A mosapride organic acid salt

Abstract

The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a mosapride organic acid salt and a preparation method thereof. The mosapride organic acid salt provided by the present invention is formed by mosapride and 5-sulfosalicylic acid or sulfamic acid, specifically a methanol complex of mosapride 5-sulfosalicylate and a mosapride sulfamate trihydrate. The mosapride organic acid salt provided by the present invention has high solubility and good 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 salt and a preparation method thereof. Background Art

[0002] Mosapride, sold under the brand name Gasmotin@, has the chemical name of (+ / -)-4-amino-5-chloro-2-ethoxy-N-[(4-fluorobenzyl)-morpholin-2-ylmethyl]benzamide citrate dihydrate. It 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 receptors in the enteric plexus, which increases the release of acetylcholine, thereby enhancing gastrointestinal motility and gastric emptying.

[0003] Mosapride has currently been 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; the treatment of patients with type 2 diabetes to improve insulin action; the treatment of patients with gastroparesis; and the treatment of patients with opiate-induced respiratory depression.

[0004] 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 citrate dihydrate reported in Patent WO2011107903A1, which have low solubility in a hydrochloric acid solution at pH 1.0 and often encounter problems of low dissolution or even unqualified dissolution in the actual production of mosapride citrate oral solid preparations.

[0005] Regarding the study on the stability of mosapride, "Determination of the Stability of Mosapride Citrate by HPLC", Clinical Rational Drug Use, Vol. 8, No. 8A, August 2015, reported that the mosapride solid showed no obvious degradation 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.

[0006] Patent CN111505154A discloses a method for detecting five key impurities in mosapride citrate and its preparations.

[0007] The specific structures of the five impurities are:

[0008]

[0009]

[0010]

[0011] 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 defluorination 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, 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

[0012] In view of the above disadvantages, the present invention provides a mosapride organic acid salt with high purity and high solubility, providing a better basis for the pharmaceutical application of mosapride, so as to more efficiently exert the medicinal value of mosapride.

[0013] The content of the present invention is as follows:

[0014] A mosapride organic acid salt, wherein the mosapride organic acid salt is formed by mosapride and an organic acid, and the organic acid is selected from 5-sulfosalicylic acid or sulfamic acid.

[0015] The salt formed by mosapride and 5-sulfosalicylic acid:

[0016] In one embodiment, the mosapride organic acid salt can also be combined with methanol. The present invention relates to a mosapride 5-sulfosalicylate, specifically a methanol complex of mosapride 5-sulfosalicylate, wherein the molar ratio of mosapride, 5-sulfosalicylic acid and methanol is 2:2:1.

[0017] Preferably, the methanol complex of mosapride 5-sulfosalicate can be characterized by having one or more of the following physical characteristics:

[0018] (a) having X-ray diffraction peaks at 2θ including 6.42±0.2°, 9.21±0.2°, 11.70±0.2°, 13.21±0.2°; preferably, having X-ray diffraction peaks at 2θ including 6.42±0.2°, 9.21±0.2°, 11.70±0.2°, 13.21±0.2°, 13.60±0.2°, 14.49±0.2°, 16.40±0.2°, 17.45±0.2°, 18.52±0.2°, 19.41±0.2°, 20.73±0.2°, 23.74±0.2°; more preferably, having X-ray diffraction peaks at 2θ including 6.42±0.2°, 7.31±0.2°, 9.21±0.2°, 11.70±0.2°, 13.21±0.2°, 13.60±0.2°, 14.49±0.2°, 16.40±0.2°, 16.83±0.2°, 17.45±0.2°, 18.30±0.2°, 18.52±0.2°, 19.41±0.2°, 20.73±0.2°, 21.70±0.2°, 22.20±0.2°, 23.74±0.2°, 24.63±0.2°, 25.72±0.2°; even more preferably, having an X-ray diffraction pattern as shown in Figure 1 ;

[0019] (b) having crystallographic parameters: triclinic system, space group P-1; unit cell parameters: α = 90.7014(13)°, β = 93.5995(15)°, γ = 98.1085(13)°, unit cell volume ;

[0020] (c) The DSC detection spectrum shows an endothermic peak, with an endothermic peak in the temperature range of 263.27 - 289.28 °C, and its peak value is 266.68 °C.

[0021] The salt formed by mosapride and sulfamic acid:

[0022] In one embodiment, the mosapride organic acid salt can also combine with water. The present invention relates to a mosapride sulfamate, specifically mosapride sulfamic acid trihydrate, wherein the molar ratio of mosapride, sulfamic acid, and water is 1:1:3.

[0023] Mosapride sulfamic acid trihydrate can be characterized by having one or more of the following physical characteristics:

[0024] (a) having X-ray diffraction peaks at 2θ including 6.89 ± 0.2°, 7.27 ± 0.2°, 8.32 ± 0.2°, 8.63 ± 0.2°, 11.19 ± 0.2°, 17.29 ± 0.2°, 21.81 ± 0.2°, 25.69 ± 0.2°; preferably, having X-ray diffraction peaks at 2θ including 6.89 ± 0.2°, 7.27 ± 0.2°, 8.32 ± 0.2°, 8.63 ± 0.2°, 10.71 ± 0.2°, 10.89 ± 0.2°, 11.19 ± 0.2°, 11.55 ± 0.2°, 12.34 ± 0.2°, 16.79 ± 0.2°, 17.29 ± 0.2°, 19.22 ± 0.2°, 21.81 ± 0.2°, 23.18 ± 0.2°, 24.11 ± 0.2°, 24.55 ± 0.2°, 25.12 ± 0.2°, 26.42 ± 0.2°, 25.69 ± 0.2°, 29.54 ± 0.2°, 31.66 ± 0.2°, 32.79 ± 0.2°; more preferably, having an X-ray diffraction pattern as shown in Figure 5 ;

[0025] (b) having crystallographic parameters: triclinic system, space group P-1; unit cell parameters: α = 85.8270(10)°, β = 80.2660(10)°, γ = 81.1930(10)°, unit cell volume ;

[0026] (c) The DSC detection spectrum shows having two endothermic peaks, and the temperature ranges are 61.48 - 133.84 °C and 200.65 - 221.17 °C respectively.

[0027] Preparation and characterization of mosapride organic salts:

[0028] Mosapride can be obtained commercially or prepared according to the synthesis methods disclosed in the prior art.

[0029] The methods that can be used to prepare mosapride organic salts are described in Examples 1 - 10. Among them, Examples 1 - 5 describe the preparation method of the methanol complex of mosapride 5-sulfosalicylate, and Examples 6 - 10 describe the preparation method of mosapride aminosulfonate trihydrate.

[0030] A variety of tests were carried out to physically characterize mosapride organic salts, including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The method for testing the solubility of mosapride organic salts is described in Verification Example 1, and the method for testing the stability of mosapride organic salts is described in Verification Example 2.

[0031] Methanolic solvate of mosapride 5-sulfosalicylate:

[0032] The methanolic solvate of mosapride 5-sulfosalicylate can be prepared by crystallization using various solvents employed in polymorph screening processes and under various crystallization conditions (e.g., fast and slow evaporation, cooling of saturated solutions, grinding methods, addition of solvents and anti-solvents). Examples 1-5 summarize a method for preparing the methanolic solvate of mosapride 5-sulfosalicylate, which specifically includes the following process: Mosapride and 5-sulfosalicylic acid are placed in solvent A, heated and dissolved. After the solution becomes clear, it is cooled for crystallization, and then filtered and dried to obtain the methanolic solvate of mosapride 5-sulfosalicylate.

[0033] Preferably, the solvent A is a mixed solvent of methanol and solvent B.

[0034] Preferably, the solvent B is selected from at least one of acetone, ethanol, and acetonitrile.

[0035] More preferably, the solvent B is a mixed solvent of ethanol and acetone.

[0036] Preferably, in the solvent A, the volume fraction of methanol is 20-50%.

[0037] Preferably, the temperature for heating and dissolving is 56-64 °C

[0038] Preferably, the molar ratio of mosapride to the organic acid in the feed is 1:1.1-1.3.

[0039] Preferably, the temperature for cooling and crystallization is 1-10 °C, and more preferably 6-9 °C.

[0040] Preferably, the mass-volume ratio of mosapride to solvent A is 10-25:1, where the mass is in mg and the volume is in mL.

[0041] Preferably, the time for cooling and crystallization is 30-60 hours.

[0042] Preferably, the temperature for drying is 55-65 °C.

[0043] Preferably, the time for drying is 12-20 hours.

[0044] Figure 1 The characteristic XRPD spectrum of the methanolic solvate of mosapride 5-sulfosalicylate is shown The main X-ray diffractions expressed as 2θ and their relative intensities are summarized in Table 1.

[0045] Table 1 Characteristic XRPD peaks of the methanolic solvate of mosapride 5-sulfosalicylate (CuKα)

[0046]

[0047]

[0048] The set of the above XRPD peak positions or a subset thereof can be used to identify the methanol solvate of mosapride 5-sulfosalicylic acid.

[0049] Figure 4 is the DSC / TGA diagram of the methanol solvate of mosapride 5-sulfosalicylic acid. TGA analysis shows that in the temperature range of 263.27 - 289.28 °C, the methanol solvate of mosapride 5-sulfosalicylic acid exhibits a large weight loss, indicating that the eutectic has an endothermic peak with a peak value of 266.68 °C.

[0050] Mosapride aminosulfonate trihydrate:

[0051] Mosapride aminosulfonate trihydrate can be prepared by crystallization using various solvents and under various crystallization conditions (such as fast and slow evaporation, cooling of saturated solution, grinding method, addition of solvent and antisolvent) used in the polymorph screening process. Examples 6 - 10 summarize a method for preparing mosapride aminosulfonate trihydrate, which specifically includes the following process: placing mosapride and aminosulfonic acid in solvent A, heating and dissolving, after the solution becomes clear, cooling for crystallization, and filtering and drying to obtain mosapride aminosulfonate trihydrate.

[0052] Preferably, the solvent A is a mixture of water and organic solvent C.

[0053] Preferably, the organic solvent C is selected from one or a mixture of at least two of acetone, methanol, ethanol, and acetonitrile.

[0054] Preferably, the volume fraction of water in the solvent A is 5 - 15%.

[0055] Preferably, the temperature for heating and dissolving is 56 - 64 °C

[0056] Preferably, the molar ratio of mosapride to the organic acid in the feed is 1:1.1 - 1.3.

[0057] Preferably, the temperature for cooling and crystallization is 1 - 10 °C, more preferably 6 - 9 °C.

[0058] Preferably, the mass - volume ratio of mosapride to the solvent A is 10 - 25:1, where the mass is in mg and the volume is in mL.

[0059] Preferably, the time for cooling and crystallization is 30 - 60 hours.

[0060] Preferably, the drying temperature is 55 to 65 °C.

[0061] Preferably, the drying time is 12 to 20 hours.

[0062] Figure 5 The characteristic XRPD spectrum of mosapride aminosulfonate trihydrate is shown The main X-ray diffractions expressed as 2θ and their relative intensities are summarized in Table 2.

[0063] Table 2 Characteristic XRPD peaks of mosapride aminosulfonate trihydrate (CuKα)

[0064]

[0065]

[0066]

[0067] The set of the above XRPD peak positions or a subset thereof can be used to identify mosapride aminosulfonate trihydrate.

[0068] Figure 8 is the DSC / TGA diagram of mosapride aminosulfonate trihydrate. TGA analysis shows that in the temperature ranges of 61.48 to 133.84 °C and 200.65 to 221.17 °C, mosapride aminosulfonate trihydrate exhibits two relatively large weight losses, indicating that the crystal has two endothermic peaks, and their peak values are 93.88 °C and 210.21 °C respectively.

[0069] Confirmation of the structure of mosapride organic acid salt:

[0070] For the mosapride organic acid salt provided by the present invention, X-ray single crystal diffraction test analysis is carried out. The X-ray single crystal diffraction instrument and test conditions involved in the present invention are: Rigaku XtaLAB Synergy X-ray single crystal diffractometer, the test temperature is 293(2)K, CuKa radiation is used, data is collected in the ω scanning mode and Lp correction is carried out. 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.

[0071] The crystallographic data obtained by testing and analyzing the methanolate of mosapride 5-sulfosalicylate prepared by the present invention are shown in Table 3, and its crystallographic parameters are: triclinic system, space group P-1; unit cell parameters are: α = 90.7014(13)°, β = 93.5995(15)°, γ = 98.1085(13)°, unit cell volume

[0072] Table 3 Main crystallographic data of mosapride 5-sulfosalicylate methanolate

[0073]

[0074]

[0075]

[0076] The ORTEP diagram of mosapride 5-sulfosalicylate methanolate prepared by the present invention shows that two molecules of mosapride combine with two molecules of 5-sulfosalicylic acid and one molecule of methanol, as Figure 2 shown; the hydrogen bond diagram of mosapride 5-sulfosalicylate methanolate shows that mosapride and 5-sulfosalicylic acid are connected into a three-dimensional structure through intermolecular hydrogen bonds, as Figure 3 shown.

[0077] The crystallographic data obtained by testing and analyzing mosapride aminosulfonate trihydrate prepared by the present invention are shown in Table 4, and its crystallographic parameters are: triclinic system, space group P-1; unit cell parameters are: α = 85.8270(10)°, β = 80.2660(10)°, γ = 81.1930(10)°, unit cell volume

[0078] Table 4 Main crystallographic data of mosapride aminosulfonate trihydrate

[0079]

[0080]

[0081] The ORTEP diagram of mosapride aminosulfonate trihydrate prepared by the present invention shows that one molecule of mosapride combines with one molecule of aminosulfonic acid and three molecules of water, as Figure 6 shown; the hydrogen bond diagram of mosapride aminosulfonate trihydrate shows that mosapride, aminosulfonic acid and water are connected into a three-dimensional structure through intermolecular hydrogen bonds, as Figure 7 shown.

[0082] The mosapride organic acid salts prepared by the method of the present invention have the following advantages over the currently reported mosapride crystal forms:

[0083] (1) High solubility. The solubility of mosapride 5-sulfosalicylate methanolate in water and phosphate buffer at pH 6.8 can reach 0.68 mg / mL and 0.67 mg / mL respectively, while mosapride citrate dihydrate is almost insoluble in water and phosphate buffer at pH 6.8.

[0084] (2) Good stability. The methanolate of mosapride 5-sulfosalicylate has good stability in high-temperature environments, and the amounts of impurity C and impurity D generated are relatively small. Description of the Drawings

[0085] Figure 1 : X-ray powder diffraction pattern of the methanolate of mosapride 5-sulfosalicylate;

[0086] Figure 2 : ORTEP diagram of the methanolate of mosapride 5-sulfosalicylate;

[0087] Figure 3 : Hydrogen bond diagram of the methanolate of mosapride 5-sulfosalicylate;

[0088] Figure 4 : DSC / TGA diagram of the methanolate of mosapride 5-sulfosalicylate;

[0089] Figure 5 : X-ray powder diffraction pattern of mosapride aminosulfonate trihydrate;

[0090] Figure 6 : ORTEP diagram of mosapride aminosulfonate trihydrate;

[0091] Figure 7 : Hydrogen bond diagram of mosapride aminosulfonate trihydrate;

[0092] Figure 8 : DSC / TGA diagram of mosapride aminosulfonate trihydrate. Detailed Description of the Embodiments

[0093] The present invention will be further described below through the description of 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 required by the present invention.

[0094] Preparation of the methanolate of mosapride 5-sulfosalicylate:

[0095] The 5-sulfosalicylic acid used in the present invention is 5-sulfosalicylic acid with two molecules of crystal water, and its molecular weight is 254.21.

[0096] Example 1

[0097] Dissolve 2.5 g of mosapride and 1.8 g of 5-sulfosalicylic acid in 120 mL of a mixed solvent (40 mL of methanol, 40 mL of acetone, and 40 mL of ethanol), heat to 60 °C, and after dissolution, filter. Control the temperature at 6 - 9 °C for crystallization for 45 hours, then filter, wash the filter cake with methanol, and dry the filter cake at 60 °C for 15 h to obtain 3.62 g of the methanol complex of mosapride 5-sulfosalicylate. The yield is 93.50% and the purity is 99.97%.

[0098] Example 2

[0099] Dissolve 2.5 g of mosapride and 1.65 g of 5-sulfosalicylic acid in 160 mL of a mixed solvent (32 mL of methanol, 50 mL of acetone, and 78 mL of ethanol), heat to 56 °C, and after dissolution, filter. Control the temperature at 1 - 5 °C for crystallization for 30 hours, then filter, wash the filter cake with methanol, and dry the filter cake at 50 °C for 12 h to obtain 3.59 g of the methanol complex of mosapride 5-sulfosalicylate. The yield is 92.62% and the purity is 99.95%.

[0100] Example 3

[0101] Dissolve 2.5 g of mosapride and 1.95 g of 5-sulfosalicylic acid in 250 mL of a mixed solvent (125 mL of methanol, 80 mL of acetone, and 45 mL of ethanol), heat to 64 °C, and after dissolution, filter. Control the temperature at 6 - 9 °C for crystallization for 60 hours, then filter, wash the filter cake with methanol, and dry the filter cake at 55 °C for 20 h to obtain 3.58 g of the methanol complex of mosapride 5-sulfosalicylate. The yield is 92.41% and the purity is 99.93%.

[0102] Example 4

[0103] Dissolve 2.5 g of mosapride and 1.65 g of 5-sulfosalicylic acid in 100 mL of a mixed solvent (15 mL of methanol, 45 mL of ethanol, and 40 mL of acetonitrile), heat to 70 °C, and after dissolution, filter. Control the temperature at -1 - -5 °C for crystallization for 35 hours, then filter, wash the filter cake with methanol, and dry the filter cake at 70 °C for 12 h to obtain 3.45 g of the methanol complex of mosapride 5-sulfosalicylate. The yield is 89.10% and the purity is 99.68%.

[0104] Example 5

[0105] Dissolve 2.5 g of mosapride and 1.5 g of 5-sulfosalicylic acid in 100 mL of a mixed solvent (60 mL of methanol and 40 mL of acetone), heat to 50 °C, and after dissolution, filter. Control the temperature at 10 - 15 °C for crystallization for 25 hours, then filter, wash the filter cake with ethanol, and dry the filter cake at 65 °C for 12 h to obtain 3.34 g of the methanol complex of mosapride 5-sulfosalicylate, with a yield of 86.15% and a purity of 99.52%.

[0106] Preparation of Mosapride Sulfamic Acid Trihydrate:

[0107] Example 6

[0108] Dissolve 2.5 g of mosapride and 0.69 g of sulfamic acid in 132 mL of a mixed solvent (80 mL of acetone, 40 mL of ethanol, and 12 mL of water). Heat to 60 °C. After dissolution, filter. Control the temperature at 6 - 9 °C for crystallization for 45 hours. Filter, wash the filter cake with ethanol, and dry the filter cake at 60 °C for 15 h to obtain 3.12 g of mosapride sulfamic acid trihydrate. The yield is 92.25% and the purity is 99.92%.

[0109] Example 7

[0110] Dissolve 2.5 g of mosapride and 0.63 g of sulfamic acid in 165 mL of a mixed solvent (60 mL of acetone, 80 mL of ethanol, and 25 mL of water). Heat to 56 °C. After dissolution, filter. Control the temperature at 1 - 5 °C for crystallization for 30 hours. Filter, wash the filter cake with ethanol, and dry the filter cake at 50 °C for 12 h to obtain 3.06 g of mosapride sulfamic acid trihydrate. The yield is 90.36% and the purity is 99.89%.

[0111] Example 8

[0112] Dissolve 2.5 g of mosapride and 0.75 g of sulfamic acid in 250 mL of a mixed solvent (137 mL of acetone, 100 mL of ethanol, and 13 mL of water). Heat to 64 °C. After dissolution, filter. Control the temperature at 6 - 9 °C for crystallization for 60 hours. Filter, wash the filter cake with ethanol, and dry the filter cake at 55 °C for 20 h to obtain 3.04 g of mosapride sulfamic acid trihydrate. The yield is 89.85% and the purity is 99.81%.

[0113] Example 9

[0114] Dissolve 2.5 g of mosapride and 0.63 g of sulfamic acid in 100 mL of a mixed solvent (60 mL of ethanol, 20 mL of acetonitrile, and 20 mL of water). Heat to 70 °C. After dissolution, filter. Control the temperature at -1 - -5 °C for crystallization for 35 hours. Filter, wash the filter cake with ethanol, and dry the filter cake at 70 °C for 12 h to obtain 2.90 g of mosapride sulfamic acid trihydrate. The yield is 85.66% and the purity is 99.64%.

[0115] Example 10

[0116] Dissolve 2.5 g of mosapride and 0.57 g of sulfamic acid in 120 mL of a mixed solvent (50 mL of methanol, 65 mL of acetone, and 5 mL of water). Heat to 50 °C. After dissolution, filter. Control the temperature at 10 - 15 °C to crystallize for 25 hours. Then filter, and wash the filter cake with ethanol. Dry the filter cake at 65 °C for 12 h to obtain 2.82 g of mosapride sulfamate trihydrate, with a yield of 83.53% and a purity of 99.31%.

[0117] Verification Example 1, Solubility Test

[0118] 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 and water respectively. Take appropriate amounts of mosapride 5-sulfosalicylate methanolate prepared in Example 1, mosapride sulfamate trihydrate prepared in Example 6, 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 and water in turn. Place the samples in a water bath thermostatic oscillator and equilibrate at 37 °C and 200 r / min for 24 h. Sampling, 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.

[0119] Table 5 Solubility of Mosapride Organic Salts

[0120]

[0121] The solubilities of mosapride 5-sulfosalicylate methanolate and mosapride sulfamate trihydrate prepared in the examples of the present invention are much higher than the solubility of mosapride citrate dihydrate.

[0122] Verification Example 2, High Temperature Stability Test of Mosapride Organic Salts

[0123] Take about 10 mg each of mosapride 5-sulfosalicylate methanolate, mosapride sulfamate trihydrate, and mosapride citrate dihydrate, place them in a 10 ml volumetric flask, put them in an oven at 105 °C for 1 h, take them out, let them cool, dissolve with methanol and dilute to the mark, shake well, centrifuge, take the supernatant as the test solution, take 10 μl and inject it into the liquid chromatograph, record the chromatogram, and use the HPLC method for purity detection. The method can refer to the method in Appendix VD of the second part of the Chinese Pharmacopoeia 2015 edition. The results are shown in Table 6.

[0124] Table 6 Results of High Temperature Stability Test of Mosapride Organic Salts

[0125]

[0126]

[0127] Note: / indicates not detected

[0128] Conclusion: After 1-hour high-temperature stability test at 105 °C, the purity of mosapride 5-sulfosalicylate methanol complex slightly decreased to 98.93%, impurity C was 0.26%, and impurity D was 0.53%; after 1-hour high-temperature stability test, the purity of mosapride aminosulfonate trihydrate decreased to 94.16%, and impurity D significantly increased to 3.12%; after 1-hour high-temperature stability test, the purity of mosapride citrate dihydrate decreased to 93.76%, and impurity D significantly increased to 3.27%.

Claims

1. A mosapride organic acid salt, characterized in that, The mosapride organic acid salt is formed from mosapride and an organic acid, wherein the organic acid is selected from 5-sulfosalicylic acid or sulfamic acid; The mosapride organic acid salt is a methanol solvate of mosapride 5-sulfosalicylate. Using Cu-Kα radiation, the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 6.42±0.2°, 9.21±0.2°, 11.70±0.2°, and 13.21±0.2°; The mosapride organic acid salt is a mosapride sulfamic acid trihydrate. Using Cu-Kα radiation, the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 6.89±0.2°, 7.27±0.2°, 8.32±0.2°, 8.63±0.2°, 11.19±0.2°, 17.29±0.2°, 21.81±0.2°, and 25.69±0.2°; 2. The mosapride organic acid salt according to claim 1, characterized in that, For the methanol solvate of mosapride 5-sulfosalicylate, using Cu-Kα radiation, the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 6.42±0.2°, 9.21±0.2°, 11.70±0.2°, 13.21±0.2°, 13.60±0.2°, 14.49±0.2°, 16.40±0.2°, 17.45±0.2°, 18.52±0.2°, 19.41±0.2°, 20.73±0.2°, and 23.74±0.2°; 3. The mosapride organic acid salt according to claim 1, wherein The methanol solvate of mosapride 5-sulfosalicylate has an X-ray diffraction pattern as shown in Figure 1; 4. The mosapride organic acid salt according to claim 1, wherein For the mosapride sulfamic acid trihydrate, using Cu-Kα radiation, the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 6.89±0.2°, 7.27±0.2°, 8.32±0.2°, 8.63±0.2°, 10.71±0.2°, 10.89±0.2°, 11.19±0.2°, 11.55±0.2°, 12.34±0.2°, 16.79±0.2°, 17.29±0.2°, 19.22±0.2°, 21.81±0.2°, 23.18±0.2°, 24.11±0.2°, 24.55±0.2°, 25.12±0.2°, 26.42±0.2°, 25.69±0.2°, 29.54±0.2°, 31.66±0.2°, and 32.79±0.2°; 5. The mosapride organic acid salt according to claim 1, wherein The mosapride sulfamic acid trihydrate has an X-ray diffraction pattern as shown in Figure 5; 6. A preparation method of the mosapride organic acid salt as described in claim 1, characterized in that, The specific preparation steps include: placing mosapride and an organic acid in solvent A, heating to dissolve, and after the solution becomes clear, cooling to crystallize, filtering and drying to obtain the mosapride organic acid salt; when the mosapride organic acid salt is a methanol solvate of mosapride 5-sulfosalicylate, solvent A is a mixed solvent of methanol and solvent B, and solvent B is selected from at least one of acetone, ethanol, and acetonitrile. In solvent A, the volume fraction of methanol is 20-50%; When the mosapride organic acid salt is mosapride aminosulfonate trihydrate, the solvent A is a mixture of water and an organic solvent C, and the organic solvent C is selected from one or at least two of acetone, methanol, ethanol, and acetonitrile, and the volume fraction of water in the solvent A is 5-15%.

7. The preparation method according to claim 6, characterized in that, The temperature during the heating and dissolution is 56-64 °C.

8. The preparation method according to claim 6, characterized in that, The molar ratio of the charged mosapride to the organic acid is 1:1.1-1.

3.

9. The preparation method according to claim 6, characterized in that, The temperature for cooling and crystallization is 1-10 °C.

10. Use of the mosapride organic acid salt 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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