CN114671826A - Mosapride organic acid crystal - Google Patents

Mosapride organic acid crystal Download PDF

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CN114671826A
CN114671826A CN202011549361.3A CN202011549361A CN114671826A CN 114671826 A CN114671826 A CN 114671826A CN 202011549361 A CN202011549361 A CN 202011549361A CN 114671826 A CN114671826 A CN 114671826A
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mosapride
organic acid
methanol
acid
oxalate
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夏祥来
翟立海
郑家芳
王聚聚
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Lunan Pharmaceutical Group Corp
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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a mosapride organic acid crystal and a preparation method thereof.

Description

Mosapride organic acid crystal
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a mosapride organic acid crystal and a preparation method thereof.
Background
Mosapride (Mosapride) is available under the trade name Gasmotin @ and has the chemical name (+/-) -4-amino-5-chloro-2-ethoxy-N- [ 4-fluorobenzyl) -morpholin-2-ylmethyl]Benzamide citric acid eutectic dihydrate. To be provided with
Figure BDA0002857396660000011
Branded for marketing, indicated for gastrointestinal symptoms associated with chronic gastritis (heartburn, nausea/vomiting). Mosapride stimulates serotonin 5-HT4 receptors in the gastrointestinal plexus, which increases acetylcholine release, thereby enhancing gastrointestinal motility and gastric emptying.
Mosapride is currently approved for the treatment of gastrointestinal symptoms associated with chronic gastritis, including heartburn, nausea, vomiting, and gastroesophageal reflux disease (GERD). Mosapride is also in phase iil clinical trials for the treatment of gastrointestinal dumping syndrome or post-gastrectomy syndrome. Other clinical studies have been initiated with mosapride for the treatment of constipation in patients with Parkinson's disease; treating a patient with type 2 diabetes to improve insulin action; treating a patient with gastroparesis; and treating patients suffering from opiate (opiate) -induced respiratory depression.
At present, few reports on the crystal forms of mosapride are reported, and the crystal forms disclosed in the prior art comprise mosapride ethanol solvate reported in patent JP2011225491A, mosapride monohydrate crystal form reported in patent KR20090044694A and citric acid dihydrate reported in patent WO2011107903A1, and the mosapride hydrochloride crystal forms have low solubility in hydrochloric acid solution with pH of 1.0, and often have the problem of low dissolution rate or even unqualified dissolution rate in the actual production of mosapride citrate oral solid preparation.
For the study on the stability of mosapride, the stability of mosapride citrate is measured by an HPLC method, and the stability of mosapride citrate is measured by a reasonable clinical medication method, namely, the period 8A of volume 8 of 2015 8 of 8 months, the mosapride solid is reported to be not obviously degraded after being irradiated by 4500Lx for 10 days, and the main peak is reduced by about 10.0 percent under the conditions of high temperature of 3 hours and oxidation of 5 hours, but no specific impurity structure is disclosed.
Patent CN111505154A discloses a method for detecting five key impurities in mosapride citrate and a preparation thereof, and the concrete structures of the five impurities are as follows:
Figure BDA0002857396660000021
wherein, the impurity A is an intermediate for synthesizing the mosapride and is also a degradation product, and the degradation path is generated by hydrolyzing the mosapride; the impurity B is a defluorinated product of the mosapride and is a byproduct generated in the synthesis process of the bulk drug mosapride; the impurity C is a degradation product of mosapride and is generated under the conditions of heating, illumination or acidity; the impurity D is a condensation product of mosapride and citric acid, and is generated under the heating condition; impurity E is an oxidation product of mosapride, produced under light or oxidation conditions.
Disclosure of Invention
In view of the defects, the invention provides the mosapride organic acid crystal with high stability, which provides a better basis for the application of mosapride medicaments, thereby more efficiently exerting the medicinal value of mosapride.
The invention comprises the following contents:
the mosapride organic acid crystal is formed by mosapride and an organic acid, wherein the organic acid is selected from one of oxalic acid or gallic acid.
Mosapride oxalate:
in one embodiment, the present invention relates to a mosapride oxalate wherein the molar ratio of mosapride to oxalic acid is 1:1.
Preferably, mosapride oxalate may be characterized as having one or more of the following physical characteristics:
(a) has X-ray diffraction peaks at 2 theta including 6.22 +/-0.2 degrees, 7.16 +/-0.2 degrees, 18.39 +/-0.2 degrees, 20.45 +/-0.2 degrees, 24.45 +/-0.2 degrees, 25.92 +/-0.2 degrees, 27.65 +/-0.2 degrees; preferably, has X-ray diffraction peaks at 2 θ comprising 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 °; further preferably, the compound has an X-ray powder diffraction pattern as shown in figure 1;
(b) having crystallographic parameters: monoclinic system, space group P21C; the unit cell parameters are:
Figure BDA0002857396660000031
Figure BDA0002857396660000032
α is 90 °, β is 95.346(3 °), γ is 90 °, unit cell volume
Figure BDA0002857396660000033
The unit cell structure of (1);
(c) the DSC detection spectrum has two endothermic peaks with the temperature ranges of 115.59-137.36 ℃ and 166.88-273.72 ℃, and the peak values are 130.66 ℃ and 226.78 ℃ respectively.
Mosapride gallic acid eutectic methanol monohydrate:
in one embodiment, the invention relates to a mosapride gallic acid crystal, in particular to a mosapride gallic acid eutectic methanol monohydrate, wherein the molar ratio of mosapride to gallic acid to methanol to water is 2: 1: 1:1.
mosapride gallic acid eutectic methanol monohydrate can be characterized as having one or more of the following physical characteristics:
(a) having X-ray diffraction peaks at 2 θ comprising 3.02 ± 0.2 °, 6.09 ± 0.2 °, 8.80 ± 0.2 °, 10.37 ± 0.2 °, 21.54 ± 0.2 °; preferably, X-ray diffraction peaks at 2 θ 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, an X-ray powder diffraction pattern as shown in fig. 5;
(b) having crystallographic parameters: triclinic system, space group is P-1; the unit cell parameters are as follows:
Figure BDA0002857396660000034
Figure BDA0002857396660000035
a is 98.3146(9) °, β is 91.1971(9) °, γ is 99.6521(9) °, unit cell volume
Figure BDA0002857396660000036
Figure BDA0002857396660000037
The unit cell structure of (1);
(c) the DSC detection spectrum has an endothermic peak at 175.15 ℃ with the temperature range of 164.54-223.35 ℃.
Preparation and characterization of mosapride organic acid crystals:
mosapride can be obtained commercially or prepared according to synthetic methods disclosed in the prior art.
Examples 1 to 10 describe methods that can be used for preparing mosapride organic acid crystals, wherein examples 1 to 5 describe methods for preparing mosapride oxalate, and examples 6 to 10 describe methods for preparing mosapride gallic acid eutectic methanol monohydrate.
Various tests were performed to physically characterize the crystals of mosapride organic acid, including X-ray powder diffraction (XRPD), Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA). The method for examining the solubility of the crystals of mosapride organic acid is described in the validation example 1, and the method for examining the stability of the crystals of mosapride organic acid is described in the validation example 2.
Mosapride oxalate:
mosapride oxalate can be prepared by crystallization from a variety of solvents used in polymorph screening and under a variety of crystallization conditions (e.g., rapid and slow evaporation, cooling of saturated solutions, trituration, solvent and anti-solvent addition). Examples 1-5 summarize a method for preparing mosapride oxalate, comprising the following steps: the mosapride and the oxalic acid are put into an organic solvent, heated and dissolved, the solution is clarified, cooled and crystallized, filtered and dried to obtain the mosapride oxalate.
Preferably, the organic solvent is a mixed solvent of at least two selected from methanol, acetone, isopropanol and tetrahydrofuran; further preferred is a mixed solution of methanol and tetrahydrofuran.
Preferably, the molar ratio of the mosapride to the oxalic acid is 1: 0.9 to 1.2; more preferably 1:1.05 to 1.15.
Preferably, the temperature for dissolving and heating is 60-80 ℃.
Preferably, the mass-to-volume ratio of the mosapride to the organic solvent in the system is 20-35: 1, wherein the mass is mg and the volume is mL.
Preferably, the temperature control crystallization temperature is 5-15 ℃, and further preferably 6-8 ℃.
Preferably, the crystallization time is 6-9 hours.
Preferably, the drying temperature is 60-80 ℃, and the drying time is 10-13 hours.
The process for the preparation of mosapride oxalate according to the invention is described in further detail below:
dissolving mosapride and oxalic acid in a molar ratio of 1:1.05 in a mixed solvent of methanol and tetrahydrofuran, heating to 60 ℃, dissolving the compound, filtering after the reaction is finished, standing the filtrate, controlling the temperature to be 6-8 ℃ for crystallization, filtering, leaching a filter cake with methanol, and drying in vacuum at 70 ℃ to obtain the mosapride oxalate.
Figure 1 shows a characteristic XRPD spectrum of mosapride oxalate (Cu-ka,
Figure BDA0002857396660000041
) The main X-ray diffraction patterns, expressed as 2 θ, and their relative intensities are summarized in table 1.
TABLE 1 characteristic XRPD peaks (Cu-Ka) of mosapride oxalate
Figure BDA0002857396660000042
Figure BDA0002857396660000051
Figure BDA0002857396660000061
The above-described collection of XRPD peak positions, or a subset thereof, can be used to identify mosapride oxalate.
FIG. 4 is a DSC/TGA chart of mosapride oxalate, wherein the DSC shows that mosapride oxalate has two endothermic peaks with temperature ranges of 115.59-137.36 ℃ and 166.88-273.72 ℃, and the peak values are 130.66 ℃ and 226.78 ℃ respectively.
Mosapride gallic acid eutectic methanol monohydrate:
the co-crystal methanol monohydrate of mosapride gallic acid can be prepared by various solvents used in the polymorph screening process and crystallization under various crystallization conditions (e.g., rapid and slow evaporation, cooling of saturated solution, milling, solvent and anti-solvent addition). Embodiments 6 to 10 summarize a method for preparing mosapride gallic acid eutectic methanol monohydrate, specifically comprising the following processes: the mosapride and the gallic acid are put into an organic solvent, heated and dissolved, and the solution is cooled and crystallized after being clarified, filtered and dried.
Preferably, the organic solvent is a mixed solvent of methanol, water and/or an organic solvent A, and 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%.
Further preferably, the organic solvent is methanol and water, and more preferably, the volume fraction of methanol in the organic solvent is 50%, and the volume fraction of water is 50%.
Preferably, the organic solvent A is selected from one of acetone and ethanol.
Preferably, the feeding molar ratio of the mosapride to the gallic acid is 1: 0.45-0.65, and more preferably 1: 0.5-0.6.
Preferably, the temperature for dissolving and heating is 60-80 ℃.
Preferably, the mass-to-volume ratio of the mosapride to the organic solvent in the system is 20-35: 1, wherein the mass is mg and the volume is mL.
Preferably, the temperature control crystallization temperature is 5-15 ℃, and further preferably 8-10 ℃.
Preferably, the crystallization time is 10-13 hours.
Preferably, the drying temperature is 60-80 ℃, and the drying time is 12-15 hours.
The following process further details the preparation process of the eutectic methanol monohydrate of mosapride gallic acid of the present invention:
dissolving mosapride and gallic acid in a molar ratio of 1:0.55 in a mixed solvent of methanol and water in a volume ratio of 1:1, heating to 75 ℃, dissolving the compound, filtering after the reaction is finished, standing the filtrate, controlling the temperature to be 8-10 ℃ for crystallization, filtering, leaching a filter cake with methanol, and drying in vacuum at 70 ℃ to obtain the mosapride gallic acid eutectic methanol monohydrate.
Figure 5 shows a characteristic XRPD spectrum of mosapride gallic acid eutectic methanol monohydrate (Cu-ka,
Figure BDA0002857396660000062
Figure BDA0002857396660000071
) The main X-ray diffraction and its relative intensity, expressed as 2 θ, are summarized in table 2.
TABLE 2 characteristic XRPD peak (CuK. alpha.) of eutectic methanol monohydrate of mosapride gallic acid
Figure BDA0002857396660000072
Figure BDA0002857396660000081
The above-described set of XRPD peak positions, or a subset thereof, can be used to identify mosapride gallic acid eutectic methanol monohydrate.
FIG. 8 is a DSC/TGA diagram of the eutectic methanol monohydrate of mosapride gallic acid, wherein a DSC spectrogram shows an endothermic peak with a temperature range of 164.54-223.35 ℃ and a peak value of 175.15 ℃.
Confirmation of the crystal structure of mosapride organic acid:
the mosapride organic acid crystal provided by the invention is subjected to X-ray single crystal diffraction test analysis. The X-ray single crystal diffraction instrument and the test conditions related by the invention are as follows: the physical ray single crystal diffraction instrument and the test conditions are as follows: the XtaLAB Synergy X-ray single crystal diffractometer tests the temperature 293(2) K, uses Cu-Ka radiation, collects data in an omega scanning mode and corrects Lp. Analyzing the structure by a direct method, finding out all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and refining the structure by a least square method.
The mosapride oxalate prepared by the invention is tested and analyzed, the obtained crystallographic data are shown in Table 3, the crystallographic parameters are monoclinic system, and the space group is P21C; the unit cell parameters are:
Figure BDA0002857396660000082
α is 90 °, β is 95.346(3 °), γ is 90 °, unit cell volume
Figure BDA0002857396660000083
TABLE 3 Primary crystallographic data for mosapride oxalate
Figure BDA0002857396660000091
Figure BDA0002857396660000101
The ORTEP chart for the preparation of mosapride oxalate of the present invention shows that one molecule of mosapride binds one molecule of oxalic acid, as shown in figure 2; 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 shown in fig. 3.
The eutectic methanol monohydrate of the mosapride gallic acid prepared by the invention is tested and analyzed, the obtained crystallographic data are shown in table 4, and the crystallographic parameters are as follows: triclinic system, space group is P-1; the unit cell parameters are:
Figure BDA0002857396660000102
Figure BDA0002857396660000103
α＝98.3146(9)°，β＝91.1971(9) ° gamma 99.6521(9) ° unit cell volume
Figure BDA0002857396660000104
Table 4 main crystallographic data for mosapride gallic acid eutectic methanol monohydrate
Figure BDA0002857396660000105
Figure BDA0002857396660000111
The ORTEP chart of the eutectic methanol monohydrate of mosapride gallic acid prepared by the invention shows that two molecules of mosapride combine one molecule of gallic acid, one molecule of methanol and one molecule of water, as shown in fig. 6; the hydrogen bond diagram of eutectic methanol monohydrate of mosapride gallic acid shows that mosapride and gallic acid are connected into a three-dimensional structure through intermolecular hydrogen bonds, as shown in fig. 7.
Compared with the currently reported mosapride crystal form, the mosapride organic acid crystal prepared by the method has the following advantages:
(1) the solubility of the mosapride oxalate in water and the phosphate buffer solution with the pH value of 6.8 can respectively reach 0.96mg/mL and 0.98mg/mL, while the mosapride citrate dihydrate is almost insoluble in water and the phosphate buffer solution with the pH value of 6.8.
(2) The stability is good, the photostability of the mosapride oxalate is good, and the purity is hardly reduced through a photostability experiment.
Drawings
FIG. 1: an X-ray powder diffraction pattern of mosapride oxalate;
FIG. 2: ORTEP profile of mosapride oxalate;
FIG. 3: hydrogen bonding diagram for mosapride oxalate;
FIG. 4: DSC/TGA chart of mosapride oxalate,
FIG. 5: an X-ray powder diffraction pattern of the eutectic methanol monohydrate of mosapride gallic acid;
FIG. 6: ORTEP plot of mosapride gallic acid eutectic methanol monohydrate;
FIG. 7: hydrogen bond diagram of eutectic methanol monohydrate of mosapride gallic acid;
FIG. 8: DSC/TGA graph of eutectic methanol monohydrate of mosapride gallic acid.
Detailed Description
The invention will be further described by the following description of specific embodiments, it being properly understood that: the examples of the present invention are provided for illustration only and not for limitation of the present invention. Therefore, simple modifications of the present invention in the process of the present invention are within the scope of the claimed invention.
Preparation of mosapride oxalate:
example 1
Dissolving 2.5g of mosapride and 0.59g of oxalic acid in 100mL of mixed solvent (50 mL of methanol and 50mL of tetrahydrofuran), heating to 60 ℃, dissolving, filtering, controlling the temperature to be 6-8 ℃ for crystallization for 8.5 hours, filtering, leaching a filter cake with methanol, and drying the filter cake at 70 ℃ for 12 hours to obtain 2.85g of mosapride oxalate. The yield is 94.2 percent, and the purity is 99.96 percent.
Example 2
Dissolving 2.5g of mosapride and 0.53g of oxalic acid in 80mL of mixed solvent (50 mL of methanol and 30mL of acetone), heating to 60 ℃, dissolving, filtering, controlling the temperature to be 5-7 ℃, crystallizing for 6 hours, filtering, leaching a filter cake with methanol, and drying the filter cake at 70 ℃ for 11 hours to obtain 2.80g of mosapride oxalate. The yield was 92.8% and the purity was 99.93%.
Example 3
Dissolving 2.5g of mosapride and 0.61g of oxalic acid in 125mL of mixed solvent (methanol 45mL + isopropanol 80mL), heating to 80 ℃, dissolving, filtering, controlling the temperature to be 8-10 ℃ for crystallization for 9 hours, filtering, leaching a filter cake with methanol, and drying the filter cake at 80 ℃ for 13 hours to obtain 2.79g of mosapride oxalate. The yield is 92.3 percent, and the purity is 99.90 percent.
Example 4
Dissolving 2.5g of mosapride and 0.48g of oxalic acid in 70mL of mixed solvent (35 mL of acetone and 35mL of isopropanol), heating to 82 ℃, dissolving, filtering, controlling the temperature to be 13-15 ℃ for crystallization for 15 hours, filtering, leaching a filter cake with ethanol, and drying the filter cake at 60 ℃ for 11 hours to obtain 2.65g of mosapride oxalate. The yield was 87.6% and the purity 98.91%.
Example 5
Dissolving 2.5g of mosapride and 0.70g of oxalic acid in 135mL of mixed solvent (methanol 100mL and acetone 35mL), heating to 50 ℃, dissolving, filtering, controlling the temperature to be-2-0 ℃ for crystallization for 5 hours, filtering, leaching a filter cake with methanol, and drying the filter cake at 70 ℃ for 10 hours to obtain 2.49g of mosapride oxalate. The yield was 82.6% and the purity was 99.21%.
Preparation of eutectic methanol monohydrate of mosapride gallic acid:
example 6
Dissolving 5.0g of mosapride and 1.1g of gallic acid in 170mL of mixed solvent (85 mL of methanol and 85mL of water), heating to 75 ℃, dissolving, filtering, controlling the temperature to be 10-12 ℃ for crystallization for 11 hours, filtering, leaching a filter cake with methanol, and drying the filter cake at 70 ℃ for 13 hours to obtain 5.78g of mosapride gallic acid eutectic methanol monohydrate. The yield is 92.11 percent, and the purity is 99.92 percent.
Example 7
Dissolving 5.0g of mosapride and 1.2g of gallic acid in 142mL of mixed solvent (methanol 42mL + water 100mL), heating to 70 ℃, dissolving, filtering, controlling the temperature to be 5-7 ℃, crystallizing for 10 hours, filtering, leaching filter cake with methanol, drying the filter cake at 60 ℃ for 15 hours, and obtaining 5.71g of mosapride gallic acid eutectic methanol monohydrate. The yield was 91.02%, and the purity was 99.89%.
Example 8
Dissolving 5.0g of mosapride and 1.0g of gallic acid in 250mL of mixed solvent (50 mL of methanol and 200mL of water), heating to 80 ℃, dissolving, filtering, controlling the temperature to be 12-15 ℃ for crystallization for 13 hours, filtering, leaching a filter cake with methanol, and drying the filter cake at 80 ℃ for 12 hours to obtain 5.72g of mosapride gallic acid eutectic methanol monohydrate. The yield was 91.16% and the purity was 99.87%.
Example 9
Dissolving 5.0g of mosapride and 0.90g of gallic acid in 150mL of mixed solvent (30 mL of methanol, 45mL of acetone and 75mL of water), heating to 60 ℃, dissolving, filtering, controlling the temperature to be-2-0 ℃, crystallizing for 15 hours, filtering, leaching a filter cake with methanol, and drying the filter cake at 70 ℃ for 13 hours to obtain 5.42g of mosapride gallic acid eutectic methanol monohydrate. The yield was 86.21% and the purity was 99.13%.
Example 10
Dissolving 5.0g of mosapride and 1.3g of gallic acid in 280mL of mixed solvent (methanol 150mL, water 86mL and ethanol 44mL), heating to 82 ℃, dissolving, filtering, controlling the temperature to be 18-20 ℃, crystallizing for 20 hours, filtering, leaching a filter cake with methanol, and drying the filter cake at 70 ℃ for 13 hours to obtain 5.62g of mosapride gallic acid eutectic methanol monohydrate. The yield was 89.40%, and the purity was 98.91%.
Verification example 1, solubility test
According to the method of pharmacopoeia, the dosage is reduced in the same proportion for saving materials. Respectively preparing a phosphate buffer solution with the pH value of 6.8, a hydrochloric acid solution with the pH value of 1.0 and water, respectively taking a proper amount of mosapride oxalate, a proper amount of mosapride gallic acid eutectic methanol monohydrate and mosapride dihydrate citrate prepared according to the method disclosed by WO2011107903A1, sequentially putting the mosapride oxalate, the mosapride gallic acid eutectic methanol monohydrate and the citric acid mosapride dihydrate into a test tube with a plug and containing the phosphate buffer solution with the pH value of 6.8, the hydrochloric acid solution with the pH value of 1.0 and the water, putting a sample into a water bath constant temperature oscillator, balancing for 24 hours under the conditions of 37 ℃ and 200r/min, sampling, filtering by a 0.45 mu m microporous filter membrane, taking a subsequent filtrate, diluting the subsequent filtrate to a linear range by using the water solution as a blank solution, measuring the absorbance at a position with the wavelength of 274nm until the absorbance is not changed any more. The test results are shown in Table 5.
TABLE 5 solubility of Mosapride organic acid crystals
Figure BDA0002857396660000141
The solubility of the mosapride oxalate and the mosapride gallic acid eutectic methanol monohydrate prepared in the embodiment of the invention are both far higher than that of the mosapride dihydrate citrate.
Verification example 2 photostability test of Mosapride organic acid crystals
Mosapride oxalate, mosapride gallic acid eutectic methanol monohydrate and a proper amount of mosapride dihydrate citrate (about 10mg of mosapride) prepared by the method disclosed in WO2011107903A1 are respectively placed in an open clean container, the stability of illumination (4500Lx +/-500 Lx) is respectively tested, and sampling detection is carried out at the end of 0 day, at the end of 5 days and at the end of 10 days, and the results are shown in Table 6.
The specific stability investigation method can refer to the method in the second part of the Chinese pharmacopoeia 2015, appendix XIXC; the HPLC method for purity detection can be referred to the method of VD in the second part of the pharmacopoeia 2015 edition.
TABLE 6 results of solid state light illumination (4500Lx + -500 Lx) stability test
Figure BDA0002857396660000142
Figure BDA0002857396660000151
Remarking: indicates no detection
As can be seen from Table 6, the purity of mosapride oxalate is almost unchanged through a light test, the content of photosensitive impurity C and photosensitive impurity E of mosapride gallic acid eutectic methanol monohydrate is increased after the light test, the purity of citric acid mosapride dihydrate is reduced through the light test, and particularly the content of photosensitive impurity E is obviously increased.

Claims (10)

1. The mosapride organic acid crystal is characterized by being formed by mosapride and an organic acid, wherein the organic acid is selected from one of gallic acid or oxalic acid.
2. The crystalline mosapride organic acid of claim 1, wherein the crystalline mosapride organic acid is mosapride oxalate and has an X-ray diffraction pattern, expressed in terms of 2 Θ, having 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 ° using Cu-ka radiation.
3. The crystalline mosapride organic acid of claim 2, wherein the mosapride oxalate, when irradiated with Cu-ka, has an X-ray diffraction pattern, expressed in 2 Θ, having 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 °, preferably having an X-ray powder diffraction pattern as shown in fig. 1.
4. The mosapride organic acid crystal of claim 1, which is mosapride gallic acid eutectic methanol monohydrate and has characteristic peaks at 3.02 ± 0.2 °, 6.09 ± 0.2 °, 8.80 ± 0.2 °, 10.37 ± 0.2 °, 21.54 ± 0.2 ° in an X-ray diffraction pattern expressed in terms of 2 Θ using Cu-ka radiation.
5. The crystalline mosapride organic acid of claim 4, wherein the mosapride gallic acid eutectic methanol monohydrate has characteristic peaks in the X-ray diffraction pattern, expressed in 2 Θ using Cu-Ka radiation, 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 °, preferably having the X-ray diffraction powder pattern shown in fig. 5.
6. A method for preparing mosapride organic acid crystals according to claim 1, which comprises the following specific steps: dissolving mosapride and organic acid in an organic solvent, heating for dissolving, cooling for crystallization after the solution is clarified, filtering and drying to obtain the mosapride organic acid crystal.
7. The method according to claim 6, wherein the temperature for the dissolution heating is 60 to 80 ℃.
8. The preparation method according to claim 6, wherein the mass-to-volume ratio of the mosapride to the organic solvent is 20-35: 1, wherein the mass is mg and the volume is mL.
9. The preparation method according to claim 6, wherein the temperature for cooling and crystallization is 5-15 ℃.
10. Use of the crystalline mosapride organic acid according to any one of claims 1 to 5 as an active ingredient for the preparation of a medicament for the treatment of functional dyspepsia.
CN202011549361.3A 2020-12-24 2020-12-24 Mosapride organic acid crystal Pending CN114671826A (en)

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