Background
Mosapride (Mosapride) is commercially available under the trade name "Gasmotin @", and the chemical name is (+/-) -4-amino-5-chloro-2-ethoxy-N- [ 4-fluorobenzyl) -morpholin-2-ylmethyl ] benzamide citrate dihydrate. To be used forBranding is applicable to 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 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 a patient suffering from type 2 diabetes to improve insulin action; treating a patient suffering from gastroparesis; and treating a patient suffering from opiate (opiate) -induced respiratory depression.
At present, few reports about the crystal forms of mosapride are provided, the crystal forms disclosed in the prior art comprise mosapride ethanol solvate reported by patent JP2011225491A, mosapride monohydrate crystal form reported by patent KR20090044694A and citric acid dihydrate reported by patent WO2011107903A1, the solubility of the mosapride in hydrochloric acid solution with the pH of 1.0 is small, and the problem of low or even unqualified dissolution rate is often encountered in the actual production of mosapride citrate oral solid preparations.
For the study of the stability of mosapride, the clinical reasonable medicine 2015, 8 months, 8 volumes, 8A of the clinical reasonable medicine of the stability of mosapride citrate measured by an HPLC method reports that the mosapride solid is not obviously degraded after 10 days under 4500Lx light, and the main peak is reduced by about 10.0 percent under high temperature for 3 hours and oxidation for 5 hours, but the specific impurity structure is not disclosed.
Patent CN111505154a discloses a method for detecting five key impurities in mosapride citrate and its preparation,
The specific structure of the five impurities is as follows:
wherein, the impurity A is an intermediate of mosapride synthesis and is also a degradation product, and the degradation path is generated by hydrolysis of mosapride; impurity B is a defluorination product of mosapride, and is a byproduct generated in the synthesis process of the crude drug mosapride; impurity C is a degradation product of mosapride, and is generated under the condition of heating or illumination or acidity; impurity D is the condensation product of mosapride and citric acid, and is produced under heating; impurity E is the oxidation product of mosapride, produced under light or oxidizing conditions.
Despite the beneficial activity of mosapride, there remains a need for novel compounds for treating the aforementioned diseases and conditions.
Disclosure of Invention
In view of the defects in the prior art, the invention provides a mosapride-succinic acid eutectic crystal.
In a first aspect of the present invention, there is provided a mosapride-succinic acid co-crystal having characteristic peaks at 5.93±0.2°,8.13±0.2°,9.53±0.2°,17.73±0.2°, and 23.70±0.2° using Cu-ka radiation.
Preferably, the mosapride-succinic acid co-crystal uses Cu-K alpha radiation, and the X-ray diffraction spectrum expressed in 2 theta has a characteristic peak at 5.93±0.2°,8.13±0.2°,9.53±0.2°,10.51±0.2°,17.73±0.2°,19.36±0.2°,21.72±0.2°,22.87±0.2°,23.70±0.2°,26.45±0.2°.
Preferably, the mosapride-succinic acid co-crystal uses Cu-K alpha radiation, and the X-ray diffraction spectrum expressed in 2 theta has a characteristic peak at 5.93±0.2°,8.13±0.2°,9.53±0.2°,10.51±0.2°,13.30±0.2°,14.98±0.2°,17.73±0.2°,18.71±0.2°,19.36±0.2°,20.06±0.2°,21.72±0.2°,22.87±0.2°,23.23±0.2°,23.70±0.2°,25.25±0.2°,25.81±0.2°,26.12±0.2°,26.45±0.2°.
Further preferably, the mosapride-succinic acid co-crystal uses Cu-ka radiation, and the characteristic peak conforms to an X-ray powder diffraction pattern as shown in fig. 1.
Preferably, the mosapride-succinic acid eutectic has the following crystallographic parameters: triclinic system, the space group is P-1; unit cell parameters: α= 89.7760 (10) °, β= 74.1490 (10) °, γ= 69.7320 (10) °, unit cell volume/>
The invention provides a preparation method of a mosapride-succinic acid eutectic crystal, which specifically comprises the following steps: dissolving mosapride and succinic acid in a mixed solvent of acetone and an organic solvent A, performing ultrasonic heating and dissolving, filtering after the reaction is finished, standing filtrate for controlling Wen Xijing, and filtering and drying to obtain the mosapride-succinic acid eutectic.
Preferably, the organic solvent A is selected from one or a combination of methanol, ethanol, isopropanol and acetonitrile, and more preferably one or a combination of methanol and acetonitrile.
Preferably, the volume fraction of the acetone in the mixed solvent is 70-100%.
Preferably, the molar ratio of the mosapride to the succinic acid is 1:2.0-3.0, and more preferably 1:2.05-2.25.
Preferably, the heating reaction temperature is 40 to 55 ℃, and more preferably 45 to 50 ℃.
Preferably, the mass-volume ratio of the mosapride and the mixed solvent is 15-24:1, wherein the mass is in mg and the volume is in mL.
Preferably, the temperature of the temperature-controlled crystallization is 16-26 ℃.
Preferably, the crystallization time is 24 to 72 hours, more preferably 24 to 48 hours.
Preferably, the drying temperature is 35-55 ℃ and the drying time is 26-50 hours.
The following further details the preparation method of the co-crystal of mosapride and succinic acid in the invention:
And (3) dissolving mosapride and succinic acid in a molar ratio of 1:2.15-2.25 in a mixed solvent of acetone and an organic solvent A, ultrasonically heating to 45-50 ℃, dissolving the compound, continuously ultrasonically heating for 10-25 min, filtering after the reaction is finished, standing filtrate, crystallizing at a temperature of 16-26 ℃, filtering, leaching the filter cake by using acetone, and vacuum-drying at a temperature of 40-50 ℃ to obtain the mosapride-succinic acid eutectic.
In a third aspect of the invention, there is provided a pharmaceutical composition comprising a mosapride-succinic acid co-crystal according to the invention.
The preparation method of the pharmaceutical composition of the invention can be as follows: the compounds of the present invention are formulated into useful dosage forms by combining them with pharmaceutically acceptable solid or liquid carriers, and optionally with pharmaceutically acceptable adjuvants and excipients, using standard and conventional techniques.
In a fourth aspect of the invention, there is provided an application of a mosapride-succinic acid co-crystal as an active ingredient in preparing a medicament for treating functional dyspepsia and gastropathy.
Confirmation of crystal structure:
The moxapride-succinic acid eutectic crystal provided by the invention is subjected to X-ray single crystal diffraction test analysis. The X-ray single crystal diffractometer and the testing conditions related by the invention are as follows: the temperature 293 (2) K was measured using a XtaLAB Synergy X-ray single crystal diffractometer, and data was collected by omega scanning using CuKa radiation and corrected for Lp. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
The crystallography data obtained by testing and analyzing the mosapride-succinic acid eutectic prepared by the invention are shown in table 1, and the crystallography parameters are as follows: triclinic system, the space group is P-1; unit cell parameters: α= 89.7760 (10) °, β= 74.1490 (10) °, γ= 69.7320 (10) °, unit cell volume/>
ORTEP diagram of the mosapride-succinic acid eutectic prepared by the invention shows that one molecule of mosapride is combined with two molecules of succinic acid, as shown in figure 2; the hydrogen bond diagram of the mosapride-succinic acid eutectic shows that mosapride and succinic acid are connected into a three-dimensional structure through intermolecular hydrogen bonds, as shown in figure 3.
TABLE 1 principal crystallographic data of Mosapride-butanedioic acid Co-crystals
The X-ray powder diffraction test instrument and test conditions related in the invention: x-ray powder diffractometer: PANALYTICAL EMPYREAN; cu-K alpha; sample stage: a flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40mA; divergence slit: 1/4; anti-scatter slit: 1, a step of; a cable pull slit: 0.04rad; step size: 0.5s; scanning range: 3-50 deg.
According to the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in FIG. 1 and Table 2.
TABLE 2 PXRD peaks for Moxapride-butanedioic acid co-crystals
TGA/DSC thermal analysis tester and test conditions in the invention: TGA/DSC thermal analyzer: METTLER TOLEDO TGA/DSC < 3+ >; dynamic temperature section: 30-300 ℃; heating rate: 10 ℃/min; program segment gas N2; gas flow rate: 50mL/min; crucible: 40 μl of aluminum crucible.
The TGA/DSC test result of the mosapride-succinic acid eutectic prepared by the method is shown in figure 4, and a DSC detection spectrogram shows that the eutectic has an endothermic peak, the temperature range is 164.50-176.74 ℃, and the peak value is 168.71 ℃.
The mosapride-succinic acid eutectic prepared by the method has the following advantages compared with the currently reported mosapride crystal form:
(1) The solubility of the mosapride-succinic acid eutectic prepared by the method is high, and the solubility of the mosapride-succinic acid eutectic in hydrochloric acid with the pH value of 1.0 reaches 5.79mg/mL, which is higher than the solubility of the existing crystal form of mosapride.
(2) The stability is good, and after the mosapride-succinic acid eutectic prepared by the method is subjected to hydrolysis test in a hot solution, the purity change is small, and the generated hydrolysis impurity A is small.
Detailed Description
The invention is further illustrated by the following description of specific embodiments with the understanding that: the examples of the present invention are merely illustrative of the present invention and are not intended to be limiting. Therefore, simple modifications to the invention, which are within the scope of the claimed invention, are possible with the method of the invention.
Example 1
211Mg of mosapride and 124.0mg of succinic acid are dissolved in 12.0mL of mixed solvent (10.0 mL of acetone and 2.0mL of methanol), ultrasonic heating is carried out to 50 ℃, ultrasonic treatment is continued for 15min after dissolution, filtration is carried out, standing and crystallization are carried out for 36 hours at 16-20 ℃, filtration is carried out, and drying is carried out at 45 ℃ for 40 hours, thus 305.4mg of mosapride-succinic acid eutectic is obtained. The yield is 92.82 percent and the purity is 99.95 percent.
Example 2
211Mg of mosapride and 121.0mg of succinic acid are dissolved in 10.0mL of acetone, ultrasonic heating is carried out to 45 ℃, ultrasonic treatment is continued for 20min after dissolution, filtration is carried out, standing crystallization is carried out for 48 hours at 20-26 ℃, filtration is carried out, and drying is carried out at 55 ℃ for 30 hours, thus 301.9mg of mosapride-succinic acid eutectic is obtained. The yield was 91.76% and the purity was 99.93%.
Example 3
211Mg of mosapride and 132.9mg of succinic acid are dissolved in 14.0mL of mixed solvent (10.0 mL of acetone and 4.0mL of acetonitrile), ultrasonic heating is carried out to 50 ℃, ultrasonic treatment is continued for 25min after dissolution, filtration is carried out, standing crystallization is carried out for 24 hours at 16-20 ℃, filtration is carried out, and drying is carried out at 45 ℃ for 45 hours, thus 300.6mg of mosapride-succinic acid eutectic is obtained. The yield was 91.35% and the purity was 99.94%.
Example 4
211Mg of mosapride and 118.1mg of succinic acid are dissolved in 9.0mL of mixed solvent (5.0 mL of acetone and 4.0mL of ethanol), ultrasonic heating is carried out to 40 ℃, ultrasonic treatment is continued for 10min after dissolution, filtration is carried out, standing crystallization is carried out for 72 h at 20-26 ℃, filtration is carried out, and drying is carried out for 35 h at 55 ℃ to obtain 295.6mg of mosapride-succinic acid eutectic. The yield is 89.85 percent and the purity is 99.86 percent.
Example 5
211Mg of mosapride and 177.1mg of succinic acid are dissolved in 16.0mL of mixed solvent (8.0 mL of acetone and 8.0mL of isopropanol), ultrasonic heating is carried out to 50 ℃, ultrasonic treatment is continued for 30min after dissolution, filtration is carried out, standing and crystallization are carried out for 72 hours at 16-20 ℃, filtration is carried out, and drying is carried out at 60 ℃ for 60 hours, thus 290.1mg of mosapride-succinic acid eutectic is obtained. The yield was 88.16% and the purity was 99.82%.
Example 6
211Mg of mosapride and 115.1mg of succinic acid are dissolved in 8.0mL of mixed solvent (4.0 mL of acetone and 4.0mL of tetrahydrofuran), ultrasonic heating is carried out to 35 ℃, ultrasonic treatment is continued for 30min after dissolution, filtration is carried out, standing and crystallization are carried out for 75 hours at 10-15 ℃, filtration is carried out, and drying is carried out for 48 hours at 55 ℃ to obtain 277.5mg of mosapride-succinic acid eutectic. The yield thereof was found to be 84.35% and the purity thereof was found to be 99.41%.
Example 7
211Mg of mosapride and 183.0mg of succinic acid are dissolved in 17.0mL of mixed solvent (9.0 mL of acetone and 6.0mL of n-butanol), ultrasonic heating is carried out to 60 ℃, ultrasonic treatment is continued for 15min after dissolution, filtration is carried out, standing crystallization is carried out for 50 h at 26-30 ℃, filtration is carried out, and drying is carried out for 75 h at 30 ℃ to obtain 276.7mg of mosapride-succinic acid eutectic. The yield is 84.10 percent and the purity is 99.28 percent.
1. Solubility test
The method of the reference pharmacopoeia is used for saving materials and reducing the dosage in the same proportion. Taking a proper amount of mosapride-succinic acid eutectic prepared in examples 1-7 respectively, sequentially placing mosapride citrate dihydrate prepared according to the method disclosed in WO2011107903A1 into a test tube with a plug of hydrochloric acid solution with pH of 1.0, placing a sample into a water bath constant temperature oscillator, balancing for 24 hours at 37 ℃ under the condition of 200r/min, sampling, filtering with a 0.45 mu m microporous filter membrane, taking a subsequent filtrate, diluting with water to a linear range, taking an aqueous solution as a blank solution, and measuring absorbance at a wavelength of 274nm until the absorbance is not changed any more. The test results are shown in Table 3.
TABLE 3 solubility of Moxapride-butanedioic acid co-crystals
The solubility of the mosapride-succinic acid eutectic sample prepared in the embodiment of the invention is far higher than that of mosapride citrate dihydrate.
2. Stability test of Mosapride-succinic acid Co-crystals in Hot solution
Taking proper amounts of each of the mosapride-succinic acid eutectic crystal and the mosapride citrate dihydrate (about 10 mg) respectively, adding 10mL of water to disperse, shaking, placing in a water bath at 75 ℃ for 10 hours, adding methanol to dilute to 10mL, shaking for 30 minutes, centrifuging, taking the supernatant as a test solution, and referring to a method of the second appendix VD of the 2015 edition of Chinese pharmacopoeia by an HPLC method for purity detection. The results are shown in Table 4.
TABLE 4 results of thermal stability test of solutions
Remarks: /indicate no detection
Conclusion: the mosapride-succinic acid eutectic is dissolved in the solution, the purity is slightly reduced after 10 hours of thermal stability test, the purity is 99.54%, and the hydrolysis impurity A is 0.22%; mosapride citrate dihydrate was dissolved in the solution and after 10 hours of thermal stability test the purity was reduced to 95.70% and the hydrolytic impurity A was significantly increased to 2.17%.