CN115947699B - Epalrestat eutectic crystal taking nicotinamide as precursor and preparation method thereof - Google Patents
Epalrestat eutectic crystal taking nicotinamide as precursor and preparation method thereof Download PDFInfo
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- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 title claims abstract description 130
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- 229950010170 epalrestat Drugs 0.000 title claims abstract description 100
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
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Abstract
The invention belongs to the technical field of pharmaceutical chemistry and crystallization processes, and relates to epalrestat eutectic taking nicotinamide as a precursor and a preparation method thereof. Is formed by combining nicotinamide and epalrestat according to a molar ratio of 1:1; using Cu-ka radiation, the X-ray powder diffraction spectrum has sharp diffraction peaks. The epalrestat eutectic crystal taking nicotinamide as a precursor provided by the invention obviously improves the water solubility of epalrestat and the chemical stability in storage, and can effectively reduce the production, storage and transportation costs.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry and crystallization processes, and relates to epalrestat eutectic taking nicotinamide as a precursor and a preparation method thereof.
Background
The information disclosed in the background of the invention is intended to enhance an understanding of the general background of the invention, and this disclosure should not necessarily be taken as an acknowledgement or any form of suggestion that this information has become known to a person of ordinary skill in the art.
Epalrestat is mainly used for treating diabetic complications, such as neuropathy, corneal epithelial lesions, retinopathy, microangiopathy and the like, and can also be used for treating or preventing various diseases. According to the research of the inventor, the epalrestat has poor water solubility and belongs to insoluble medicines; meanwhile, the effective active substance of epalrestat is in a Z/E configuration, and epalrestat is easily isomerized to generate inactive substances in three configurations of Z/Z, E/E and E/Z under the condition of illumination or in a solution state. Therefore, the eutectic substance which improves the solubility of epalrestat and can stabilize the Z/E configuration of epalrestat is extremely important for storing, transporting and using epalrestat.
So far, few reports on epalrestat co-crystals are relevant: patent CN103951634B discloses a method for preparing an epalrestat and hydroxypiperidine co-crystal; patent CN102216281B discloses a method for preparing an epalstat and neocholine co-crystal; patent US2009051693 discloses a process for the preparation of epalrestat betaine co-crystals. However, the precursor of the three epalrestat co-crystals is only one medical intermediate, has high toxicity and no medicinal value, and cannot be truly applied to actual treatment.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide epalrestat eutectic crystal taking nicotinamide as a precursor and a preparation method thereof. The epalrestat eutectic crystal taking nicotinamide as a precursor provided by the invention obviously improves the water solubility of epalrestat and the chemical stability in storage, and can effectively reduce the production, storage and transportation costs.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
in one aspect, the epalrestat eutectic with nicotinamide as a precursor is formed by combining nicotinamide and epalrestat according to a molar ratio of 1:1; using Cu-ka radiation, the X-ray powder diffraction spectrum has sharp diffraction peaks.
Nicotinamide (i.e. vitamin B) 3 NCT) is white crystalline powder, is easily dissolved in water, is a coenzyme for many dehydrogenases, is easily absorbed by the gastrointestinal tract, can be distributed to the whole body tissues after absorption, and is used for supplementing nutrition, treating viral myocarditis, glossitis, dermatitis and the like. Nicotinamide has been shown to be a good quality eutectic precursor as a non-toxic low toxicity drug for GRAS standards. Therefore, the invention aims at co-crystallizing epalrestat and nicotinamide by a crystal engineering technology based on the supermolecular chemistry principleBy utilizing the characteristic of the water solubility of the nicotinamide of far Gao Yuyi Pa, the solubility of the epalrestat is improved on the premise of not changing the self-drug action of the epalrestat, and a foundation is laid for improving the bioavailability and the curative effect of the epalrestat.
On the other hand, the preparation method of the epalrestat eutectic taking nicotinamide as a precursor comprises the steps of ball milling epalrestat and nicotinamide under the condition of adding an organic solvent, so as to obtain the epalrestat eutectic; the volume ratio of the total mass of epalrestat and nicotinamide to the organic solvent is 4.0-5.0:1 g/mL.
In a third aspect, a pharmaceutical composition comprises the epalrestat co-crystal taking nicotinamide as a precursor and a pharmaceutical excipient.
In a fourth aspect, the present invention provides an application of the epalrestat co-crystal or pharmaceutical composition using nicotinamide as a precursor in preparing a medicament for treating diabetic complications.
The beneficial effects of the invention are as follows:
aiming at the problems of poor water solubility of epalrestat and poor chemical stability in the storage process, the invention synthesizes the eutectic with the molar ratio of 1:1 by the technical means of eutectic with nicotinamide, thereby achieving the dual purposes of improving the water solubility and the chemical stability. The eutectic obviously improves the water solubility of epalrestat and the chemical stability in storage, and can effectively reduce the production, storage and transportation costs.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 shows the hydrogen nuclear magnetic resonance spectrum of the co-crystal of epalrestat and nicotinamide according to example 1 of the present invention 1 H-NMR) map;
FIG. 2 is an X-ray powder diffraction (PXRD) pattern of the co-crystal of epalrestat and nicotinamide according to example 1 of the invention;
FIG. 3 is a Differential Scanning Calorimetric (DSC) plot of the co-crystal of epalrestat and nicotinamide according to example 1 of the present invention;
FIG. 4 is an Infrared (IR) diagram of the co-crystal of epalrestat and nicotinamide according to example 1 of the present invention.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present invention. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
In view of the poor water solubility of epalrestat and the easy isomerization of epalrestat active substance in Z/E configuration under illumination condition or solution state, the invention provides epalrestat eutectic crystal taking nicotinamide as precursor and a preparation method thereof.
According to an exemplary embodiment of the invention, an epalrestat eutectic taking nicotinamide as a precursor is provided, and is formed by combining nicotinamide and epalrestat according to a molar ratio of 1:1; using Cu-ka radiation, the X-ray powder diffraction spectrum has sharp diffraction peaks.
In some embodiments, the assay conditions using Cu-ka radiation are: the voltage is 40+/-4 kilovolts, the current is 40+/-4 milliamps, and the angle range of 2 theta is 3-40 degrees; the step length is 0.02+/-0.002 degrees; the speed is 0.1.+ -. 0.01 seconds/step.
In some embodiments, the characteristic peaks of the X-ray powder diffraction spectrum have a 2θ angle of: 9.56+ -0.2 °, 13.92+ -0.2 °, 22.53+ -0.2 °, 25.56+ -0.2 °.
In some embodiments, the characteristic peaks of the X-ray powder diffraction spectrum have a 2θ angle of: 9.56+ -0.2 °, 13.92+ -0.2 °, 14.92+ -0.2 °, 16.06+ -0.2 °, 17.72+ -0.2 °, 22.53+ -0.2 °, 23.03+ -0.2 °, 25.56+ -0.2 °.
In some embodiments, the X-ray powder diffraction spectrum is as shown in fig. 2.
In some embodiments, the nmr hydrogen spectrum data is: 1 H NMR(600MHz,DMSO-d 6 )δ13.46(s,1H),8.73(dd,J＝4.5,1.6Hz,2H),7.83(dd,J＝4.5,1.6Hz,2H),7.63(s,1H),7.50–7.43(m,4H),7.39–7.37(m,2H),4.73(s,2H),2.22(s,3H)。
in some embodiments, the infrared spectrum is at 3359, 3174, 1700, 1686, 1629, 1572, 1564, 1367, 1326, 1229, 1191, 1114, 1056, 979, 938, 882, 745, 694, 602cm -1 With characteristic peaks.
In some embodiments, the melting point is 209±2 ℃.
In another embodiment of the invention, the invention provides a preparation method of the epalrestat eutectic with nicotinamide as a precursor, which is obtained by ball milling epalrestat and nicotinamide under the condition of adding an organic solvent; the volume ratio of the total mass of epalrestat and nicotinamide to the organic solvent is 4.0-5.0:1 g/mL.
In some embodiments, the organic solvent is one or more of ethanol, methanol, isopropanol, tetrahydrofuran, acetone, acetonitrile, preferably ethanol.
In some embodiments, the molar ratio of epalrestat to nicotinamide is 1:1.
In some embodiments, the ball milling employs a planetary ball mill.
In some embodiments, stainless steel milling balls are added during ball milling. The mass of the stainless steel grinding ball is 2-10 times, preferably 3-5 times of the total mass of epalrestat and nicotinamide.
In some embodiments, the ball milling is performed at a rotational speed of 100 to 1000 rpm, preferably 300 to 6000 rpm, and more preferably 500 rpm.
In some embodiments, the milling time is 1 to 5 minutes, the interval is 1 to 5 minutes, and the number of cycles is 1 to 5.
The third embodiment of the invention provides a pharmaceutical composition, which comprises the epalrestat eutectic taking nicotinamide as a precursor and pharmaceutical excipients.
The pharmaceutical excipients are pharmaceutical carriers and/or excipients. Such as alumina, aluminum stearate, lecithin, etc., and such excipients as fillers, lubricants, disintegrants, binders, etc.
The fourth embodiment of the invention provides an application of the epalrestat eutectic or the pharmaceutical composition taking nicotinamide as a precursor in preparing a medicament for treating diabetic complications.
More specifically, the diabetic complications include neuropathy, corneal epithelial lesions, retinopathy and/or microangiopathy, and the like.
The present application is further illustrated below in conjunction with specific embodiments. It should be understood that these examples are illustrative only of the present application and are not intended to limit the scope of the present application. The specific material ratios, process conditions, and results thereof described in the examples herein below are illustrative of the present application and should not be nor should they be used to limit the invention as detailed in the claims. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or materials used in this application are all commercially available in conventional manners, and unless specifically indicated otherwise, are all used in conventional manners in the art or according to the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present application. The preferred methods and materials described herein are presented for illustrative purposes only.
The detection instrument and the method are as follows:
the instrument used for X-ray powder diffraction (XRPD) was Bruker D8 Advance diffractometer, using K.alpha.radiation for Cu, at 40 kilovolts and 40 milliamps. The instrument corrects the peak position with the instrument's own standard sample prior to use. The acquisition software was Diffrac Plus XRD Commander and the analysis software was MDI jack 6.0. Samples were tested at room temperature and the samples to be tested were placed on an organic slide. The detailed detection conditions were as follows: 2 theta angle range: 3-40 degrees; step size: 0.02 °; speed of: 0.1 seconds/step. Unless otherwise specified, the samples were not ground prior to testing.
Differential scanning calorimetric analysis (DSC) data were obtained from a DSC1 differential scanning calorimeter, mertretolidol, and the instrument control software and analysis software were all self-contained. The sample was heated from 60 ℃ to 300 ℃ at a heating rate of 10 ℃/min, while the software recorded the thermal change of the sample during the heating.
Infrared analysis (IR) was performed using a front infrared spectrum analyzer from PerkinElmer, usa, at room temperature, with the following detection ranges: 4000-350 cm -1 Wavenumber.
Example 1
1.59g of epalrestat and 0.61g of nicotinamide are respectively weighed accurately by an analytical balance in a 50ml grinding tank, 0.5ml of absolute ethyl alcohol is added by a micropipette, and 20g of grinding balls are placed. The milling pot was placed in a planetary ball mill BM6pro, set at 500 rpm, set at 5 min milling time, 3 min intervals, and cycled 5 times. And after the operation is finished, the grinding tank is taken down, and a sample is scraped by a cleaning scraper, so that the epalrestat and nicotinamide eutectic crystal is obtained.
The nuclear magnetic hydrogen spectrum data of the epalrestat and nicotinamide eutectic prepared in the embodiment are as follows: 1 H NMR(600MHz,DMSO-d 6 ) Delta 13.46 (s, 1H), 8.73 (dd, j=4.5, 1.6hz, 2H), 7.83 (dd, j=4.5, 1.6hz, 2H), 7.63 (s, 1H), 7.50-7.43 (m, 4H), 7.39-7.37 (m, 2H), 4.73 (s, 2H), 2.22 (s, 3H). The test results are shown in FIG. 1. Of these, 8.73 (dd, j=4.5, 1.6hz,2 h), 7.83 (dd, j=4.5, 1.6hz,2 h) were ascribed to the chemical shift characteristic signal of nicotinamide, the remainder being characteristic peaks of epalrestat. The nuclear magnetic data show that the synthesized eutectic is the eutectic with the mass ratio of epalrestat to nicotinamide substance being 1:1.
The X-ray powder diffraction pattern of the epalrestat and nicotinamide eutectic prepared in the example is shown in fig. 2, and the characteristic peaks are at 9.56 °,13.92 °,14.92 °,16.06 °,17.72 °,22.53 °,23.03 ° and 25.56 °. In the figure, the PXRD characteristic peak of the co-crystal of epalrestat and nicotinamide is different from the epalrestat serving as a raw material and the precursor nicotinamide. The PXRD spectrum peaks of the 3 curves are changed greatly, and the generation of a new phase is proved.
The differential scanning calorimetric analysis (DSC) chart of the epalrestat and nicotinamide eutectic prepared in the embodiment is shown in figure 3, which shows that the melting point of the epalrestat and nicotinamide eutectic is 209 ℃, the melting point of nicotinamide is 130 ℃, the melting point of epalrestat is 227 ℃, and the melting point of the eutectic is different from the melting points of the raw materials and the precursor, thus proving that a new phase is generated.
The infrared spectrum of the epalrestat and nicotinamide co-crystal prepared in this example is shown in FIG. 4, at 3359, 3174, 1700, 1686, 1629, 1572, 1564, 1367, 1326, 1229, 1191, 1114, 1056, 979, 938, 882, 745, 694, 602cm -1 With characteristic peaks. Due to hydrogen bonding, the IR spectrum peak of the epalrestat and nicotinamide co-crystal is red-shifted and blue-shifted. The significant difference in infrared spectra demonstrated the presence of intermolecular hydrogen bonds between epalrestat and nicotinamide, further demonstrating the formation of the co-crystal of epalrestat and nicotinamide.
Example 2
1.59g of epalrestat and 0.61g of nicotinamide are respectively weighed accurately by an analytical balance in a 50ml grinding pot, 0.5ml of methanol is added by a micropipette, and the mixture is placed in a grinding ball of 16g. The milling pot was placed in a planetary ball mill BM6pro, set at 600 rpm, set at 4 min milling time, 2 min intervals, and cycled 5 times. And after the operation is finished, the grinding tank is taken down, and a sample is scraped by a cleaning scraper, so that the epalrestat and nicotinamide eutectic crystal is obtained.
Example 3
1.59g of epalrestat and 0.61g of nicotinamide are respectively weighed accurately by an analytical balance in a 50ml grinding pot, 0.2ml of tetrahydrofuran is added by a micropipette, and 18g of grinding balls are placed. The milling pot was placed in a planetary ball mill BM6pro, set at 500 rpm, set at 5 min milling time, 2 min intervals, and cycled 3 times. And after the operation is finished, the grinding tank is taken down, and a sample is scraped by a cleaning scraper, so that the epalrestat and nicotinamide eutectic crystal is obtained.
Example 4
1.59g of epalrestat and 0.61g of nicotinamide are respectively weighed accurately by an analytical balance in a 50ml grinding pot, 0.2ml of acetone is added by a micropipette, and 20g of grinding balls are placed. The milling pot was placed in a planetary ball mill BM6pro, set at 500 rpm, set at 4 min milling time, 2 min intervals, and cycled 3 times. And after the operation is finished, the grinding tank is taken down, and a sample is scraped by a cleaning scraper, so that the epalrestat and nicotinamide eutectic crystal is obtained.
Example 5: solubility determination
Taking 10mg of epalrestat obtained in example 1, nicotinamide eutectic crystals and epalrestat raw materials respectively, putting the materials into different 250mL triangular flasks with plugs, adding 100mL of water, performing ultrasound for 30min (light-shielding operation in the ultrasound process), standing to room temperature after the ultrasound is finished, filtering, and taking the subsequent filtrate as a sample solution respectively.
Preparing a reference substance solution: taking reference substance 10mg, precisely weighing, placing into a 100mL measuring flask, adding 30mL of methanol for ultrasonic dissolution, adding flow for dilution to scale, and shaking uniformly.
Conditions for high performance liquid chromatography detection: octadecylsilane chemically bonded silica is used as a filler, methanol and acetic acid solution with the volume concentration of 0.4 percent are used as the filler according to the volume ratio of 65: the mixed solution of 35 is taken as a mobile phase for isocratic elution; the flow rate is 1.0mL/min; the detection wavelength is 290nm; the column temperature is 30 ℃; the sample volume was 20. Mu.L.
Precisely measuring the sample solution and the reference substance solution, respectively injecting into high performance liquid chromatograph, detecting according to the detection conditions of the high performance liquid chromatograph, and recording the chromatogram to 3 times of the retention time of the main component peak. And calculating the content of epalrestat in the test sample according to an external standard method and the peak area.
The results were: the solubility of the epalrestat raw material in water is 9.0 mug/mL; the solubility of the epalrestat and nicotinamide co-crystal in water was 67.8 μg/mL.
Example 6: stability determination
The epalrestat original ground product coated tablet is purchased from Xiaoye pharmaceutical products industry Co., ltd, 50mg of specification 10s; the epalrestat eutectic obtained in example 1 is used as a raw material, and the epalrestat eutectic coated tablet is prepared according to the preparation method of the epalrestat original ground product coated tablet.
The epalrestat eutectic coated tablet and the original ground product coated tablet are placed in a constant temperature and humidity box with the temperature of 40+/-2 ℃ and the humidity of 75+/-5%, and the acceleration test is carried out, and the results are shown in table 1.
TABLE 1 accelerated test results of Epalrestat eutectic coated tablets and freshly ground coated tablets
As can be seen from table 1: the quality and stability of the coated tablet prepared from the epalrestat eutectic are better than those of the original ground coated tablet.
Comparative example
1.60g of epalrestat and 0.92g of saccharin are respectively weighed accurately by an analytical balance in a 50mL grinding tank, 0.5mL of ethanol is added by a micropipette, and the mixture is placed into 16g of grinding balls. The milling pot was placed in a planetary ball mill BM6pro, set at a rotational speed of 500 revolutions per minute, set at 3 minutes milling time, 2 minutes apart, and cycled 5 times. And after the operation is finished, the grinding tank is taken down, and a sample is scraped by a cleaning scraper, so that the epalrestat saccharin eutectic is obtained.
The solubility measurement method of example 5 was used, and the measurement result was: the solubility of the epalrestat raw material in water is 9.0 mug/mL; the solubility of epalrestat saccharin co-crystals in water was 2.7 μg/mL.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. The epalrestat eutectic crystal taking nicotinamide as a precursor is characterized by being formed by combining nicotinamide and epalrestat according to a molar ratio of 1:1; using Cu-ka radiation, the X-ray powder diffraction spectrum has sharp diffraction peaks;
the 2 theta angle of the characteristic peak of the X-ray powder diffraction spectrum is as follows: 9.56+ -0.2 °, 13.92+ -0.2 °, 14.92+ -0.2 °, 16.06+ -0.2 °, 17.72+ -0.2 °, 22.53+ -0.2 °, 23.03+ -0.2 °, 25.56+ -0.2 °.
2. The epalrestat co-crystal with nicotinamide as a precursor according to claim 1, wherein the measurement conditions using Cu-ka radiation are: the voltage is 40+/-4 kilovolts, the current is 40+/-4 milliamps, and the angle range of 2 theta is 3-40 degrees; the step length is 0.02+/-0.002 degrees; the speed is 0.1.+ -. 0.01 seconds/step.
3. The epalrestat co-crystal with nicotinamide as a precursor according to claim 1, wherein the X-ray powder diffraction spectrum is shown in fig. 2.
4. The nicotinamide-precursor epalrestat co-crystal of claim 1, wherein the infrared spectra are at 3359, 3174, 1700, 1686, 1629, 1572, 1564, 1367, 1326, 1229, 1191, 1114, 1056, 979, 938, 882, 745, 694, 602cm -1 With characteristic peaks.
5. The epalrestat co-crystal with nicotinamide as a precursor according to claim 1, wherein the melting point is 209±2 ℃.
6. A preparation method of epalrestat eutectic with nicotinamide as a precursor, as claimed in claim 1, is characterized in that epalrestat 1.59g and nicotinamide 0.61g are respectively and accurately weighed into a 50ml grinding tank, absolute ethyl alcohol 0.5ml is added by a micropipette, and the mixture is put into a grinding ball 20 g;
placing a grinding tank into a planetary ball mill BM6pro, setting the rotating speed to be 500 revolutions per minute, setting the grinding time to be 5 minutes, and cycling for 5 times at intervals of 3 minutes;
after the operation is finished, the grinding tank is taken down, and a sample is scraped by a cleaning scraper, so that the epalrestat and nicotinamide eutectic crystal is obtained;
the X-ray powder diffraction pattern of the prepared epalrestat and nicotinamide eutectic is shown in figure 2.
7. A pharmaceutical composition, characterized by comprising the epalrestat eutectic crystal taking nicotinamide as a precursor and a pharmaceutical excipient according to any one of claims 1-5.
8. Use of the epalrestat co-crystal taking nicotinamide as a precursor according to any one of claims 1-5 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating diabetic complications.
9. The use according to claim 8, wherein the diabetic complications comprise neuropathy, corneal epithelial lesions, retinopathy and/or microvascular lesions.
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|---|---|---|---|---|
| US5811547A (en) * | 1992-10-14 | 1998-09-22 | Nippon Shinyaju Co., Ltd. | Method for inducing crystalline state transition in medicinal substance |
| WO2010011926A2 (en) * | 2008-07-25 | 2010-01-28 | Bionevia Pharmaceuticals, Inc. | A novel betaine cocrystal of epalrestat |
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| PL2326632T3 (en) * | 2008-09-06 | 2017-10-31 | Bionevia Pharmaceuticals Inc | Novel choline cocrystal of epalrestat |
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|---|---|---|---|---|
| US5811547A (en) * | 1992-10-14 | 1998-09-22 | Nippon Shinyaju Co., Ltd. | Method for inducing crystalline state transition in medicinal substance |
| WO2010011926A2 (en) * | 2008-07-25 | 2010-01-28 | Bionevia Pharmaceuticals, Inc. | A novel betaine cocrystal of epalrestat |
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| Jingjing Sun,et al.."Novel Drug−Drug Multicomponent Crystals of Epalrestat− Metformin: Improved Solubility and Photostability of Epalrestat and Reduced Hygroscopicity of Metformin".《Cryst. Growth Des.》.2022,第22卷第1005−1016页. * |
| Min Li,et al.."Drug−Drug Multicomponent Crystals of Epalrestat: A Novel Form of the Drug Combination and Improved Solubility and Photostability of Epalrestat".《Cryst. Growth Des.》.2022,第22卷第5027−5035页. * |
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