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WO2022067724A1 - 一种sglt-2抑制剂·肌氨酸共晶体及其制备方法和应用 - Google Patents

一种sglt-2抑制剂·肌氨酸共晶体及其制备方法和应用 Download PDF

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WO2022067724A1
WO2022067724A1 PCT/CN2020/119547 CN2020119547W WO2022067724A1 WO 2022067724 A1 WO2022067724 A1 WO 2022067724A1 CN 2020119547 W CN2020119547 W CN 2020119547W WO 2022067724 A1 WO2022067724 A1 WO 2022067724A1
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sglt
inhibitor
sarcosine
crystal
dapagliflozin
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French (fr)
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贾慧娟
侯伟
任晓慧
郭亮
董艳阳
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Beijing Creatron Institute Of Pharmaceutical Research Co Ltd
Tianjin Creatron Biotechnology Co Ltd
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Beijing Creatron Institute Of Pharmaceutical Research Co Ltd
Tianjin Creatron Biotechnology Co Ltd
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Priority to US18/029,062 priority Critical patent/US20230372375A1/en
Priority to EP20955749.5A priority patent/EP4206212A4/en
Priority to PCT/CN2020/119547 priority patent/WO2022067724A1/zh
Priority to CN202080104942.8A priority patent/CN116249699A/zh
Publication of WO2022067724A1 publication Critical patent/WO2022067724A1/zh
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Definitions

  • the invention relates to the technical field of chemical pharmacy, in particular to an SGLT-2 inhibitor-sarcosine co-crystal and a preparation method and application thereof.
  • SGLT-2 inhibitors Chinese called sodium-glucose co-transporters 2 (sodium-dependent glucose transporters 2, SGLT-2) inhibitors, can inhibit the reabsorption of glucose by the kidneys, so that excess glucose is excreted in the urine, So as to achieve the purpose of lowering blood sugar.
  • Faxiga active ingredient is Dapagliflozin
  • Invokana active ingredient is canagliflozin, Canagliflozin
  • Jardiance active ingredient is Enpagliflozin) Net
  • Empagliflozin Empagliflozin
  • Suglat active ingredient is Epagliflozin, Ipagliflozin
  • Tofogliflozin preparation products Tofogliflozin.
  • Faxiga, Invokana and Jardiance have been approved by the US FDA and EMA for many years. They combine diet and exercise to improve blood sugar control in adult patients with type 2 diabetes, reduce the risk of type 2 diabetes and cardiovascular disease or more. Clinical efficacy and safety have been demonstrated in adults with various cardiovascular risk factors at risk of hospitalization for heart failure.
  • WO03099836A1/CN100534997C discloses the synthesis and purification method of dapagliflozin to obtain dapagliflozin amorphous glassy solid.
  • This vitreous solid is easily softened when heated, forms an oily substance, and is easy to absorb moisture and deteriorate, resulting in the inability of the active ingredient to be uniformly distributed in the product and unable to be used in the production of preparations.
  • WO2008/002824A1/US7919598B2/CN1014792878 discloses the preparation and physicochemical properties of the medicinal crystal form of dapagliflozin (S)-propylene glycol hydrate used in Faxiga, which is accompanied by desolvation between 45 and 100°C.
  • US8513202/CN101573368B discloses that the medicinal crystal form used by Invokana is canagliflozin hemihydrate, whose melting point is 97-100°C; The melting point is 71-92°C.
  • the above-mentioned active ingredient crystal form is suitable for preparation production, and the production process of its preparation composition cannot adopt the powder direct pressing process, otherwise there will be uneven mixing, sticking, and content that does not meet the requirements due to electrostatic adsorption.
  • Drug co-crystal is a crystal formed by the combination of drug molecules and co-crystal reagents under the action of hydrogen bonds or other non-covalent bonds. It is the focus and frontier of international crystal engineering research.
  • the ligands or solvents used in the pharmaceutical crystal forms or co-crystals of the existing SGLT-2 inhibitors are chiral reagents or chiral ligands, which are expensive, and the cost of the final drug is relatively high.
  • the SGLT-2 inhibitors disclosed in the prior art all need to pass some special purification means before the final crystallization, salification, and co-crystal preparation process steps to purify the SGLT-2 inhibitor crude product or intermediate to 99%. % and above, the subsequent steps of crystallization, salt formation, and eutectic formation are carried out.
  • the process impurities generated during the preparation of SGLT-2 inhibitors such as ring-opening impurities, five-membered ring impurities, diastereomers, dimers and a large number of non-specific impurities, are difficult to remove by simple solvent recrystallization.
  • the introduction of a separate purification step in the process not only prolongs the production cycle, but also significantly increases the production cost, and at the same time, it is difficult to ensure the batch-to-batch quality reproducibility and stability of the batch production process.
  • the technical problem to be solved by the present invention is to provide a SGLT-2 inhibitor-sarcosine co-crystal and its preparation method and application, and to prepare a kind of simple process, high reproducibility, controllable crystal form and quality , A co-crystal of SGLT-2 inhibitor suitable for scale-up production of preparation compositions, storage of raw materials, good production process stability, and strong impurity removal ability at the same time.
  • the present invention provides an SGLT-2 inhibitor ⁇ sarcosine co-crystal.
  • the SGLT-2 inhibitor can form a co-crystal with sarcosine, preferably, the SGLT-2 inhibitor includes but is not limited to dapagliflozin, Ligagliflozin, canagliflozin, togagliflozin, ipagliflozin, lupagliflozin, soxagliflozin, canagliflozin, begagliflozin, ipagliflozin, ipagliflozin, henggliflozin Net, Repagliflozin, Tagagliflozin, Vanpagliflozin, (2'R,3'R,4'S,5'S,6'R)-6-(4-ethoxybenzyl)-6'-(hydroxymethyl)- 7-methyl-3',4',5',6'-tetrahydrospiro[benzo[d][1,3]
  • the SGLT-2 inhibitor ⁇ sarcosine co-crystal is in a sufficient crystal form.
  • the common names of the SGLT-2 inhibitors shown in Table 1 above to form co-crystals with sarcosine are: dapagliflozin-sarcosine co-crystal, empagliflozin-sarcosine co-crystal, canagliflozin Net ⁇ sarcosine co-crystal, topagliflozin ⁇ sarcosine co-crystal, ipagliflozin ⁇ sarcosine co-crystal, lupagliflozin ⁇ sarcosine co-crystal, soxagliflozin ⁇ sarcosine co-crystal Crystal, gaggliflozin ⁇ sarcosine co-crystal, bepagliflozin ⁇ sarcosine co-crystal, ipagliflozin ⁇ sarcosine co-crystal, henpagliflozin ⁇ sarcosine co-crystal, empaglifl
  • the molar ratio of the SGLT-2 inhibitor to sarcosine is preferably 1:(0.5-5); in some specific embodiments of the present invention , the molar ratio of SGLT-2 inhibitor to sarcosine is preferably 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:0.95, 1:1.0, 1:1.05, 1:1.1, 1:1.2, 1: 1.3, 1: 1.4, 1: 1.5, 1: 1.6, 1: 1.7, 1: 1.8, 1: 1.9 or 1: 2.0; or the range value with the above ratio as the upper or lower limit; more preferably, SGLT- 2 Molar ratio of inhibitor to sarcosine 1:0.8, 1:0.9, 1:0.95, 1:1.0, 1:1.05, 1:1.1, 1:1.2 or 1:1.3, 1:1.4 or 1:1.5 .
  • the ligand of the SGLT-2 inhibitor ⁇ sarcosine co-crystal of the present invention is sarcosine, and sarcosine itself is a sports nutrition supplement.
  • sarcosine As a food additive or a sports nutrition supplement, the maximum daily dosage for adults can reach 2 grams or more.
  • Sarcosine is a metabolite of glycine in the human body and is widely distributed in the muscles and other tissues of the human body.
  • Food-grade sarcosine has a low market price and controllable quality. Its chemical formula is C 3 H 7 NO 2 , its CAS number is 107-97-1, and its structural formula is as follows:
  • the prepared SGLT-2 inhibitor ⁇ sarcosine co-crystal has higher safety and lower cost.
  • the SGLT-2 inhibitor ⁇ sarcosine co-crystal has the structure shown in formula I:
  • R 1 , R 2 , R 3 , R 4 and X are respectively selected from the structures shown in Table 2 below:
  • the SGLT-2 inhibitor ⁇ sarcosine co-crystal has the structure shown in formula II:
  • R 5 and R 6 are respectively selected from the structures shown in Table 3 below:
  • the co-crystal of the SGLT-2 inhibitor and sarcosine of the present invention can be a solvate or hydrate of the co-crystal or a solvate hydrate of the co-crystal, and the co-crystal of SGLT-2 and sarcosine can pass X-rays
  • the powder diffraction (XRPD) pattern is characterized by the diffraction angle 2 ⁇ of the characteristic diffraction peak at a specific position.
  • the XRPD instrument used is: RigakuD/max-RB, and the test conditions are: CuK ⁇ light source, 40kV voltage, 100mA current, narrow The slit is 1°, 0.3mm, and the acquisition software is: LJ51. Detection was performed using Cu-K ⁇ radiation.
  • the XRPD spectrum of the dapagliflozin ⁇ sarcosine co-crystal has characteristic peaks at the following positions: 3.8 ⁇ 0.2°, 10.6 ⁇ 0.2°, 13.7 ⁇ 0.2°, 17.0 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.1 ⁇ 0.2°, 21.4 ⁇ 0.2°, 22.1 ⁇ 0.2°, 23.0 ⁇ 0.2°, 25.4 ⁇ 0.2°, 27.6 ⁇ 0.2°, 33.6 ⁇ 0.2°.
  • the dapagliflozin ⁇ sarcosine co-crystal using Cu-K ⁇ radiation and X-ray powder diffraction (XRPD) pattern represented by diffraction angle 2 ⁇ , has characteristic peaks at the following positions: 3.77 ⁇ 0.2°, 10.66 ⁇ 0.2°, 11.21 ⁇ 0.2°, 13.67 ⁇ 0.2°, 14.94 ⁇ 0.2°, 16.96 ⁇ 0.2°, 17.98 ⁇ 0.2°, 18.60 ⁇ 0.2°, 19.59 ⁇ 0.2°, 20.10 ⁇ 0.2°, 20.34 ⁇ 0.2°, and 33.62 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the XRPD spectrum of the canagliflozin ⁇ sarcosine co-crystal has characteristic peaks at the following positions: 3.6 ⁇ 0.2°, 7.1 ⁇ 0.2°, 10.6 ⁇ 0.2°, 14.1 ⁇ 0.2°, 16.8 ⁇ 0.2°, 17.3 ⁇ 0.2°, 18.3 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.1 ⁇ 0.2°, 22.1 ⁇ 0.2°, 22.9 ⁇ 0.2°, 25.4 ⁇ 0.2°, 28.2 ⁇ 0.2°, 33.6 ⁇ 0.2°.
  • the canagliflozin ⁇ sarcosine co-crystal using the X-ray powder diffraction (XRPD) pattern represented by Cu-K ⁇ radiation with diffraction angle 2 ⁇ , has characteristic peaks at the following positions: 3.63 ⁇ 0.2°, 3.63 ⁇ 0.2°, 7.10 ⁇ 0.2°, 10.60 ⁇ 0.2°, 14.08 ⁇ 0.2°, 15.93 ⁇ 0.2°, 16.77 ⁇ 0.2°, 17.34 ⁇ 0.2°, 18.32 ⁇ 0.2°, 18.79 ⁇ 0.2°, 19.60 ⁇ 0.2°, 20.30 ⁇ 0.2°, 20.60 ⁇ 0.2°, 21.11 ⁇ 0.2°, 22.06 ⁇ 0.2°, 22.89 ⁇ 0.2°, 25.41 ⁇ 0.2°, 28.29 ⁇ 0.2° and 33.46 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • infrared absorption spectrum is used to characterize the structure of the SGLT-2 inhibitor-sarcosine co-crystal.
  • the instrument model of the infrared spectrometer is: Thermo Nicolet 6700 FT-IR Spectrometer, the test conditions are: KBr tablet method, and the scanning range is 450-4000cm-1. Characterized by the characteristic absorption peak of infrared spectrum.
  • the infrared spectrum of the SGLT-2 inhibitor-sarcosine co-crystal of the present invention has characteristic absorption peaks at least at the following positions: 3540 ⁇ 10cm -1 , 2691 ⁇ 5cm -1 , 2603 ⁇ 5cm -1 , 2420 ⁇ 5cm -1 .
  • the infrared spectrum of the dapagliflozin ⁇ sarcosine co-crystal has characteristic absorption peaks at the following positions: 3543.67 ⁇ 10cm -1 , 3161.94 ⁇ 10cm -1 , 2690.95 ⁇ 5cm -1 , 2603.78 ⁇ 5cm -1 , 2419.39 ⁇ 5cm -1 , 2360.665cm -1 , 1599.61 ⁇ 5cm -1 , 1510.92 ⁇ 5cm -1 , 1291.19 ⁇ 5cm -1 , 1045.97cm -1 .
  • the infrared spectrum of the canagliflozin ⁇ sarcosine co-crystal has characteristic absorption peaks at least at the following positions: 3543.82 ⁇ 10cm -1 , 3153.82 ⁇ 10cm -1 , 2690.68 ⁇ 5cm - 1 , 2603.06 ⁇ 5cm -1 , 2419.53 ⁇ 5cm -1 , 1596.33 ⁇ 5cm -1 , 1507.48 ⁇ 5cm -1 , 1086.11 ⁇ 5cm -1 , 1062.19 ⁇ 5cm -1 , 829.61 ⁇ 5cm -1 .
  • the SGLT-2 inhibitor ⁇ sarcosine co-crystal is characterized by differential scanning calorimetry, the instrument model used is: SII-DSC6220, analysis method parameters: temperature range: 30°C-250°C, Scan rate: 10°C/min, protective gas: nitrogen, 50ml/min.
  • DSC differential scanning calorimetry
  • the melting point of the dapagliflozin ⁇ sarcosine co-crystal provided by the present invention is about 149.0°C, which is higher than that of the marketed dapagliflozin (S)-propylene glycol monohydrate.
  • the melting point of the hydrate is 70°C, and the suitable melting point makes the preparation difficult to melt and agglomerate during the tablet granulation and compression process, resulting in sticking or unqualified uniformity.
  • the co-crystal prepared by the present invention is more convenient to simplify the preparation production process. ,reduce manufacturing cost.
  • thermogravimetric analysis method is used to detect the SGLT-2 inhibitor-sarcosine co-crystal provided by the present invention.
  • the instrument model of the thermogravimetric analyzer used is: SII-TG/DTA6200, and the parameters of the analysis method: temperature range: 30°C -350°C, scan rate: 10°C/min, protective gas: nitrogen, 200ml/min.
  • TGA thermogravimetric analysis
  • the co-crystal structure of the SGLT-2 inhibitor ⁇ sarcosine is also detected by proton nuclear magnetic resonance spectroscopy.
  • the instrument model used is: BrukerAVANCE600, the resonance frequency: 600MHz, and the solvent used: deuterated methanol.
  • the results show that in the hydrogen nuclear magnetic resonance (HNMR) spectrum, in addition to the resonance peak with the SGLT-2 inhibitor structure, there is a resonance peak of -CH3 in the range of chemical shift 2.4-3.2ppm, and a resonance peak in the range of 3.0-4.0ppm.
  • the -CH2- peak, the -CH2- peak may or may not coincide with other resonance peaks on the SGLT-2 structure, indicating the presence of sarcosine results.
  • the invention provides the preparation method of the above-mentioned SGLT-2 inhibitor ⁇ sarcosine co-crystal, comprising the following steps:
  • the source of the SGLT-2 inhibitor is not particularly limited, and can be generally commercially available or prepared according to methods well known to those skilled in the art, and can be pure, crude or intermediate.
  • the solvent in the SGLT-2 inhibitor solution is selected from different single solvents or mixed solvents among C1-C10 alcohols, C3-C10 ketones, ethers, and nitriles.
  • the solvent is one or more of ethanol, acetone, tetrahydrofuran and acetonitrile; more preferably, ethanol.
  • the solvent of the sarcosine solution is preferably water.
  • the molar ratio of the SGLT-2 inhibitor and sarcosine is preferably 1:(0.5-5.0), more preferably 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:0.95, 1:1.0 , 1:1.05, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2.0.
  • the dosage of the SGLT-2 inhibitor and sarcosine is strictly added according to the molar ratio of the two in the co-crystal, so that the SGLT-2 inhibitor and sarcosine just form a co-crystal, There was no excess SGLT-2 inhibitor or sarcosine in the system.
  • the system after mixing the SGLT-2 inhibitor solution and the sarcosine solution, if the system is not clear, the system can be made clear by heating.
  • the temperature of the standing crystallization or cooling crystallization is preferably -20°C to 40°C.
  • the crystallization temperature is preferably: -15°C to 35°C, -10°C to 30°C °C, -5°C ⁇ 30°C, 0°C ⁇ 30°C, 5°C ⁇ 30°C, 10°C ⁇ 30°C, 15°C ⁇ 30°C or 20°C ⁇ 30°C.
  • the time for standing crystallization or cooling crystallization is preferably 4-48 hours, preferably 4-24 hours, 4-16 hours, 4-12 hours, more preferably 8-12 hours.
  • the drying temperature is preferably 20°C to 80°C, more preferably 30°C to 80°C.
  • the obtained SGLT-2 inhibitor ⁇ sarcosine co-crystal may be a co-crystal solvate, a co-crystal solvate hydrate, or a co-crystal hydrate.
  • the preparation method of the above-mentioned SGLT-2 inhibitor-sarcosine co-crystal provided by the present invention is simple in process, easy to implement, short in period, stable in the obtained crystal form, and is not affected by crystallization conditions, storage conditions, and environment. or mixed crystal phenomenon.
  • the SGLT-2 inhibitor ⁇ sarcosine co-crystal prepared by the invention has no single impurity exceeding 0.1%, and the total amount of impurities is less than 0.5%.
  • the crude SGLT-2 inhibitor (or intermediate) is mixed with sarcosine, stirred at room temperature, and solid-liquid separated to obtain the sarcosine compound of the SGLT-2 inhibitor. It has significant purification effect, and after purification, the purity of SGLT-2 inhibitor is not less than 99%.
  • the diastereoisomeric impurities produced in the preparation process have the following reaction equation:
  • the generation mechanism of the above-mentioned five-membered ring impurity is:
  • the general chemical structure of the dimer impurity is as follows:
  • X is halogen (bromo Br or iodine I); M is magnesium, Mg; P is a protecting group, such as tetramethylsilane TMS.
  • R 1 to R 5 are the same as above, and are not repeated here.
  • the middle of the previous step can be removed.
  • Impurities such as body or material residues, these impurities are difficult to purify by simple liquid-liquid extraction or solvent recrystallization due to the similar polarity and structure to the target API.
  • the crude SGLT-2 inhibitor forms with sarcosine.
  • the sarcosinate can increase the purity of the crude SGLT-2 inhibitor from 78% to more than 99% at one time, and significantly reduce the number of impurities and the total detected amount of impurities.
  • the sarcosinate of the obtained high-purity SGLT-2 inhibitor is simply dissociated to obtain a higher-purity free SGLT-2 inhibitor, which is then used directly as the target component or prepared into other medicinal crystal forms or Medicinal co-crystals.
  • the invention provides a kind of purification method of SGLT-2 inhibitor, comprising the following steps:
  • the crude product of SGLT-2 inhibitor is mixed with sarcosine, stirred at room temperature, and solid-liquid separated to obtain a sarcosinate of SGLT-2 inhibitor.
  • the crude product of the SGLT-2 inhibitor is dissolved in a solvent
  • the solvent is preferably a different single solvent among C1-C10 alcohols, C3-C10 ketones, ethers, and nitriles, or these solvents are combined with A mixed solvent of water or a mixed solvent of the above-mentioned solvents.
  • the solvent is one or more of ethanol, acetone, tetrahydrofuran and acetonitrile, or one or more of ethanol, acetone, tetrahydrofuran and acetonitrile mixed with water; more preferably ethanol.
  • the sarcosine is dissolved in a solvent, and the solvent is preferably water.
  • the molar ratio of the crude SGLT-2 inhibitor to sarcosine is preferably 1: (0.5-5.0). In some embodiments, the molar ratio of the crude SGLT-2 inhibitor to sarcosine is preferably 1:0.7, 1 : 0.8, 1: 0.9, 1: 0.95, 1: 1.0, 1: 1.05, 1: 1.1, 1: 1.2, 1: 1.3, 1: 1.4, 1: 1.5, 1: 1.6, 1: 1.7, 1: 1.8 , 1:1.9, 1:2.0 or 1:3.0; the more preferred molar ratio of crude SGLT-2 inhibitor to sarcosine is 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0 and 1:3.0.
  • the above-mentioned sarcosine is added in excess, and the obtained sarcosine compound of the SGLT-2 inhibitor comprises part of the co-crystal formed by the SGLT-2 inhibitor and sarcosine, and part of the excess sarcosine. Creatine.
  • the above-mentioned method for solid-liquid separation is preferably static crystallization or cooling crystallization.
  • the temperature of the standing crystallization or cooling crystallization is preferably -20°C to 40°C, more preferably -10°C to 40°C, 0-40°C, 10-40°C, 15-40°C , 20-40°C, 20-35°C, or 20°C ⁇ 30°C.
  • the stirring time is preferably 6-16 hours, more preferably 6-14 hours, 7-13 hours, or 8-12 hours.
  • the SGLT-2 inhibitor and the sarcosinate are obtained, and the solid is obtained by solid-liquid separation, and the solid is preferably dried.
  • the drying temperature is preferably 20°C to 80°C, more preferably 30°C to 80°C.
  • the present invention after obtaining the sarcosinate of SGLT-2 inhibitor, it also includes:
  • the sarcosinate of the above-mentioned SGLT-2 inhibitor was dissociated to obtain a free pure product of the SGLT-2 inhibitor.
  • the HPLC-normalized purity of the free-state pure product of the SGLT-2 inhibitor is not less than 99%.
  • the final pharmaceutical crystal form of the SGLT-2 inhibitor is prepared by recrystallization or co-crystallization.
  • the final pharmaceutical crystal form of the SGLT-2 inhibitor is selected from pure SGLT-2 inhibitor, solvate, hydrate, solvate hydrate, co-crystal or double salt.
  • the present invention has no special limitation on the preparation process or source of the crude product of the SGLT-2 inhibitor, and can be the SGLT-2 inhibitor prepared according to methods well known to those skilled in the art, such as the methods described in patent documents WO03099836A1 and CN100534997C Crude product of the agent.
  • the SGLT-2 inhibitor of the following structural formula 1 in the crude product or intermediate of the SGLT-2 inhibitor should not be less than 70%, preferably not less than 75%.
  • R1, R2, R3, R4 and X are shown in Table 2.
  • the method of the dissociation is not particularly limited in the present invention, and can be a method well known to those skilled in the art.
  • the liquid-liquid extraction method can be used for dissociation, the organic phase is collected, and concentrated to obtain the free pure product of the SGLT-2 inhibitor.
  • the experimental results show that the purification method provided by the present invention can significantly remove non-specific impurities and specific impurities, diastereomer impurities, five-membered ring impurities, ring-opening impurities and dimer impurities.
  • the number of impurities is reduced by more than 90%, and the total amount of detected impurities and the detected amount of a single impurity are removed by more than 95%.
  • the number of impurities in the SGLT-2 inhibitor sarcosinate or the free body of the SGLT-2 inhibitor obtained after purification is less than 6, and the total impurity content is less than 1.0%.
  • the above purification method provided by the present invention can be used as an intermediate in the preparation process of SGLT-2 inhibitor, and can also be used as a crude product before salification, co-crystallization and crystallization.
  • the chemical structure of the SGLT-2 inhibitor intermediate is similar to Intermediate or crude product with the same structure as the target SGLT-2 inhibitor.
  • the final medicinal crystal form of the SGLT-2 inhibitor can be directly prepared by using the free state pure product of the SGLT-2 inhibitor as a raw material;
  • the final medicinal crystal form of the SGLT-2 inhibitor is prepared by recrystallization or co-crystallization.
  • the final pharmaceutical crystal form of the SGLT-2 inhibitor is preferably a pure SGLT-2 inhibitor, a solvate, a hydrate, a solvate hydrate, a co-crystal or a double salt or the like.
  • the present invention provides a pharmaceutical composition, comprising the above SGLT-2 inhibitor ⁇ sarcosine co-crystal, or the SGLT-2 inhibitor ⁇ sarcosine co-crystal prepared by the above preparation method, or the SGLT-2 inhibitor obtained by the above purification method.
  • a pharmaceutical composition comprising the above SGLT-2 inhibitor ⁇ sarcosine co-crystal, or the SGLT-2 inhibitor ⁇ sarcosine co-crystal prepared by the above preparation method, or the SGLT-2 inhibitor obtained by the above purification method.
  • Pure product in free state, or the final pharmaceutical crystal form of SGLT-2 inhibitor prepared by recrystallization or co-crystal such as pure product, solvate, hydrate, solvate hydrate of SGLT-2 inhibitor , co-crystals or double salts, etc., as well as pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles or their combinations.
  • the particles of the active ingredient may be reduced to a suitable size by some physical means such as grinding, sieving.
  • the SGLT-2 inhibitor ⁇ sarcosine co-crystal provided by the present invention has high stability, and as an active ingredient, it is favorable for uniform distribution in pharmaceutical composition products. Due to the high melting point, during the crushing or grinding process, it will not melt or stick into agglomerates or electrostatic adsorption due to heat generation, and the crystal form will not change during the entire grinding or grinding process, and the final pharmaceutical composition will be obtained. , the active ingredient content is uniform, conforms to the labeled amount, and has high repeatability.
  • the present invention provides the above-mentioned SGLT-2 inhibitor-sarcosine co-crystal or the SGLT-2 inhibitor-sarcosine co-crystal prepared by the above-mentioned preparation method, or the free-state pure product of the SGLT-2 inhibitor obtained by the above-mentioned purification method, or The final pharmaceutical crystal form of SGLT-2 inhibitor prepared by recrystallization or co-crystal, such as pure SGLT-2 inhibitor, solvate, hydrate, solvate hydrate, co-crystal or double salt, etc., Or the application of the above pharmaceutical composition in the preparation of medicines for preventing, treating or alleviating diabetes and its complications, treating and preventing or alleviating cardiovascular and cerebrovascular diseases and nephropathy caused by non-diabetes.
  • the present invention provides the above-mentioned SGLT-2 inhibitor-sarcosine co-crystal or the SGLT-2 inhibitor-sarcosine co-crystal prepared by the above-mentioned preparation method, or the free-state pure product of the SGLT-2 inhibitor obtained by the above-mentioned purification method, or
  • the final pharmaceutical crystal form of SGLT-2 inhibitor such as pure SGLT-2 inhibitor, solvate, hydrate, solvate hydrate, co-crystal or double salt, etc., is prepared by recrystallization or co-crystal, or Application of the above pharmaceutical composition in the preparation of a medicament for lowering blood pressure.
  • the diabetes and its complications include but are not limited to:
  • Essential hypertension type 2 diabetes with hypertension, nephropathy with type 2 diabetes, nephropathy with hypertension and diabetes, nephropathy, type 1 diabetes, nephropathy with type 1 diabetes, liver fibrosis, insulin resistance, hyperglycemia , one or more of hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity.
  • the above-mentioned SGLT-2 inhibitor-sarcosine co-crystal of the present invention or the free-state pure product of the SGLT-2 inhibitor obtained by the above purification method, or the final medicinal crystal form of the SGLT-2 inhibitor prepared by recrystallization or co-crystal , such as SGLT-2 inhibitor pure product, solvate, hydrate, solvate hydrate, co-crystal or double salt, etc., or the pharmaceutical composition is used in the preparation for the prevention, treatment or alleviation of diabetes and its complications , drugs for cardiovascular and cerebrovascular diseases, or when preparing drugs for lowering blood pressure or drugs for non-diabetic nephropathy, it can be used alone or in combination with other drugs.
  • the present invention provides a method for preventing, treating or alleviating diabetes and its complications, comprising mixing the above SGLT-2 inhibitor-sarcosine co-crystal or the SGLT-2 inhibitor-sarcosine co-crystal prepared by the above preparation method , or the free-state pure product of SGLT-2 inhibitor obtained by the above purification method, or the final medicinal crystal form of SGLT-2 inhibitor prepared by recrystallization or co-crystallization, such as pure product of SGLT-2 inhibitor, solvate, A hydrate, a solvate hydrate, a co-crystal or a double salt, etc., or the above-mentioned pharmaceutical composition is contacted with a biological specimen.
  • the present invention provides a method for lowering blood pressure, comprising the above-mentioned SGLT-2 inhibitor-sarcosine co-crystal or the SGLT-2 inhibitor-sarcosine co-crystal prepared by the above-mentioned preparation method, or the SGLT obtained by the above-mentioned purification method -2 pure free state inhibitor, or the final pharmaceutical crystal form of SGLT-2 inhibitor prepared by recrystallization or co-crystal, such as pure SGLT-2 inhibitor, solvate, hydrate, solvate hydrate , co-crystals or double salts, etc., or the above-mentioned pharmaceutical compositions are in contact with biological specimens.
  • the present invention provides a method for treating non-diabetic nephropathy, comprising the above-mentioned SGLT-2 inhibitor-sarcosine co-crystal or the SGLT-2 inhibitor-sarcosine co-crystal prepared by the above preparation method, or the above-mentioned purification
  • the free state pure product of the SGLT-2 inhibitor obtained by the method, or the final medicinal crystal form of the SGLT-2 inhibitor, such as the pure product, solvate, hydrate, solvent of the SGLT-2 inhibitor, prepared by recrystallization or co-crystallization hydrates, co-crystals or double salts, etc., or the above-mentioned pharmaceutical compositions are contacted with biological specimens.
  • the present invention provides an SGLT-2 inhibitor ⁇ sarcosine co-crystal. Has the following beneficial effects:
  • the drug co-crystal has high stability. During the production process or storage process of the preparation composition, the crystal form is not easy to change; the storage or preparation process temperature is high or the preparation production process will not be melted by heat, and no sticking will occur. Crush, agglomerate or generate static electricity, with better mixing uniformity;
  • the sarcosine co-crystal of the SGLT-2 inhibitor does not change the solubility of the drug used as the bulk drug for oral solid preparations in different pH physiological media, which is very important to ensure the absorption of oral solid preparations;
  • the final intermediate or crude product of SGLT-2 inhibitor can be purified and dissociated by sarcosine compound to obtain SGLT-2 inhibitor with a purity of more than 99%
  • the free form can be recrystallized, co-crystallized, or co-crystallized with sarcosine according to the needs of the target API, without the need for additional tedious impurity removal steps.
  • Fig. 1 is the X-ray powder diffraction pattern (XRPD) and single crystal diffraction pattern of the dapagliflozin-sarcosine co-crystal prepared in Example 1;
  • Fig. 2 is the infrared spectrum analysis figure (IR) of the dapagliflozin ⁇ sarcosine co-crystal prepared in Example 1;
  • FIG. 3 is the differential scanning calorimetry (DSC) of the dapagliflozin-sarcosine co-crystal prepared in Example 1;
  • FIG. 4 is a thermogravimetric analysis chart (TGA) of the dapagliflozin-sarcosine co-crystal prepared in Example 1;
  • FIG. 5 is the hydrogen nuclear magnetic resonance spectrum (H-NMR) of the dapagliflozin-sarcosine co-crystal prepared in Example 1;
  • Figure 6 is the X-ray powder diffraction pattern (XRPD) of the canagliflozin-sarcosine co-crystal prepared in Example 12;
  • Fig. 7 is the infrared spectrum analysis chart (IR) of the canagliflozin ⁇ sarcosine co-crystal prepared in Example 12;
  • Figure 8 is a differential scanning calorimetry (DSC) of the canagliflozin-sarcosine co-crystal prepared in Example 12;
  • FIG. 9 is a thermogravimetric analysis chart (TGA) of the canagliflozin-sarcosine co-crystal prepared in Example 12;
  • Figure 10 is the hydrogen nuclear magnetic resonance spectrum (H-NMR) of the canagliflozin-sarcosine co-crystal prepared in Example 12;
  • Figure 11 is an ellipsoid diagram of the molecular structure of the single crystal structure of the dapagliflozin-sarcosine co-crystal.
  • the sarcosine raw material used in the present invention is commercially available.
  • the dapagliflozin raw materials used in the present invention can be obtained commercially, or prepared according to known methods, such as the method described in the patent document CN100534997C.
  • the solvent used in the present invention is not particularly limited, and commercially available conventional solvents can be used.
  • XRPD X-ray powder diffraction
  • the instrument model of X-single crystal diffraction Gemini E single crystal diffractometer, the crystal analysis software is Shelx97; CuKa is used as the X-ray light source.
  • IR Infrared spectral analysis
  • DSC Differential scanning calorimetry
  • thermogravimetric analysis (TGA) data the instrument model used is: SII-TG/DTA6200, analysis method parameters: temperature range: 30°C-350°C, scan rate: 10°C/min, protective gas: nitrogen, 200 ml /minute.
  • Hydrogen nuclear magnetic resonance (HNMR) data were collected, the instrument model used was: BrukerAVANCE600, the resonance frequency: 600 MHz, and the solvent used: deuterated methanol.
  • liquid phase test conditions involved in the present invention are as follows: the chromatographic column is Kromasil KR100-5-C18, 4.6 ⁇ 250 mm; mobile phase A: 0.1% phosphoric acid; mobile phase B: acetonitrile; detection wavelength: 220 nm; flow rate: 0.8 mL/min; Injection volume: 20 ⁇ L; column temperature: 35 °C; liquid phase conditions are shown in Table 4 below:
  • reagents such as canagliflozin and sarcosine, are generally commercially available unless the source is specified.
  • Dapagliflozin used in the following examples was prepared according to patent document WO03099836A1.
  • XRPD X-ray powder diffraction
  • IR infrared spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • H-NMR nuclear magnetic resonance spectroscopy
  • the dapagliflozin ⁇ sarcosine co-crystal using the X-ray powder diffraction (XRPD) pattern represented by the diffraction angle 2 ⁇ of Cu-K ⁇ radiation, has the characteristic peaks and their relative intensities as shown in Table 5 below, and the diffraction angle
  • the 2 ⁇ error is ⁇ 0.2°:
  • the dapagliflozin ⁇ sarcosine co-crystal has absorption peaks at the following positions: 3543.67 ⁇ 10cm -1 , 3161.94 ⁇ 10cm -1 , 2888.82 ⁇ 5cm - in the infrared absorption (IR) spectrum measured by the KBr tablet method.
  • the differential scanning calorimetry (DSC) spectrum of dapagliflozin ⁇ sarcosine co-crystal shows an endothermic peak in the range of 140.0°C ⁇ 155.0°C, and the peak is 149.0°C, which is the melting temperature.
  • thermogravimetric analysis (TGA) spectrum of dapagliflozin ⁇ sarcosine co-crystal shows no obvious weight loss before 150°C; the TGA-DTA image has a broad endothermic peak in the range of 190°C-230°C.
  • TGA thermogravimetric analysis
  • the solid product was dissolved with 3 times the volume of methyl tert-butyl ether, added to 150ml of n-heptane solution, and a white solid was precipitated, filtered under nitrogen protection, the filter cake was collected, and vacuum-dried at 40 °C to obtain free dapagliflozin free
  • the pure product was 19.5 g (yield 80%).
  • Dapagliflozin crude product (batch number: 20200703-3, yellow foamy solid) prepared by the method provided by patent document WO03099836A1, and detect impurities before purification.
  • XRPD X-ray powder diffraction
  • IR infrared spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • 1 H- NMR hydrogen nuclear magnetic resonance
  • the canagliflozin ⁇ sarcosine co-crystal using the X-ray powder diffraction (XRPD) pattern represented by the diffraction angle 2 ⁇ of Cu-K ⁇ radiation, has the characteristic peaks and their relative intensities as shown in Table 9 below, and the diffraction angle
  • the 2 ⁇ error is ⁇ 0.2°:
  • the canagliflozin ⁇ sarcosine co-crystal has absorption peaks at the following positions: 3543.82 ⁇ 10cm -1 , 3153.82 ⁇ 10cm -1 , 2690.68 ⁇ 5cm - in the infrared absorption (IR) spectrum measured by the KBr tablet method 1 , 2603.06 ⁇ 5cm -1 , 2419.53 ⁇ 5cm -1 , 1596.33 ⁇ 5cm -1 , 1507.48 ⁇ 5cm -1 , 1411.84 ⁇ 5cm -1 , 1382.27 ⁇ 5cm -1 , 1321.84 ⁇ 5cm -1 , 1233.44 ⁇ 5cm -1 , 1086.11 ⁇ 5cm -1 , 1062.19 ⁇ 5cm -1 , 829.61 ⁇ 5cm -1 , 799.52 ⁇ 5cm -1 , 537.55 ⁇ 5cm -1 .
  • the differential scanning calorimetry (DSC) spectrum of canagliflozin ⁇ sarcosine co-crystal shows an endothermic peak in the range of 160.0°C ⁇ 180.0°C, and the peak is 179.5°C, which is the melting temperature.
  • thermogravimetric analysis (TGA) spectrum of canagliflozin ⁇ sarcosine co-crystal shows no obvious weight loss before 150°C; the TGA-DTA graph has a wide endothermic peak in the range of 190°C-230°C.
  • the single crystal of dapagliflozin-sarcosine co-crystal was obtained by culturing in the mixed solvent system of ethanol/water by slow evaporation of solvent, and X-ray single crystal diffraction was used to characterize it:
  • the Flack parameter that characterizes the absolute configuration is 0.03, which is less than 0.2.
  • the absolute configuration of the chiral center of the dapagliflozin-sarcosine co-crystal is determined by single crystal structure analysis as follows:
  • composition is composed of dapagliflozin and sarcosine 1:1.
  • Dapagliflozin ⁇ sarcosine co-crystal and Dapagliflozin (S)-propylene glycol monohydrate were used for influencing factor experiments, and the two crystal forms were taken at high temperature of 60°C ⁇ 2°C, light of 4500LX ⁇ 500LX, Under the condition of high humidity RH75% ⁇ 5% for 10 days, the physical stability and chemical stability of the two crystal forms were investigated. The results are shown in Table 13, Table 14 and Table 15 below:
  • the dapagliflozin-sarcosine co-crystal did not increase the number of detected related substances and the total detected amount of impurities under all the experimental conditions investigated, while dapagliflozin (S)- Propylene glycol monohydrate, the number of impurities and total impurities increased at a high temperature of 60 °C, the number of impurities increased from 6 to 13 at 0 days, and the dapagliflozin-sarcosine co-crystal influence factors for 10 days under each condition The number and amount of impurities detected at the bottom were consistent with 0 days, and showed no trend of change.
  • the XRPD and 0-day XRPD results of the 10-day samples were investigated by the influencing factors and each condition.
  • the dapagliflozin co-crystal was investigated for 10 days by the influencing factors and each condition, and the crystal form did not change.
  • the canagliflozin ⁇ sarcosine co-crystal and canagliflozin hemihydrate (original crystal form) were used for the influencing factor experiment, and the materials of the two crystal forms were taken at high temperature of 60°C ⁇ 2°C, light of 4500LX ⁇ 500LX, Under the condition of high humidity RH75% ⁇ 5% for 10 days, the physical stability and chemical stability of the two crystal forms were investigated. The results are shown in Table 16 and Table 17 below:
  • the canagliflozin-sarcosine co-crystal was exposed for 10 days under the conditions of high temperature of 60°C and high humidity of 75%.
  • the number of detected impurities and the The detected amount did not show an increasing trend; under the condition of light 5000LX for 10 days, canagliflozin eutectic detected 2 new impurities, but the maximum detected amount was about 0.05%; the impurities were detected under the light condition of hemihydrate.
  • Canagliflozin hemihydrate loses about 1.0% in weight under high temperature at 60°C for 10 days, and under high humidity RH75% for 10 days, canagliflozin hemihydrate gains about 2.1% in weight, while canagliflozin ⁇
  • Under the conditions of high temperature of 60°C and high humidity of 75% of sarcosine co-crystal there is basically no change in weight gain and loss, indicating that the physical stability of the crystal form of canagliflozin-sarcosine co-crystal prepared by the present invention is better than that of canagliflozin. Hydrate.
  • the XRPD and 0-day XRPD results of the 10-day sample were investigated by the influencing factors and various conditions.
  • the canagliflozin cocrystal was investigated for 10 days under the influencing factors and each condition. type has not changed.
  • the dapagliflozin-sarcosine co-crystal does not have hygroscopicity.
  • the dapagliflozin-sarcosine co-crystal powder state is more favorable for sieving, the sieving loss is small, the yield is high, and there is basically no electrostatic effect.
  • the D90 of the dapagliflozin co-crystals were 89.93 ⁇ m, respectively, and the particle size distribution was conducive to uniform mixing in the preparation process of the pharmaceutical composition, especially for small-sized preparations.
  • the bulk density and tap density of dapagliflozin-sarcosine co-crystal and dapagliflozin-(S)-propanediol monohydrate are slightly different.
  • the angle of repose is smaller, and the fluidity is better than that of dapagliflozin-(S)-propanediol monohydrate.
  • FH laboratory mixer (0.5L hopper) was used to mix the prescription materials shown in Table 20, the rotation speed was 8rpm, and the time was 30min. A total of 5 points were taken from different positions in the hopper to detect the content of the main drug, calculate the RSD, and evaluate the difficulty of mixing. The results are shown in Table 23.
  • Dosage (g) Main drug (the dosage is calculated by dapagliflozin) 10.0 microcrystalline cellulose 171.5 anhydrous lactose 50.0 Crospovidone 10.0 Croscarmellose sodium 4.0 silica 3.75
  • the formulation mixing uniformity of the dapagliflozin-sarcosine co-crystal as the main drug is the best, which meets the requirements of preparation production.
  • Dapagliflozin-(S)-propylene glycol monohydrate is easy to agglomerate and is difficult to mix uniformly.
  • the solubility in different pH media is still between 1.4 and 1.6 mg/ml , which is consistent with the solubility of dapagliflozin-(S)-propanediol monohydrate reported in the literature; according to the solubility of canagliflozin-sarcosine co-crystal in different pH media, the solubility is about 30 ⁇ g/ml, which is almost insoluble.
  • canagliflozin hemihydrate is almost insoluble in water (1g cannot be dissolved in 10000ml), and the solubility of the two in aqueous solution is basically the same.
  • the canagliflozin co-crystal is more suitable for the large-scale industrial production of formulation compositions.

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Abstract

提供了一种SGLT-2抑制剂·肌氨酸共晶体及其制备方法和应用。以肌氨酸为配体，具有较高的安全性和较低的成本；药物共晶体具有较高的稳定性，在制剂组合物生产过程或贮藏过程中，晶型不易发生改变；不会遇热熔融，不会发生粘冲、聚团或产生静电，具有更好的混合均匀性；在制备的药物组合物中分布均匀，使得药物组合物具有更好的体内释放、吸收和药效，且批间差异小；具有较高的稳定性，更利于贮藏、运输；制备工艺简单，重现性高，且析晶时间短，工艺条件要求低，具有更高的经济效益；制备过程中不使用不安全溶剂；可同时对SGLT-2抑制剂粗品或中间体进行纯化。

Description

一种SGLT-2抑制剂·肌氨酸共晶体及其制备方法和应用 技术领域
本发明涉及化学制药技术领域，尤其涉及一种SGLT-2抑制剂·肌氨酸共晶体及其制备方法和应用。
背景技术
根据国际糖尿病联合会发布的第9版《全球糖尿病地图，(IDF Diabetes Atlas)》，目前全球范围内在20岁～79岁人群中有4.63亿人患有糖尿病，其中绝大多数为2型糖尿病。到2030年与2045年，预计这一数字将分别达到5.78亿(10.2％)与7亿(10.9％)。IDF报告指出：全球糖尿病患者中有32％患有心血管疾病；超过80％的终末期肾脏疾病是由糖尿病或高血压或两者同时引起；糖尿病足和下肢并发症影响4000万～6000万糖尿病患者。
SGLT-2抑制剂，中文名为钠-葡萄糖协同转运蛋白2(sodium-dependent glucose transporters 2，SGLT-2)抑制剂，可以抑制肾脏对葡萄糖的重吸收，使过量的葡萄糖从尿液中排出，从而达到降低血糖的目的。目前已经上市的SGLT-2抑制剂(按商品名)有：Faxiga(活性成分为达格列净，Dapagliflozin)、Invokana(活性成分为卡格列净，Canagliflozin)、Jardiance(活性成分为恩格列净，Empagliflozin)、Suglat(活性成分为依格列净，Ipagliflozin)以及托格列净制剂产品(Tofogliflozin)。上述SGLT-2抑制剂中Faxiga、Invokana和Jardiance均已经被美国FDA和EMA批准上市多年，其结合饮食和锻炼，改善II型糖尿病成人患者的血糖控制、降低患2型糖尿病和心血管疾病或多种心血管危险因素的成人因心力衰竭住院的风险的临床有效性和安全性是已经被证实了的。
现有技术WO03099836A1/CN100534997C中公开了达格列净的合成以及纯化方法，得到了达格列净无定型玻璃状固体。这种玻璃状固体受热易软化、形成油状物、易吸潮变质，导致活性成分无法在产品中均匀分布，无法用于制剂生产。WO2008/002824A1/US7919598B2/CN1014792878中公开了Faxiga中使用的药用晶型达格列净(S)-丙二醇水合物晶型的制备、物理化学特性，其 在45～100℃之间伴随脱溶剂。US8513202/CN101573368B公开了Invokana使用的药用晶型为卡格列净半水合物，其熔点为97～100℃；WO2014159151A1中公开了托格列净用药晶型的制备，其晶型为水合物，熔点为71-92℃。上述活性成分晶型为适应制剂生产，其制剂组合物的生产工艺无法采用粉末直压工艺，否则会出现混合不均匀、粘冲、由于静电吸附导致含量不符合要求等。
药物共晶，是药物分子与共晶试剂在氢键或其他非共价键的作用下，结合而成的晶体，是目前国际晶体工程学研究的焦点和前沿。
研究表明，达格列净·L-脯氨酸共晶存在多晶型，且制备工艺条件比较苛刻：-20℃析晶三天，一方面要求高能耗的低温控制，同时仅成共晶步骤就需要三天，延长了整个生产周期。托格列净·L-脯氨酸共晶体在晶型稳定性、引湿性、静电、流动性、化学稳定性等方面还不如低熔点的水合物晶型。因此，目前上市产品并未采用托格列净·L-脯氨酸共晶体，而是采用了熔点为71-92℃的水合物晶型。
另外，现有的SGLT-2抑制剂的药用晶型或共晶使用的配体或溶剂为手性试剂或手性配体，价格昂贵，最终获得的药物成本较高。
现有技术公开的SGLT-2抑制剂在进行最终的结晶析晶、成盐、共晶制备工艺步骤前均需要通过某种特殊的纯化手段，将SGLT-2抑制剂粗品或中间体纯化至99％以上纯度再进行后续的结晶析晶、成盐、成共晶步骤。尤其对SGLT-2抑制剂制备过程产生的工艺杂质，如开环杂质、五元环杂质、非对映异构体、二聚体以及大量的非特异杂质等难于通过简单的溶剂重结晶去除，工艺中引入单独的纯化步骤，不仅延长了生产周期，也显著提高了生产成本，同时难以保证批量生产过程的批间质量重现性与稳定性。
综上，针对SGLT-2抑制剂，开发更有利于制剂生产、晶型制备简单、易重现、成本低，质量稳定、安全的药用晶型对降低临床用药成本，提高上市产品的安全性、有效性和可控性具有重大意义。
发明内容
鉴于此，本发明要解决的技术问题在于提供一种SGLT-2抑制剂·肌氨酸共晶体及其制备方法和应用，制备出一种工艺简单、重现性高、晶型及质量 可控、适合制剂组合物放大生产、原料药贮藏、生产过程稳定性好、同时兼具除杂能力强的SGLT-2抑制剂的共晶体。
为达到上述目的，本发明提供了一种SGLT-2抑制剂·肌氨酸共晶体。
本发明中，所述SGLT-2抑制剂，包含经典的葡萄糖苷结构，均可与肌氨酸形成共晶体，优选的，所述SGLT-2抑制剂包括但不限于达格列净、恩格列净、卡格列净、托格列净、伊格列净、鲁格列净、索格列净、加格列净、贝格列净、艾格列净、埃格列净、恒格列净、瑞格列净、泰格列净、万格列净、(2'R,3'R,4'S,5'S,6'R)-6-(4-ethoxybenzyl)-6'-(hydroxymethyl)-7-methyl-3',4',5',6'-tetrahydrospiro[benzo[d][1,3]dioxine-4,2'-pyran]-3',4',5'-triol，具体结构式如表1所示：
表1 SGLT-2抑制剂结构及命名
Figure PCTCN2020119547-appb-000001
Figure PCTCN2020119547-appb-000002
Figure PCTCN2020119547-appb-000003
Figure PCTCN2020119547-appb-000004
本发明优选的，所述SGLT-2抑制剂·肌氨酸共晶体是一种充分的结晶形态。
上述表1所示的SGLT-2抑制剂与肌氨酸形成共晶体后的通常命名分别为：达格列净·肌氨酸共晶，恩格列净·肌氨酸共晶，卡格列净·肌氨酸共晶，托格列净·肌氨酸共晶，伊格列净·肌氨酸共晶，鲁格列净·肌氨酸共晶，索格列净·肌氨酸共晶，加格列净·肌氨酸共晶，贝格列净·肌氨酸共晶，艾格列净·肌氨酸共晶，恒格列净·肌氨酸共晶，埃格列净·肌氨酸共晶、瑞格列净·肌氨酸共晶，万格列净·肌氨酸共晶等。
本发明中，所述SGLT-2抑制剂·肌氨酸共晶体中，SGLT-2抑制剂与肌氨酸的摩尔比优选为1：(0.5～5)；在本发明的一些具体实施例中，SGLT-2抑制剂与肌氨酸摩尔比优选为1：0.6、1：0.7、1：0.8、1：0.9、1：0.95、1：1.0、1：1.05、1：1.1、1：1.2、1：1.3、1：1.4、1：1.5、1：1.6、1：1.7、1：1.8、1：1.9或1：2.0；或者以上述比例为上限或下限的范围值；进一步优选的，SGLT-2抑制剂与肌氨酸的摩尔比为1：0.8、1：0.9、1：0.95、1：1.0、1：1.05、1：1.1、1：1.2或1：1.3、1：1.4或1：1.5。
本发明所述SGLT-2抑制剂·肌氨酸共晶体的配体为肌氨酸，肌氨酸本身为运动营养补充剂，作为食品添加剂或运动营养补充剂，成人每日最大用量可达2克以上。肌氨酸是甘氨酸在人体内的代谢产物，并广泛分布于人体的肌肉和其他组织中。
食品级肌氨酸市售价格很低，质量可控，其化学式为C 3H 7NO 2，CAS号为107-97-1，结构式如下所示：
Figure PCTCN2020119547-appb-000005
因此，制备的SGLT-2抑制剂·肌氨酸共晶体具有较高的安全性，以及较低的成本。
本发明优选的，所述SGLT-2抑制剂·肌氨酸共晶体具有式Ⅰ所示结构：
Figure PCTCN2020119547-appb-000006
其中，R 1、R 2、R 3、R 4及X分别选自下表2所示结构：
表2
Figure PCTCN2020119547-appb-000007
上述表2中，虚线表示连接的位置。
进一步优选的，所述SGLT-2抑制剂·肌氨酸共晶体具有式Ⅱ所示结构：
Figure PCTCN2020119547-appb-000008
其中，R 5、R 6分别选自下表3所示结构：
表3
Figure PCTCN2020119547-appb-000009
本发明所述SGLT-2抑制剂与肌氨酸共晶体，可以是共晶体的溶剂化物或水合物或共晶体的溶剂化物水合物，SGLT-2与肌氨酸的共晶体可通过X-射线粉末衍射(XRPD)图谱中在特定位置的特征衍射峰的衍射角2θ来表征，所使用的XRPD的仪器型号为：RigakuD/max-RB，测试条件为：CuKα光源，40kV电压，100mA电流，狭缝1°，0.3mm，采集软件为:LJ51。使用Cu-Kɑ辐射进行检测。
本发明所述SGLT-2抑制剂与肌氨酸共晶体的XRPD谱图中除具有SGLT-2抑制剂共晶部分的特征衍射峰外，还在以下位置有特征峰：10.6±0.2°、19.6±0.2°、22.1±0.2°、33.6±0.2°。
在本发明的一些具体实施例中，所述达格列净·肌氨酸共晶体的XRPD谱图在以下位置具有特征峰：3.8±0.2°、10.6±0.2°、13.7±0.2°、17.0±0.2°、18.0±0.2°、18.6±0.2°、19.6±0.2°、20.1±0.2°、21.4±0.2°、22.1±0.2°、23.0±0.2°、25.4±0.2°、27.6±0.2°、33.6±0.2°。
进一步优选的，所述达格列净·肌氨酸共晶体，使用Cu-Kɑ辐射以衍射角2θ表示的X-射线粉末衍射(XRPD)图谱，在以下位置具有特征峰：3.77±0.2°、10.66±0.2°、11.21±0.2°、13.67±0.2°、14.94±0.2°、16.96±0.2°、17.98±0.2°、18.60±0.2°、19.59±0.2°、20.10±0.2°、20.34±0.2°、21.40±0.2°、22.10±0.2°、22.46±0.2°、22.96±0.2°、24.87±0.2°、25.22±0.2°、25.48±0.2°、26.23±0.2°、27.61±0.2°、28.48±0.2°及33.62±0.2°。
在本发明的一些具体实施例中，所述卡格列净·肌氨酸共晶体的XRPD谱图在以下位置具有特征峰：3.6±0.2°、7.1±0.2°、10.6±0.2°、14.1±0.2°、16.8±0.2°、17.3±0.2°、18.3±0.2°、18.8±0.2°、19.6±0.2°、20.3±0.2°、21.1±0.2°、22.1±0.2°、22.9±0.2°、25.4±0.2°、28.2±0.2°、33.6±0.2°。
进一步优选的，所述卡格列净·肌氨酸共晶体，使用Cu-Kɑ辐射以衍射角2θ表示的X-射线粉末衍射(XRPD)图谱，在以下位置具有特征峰：3.63±0.2°、3.63±0.2°、7.10±0.2°、10.60±0.2°、14.08±0.2°、15.93±0.2°、16.77±0.2°、17.34±0.2°、18.32±0.2°、18.79±0.2°、19.60±0.2°、20.30±0.2°、20.60±0.2°、21.11±0.2°、22.06±0.2°、22.89±0.2°、25.41±0.2°、28.29±0.2°及33.46±0.2°。
本发明采用红外吸收光谱对所述SGLT-2抑制剂·肌氨酸共晶体结构进行表征，如采用KBr压片法进行SGLT-2抑制剂·肌氨酸共晶体的红外光谱测定，所使用的红外光谱仪的仪器型号为：Thermo Nicolet 6700 FT-IR Spectrometer，测试条件为：KBr压片法，扫描范围450-4000cm-1。以红外光谱的特征吸收峰来进行表征。
本发明所述SGLT-2抑制剂·肌氨酸共晶体的红外光谱至少在以下位置具有特征吸收峰：3540±10cm -1、2691±5cm -1、2603±5cm -1、2420±5cm -1。
在本发明的一些具体实施例中，所述达格列净·肌氨酸共晶体的红外光谱在以下位置具有特征吸收峰：3543.67±10cm -1、3161.94±10cm -1、2690.95±5cm -1、2603.78±5cm -1、2419.39±5cm -1、2360.665cm -1、1599.61±5cm -1、1510.92±5cm -1、1291.19±5cm -1、1045.97cm -1。
在本发明的一些具体实施例中，所述卡格列净·肌氨酸共晶体的红外光谱至少在以下位置具有特征吸收峰：3543.82±10cm -1、3153.82±10cm -1、2690.68±5cm -1、2603.06±5cm -1、2419.53±5cm -1、1596.33±5cm -1、1507.48±5cm -1、1086.11±5cm -1、1062.19±5cm -1、829.61±5cm -1。
本发明通过差示扫描量热法对所述SGLT-2抑制剂·肌氨酸共晶体进行表征，所使用的仪器型号为：SII-DSC6220，分析方法参数：温度范围：30℃-250℃，扫描速率：10℃/分钟，保护气体：氮气，50毫升/分钟。得到的差示扫描量热(DSC)谱图中，在100℃及以上有明显的吸热峰，优选在120℃及以上具有明显的吸热峰。
根据差示扫描量热(DSC)谱图数据，表明本发明提供的达格列净·肌氨酸共晶的熔点大约在149.0℃，高于已上市的达格列净(S)-丙二醇一水合物的熔点70℃，合适的熔点使得制剂在片剂制粒、压片过程中，不易熔融、聚团，导致粘冲或均匀度不合格，本发明制备的共晶体更便于简化制剂生产工艺，降低生产成本。
采用热重分析法对本发明提供的SGLT-2抑制剂·肌氨酸共晶体进行检测，所使用的热重分析仪的仪器型号为：SII-TG/DTA6200，分析方法参数：温度范围：30℃-350℃，扫描速率：10℃/分钟，保护气体：氮气，200毫升/分钟。热重分析(TGA)谱图中在120℃前无明显失重；在TGA-DTA谱图的190℃-230℃有较宽吸热峰。
本发明还通过核磁共振氢谱对所述SGLT-2抑制剂·肌氨酸共晶体结构进行了检测。所使用的仪器型号为：BrukerAVANCE600，共振频率：600MHz，使用溶剂：氘代甲醇。结果表明，核磁共振氢谱(HNMR)中，除具有SGLT-2抑制剂结构的共振峰外，在化学位移2.4～3.2ppm范围内有-CH 3的共振峰、在3.0-4.0ppm范围内有-CH 2-峰，-CH 2-峰可以与SGLT-2结构上的其他共振峰重合或不重合，表明了肌氨酸结果的存在。
本发明提供了上述SGLT-2抑制剂·肌氨酸共晶体的制备方法，包括以下步骤：
将SGLT-2抑制剂的溶液和肌氨酸的溶液混合，静置析晶或降温析晶，固液分离，得到SGLT-2抑制剂·肌氨酸共晶体。
本发明中，对所述SGLT-2抑制剂的来源并无特殊限定，可以为一般市售或按照本领域技术人员熟知的方法制备，可以为纯品，也可以为粗品或中间体。
本发明优选的，所述SGLT-2抑制剂溶液中的溶剂选自C1-C10醇类、C3-C10酮类、醚类、腈类中的不同单一溶剂或混合溶剂。进一步优选的，所述溶剂为乙醇、丙酮、四氢呋喃和乙腈中的一种或多种；进一步优选为乙醇。
所述肌氨酸溶液的溶剂优选为水。
所述SGLT-2抑制剂和肌氨酸的摩尔比优选为1：(0.5～5.0)，进一步优选为1：0.6、1：0.7、1：0.8、1：0.9、1：0.95、1：1.0、1：1.05、1：1.1、1：1.2、1：1.3、1：1.4、1：1.5、1：1.6、1：1.7、1：1.8、1：1.9或1：2.0。
本发明在制备共晶体的过程中，所述SGLT-2抑制剂和肌氨酸的用量严格按照共晶体中二者的摩尔比添加，使得SGLT-2抑制剂和肌氨酸恰好形成共晶体，体系中并无过量的SGLT-2抑制剂或肌氨酸存在。
本发明中，将SGLT-2抑制剂溶液和肌氨酸溶液混合后，如果体系不澄清，可以通过加热的方式使体系澄清。
本发明优选的，所述静置析晶或降温析晶的温度优选为-20℃～40℃，在一些实施例中，析晶温度优选为：-15℃～35℃、-10℃～30℃、-5℃～30℃、0℃～30℃、5℃～30℃、10℃～30℃、15℃～30℃或20℃～30℃。
本发明优选的，所述静置析晶或降温析晶的时间优选为4-48小时，优选4-24小时，4-16小时，4-12小时，更优选8-12小时。
本发明中，得到SGLT-2抑制剂·肌氨酸共晶体后，优选对其进行干燥处理，所述干燥的温度优选为20℃～80℃，进一步优选为30℃～80℃。
所得到的SGLT-2抑制剂·肌氨酸共晶体可以为共晶体的溶剂化物、共晶体的溶剂化物水合物或共晶体的水合物。
本发明提供的上述SGLT-2抑制剂·肌氨酸共晶体的制备方法工艺简单，容易实现，周期短，得到的晶型稳定，不受析晶条件影响或贮藏条件、环境影响而出现转晶或混晶现象。
本发明制备得到的SGLT-2抑制剂·肌氨酸共晶体中无超过0.1％的单个杂质，杂质总量小于0.5％。
本发明中，将SGLT-2抑制剂粗品(或称中间体)与肌氨酸混合，室温搅拌，固液分离，得到SGLT-2抑制剂的肌氨酸合物，对SGLT-2抑制剂粗品具有显著的纯化效果，经过纯化后，SGLT-2抑制剂的纯度不低于99％。
由于SGLT-2抑制剂的化学结构中大部分都带有经典的葡萄糖糖苷结构或葡萄糖苷结构衍生物，其制备工艺中都无法避免地产生对应异构体杂质、开环杂质、五元环杂质或二聚体杂质，因此，成盐、成共晶、溶剂化物或水合物对这些特定的工艺杂质及非特异性工艺杂质、工艺副产物的去除能力对活性成分的制备收率、生产周期及生产成本影响非常大。
例如，制备工艺过程中产生的非对映异构体杂质，其反应方程式如下：
Figure PCTCN2020119547-appb-000010
或上述SGLT-2抑制剂制备工艺中也会产生下述杂质2(五元环杂质)：
Figure PCTCN2020119547-appb-000011
上述五元环杂质的产生机理为：
Figure PCTCN2020119547-appb-000012
或者上述SGLT-2抑制剂制备工艺中也会产生下述杂质3(开环杂质)：
Figure PCTCN2020119547-appb-000013
开环杂质的生成过程如下：
Figure PCTCN2020119547-appb-000014
或者上述SGLT-2抑制剂制备工艺中也会因反应条件的剧烈发生分子间的聚合反应生成二聚体杂质4(二聚体杂质)：
二聚体杂质的化学结构通式如下：
Figure PCTCN2020119547-appb-000015
上述二聚体杂质的生成过程如下：
Figure PCTCN2020119547-appb-000016
其中，X为卤素(溴Br或碘I)；M为镁，Mg；P为保护基团，如四甲基硅烷TMS。
R 1～R 5的范围同上，在此不再赘述。
工艺中除产生由于SGLT-2抑制剂结构中经典的葡萄糖苷结构相关的特异性(非对映异构体杂质、五元环杂质、开环杂质及二聚体杂质)的工艺杂质外，也会产生大量的非特异性杂质，上述特异性杂质和非特异性杂质是在SGLT-2抑制剂中间体或粗品中很难通过简单的萃取、溶剂重结晶一次性去除到作为药用允许的杂质限度以下。
令人意外的，使用本发明的方法，通过将SGLT-2抑制剂粗品与肌氨酸形成肌氨酸合物，能去除95％以上SGLT-2抑制剂粗品中含有的工艺杂质、上一步中间体或物料残留等杂质，这些杂质由于极性与目标API相近，结构相似，很难通过简单的液-液萃取或溶剂重结晶达到纯化的目的，通过SGLT-2抑制剂粗品与肌氨酸形成肌氨酸合物，可一次性将SGLT-2抑制剂粗品的纯度由78％提高至99％以上，杂质个数及总杂检出量显著降低。或者所得高纯度的SGLT-2抑制剂的肌氨酸合物经过简单的解离，得到更高纯度的游离态的SGLT-2抑制剂，然后直接作为目标成分使用或再制备其他药用晶型或药用共晶体。
具体的，本发明提供了一种SGLT-2抑制剂的纯化方法，包括以下步骤：
将SGLT-2抑制剂的粗品与肌氨酸混合，室温搅拌，固液分离，得到SGLT-2抑制剂的肌氨酸合物。
本发明优选的，所述SGLT-2抑制剂的粗品溶解于溶剂中，所述溶剂优选为C1-C10醇类、C3-C10酮类、醚类、腈类中的不同单一溶剂或这些溶剂与水的混合溶剂或上述溶剂的混合溶剂。进一步优选的，所述溶剂为乙醇、丙酮、四氢呋喃和乙腈中的一种或多种，也可以是乙醇、丙酮、四氢呋喃和乙腈中的一种或多种与水混合；进一步优选为乙醇。
本发明优选的，所述肌氨酸溶解于溶剂中，所述溶剂优选为水。
所述SGLT-2抑制剂粗品和肌氨酸的摩尔比优选为1：(0.5～5.0)，在一些实施例中，SGLT-2抑制剂粗品与肌氨酸摩尔比优选为1：0.7、1：0.8、1：0.9、1：0.95、1：1.0、1：1.05、1：1.1、1：1.2、1：1.3、1：1.4、1：1.5、1：1.6、1：1.7、1：1.8、1：1.9、1：2.0或1：3.0；更优选的SGLT-2抑制剂粗品与肌氨酸的摩尔比为1：1.0、1：1.1、1：1.2、1：1.3、1：1.4、1：1.5、1：1.6、1：1.7、1：1.8、1：1.9、1：2.0及1：3.0。
本发明中，在纯化过程中，上述肌氨酸为过量加入，得到的SGLT-2抑制剂的肌氨酸合物包含部分SGLT-2抑制剂和肌氨酸形成的共晶体，和部分过量的肌氨酸。
本发明优选的，上述固液分离的方法优选为静置析晶或降温析晶。
本发明优选的，所述静置析晶或降温析晶的温度优选为-20℃～40℃，进一步优选为-10℃～40℃、0-40℃、10-40℃、15-40℃、20-40℃、20-35℃、或20℃～30℃。
本发明优选的，所述搅拌的时间优选为6-16小时，进一步优选为6-14小时、7-13小时、或8-12小时。
本发明中，得到SGLT-2抑制剂与肌氨酸合物，通过固液分离得到固体，优选对其进行干燥处理，所述干燥的温度优选为20℃～80℃，进一步优选为30℃～80℃。
本发明优选的，得到SGLT-2抑制剂的肌氨酸合物后，还包括：
将上述SGLT-2抑制剂的肌氨酸合物解离，得到SGLT-2抑制剂游离态纯品。
本发明优选的，所述SGLT-2抑制剂游离态纯品的HPLC归一化纯度不低于99％。
然后通过重结晶或共晶方式制备SGLT-2抑制剂最终的药用晶型。
本发明优选的，所述SGLT-2抑制剂最终的药用晶型选自SGLT-2抑制剂纯品、溶剂合物、水合物、溶剂合物水合物、共晶体或复盐。
本发明对所述SGLT-2抑制剂的粗品的制备工艺或来源并无特殊限定，可以为按照本领域技术人员熟知的方法，例如专利文献WO03099836A1、CN100534997C中所记载的方法制备的SGLT-2抑制剂的粗品。所述SGLT-2 抑制剂粗品或中间体中含下述结构式1的SGLT-2抑制剂不应低于70％，优选不低于75％。
Figure PCTCN2020119547-appb-000017
其中R1、R2、R3、R4及X如表2所示。
本发明对所述解离的方法并无特殊限定，可以为本领域技术人员熟知的方法。
在本发明的一些具体实施例中，可采用液-液萃取的方法进行解离，收集有机相，浓缩、得到SGLT-2抑制剂游离态纯品。
实验结果表明，本发明提供的上述纯化方法，可对非特异性杂质和特异性杂质、非对映异构体杂质、五元环杂质、开环杂质及二聚体杂质具有显著的去除效果。杂质个数降低90％以上、检出的杂质总量、单个杂质检出量等均去除掉95％以上。纯化后得到的SGLT-2抑制剂肌氨酸合物或SGLT-2抑制剂游离体中杂质个数低于6个，总杂含量小于1.0％。
本发明提供的上述纯化方法，可以用在SGLT-2抑制剂制备工艺中间体，也可以用于成盐、成共晶、析晶前的粗品，优选SGLT-2抑制剂中间体的化学结构与目标SGLT-2抑制剂结构相同的中间体或粗品。
本发明优选的，得到SGLT-2抑制剂游离态纯品后，还可以以所述SGLT-2抑制剂游离态纯品为原料，直接制备SGLT-2抑制剂最终的药用晶型；
或者以所述SGLT-2抑制剂游离态纯品为原料，通过重结晶或共晶方式制备SGLT-2抑制剂最终的药用晶型。
本发明中，所述SGLT-2抑制剂最终的药用晶型优选为SGLT-2抑制剂纯品、溶剂合物、水合物、溶剂合物水合物、共晶体或复盐等。
本发明提供了一种药物组合物，包括上述SGLT-2抑制剂·肌氨酸共晶体，或上述制备方法制备的SGLT-2抑制剂·肌氨酸共晶体，或上述纯化方法得到的SGLT-2抑制剂游离态纯品，或通过重结晶或共晶方式制备的SGLT-2抑制剂最终的药用晶型，如SGLT-2抑制剂纯品、溶剂合物、水合物、溶剂合物水 合物、共晶体或复盐等，以及药学上可接受的载体，赋形剂，稀释剂，辅剂，媒介物或它们的组合。
当活性成分以低剂量给药时，为了保证活性成分均匀分布，活性成分的颗粒可能会通过某些物理方式如磨碎、过筛而减少至适合大小。本发明提供的SGLT-2抑制剂·肌氨酸共晶体具有较高的稳定性，作为活性成分，有利于在药用组合物产品中均匀分布。由于具有较高的熔点，粉碎或研磨过程中，不会由于发热而融化或粘成团块或静电吸附等，在整个磨碎或粉碎过程中晶型不会发生改变，最终得到的药物组合物，活性成分含量均匀，符合标示量，且具有较高的可重复性。
本发明提供了上述SGLT-2抑制剂·肌氨酸共晶体或上述制备方法制备的SGLT-2抑制剂·肌氨酸共晶体，或上述纯化方法得到的SGLT-2抑制剂游离态纯品，或通过重结晶或共晶方式制备的SGLT-2抑制剂最终的药用晶型，如SGLT-2抑制剂纯品、溶剂合物、水合物、溶剂合物水合物、共晶体或复盐等，或上述药物组合物，在制备用于预防、治疗或减轻糖尿病及其并发症、治疗及预防或减轻心脑血管疾病、非糖尿病引起的肾病的药物中的应用。
本发明提供了上述SGLT-2抑制剂·肌氨酸共晶体或上述制备方法制备的SGLT-2抑制剂·肌氨酸共晶体，或上述纯化方法得到的SGLT-2抑制剂游离态纯品，或通过重结晶或共晶方式制备SGLT-2抑制剂最终的药用晶型，如SGLT-2抑制剂纯品、溶剂合物、水合物、溶剂合物水合物、共晶体或复盐等，或上述药物组合物，在制备用于降血压的药物中的应用。
本发明优选的，所述糖尿病及其并发症包括但不限于：
原发性高血压、合并高血压的2型糖尿病、合并2型糖尿病的肾病、合并高血压和糖尿病的肾病、肾病、1型糖尿病、1型糖尿病的肾病、肝纤维化、胰岛素抵抗、高血糖、高胰岛素血症、脂肪酸或甘油的升高的血含量、高脂血、血脂障碍、肥胖中的一种或多种。
本发明上述SGLT-2抑制剂·肌氨酸共晶体，或上述纯化方法得到的SGLT-2抑制剂游离态纯品，或通过重结晶或共晶方式制备SGLT-2抑制剂最终的药用晶型，如SGLT-2抑制剂纯品、溶剂合物、水合物、溶剂合物水合物、共晶体或复盐等，或药物组合物在应用于制备用于预防、治疗或减轻糖尿病 及其并发症、心脑血管疾病的药物，或制备用于降血压的药物或非糖尿病引起的肾病的药物时，可以单独使用，或与其他药物联合使用。
本发明提供了一种预防、治疗或减轻糖尿病及其并发症的方法，包括将上述SGLT-2抑制剂·肌氨酸共晶体或上述制备方法制备的SGLT-2抑制剂·肌氨酸共晶体，或上述纯化方法得到的SGLT-2抑制剂游离态纯品，或通过重结晶或共晶方式制备SGLT-2抑制剂最终的药用晶型，如SGLT-2抑制剂纯品、溶剂合物、水合物、溶剂合物水合物、共晶体或复盐等，或上述药物组合物与生物标本接触。
本发明提供了一种降血压的方法，包括将上述SGLT-2抑制剂·肌氨酸共晶体或上述制备方法制备的SGLT-2抑制剂·肌氨酸共晶体，或上述纯化方法得到的SGLT-2抑制剂游离态纯品，或通过重结晶或共晶方式制备SGLT-2抑制剂最终的药用晶型，如SGLT-2抑制剂纯品、溶剂合物、水合物、溶剂合物水合物、共晶体或复盐等，或上述药物组合物与生物标本接触。
本发明提供了一种治疗非糖尿病引起的肾病的方法，包括将上述SGLT-2抑制剂·肌氨酸共晶体或上述制备方法制备的SGLT-2抑制剂·肌氨酸共晶体，或上述纯化方法得到的SGLT-2抑制剂游离态纯品，或通过重结晶或共晶方式制备SGLT-2抑制剂最终的药用晶型，如SGLT-2抑制剂纯品、溶剂合物、水合物、溶剂合物水合物、共晶体或复盐等，或上述药物组合物与生物标本接触。
与现有技术相比，本发明提供了一种SGLT-2抑制剂·肌氨酸共晶体。具有以下有益效果：
1、以肌氨酸为配体，具有较高的安全性和较低的成本；
2、药物共晶体具有较高的稳定性，在制剂组合物生产过程或贮藏过程中，晶型不易发生改变；贮藏或制备过程温度高或制剂生产工艺中不会遇热熔融，不会发生粘冲、聚团或产生静电，具有更好的混合均匀性；
3、作为活性成分，在制备的药物组合物中分布均匀，使得药物组合物具有更好的体内释放、吸收和药效，且批间差异小；
4、SGLT-2抑制剂的肌氨酸共晶体不改变作为口服固体制剂原料药使用的药物在不同pH生理介质中的溶解度，这对保证口服固体制剂的吸收非常重要；
5、具有较高的物理稳定性和化学稳定性，更利于贮藏、运输；
6、制备工艺简单，重现性高，且析晶时间短，工艺条件要求低，具有更高的经济效益；
7、制备过程中，不使用不安全溶剂；
8、在SGLT-2抑制剂制备工艺过程中，可以对SGLT-2抑制剂最后的中间体或粗品通过成肌氨酸合物进行纯化、解离，得到纯度99％以上的SGLT-2抑制剂游离体，再根据目标API需要，或进行后续的重结晶、共晶，或与肌氨酸成共晶，无需另外进行繁琐的除杂步骤。
附图说明
图1为实施例1制备的达格列净·肌氨酸共晶的X-射线粉末衍射图(XRPD)及单晶衍射图；
图2为实施例1制备的达格列净·肌氨酸共晶的红外光谱分析图(IR)；
图3为实施例1制备的达格列净·肌氨酸共晶的差示扫描量热图(DSC)；
图4为实施例1制备的达格列净·肌氨酸共晶的热重分析图(TGA)；
图5为实施例1制备的达格列净·肌氨酸共晶的核磁共振氢谱图(H-NMR)；
图6为实施例12制备的卡格列净·肌氨酸共晶的X-射线粉末衍射图(XRPD)；
图7为实施例12制备的卡格列净·肌氨酸共晶的红外光谱分析图(IR)；
图8为实施例12制备的卡格列净·肌氨酸共晶的差示扫描量热图(DSC)；
图9为实施例12制备的卡格列净·肌氨酸共晶的热重分析图(TGA)；
图10为实施例12制备的卡格列净·肌氨酸共晶的核磁共振氢谱图(H-NMR)；
图11为达格列净·肌氨酸共晶的单晶结构分子结构椭球形图。
具体实施方式
本发明所使用的肌氨酸原料，可以商购获得。
本发明所使用的达格列净原料，可以商购获得，或按照已知方法，例如专利文献CN100534997C中所记载的方法进行制备。
本发明所使用的溶剂没有特别的限制，可采用商购的常规溶剂。
采集数据所用的仪器及方法：
采集X-射线粉末衍射(XRPD)数据，所使用的仪器型号为：RigakuD/max-RB，测试条件为：CuKα光源，40kV电压，100mA电流，狭缝1°，1°，0.3mm，采集软件为:LJ51。
X-单晶衍射的仪器型号：Gemini E单晶衍射仪，晶体解析软件为Shelx97；CuKa作为X-射线光源。
采集红外光谱分析(IR)数据，所使用的仪器型号为：Thermo Nicolet 6700 FT-IR Spectrometer，测试条件为：KBr压片法，扫描范围450-4000cm -1。
采集差示扫描量热(DSC)数据，所使用的仪器型号为：SII-DSC6220，分析方法参数：温度范围：30℃-250℃，扫描速率：10℃/分钟，保护气体：氮气，50毫升/分钟。
采集热重分析(TGA)数据，所使用的仪器型号为：SII-TG/DTA6200，分析方法参数：温度范围：30℃-350℃，扫描速率：10℃/分钟，保护气体：氮气，200毫升/分钟。
采集核磁共振氢谱(HNMR)数据，所使用的仪器型号为：BrukerAVANCE600，共振频率：600MHz，使用溶剂：氘代甲醇。
本发明涉及的液相测试条件为：色谱柱为Kromasil KR100-5-C18，4.6×250mm；流动相A：0.1％磷酸；流动相B：乙腈；检测波长：220nm；流速：0.8mL/min；进样量：20μL；柱温：35℃；液相条件如下表4所示：
表4液相测试条件
t(min) 0 25 30 35 40 45 45.1 60
B(％) 30 45 50 70 70 90 30 30
应当说明的是，本发明技术方案中所涉及的数值或数值端点，其含义或意义的保护范围并不局限于数字本身，本领域技术人员能够理解，它们包含了那些已被本领域广为接受的可允许误差范围，例如实验误差、测量误差、统计误差和随机误差等等，而这些误差范围均包含在本发明的范围之内。
为了进一步说明本发明，下面结合实施例对本发明提供的SGLT-2抑制剂·肌氨酸共晶体及其制备方法和应用进行详细描述，但是以下的实施例对本发明的保护范围不构成任何限制。
以下实施例中，没有特别指明出处的，所有试剂，卡格列净、肌氨酸等，均为一般市售。
以下实施例所采用的达格列净，按照专利文献WO03099836A1制备得到。
实施例1达格列净·肌氨酸共晶的制备
向1000mL三口瓶中加入500mL无水乙醇，开启搅拌，加入按专利文献WO03099836A1提供的方法制备的100g达格列净(HPLC归一化纯度≥95％)搅拌至体系溶清。另取100mL三口瓶，加入30mL纯化水，开启搅拌，加入21.80g肌氨酸，搅拌至体系溶清后，将此溶液加至上述达格列净的乙醇溶液中。于20℃～30℃保温搅拌析晶5小时，过滤，收集的固体在30℃～40℃真空干燥6小时，得到113g白色固体，HPLC归一化纯度为99.93％，无归一化含量超过0.1％的杂质。
通过X-射线粉末衍射图(XRPD)、红外光谱分析图(IR)、差示扫描量热图(DSC)、热重分析图(TGA)、核磁共振氢谱图(H-NMR)，详见图1-图5，确认为达格列净·肌氨酸共晶体。
1HNMR(600MHz,MeOD)δ7.343-7.329(d，1H，J＝8.4Hz)，7.315-7.312(d，1H，J＝1.8Hz)7.276-7.259(dd，1H，J＝8.4，1.8Hz)，7.091-7.077(d，2H，J＝8.4Hz)，6.795-6.781(d，2H，J＝8.4Hz)，4.089-4.073(d，1H，J＝9.6Hz)，4.055-3.977(q，2H，J＝15.0Hz)，3.994-3.959(q，2H，J＝7.2Hz)，3.876-3.854(dd，1H，J＝12.0，1.8Hz)，3.697-3.668(dd，1H，J＝12.0，5.4Hz)，3.467(s，2H)3.461-3.431(m，1H)，3.409-3.370(m，2H)，3.283-3.268(m，1H)，2.665(s，3H)，1.360-1.337(t，3H，J＝7.2Hz)。
根据 1HNMR谱图数据，可以得知，达格列净和肌氨酸的摩尔比为1:1。
所述达格列净·肌氨酸共晶，使用Cu-Kɑ辐射以衍射角2θ表示的X-射线粉末衍射(XRPD)图谱，具有如下表5所示的特征峰及其相对强度，衍射角2θ误差为±0.2°：
表5达格列净·肌氨酸共晶XRPD特征峰及其相对强度
No. 衍射角2θ D I/Io No. 衍射角2θ D I/Io
1 3.765 23.4510 72.3 10 20.343 4.3618 57.3
2 10.656 8.2953 40.8 11 21.404 4.1479 32.2
3 11.210 7.8862 16.4 12 22.096 4.0196 16.7
4 13.674 6.4705 51.0 12 22.962 3.8699 100
5 14.939 5.9253 17.7 13 25.482 3.4927 29.0
6 16.956 5.2247 44.8 14 27.606 3.2285 60.6
7 17.977 4.9301 89.6 15 30.435 2.9346 15.3
8 18.602 4.7658 51.6 16 33.617 2.6637 12.6-
9 19.588 4.5283 95.2 -- -- -- --
所述达格列净·肌氨酸共晶，用KBr压片法测得的红外吸收(IR)图谱在以下位置具有吸收峰：3543.67±10cm -1、3161.94±10cm -1、2888.82±5cm -1、2690.95±5cm -1、2603.78±5cm -1、2419.39±5cm -1、2360.66±5cm -1、1599.61±5cm -1、1510.92±5cm -1、1291.19±5cm -1、1045.97±5cm -1、812.44±5cm -1cm -1。
达格列净·肌氨酸共晶的差示扫描量热(DSC)谱图，在140.0℃～155.0℃范围内有吸热峰，峰值为149.0℃，为熔解温度。
达格列净·肌氨酸共晶的热重分析(TGA)谱图，在150℃之前无明显失重；TGA-DTA图190℃-230℃范围内有较宽吸热峰。根据热重分析(TGA)谱图，以及水分测量仪(仪器型号：Metrohm 915-KF)显示的含水量：0.10％，表明本发明所述达格列净·肌氨酸共晶为无水，无溶剂合物形式存在。
实施例2：达格列净·肌氨酸共晶的制备
向100mL三口瓶中加入50mL无水乙醇，开启搅拌，加入按专利文献WO03099836A1提供的方法制备的10g达格列净(HPLC归一化纯度≥95％)搅拌至体系溶清。另取10mL单口瓶，加入2mL纯化水，开启搅拌，加入1.10g肌氨酸，搅拌至体系溶清后，将此溶液加至上述达格列净的乙醇溶液中。在10℃～20℃保温搅拌析晶5小时，过滤，收集的固体在40℃～50℃真空干燥4小时，得到达格列净·肌氨酸共晶的白色固体4.8g，HPLC归一化纯度为99.89％，无归一化含量超过0.1％的杂质。
实施例3：达格列净·肌氨酸共晶的制备
向100mL三口瓶中加入50mL无水乙醇，开启搅拌，加入按专利文献WO03099836A1提供的方法制备的10g达格列净(HPLC归一化纯度≥95％)搅拌至体系溶清。另取10mL单口瓶，加入5.0mL纯化水，开启搅拌，加入3.27g肌氨酸，搅拌至体系溶清后，将此溶液加至上述达格列净的乙醇溶液中。 在-10℃～10℃保温搅拌析晶5小时，过滤，收集的固体在50℃-60℃真空干燥4小时，得到达格列净·肌氨酸共晶的白色固体10.85g，HPLC归一化纯度为99.87％，无归一化含量超过0.1％的杂质。
实施例4：达格列净·肌氨酸共晶的制备
向100mL三口瓶中加入50mL乙腈，开启搅拌，加入按专利文献WO03099836A1提供的方法制备的10g达格列净(HPLC归一化纯度≥95％)搅拌至体系溶清。另取10mL单口瓶，加入3.0mL纯化水，开启搅拌，加入2.18g肌氨酸，搅拌至体系溶清后，将此溶液加至上述达格列净的乙腈溶液中。在30℃～40℃保温搅拌析晶5小时，过滤，收集的固体在70℃～80℃真空干燥4小时，得到达格列净·肌氨酸共晶的白色固体9.70g，HPLC归一化纯度为99.90％，无归一化含量超过0.1％的杂质。
实施例5：达格列净·肌氨酸共晶的制备
向100mL三口瓶中加入50mL四氢呋喃，开启搅拌，加入按专利文献WO03099836A1提供的方法制备的10g达格列净(HPLC归一化纯度≥95％)搅拌至体系溶清。另取10mL单口瓶，加入3.0mL纯化水，开启搅拌，加入2.20g肌氨酸，搅拌至体系溶清后，将此溶液加至上述达格列净的四氢呋喃溶液中。在20℃～30℃保温搅拌析晶5小时，过滤，收集的固体在60℃～70℃真空干燥4小时，得到达格列净·肌氨酸共晶的白色固体9.15g，HPLC归一化纯度为99.73％，无归一化含量超过0.1％的杂质。
实施例6：达格列净·肌氨酸共晶的制备
向100mL三口瓶中加入50mL丙酮，开启搅拌，加入按专利文献WO03099836A1提供的方法制备的10g达格列净(HPLC归一化纯度≥95％)搅拌至体系溶清。另取10mL单口瓶，加入3.0mL纯化水，开启搅拌，加入2.10g肌氨酸，搅拌至体系溶清后，将此溶液加至上述达格列净的丙酮溶液中。在20℃～30℃保温搅拌析晶5小时，过滤，收集的固体在20℃～30℃真空干燥6小时，得到达格列净·肌氨酸共晶的白色固体10.13g，HPLC归一化纯度为99.82％，无归一化含量超过0.1％的杂质。
实施例7：达格列净·肌氨酸共晶的制备
向100mL三口瓶中加入25mL丙酮和25mL无水乙醇，开启搅拌，加入按专利文献WO03099836A1提供的方法制备的10g达格列净(HPLC归一化 纯度≥95％)搅拌至体系溶清。另取10mL单口瓶，加入3.0mL纯化水，开启搅拌，加入2.15g肌氨酸，搅拌至体系溶清后，将此溶液加至上述达格列净的丙酮和乙醇的溶液中。在20℃～30℃保温搅拌析晶5小时，过滤，收集的固体在30℃～40℃真空干燥6小时，得到达格列净·肌氨酸共晶的白色固体10.89g，HPLC归一化纯度为99.82％，无归一化含量超过0.1％的杂质。
实施例8：达格列净粗品的纯化
向250mL三口瓶中加入150mL无水乙醇，开启搅拌，加入按专利文献WO03099836A1提供的方法制备的达格列净粗品35g(HPLC归一化纯度78.04％)搅拌至体系溶清。另取50mL单口瓶，加入10mL纯化水，开启搅拌，加入9.00g肌氨酸，搅拌至体系溶清后，将此溶液加至上述达格列净的无水乙醇的溶液中。在20℃～30℃保温搅拌析晶5小时，过滤，收集的固体在30℃～40℃真空干燥6小时，得到25.4g达格列净的肌氨酸合物，为白色固体，HPLC归一化纯度为99.37％。
向250mL三口瓶中，加入50mL纯化水以及150mL的甲基叔丁基醚，加入上述所得达格列净的肌氨酸合物25g，搅拌溶清收集有机相，有机相用50ml纯化水洗涤3次，有机相减压蒸除溶剂，30℃～40℃真空干燥6小时，得到19.5g达格列净的白色固体(HPLC归一化纯度99.98％)。
对比例1：
向3000mL三口瓶中加600ml甲基叔丁基醚，开启搅拌，加入按专利文献WO03099836A1提供的方法制备的达格列净粗品35g(HPLC归一化纯度78.04％)，搅拌至体系溶清，按专利文献WO2008002824A1制备达格列净(S)-丙二醇一水合物的实施例6的方法，继续加入6.51g(S)-1，2-丙二醇，1.54g纯化水，0.35g达格列净(S)-丙二醇一水合物晶种，在20℃～30℃保温搅拌析晶5小时，加入1200mL的环己烷，过滤，收集的固体在20℃～25℃真空干燥4小时，得到达格列净(S)-丙二醇一水合物25g类白色固体(HPLC归一化纯度为93.59％)。
向250mL三口瓶中，加入50mL纯化水以及150mL的甲基叔丁基醚，加入上述所得达格列净(S)-丙二醇一水合物20g，搅拌溶清分出有机相，有机相使用50ml纯化水洗涤3次，将有机相减压蒸除溶剂，得到18g达格列净的浅黄色泡沫状固体(HPLC归一化纯度为95.78％)。
实施例9：达格列净中间体的纯化
向250mL三口瓶中加入150mL无水乙醇，开启搅拌，加入按专利文献WO03099836A1提供的方法制备的达格列净粗品(批号：20200416-2，黄色泡状固体)30g，纯化前杂质检出情况见下表6所示。搅拌至体系溶清。另取50mL单口瓶，加入9mL纯化水，开启搅拌，加入7.55g肌氨酸，搅拌至体系溶清后，将此溶液加至上述达格列净的无水乙醇的溶液中。在20℃～30℃保温搅拌析晶5小时，过滤，收集的固体在30℃～40℃真空干燥6小时，得到25g达格列净的肌氨酸合物，为白色固体，批号为202000714-1，纯化后杂质检出情况见下表6所示。
向反应瓶中投入250ml(以达格列净肌氨酸合物计)的纯化水，开启搅拌，加入达格列净肌氨酸合物，加入250ml(以达格列净肌氨酸合物计)的甲基叔丁基醚。氮气保护，20～30℃搅拌，静置、分液，收集有机相。有机相用250ml的纯化水洗涤两遍，分液后有机相减压脱溶，得发泡状固体产品。固体产品用3倍体积甲基叔丁基醚溶清，加入150ml正庚烷溶液中，析出白色固体，氮气保护下过滤，收集滤饼，40℃下真空干燥得到游离后的达格列净游离体纯品19.5g(收率为80％)。
表6
Figure PCTCN2020119547-appb-000018
Figure PCTCN2020119547-appb-000019
对比例2：
向3000mL三口瓶中加520ml甲基叔丁基醚，开启搅拌，加入按专利文献WO03099836A1提供的方法制备的达格列净粗品(批号：20200416-2，黄色泡状固体)30g，纯化前杂质检出情况见表6所示，搅拌至体系溶清，按专利文献WO2008002824A1制备达格列净(S)-丙二醇一水合物的实施例6的方法，继续加入5.58g(S)-1，2-丙二醇，1.32g纯化水，0.30g达格列净(S)-丙二醇一水合物晶种，在20℃～30℃保温搅拌析晶8小时，加入1030mL的环己烷，过滤，收集的固体在20℃～25℃真空干燥4小时，得到达格列净(S)-丙二醇一水合物23g类白色固体，批号为20200714-4，纯化后杂质检出结果见表6所示。
对比例3：
向500mL单口瓶中加入170mL异丙醇，然后加入按专利文献WO03099836A1提供的方法制备的达格列净粗品35g(HPLC:87.87％)，搅拌至体系溶清。
向1000mL三口瓶中加17ml纯化水，开启搅拌，加入19.71g L-脯氨酸，将体系加热至80℃，加入170mL异丙醇，然后迅速搅拌下加入上述达格列净的异丙醇溶液，缓慢降至室温，在20℃～30℃保温搅拌析晶5小时，过滤，使 用20mL异丙醇、20mL正己烷洗涤滤饼，收集的固体在30℃～40℃真空干燥4小时，得到33.21g达格列净双L-脯氨酸共晶的类白色固体(HPLC：97.41％)。
向250mL三口瓶中，加入50mL纯化水以及150mL的甲基叔丁基醚，加入上述所得达格列净双L-脯氨酸共晶25g，搅拌溶清分出有机相，有机相使用50ml纯化水洗涤3次，将有机相减压蒸除溶剂，得到14.8g达格列净的类白色泡沫状固体(HPLC：98.27％)。
实施例10：达格列净粗品的纯化
向250mL三口瓶中加入150mL无水乙醇，开启搅拌，加入按专利文献WO03099836A1提供的方法制备的达格列净粗品(批号：20200602,黄色泡状固体)30g，纯化前杂质检出情况见下表7所示，搅拌至体系溶清。另取50mL单口瓶，加入10mL纯化水，开启搅拌，加入9.79g肌氨酸，搅拌至体系溶清后，将此溶液加至上述达格列净的无水乙醇的溶液中。在20℃～30℃保温搅拌析晶5小时，过滤，收集的固体在30℃～40℃真空干燥6小时，得到23g达格列净的肌氨酸合物，为白色固体，批号为202000714-2，杂质检出情况见下表7所示。
表7
Figure PCTCN2020119547-appb-000020
Figure PCTCN2020119547-appb-000021
对比例4：
向3000mL三口瓶中加600ml甲基叔丁基醚，开启搅拌，加入按专利文献WO03099836A1提供的方法制备的达格列净粗品30g(批号：202000602,黄色泡状固体)，纯化前杂质检出情况见表7所示。搅拌至体系溶清，按专利文献WO2008002824A1制备达格列净(S)-丙二醇一水合物的实施例6的方法，继续加入5.58g(S)-1，2-丙二醇，1.54g纯化水，0.30g达格列净(S)-丙二醇一水合物晶种，在20℃～30℃保温搅拌析晶8小时，加入1030mL的环己烷，过滤，收集的固体在20℃～25℃真空干燥4小时，得到达格列净(S)-丙二醇一水合物24g类白色固体，批号为202000714-5，纯化后杂质检出结果见表7所示。
实施例11：达格列净粗品的纯化
向250mL三口瓶中加入150mL无水乙醇，开启搅拌，加入按专利文献WO03099836A1提供的方法制备的达格列净粗品(批号：20200703-3，黄色泡状固体)30g，纯化前杂质检出情况见下表8所示，搅拌至体系溶清。另取50mL单口瓶，加入10mL纯化水，开启搅拌，加入9.8g肌氨酸，搅拌至体系溶清后，将此溶液加至上述达格列净的无水乙醇的溶液中。在20℃～30℃保温搅拌析晶5小时，过滤，收集的固体在30℃～40℃真空干燥6小时，得到21g达格列净的肌氨酸合物，为白色固体，批号为20200714-3，纯化后杂质检出结果见下表8所示。
表8
Figure PCTCN2020119547-appb-000022
Figure PCTCN2020119547-appb-000023
对比例5：
向3000mL三口瓶中加600ml甲基叔丁基醚，开启搅拌，加入按专利文献WO03099836A1提供的方法制备的达格列净粗品(批号：20200703-3，黄色泡状固体)30g，纯化前杂质检出情况见表8所示，搅拌至体系溶清，按专利文献WO2008002824A1制备达格列净(S)-丙二醇一水合物的实施例6的方法，继续加入5.58g(S)-1，2-丙二醇，1.54g纯化水，0.30g达格列净(S)-丙二醇一水合物晶种，在20℃～30℃保温搅拌析晶8小时，加入1030mL的环己烷，过滤，收集的固体在20℃～25℃真空干燥4小时，得到达格列净(S)-丙二醇一水合物20g类白色固体，批号为20200714-6，纯化后杂质检出情况见表8所示。
对比例6：
向100mL三口瓶中加入50mL无水乙醇，开启搅拌，加入10g达格列净(0.025mol，HPLC:>99％)搅拌至体系溶清。另取10mL单口瓶，加入2mL纯化水，开启搅拌，加入2.20g L-丙氨酸(0.025mol)搅拌至体系溶清后，将此溶液加至上述达格列净的乙醇溶液中。于-10℃～10℃保温搅拌15小时，未见固体析出，减压蒸除溶剂得到白色固体，测定熔点，为约70℃融化且有轻微不融化的颗粒，确认为达格列净与L-丙氨酸的物理混合物，没有形成共晶。
实施例12：卡格列净·肌氨酸共晶体的制备
向100mL三口瓶中加入25mL无水乙醇，开启搅拌，加入5.00g卡格列净(HPLC:>99％)搅拌至体系溶清。另取10mL单口瓶，加入3mL纯化水，开启搅拌，加入1.00g肌氨酸，搅拌至体系溶清后，将该溶液加至上述卡格列净的乙醇溶液中。在20℃～30℃保温搅拌析晶5小时，过滤，收集的固体在30℃～40℃真空干燥6小时，得到5.16g白色固体(HPLC：99.96％)。
通过X-射线粉末衍射图(XRPD)、单晶衍射、红外光谱分析图(IR)、差示扫描量热图(DSC)、热重分析图(TGA)、核磁共振氢谱图( 1H-NMR)，详见图6-图10，确认该白色固体为卡格列净·肌氨酸共晶。
1HNMR(600MHz,MeOD)δ7.535-7.511(m，2H)，7.306(s，1H)7.241-7.228(d，1H，J＝7.8Hz)，7.161-7.148(d，1H，J＝7.8Hz)，7.102-7.096(d，1H，J＝3.6Hz)，7.072-7.043(t，2H，J＝9.0Hz)，6.697-6.691(d，1H，J＝3.6Hz)，4.174-4.098(m，3H)，3.887-3.868(d，1H，J＝11.4Hz)，3.709-3.680(dd，1H，J＝12.0，5.4Hz)，3.487-3.465(m，3H)，3.429-3.368(m，3H)，2.663(s，3H)，2.294(s，3H)。
根据 1HNMR谱图数据，可以得知，卡格列净和肌氨酸的摩尔比为1:1。
所述卡格列净·肌氨酸共晶，使用Cu-Kɑ辐射以衍射角2θ表示的X-射线粉末衍射(XRPD)图谱，具有如下表9所示的特征峰及其相对强度，衍射角2θ误差为±0.2°：
表9卡格列净·肌氨酸共晶XRPD特征峰及其相对强度
No. 衍射角2θ D I/Io No. 衍射角2θ D I/Io
1 3.625 24.3531 67.7 11 20.296 4.3719 80.1
2 7.096 12.4468 26.4 12 20.597 4.3086 24.2
3 10.595 8.3430 62.8 13 21.110 4.2051 47.2
4 14.077 6.2861 22.7 14 22.062 4.0257 20.2
5 15.933 5.5579 13.0 15 22.887 3.8824 77.0
6 16.768 5.2829 47.7 16 25.414 3.5018 29.1
7 17.338 5.1104 42.7 17 27.544 3.2356 18.5
8 18.322 4.8381 31.2 18 28.287 3.1523 45.7
9 18.791 4.7184 100 19 33.763 2.6525 5.1
10 19.603 4.5248 48.2 -- -- --- -
所述卡格列净·肌氨酸共晶，用KBr压片法测得的红外吸收(IR)图谱在以下位置具有吸收峰：3543.82±10cm -1、3153.82±10cm -1、2690.68±5cm -1、2603.06±5cm -1、2419.53±5cm -1、1596.33±5cm -1、1507.48±5cm -1、1411.84±5cm -1、1382.27±5cm -1、1321.84±5cm -1、1233.44±5cm -1、1086.11±5cm -1、1062.19±5cm -1、829.61±5cm -1、799.52±5cm -1、537.55±5cm -1。
卡格列净·肌氨酸共晶的差示扫描量热(DSC)谱图，在160.0℃～180.0℃范围内有吸热峰，峰值为179.5℃，为熔解温度。
卡格列净·肌氨酸共晶的热重分析(TGA)谱图，在150℃之前无明显失重；TGA-DTA图190℃-230℃范围内有较宽吸热峰。
实施例13
利用溶剂缓慢挥发法，在乙醇/水混合溶剂体系中，培养得到达格列净·肌氨酸共晶的单晶，对其进行X-射线单晶衍射表征：
达格列净·肌氨酸共晶的单晶结构如图11所示：
表10单晶结构数据及结构精修参数
Figure PCTCN2020119547-appb-000024
Figure PCTCN2020119547-appb-000025
表11分级原子坐标
原子 X Y Z
Cl1 -7182(3) -8107.4(19) -647.6(3)
O1 -8732(8) -155(5) -162.7(9)
O8 -3180(7) 101(6) -1868.7(9)
O3 -1237(7) -3339(5) -1524.7(9)
O2 -4307(8) -6295(5) -1930.6(8)
O7 -4744(8) -1431(5) -1541.5(10)
O4 1151(8) -3283(9) -2038.1(10)
O6 -2966(10) -8370(7) -2359.5(10)
C16 -7078(12) -2509(8) -346.7(13)
C17 -8771(11) -1394(7) -337.2(12)
C22 -4852(11) -408(7) -1724.2(13)
C7 -4751(11) -5779(7) -1444.3(12)
N1 -9023(9) -493(7) -1629.0(11)
C8 -3640(11) -7062(7) -1341.1(12)
C21 -7086(13) 1522(7) 174.5(13)
C15 -7308(11) -3743(7) -534.5(13)
C20 -6743(12) 55(8) 14.4(13)
C6 -4063(11) -5096(7) -1725.4(12)
C5 -1605(10) -4478(7) -1734.1(12)
C11 -7407(11) -5855(7) -1044.3(11)
C2 -3907(11) -5779(8) -2214.4(12)
C18 -10675(11) -1530(8) -514.6(13)
O5 -1153(9) -4729(11) -2528.7(10)
原子 X Y Z
C14 -9196(11) -3877(8) -711.7(12)
C23 -7161(11) 287(7) -1788.6(13)
C9 -4365(11) -7751(7) -1091.8(12)
C10 -6252(11) -7149(8) -949.1(12)
C13 -9564(11) -5221(7) -907.3(12)
C4 -1128(12) -3904(10) -2033.6(13)
C19 -10885(11) -2734(8) -699.1(12)
C12 -6588(10) -5163(7) -1294.8(12)
C3 -1454(11) -5194(11) -2240.6(13)
C24 -9140(11) -136(9) -1319.1(14)
C1 -4458(13) -7105(9) -2405.5(13)
H3 -2397 -2776 -1514
H4 1366 -2823 -2192
H6 -3222 -8744 -2199
H16 -5773 -2436 -227
H1C -8841 -1515 -1649
H1D -10389 -240 -1709
H8 -2372 -7473 -1442
H21A -7245 2364 40
H21B -5760 1707 297
H21C -8475 1450 290
H15 -6147 -4499 -540
H20A -5340 112 -103
H20B -6584 -806 148
H6A -5150 -4256 -1774
H5 -535 -5340 -1695
H2 -4989 -4927 -2257
H18 -11845 -780 -508
H5A 161 -4354 -2549
H23A -7139 1378 -1737
H23B -7469 209 -1994
H9 -3588 -8618 -1020
H13A -10638 -4912 -1059
原子 X Y Z
H13B -10309 -6046 -798
H4A -2244 -3077 -2080
H19 -12186 -2796 -820
H12 -7302 -4262 -1362
H3A -355 -6032 -2195
H24A -9248 968 -1293
H24B -7756 -516 -1225
H24C -10493 -626 -1236
H1A -6061 -7429 -2372
H1B -4333 -6775 -2606
解析结果
1)X-射线单晶衍射表征及结构解析表明，该晶体属正交晶系，空间群P212121，其晶胞参数：
表12晶胞参数
Figure PCTCN2020119547-appb-000026
2)表征绝对构型的参数Flack parameter为0.03，小于0.2，通过单晶结构解析确定了达格列净·肌氨酸共晶的手性中心绝对构型如下所示：
Figure PCTCN2020119547-appb-000027
3)通过分子椭球图，可以确定组成成分为达格列净与肌氨酸1:1组成。
4)如下基团，以氢键进行成键，成为共晶。
Figure PCTCN2020119547-appb-000028
实验例1：达格列净·肌氨酸共晶与达格列净(S)-丙二醇一水合物影响因素对比实验
将达格列净·肌氨酸共晶与达格列净(S)-丙二醇一水合物做影响因素实验，取两种晶型的物料分别于高温60℃±2℃、光照4500LX±500LX、高湿RH75％±5％条件下裸放10天，考察两种晶型的物理稳定性及化学稳定性，结果如下表13、表14、表15所示：
表13达格列净·肌氨酸共晶影响因素结果
Figure PCTCN2020119547-appb-000029
表14达格列净(S)-丙二醇一水合物影响因素结果
Figure PCTCN2020119547-appb-000030
Figure PCTCN2020119547-appb-000031
表15达格列净·肌氨酸共晶影响因素10天晶型稳定性
Figure PCTCN2020119547-appb-000032
Figure PCTCN2020119547-appb-000033
根据上述的影响因素实验结果可知，达格列净·肌氨酸共晶在所有考察实验条件下，有关物质检出个数及总杂检出量没有增长，而达格列净(S)-丙二醇一水合物，经高温60℃杂质个数及总杂均有增长，杂质个数由0天的6个增加至13个，而达格列净·肌氨酸共晶影响因素10天各条件下检出的杂质个数和检出量均与0天一致，未呈现出变化趋势。由影响因素各条件考察10天样品的XRPD及0天XRPD结果，达格列净共晶体经影响因素各条件考察10天，晶型未发生变化。
实验例2：卡格列净·肌氨酸共晶与卡格列净半水合物影响因素结果对比
将卡格列净·肌氨酸共晶与卡格列净半水合物(原研晶型)做影响因素实验，取两种晶型的物料分别于高温60℃±2℃、光照4500LX±500LX、高湿RH75％±5％条件下裸放10天，考察两种晶型的物理稳定性及化学稳定性，结果如下表16、表17所示：
表16卡格列净·肌氨酸共晶与卡格列净半水合物影响因素结果对比
Figure PCTCN2020119547-appb-000034
根据上述的影响因素实验结果可知，卡格列净·肌氨酸共晶经高温60℃、高湿RH75％条件下裸放10天，与0天检测结果相比，检出的杂质个数及检出量均未呈现增长趋势；光照5000LX条件下放置10天，卡格列净共晶检出2个新增杂质，但最大检出量约为0.05％；半水合物光照条件下杂质检出个数新增1个；卡格列净·肌氨酸共晶体的化学稳定性不差于卡格列净半水合物。高温60℃条件裸放10天，卡格列净半水合物减重约1.0％，高湿RH75％条件放置10天，卡格列净半水合物增重约2.1％，而卡格列净·肌氨酸共晶高温60℃、高湿RH75％条件下，增失重基本无变化，说明本发明制备的卡格列净·肌氨酸共晶的晶型物理稳定性优于卡格列净半水合物。
表17卡格列净·肌氨酸共晶影响因素10天晶型稳定性
Figure PCTCN2020119547-appb-000035
由影响因素各条件考察10天样品的XRPD及0天XRPD结果，卡格列净共晶经影响因素各条件考察10天，其特征衍射角与0天检测结果相比，基本一致，因此，晶型未发生变化。
实验例3：达格列净·肌氨酸共晶引湿性实验
将达格列净·肌氨酸共晶做引湿性实验，结果如下表18所示：
表18达格列净·肌氨酸共晶引湿性实验结果
Figure PCTCN2020119547-appb-000036
根据上述数据可知，达格列净·肌氨酸共晶不具有引湿性。
实验例4：过筛对比
采用直径20cm的圆形筛，目数80目，采用8411型电动振荡筛(绍兴市上虞区道墟越州土工仪器厂)，转速1400转/分，对达格列净·肌氨酸共晶、达格列净(S)丙二醇合物水合物各30g进行过筛，时间20分钟，收集筛下托盘中物料，观察过筛后现象，包括筛上物料残留情况及大颗粒物料情况，观察筛网对物料吸附情况，结果如下表19所示：
表19过筛结果对比
Figure PCTCN2020119547-appb-000037
对以上收率结果进行单因素方差分析，结果如下表20所示：
表20过筛收率方差分析结果
差异源 SS df MS F P-value
组间 51.627 1 51.627 20.85 0.01
由上数据可知，两种物料过筛收率方差分析结构，二者有显著性差异。
根据过筛收率和过筛后观察到的现象可知，达格列净·肌氨酸共晶粉体状态更利于过筛，过筛损失小，收率高，基本无静电作用。
实验例5：达格列净·肌氨酸共晶体与达格列净-(S)丙二醇一水合物粒径及流动性对比
采用激光粒度仪，以水为分散剂检测达格列净·肌氨酸共晶体与达格列净-(S)-丙二醇一水合物粒径分布。采用BT-1000粉体综合特性测试仪，分别测定达格列净·肌氨酸共晶与达格列净-(S)-丙二醇一水合物休止角、松密度、振实密度。结果如下表21、表22所示：
表21粒径检测结果
品名 D10(微米) D50(微米) D90(微米)
达格列净·肌氨酸共晶体 5.151 24.83 89.93
达格列净-(S)-丙二醇一水合物 2.492 61.55 256.2
根据以上结果可知，达格列净共晶体D90为分别为89.93μm，粒径分布有利于药物组合物制备工艺过程混合均匀，尤其对于小规格制剂。
表22流动性检测结果
品名 休止角(°) 松密度(g/ml) 振实密度(g/ml)
达格列净·肌氨酸共晶体 40 0.40 0.58
达格列净-(S)-丙二醇一水合物 48 0.35 0.53
根据以上结果可知，达格列净·肌氨酸共晶体与达格列净-(S)-丙二醇一水合物的松密度与振实密度略有差异，达格列净·肌氨酸共晶体的休止角较小，流动性优于达格列净-(S)-丙二醇一水合物。
实验例6：制剂生产过程中混合难易程度对比
采用FH实验室型混合机(0.5L料斗)对表20所示处方物料进行混合，转速8rpm，时间30min，料斗中不同位置共取5点检测主药含量，计算RSD，评估混合难易程度，结果如表23所示。
表23处方组成
处方组成 用量(g)
主药(投料量以达格列净计) 10.0
微晶纤维素 171.5
无水乳糖 50.0
交联聚维酮 10.0
交联羧甲基纤维素钠 4.0
二氧化硅 3.75
硬脂酸镁 2.5
表24流动性检测结果
Figure PCTCN2020119547-appb-000038
根据以上结果可知，采用同样的处方，同样的混合工艺，达格列净·肌氨酸共晶体为主药的处方混合均匀度最好，满足制剂生产要求。达格列净-(S)-丙二醇一水合物容易聚团，较难混合均匀。
实验例7：达格列净·肌氨酸共晶体、卡格列净·肌氨酸共晶体在不同pH缓冲盐溶液中的溶解度考察
取达格列净·肌氨酸共晶、卡格列净·肌氨酸共晶适量，分别加入pH 1.0盐酸、pH 3.0柠檬酸盐缓冲液、pH 4.0醋酸盐缓冲液、pH 6.8磷酸盐缓冲液、水、人工胃液、人工肠液中，置25℃恒温空气浴摇床中振摇，分别于12h、24h，13000rpm/min离心10分钟，取上清液分析，结果见下表25所示：
表25溶解度考察(25℃)
Figure PCTCN2020119547-appb-000039
根据测定结果，达格列净·肌氨酸共晶的熔点虽然较达格列净-(S)-丙二醇一水合物高，但不同pH介质中的溶解度仍在1.4～1.6mg/ml之间，与文献报道的达格列净-(S)-丙二醇一水合物的溶解度一致；根据卡格列净·肌氨酸共晶在不同pH介质中溶解度约为30μg/ml，属几乎不溶。而根据卡格列净 日本IF文件，卡格列净半水合物为水中几乎不溶(1g在10000ml中不能溶解)，二者在水溶液中的溶解度基本一致。但根据卡格列净共晶的物理化学性质及晶型的物理稳定性，卡格列净共晶更适合制剂组合物的工业化大生产。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (38)

  1. 一种SGLT-2抑制剂·肌氨酸共晶体。
  2. 根据权利要求1所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，X-射线粉末衍射图在2θ±0.2°位置有衍射峰，所述2θ±0.2°为10.6±0.2°、19.6±0.2°、22.1±0.2°、33.6±0.2°。
  3. 根据权利要求1所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，红外光谱中至少在以下位置具有特征吸收峰：3540±10cm -1、2691±5cm -1、2603±5cm -1、2420±5cm -1。
  4. 根据权利要求1所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，热重分析谱图中在190℃-230℃有较宽吸热峰。
  5. 根据权利要求1所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，核磁共振氢谱(HNMR，600MHz,MeOD)中除具有SGLT-2抑制剂结构的共振峰外，在化学位移2.4～3.2ppm范围内有-CH 3的峰、在3.0-4.0ppm范围内有-CH 2-峰。
  6. 根据权利要求1所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，所述SGLT-2抑制剂为达格列净、恩格列净、卡格列净、托格列净、伊格列净、鲁格列净、索格列净、加格列净、贝格列净、艾格列净、埃格列净、恒格列净、瑞格列净、泰格列净、万格列净中的任意一种，或式a所示结构：
    Figure PCTCN2020119547-appb-100001
  7. 根据权利要求1所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，所述SGLT-2抑制剂·肌氨酸共晶体中无超过0.1％的单个杂质。
  8. 根据权利要求1所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，具有式Ⅰ所示结构：
    Figure PCTCN2020119547-appb-100002
    其中，R 1、R 2、R 3、R 4、X的范围如下表所示：
    Figure PCTCN2020119547-appb-100003
  9. 根据权利要求1所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，具有式Ⅱ所示结构：
    Figure PCTCN2020119547-appb-100004
    其中，R 5为Cl，R 6选自以下任一结构：
    Figure PCTCN2020119547-appb-100005
    或者R 5为甲基，R 6为
    Figure PCTCN2020119547-appb-100006
    或者R 5为F，R 6为
    Figure PCTCN2020119547-appb-100007
  10. 根据权利要求1所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，所述SGLT-2抑制剂与肌氨酸的摩尔比为1：(0.5～5.0)，在一些实施例中，SGLT-2抑制剂与肌氨酸摩尔比优选为1：0.6、1：0.7、1：0.8、1：0.9、1：0.95、1：1.0、1：1.05、1：1.1、1：1.2、1：1.3、1：1.4、1：1.5、1：1.6、1：1.7、1：1.8、1：1.9或1：2.0；更优选的SGLT-2抑制剂与肌氨酸的摩尔比为 1：0.8、1：0.9、1：0.95、1：1.0、1：1.05、1：1.1、1：1.2或1：1.3、1：1.4或1：1.5。
  11. 根据权利要求1所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，所述SGLT-2抑制剂为达格列净，所述SGLT-2抑制剂·肌氨酸共晶体X-射线粉末衍射图在2θ±0.2°位置有衍射峰，所述2θ±0.2°为3.8±0.2°、10.6±0.2°、13.7±0.2°、17.0±0.2°、18.0±0.2°、18.6±0.2°、19.6±0.2°、20.1±0.2°、21.4±0.2°、22.1±0.2°、23.0±0.2°、25.4±0.2°、27.6±0.2°、33.6±0.2°。
  12. 根据权利要求11所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，利用溶剂缓慢挥发法，在乙醇/水混合溶剂体系中，培养得到达格列净·肌氨酸共晶体的单晶，所述共晶体的单晶的晶胞参数如下：
    晶胞大小：
    Figure PCTCN2020119547-appb-100008
    α＝90°、β＝90°、γ＝90°
    空间群＝P212121
    分子/不对称单元＝4
    其中所述共晶体的单晶结构的测量在T＝112进行，且其分级原子坐标如表11中所列。
  13. 根据权利要求11所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，所述共晶体的红外光谱在以下位置具有特征吸收峰：3543.67±10cm -1、3161.94±10cm -1、2690.95±5cm -1、2603.78±5cm -1、2419.39±5cm -1、2360.665cm -1、1599.61±5cm -1、1510.92±5cm -1、1291.19±5cm -1、1045.97cm -1。
  14. 根据权利要求11所述的SGLT-2抑制剂·肌氨酸共晶体，所述共晶体在DSC谱图中，在140.0℃～155.0℃范围内有吸热峰，峰值为149.0℃，为熔解温度。
  15. 根据权利要求11所述的SGLT-2抑制剂·肌氨酸共晶体，所述共晶体在TGA-DTA谱图中150℃以前无明显失重，在190℃-230℃范围内有较宽吸热峰。
  16. 根据权利要求11所述的SGLT-2抑制剂·肌氨酸共晶体，所述共晶体在核磁共振氢谱以下位置具有共振峰：HNMR(600MHz,MeOD)δ7.343-7.329(d，1H，J＝8.4Hz)，7.315-7.312(d，1H，J＝1.8Hz)7.276-7.259(dd，1H， J＝8.4，1.8Hz)，7.091-7.077(d，2H，J＝8.4Hz)，6.795-6.781(d，2H，J＝8.4Hz)，4.089-4.073(d，1H，J＝9.6Hz)，4.055-3.977(q，2H，J＝15.0Hz)，3.994-3.959(q，2H，J＝7.2Hz)，3.876-3.854(dd，1H，J＝12.0，1.8Hz)，3.697-3.668(dd，1H，J＝12.0，5.4Hz)，3.467(s，2H)3.461-3.431(m，1H)，3.409-3.370(m，2H)，3.283-3.268(m，1H)，2.665(s，3H)，1.360-1.337(t，3H，J＝7.2Hz)。
  17. 根据权利要求1所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，所述SGLT-2抑制剂为卡格列净，所述SGLT-2抑制剂·肌氨酸共晶体X-射线粉末衍射图在2θ±0.2°位置有衍射峰，所述2θ±0.2°为3.6±0.2°、7.1±0.2°、10.6±0.2°、14.1±0.2°、16.8±0.2°、17.3±0.2°、18.3±0.2°、18.8±0.2°、19.6±0.2°、20.3±0.2°、21.1±0.2°、22.1±0.2°、22.9±0.2°、25.4±0.2°、28.2±0.2°、33.6±0.2°。
  18. 根据权利要求17所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，所述共晶体的红外光谱在以下位置具有特征吸收峰：3543.82±10cm -1、3153.82±10cm -1、2690.68±5cm -1、2603.06±5cm -1、2419.53±5cm -1、1596.33±5cm -1、1507.48±5cm -1、1086.11±5cm -1、1062.19±5cm -1、829.61±5cm -1。
  19. 根据权利要求17所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，所述共晶体在DSC谱图中，在160.0℃～180.0℃范围内有吸热峰，峰值为179.5℃，为熔解温度。
  20. 根据权利要求17所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，所述共晶体在TGA-DTA谱图中150℃以前无明显失重，在190℃-230℃范围内有较宽吸热峰。
  21. 根据权利要求1所述的SGLT-2抑制剂·肌氨酸共晶体，其特征在于，所述共晶体，在核磁共振氢谱HNMR(600MHz,MeOD)以下位置具有共振峰：δ7.535-7.511(m，2H)，7.306(s，1H)7.241-7.228(d，1H，J＝7.8Hz)，7.161-7.148(d，1H，J＝7.8Hz)，7.102-7.096(d，1H，J＝3.6Hz)，7.072-7.043(t，2H，J＝9.0Hz)，6.697-6.691(d，1H，J＝3.6Hz)，4.174-4.098(m，3H)，3.887-3.868(d，1H，J＝11.4Hz)，3.709-3.680(dd，1H，J＝12.0，5.4Hz)，3.487-3.465(m，3H)，3.429-3.368(m，3H)，2.663(s，3H)，2.294(s，3H)。
  22. SGLT-2抑制剂·肌氨酸共晶体的制备方法，包括以下步骤：
    将SGLT-2抑制剂的溶液和肌氨酸的溶液混合，静置析晶或降温析晶，固液分离，得到SGLT-2抑制剂·肌氨酸共晶体。
  23. 根据权利要求22所述的制备方法，其特征在于，所述SGLT-2抑制剂和所述肌氨酸的摩尔比为1：(0.5～5.0)，在一些实施例中，SGLT-2抑制剂与肌氨酸摩尔比优选为1：0.6、1：0.7、1：0.8、1：0.9、1：0.95、1：1.0、1：1.05、1：1.1、1：1.2、1：1.3、1：1.4、1：1.5、1：1.6、1：1.7、1：1.8、1：1.9或1：2.0。
  24. 根据权利要求22所述的制备方法，其特征在于，所述SGLT-2抑制剂的溶液中的溶剂选自C1-C10醇类、C3-C10酮类、醚类、腈类中的不同单一溶剂或混合溶剂；
    所述肌氨酸的溶液中的溶剂选自水。
  25. 根据权利要求22所述的制备方法，其特征在于，所述静置析晶或降温析晶的温度为-20℃～40℃；在一些实施例中，析晶温度优选为：-15℃～35℃、-10℃～30℃、-5℃～30℃、0℃～30℃、5℃～30℃、10℃～30℃、15℃～30℃及20℃～30℃。
  26. 根据权利要求22所述的制备方法，其特征在于，所述静置析晶或降温析晶的时间为4-48小时，优选4-24小时，4-16小时，4-12小时，更优选8-12小时。
  27. 一种SGLT-2抑制剂粗品的纯化方法，包括以下步骤：
    将SGLT-2抑制剂的粗品与肌氨酸混合，室温搅拌，固液分离，得到SGLT-2抑制剂的肌氨酸合物；
    将SGLT-2抑制剂的肌氨酸合物解离，得到SGLT-2抑制剂游离态纯品。
  28. 根据权利要求27所述的纯化方法，其特征在于，所述SGLT-2抑制剂的粗品与肌氨酸的摩尔比为1：(0.5～5.0)，在一些实施例中，SGLT-2抑制剂粗品与肌氨酸的摩尔比优选为1：0.7、1：0.8、1：0.9、1：0.95、1：1.0、1：1.05、1：1.1、1：1.2、1：1.3、1：1.4、1：1.5、1：1.6、1：1.7、1：1.8、1：1.9、1：2.0或1：3.0；更优选的SGLT-2抑制剂粗品与肌氨酸的摩尔比为1：1.0、1：1.1、1：1.2、1：1.3、1：1.4、1：1.5、1：1.6、1：1.7、1：1.8、1：1.9、1：2.0及1：3.0。
  29. 根据权利要求27所述的纯化方法，其特征在于，还包括：
    以所述SGLT-2抑制剂游离态纯品为原料，直接制备SGLT-2抑制剂最终的药用晶型；
    或者以所述SGLT-2抑制剂游离态纯品为原料，通过重结晶或共晶方式制备SGLT-2抑制剂最终的药用晶型。
  30. 根据权利要求29所述的纯化方法，其特征在于，所述SGLT-2抑制剂最终的药用晶型选自SGLT-2抑制剂纯品、溶剂合物、水合物、溶剂合物水合物、共晶体或复盐。
  31. 根据权利要求27所述的纯化方法，其特征在于，所述SGLT-2抑制剂游离态纯品的HPLC归一化纯度不低于99％。
  32. 药物组合物，其特征在于，包括权利要求1～21任一项所述的SGLT-2抑制剂·肌氨酸共晶体，或权利要求22～26任一项所述的制备方法制备的SGLT-2抑制剂·肌氨酸共晶体，或权利要求27～31任一项所述的纯化方法得到的SGLT-2抑制剂游离态纯品，以及药学上可接受的载体，赋形剂，稀释剂，辅剂，媒介物或它们的组合。
  33. 权利要求1～21任一项所述的SGLT-2抑制剂·肌氨酸共晶体，或权利要求22～26任一项所述的制备方法制备的SGLT-2抑制剂·肌氨酸共晶体，或权利要求27～31任一项所述的纯化方法得到的SGLT-2抑制剂游离态纯品，或权利要求32所述的药物组合物，在制备用于预防、治疗或减轻心脑血管疾病、糖尿病及其并发症、非糖尿病引起的肾病的药物中的应用。
  34. 根据权利要求33所述的应用，其特征在于，所述糖尿病及其并发症选自原发性高血压、合并高血压的2型糖尿病、合并2型糖尿病的肾病、合并高血压和糖尿病的肾病、肾病、1型糖尿病、1型糖尿病的肾病、肝纤维化、胰岛素抵抗、高血糖、高胰岛素血症、脂肪酸或甘油的升高的血含量、高脂血、血脂障碍、肥胖中的一种或多种。
  35. 权利要求1～21任一项所述的SGLT-2抑制剂·肌氨酸共晶体，或权利要求22～26任一项所述的制备方法制备的SGLT-2抑制剂·肌氨酸共晶体，或权利要求27～31任一项所述的纯化方法得到的SGLT-2抑制剂游离态纯品或权利要求32所述的药物组合物，在制备用于降血压的药物中的应用。
  36. 一种预防、治疗或减轻糖尿病及其并发症的方法，包括将权利要求1～21任一项所述的SGLT-2抑制剂·肌氨酸共晶体，或权利要求22～26任一项所述的制备方法制备的SGLT-2抑制剂·肌氨酸共晶体，或权利要求27～31任一项所述的纯化方法得到的SGLT-2抑制剂游离态纯品，或权利要求32所述的药物组合物与生物标本接触。
  37. 一种降血压的方法，包括将权利要求1～21任一项所述的SGLT-2抑制剂·肌氨酸共晶体，或权利要求22～26任一项所述的制备方法制备的SGLT-2抑制剂·肌氨酸共晶体，或权利要求27～31任一项所述的纯化方法得到的SGLT-2抑制剂游离态纯品，或权利要求32所述的药物组合物与生物标本接触。
  38. 一种治疗非糖尿病引起的肾病的方法，包括将权利要求1～21任一项所述的SGLT-2抑制剂·肌氨酸共晶体，或权利要求22～26任一项所述的制备方法制备的SGLT-2抑制剂·肌氨酸共晶体，或权利要求27～31任一项所述的纯化方法得到的SGLT-2抑制剂游离态纯品，或权利要求32所述的药物组合物与生物标本接触。
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