CN113336718A - Epalrestat-metformin salt and preparation method and application thereof - Google Patents
Epalrestat-metformin salt and preparation method and application thereof Download PDFInfo
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- 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
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
- C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
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Abstract
The invention discloses an epalrestat-metformin salt and a preparation method and application thereof, wherein the molecular formula of the epalrestat-metformin salt is C19H24N6O3S2Molecular weight is 448.6; the epalrestat-metformin salt is in a crystalline state, and the preparation method comprises the following steps: dissolving epalrestat and metformin in a solvent according to a molar ratio of 1:0.8-1:1.2 to obtain a mixture; the mixture reacts and crystallizes for 12 to 48 hours at the temperature of between 15 and 60 ℃; and (3) carrying out solid-liquid separation on the obtained product, and drying to obtain the epalrestat-metformin salt. The epalrestat and the metformin salt provided by the invention have greatly improved strong hygroscopicity compared with metformin monad, and are relatively good in hygroscopicityCompared with epalrestat single product, the solubility of the epalrestat single product is greatly improved, and simultaneously, the preparation method has simple operation, easy control of crystallization process and good reproducibility of salt form.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to epalrestat-metformin salt and a preparation method and application thereof.
Background
Complex diseases such as infectious diseases, aids, cancer, diabetes and cardiovascular diseases have become important factors that limit the improvement of human life expectancy, and since monotherapy (i.e. targeting specific receptors) has insignificant effects in the treatment of many complex diseases, drug combination has become a widely accepted drug development strategy, and drug combination is generally achieved by means of compound preparations or simultaneous administration of multiple drugs. The compound preparation refers to that two or more than two pharmaceutically active molecules (APIs) are combined in a single dose, so that the compound preparation not only has more effective treatment effect than single administration, but also has the advantages of reducing prescription amount and management cost, increasing patient compliance and the like, and is concerned in recent years. However, according to the recently used compound preparations in clinical use, the advantages are greatly reduced due to problems of poor stability, large difference in solubility between parent drug substances, incompatibility, and the like in the formulation stage.
Epalrestat (C)15H13NO3S2) Carboxylic acid type anti-type 2 diabetes drugs are useful for preventing, ameliorating and treating peripheral nerve disorders (numbness and pain) associated with diabetes, are aldose reductase inhibitors, and also act by reversibly inhibiting aldose reductase, which converts glucose into sorbitol in polyol metabolism associated with the pathogenesis of diabetic complications. However, the poor physicochemical properties (low solubility) of epalrestat seriously affect its bioavailability and thus therapeutic efficacy, and related researchers have attempted to effectively improve its physicochemical properties by forming different solid forms such as salts, co-crystals, etc. For example, U.S. patent publication (US2011/0275681a1) discloses a novel solid form of epalrestat, which discloses a solid form of an epalrestat salt anhydride, specifically, an anhydride such as epalrestat sodium salt or epalrestat potassium salt. International patent application (WO 2)010011922a2) also reported the solid form of epalrestat, but only discloses the epalrestat salt in anhydrous form, which has disadvantages in terms of solubility and stability, and chinese patent (CN201410190918.7) provides a solid form of epalrestat crystalline salt hydrate and hydroxypiperidine cocrystal, although the solubility of epalrestat is improved to some extent, the ligand selected has no any therapeutic effect or even toxicity. If the epalrestat and other clinically combined medicines for treating diabetes are prepared into the eutectic crystal, the adverse physicochemical properties of the epalrestat can be effectively improved, useless and even toxic substances can not be introduced, and the synergistic effect on the treatment effect is realized.
Metformin (C4H11N5) is a biguanide oral hypoglycemic agent, is different from epalrestat in the mechanism aspect of treating diabetes, mainly increases anaerobic glycolysis and utilization of glucose, increases glucose oxidation and metabolism of skeletal muscle and adipose tissue, reduces the absorption of glucose by intestinal tracts, inhibits the generation and output of glycogen, improves insulin resistance, and can effectively prevent the generation of complications while treating diabetes and generate synergistic effect on drug effect by combining the metformin and the epalrestat.
Epalrestat is a class II drug (BCS II) in the biopharmaceutical classification system, has low solubility, greatly limiting its drug efficacy. Metformin is unstable and is very hygroscopic. Traditional combinations do not improve their poor physicochemical properties. Therefore, if the epalrestat and the prochloraz are combined to prepare a new salt form, the solubility of the epalrestat can be improved, the hygroscopicity of the metformin can be reduced, the industrial cost in the production and storage processes can be greatly reduced on the premise of ensuring the advantages of drug combination, and the prochloraz has great value in the field of diabetes treatment.
Disclosure of Invention
The epalrestat-metformin salt has greatly reduced hygroscopicity compared with metformin, greatly improved solubility compared with epalrestat, simple preparation method operation, easy control of crystallization process and good reproducibility of salt form.
One of the purposes of the invention is to provide epalrestat-metformin salt, and the molecular formula of the epalrestat-metformin salt is C19H24N6O3S2Molecular weight of 448.6, and chemical structural formula as follows:
the epalrestat-metformin salt is in a crystalline state, and has characteristic peaks at 10.87 +/-0.20 degrees, 11.34 +/-0.20 degrees, 12.70 +/-0.20 degrees, 12.90 +/-0.20 degrees, 15.00 +/-0.20 degrees, 16.29 +/-0.20 degrees, 16.37 +/-0.20 degrees, 16.67 +/-0.20 degrees, 17.48 +/-0.20 degrees, 19.27 +/-0.20 degrees, 19.64 +/-0.20 degrees, 20.28 +/-0.20 degrees, 20.99 +/-0.20 degrees, 21.81 +/-0.20 degrees, 22.92 +/-0.20 degrees, 24.00 +/-0.20 degrees, 24.50 +/-0.20 degrees, 25.05 +/-0.20 degrees, 26.10 +/-0.20 degrees and 26.88 +/-0.20 degrees in the diffraction angle of X-ray powder diffraction represented by the 2 theta angle.
Preferably, the liquid nuclear magnetic resonance hydrogen spectrum of the epalrestat-metformin salt1H-NMR(DMSO-d6)δ：7.58(d,2H),7.20(s,2H),7.13(d,2H),6.61(s,4H),5.73(s,1H),2.92(s,6H),2.82(s,2H),2.30(s,3H),1.21(m,4H),0.82(t,3H)。
Preferably, the epalrestat-metformin salt has a differential scanning calorimetry analysis map with a characteristic melting peak at 215.7 +/-5 ℃.
The second purpose of the present invention is to provide a method for preparing epalrestat-metformin salt according to the first purpose, which comprises the following steps:
and (3) forming supersaturated solution of epalrestat and metformin in a solvent, and carrying out reaction crystallization to obtain the epalrestat-metformin salt.
Preferably, the molar ratio of epalrestat to metformin is 1:0.8-1: 1.2.
Preferably, the adding amount of the epalrestat and the solvent is within the range of 12.5-22.5mg/mL
Preferably, the organic solvent comprises any one of ethanol, acetonitrile, ethyl acetate, methyl acetate or isopropyl acetate or a combination of at least two thereof.
Preferably, the temperature of the reaction crystallization is 15-60 ℃, and the time of the reaction crystallization is 12-48 h.
Preferably, the preparation method further comprises the steps of sequentially carrying out solid-liquid separation, washing and drying on the mixture obtained after the reaction crystallization.
The invention also aims to provide the application of epalrestat-metformin salt in preparing the medicament for preventing and treating diabetes.
The invention has the beneficial effects that: the invention improves the dissolution rate and solubility of the epalrestat on the basis of combined medication to a great extent, the dissolution rate in the previous minute is about 30 times of the epalrestat, and the equilibrium solubility is also twice of the epalrestat. Meanwhile, the invention also well reduces the hygroscopicity of the metformin, and the weight of the epalrestat-metformin salt is not obviously increased when the relative humidity is from 20% to 70%. When the relative humidity reaches 95%, the weight of the epalrestat-metformin salt is increased by only 0.25%. While the weight of metformin changes rapidly with increasing RH%, the weight of metformin increases by 63% when RH% reaches 95%. Therefore, compared with metformin, the epalrestat-metformin salt form provided by the invention has the advantages that the hygroscopicity is greatly reduced, and the dissolution rate and the solubility are greatly improved, compared with epalrestat, meanwhile, the preparation method is simple to operate, the reaction is carried out in one step, the crystallization process is easy to control, and the reproducibility of the salt form is good.
Drawings
FIG. 1 is an X-ray powder diffraction (XRPD) pattern of epalrestat-metformin salt provided by the present invention;
FIG. 2 is a Differential Scanning Calorimetry (DSC) chart of epalrestat-metformin salt provided by the present invention;
FIG. 3 shows liquid nuclear magnetism of epalrestat-metformin salt (I) according to the present invention1H-NMR) chart;
FIG. 4 is a dynamic moisture sorption (DVS) diagram of epalrestat-metformin salt provided by the present invention;
FIG. 5 is an XRPD pattern of epalrestat-metformin salt provided by the present invention after dynamic moisture adsorption;
FIG. 6 is a graph of dynamic moisture sorption (DVS) of metformin provided by the present invention;
FIG. 7 shows the dissolution of the powder of epalrestat-metformin salt and epalrestat raw material in a phosphate buffer solution having a pH of 6.8 within 300 minutes.
Detailed Description
The present invention will be described in further detail below with reference to the accompanying drawings and examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. Any modifications and variations made on the basis of the present invention are still within the scope of the present invention.
It is noted that in X-ray powder diffraction spectroscopy, the diffraction pattern obtained from a crystalline compound tends to be characteristic for a particular crystalline form, where the relative intensities of characteristic peaks may vary due to the dominant orientation effect resulting from differences in crystallization conditions, particle size, and other measurement conditions. Thus, the relative intensities of the diffraction peaks are not characteristic of the crystal aimed at. To judge whether or not, at the same time as the known crystalline phase, it is more important to note the relative positions of the peaks rather than their relative intensities. Furthermore, for any given crystallization, the position of the peaks may deviate somewhat due to equipment and operating conditions, and characteristic peaks within the error range may be considered to be the same characteristic peak, as is also well known in the crystallography art. For example, the position of the peak may shift due to a change in temperature when analyzing the sample, sample movement, calibration of the instrument, or the like, and the measurement error of the 2 θ value is sometimes about ± 0.2 °. Therefore, this error should be taken into account when determining each crystalline structure. For the same crystal of the same compound, the peak positions of the XPRD spectrum have similarity as a whole, and the relative intensity error may be large.
(1) Instrument for XRPD testing: an X-ray powder diffractometer;
the instrument model is as follows: rigaku D/max-2500, Japan;
the test method comprises the following steps: cu target Ka, voltage 40KV, current 100mA, test angle 2-40 degrees, step length 8 degrees/min, exposure time 0.2s, light tube slit width 1mm, detector slit width 2.7 mm.
(2) DSC instrument: differential calorimetric scanner
The instrument model is as follows: mettler Toledo DSC1/500 from Mettler Toledo company
The test method comprises the following steps: the heating rate is 10 ℃/min, and the flow rate of protective gas nitrogen is 50 mL/min.
(3) TGA test instruments: thermogravimetric analyzer;
the instrument model is as follows: TGA/DSC 1;
the test method comprises the following steps: the atmosphere is nitrogen, and the heating rate is 10 ℃/min;
(4) moisture absorption test instrument: dynamic steam adsorption instrument
The instrument model is as follows: DVS Intrasic of UK national surface measurement systems
The test method comprises the following steps: the samples were studied in a humidity range of 20-95% RH (relative humidity) at 25 ℃. The humidity was gradually increased at 5% humidity. The weight change was less than 0.02% over a period of 10 minutes, with a maximum hold time of 30 minutes.
(4) In vitro dissolution rate test the instrument used: an ultraviolet spectrometer;
the instrument model is as follows: UV-2600;
the test method comprises the following steps: the absorbance of the solution was measured at a maximum wavelength of 388.8nm, and the concentration of the drug in the solution was calculated by measuring a standard curve.
Example 1
Putting 32.0mg of epalrestat and 12.9mg of metformin (the molar ratio is 1:1) into a 4mL sample bottle, adding 2mL of ethanol, performing ultrasonic treatment to dissolve the epalrestat and the metformin into a supersaturated state, reacting and crystallizing for 24 hours at 15 ℃, centrifuging the suspension, removing the supernatant, and drying the centrifuged solid in a 105 ℃ forced air drying oven for 3 hours to obtain the epalrestat-metformin salt.
Fig. 1 is an XRD pattern of the product prepared in example 1, and it is understood from fig. 1 that characteristic peaks are present at 10.87, 11.34, 12.70, 12.90, 15.00, 16.29, 16.37, 16.67, 17.48, 19.27, 19.64, 20.28, 20.99, 21.81, 22.92, 24.00, 24.50, 25.05, 26.10 and 26.88, expressed as diffraction angle 2 θ.
FIG. 2 is a DSC chart of the product obtained in example 1, and it can be seen from FIG. 2 that the differential scanning calorimetry of the epalrestat-metformin salt obtained in this example has a sharp endothermic peak at 215.7 ℃, which is the melting point of epalrestat-metformin salt.
FIG. 3 shows the liquid NMR spectrum of the product of example 1, wherein the chemical shifts are shown in FIG. 3: 7.58(d,2H),7.20(s,2H),7.13(d,2H),6.61(s,4H),5.73(s,1H),2.92(s,6H),2.82(s,2H),2.30(s,3H),1.21(m,4H),0.82(t,3H)
The following performance tests were performed on the product obtained in this example:
(1) moisture absorption test
The experimental method comprises the following steps: the epalrestat-metformin salt and the metformin serving as a raw material drug obtained in the example were subjected to a dynamic vapor adsorption experiment using DVS intrarisic of british surface measurement system, and a sample was studied under a condition of 25 ℃ with a humidity range of 20 to 95% RH (relative humidity). As shown in fig. 4, the weight of epalrestat-metformin salt did not increase significantly when the relative humidity was from 20% to 70%. When the relative humidity reaches 95%, the weight of the epalrestat-metformin salt is increased by only 0.25%. The tested epalrestat-metformin salt is subjected to X-ray powder diffraction characterization, and the crystal form of the epalrestat-metformin salt is not changed, as shown in figure 5. However, for the drug substance metformin, the weight change of metformin is rapid with the increase of RH%, and when RH% reaches 95%, the weight of metformin increases by 63%, as shown in fig. 6. The experimental results show that epalrestat-metformin salt can greatly reduce the high hygroscopicity of the raw material drug metformin.
(2) Powder dissolution test
The experimental conditions are as follows: dissolution experiments were performed using a dissolution tester model RC-6. The dissolution medium was 300mL of a phosphate buffer solution having a pH of 6.8. The rotation speed was controlled at 100rpm and the temperature was controlled at 37 ℃. The samples used therein were epalrestat-metformin salt and epalrestat raw material in the present invention, respectively, and in order to reduce the influence of particle size on the dissolution results, the samples were sieved with 80 mesh and 160 mesh sieves, respectively. Sampling 2ml after 1min,3min,5min,10min,15min,20min,30min,45min,60min,120min,180min,240min and 300min, filtering the sampled sample through a 0.45 μm microporous membrane, diluting properly, and quantifying by an ultraviolet spectrometer. The results are shown in fig. 7, wherein the dissolution rate and dissolution rate of the epalrestat-metformin salt are far greater than those of the epalrestat raw material.
Example 2
Putting 32.0mg of epalrestat and 11.9mg of metformin (the molar ratio is 1:0.92) into a 4mL sample bottle, adding 2mL of isopropyl acetate, performing ultrasonic treatment to dissolve the isopropyl acetate and make the isopropyl acetate in a supersaturated state, reacting and crystallizing at 60 ℃ for 12 hours, centrifuging the suspension, removing the supernatant, and drying the centrifuged solid in a 60 ℃ forced air drying box for 1 hour to obtain the epalrestat-metformin salt.
XRD test of the product obtained in example 2 shows characteristic peaks at diffraction angles 2 theta of 0.87, 11.34, 12.70, 12.90, 15.00, 16.29, 16.37, 16.67, 17.51, 19.27, 19.64, 20.28, 20.99, 21.81, 22.92, 24.00, 24.50, 25.10, 26.10 and 26.88. Therefore, the product is the epalrestat-metformin salt.
DSC test of the product obtained in example 2 revealed that a sharp endothermic peak at 216.4 ℃ was a melting point of epalrestat-metformin salt.
When the hygroscopicity test and the powder dissolution test were carried out in example 2 in the same manner as in example 1, it was found from the test results that epalrestat-metformin salt well reduced the hygroscopicity of metformin and improved the solubility and dissolution rate of epalrestat.
Example 3
Putting 32.0mg of epalrestat and 15.4mg of metformin (the molar ratio is 1:1.19) into a 4mL sample bottle, adding 2mL of acetonitrile and ethyl acetate for mixing, performing ultrasonic treatment to dissolve the mixture and make the mixture in a supersaturated state, reacting and crystallizing the mixture at 60 ℃ for 48 hours, centrifuging the suspension, removing the supernatant, and drying the centrifuged solid at room temperature of 25 ℃ for 12 hours to obtain the epalrestat-metformin salt.
XRD tests were carried out on the product obtained in example 3, and the test product had characteristic peaks at diffraction angles 2 theta of 0.87, 11.34, 12.78, 12.90, 15.00, 16.29, 16.37, 16.67, 17.48, 19.27, 19.64, 20.28, 20.99, 21.81, 22.87, 24.00, 24.50, 25.05, 26.10 and 26.88. Therefore, the product is the epalrestat-metformin salt.
DSC test of the product obtained in example 3 revealed that a sharp endothermic peak at 215.9 ℃ was a melting point of epalrestat-metformin salt.
When the hygroscopicity test and the powder dissolution test were carried out in example 3 in the same manner as in example 1, it was found from the test results that epalrestat-metformin salt well reduced the hygroscopicity of metformin and improved the solubility and dissolution rate of epalrestat.
Example 4
Putting 32.0mg of epalrestat and 12.9mg of metformin (the molar ratio is 1:1) into a 4mL sample bottle, adding 2mL of methyl acetate, performing ultrasonic treatment to dissolve the methyl acetate and make the methyl acetate in a supersaturated state, reacting and crystallizing the mixture at room temperature for 24 hours, centrifuging the suspension, removing a supernatant, and drying the centrifuged solid in a forced air drying oven at 40 ℃ for 3 hours to obtain the epalrestat-metformin salt.
An XRD test was performed on the product obtained in example 4, and the test product had characteristic peaks at diffraction angles 2 θ of 0.87, 11.34, 12.70, 12.90, 15.00, 16.29, 16.37, 16.67, 17.48, 19.27, 19.64, 20.28, 20.99, 21.81, 22.92, 24.00, 24.50, 25.05, 26.10, 26.88. Therefore, the product is the epalrestat-metformin salt.
DSC test of the product obtained in example 4 revealed that a sharp endothermic peak at 215.9 ℃ was a melting point of epalrestat-metformin salt.
When example 4 was subjected to the hygroscopicity test and the powder dissolution test in the same manner as in example 1, it was found from the test results that epalrestat-metformin salt well reduced the hygroscopicity of metformin and improved the solubility and dissolution rate of epalrestat.
Example 5
Putting 32.0mg of epalrestat and 12.9mg of metformin (the molar ratio is 1:1) into a 4mL sample bottle, adding 2mL of ethanol, performing ultrasonic treatment to dissolve the epalrestat and the metformin into a supersaturated state, reacting and crystallizing for 48 hours at room temperature, centrifuging the suspension, removing a supernatant, and drying the centrifuged solid in a 110 ℃ forced air drying oven for 3 hours to obtain the epalrestat-metformin salt.
XRD was conducted on the product obtained in example 5, and the product was tested to have characteristic peaks at diffraction angles 2 theta of 0.87, 11.34, 12.70, 12.90, 15.00, 16.55, 16.37, 16.67, 17.48, 19.27, 19.64, 20.28, 20.99, 22.30, 22.92, 24.30, 24.50, 25.05, 26.10, 26.88. Therefore, the product is the epalrestat-metformin salt.
DSC measurement of the product obtained in example 5 revealed that a sharp endothermic peak at 215.7 ℃ was a melting point of epalrestat-metformin salt.
When example 5 was subjected to the hygroscopicity test and the powder dissolution test in the same manner as in example 1, it was found from the test results that epalrestat-metformin salt well reduced the hygroscopicity of metformin and improved the solubility and dissolution rate of epalrestat.
Example 6
Putting 32.0mg of epalrestat and 15.4mg of metformin (the molar ratio is 1:1.19) into a 4mL sample bottle, adding 2mL of mixture of methyl acetate and ethyl acetate, carrying out ultrasonic treatment to dissolve the mixture and enable the mixture to be in a supersaturated state, reacting and crystallizing the mixture at 50 ℃ for 24 hours, centrifuging the suspension, removing the supernatant, and drying the centrifuged solid at room temperature of 25 ℃ for 12 hours to obtain the epalrestat-metformin salt.
An XRD test was carried out on the product obtained in example 6, which was found to have characteristic peaks at diffraction angles 2 θ of 0.87, 11.34, 12.78, 12.90, 15.00, 16.29, 16.37, 16.67, 17.37, 19.27, 19.64, 20.28, 20.99, 21.81, 22.87, 24.50, 25.05, 25.80, 26.88. Therefore, the product is the epalrestat-metformin salt.
DSC measurement of the product obtained in example 6 revealed that a sharp endothermic peak at 216.1 ℃ was a melting point of epalrestat-metformin salt.
When the hygroscopicity test and the powder dissolution test were carried out in example 6 in the same manner as in example 1, it was found from the test results that epalrestat-metformin salt well reduced the hygroscopicity of metformin and improved the solubility and dissolution rate of epalrestat.
Comparative example 1
The only difference from example 1 is that ethanol was replaced by acetone.
The solid obtained in the comparison 1 is tested, and the crystal form of the solid is different from that of the epalrestat-metformin salt; as can be seen from comparison with example 1, if the solvent system is changed, the crystal form of epalrestat-metformin salt cannot be obtained.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (9)
1. The epalrestat-metformin salt is characterized in that the molecular formula of the epalrestat-metformin salt is C19H24N6O3S2Molecular weight of 448.6, and chemical structural formula as follows:
the epalrestat-metformin salt is in a crystalline state, and has characteristic peaks at diffraction angles expressed by 2 theta angles of 10.81 +/-0.20 degrees, 12.86 +/-0.20 degrees, 14.92 +/-0.20 degrees, 16.32 +/-0.20 degrees and 19.61 +/-0.20 degrees in X-ray powder diffraction measured by using Cu-Kalpha rays.
2. The epalrestat-metformin salt according to claim 1, wherein said epalrestat-metformin salt has a characteristic melting peak at 215.7 ± 5 ℃ in a differential scanning calorimetry analysis spectrum.
3. The process for preparing epalrestat-metformin salt according to claim 1 or 2, characterized in that the process comprises the steps of:
and forming supersaturated solution of epalrestat and metformin in a solvent, reacting, crystallizing, filtering and drying to obtain the epalrestat-metformin salt.
4. The preparation method according to claim 3, wherein the mass ratio of epalrestat to metformin is 1:0.8-1: 1.2.
5. The method according to claim 3, wherein the organic solvent comprises any one or a combination of at least two of ethanol, acetonitrile, ethyl acetate, methyl acetate, or isopropyl acetate.
6. The process according to claim 3, wherein the epalrestat is added in an amount of 12.5 to 22.5mg/mL relative to the solvent.
7. The preparation method according to claim 3, wherein the temperature of the reaction crystallization is 15-60 ℃, and the time of the reaction crystallization is 12-48 h.
8. The preparation method according to claim 3, further comprising subjecting the mixture obtained after the reaction crystallization to solid-liquid separation, washing, and drying in this order.
9. The use of epalrestat-metformin salt according to claim 1 or 2 for the preparation of a medicament for the prevention and treatment of diabetes.
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| WO2010011922A2 (en) * | 2008-07-25 | 2010-01-28 | Bionevia Pharmaceuticals, Inc. | Novel crystalline salts of epalrestat |
| WO2010011926A2 (en) * | 2008-07-25 | 2010-01-28 | Bionevia Pharmaceuticals, Inc. | A novel betaine cocrystal of epalrestat |
| CN102216281A (en) * | 2008-09-06 | 2011-10-12 | 碧奥尼维亚制药股份有限公司 | Novel choline cocrystal of epalrestat |
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| CN115925650A (en) * | 2022-12-13 | 2023-04-07 | 山东达因海洋生物制药股份有限公司 | Epalrestat eutectic crystal and preparation method and application thereof |
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