CN114315750A

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Info

Publication number: CN114315750A
Application number: CN202011054938.3A
Authority: CN
Inventors: 路来菊; 翟立海; 余军厚; 郑家芳
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2020-09-29
Filing date: 2020-09-29
Publication date: 2022-04-12
Anticipated expiration: 2040-09-29
Also published as: CN114315750B

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a mosapride-succinic acid eutectic crystal and a preparation method thereof, wherein the molar ratio of mosapride to succinic acid in the mosapride-succinic acid eutectic crystal is 1:2, Cu-Kalpha radiation is used, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 5.93 +/-0.2 degrees, 8.13 +/-0.2 degrees, 9.53 +/-0.2 degrees, 17.73 +/-0.2 degrees and 23.70 +/-0.2 degrees.

Description

Mosapride-succinic acid eutectic crystal

Technical Field

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a mosapride-succinic acid eutectic 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 citrate dihydrate. To be provided with

Branded for marketing, indicated for gastrointestinal symptoms associated with chronic gastritis (heartburn, nausea/vomiting). MosaprideStimulates 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 using mosapride for treating constipation in patients with Parkinson's disease; treating a patient withtype 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, the solubility of the mosapride monohydrate crystal form in hydrochloric acid solution with pH of 1.0 is small, and the problem of low dissolution rate or even unqualified dissolution rate is often encountered in the practical production of mosapride citrate oral solid preparation.

For the study on stability of mosapride, the 'stability of mosapride citrate measured by HPLC method' in the 8 th period A of 8 th volume in 8 months in 2015 for clinical rational use, it is reported that mosapride solid is not obviously degraded after 10 days under 4500Lx illumination, and the main peak is reduced by about 10.0% under 3h at high temperature and 5h of oxidation, but no specific impurity structure is disclosed.

Patent CN111505154A discloses a method for detecting five key impurities in mosapride citrate and a preparation thereof,

the concrete structure of five kinds of impurity is:

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.

Despite the advantageous 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 of the prior art, the invention provides a mosapride-succinic acid eutectic crystal.

According to the first aspect of the invention, the mosapride-succinic acid eutectic is characterized in that a Cu-Kalpha radiation is used, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 5.93 +/-0.2 degrees, 8.13 +/-0.2 degrees, 9.53 +/-0.2 degrees, 17.73 +/-0.2 degrees, and 23.70 +/-0.2 degrees.

Preferably, the mosapride-succinic acid eutectic crystal has characteristic peaks at 5.93 +/-0.2 degrees, 8.13 +/-0.2 degrees, 9.53 +/-0.2 degrees, 10.51 +/-0.2 degrees, 17.73 +/-0.2 degrees, 19.36 +/-0.2 degrees, 21.72 +/-0.2 degrees, 22.87 +/-0.2 degrees, 23.70 +/-0.2 degrees and 26.45 +/-0.2 degrees in an X-ray diffraction spectrum expressed by 2 theta by using Cu-Kalpha radiation.

Preferably, the mosapride-succinic acid eutectic crystal has characteristic peaks 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 ° and 26.45 +/-0.2 ° in an X-ray diffraction spectrum expressed by 2 theta by using Cu-Kalpha radiation.

Further preferably, the mosapride-succinic acid eutectic crystal is radiated by Cu-Ka, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 1.

Preferably, the mosapride-succinic acid eutectic has the crystallographic parameters of: triclinic system, space group is P-1; unit cell parameters:

a is 89.7760(10) °, β is 74.1490(10) °, γ is 69.7320(10) °, unit cell volume

The second aspect of the invention provides a preparation method of 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, ultrasonically heating for dissolving, filtering after the reaction is finished, standing the filtrate for crystallization under controlled temperature, filtering and drying to obtain the mosapride-succinic acid eutectic crystal.

Preferably, the organic solvent a is selected from one or a combination of methanol, ethanol, isopropanol, and acetonitrile, and more preferably from one or a combination of methanol and acetonitrile.

Preferably, the volume fraction of 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 40-55 ℃, and further preferably 45-50 ℃.

Preferably, the mass-to-volume ratio of the mosapride to the mixed solvent is 15-24: 1, wherein the mass is mg and the volume is mL.

Preferably, the temperature of the temperature-controlled crystallization is 16-26 ℃.

Preferably, the crystallization time is 24 to 72 hours, and more preferably 24 to 48 hours.

Preferably, the drying temperature is 35-55 ℃, and the drying time is 26-50 hours.

The following contents further detail the preparation method of the mosapride-succinic acid eutectic crystal of the invention:

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 a compound, continuously ultrasonically heating for 10-25 min, filtering after the reaction is finished, standing filtrate, controlling the temperature to 16-26 ℃ for crystallization, filtering, leaching a filter cake with acetone, and vacuum drying at 40-50 ℃ to obtain the mosapride-succinic acid eutectic crystal.

In a third aspect of the invention, a pharmaceutical composition containing the mosapride-succinic acid eutectic crystal is provided.

The preparation method of the pharmaceutical composition of the invention can be as follows: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques to prepare useful dosage forms.

In a fourth aspect of the invention, the invention provides an application of mosapride-succinic acid eutectic crystal as an active ingredient in preparing a medicament for treating functional dyspepsia and gastropathy.

Confirmation of crystal structure:

the mosapride-succinic acid eutectic 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 chemistry XtaLAB Synergy X-ray single crystal diffractometer measures the temperature 293(2) K, uses CuKa radiation, collects data in an omega scanning mode and carries out Lp correction. 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 crystallographic data obtained by testing and analyzing the mosapride-succinic acid eutectic crystal prepared by the invention are shown in table 1, and the crystallographic parameters are as follows: triclinic system, space group is P-1; unit cell parameters:

The ORTEP chart 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 fig. 3.

TABLE 1 Main crystallographic data of Mosapride-succinic acid cocrystal

The X-ray powder diffraction test instrument and the test conditions involved in the invention are as follows: x-ray powder diffractometer: PANalytical em copy; Cu-K alpha; a sample stage: a flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40 mA; divergent slit: 1/4, respectively; anti-scattering slit: 1; rope pulling of a slit: 0.04 rad; step length: 0.5 s; scanning range: 3 to 50 degrees.

According to the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are detailed in FIG. 1 and Table 2.

TABLE 2 PXRD peaks of mosapride-succinic acid cocrystal

The TGA/DSC thermal analysis tester and the test conditions in the invention are as follows: TGA/DSC thermogram: METTLER TOLEDO TGA/DSC3 +; dynamic temperature section: 30-300 ℃; heating rate: 10 ℃/min; segment gas N₂(ii) a Gas flow rate: 50 mL/min; crucible: an aluminum crucible of 40. mu.l.

The TGA/DSC test result of the mosapride-succinic acid eutectic crystal prepared by the method is shown in figure 4, and a DSC test spectrogram shows that the eutectic crystal has an endothermic peak, the temperature range is 164.50-176.74 ℃, and the peak value is 168.71 ℃.

Compared with the currently reported mosapride crystal form, the mosapride-succinic acid eutectic crystal prepared by the method has the following advantages:

(1) the solubility of the mosapride-succinic acid eutectic crystal prepared by the invention in hydrochloric acid with the pH value of 1.0 is 5.79mg/mL, which is higher than the solubility of the existing crystal form of mosapride.

(2) The mosapride-succinic acid eutectic crystal prepared by the invention has good stability, the purity of the mosapride-succinic acid eutectic crystal is not greatly changed after a hydrolysis test in a hot solution, and the generated hydrolysis impurity A has less quantity.

Drawings

FIG. 1: an X-ray powder diffraction pattern of the mosapride-succinic acid eutectic crystal;

FIG. 2: ORTEP diagram of mosapride-succinic acid co-crystal;

FIG. 3: hydrogen bond diagram of mosapride-succinic acid eutectic;

FIG. 4: DSC/TGA diagram of the moxapride-succinic acid eutectic.

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.

Example 1

Dissolving 211mg of mosapride and 124.0mg of succinic acid in 12.0mL of mixed solvent (10.0mL of acetone and 2.0mL of methanol), ultrasonically heating to 50 ℃, continuously ultrasonically treating for 15min after dissolving, filtering, standing at 16-20 ℃ for crystallization for 36 hours, filtering, and drying at 45 ℃ for 40 hours to obtain 305.4mg of mosapride-succinic acid eutectic crystal. The yield was 92.82%, and the purity was 99.95%.

Example 2

Dissolving 211mg of mosapride and 121.0mg of succinic acid in 10.0mL of acetone, ultrasonically heating to 45 ℃, continuously ultrasonically heating for 20min after dissolving, filtering, standing at 20-26 ℃ for crystallization for 48 hours, filtering, and drying at 55 ℃ for 30 hours to obtain 301.9mg of mosapride-succinic acid eutectic crystal. The yield was 91.76%, and the purity was 99.93%.

Example 3

Dissolving the mosapride 211mg and the succinic acid 132.9mg in 14.0mL of mixed solvent (10.0mL of acetone and 4.0mL of acetonitrile), ultrasonically heating to 50 ℃, continuously ultrasonically treating for 25min after dissolving, filtering, standing at 16-20 ℃ for crystallization for 24 hours, filtering, and drying at 45 ℃ for 45 hours to obtain 300.6mg of mosapride-succinic acid eutectic crystal. The yield was 91.35%, and the purity was 99.94%.

Example 4

Dissolving the mosapride 211mg and the succinic acid 118.1mg in 9.0mL of mixed solvent (5.0mL of acetone and 4.0mL of ethanol), ultrasonically heating to 40 ℃, continuously ultrasonically heating for 10min after dissolving, filtering, standing at 20-26 ℃ for crystallization for 72 hours, filtering, and drying at 55 ℃ for 35 hours to obtain 295.6mg of mosapride-succinic acid eutectic crystal. The yield was 89.85%, and the purity was 99.86%.

Example 5

Dissolving the mosapride 211mg and the succinic acid 177.1mg in 16.0mL of mixed solvent (8.0mL of acetone and 8.0mL of isopropanol), ultrasonically heating to 50 ℃, continuously ultrasonically treating for 30min after dissolving, filtering, standing at 16-20 ℃ for crystallization for 72 hours, filtering, and drying at 60 ℃ for 60 hours to obtain 290.1mg of mosapride-succinic acid eutectic crystal. The yield was 88.16%, and the purity was 99.82%.

Example 6

Dissolving 211mg of mosapride and 115.1mg of succinic acid in 8.0mL of mixed solvent (4.0mL of acetone and 4.0mL of tetrahydrofuran), ultrasonically heating to 35 ℃, continuously ultrasonically heating for 30min after dissolving, filtering, standing at 10-15 ℃ for crystallization for 75 hours, filtering, and drying at 55 ℃ for 48 hours to obtain 277.5mg of mosapride-succinic acid eutectic crystal. The yield was 84.35%, and the purity was 99.41%.

Example 7

Dissolving 211mg of mosapride and 183.0mg of succinic acid in 17.0mL of mixed solvent (9.0mL of acetone and 6.0mL of n-butanol), ultrasonically heating to 60 ℃, continuously ultrasonically treating for 15min after dissolving, filtering, standing at 26-30 ℃ for crystallization for 50 hours, filtering, and drying at 30 ℃ for 75 hours to obtain 276.7mg of mosapride-succinic acid eutectic crystal. The yield was 84.10%, and the purity was 99.28%.

1. Solubility test

According to the method of pharmacopoeia, the dosage is reduced in the same proportion for saving materials. The mosapride-succinic acid eutectic preparation prepared in examples 1-7 and the mosapride dihydrate citrate prepared by the method disclosed in WO2011107903a1 were sequentially put into a test tube with a plug containing a hydrochloric acid solution of ph1.0, a sample was put into a water bath constant temperature oscillator, equilibrated at 37 ℃ and 200r/min for 24 hours, sampled, filtered through a 0.45 μm microporous membrane, and the filtrate was taken out, diluted with water to a linear range, and the absorbance was measured at a wavelength of 274nm using an aqueous solution as a blank solution until the absorbance no longer changed. The test results are shown in Table 3.

TABLE 3 solubility of mosapride-succinic acid cocrystal

The solubility of the mosapride-succinic acid eutectic sample prepared in the embodiment of the invention is far higher than that of mosapride dihydrate citrate.

2. Stability test of mosapride-succinic acid eutectic in hot solution

Respectively taking a proper amount of mosapride-succinic acid eutectic and mosapride citrate dihydrate (about 10mg of mosapride citrate), adding 10mL of water for dispersion, shaking, placing in a water bath at 75 ℃ for 10 hours, adding methanol for dilution to 10mL, shaking for 30 minutes, centrifuging, taking the supernatant as a test solution, and performing a HPLC (high performance liquid chromatography) method for purity detection by referring to a method in appendix VD in the second part of the pharmacopoeia 2015 edition. The results are shown in Table 4.

TABLE 4 solution thermal stability test results

Remarking: indicates no detection

And (4) conclusion: the mosapride-succinic acid eutectic is dissolved in the solution, the purity is slightly reduced to 99.54 percent after 10-hour thermal stability test, and the hydrolysis impurity A is 0.22 percent; the mosapride citrate dihydrate is dissolved in the solution, the purity is reduced to 95.70 percent after 10-hour thermal stability test, and the hydrolysis impurity A is obviously increased to 2.17 percent.

Claims

1. The mosapride-succinic acid eutectic crystal is characterized in that an X-ray diffraction spectrum expressed by 2 theta by using Cu-Kalpha radiation has characteristic peaks at 5.93 +/-0.2 degrees, 8.13 +/-0.2 degrees, 9.53 +/-0.2 degrees, 17.73 +/-0.2 degrees and 23.70 +/-0.2 degrees.

2. The mosapride-succinic acid co-crystal of claim 1, wherein the X-ray diffraction spectrum, expressed in terms of 2 Θ, using Cu-ka radiation has characteristic peaks 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 °.

3. The mosapride-succinic acid co-crystal of claim 1, wherein an X-ray diffraction spectrum expressed in terms of 2 Θ using Cu-ka radiation has characteristic peaks 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 °.

4. The mosapride-succinic acid co-crystal of claim 1, wherein the characteristic peak of the X-ray diffraction spectrum expressed in terms of 2 Θ using Cu-K α radiation corresponds to the X-ray powder diffraction pattern shown in fig. 1.

5. The mosapride-succinic acid co-crystal according to any one of claims 1 to 4, wherein the crystallographic parameters are: triclinic system, space group is P-1; the unit cell parameters are:

6. A method for preparing the mosapride-succinic acid eutectic crystal according to claim 1, which comprises the following specific preparation steps: dissolving mosapride and succinic acid in a mixed solvent of acetone and an organic solvent A, ultrasonically heating for dissolving, filtering after the reaction is finished, standing the filtrate for crystallization at a controlled temperature, filtering and drying to obtain the mosapride-succinic acid eutectic.

7. The method according to claim 6, wherein the organic solvent A is selected from methanol, ethanol, isopropanol, acetonitrile or a combination thereof, preferably from methanol and acetonitrile or a combination thereof.

8. The method according to claim 6, wherein the molar ratio of mosapride to succinic acid is 1:2.0 to 3.0, preferably 1:2.05 to 2.25.

9. A pharmaceutical composition, which comprises the mosapride-succinic acid eutectic crystal as claimed in any one of claims 1 to 4, and pharmaceutically acceptable other auxiliary material components.

10. Use of the mosapride-succinic acid co-crystal as claimed in any one of claims 1 to 4 as an active ingredient for the preparation of a medicament for the treatment of functional dyspepsia and gastric disorders.