 24.45±0.2°, 25.92±0.2°, 27.65±0.2°; The mosapride organic acid crystal is mosapride gallic acid cocrystal methanol monohydrate. Using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at 3.02±0.2°, 6.09±0.2°, 8.80±0.2°, 10.37±0.2°, 21.54±0.2°; 2. The mosapride organic acid crystal according to claim 1, wherein For the mosapride oxalate, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at 6.22±0.2°, 7.16±0.2°, 7.56±0.2°, 9.26±0.2°, 14.43±0.2°, 17.51±0.2°, 18.39±0.2°, 20.45±0.2°, 22.97±0.2°, 24.45±0.2°, 25.17±0.2°, 25.92±0.2°, 27.65±0.2°; 3. The mosapride organic acid crystal according to claim 1, wherein The mosapride oxalate has an X-ray powder diffraction pattern as shown in Figure 1; 4. The mosapride organic acid crystal according to claim 1, characterized in that, For the mosapride gallic acid cocrystal methanol monohydrate, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at 3.02±0.2°, 5.75±0.2 °, 6.09±0.2°, 8.80±0.2°, 10.37±0.2°, 13.69±0.2°, 15.34±0.2°, 19.69±0.2°, 21.08±0.2°, 21.54±0.2°, 22.25±0.2°, 23.58±0.2°, 24.36±0.2°, 24.68±0.2°, 25.08±0.2°, 26.83±0.2°, 28.70±0.2°; 5. The mosapride organic acid crystal according to claim 1, wherein The mosapride gallic acid cocrystal methanol monohydrate has an X-ray powder diffraction pattern as shown in Figure 5; 6. The preparation method of the mosapride organic acid crystal according to claim 1, characterized in that, The specific preparation steps include: dissolving mosapride and organic acid in an organic solvent, heating for dissolution, after the solution becomes clear, cooling for crystallization, and filtering and drying to obtain the mosapride organic acid crystal; When preparing mosapride oxalate, the organic solvent is selected from at least two or more of methanol, acetone, isopropanol, and tetrahydrofuran as a mixed solvent; When preparing mosapride gallic acid cocrystal methanol monohydrate, the organic solvent is a mixed solvent of methanol, water, and / or organic solvent A, and the organic solvent A is selected from one of acetone and ethanol; 7. The preparation method according to claim 6, wherein The temperature for dissolving and heating is 60-80°C; 8. The preparation method according to claim 6, characterized in that, The mass-volume ratio of mosapride to the organic solvent is 20-35:1, where the mass is in mg and the volume is in mL; 9. The preparation method according to claim 6, characterized in that, The temperature for cooling and crystallization is 5-15°C.

10. Use of the mosapride organic acid crystal according to any one of claims 1 to 5 as an active ingredient for preparing a medicament for treating functional dyspepsia gastropathy.

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