AU2021106179A4 - New crystalline form of epalrestat as well as preparation method and application thereof - Google Patents

New crystalline form of epalrestat as well as preparation method and application thereof Download PDF

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AU2021106179A4
AU2021106179A4 AU2021106179A AU2021106179A AU2021106179A4 AU 2021106179 A4 AU2021106179 A4 AU 2021106179A4 AU 2021106179 A AU2021106179 A AU 2021106179A AU 2021106179 A AU2021106179 A AU 2021106179A AU 2021106179 A4 AU2021106179 A4 AU 2021106179A4
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epalrestat
crystalline form
new crystalline
present disclosure
acid
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Huanying CAO
Zhongwei Cheng
Wei Guo
Shuwang HE
Xing Hu
Shiqiang YAN
Jie Yang
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Shandong Dyne Marine Biopharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
    • C07B37/04—Substitution
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

OF THE DISCLOSURE Disclosed are a new crystalline form of epalrestat and a preparation method and application thereof, belonging to the field of medical technology. The X-ray powder diffraction pattern of the new crystalline form of epalrestat shows characteristic peaks at diffraction angles 20 of 6.390.2, 7.57+0.20, 12.69+0.20, 14.67+0.20, 15.04+0.20, 21.790.2, 24.360.2, 25.590.2, 27.300.20 and 31.480.20. The new crystalline form of epalrestat has good water solubility and dissolution performance, which improves the bioavailability of epalrestat; moreover, the new crystalline form of epalrestat has very good fluidity, the angle of repose can reach less than or equal to 260, the compressibility is less than 10%, the Hausner ratio is between 1.00-1.11, which is very suitable for the production of the prodrugs or pharmaceutical preparations.

Description

NEW CRYSTALLINE FORM OF EPALRESTAT AS WELL AS PREPARATION METHOD AND APPLICATION THEREOF TECHNICAL FIELD
[01] The present disclosure relates to the field of medical technology, in particular to a new crystalline form of epalrestat as well as its preparation method and application thereof.
BACKGROUNDART
[02] Epalrestat, a new type of aldose reductase inhibitor developed by Ono Corporation of Japan, was first marketed in Japan in 1992 for the treatment of diabetic complications such as neuropathy, comeal epithelial disease, retinopathy and microvascular disease, etc. One of the causes of diabetic complications is abnormal osmotic pressure caused by hyperactive polyol metabolism. Aldose reductase inhibitors can effectively treat diabetic complications by inhibiting the rate-limiting enzyme that converts glucose to sorbitol in polyol metabolism to fundamentally solve the abnormal osmotic pressure of some tissues.
[03] Epalrestat, with the chemical name of -[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineacetic acid has the chemical structure shown as follows: 0
N-COOH
[04] S
[05] There are three crystalline forms of epalrestat reported in the literature-crystalline form A, crystalline form B and crystalline form C.
[06] JP20044210702S and JP20044210703A disclosed a preparation method of epalrestat crystalline form A and epalrestat crystalline form B, respectively; CN105272934A disclosed a preparation method of epalrestat crystalline form C.
[07] In addition, epalrestat solvates and epalrestat co-crystals are also reported in the literature: JP2017-43605A disclosed a DMF solvate of epalrestat; US2009051693 disclosed a preparation method of the betaine co-crystal of epalrestat; CN103951634B disclosed a preparation method of the hydroxypiperidine co-crystal of epalrestat crystalline salt hydrate.
[08] The phenomenon that the same drug molecule forms multiple crystalline forms is called drug polymorphism. Different crystalline forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioequivalence, etc., thereby affecting the stability, bioavailability and efficacy of the drug. This phenomenon is particularly prominent in oral solid preparations. Drug polymorphism is one of the important factors that affect the quality and clinical efficacy of drugs. Therefore, drug polymorphism and the preparation technology thereof have very important significance for solid pharmaceutical preparations.
[09] Epalrestat is poorly water-soluble, and the solubility of different crystalline forms will affect its dissolution in pharmaceutical compositions, thereby affecting the bioavailability of the drug in the human body. Therefore, the research and preparation of the new crystalline form of epalrestat has very important significance.
SUMMARY
[10] In view of this, the purpose of the present disclosure is to provide a new crystalline form of epalrestat and its preparation method and application thereof. The new crystalline form of epalrestat provided by the present disclosure has good water solubility and dissolution performance, which can improve the bioavailability of epalrestat.
[11] In order to achieve the above purpose of the disclosure, the present disclosure provides the following technical schemes:
[12] The present disclosure provides a new crystalline form of epalrestat, of which the X-ray powder diffraction pattern shows characteristic peaks at diffraction angles 20 of 6.39+0.20, 7.570.20, 12.69+0.20, 14.67+0.20, 15.04+0.20, 21.790.20, 24.36+0.20, 25.590.20, 27.300.20 and 31.48+0.20, where the relative intensity of the peak at 6.39+0.20 is the strongest;
[13] Preferably, the X-ray powder diffraction pattern of the new crystalline form of epalrestat also shows characteristic peaks at diffraction angles 20 of 13.300.20, 16.57+0.20, 19.59+0.20, 26.59+0.20, 30.08+0.20, 31.79+0.20 and 37.850.20;
[14] Preferably, a peak height and a relative intensity corresponding to the diffraction angle 20 in the X-ray powder diffraction pattern are shown in Table 1:
[15] Table 1 Peak height and relative intensity corresponding to the diffraction angle
[16]
20 (°) peak height relative intensity
6.39+0.20 3241 100 7.57+0.20 993 30.6 12.69+0.20 982 30.3 13.30+0.20 515 15.9 14.67+0.20 891 27.5 15.04+0.20 1109 34.2 16.57+0.20 528 16.3 19.59+0.20 594 18.3 21.79+0.20 1323 40.8 24.36+0.20 892 27.5 25.59+0.20 1138 35.1 26.59+0.20 580 17.9 27.30+0.20 1452 44.8 30.08+0.20 561 17.3 31.48+0.20 1021 31.5 31.79+0.20 871 26.8
37.85+0.2° 605 18.7
[171 .
[18] Preferably, the infrared absorption spectrum has characteristic peaks at the following positions: 3252 cm-1, 1747 cm-1, 1686 cm-1, 1563 cm-1,1417 cm-1, 1362 cm-1, 1339 cm-1, 1184 cm-1, 1117 cm-1, 1066 cm-1, 933 cm-1, 884 cm-1, 739 cm-1, 694 cm-1,587 cm-1, 550 cm-1, 515 cm-1 and 479 cm-1.
[19] Preferably, the differential scanning calorimetry spectrum has an endothermic peak at 225.16-227.50°C.
[20] Preferably, the thermogravimetric analysis pattern shows a smooth straight line in the region of 90-225°C, and the sample begins to decompose after 240 ±5°C.
[21] The present disclosure also provides a method for preparing the new crystalline form of epalrestat including the following steps:
[22] Subjecting 3-carboxymethylrhodanine and a-methylcinnamaldehyde in a reaction system including a reaction solvent, an organic basic catalyst and a phase transfer catalyst to obtain a condensation reaction solution;
[23] Mixing the condensation reaction solution and an acid to obtain a crude epalrestat;
[24] Mixing the crude epalrestat, an alcohol solvent and the acid to obtain the new crystalline form of epalrestat.
[25] Preferably, the temperature of the condensation reaction is 50-70°C, and the time of the condensation reaction is 1.0-3.0 h;
[26] Preferably, in the mixture of the crude epalrestat, the alcohol solvent and the acid, the molar ratio of the acid to the epalrestat in the crude epalrestat is more than or equal to 1:1.
[27] The present disclosure also provides the application of the new crystalline form of epalrestat described in the above technical scheme or the new crystalline form of epalrestat described in the above technical scheme in the preparation of aldose reductase inhibitor drugs.
[28] The present disclosure provides a new crystalline form of epalrestat, of which the X-ray powder diffraction pattern shows characteristic peaks at diffraction angles 20 of 6.390.2, 7.57+0.20, 12.69+0.20, 14.67+0.20, 15.040.20, 21.79+0.20, 24.360.20, 25.590.2, 27.300.20 and 31.48+0.20, where the relative intensity of the peak at 6.390.20 is the strongest. The new crystalline form of epalrestat provided by the present disclosure has good water solubility and dissolution performance, which improves the bioavailability of epalrestat; moreover, the new crystalline form of epalrestat provided by the present disclosure has good fluidity, the angle of repose can reach less than or equal to 260, the compressibility is less than 10%, the Hausner ratio is between 1.00-1.11, which is very suitable for the production of the prodrugs or pharmaceutical preparations.
[29] The present disclosure also provides a method for preparing the new crystalline form of epalrestat including the following steps: subjecting 3-carboxymethylrhodanine and a-methylcinnamaldehyde in a reaction system including a reaction solvent, an organic basic catalyst and a phase transfer catalyst to obtain a condensation reaction solution; mixing the condensation reaction solution and acid to obtain a crude epalrestat; and mixing the crude epalrestat, an alcohol solvent and the acid to obtain the new crystalline form of epalrestat. The preparation method provided by the disclosure can successfully prepare the new crystalline form of epalrestat and has simple operation.
[30] The present disclosure also provides the application of the new crystalline form of epalrestat described in the above technical scheme or the new crystalline form of epalrestat described in the above technical scheme in the preparation of aldose reductase inhibitor drugs. The aldose reductase inhibitor drug obtained by using the new crystalline form of epalrestat provided by the present disclosure has better dissolution performance.
BRIEF DESCRIPTION OF THE DRAWINGS
[31] FIG.1 is an X-ray powder diffraction (XRD) pattern of the new crystalline form of epalrestat in Example 1 of the present disclosure;
[32] FIG. 2 is an infrared absorption (IR) spectrum of the new crystalline form of epalrestat in Example 1 of the present disclosure;
[33] FIG. 3 is a differential scanning calorimetry (DSC) spectrum of the new crystalline form of epalrestat in Example 1 of the present disclosure;
[34] FIG. 4 is a thermogravimetric analysis (TGA) spectrum of the new crystalline form of epalrestat in Example 1 of the present disclosure;
[35] FIG. 5 is a hydrogen nuclear magnetic resonance spectrum (1H-NMR) of the new crystalline form of epalrestat in Example 1 of the present disclosure;
[36] FOG. 6 is a high performance liquid phase (HPLC) spectrum of the new crystalline form of epalrestat in Example 1 of the present disclosure;
[37] FIG. 7 is a high-power microscope image of the crystal habit of the new crystalline form of epalrestat in Example 1 of the present disclosure;
[38] FIG. 8 shows the dissolution curve of self-developed coated tablets and original coated tablets prepared from the new crystalline form of epalrestat in Example 1 of the present disclosure in a 0.1 wt% sodium dodecyl sulfonate solution with a pH of 6.8.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[39] The present disclosure provides a new crystalline form of epalrestat, of which the X-ray powder diffraction pattern is shown in FIG. 1. There are characteristic diffraction peaks at diffraction angle 20 of 6.390.2, 7.57+0.2°, 12.69+0.20, 14.67+0.20, 15.040.20, 21.790.20, 24.360.20, 25.590.2, 27.300.20, 31.480.20, wherein the relative intensity of the peak at 6.39+0.20 is the strongest. In the present disclosure, it is preferable to use Cu-Ka radiation to obtain the X-ray powder diffraction pattern of the new crystalline form of epalrestat.
[40] In the present disclosure, the X-ray powder diffraction pattern of the new crystalline form of epalrestat preferably shows characteristic diffraction peaks at diffraction angle 20 of 13.300.20, 16.570.20, 19.590.20, 26.590.20, 30.080.20, 31.79+0.20, 37.85+0.20.
[41] In the present disclosure, the X-ray powder diffraction pattern of the new crystalline form of epalrestat, as measured using Cu-Ka radiation, is shown in FIG. 1, and the peak height and relative intensity corresponding to the diffraction angle 20 are shown in Table 1.
[421 Table 1 Peak height and relative intensity corresponding to the diffraction angle
[43]
20 (°) peak height relative intensity
6.39+0.20 3241 100 7.57+0.20 993 30.6 12.69+0.20 982 30.3 13.30+0.20 515 15.9 14.67+0.20 891 27.5 15.04+0.20 1109 34.2 16.57+0.20 528 16.3 19.59+0.20 594 18.3 21.79+0.20 1323 40.8 24.36+0.20 892 27.5 25.59+0.20 1138 35.1 26.59+0.20 580 17.9 27.30+0.20 1452 44.8 30.08+0.20 561 17.3 31.48+0.20 1021 31.5 31.79+0.20 871 26.8 37.85+0.20 605 18.7
[441 In the present disclosure, the infrared absorption spectrum of the new crystalline form of epalrestat is shown in FIG. 2. The infrared absorption spectrum of the new crystalline form of epalrestat has characteristic peaks at the following position: 3252 cm-1, 1747 cm-1, 1686 cm-1, 1563 cm-1, 1417 cm-1, 1362 cm-1, 1339 cm-1, 1184 cm-1, 1117 cm-1, 1066 cm-1, 933 cm-1, 884 cm-1, 739 cm-1, 694 cm-1, 587 cm-1, 550 cm-1, 515 cm and 479 cm- .
[45] In the present disclosure, the differential scanning calorimetry spectrum of the new crystalline form of epalrestat is shown in FIG. 3, and the differential scanning calorimetry spectrum of the new crystalline form of epalrestat has endothermic peaks at 225.16-227.50 0 C.
[46] In the present disclosure, the thermogravimetric analysis spectrum of the new crystalline form of epalrestat is shown in FIG. 4; the thermogravimetric analysis spectrum of the new crystalline form of epalrestat shows a smooth straight line in the region of 90-225 0 C, and the sample begins to decompose after 240 ±5°C.
[47] The present disclosure also provides a method for preparing the new crystalline form of epalrestat including the following steps:
[48] Subjecting 3-carboxymethylrhodanine and a-methylcinnamaldehyde in a reaction system including a reaction solvent, an organic basic catalyst and a phase transfer catalyst to obtain a condensation reaction solution;
[49] Mixing the condensation reaction solution and the acid to obtain a crude epalrestat;
[50] Mixing the crude epalrestat, an alcohol solvent and the acid to obtain the new crystalline form of epalrestat.
[51] In the present disclosure, unless otherwise specified, the raw materials used in the present disclosure are preferably commercially available products.
[52] In the present disclosure, 3-carboxymethylrhodanine and a-methylcinnamaldehyde are subjected to a condensation reaction in a reaction system including a reaction solvent, an organic basic catalyst and a phase transfer catalyst to obtain a condensation reaction solution.
[53] In the present disclosure, the reaction solvent is preferably water, and the water is preferably purified water. In the present disclosure, the organic basic catalyst preferably includes 3-dimethylaminopropylamine. In the present disclosure, the phase transfer catalyst preferably includes polyethylene glycol, and the polyethylene glycol preferably includes one or more of polyethylene glycol 200, polyethylene glycol 400, and polyethylene glycol 800, and more preferably polyethylene glycol 400.
[54] In the present disclosure, the molar ratio of the 3-carboxymethyrhodanine and a-methylcinnamaldehyde is preferably 1: (1.1-1.3), and more preferably 1: 1.2.
[55] In the present disclosure, the molar ratio of the organic basic catalyst and 3-carboxymethylrhodanine is preferably (7-9): 10, and more preferably 8:10.
[56] In the present disclosure, the amount ratio of the phase transfer catalyst and 3-carboxymethyrhodanine is preferably (70-90) mL: 80 mmol, and more preferably 80 mL: 80 mmol.
[57] In the present disclosure, the amount ratio of the reaction solvent and 3-carboxymethyrhodanine is preferably (300-340) mL: 80 mmol, and more preferably 320 mL: 80 mmol.
[58] In the present disclosure, the adding order of the 3-carboxymethylrhodanine, a-methylcinnamaldehyde, reaction solvent, organic basic catalyst and phase transfer catalyst is preferably as follows: mixing the reaction solvent and the phase transfer catalyst to obtain a phase transfer catalyst solution; sequentially adding 3-carboxymethylrhodanine and a-methylcinnamaldehyde to the phase transfer catalyst solution; and then adding an organic basic catalyst dropwise. In the present disclosure, the dropping rate of the organic basic catalyst is preferably 1-10 mL/min, and more preferably 5 mL/min.
[59] In the present disclosure, the temperature of the condensation reaction is preferably 50-70°C, and more preferably 60°C; the time of the condensation reaction is preferably 1.0 -3.0 h, and more preferably 2.0 h; the time of the condensation reaction is preferably started after the addition of the organic basic catalyst is completed. In the present disclosure, the condensation reaction is preferably carried out under stirring, and the rotation speed of the stirring is preferably 100-400 rpm, and more preferably 300 rpm.
[60] After the condensation reaction solution is obtained, the present disclosure mixes the condensation reaction solution and the acid to obtain the crude epalrestat.
[61] In the present disclosure, after the condensation reaction is completed, the condensation reaction solution can be obtained; after the condensation reaction is completed, it is preferable to stop the heating condensation reaction system and add an acid to the condensation reaction solution.
[62] In the present disclosure, the acid preferably includes an inorganic acid and/or an organic acid; the inorganic acid preferably includes one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and hydrobromic acid, more preferably hydrochloric acid, the mass percentage of the hydrochloric acid is preferably 36-38%. In the present disclosure, the organic acid preferably includes one or more of formic acid, acetic acid, trifluoroacetic acid, lactic acid, benzoic acid, succinic acid, fumaric acid, maleic acid, citric acid, tartaric acid, succinic acid, methanesulfonic acid, ethylsulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
[63] In the present disclosure, in the mixture of the condensation reaction solution and the acid, the molar ratio of the acid solution and the organic basic catalyst is preferably more than or equal to 1 : 1.
[64] In the present disclosure, after mixing the condensation reaction solution and the acid, it preferably further includes: cooling the condensation reaction system to room temperature, and then filtering the resulting solution to obtain a solid; and then subjecting the obtained solid to a first washing and a first drying to obtain the crude epalrestat.
[65] In the present disclosure, the reagent for the first washing is preferably purified water, and the amount of the purified water is not specifically limited in the present disclosure; the method of the first washing is preferably elution. In the present disclosure, the first drying method is preferably vacuum drying; the temperature of the vacuum drying is preferably 40°C, and the time is preferably 2.0 h.
[66] In the present disclosure, after obtaining the crude epalrestat, the crude epalrestat, an alcohol solvent and an acid are mixed to obtain the new crystalline form of epalrestat.
[67] In the present disclosure, the alcohol solvent preferably includes a monohydric alcohol, and the monohydric alcohol preferably includes one or more of methanol, ethanol, isopropanol, and n-butanol, and more preferably methanol. In the present disclosure, the type of the acid solution is preferably the same as the type of the acid solution described in the above technical scheme, and will not be repeated here.
[68] In the present disclosure, the amount ratio of the crude epalrestat to the alcohol solvent is preferably 1 g: (5-50) mL, and more preferably 16 g: 100 mL. In the present disclosure, in the mixture of the crude epalrestat, the alcohol solvent and the acid solution, the molar ratio of the acid solution and the epalrestat in the crude epalrestat is preferably more than or equal to 1 : 1.
[69] In the present disclosure, the order of mixing the crude epalrestat, the alcohol solvent and the acid solution is preferably: dispersing the crude epalrestat in the alcohol solvent, and then adding the acid solution dropwise under stirring. In the present disclosure, the dropping rate of the acid solution is preferably 1-10 mL/min, and more preferably 5 mL/min. In the present disclosure, the rotation speed of the stirring is preferably 100-400 rpm, and more preferably 300 rpm.
[70] In the present disclosure, the refining is preferably carried out under heating and stirring conditions, the temperature of the heating and stirring is preferably 60-80°C, and the time is preferably 2.0 h. In the present disclosure, the rotational speed of the heating and stirring is preferably the same as that of the stirring of adding dropwise the acid solution, and will not be repeated here.
[71] After the refining, the present disclosure preferably further includes post-treatment of the obtained refining system. The post-treatment preferably includes cooling the refining system to room temperature, filtering to obtain a solid, and sequentially subjecting the obtained solid to a second washing and a second drying to obtain the new crystalline form of epalrestat.
[72] In the present disclosure, the reagent for the second washing is preferably anhydrous methanol. The present disclosure does not specifically limit the amount of the reagent for the second washing; the second washing method is preferably elution. In the present disclosure, the second drying method is preferably vacuum drying, and the temperature of the vacuum drying is preferably 30-60°C, and more preferably 40°C; the time is preferably 1.0-6.0 h, and more preferably 2.0 h.
[73] The present disclosure also provides the application of the new crystalline form of epalrestat described in the above technical scheme or the new crystalline form of epalrestat obtained by the preparation method described in the above technical scheme in the preparation of aldose reductase inhibitor drugs.
[74] In the present disclosure, the aldose reductase inhibitor drug is preferably an aldose reductase inhibitor pharmaceutical composition.
[75] In the present disclosure, the dosage form of the aldose reductase inhibitor drug composition preferably but does not include tablets, capsules and injections.
[76] In the present disclosure, the aldose reductase inhibitor pharmaceutical composition preferably further includes a pharmaceutically acceptable carrier or excipient.
[77] The new crystalline form of epalrestat provided by the present disclosure and a preparation method and application thereof will be described in detail below in conjunction with examples, but they should not be understood as limiting the scope of protection of the present disclosure.
[78] Example 1
[79] 320 mL of purified water and 80 mL of polyethylene glycol 400 were sequentially added into a 1000 mL three-necked round-bottom flask, then 3-carboxymethylrhodanine (15.3 g, 80 mmol) and a-methylcinnamaldehyde (14.0 g, 96 mmol) were sequentially added thereto under stirring at room temperature, after the completion of the addition, 3-dimethylaminopropylamine (8.0 mL, 64 mmol) was added dropwise at a rate of 5 mL/min. After that, the temperature was increased to 60°C, the temperature was kept, and the system was stirred (the rotation speed of 300 rpm) for 2.0 h. The heating was turned off to make the system cooled naturally, and 20.0 mL of concentrated hydrochloric acid was added dropwise to the reaction system. After the reaction system was cooled to 25°C, it was filtered to obtain a filter cake. The filter cake was eluted with 100 mL of purified water and dried under vacuum at 40°C for 2.0 h to obtain the crude yellow solid epalrestat (24.5 g, 96%).
[80] The crude epalrestat (16.0 g, 50 mmol) was suspended in 100 mL of anhydrous methanol in a 250 mL round-bottom flask, stirred at room temperature (the rotation speed of 300 rpm), and 5 mmol concentrated hydrochloric acid was added dropwise at a speed of 5 mL/min; the temperature was increased to 60°C, and the system was stirred with heat preservation for 2.0 h. The heating was turned off to make the system cooled down naturally. After the reaction system was cooled down to 25°C, it was filtered to obtain a filter cake, the filter cake was eluted with 20 mL of anhydrous methanol and dried under vacuum at 40°C for 2.0 h to obtain 13.9 g of yellow solid epalrestat with a yield of 87%, a purity of 99.868%, an angle of repose of 25.6, a compression coefficient (%) of 9, and a Hausner ratio of 1.05.
[81] The X-ray powder diffraction (XRD) pattern of the new crystalline form of epalrestat obtained in Example 1 of the present disclosure, as measured using Cu-Ka radiation, is shown in FIG. 1; it can be seen from FIG. 1 that there are characteristic diffraction peaks at diffraction angles 20 of 6.390.2, 7.57+0.2°, 12.69+0.20, 13.300.20, 14.67+0.2, 15.04+0.20, 16.57+0.20, 19.59+0.20, 21.79±0.20, 24.360.20, 25.59+0.20, 26.59+0.20, 27.30+0.20, 30.08+0.20, 31.48+0.20, 31.79+0.20, and 37.850.20; the relative intensity of the peak at 6.390.20 is the strongest; it is proved to be a new crystalline form of epalrestat.
[82] FIG. 2 is the infrared absorption (IR) spectrum of the new crystalline form of epalrestat in Example 1 of the present disclosure; it can be seen from FIG. 2 that the infrared absorption spectrum shows peaks at the following positions: 3252 cm-1 , 1747 cm- 1, 1686 cm- 1, 1563 cm- 1, 1417 cm- 1, 1362 cm- 1, 1339 cm- 1, 1184 cm- 1, 1117 cm- 1
, 1066 cm-1, 933 cm-1, 884 cm-1, 739 cm-1, 694 cm-1, 587 cm-1, 550 cm-1, 515 cm-1, and 479 cm-1;it is proved to be a new crystalline form of epalrestat.
[83] FIG. 3 is the differential scanning calorimetry (DSC) spectrum of the crystalline form of epalrestat in Example 1 of the present disclosure; it can be seen from FIG. 3 that the crystalline form of epalrestat has an endotherm peak at 225.16-227.50 0 C, which is the melting peak temperature, indicating that it has excellent thermal stability.
[84] FIG. 4 is the thermogravimetric analysis (TGA) spectrum of the new crystalline form of epalrestat in Example 1 of the present disclosure; it can be seen from FIG. 4 that there is a smooth straight line in the region of 90-225C, indicating that the new crystal of epalrestat does not contain adsorbed water or volatile substances, and has excellent thermal stability; and the sample begins to decompose after about 240 ±5°C.
[85] FIG. 5 is the hydrogen nuclear magnetic resonance spectrum (H-NMR) of the new crystalline form of epalrestat in Example 1 of the present disclosure. It can be seen from FIG. 5 that the substance obtained in Example 1 is epalrestat.
[86] 10 mg of the crystalline form of epalrestatin obtained in Example 1 was precisely weighed, and placed in a 100 mL measuring flask, 30 mL of methanol was added to dissolve ultrasonically, and a mobile phase (a mixture of methanol and acetic acid with a volume concentration of 0.4% in a volume ratio of 65 : 35) was added to dilute the solution to the mark, and the solution was shaken evenly to get the sample; the purity of the sample was determined using a high-performance liquid chromatography; the parameters of the high-performance liquid chromatography include: using octadecylsilane-bonded silica gel as a filler; using the mixture of methanol and acetic acid with a volume concentration of 0.4% in a volume ratio of 65 : 35 as the mobile phase for isocratic elution; the flow rate of 1.0 mL/min; the detection wavelength of 290 nm; the column temperature of 30°C; and the injection volume of 20 L. The results are shown in FIG. 6; it can be seen from FIG. 6 that the purity of the new crystalline form of epalrestat obtained in Example 1 is as high as 99.868%, and the amount of impurities is less than 0.1%.
[87] FIG. 7 is a high-power microscope image of the crystal habit of the new crystalline form of epalrestat in Example 1 of the present disclosure. It can be seen from FIG. 7 that the crystal habit of the new crystalline form of epalrestat is a diamond-shaped flaky crystal habit.
[88] Solubility determination:
[89] 10 mg of the new crystalline form of epalrestat obtained in Example 1 was taken and put in a 250 mL Erlenmeyer flask with a stopper, 100 mL of water was added, and subjected to ultrasonic treatment for 30 min (the ultrasonic treatment was carried out in the dark). After the ultrasonic treatment, the resulting system was allowed to reach room temperature, and filtered to obtain a filtrate, and the filtrate was taken as the test solution.
[90] The preparation of the reference solution: 10 mg of the reference substance was accurately weighed and placed in a 100 mL measuring flask, 30 mL of methanol was added thereto for ultrasonic dissolution, the resulting solution was diluted by flow to the mark, and shaken evenly.
[91] HPLC detection conditions: octadecylsilane-bonded silica gel was used as filler, a mixture of methanol and acetic acid solution with a volume concentration of 0.4% in a volume ratio of 65 : 35 was used as the mobile phase for isocratic elution; The flow rate was 1.0 mL/min; the detection wavelength was 290 nm; the column temperature was °C; and the injection volume was 20 [L.
[92] The test solution and the reference solution were precisely measured, injected into the high performance liquid chromatograph respectively, and detected according to the above detection conditions of the high performance liquid chromatography, and the chromatogram was recorded as long as 3 times the retention time of the principal component peak, the content of epalrestat in the test product was calculated by peak area according to external standard method.
[93] The results are as follows: the solubility of the reference substance in water is 1.827 [g/mL; the solubility of the new crystalline form of epalrestat in water is 2.307 pg/mL.
[94] Study on in vitro dissolution curve and stability of coated tablets prepared from new crystalline form of epalrestat
[95] Epalrestat is BCS II. The plasma concentration of epalrestat tablets can be measured 60 min after oral administration, and the absorption is good. The absorption site of epalrestat tablets is mainly in the intestine. Therefore, the most specific dissolution curve of the epalrestat tablets in vitro and in vivo is the medium using a solution with a pH value of 6.8.
[96] The original epalrestat coated tablets were purchased from Ono Pharmaceutical Industry Co., Ltd., with a specification of 50 mg * 10 s; using the new crystalline form of epalrestat obtained in Example 1 as raw materials, a self-developed coated tablet was prepared according to the preparation method of the original epalrestat coated tablet.
[97] The self-developed coated tablets and the original coated tablets were placed in a 0.1 wt% sodium dodecyl sulfonate solution with a pH value of 6.8 to detect the dissolution curves. The results are shown in FIG. 8. It can be seen from FIG. 8 that the self-developed coated tablets and the original research coated tablets are bioequivalent in vitro.
[98] The self-developed coated tablets and the original coated tablets were placed in a temperature humidity chamber with a temperature of 40± 2C and a humidity of 75 % for accelerated testing. The results are shown in Table 2.
[99] Table 2 Accelerated test results of self-developed coated tablets and original coated tablets
[100] time sample isomer impurity total purities
the self-developed 0.068% 0.132% 0 days the original 0.171% 0.285%
the self-developed 0.078% 0.152% acceleration for 1 month the original 0.201% 0.315%
the self-developed 0.079% 0.155% acceleration for 2 months the original 0.221% 0.334%
the self-developed 0.083% 0.174% acceleration for 3 months the original 0.255% 0.352%
[101] It can be seen from Table 2 that the quality and stability of the self-developed coated tablets prepared from the new crystalline form of epalrestat are better than those of the original coated tablets.
[102] Example 2
[103] 320 mL of purified water and 80 mL of polyethylene glycol 400 were sequentially added into a 1000 mL three-necked round-bottom flask, then 3-carboxymethylrhodanine (15.3 g, 80 mmol) and a-methylcinnamaldehyde (14.0 g, 96 mmol) were sequentially added under stirring at room temperature, after the completion of the addition, 3-dimethylaminopropylamine (8.0 mL, 64 mmol) was added dropwise at a rate of 5 mL/min. After the dripping was completed, the temperature was increased to 60°C, and the system was stirred with heat preservation (the rotation speed of 300 rpm) for 2.0 h. The heating was turned off to make the system cooled naturally, and 20.0 mL of concentrated hydrochloric acid was added dropwise to the reaction system. After the reaction system was cooled to 25°C, it was filtered to obtain a filter cake. The filter cake was eluted with 100 mL of purified water and dried under vacuum at 40°C for 2.0 h to obtain the crude yellow solid epalrestat (24.5 g, 96%).
[104] The crude epalrestat (16.0 g, 50 mmol) was suspended in 120 mL of isopropanol in a 250 mL round bottom flask, stirred at room temperature (the rotation speed of 300 rpm), and 5 mmol concentrated hydrochloric acid was added dropwise at a speed of 5 mL/min; the temperature was increased to 80°C, and the system was stirred with heat preservation for 2.0 h. The heating was turned off to make the system cooled down naturally. After the reaction system was cooled to 25°C, it was filtered to obtain a filter cake, the filter cake was eluted with 20 mL of isopropanol and dried under vacuum at °C for 2.0 h to obtain 12.5 g of yellow solid epalrestat with a yield of 78%, a purity of 99.778%, an angle of repose of 25.8, a compression coefficient (%) of 9, and a Hausner ratio of 1.06.
[105] According to X-ray powder diffraction test, it is the same new crystalline form as Example 1.
[106] Example 3
[107] 320 mL of purified water and 80 mL of polyethylene glycol 400 were sequentially added into a 1000 mL three-necked round-bottom flask, then 3-carboxymethylrhodanine (15.3 g, 80 mmol) and a-methylcinnamaldehyde (14.0 g, 96 mmol) were sequentially added under stirring at room temperature, after the completion of the addition, 3-dimethylaminopropylamine (8.0 mL, 64 mmol) was added dropwise at a rate of 5 mL/min. After the dripping was completed, the temperature was increased to 60°C, and the system was stirred with heat preservation (the rotation speed of 300 rpm) for 2.0 h. The heating was turned off to make the system cooled naturally, and 20.0 mL of concentrated hydrochloric acid was added dropwise to the reaction system. After the reaction system was cooled to 25°C, it was filtered to obtain a filter cake. The filter cake was eluted with 100 mL of purified water and dried under vacuum at 40°C for 2.0 h to obtain the crude yellow solid epalrestat (24.5 g, 96%).
[108] The crude epalrestat (16.0 g, 50 mmol) was suspended in 120 mL of anhydrous ethanol in a 250 mL round bottom flask, stirred at room temperature (the rotation speed of 300 rpm), and 5 mmol concentrated hydrochloric acid was added dropwise at a speed of 5 mL/min; the temperature was increased to 80°C, and the system was stirred with heat preservation for 2.0 h. The heating was turned off to make the system cooled down naturally. After the reaction system was cooled to 25°C, it was filtered to obtain afilter cake, the filter cake was eluted with 20 mL of anhydrous ethanol and dried under vacuum at 60°C for 2.0 h to obtain 12.8 g of yellow solid epalrestat with a yield of 80%, a purity of 99.798%, an angle of repose of 25.1°, a compression coefficient (%) of 8, and a Hausner ratio of 1.02.
[109] According to X-ray powder diffraction test, it is the same new crystalline form as Example 1.
[110] Example 4
[111] 320 mL of purified water and 80 mL of polyethylene glycol 400 were sequentially added into a 1000 mL three-necked round-bottom flask, then 3-carboxymethylrhodanine (15.3 g, 80 mmol) and a-methylcinnamaldehyde (14.0 g, 96 mmol) were sequentially added under stirring at room temperature, after the completion of the addition, 3-dimethylaminopropylamine (8.0 mL, 64 mmol) was added dropwise at a rate of 5 mL/min. After the dripping was completed, the temperature was increased to 60°C, and the system was stirred with heat preservation (the rotation speed of 300 rpm) for 2.0 h. The heating was turned off to make the system cooled naturally, and 20.0 mL of concentrated hydrochloric acid was added dropwise to the reaction system. After the reaction system was cooled to 25°C, it was filtered to obtain a filter cake. The filter cake was eluted with 100 mL of purified water and dried under vacuum at 40°C for 2.0 h to obtain the crude yellow solid epalrestat (24.5 g, 96%).
[112] The crude epalrestat (16.0 g, 50 mmol) was suspended in 150 mL of anhydrous methanol in a 250 mL round bottom flask, stirred at room temperature (the rotation speed of 300 rpm), and 5 mmol concentrated hydrochloric acid was added dropwise at a speed of 5 mL/min; the temperature was increased to 60°C, and the system was stirred with heat preservation for 2.0 h. The heating was turned off to make the system cooled down naturally. After the reaction system was cooled to 25°C, it was filtered to obtain a filter cake, the filter cake was eluted with 20 mL of anhydrous methanol and dried under vacuum at 60°C for 2.0 h to obtain 13.4 g of yellow solid epalrestat with a yield of 84%, a purity of 99.818%, an angle of repose of 25.7, a compression coefficient (%) of 9, and a Hausner ratio of 1.09.
[113] According to X-ray powder diffraction test, it is the same new crystalline form as Example 1.
[114] The above are only the preferred embodiments of the present disclosure. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present disclosure, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present disclosure.

Claims (5)

WHAT IS CLAIMED IS:
1. A new crystalline form of epalrestat, wherein an X-ray powder diffraction pattern shows characteristic peaks at diffraction angles 20 of 6.390.2, 7.570.2, 12.690.20, 14.67+0.20, 15.04+0.20, 21.79+0.20, 24.36+0.20, 25.590.20, 27.300.20 and 31.48+0.20, where the relative intensity of the peak at 6.39+0.20 is the strongest; The X-ray powder diffraction pattern of the new crystalline form of epalrestat also shows characteristic peaks at diffraction angles 20 of 13.30+0.20, 16.57+0.20, 19.59+0.20, 26.59+0.20, 30.08+0.20, 31.79+0.20 and 37.850.20; A peak height and a relative intensity corresponding to the diffraction angle 20 in the X-ray powder diffraction pattern are shown in Table 1: Table 1 Peak height and relative intensity corresponding to the diffraction angle 20
20 (°) peak height relative intensity
6.39+0.20 3241 100 7.57+0.20 993 30.6 12.69+0.20 982 30.3 13.30+0.20 515 15.9 14.67+0.20 891 27.5 15.04+0.20 1109 34.2 16.57+0.20 528 16.3 19.59+0.20 594 18.3 21.79+0.20 1323 40.8 24.36+0.20 892 27.5 25.59+0.20 1138 35.1 26.59+0.20 580 17.9 27.30+0.20 1452 44.8 30.08+0.20 561 17.3 31.48+0.20 1021 31.5 31.79+0.20 871 26.8 37.85+0.20 605 18.7 A method for preparing the new crystalline form of epalrestat includes the following steps: Subjecting 3-carboxymethylrhodanine and a-methylcinnamaldehyde in a reaction system including a reaction solvent, an organic basic catalyst and a phase transfer catalyst to obtain a condensation reaction solution; Mixing the condensation reaction solution and an acid to obtain a crude epalrestat; Mixing the crude epalrestat, alcohol solvent and the acid to obtain the new crystalline form of epalrestat.
2. The new crystalline form of epalrestat according to claim 1, wherein an infrared absorption spectrum has characteristic peaks at the following positions: 3252 cm-1 , 1747 cm- 1, 1686 cm- 1, 1563 cm- 1,1417 cm- 1, 1362 cm- 1, 1339 cm- 1, 1184 cm- 1, 1117 cm- 1 ,
1066 cm-1, 933 cm-1, 884 cm-1, 739 cm-1, 694 cm-1,587 cm-1, 550 cm-1, 515 cm-1 and 479 cm 1 .
3. The new crystalline form of epalrestat according to claim 1, wherein a differential scanning calorimetry spectrum has an endothermic peak at 225.16-227.50 C.0
4. The new crystalline form of epalrestat according to claim 1, wherein a thermogravimetric analysis pattern shows a smooth straight line in the region of -225 0C, and the sample begins to decompose after 240 ±50 C.
5. The new crystalline form of epalrestat according to claim 1, wherein the temperature of the condensation reaction is 50-70 0C, and the time of the condensation reaction is 1.0 -3.0 h; In a mixture of the crude epalrestat, the alcohol solvent and the acid solution, the molar ratio of the acid solution to the epalrestat in the crude epalrestat is more than or equal to 1:1.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114456125A (en) * 2022-03-10 2022-05-10 山东达因海洋生物制药股份有限公司 Preparation method of small-particle-size epalrestat crystals

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114456125A (en) * 2022-03-10 2022-05-10 山东达因海洋生物制药股份有限公司 Preparation method of small-particle-size epalrestat crystals
CN114456125B (en) * 2022-03-10 2022-11-15 山东达因海洋生物制药股份有限公司 Preparation method of small-particle-size epalrestat crystals

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