阅读说明：本技术 普罗布考单琥珀酸酯的多晶型 (Polymorphic forms of probucol monosuccinate ) 是由 王冠茹 李亚平 王瑶 顾王文 于 2019-01-14 设计创作，主要内容包括：本发明涉及普罗布考单琥珀酸酯的新型固体存在形态。更具体而言,本发明涉及普罗布考单琥珀酸酯的晶型I、晶型II、晶型III、晶型IV、无定形状态,其制备方法、形成条件及含有这些固体存在形态的组合物。多晶型现象直接影响药物的制剂加工性能,并且会影响药物的稳定性、溶解度和生物利用度,进而影响到药物的质量、安全性、有效性及其应用。因此,在药品研发中,应全面考虑药品的多晶型问题。因此,对药物晶型的控制与考察是非常必要的。(The present invention relates to a novel solid form of probucol monosuccinate. More particularly, the present invention relates to crystalline form I, crystalline form II, crystalline form III, crystalline form IV, amorphous state of probucol monosuccinate, methods of preparation thereof, conditions of formation thereof and compositions containing these solid forms. Polymorphism directly affects the formulation processability of a drug and can affect the stability, solubility and bioavailability of the drug, thereby affecting the quality, safety, effectiveness and application of the drug. Therefore, in drug development, the problem of polymorphism of drugs should be fully considered. Therefore, control and investigation of the drug crystal form are very necessary.)

1. Crystalline form I of probucol monosuccinate characterized by a powder X-ray diffraction pattern obtained by irradiation with radiation from Cu-K α, said pattern having characteristic peaks at 2 theta angles of 6.015 °, 8.997 °, 12.277 °, 13.474 °, 14.150 °, 14.994 °, 17.453 °, 18.010 °, 21.046 °, 21.737 °, 25.918 °, 27.122 °, 28.338 °, 30.197 °, 31.150 °, 33.308 °, 33.625 °, 34.045 °, 36.650 °, 37.266 °, wherein each peak has an error amplitude of ± 0.200 °.

2. Crystalline form I of probucol monosuccinate of claim 1, wherein: characterised by an infra-red spectrum showing 3639.88cm^-1，2963.39cm^-1，2681.54cm^-1，2587.65cm^-1，1763.97cm^-1，1723.71cm^-1，1570.04cm^-1，1482.97cm^-1，1425.03cm^-1，1359.76cm^-1，1345.57cm^-1，1309.88cm^-1，1255.75cm^-1，1232.79cm^-1，1185.32cm^-1，1150.60cm^-1，1132.67cm^-1，1103.11cm^-1，987.09cm^-1，929.10cm^-1，888.88cm^-1A positional absorption band, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

3. Crystalline form I of probucol monosuccinate of claim 1, wherein: characterized by Raman spectroscopy, which showed 3163.59cm^-1，2970.20cm^-1，2929.34cm^-1，1572.06cm^-1，1467.64cm^-1，1442.12cm^-1，1414.28cm^-1，1268.10cm^-1，1205.45cm^-1，1142.80cm^-1，927.02cm^-1，903.81cm^-1，880.61cm^-1，811.00cm^-1，726.86cm^-1，657.88cm^-1，550.45cm^-1Positional absorption peaks, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

4. A process for the preparation of crystalline form I of probucol monosuccinate according to any of claims 1 to 3, wherein said crystalline form I is selected from one of the following processes:

(1) and (4) volatilization and crystallization:

preparing probucol monosuccinate solid, adding a solvent, uniformly mixing, and dissolving; slowly volatilizing to dryness at 0-65 ℃, preferably 15-30 ℃ or 40-65 ℃, and collecting solids to obtain a crystal form I of the probucol monosuccinic acid ester; or

(2) Suspension crystallization:

taking the solid of the probucol monosuccinate, stirring and balancing the solid with a solvent for at least 24 hours at the temperature of 0-65 ℃, filtering the solution, and drying the solid part in the air for 10-30 min to obtain a crystal form I of the probucol monosuccinate; volatilizing the solvent in vacuum in the liquid part to separate out a solid to obtain a crystal form I of the probucol monosuccinate; or

(3) Anti-solvent crystallization:

taking a small glass bottle filled with a solvent with high solubility to the probucol monosuccinate, dissolving the solid of the probucol monosuccinate in the small glass bottle, taking a large glass bottle filled with an anti-solvent with high insolubility to the probucol monosuccinate, putting the small glass bottle into the large glass bottle in a mode of sleeving the large glass bottle with the small glass bottle, sealing the large glass bottle, standing at room temperature for more than 3 days, continuously volatilizing a poor solvent into the solution, precipitating out the precipitate, and obtaining the crystal form I of the probucol monosuccinate.

5. The method of claim 4, wherein:

in the method (1), the solvent is one or a mixture of two or more selected from methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, ethyl acetate, methyl tert-butyl ether, n-hexane, toluene, methyl isobutyl ketone, chloroform, dichloromethane, isopropyl acetate, petroleum ether, isoamyl alcohol, n-heptane, nitromethane and water; preferably one or a mixture of two or more selected from methyl ethyl ketone, nitromethane, trichloromethane, acetonitrile, methanol and n-heptane;

more preferably, when the volatilization temperature is 15-30 ℃, the solvent is a mixture of methyl ethyl ketone and nitromethane;

more preferably, when the volatilization temperature is 40-65 ℃, the solvent is selected from a mixture of trichloromethane and acetonitrile, and a mixture of methanol and n-heptane;

in the method (2), the solvent is one or a mixture of two or more of water, acetonitrile, n-hexane, n-heptane, petroleum ether, methanol, ethanol and isopropanol; preferably selected from acetonitrile, n-hexane, n-heptane, petroleum ether, mixed solvent of methanol and water, mixed solvent of ethanol and water, mixed solvent of isopropanol and water, and mixed solvent of acetonitrile and water;

more preferably, when the suspension temperature is 10-30 ℃, the solvent is one or two of acetonitrile and petroleum ether;

more preferably, when the suspension temperature is 40-65 ℃, the solvent is selected from one or more of acetonitrile, n-hexane, n-heptane and petroleum ether;

in the method (3), the combination of the solvent and the antisolvent is a combination of chloroform and n-hexane.

6. Crystalline form II of probucol monosuccinate characterized by a powder X-ray diffraction pattern obtained by irradiation with Cu-K α radiation having characteristic peaks at 2 θ angles of 4.996 °, 7.430 °, 9.896 °, 14.877 °, 16.938 °, 17.340 °, 19.001 °, 22.364 °, 24.921 °, 27.426 °, 35.048 °, 37.505 °, 37.725 °, wherein each peak has an error amplitude of ± 0.200 °.

7. Crystalline form II of probucol monosuccinate of claim 6, wherein: characterised by an infra-red spectrum showing 3638.06cm^-1，2966.72cm^-1，2873.77cm^-1，2674.28cm^-1，1755.00cm^-1，1712.44cm^-1，1569.90cm^-1，1482.18cm^-1，1425.05cm^-1，1364.44cm^-1，1312.57cm^-1，1290.82cm^-1，1261.66cm^-1，1235.70cm^-1，1189.56cm^-1，1158.49cm^-1，1103.26cm^-1，986.72cm^-1，954.50cm^-1，886.39cm^-1，770.71cm^-1，724.19cm^-1，642.73cm^-1，599.83cm^-1A positional absorption band, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

8. Crystalline form II of probucol monosuccinate of claim 6, wherein: characterized by Raman spectroscopy, which showed 3162.99cm^-1，2967.64cm^-1，2917.97cm^-1，1577.02cm^-1，1467.88cm^-1，1443.37cm^-1，1407.73cm^-1，1267.40cm^-1，1196.12cm^-1，1133.75cm^-1，935.51cm^-1，884.28cm^-1，839.73cm^-1，808.54cm^-1，723.90cm^-1，643.71cm^-1，561.29cm^-1，523.42cm^-1Positional absorption peaks, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

9. A process for the preparation of crystalline form II of probucol monosuccinate of any of claims 6 to 8, wherein said crystalline form II is selected from one of the following:

(1) cooling crystallization from hot concentrated solution

Taking the probucol monosuccinate solid, adding a solvent, uniformly mixing and dissolving; heating to 60 deg.C until completely dissolved; then putting the crystal into a refrigerator at 4 ℃ to precipitate crystals, and filtering to obtain a crystal form II of the probucol monosuccinate; or

(2) Volatile crystal

And adding a solvent into the crystalline form I solid of the probucol monosuccinate, uniformly mixing, volatilizing at the temperature of 15-30 ℃, and collecting the solid to obtain the crystalline form II of the probucol monosuccinate.

10. The method of claim 9, wherein:

in the method (1), the solvent is acetonitrile;

in the method (2), the solvent is methanol.

11. Crystalline form III of probucol monosuccinate characterized by a powder X-ray diffraction pattern obtained by irradiation with Cu-K α radiation having characteristic peaks at 2 θ angles of 8.249 °, 9.796 °, 11.019 °, 12.757 °, 14.326 °, 14.685 °, 15.984 °, 16.501 °, 16.981 °, 17.916 °, 18.414 °, 18.623 °, 19.177 °, 19.615 °, 20.718 °, 22.194 °, 23.835 °, 24.868 °, 28.459 °, 28.785 °, 34.664 °, wherein each peak has an error amplitude of ± 0.200 °.

12. Crystalline form III of probucol monosuccinate of claim 11, wherein: characterised by an infra-red spectrum showing 3620.12cm^-1，2962.28cm^-1，2687.64cm^-1，1753.47cm^-1，1723.43cm^-1，1572.47cm^-1，1483.15cm^-1，1469.51cm^-1，1425.25cm^-1，1366.88cm^-1，1310.96cm^-1，1262.35cm^-1，1233.87cm^-1，1189.14cm^-1，1156.59cm^-1，1100.92cm^-1，1062.13cm^-1，1025.69cm^-1，986.77cm^-1，928.96cm^-1，886.62cm^-1，844.70cm^-1，810.65，771.65cm^-1，725.69cm^-1，642.07cm^-1，619.21cm^-1，598.80cm^-1A positional absorption band, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

13. Crystalline form III of probucol monosuccinate of claim 11, wherein: characterized by Raman spectroscopy, which showed 3163.94cm^-1，2964.87cm^-1，2920.30cm^-1，1572.12cm^-1，1458.47cm^-1，1409.44cm^-1，1277.97cm^-1，1199.97cm^-1，1135.35cm^-1，930.34cm^-1，881.31cm^-1，838.97cm^-1，810.00cm^-1，726.28cm^-1，640.64cm^-1，549.28cm^-1，529.22cm^-1Positional absorption peaks, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

14. A process for the preparation of crystalline form III of probucol monosuccinate of any of claims 11 to 13, wherein said crystalline form III is selected from one of the following:

(1) and (4) volatilization and crystallization:

preparing probucol monosuccinate solid, adding a solvent, uniformly mixing, and dissolving; slowly volatilizing to dryness at 0-65 ℃, preferably 15-30 ℃ or 40-65 ℃, and collecting solids to obtain a crystal form III of the probucol monosuccinic acid ester; or

(2) Suspension crystallization:

taking the solid of the probucol monosuccinate, stirring and balancing the solid with a solvent for at least 24 hours at the temperature of 0-65 ℃, filtering the solution, and drying the solid part in the air for 10-30 min to obtain a crystal form III of the probucol monosuccinate; volatilizing the solvent in vacuum in the liquid part to separate out a solid to obtain a crystal form III of the probucol monosuccinate; or

(3) Anti-solvent crystallization:

taking a small glass bottle filled with a solvent with high solubility to the probucol monosuccinate, dissolving the solid of the probucol monosuccinate in the small glass bottle, taking a large glass bottle filled with an anti-solvent with high insolubility to the probucol monosuccinate, putting the small glass bottle into the large glass bottle in a mode of sleeving the large glass bottle with the small glass bottle, sealing the large glass bottle, standing at room temperature for more than 3 days, continuously volatilizing a poor solvent into the solution, precipitating out the precipitate, and obtaining the crystal form III of the probucol monosuccinate.

15. The method of claim 14, wherein:

in the method (1), the solvent is one or a mixture of two or more selected from methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, ethyl acetate, methyl tert-butyl ether, n-hexane, toluene, methyl isobutyl ketone, chloroform, dichloromethane, isopropyl acetate, petroleum ether, isoamyl alcohol, n-heptane, nitromethane and water; preferably one or a mixture of two or more selected from methanol, ethanol, n-hexane, n-heptane, nitromethane, petroleum ether, acetone, dichloromethane, methyl tert-butyl ether and methyl ethyl ketone;

more preferably, when the volatilization temperature is 15-30 ℃, the solvent is selected from a mixture of methanol and n-heptane, a mixture of ethanol and nitromethane, a mixture of methanol and petroleum ether, a mixture of acetone and nitromethane, a mixture of acetone and n-heptane, a mixture of dichloromethane and n-heptane, a mixture of methyl tert-butyl ether and nitromethane, and a mixture of methyl tert-butyl ether and n-heptane;

more preferably, when the volatilization temperature is 40-65 ℃, the solvent is a mixture of methyl ethyl ketone and n-hexane;

in the method (2), the solvent is one or a mixture of two or more of water, acetonitrile, acetone, n-hexane, n-heptane, petroleum ether, methanol, ethanol and isopropanol;

preferably, the suspension temperature is 10-30 ℃, and the solvent is selected from a mixture of isopropanol and water and a mixture of acetone and water;

in the method (3), the combination of the solvent and the antisolvent is a combination of methyl t-butyl ether and n-hexane.

16. Crystalline form IV of probucol monosuccinate characterized by a powder X-ray diffraction pattern obtained by irradiation with radiation from Cu-K α, said pattern having characteristic peaks at 2 theta angles of 4.893 °, 9.031 °, 9.775 °, 10.540 °, 12.851 °, 13.312 °, 14.384 °, 14.671 °, 16.024 °, 16.196 °, 17.114 °, 17.457 °, 18.086 °, 18.626 °, 19.599 °, 21.293 °, 24.518 °, wherein each peak has an error amplitude of ± 0.200 °.

17. Crystalline form IV of probucol monosuccinate of claim 16, wherein: characterised by an infra-red spectrum showing 3619.64cm^-1，2963.32cm^-1，1754.42cm^-1，1723.24cm^-1，1573.32cm^-1，1423.66cm^-1，1367.29cm^-1，1309.85cm^-1，1261.39cm^-1，1233.73cm^-1，1190.18cm^-1，1155.68cm^-1，984.74cm^-1，927.07cm^-1，884.34cm^-1，843.37cm^-1，807.81cm^-1，771.51cm^-1，724.37cm^-1，639.67cm^-1，596.86cm^-1A positional absorption band, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

18. Crystalline form IV of probucol monosuccinate of claim 16, wherein: characterized by Raman spectroscopy, which showed 3164.08cm^-1，2965.68cm^-1，2926.25cm^-1，1574.17cm^-1，1450.32cm^-1，1279.70cm^-1，1201.87cm^-1，1136.16cm^-1，924.70cm^-1，885.25cm^-1，811.00cm^-1，725.94cm^-1，644.02cm^-1，549.29cm^-1Absorption peak at position.

19. A process for the preparation of crystalline form IV of probucol monosuccinate according to any of claims 16 to 18, characterized by being selected from one of the following processes:

(1) and (4) volatilization and crystallization:

preparing probucol monosuccinate solid, adding a solvent, uniformly mixing, and dissolving; slowly volatilizing to dryness at 0-65 ℃, preferably 15-30 ℃ or 40-65 ℃, and collecting solids to obtain a crystal form IV of the probucol monosuccinic acid ester; or

(2) Suspension crystallization:

taking the solid of the probucol monosuccinate, stirring and balancing the solid with a solvent at the temperature of 0-65 ℃ for at least 24 hours, then filtering the solution, and drying the solid part in the air for 10-30 min to obtain a crystal form IV of the probucol monosuccinate; volatilizing the solvent in vacuum in the liquid part to separate out a solid to obtain a crystal form IV of the probucol monosuccinate; or

(3) Anti-solvent crystallization:

taking a small glass bottle filled with a solvent with high solubility to the probucol monosuccinate, dissolving the solid of the probucol monosuccinate in the small glass bottle, taking a large glass bottle filled with an anti-solvent with high insolubility to the probucol monosuccinate, putting the small glass bottle into the large glass bottle in a mode of sleeving the large glass bottle with the small glass bottle, sealing the large glass bottle, standing at room temperature for more than 3 days, continuously volatilizing a poor solvent into the solution, precipitating out the precipitate, and obtaining the crystal form IV of the probucol monosuccinate.

20. The method of claim 19, wherein:

in the method (1), the solvent is selected from one, two or more than three of methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, ethyl acetate, methyl tert-butyl ether, n-hexane, toluene, methyl isobutyl ketone, chloroform, dichloromethane, isopropyl acetate, petroleum ether, isoamyl alcohol, n-heptane, nitromethane and water;

preferably, when the volatilization temperature is 15-30 ℃, the solvent is selected from methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, methyl isobutyl ketone, toluene, methyl tert-butyl ether, a mixture of methanol and acetonitrile, a mixture of methanol and nitromethane, a mixture of methanol and n-hexane, a mixture of methanol and petroleum ether, a mixture of dichloromethane, water and ethanol, a mixture of acetonitrile and ethanol, a mixture of ethanol and n-hexane, a mixture of ethanol and n-heptane, a mixture of ethanol and petroleum ether, a mixture of dichloromethane and acetonitrile, a mixture of isopropanol and nitromethane, a mixture of isopropanol and n-heptane, a mixture of isopropanol and n-hexane, a mixture of isopropanol and petroleum ether, a mixture of acetone and n-hexane, a mixture of acetone and petroleum ether, a mixture of methyl ethyl ketone and acetonitrile, A mixture of methyl ethyl ketone and water, a mixture of methyl ethyl ketone and n-hexane, a mixture of methyl ethyl ketone and n-heptane, a mixture of methyl ethyl ketone and petroleum ether, a mixture of dichloromethane and petroleum ether, a mixture of tetrahydrofuran and water, a mixture of tetrahydrofuran and petroleum ether, a mixture of trichloromethane and water and ethanol, a mixture of ethyl acetate and water, a mixture of ethyl acetate and acetonitrile, a mixture of ethyl acetate and n-heptane, a mixture of ethyl acetate and n-hexane, a mixture of ethyl acetate and petroleum ether, a mixture of trichloromethane and acetonitrile, a mixture of methyl tert-butyl ether and water, a mixture of methyl tert-butyl ether and acetonitrile, a mixture of methyl tert-butyl ether and n-hexane, a mixture of methyl tert-butyl ether and petroleum ether, a mixture of toluene and water, a mixture of toluene and acetonitrile, a mixture of toluene and nitromethane, a mixture of, A mixture of toluene and n-hexane, a mixture of toluene and n-heptane, a mixture of toluene and petroleum ether, a mixture of chloroform and n-hexane, a mixture of methyl isobutyl ketone and water and ethanol, a mixture of methyl isobutyl ketone and acetonitrile, a mixture of methyl isobutyl ketone and n-hexane, a mixture of methyl isobutyl ketone and n-heptane, a mixture of methyl isobutyl ketone and petroleum ether, a mixture of chloroform and n-heptane, a mixture of isopropyl acetate and water and ethanol, a mixture of isopropyl acetate and acetonitrile, a mixture of isopropyl acetate and n-hexane, a mixture of isopropyl acetate and n-heptane, a mixture of isopropyl acetate and petroleum ether, a mixture of chloroform and petroleum ether;

preferably, when the volatilization temperature is 40-65 ℃, the solvent is selected from methanol, a mixture of methanol and acetonitrile, a mixture of methanol and n-hexane, a mixture of methanol and petroleum ether, a mixture of dichloromethane and water and ethanol, a mixture of ethanol and acetonitrile, a mixture of ethanol and n-hexane, isopropanol, a mixture of isopropanol and acetonitrile, a mixture of isopropanol and n-hexane, a mixture of isopropanol and n-heptane, a mixture of isopropanol and petroleum ether, a mixture of isoprene and n-heptane, a mixture of dichloromethane and n-hexane, acetone, a mixture of acetone and acetonitrile, a mixture of acetone and n-hexane, a mixture of acetone and n-heptane, a mixture of acetone and petroleum ether, a mixture of dichloromethane and n-heptane, methyl ethyl ketone, a mixture of methyl ethyl ketone and acetonitrile, a mixture of methyl ethyl ketone and n-heptane, a mixture of methyl ethyl, A mixture of methyl ethyl ketone and petroleum ether, a mixture of dichloromethane and petroleum ether, a mixture of chloroform and water and ethanol, ethyl acetate, a mixture of ethyl acetate and water, a mixture of ethyl acetate and n-heptane, a mixture of ethyl acetate and petroleum ether, methyl tert-butyl ether, a mixture of methyl tert-butyl ether and acetonitrile, a mixture of methyl tert-butyl ether and nitromethane, a mixture of methyl tert-butyl ether and n-hexane, a mixture of methyl tert-butyl ether and n-heptane, a mixture of methyl tert-butyl ether and petroleum ether, a mixture of chloroform and n-hexane, toluene, a mixture of toluene and water, a mixture of toluene and acetonitrile, a mixture of toluene and n-hexane, a mixture of toluene and n-heptane, a mixture of toluene and petroleum ether, a mixture of chloroform and n-hexane, methyl isobutyl ketone, a mixture of methyl isobutyl ketone and water and ethanol, a mixture, A mixture of methyl isobutyl ketone and acetonitrile, a mixture of methyl isobutyl ketone and nitromethane, a mixture of methyl isobutyl ketone and n-hexane, a mixture of methyl isobutyl ketone and n-heptane, a mixture of methyl isobutyl ketone and petroleum ether, a mixture of trichloromethane and n-heptane, isopropyl acetate, a mixture of isopropyl acetate and water and ethanol, a mixture of isopropyl acetate and acetonitrile, a mixture of isopropyl acetate and n-hexane, a mixture of isopropyl acetate and n-heptane, a mixture of isopropyl acetate and petroleum ether, a mixture of trichloromethane and petroleum ether;

in the method (2), the solvent is one or a mixture of two or more of water, acetonitrile, n-hexane, n-heptane, petroleum ether, methanol, ethanol and isopropanol; preferably one or more of n-hexane, n-heptane, methanol, ethanol and water;

more preferably, when the suspension temperature is 10-30 ℃, the solvent is selected from n-hexane, n-heptane, a mixture of methanol and water, and a mixture of ethanol and water;

more preferably, when the suspension temperature is 40-65 ℃, the solvent is water;

in the method (3), the combination of the solvent and the antisolvent is selected from the group consisting of a combination of diethyl ether and petroleum ether, and a combination of methyl ethyl ketone and petroleum ether.

Technical Field

The present invention relates to a novel solid form of probucol monosuccinate. In particular to a crystal form I, a crystal form II, a crystal form III, a crystal form IV and an amorphous state of probucol monosuccinate, a preparation method and a forming condition thereof and a composition containing the solid existing forms.

Background

In addition to its antioxidant and cholesterol-lowering effects similar to that of probucol, it blocks the signaling of endothelial cells in blood vessels, and subsequently inhibits the production of unicellular chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (vascular cell adhesion molecule-1, VCAM-1) and other inflammatory factors, MCP-1, VCAM-1, etc. are compounds that significantly reduce the penetration of inflammatory cells to the surface of inflammatory cells, trigger chronic inflammatory responses, which are also one of the final processes responsible for atherosclerosis formation, and reduce the levels of cholesterol, as well as the cholesterol, and total cholesterol, compared to probucol-3, which are responsible for the reduction of the cholesterol-lowering effect of the pro-vascular endothelial cells, and total cholesterol-lowering effect of the pro-apo succinate L.

The known patent documents, 200480006265.7 applied by Atro Ginix corporation, 200610117784.1 applied by Guangzhou Yuantong medical science and technology Co., Ltd, 200910059730.8 applied by Sichuan university, Guangzhou Yuantong medical science and technology Co., Ltd, are the introduction of the preparation process of probucol monosuccinate or its analogues. The preparation of a white solid is described or obtained, and the specific solid form or solid mixture of the probucol monosuccinate is not explicitly disclosed.

Disclosure of Invention

The inventor finds that probucol monosuccinate

In a plurality of novel solid forms, specifically comprisingCrystalline form I, crystalline form II, crystalline form III, crystalline form IV, amorphous form of probucol monosuccinate and compositions containing these solid forms. And characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TG), Differential Scanning Calorimetry (DSC), hygroscopicity analysis (DVS), infrared spectroscopy (IR), Raman spectroscopy (Raman), and polarization photograph.

According to one aspect of the present invention, there is provided crystalline form I of probucol monosuccinate characterized by a powder X-ray diffraction Pattern (PXRD) obtained by irradiation with radiation from Cu-K α, having characteristic peaks at 2 θ angles of 6.015 °, 8.997 °, 12.277 °, 13.474 °, 14.150 °, 14.994 °, 17.453 °, 18.010 °, 21.046 °, 21.737 °, 25.918 °, 27.122 °, 28.338 °, 30.197 °, 31.150 °, 33.308 °, 33.625 °, 34.045 °, 36.650 °, 37.266 °, wherein each peak has an error amplitude of ± 0.200 °.

The crystalline form I of probucol monosuccinate was characterized by an infrared spectrum (IR) showing 3639.88cm^-1，2963.39cm^-1，2681.54cm^-1，2587.65cm^-1，1763.97cm^-1，1723.71cm^-1，1570.04cm^-1，1482.97cm^-1，1425.03cm^-1，1359.76cm^-1，1345.57cm^-1，1309.88cm^-1，1255.75cm^-1，1232.79cm^-1，1185.32cm^-1，1150.60cm^-1，1132.67cm^-1，1103.11cm^-1，987.09cm^-1，929.10cm^-1，888.88cm^-1A positional absorption band, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

The crystalline form I of probucol monosuccinate was characterized by Raman spectroscopy (Raman) which showed 3163.59cm^-1，2970.20cm^-1，2929.34cm^-1，1572.06cm^-1，1467.64cm^-1，1442.12cm^-1，1414.28cm^-1，1268.10cm^-1，1205.45cm^-1，1142.80cm^-1，927.02cm^-1，903.81cm^-1，880.61cm^-1，811.00cm^-1，726.86cm^-1，657.88cm^-1，550.45cm^-1Positional absorption peaks, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

The crystal form I of the probucol monosuccinate is white powder, and crystal transformation does not occur before melting. Further characterized by Differential Scanning Calorimetry (DSC) in which the form I exhibits an endotherm at 160.98 ℃, wherein the temperature has a margin of error of ± 1 ℃.

According to one aspect of the invention, the preparation method of the crystal form I of the probucol monosuccinate is selected from one of the following methods:

(1) and (4) volatilization and crystallization:

preparing probucol monosuccinate solid, adding a solvent, uniformly mixing, and dissolving; slowly volatilizing to dryness at 0-65 ℃, preferably 15-30 ℃ or 40-65 ℃, and collecting solids to obtain a crystal form I of the probucol monosuccinic acid ester; or

(2) Suspension crystallization:

taking the solid of the probucol monosuccinate, stirring and balancing the solid with a solvent for at least 24 hours at the temperature of 0-65 ℃, filtering the solution, and drying the solid part in the air for 10-30 min to obtain a crystal form I of the probucol monosuccinate; volatilizing the solvent in vacuum in the liquid part to separate out a solid to obtain a crystal form I of the probucol monosuccinate; or

(3) Anti-solvent crystallization:

taking a small glass bottle filled with a solvent with high solubility to the probucol monosuccinate, dissolving the solid of the probucol monosuccinate in the small glass bottle, taking a large glass bottle filled with an anti-solvent with high insolubility to the probucol monosuccinate, putting the small glass bottle into the large glass bottle in a mode of sleeving the large glass bottle with the small glass bottle, sealing the large glass bottle, standing at room temperature for more than 3 days, continuously volatilizing a poor solvent into the solution, precipitating out the precipitate, and obtaining the crystal form I of the probucol monosuccinate.

Wherein the content of the first and second substances,

in the method (1), the volatilization time of the slow volatilization is preferably over 24 h.

In the method (1), preferably, the solvent is selected from one or a mixture of two or more of methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, ethyl acetate, methyl tert-butyl ether, n-hexane, toluene, methyl isobutyl ketone, chloroform, dichloromethane, isopropyl acetate, petroleum ether, isoamyl alcohol, n-heptane, nitromethane and water; preferably one or a mixture of two or more selected from methyl ethyl ketone, nitromethane, trichloromethane, acetonitrile, methanol and n-heptane; when the solvent is a mixture of two or more solvents, the volume ratio of the solvents is not limited;

more preferably, when the volatilization temperature is 15-30 ℃, the solvent is a mixture of methyl ethyl ketone and nitromethane; preferably a mixture of methyl ethyl ketone and nitromethane in a volume ratio of 1: 1;

more preferably, when the volatilization temperature is 40-65 ℃, the solvent is selected from a mixture of trichloromethane and acetonitrile, and a mixture of methanol and n-heptane; more preferably, the solvent is selected from the group consisting of a 1:1 by volume mixture of chloroform and acetonitrile, and a 1:1 by volume mixture of methanol and n-heptane.

In the method (2), preferably, the solvent is one or a mixture of two or more selected from water, acetonitrile, n-hexane, n-heptane, petroleum ether, methanol, ethanol and isopropanol; preferably selected from acetonitrile, n-hexane, n-heptane, petroleum ether, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, a mixed solvent of isopropanol and water, and a mixed solvent of acetonitrile and water.

More preferably, when the suspension temperature is 10-30 ℃, the solvent is one or two of acetonitrile and petroleum ether;

more preferably, when the suspension temperature is 40-65 ℃, the solvent is one or more selected from acetonitrile, n-hexane, n-heptane and petroleum ether.

When the solvent is a mixture of two or more solvents, the volume ratio is not limited, but a mixture of 1:1 by volume may be selected.

In the method (3), preferably, the combination of the solvent and the antisolvent is a combination of chloroform and n-hexane.

According to one aspect of the present invention, there is provided crystalline form II of probucol monosuccinate characterized by a powder X-ray diffraction Pattern (PXRD) obtained by irradiation with radiation from Cu-K α, having characteristic peaks at 2 θ angles of 4.996 °, 7.430 °, 9.896 °, 14.877 °, 16.938 °, 17.340 °, 19.001 °, 22.364 °, 24.921 °, 27.426 °, 35.048 °, 37.505 °, 37.725 °, wherein each peak has an error amplitude of ± 0.200 °.

The crystalline form II of probucol monosuccinate was characterized by an infrared spectrum (IR) showing 3638.06cm^-1，2966.72cm^-1，2873.77cm^-1，2674.28cm^-1，1755.00cm^-1，1712.44cm^-1，1569.90cm^-1，1482.18cm^-1，1425.05cm^-1，1364.44cm^-1，1312.57cm^-1，1290.82cm^-1，1261.66cm^-1，1235.70cm^-1，1189.56cm^-1，1158.49cm^-1，1103.26cm^-1，986.72cm^-1，954.50cm^-1，886.39cm^-1，770.71cm^-1，724.19cm^-1，642.73cm^-1，599.83cm^-1A positional absorption band, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

The crystalline form II of probucol monosuccinate was characterized by Raman spectroscopy (Raman) which showed 3162.99cm^-1，2967.64cm^-1，2917.97cm^-1，1577.02cm^-1，1467.88cm^-1，1443.37cm^-1，1407.73cm^-1，1267.40cm^-1，1196.12cm^-1，1133.75cm^-1，935.51cm^-1，884.28cm^-1，839.73cm^-1，808.54cm^-1，723.90cm^-1，643.71cm^-1，561.29cm^-1，523.42cm^-1Positional absorption peaks, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

The crystal form II of the probucol monosuccinate is an anhydrous crystal form, and the form of the crystal form II is a white flaky crystal. Further characterized by Differential Scanning Calorimetry (DSC) in which the crystalline form II exhibits an endotherm at 137.66 ℃, wherein the temperature has a margin of error of ± 1 ℃.

The preparation method of the crystal form II of the probucol monosuccinate is selected from one of the following methods:

(1) cooling crystallization from hot concentrated solution

Taking the probucol monosuccinate solid, adding a solvent, uniformly mixing and dissolving; heating to 60 deg.C until completely dissolved; then putting the crystal into a refrigerator at 4 ℃ to precipitate crystals, and filtering to obtain a crystal form II of the probucol monosuccinate; or

(2) Volatile crystal

And adding a solvent into the crystalline form I solid of the probucol monosuccinate, uniformly mixing, dissolving, volatilizing at the temperature of 15-30 ℃, and collecting the solid to obtain the crystalline form II of the probucol monosuccinate.

Wherein the content of the first and second substances,

in the method (1), preferably, the solvent is acetonitrile;

in the method (2), preferably, the solvent is methanol.

According to one aspect of the present invention, there is provided crystalline form III of probucol monosuccinate characterized by a powder X-ray diffraction Pattern (PXRD) obtained by irradiation with radiation from Cu-K α, having characteristic peaks at 2 θ angles of 8.249 °, 9.796 °, 11.019 °, 12.757 °, 14.326 °, 14.685 °, 15.984 °, 16.501 °, 16.981 °, 17.916 °, 18.414 °, 18.623 °, 19.177 °, 19.615 °, 20.718 °, 22.194 °, 23.835 °, 24.868 °, 28.459 °, 28.785 °, 34.664 °, wherein each peak has an error amplitude of ± 0.200 °.

The crystalline form III of probucol monosuccinate was characterized by an Infrared (IR) spectrum showing 3620.12cm^-1，2962.28cm^-1，2687.64cm^-1，1753.47cm^-1，1723.43cm^-1，1572.47cm^-1，1483.15cm^-1，1469.51cm^-1，1425.25cm^-1，1366.88cm^-1，1310.96cm^-1，1262.35cm^-1，1233.87cm^-1，1189.14cm^-1，1156.59cm^-1，1100.92cm^-1，1062.13cm^-1，1025.69cm^-1，986.77cm^-1，928.96cm^-1，886.62cm^-1，844.70cm^-1，810.65，771.65cm^-1，725.69cm^-1，642.07cm^-1，619.21cm^-1，598.80cm^-1A positional absorption band, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

The crystalline form III of probucol monosuccinate was characterized by Raman spectroscopy (Raman) which showed 3163.94cm^-1，2964.87cm^-1，2920.30cm^-1，1572.12cm^-1，1458.47cm^-1，1409.44cm^-1，1277.97cm^-1，1199.97cm^-1，1135.35cm^-1，930.34cm^-1，881.31cm^-1，838.97cm^-1，810.00cm^-1，726.28cm^-1，640.64cm^-1，549.28cm^-1，529.22cm^-1Positional absorption peaks, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

The crystal form III of the probucol monosuccinate is an anhydrous crystal form, and the form of the crystal form III is white crystalline powder. Further characterized by Differential Scanning Calorimetry (DSC) in which the form III exhibits an endotherm at 146.59 ℃, wherein the temperature has a margin of error of ± 1 ℃.

According to one aspect of the invention, the preparation method of the crystal form III of the probucol monosuccinate is selected from one of the following methods:

(1) and (4) volatilization and crystallization:

preparing probucol monosuccinate solid, adding a solvent, uniformly mixing, and dissolving; slowly volatilizing to dryness at 0-65 ℃, preferably 15-30 ℃ or 40-65 ℃, and collecting solids to obtain a crystal form III of the probucol monosuccinic acid ester; or

(2) Suspension crystallization:

taking the solid of the probucol monosuccinate, stirring and balancing the solid with a solvent for at least 24 hours at the temperature of 0-65 ℃, filtering the solution, and drying the solid part in the air for 10-30 min to obtain a crystal form III of the probucol monosuccinate; volatilizing the solvent in vacuum in the liquid part to separate out a solid to obtain a crystal form III of the probucol monosuccinate; or

(3) Anti-solvent crystallization:

taking a small glass bottle filled with a solvent with high solubility to the probucol monosuccinate, dissolving the solid of the probucol monosuccinate in the small glass bottle, taking a large glass bottle filled with an anti-solvent with high insolubility to the probucol monosuccinate, putting the small glass bottle into the large glass bottle in a mode of sleeving the large glass bottle with the small glass bottle, sealing the large glass bottle, standing at room temperature for more than 3 days, continuously volatilizing a poor solvent into the solution, precipitating out the precipitate, and obtaining the crystal form III of the probucol monosuccinate.

Wherein the content of the first and second substances,

in the method (1), the volatilization time of the slow volatilization is preferably over 24 h.

In the method (1), preferably, the solvent is selected from one or a mixture of two or more of methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, ethyl acetate, methyl tert-butyl ether, n-hexane, toluene, methyl isobutyl ketone, chloroform, dichloromethane, isopropyl acetate, petroleum ether, isoamyl alcohol, n-heptane, nitromethane and water; preferably one or a mixture of two or more selected from methanol, ethanol, n-hexane, n-heptane, nitromethane, petroleum ether, acetone, dichloromethane, methyl tert-butyl ether and methyl ethyl ketone; when the solvent is a mixture of two or more solvents, the volume ratio of the solvents is not limited; for example, when the solvent is a mixture of two solvents, the volume ratio thereof may be 2:1, 1: 1; when the solvent is a mixture of three solvents, the volume ratio thereof may be 1:1:1, 2:2:1, etc.

More preferably, when the volatilization temperature is 15-30 ℃, the solvent is selected from a mixture of methanol and n-heptane, a mixture of ethanol and nitromethane, a mixture of methanol and petroleum ether, a mixture of acetone and nitromethane, a mixture of acetone and n-heptane, a mixture of dichloromethane and n-heptane, a mixture of methyl tert-butyl ether and nitromethane, and a mixture of methyl tert-butyl ether and n-heptane; the above mixture in a volume ratio of 1:1 is preferred;

more preferably, when the volatilization temperature is 40-65 ℃, the solvent is a mixture of methyl ethyl ketone and n-hexane; the above mixture in a volume ratio of 1:1 is preferred;

in the method (2), preferably, the solvent is one or a mixture of two or more selected from water, acetonitrile, acetone, n-hexane, n-heptane, petroleum ether, methanol, ethanol and isopropanol;

more preferably, the suspension temperature is 10-30 ℃, for example, at 25 ℃, the solvent is selected from a mixture of isopropanol and water, and a mixture of acetone and water; the above mixture in a volume ratio of 1:1 is preferred;

in the method (3), preferably, the combination of the solvent and the antisolvent is a combination of methyl tert-butyl ether and n-hexane.

According to one aspect of the present invention, there is provided crystalline form IV of probucol monosuccinate characterized by a powder X-ray diffraction Pattern (PXRD) obtained by irradiation with radiation from Cu-K α, having characteristic peaks at 2 θ angles of 4.893 °, 9.031 °, 9.775 °, 10.540 °, 12.851 °, 13.312 °, 14.384 °, 14.671 °, 16.024 °, 16.196 °, 17.114 °, 17.457 °, 18.086 °, 18.626 °, 19.599 °, 21.293 °, 24.518 °, wherein each peak has an error amplitude of ± 0.200 °.

The crystalline form IV of probucol monosuccinate was characterized by an infrared spectrum (IR) showing 3619.64cm^-1，2963.32cm^-1，1754.42cm^-1，1723.24cm^-1，1573.32cm^-1，1423.66cm^-1，1367.29cm^-1，1309.85cm^-1，1261.39cm^-1，1233.73cm^-1，1190.18cm^-1，1155.68cm^-1，984.74cm^-1，927.07cm^-1，884.34cm^-1，843.37cm^-1，807.81cm^-1，771.51cm^-1，724.37cm^-1，639.67cm^-1，596.86cm^-1A positional absorption band, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

The crystalline form IV of probucol monosuccinate was characterized by Raman spectroscopy (Raman) which showed 3164.08cm^-1，2965.68cm^-1，2926.25cm^-1，1574.17cm^-1，1450.32cm^-1，1279.70cm^-1，1201.87cm^-1，1136.16cm^-1，924.70cm^-1，885.25cm^-1，811.00cm^-1，725.94cm^-1，644.02cm^-1，549.29cm^-1Absorption peak at position.

The crystal form IV of the probucol monosuccinate is an anhydrous crystal form, and the form of the crystal form IV is a white needle crystal. Further characterized by Differential Scanning Calorimetry (DSC) in which the form IV exhibits an endotherm at 131.52 ℃, wherein the temperature has a margin of error of ± 1 ℃.

According to one aspect of the invention, the preparation method of the crystal form IV of the probucol monosuccinate is selected from one of the following methods:

(1) and (4) volatilization and crystallization:

preparing probucol monosuccinate solid, adding a solvent, uniformly mixing, and dissolving; slowly volatilizing to dryness at 0-65 ℃, preferably 15-30 ℃ or 40-65 ℃, and collecting solids to obtain a crystal form IV of the probucol monosuccinic acid ester; or

(2) Suspension crystallization:

taking the solid of the probucol monosuccinate, stirring and balancing the solid with a solvent at the temperature of 0-65 ℃ for at least 24 hours, then filtering the solution, and drying the solid part in the air for 10-30 min to obtain a crystal form IV of the probucol monosuccinate; volatilizing the solvent in vacuum in the liquid part to separate out a solid to obtain a crystal form IV of the probucol monosuccinate; or

(3) Anti-solvent crystallization:

taking a small glass bottle filled with a solvent with high solubility to the probucol monosuccinate, dissolving the solid of the probucol monosuccinate in the small glass bottle, taking a large glass bottle filled with an anti-solvent with high insolubility to the probucol monosuccinate, putting the small glass bottle into the large glass bottle in a mode of sleeving the large glass bottle with the small glass bottle, sealing the large glass bottle, standing at room temperature for more than 3 days, continuously volatilizing a poor solvent into the solution, precipitating out the precipitate, and obtaining the crystal form IV of the probucol monosuccinate.

Wherein the content of the first and second substances,

in the method (1), the volatilization time of the slow volatilization is preferably over 24 h.

In the method (1), preferably, the solvent is selected from one, two or more than three of methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, ethyl acetate, methyl tert-butyl ether, n-hexane, toluene, methyl isobutyl ketone, chloroform, dichloromethane, isopropyl acetate, petroleum ether, isoamyl alcohol, n-heptane, nitromethane and water;

preferably, when the volatilization temperature is 15-30 ℃, the solvent is selected from methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, methyl isobutyl ketone, toluene, methyl tert-butyl ether, a mixture of methanol and acetonitrile, a mixture of methanol and nitromethane, a mixture of methanol and n-hexane, a mixture of methanol and petroleum ether, a mixture of dichloromethane, water and ethanol, a mixture of acetonitrile and ethanol, a mixture of ethanol and n-hexane, a mixture of ethanol and n-heptane, a mixture of ethanol and petroleum ether, a mixture of dichloromethane and acetonitrile, a mixture of isopropanol and nitromethane, a mixture of isopropanol and n-heptane, a mixture of isopropanol and n-hexane, a mixture of isopropanol and petroleum ether, a mixture of acetone and n-hexane, a mixture of acetone and petroleum ether, a mixture of methyl ethyl ketone and acetonitrile, A mixture of methyl ethyl ketone and water, a mixture of methyl ethyl ketone and n-hexane, a mixture of methyl ethyl ketone and n-heptane, a mixture of methyl ethyl ketone and petroleum ether, a mixture of dichloromethane and petroleum ether, a mixture of tetrahydrofuran and water, a mixture of tetrahydrofuran and petroleum ether, a mixture of trichloromethane and water and ethanol, a mixture of ethyl acetate and water, a mixture of ethyl acetate and acetonitrile, a mixture of ethyl acetate and n-heptane, a mixture of ethyl acetate and n-hexane, a mixture of ethyl acetate and petroleum ether, a mixture of trichloromethane and acetonitrile, a mixture of methyl tert-butyl ether and water, a mixture of methyl tert-butyl ether and acetonitrile, a mixture of methyl tert-butyl ether and n-hexane, a mixture of methyl tert-butyl ether and petroleum ether, a mixture of toluene and water, a mixture of toluene and acetonitrile, a mixture of toluene and nitromethane, a mixture of, The solvent is selected from the group consisting of toluene and n-hexane mixture, toluene and n-heptane mixture, toluene and petroleum ether mixture, chloroform and n-hexane mixture, methyl isobutyl ketone and water and ethanol mixture, methyl isobutyl ketone and acetonitrile mixture, methyl isobutyl ketone and n-hexane mixture, methyl isobutyl ketone and n-heptane mixture, methyl isobutyl ketone and petroleum ether mixture, chloroform and n-heptane mixture, isopropyl acetate and water and ethanol mixture, isopropyl acetate and acetonitrile mixture, isopropyl acetate and n-hexane mixture, isopropyl acetate and n-heptane mixture, isopropyl acetate and petroleum ether mixture, and chloroform and petroleum ether mixture.

Preferably, when the volatilization temperature is 40-65 ℃, the solvent is selected from methanol, a mixture of methanol and acetonitrile, a mixture of methanol and n-hexane, a mixture of methanol and petroleum ether, a mixture of dichloromethane and water and ethanol, a mixture of ethanol and acetonitrile, a mixture of ethanol and n-hexane, isopropanol, a mixture of isopropanol and acetonitrile, a mixture of isopropanol and n-hexane, a mixture of isopropanol and n-heptane, a mixture of isopropanol and petroleum ether, a mixture of isoprene and n-heptane, a mixture of dichloromethane and n-hexane, acetone, a mixture of acetone and acetonitrile, a mixture of acetone and n-hexane, a mixture of acetone and n-heptane, a mixture of acetone and petroleum ether, a mixture of dichloromethane and n-heptane, methyl ethyl ketone, a mixture of methyl ethyl ketone and acetonitrile, a mixture of methyl ethyl ketone and n-heptane, a mixture of methyl ethyl, A mixture of methyl ethyl ketone and petroleum ether, a mixture of dichloromethane and petroleum ether, a mixture of chloroform and water and ethanol, ethyl acetate, a mixture of ethyl acetate and water, a mixture of ethyl acetate and n-heptane, a mixture of ethyl acetate and petroleum ether, methyl tert-butyl ether, a mixture of methyl tert-butyl ether and acetonitrile, a mixture of methyl tert-butyl ether and nitromethane, a mixture of methyl tert-butyl ether and n-hexane, a mixture of methyl tert-butyl ether and n-heptane, a mixture of methyl tert-butyl ether and petroleum ether, a mixture of chloroform and n-hexane, toluene, a mixture of toluene and water, a mixture of toluene and acetonitrile, a mixture of toluene and n-hexane, a mixture of toluene and n-heptane, a mixture of toluene and petroleum ether, a mixture of chloroform and n-hexane, methyl isobutyl ketone, a mixture of methyl isobutyl ketone and water and ethanol, a mixture, A mixture of methyl isobutyl ketone and acetonitrile, a mixture of methyl isobutyl ketone and nitromethane, a mixture of methyl isobutyl ketone and n-hexane, a mixture of methyl isobutyl ketone and n-heptane, a mixture of methyl isobutyl ketone and petroleum ether, a mixture of trichloromethane and n-heptane, isopropyl acetate, a mixture of isopropyl acetate and water and ethanol, a mixture of isopropyl acetate and acetonitrile, a mixture of isopropyl acetate and n-hexane, a mixture of isopropyl acetate and n-heptane, a mixture of isopropyl acetate and petroleum ether, a mixture of trichloromethane and petroleum ether.

When the solvent is a mixture of two or more solvents, the volume ratio of the solvents is not limited; for example, when the solvent is a mixture of two solvents, the volume ratio thereof may be 2:1, 1: 1; when the solvent is a mixture of three solvents, the volume ratio thereof may be 1:1:1, 2:2:1, etc.

In the method (2), preferably, the solvent is one or a mixture of two or more selected from water, acetonitrile, n-hexane, n-heptane, petroleum ether, methanol, ethanol and isopropanol; more preferably one or a mixture of two or more of n-hexane, n-heptane, methanol, ethanol, and water.

More preferably, when the suspension temperature is 10-30 ℃, the solvent is selected from n-hexane, n-heptane, a mixture of methanol and water, and a mixture of ethanol and water;

more preferably, when the suspension temperature is 40-65 ℃, the solvent is water.

When the solvent is a mixture of two or more solvents, the volume ratio of the solvents is not limited; for example, when the solvent is a mixture of two solvents, the volume ratio thereof may be 2:1, 1: 1; when the solvent is a mixture of three solvents, the volume ratio thereof may be 1:1:1, 2:2:1, etc.

In the method (3), preferably, the combination of the solvent and the antisolvent is selected from the group consisting of a combination of diethyl ether and petroleum ether, and a combination of methyl ethyl ketone and petroleum ether.

According to one aspect of the present invention, there is provided said amorphous form of probucol monosuccinate characterized by a powder X-ray diffraction Pattern (PXRD) obtained from irradiation with radiation from Cu-K α as shown in figure 30.

The amorphous form of probucol monosuccinate was characterized by an Infrared (IR) spectrum showing 3627.45cm^-1，2962.46cm^-1，1754.99cm^-1，1716.78cm^-1，1571.41cm^-1，1482.75cm^-1，1424.73cm^-1，1364.70cm^-1，1311.53cm^-1，1235.85cm^-1，1187.63cm^-1，1151.54cm^-1，1102.11cm^-1，1026.91cm^-1，988.12cm^-1，929.26cm^-1，886.76cm^-1，844.42cm^-1，810.11cm^-1，772.02cm^-1，725.71cm^-1，642.15cm^-1，618.50cm^-1，599.04cm^-1，546.77cm^-1，469.15cm^-1A positional absorption band, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

The amorphous form of probucol monosuccinate was characterized by Raman spectroscopy (Raman), which showed 3163.50cm^-1，2963.50cm^-1，2924.22cm^-1，1573.47cm^-1，1449.64cm^-1，1279.70cm^-1，1201.09cm^-1，1138.36cm^-1，929.34cm^-1，884.93cm^-1，806.36cm^-1，726.60cm^-1，646.49cm^-1，551.28cm^-1Positional absorption peaks, wherein each peak has + -2.00 cm^-1The error amplitude of (2).

The amorphous form of probucol monosuccinate further characterized by Differential Scanning Calorimetry (DSC) in which the amorphous form exhibits an exotherm at 78.03 ℃ and an endotherm at 122.75 ℃, wherein the temperature has a margin of error of ± 1 ℃.

The preparation method of the amorphous probucol monosuccinate is characterized in that the preparation method comprises the following steps: preparing probucol monosuccinate solid, adding a solvent, uniformly mixing, and dissolving; slowly volatilizing to be dry at 0-65 ℃, preferably 15-30 ℃ or 40-65 ℃, and collecting solids to obtain amorphous probucol monosuccinate.

Wherein the content of the first and second substances,

preferably, the volatilization time of the slow volatilization is more than 24 h.

Preferably, the solvent is selected from one or a mixture of more than two of methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, ethyl acetate, methyl tert-butyl ether, n-hexane, toluene, methyl isobutyl ketone, chloroform, dichloromethane, isopropyl acetate, petroleum ether, isoamyl alcohol, n-heptane, nitromethane and water;

preferably, when the volatilization temperature is 15-30 ℃, the solvent is selected from a mixture of dichloromethane and acetonitrile, a mixture of acetone and acetonitrile, tetrahydrofuran, a mixture of tetrahydrofuran and acetonitrile, a mixture of tetrahydrofuran and nitromethane, a mixture of tetrahydrofuran and n-hexane, a mixture of tetrahydrofuran and n-heptane, a mixture of ethyl acetate and nitromethane, a mixture of trichloromethane and acetonitrile, a mixture of methyl isobutyl ketone and nitromethane, a mixture of toluene and nitromethane, and a mixture of isopropyl acetate and nitromethane.

Preferably, when the volatilization temperature is 40-65 ℃, the solvent is selected from a mixture of methanol and nitromethane, a mixture of ethanol and n-heptane, a mixture of ethanol and petroleum ether, a mixture of dichloromethane and acetonitrile, a mixture of isopropanol and nitromethane, a mixture of dichloromethane and acetonitrile, isoamyl alcohol, a mixture of acetone and nitromethane, a mixture of methyl ethyl ketone and nitromethane, tetrahydrofuran, a mixture of tetrahydrofuran and water, a mixture of tetrahydrofuran and acetonitrile, a mixture of tetrahydrofuran and nitromethane, a mixture of tetrahydrofuran and n-hexane, a mixture of tetrahydrofuran and n-heptane, a mixture of tetrahydrofuran and petroleum ether, a mixture of ethyl acetate and acetonitrile, a mixture of ethyl acetate and nitromethane, a mixture of ethyl acetate and n-hexane, a mixture of trichloromethane and acetonitrile, A mixture of toluene and nitromethane, a mixture of isopropyl acetate and nitromethane.

When the solvent is a mixture of two or more solvents, the volume ratio of the solvents is not limited; for example, when the solvent is a mixture of two solvents, the volume ratio thereof may be 2:1, 1: 1; when the solvent is a mixture of three solvents, the volume ratio thereof may be 1:1:1, 2:2:1, etc.

The four crystal forms I, II, III and IV of the probucol monosuccinate have lower hygroscopicity, and are not easy to generate crystal transformation phenomenon. Therefore, compared with the amorphous form, the crystal form has obvious physical and chemical properties and process treatment advantages, excellent physical and chemical stability, capability of effectively removing impurity components, and excellent processability and fluidity. These advantages have a positive influence on both the quality of the medicament and the process.

Drawings

FIG. 1 is a photograph of a crystal form I of probucol monosuccinate of example 1-1 as a polarized light

FIG. 2 is an X-ray powder diffraction (XRPD) pattern of crystalline form I of probucol monosuccinate of example 1-1

FIG. 3 is a thermogravimetric analysis (TG) plot of crystalline form I of probucol monosuccinate of example 1-1

FIG. 4 is a Differential Scanning Calorimetry (DSC) chart of crystalline form I of probucol monosuccinate of example 1-1

FIG. 5 is a plot of hygroscopicity analysis (DVS) of crystalline form I of probucol monosuccinate of example 1-1

FIG. 6 is an Infrared (IR) spectrum of crystalline form I of probucol monosuccinate of example 1-1

FIG. 7 is a Raman spectrum (Raman) of crystalline form I of probucol monosuccinate of example 1-1

FIG. 8 is a photograph of a crystal form II of probucol monosuccinate of example 2-1 polarized light

FIG. 9 is an X-ray powder diffraction (XRPD) pattern of crystalline form II of probucol monosuccinate of example 2-1

FIG. 10 is a thermogravimetric analysis (TG) chart of crystalline form II of probucol monosuccinate of example 2-1

FIG. 11 is a Differential Scanning Calorimetry (DSC) chart of crystalline form II of probucol monosuccinate of example 2-1

FIG. 12 is a hygroscopicity analysis (DVS) profile of crystalline form II of probucol monosuccinate of example 2-1

FIG. 13 is an Infrared (IR) spectrum of crystalline form II of probucol monosuccinate of example 2-1

FIG. 14 is a Raman spectrum (Raman) diagram of crystalline form II of probucol monosuccinate of example 2-1

FIG. 15 is a photograph of a crystal form III of probucol monosuccinate of example 3-1 polarized light

FIG. 16 is an X-ray powder diffraction (XRPD) pattern for crystalline form III of probucol monosuccinate of example 3-1

FIG. 17 is a thermogravimetric analysis (TG) plot of crystalline form III of probucol monosuccinate of example 3-1

FIG. 18 is a Differential Scanning Calorimetry (DSC) chart of crystalline form III of probucol monosuccinate of example 3-1

FIG. 19 is a hygroscopicity analysis (DVS) profile of crystalline form III of probucol monosuccinate of example 3-1

FIG. 20 is an infrared spectrum (IR) chart of crystalline form III of probucol monosuccinate of example 3-1

FIG. 21 is a Raman spectrum (Raman) chart of crystalline form III of probucol monosuccinate of example 3-1

FIG. 22 is a photograph of a crystal form IV of probucol monosuccinate of example 4-1 polarized light

FIG. 23 is an X-ray powder diffraction (XRPD) pattern of crystalline form IV of probucol monosuccinate of example 4-1

FIG. 24 is a thermogravimetric analysis (TG) plot of crystalline form IV of probucol monosuccinate of example 4-1

FIG. 25 is a Differential Scanning Calorimetry (DSC) chart of crystalline form IV of probucol monosuccinate of example 4-1

FIG. 26 is a hygroscopicity analysis (DVS) profile of crystalline form IV of probucol monosuccinate of example 4-1

FIG. 27 is an infrared spectrum (IR) chart of crystalline form IV of probucol monosuccinate of example 4-1

FIG. 28 is a Raman spectrum (Raman) chart of crystalline form IV of probucol monosuccinate of example 4-1

FIG. 29 is a photograph of an amorphous polarized light of probucol monosuccinate of example 5-1

FIG. 30 is an amorphous X-ray powder diffraction (XRPD) pattern of probucol monosuccinate of example 5-1

FIG. 31 is a graph of thermal weight loss analysis (TG) of an amorphous form of probucol monosuccinate of example 5-1

FIG. 32 is a Differential Scanning Calorimetry (DSC) chart of the amorphous form of probucol monosuccinate of example 5-1

FIG. 33 is a plot of the amorphous hygroscopicity analysis (DVS) of probucol monosuccinate of example 5-1

FIG. 34 is an amorphous Infrared Spectrum (IR) Pattern of probucol monosuccinate of example 5-1

FIG. 35 is a Raman spectrum (Raman) chart of an amorphous form of probucol monosuccinate of example 5-1

Detailed Description

The following examples are intended to further illustrate the present invention, but they are not intended to limit or restrict the scope of the invention.