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WO2008092327A1 - Half-hydrated crystal of voglibose, the preparation thereof and pharmaceutical composition containing the same - Google Patents

Half-hydrated crystal of voglibose, the preparation thereof and pharmaceutical composition containing the same Download PDF

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Publication number
WO2008092327A1
WO2008092327A1 PCT/CN2007/003439 CN2007003439W WO2008092327A1 WO 2008092327 A1 WO2008092327 A1 WO 2008092327A1 CN 2007003439 W CN2007003439 W CN 2007003439W WO 2008092327 A1 WO2008092327 A1 WO 2008092327A1
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voglibose
crystal
hemihydrate
crystals
hemihydrate crystal
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French (fr)
Chinese (zh)
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Ligang Liu
Ruiwen Li
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PHARMAXYN LABORATORIES Ltd
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PHARMAXYN LABORATORIES Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a voglibose hemihydrate crystal.
  • the invention also relates to a process for the preparation of such voglibose hemihydrate crystals and a pharmaceutical composition comprising the hemihydrate crystals.
  • Voglibose chemical name is (1S) - (1 (hydroxy), 2, 4, 5/1, 3) -5 - [(2-hydroxy-1-(hydroxyindoleyl)ethyl)amino] - 1-Hydroxymethyl- 1 , 2, 3 , 4 -cyclohexanetetraol, a drug for the treatment of diabetes with alpha-glucosidase inhibitors, is a new type of diabetes therapeutic agent, currently in China, Korea and Listed in Japan for the treatment of postprandial hyperglycemia. Its structural formula is as shown in the following figure (I)
  • Oral administration of voglibose can competitively block disaccharide hydrolase such as maltase and sucrase present on the microvilli surface of the small intestine mucosa, resulting in digestion of the ingested polysaccharide, oligosaccharide and disaccharide into glucose,
  • the process of monosaccharides such as fructose is blocked, so that the absorption in the upper part of the duodenum and jejunum is reduced, and it is delayed to the middle and lower part of the small intestine to slowly digest and absorb, thereby avoiding a sharp rise in blood sugar after meals, and inhibiting the postprandial Hyperglycemia, and inhibition of concomitant insulin secretion, improves excessive insulin response.
  • voglibose inhibited the maltase and sucrase of pig small intestine by 22 times and 33% of acarbose, respectively. Times. Inhibition of maltase and sucrase in the small intestine of rats, voglibose is 270-fold and 190-fold higher than acarbose, respectively. On the other hand, for the inhibition of ⁇ -amylase in pigs and rats, voglibose is only 1/3000 of acarbose.
  • the activity of voglibose is much higher than that of similar acarbose, and the selectivity to ⁇ -glucosidase is much higher than that of acarbose, so the dosage is smaller and the intestinal side effects are lower.
  • Valienamine which is then used as a raw material for chemical synthesis (EP56194); it can also be prepared by chemical synthesis using D-glucose as a raw material, for example, EP260121, J. Org. Chem. 1992, 57, 3651, WO03/080561, WO2005/030698 and the like.
  • Voglibose is easily soluble in water, slightly soluble in methanol, and difficult to dissolve in ethanol.
  • a voglibose (hereinafter referred to as a voglet) in a crystalline state containing 0.5 molecules of water of crystallization.
  • Wave sugar hemihydrate crystal thermogravimetric analysis (TG), differential scanning calorimetry (DSC;), infrared spectroscopy (IR), elemental analysis, specific rotation and single Crystalline X-ray diffraction was characterized.
  • a further object of the present invention is to provide a process for the preparation of voglibose hemihydrate crystals which has fewer steps, simple and easy reagents, low contamination, high handling efficiency, high crystallization yield and high uniformity of product particle size.
  • the present invention also provides a process for preparing anhydrous crystals of voglibose from such crystallization.
  • the present invention also provides the use of such voglibose hemihydrate crystals in pharmaceutical preparations, in particular pharmaceutical compositions containing such voglibose hemihydrate crystals.
  • the inventors of the present invention studied the crystallization conditions of voglibose during the preparation of voglibose crystals, and found that pure water and short carbon chain fatty alcohols (such as methanol, ethanol, n-propanol or Isopropanol) mixed solvent method
  • pure water and short carbon chain fatty alcohols such as methanol, ethanol, n-propanol or Isopropanol
  • the hemihydrate crystal of voglibose can be obtained.
  • the amount of solvent used in the process is small, the crystallization is complete and complete, and the yield and purity are high.
  • the crystallized particles have good uniformity, good stability and are suitable for formulation production.
  • the voglibose crystals that is, voglibose hemihydrate crystals.
  • the crystallization can be characterized by its powder X-ray diffraction pattern, which is characterized by being located at 9.64 ⁇ 0.2, 16.08 ⁇ 0.2, 18.34 ⁇ 0.2, 19.26 ⁇ 0.2, 21.92 ⁇ 0.2, 22.42 ⁇ 0.2 degrees.
  • Diffraction peaks in addition to the above characteristic peaks having a relative intensity of more than 25%, the crystals may further comprise, in powder X-ray diffraction, at 12.70 ⁇ 0.2, 18.92 ⁇ 0.2, 20.10 ⁇ 0.2, 20.40 ⁇ 0.2, 21.22 ⁇ 0.2. , 24.58 ⁇ 0.2, 26.20 ⁇ 0.2, 32.86 ⁇ 0.2 degrees of diffraction peaks (see Figure 1), Table 1 is the powder X-ray diffraction data of the crystal.
  • the first peak represents the process of losing the water of crystallization of the voglibose hemihydrate crystals, corresponding to the process of losing 3% at 85-119 °C on the TG line of the crystal; the second is located at 167.3 ⁇ .
  • the peak indicates the melting process of voglibose after dehydration, and the peak temperature is consistent with the melting point of the anhydrous crystal of voglibose.
  • a single crystal X-ray ray test is performed on a single crystal of a suitable size in the voglibose hemihydrate crystal.
  • the structural formula confirms that the crystal has the formula: C 1() H 21 NO 7 *0.5H 2 O,
  • the spatial three-dimensional structure of the molecule is shown in Fig. 4; the cell packing pattern of the molecule in the A direction is shown in Fig. 5, and the figure shows that the molecules are linked by hydrogen bonding.
  • Table 2 to Table 7 below list the crystal data, atomic coordinates, bond length, bond angle, twist angle, and hydrogen bond long bond angle data.
  • the invention also provides a method for preparing the crystal. Specifically, the crude voglibose is dissolved in a small amount of hot water, added with methanol or ethanol, decolorized by adding activated carbon under heating and stirring, filtered, and hot is added to the filtrate. Hydroxide or ethanol or propanol or isopropanol, crystallizing under stirring, cooling to room temperature, filtering, Drying at 40 ° C for 12 hours under vacuum gave a white voglibose hemihydrate crystal.
  • the method is to dissolve 1 part by weight of crude voglibose in 1-3 times hot water, preferably 2 times; add 1-3 times, preferably 2 times, of methanol or ethanol.
  • Ethanol deactivated by adding activated carbon at 60 ° C for 30 minutes, filtered, and adding 3 - 10 parts of 50-70 ° C methanol or ethanol, or n-propanol, or isopropanol, preferably 5 times of 60 ° C ethanol.
  • the white crystals were precipitated under stirring, and then naturally cooled to room temperature, filtered, and dried under vacuum to obtain voglibose hemihydrate crystals.
  • the invention therefore also provides for the use of the voglibose hemihydrate crystals in pharmaceutical formulations.
  • a pharmaceutical composition or a pharmaceutical preparation containing voglibose hemihydrate crystals which can be formulated into various forms suitable for oral administration, for treating diabetes.
  • Preferred pharmaceutical formulation forms can be tablets, capsules, granules or suspensions.
  • pharmaceutically acceptable carriers in addition to voglibose hemihydrate crystals, pharmaceutically acceptable carriers, excipients and/or diluents are included, representative examples include, but are not limited to: One or more fillers, such as mannitol, starch, modified starch, lactose, dextran, calcium carbonate, yf
  • One or more binders such as lactose, starch, modified starch, microcrystalline cellulose, sucrose, hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxyethyl cellulose , mercapto cellulose, carboxymethyl cellulose, gelatin.
  • One or more disintegrants such as crosslinked polyvinylpyrrolidone, croscarmellose, microcrystalline cellulose, and the like.
  • Flavoring agents such as citric acid, aspartame and the like may also be included in the formulation of the pharmaceutical composition as needed.
  • the researchers of the present invention also studied the water loss of the novel voglibose hemihydrate crystal, and found that the voglibose hemihydrate crystals can maintain good stability from room temperature to 70 °C. Without losing crystal water, it is easy to lose crystal water at 80 - 100 ° C, and become voglibose anhydrate, by powder X-ray diffraction, TG, DSC of the voglibose anhydrate.
  • the invention therefore also provides a process for the preparation of water-free crystals of voglibose.
  • the invention is characterized in that voxelose sugar hemihydrate crystals are dried under vacuum under certain conditions to lose crystal water, and crystal form transformation occurs at the same time to obtain anhydrous crystals of voglibose.
  • the method is to dry voglibose hemihydrate crystals at 80 - 100 ° C for 4 - 24 hours, preferably at a temperature of 85 - 90 ° C, and preferably for 8 hours.
  • the positive effect of the invention is: a novel voglibose hemihydrate crystal, the purity of the crystal is very High, good particle uniformity, good stability, especially suitable for formulation production; and the process of preparing the crystal is simple and practical, the amount of solvent used is small, the crystallization is complete and the yield is high; Lapodose hemihydrate crystals are dried under vacuum and dehydrated to prepare anhydrous crystals of voglibose.
  • the method is simple, and the obtained anhydrous crystals of voglibose also have good stability and are suitable for the production of pharmaceutical preparations.
  • Figure 1 is an X-ray diffraction pattern of a voglibose hemihydrate crystalline powder.
  • Figure 2 is a thermogravimetric analysis of voglibose hemihydrate crystals.
  • Figure 3 is a differential scanning calorimetry analysis of voglibose hemihydrate crystals.
  • Fig. 4 is a molecular perspective view of voglibose hemihydrate crystals obtained by single crystal X-ray diffraction.
  • Figure 5 is a diagram of the molecular unit cell stacking in the crystal of the voglibose hemihydrate crystal, in which the molecules are connected by hydrogen bonds.
  • Figure 6 is an infrared spectrum of voglibose hemihydrate crystals.
  • Figure 7 is an X-ray diffraction pattern of voglibose powder obtained by dehydration of voglibose hemihydrate crystals.
  • Fig. 8 is a thermogravimetric analysis diagram of voglibose obtained by deicing of voglibose hemihydrate crystals.
  • Figure 9 is a differential scanning calorimetry analysis of voglibose obtained by dehydration of voglibose hemihydrate crystals. .
  • Figure 10 is an infrared photogram of voglibose obtained by dehydration of voglibose hemihydrate crystals.
  • Figure 11 is a powder X-ray ray diagram of the anhydrous crystals of voglibose obtained from anhydrous ethanol.
  • Figure 12 is a thermogravimetric analysis of the anhydrous crystals of voglibose obtained from anhydrous ethanol in the reference.
  • Figure 13 is a differential scanning calorimetry diagram of the anhydrous crystals of voglibose obtained from anhydrous ethanol in the reference.
  • Figure 14 is an infrared optical map of the anhydrous crystals of voglibose obtained from anhydrous ethanol in the reference. detailed description
  • thermogravimetric analyzer is a NETZSCH TG209 type with a heating rate of 10 °C/min.
  • the differential scanning calorimeter is a NETZSCH DSC204 type.
  • the infrared spectrometer was Bruker EQUINOX 55 and was measured by potassium bromide tableting.
  • Tetrabenzyl voglibose (300.0 g, 0.48 mol) was dissolved in 90% formic acid/methanol (1: 19, 6 L), palladium black (60 g) was added, and reacted under nitrogen for 12 hours at room temperature. Wash with decyl alcohol/water (1:1) 2L, concentrate the filtrate, remove the residue with strong acidic ion exchange resin (5L), wash with water, then elute with 0.5N ammonia water, evaporate the water and add 2 L of absolute ethanol was stirred, and the precipitated pale gray crystals were filtered and dried under vacuum for 12 hours to obtain a crude product of 110 g of voglibose.
  • the crystal powder X-ray diffraction pattern, TG, DSC, and infrared spectrum are shown in Figures 1-3 and Figure 6, respectively.
  • the crystal powder X-ray diffraction data are shown in the following table;
  • 100 g of crude voglibose (preparation method as in Example 1) was dissolved in 100 g of hot pure water.
  • 100 g of methanol, 10 g of activated carbon decolorize by heating at 60 ° C for 30 minutes, filter, add 1000 g of methanol to 50 ° C, precipitate crystals under stirring, naturally cool to room temperature, filter, and vacuum dry at 40 ° C for 12 hours to obtain 85 g Globose is semi-hydrated and crystallized.
  • Fig. 7-10 infrared spectrum of the water-depleted crystal are shown in Fig. 7-10, respectively.
  • the inventors directly prepared anhydrous crystals of voglibose, and by powder X-ray diffraction, TG, DSC, IR, elemental analysis, ratio Its crystallinity is characterized by optical rotation, etc., and its characteristics are completely consistent with the voglibose crystals obtained by the dehydration of voglibose hemihydrate crystals, indicating that water loss can be obtained by volatilose sugar hemihydrate crystals. The volagliose crystals are completely consistent with the literature.
  • voglibose hemihydrate crystals, mannitol, microcrystalline cellulose, citric acid, and aspartame are uniformly mixed, sieved and sized, added with stearic acid strontium, uniformly mixed, and tableted. 1000 tablets containing voglibose hemihydrate crystals, each containing voglibose (as an anhydride) 0.2 gram.
  • the crystal was allowed to stand at 4 CTC for 15 or 30 days, and the voglibose content and impurities in the crystal did not change significantly (see Table 8), indicating that the crystal had good stability and could be stored for a long period of time under normal conditions.
  • Voglibose crystals obtained by dehydration of voglibose hemihydrate crystals and anhydrous volatilose crystals obtained from anhydrous ethanol according to literature methods are placed at 40 ° C for 15 or 30 days, two There was no significant change in the content and impurities, indicating that both have the same good stability (test data are shown in Table 9), and there is no significant difference between the two crystals.

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  • Diabetes (AREA)
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Abstract

Provided are half-hydrated crystal of voglibose and the preparation thereof. Said half-hydrated crystal has the molecular formula of C10H21NO7 0.5H2O and the powder X-ray diffraction pattern with peaks of 2ϑ=9.64±0.2, 16.08±0.2, 18.34±0.2, 19.26±0.2, 21.92±0.2 and 22.42±0.2 degree. Also provided are the process for preparing anhydrous voglibose from said half-hydrated crystal of voglibose and the use of said half-hydrated crystal of voglibose in the pharmaceutical preparation for curing diabetes.

Description

伏格列波糖半水合结晶、 制备方法及舍有其的药物组合物 技术领域  Voglibose hemihydrate crystal, preparation method and pharmaceutical composition therewith

本发明涉及一种伏格列波糖半水合结晶。  The present invention relates to a voglibose hemihydrate crystal.

本发明同时还涉及这种伏格列波糖半水合结晶的制备方法及含有该半水 合结晶的药物组合物。 背景技术  The invention also relates to a process for the preparation of such voglibose hemihydrate crystals and a pharmaceutical composition comprising the hemihydrate crystals. Background technique

伏格列波糖， 化学名是（1S ) ― ( 1 (羟基）， 2, 4, 5/1 , 3 ) —5 - [ ( 2 -羟基 - 1 - (羟曱基）乙基）氨基] - 1- -羟曱基 - 1 , 2, 3 , 4 -环己烷四醇， 属于 α-糖苷酶抑制剂类治疗糖尿病的药物，是一种新型糖尿病治疗剂， 目前已 经在中国、 韩国及日本上市用于餐后高血糖的治疗。 其结构式如下图 （I )所  Voglibose, chemical name is (1S) - (1 (hydroxy), 2, 4, 5/1, 3) -5 - [(2-hydroxy-1-(hydroxyindoleyl)ethyl)amino] - 1-Hydroxymethyl- 1 , 2, 3 , 4 -cyclohexanetetraol, a drug for the treatment of diabetes with alpha-glucosidase inhibitors, is a new type of diabetes therapeutic agent, currently in China, Korea and Listed in Japan for the treatment of postprandial hyperglycemia. Its structural formula is as shown in the following figure (I)

Figure imgf000003_0001
Figure imgf000003_0001

( I )  (I)

伏格列波糖口服给药能竟争性阻断存在于小肠粘膜微绒毛膜表面的麦芽 糖酶和蔗糖酶等双糖水解酶，结果使摄食的多糖、寡糖和双糖消化变成葡萄糖、 果糖等单糖的过程受到阻滞，使其在十二指肠和空肠上部的吸收减少，延迟到 小肠的中下部緩緩消化吸收，从而避免了饭后的血糖急剧上升， 能抑制饭后的 高血糖， 并抑制伴随的胰岛素分泌， 改善过度的胰岛素反应。  Oral administration of voglibose can competitively block disaccharide hydrolase such as maltase and sucrase present on the microvilli surface of the small intestine mucosa, resulting in digestion of the ingested polysaccharide, oligosaccharide and disaccharide into glucose, The process of monosaccharides such as fructose is blocked, so that the absorption in the upper part of the duodenum and jejunum is reduced, and it is delayed to the middle and lower part of the small intestine to slowly digest and absorb, thereby avoiding a sharp rise in blood sugar after meals, and inhibiting the postprandial Hyperglycemia, and inhibition of concomitant insulin secretion, improves excessive insulin response.

与另一种已在临床应用的糖苷酶抑制剂类药物阿卡波糖相比，伏格列波糖 对猪小肠的麦芽糖酶和蔗糖酶的抑制作用分别为阿卡波糖的 22倍和 33倍。对 大鼠小肠的麦芽糖酶和蔗糖酶的抑制作用， 伏格列波糖分别是阿卡波糖的 270 倍和 190倍。 另一方面， 对猪和大鼠的 α-淀粉酶的抑制作用， 伏格列波糖仅为 阿卡波糖的 1/3000。  Compared with another clinically applied glycosidase inhibitor acarbose, voglibose inhibited the maltase and sucrase of pig small intestine by 22 times and 33% of acarbose, respectively. Times. Inhibition of maltase and sucrase in the small intestine of rats, voglibose is 270-fold and 190-fold higher than acarbose, respectively. On the other hand, for the inhibition of α-amylase in pigs and rats, voglibose is only 1/3000 of acarbose.

伏格列波糖的活性远高于同类的阿卡波糖，对 α-葡萄糖苷酶的选择性也远 高于阿卡波糖， 因此用药剂量更小、 肠道副作用更低。  The activity of voglibose is much higher than that of similar acarbose, and the selectivity to α-glucosidase is much higher than that of acarbose, so the dosage is smaller and the intestinal side effects are lower.

由于伏格列波糖治疗机理独特、 效果明确、 控制血糖更加平稳， 同其他药 物联合使用效果良好， 更加安全有效, 因此临床使用上受到青睐。  Because of the unique mechanism, effective effect, and stable blood sugar control of voglibose, it is safe and effective in combination with other drugs, so it is favored in clinical use.

伏格列波糖的制造方法有多种， 可以通过发酵产生井冈霉烯胺 There are many ways to manufacture voglibose, which can be produced by fermentation.

(Valienamine), 再以此为原料进行化学合成方法制造（ EP56194 ); 还可以通过 以 D -葡萄糖为原料进行化学全合成的方法制备，例如 EP260121 , J. Org. Chem. 1992, 57, 3651 , WO03/080561 , WO2005/030698等。 (Valienamine), which is then used as a raw material for chemical synthesis (EP56194); it can also be prepared by chemical synthesis using D-glucose as a raw material, for example, EP260121, J. Org. Chem. 1992, 57, 3651, WO03/080561, WO2005/030698 and the like.

伏格列波糖易溶于水， 微溶于甲醇， 在乙醇中难以溶解。 在现已经公开的  Voglibose is easily soluble in water, slightly soluble in methanol, and difficult to dissolve in ethanol. Now publicly available

确认本 文献中，伏格列波糖通过用曱醇或乙醇重结晶的方法进行精制，获得不含有结 晶水的结晶。 这种方法需要消耗大量的甲醇或乙醇， 结晶析出不充分， 因而收 率不高；获得的结晶粒径不够均匀，需要进一步粉碎处理，因而造成工序增多、 生产成本提高。 因此我们寻找了一个筒便高效地获得伏格列波糖结晶的方法， 得到一种新型的伏格列波糖半水合结晶，可用于该药物制剂的工业化生产以满 足临床应用的需求。 发明内容 Confirmation In the literature, voglibose is purified by recrystallization from decyl alcohol or ethanol to obtain crystals containing no crystal water. This method requires a large amount of methanol or ethanol to be consumed, and the crystallization is insufficient, so that the yield is not high; the obtained crystal grain size is not uniform enough, and further pulverization treatment is required, resulting in an increase in the number of steps and an increase in production cost. Therefore, we have searched for a method for efficiently obtaining voglibose crystals, and obtained a novel voglibose hemihydrate crystal which can be used for industrial production of the pharmaceutical preparation to meet the needs of clinical applications. Summary of the invention

为了克服现有的伏格列波糖品质及制备方法存在的不足之处， 本发明的 一个目的是提供一种含有 0.5分子结晶水的结晶状态的伏格列波糖 (后称为伏 格列波糖半水合结晶），其结晶的特征通过粉末 X -射线衍射、热重分析（ TG )、 差示扫描量热分析（DSC；)、 红外光谱（IR)、 元素分析、 比旋度和单晶 X -射 线衍射进行了表征。  In order to overcome the deficiencies of the existing voglibose quality and the preparation method, it is an object of the present invention to provide a voglibose (hereinafter referred to as a voglet) in a crystalline state containing 0.5 molecules of water of crystallization. Wave sugar hemihydrate crystal), its crystallization characteristics by powder X-ray diffraction, thermogravimetric analysis (TG), differential scanning calorimetry (DSC;), infrared spectroscopy (IR), elemental analysis, specific rotation and single Crystalline X-ray diffraction was characterized.

本发明进一步的目的是提供伏格列波糖半水合结晶的制备方法，该方法步 骤少、试剂简单易得、 污染小、操作筒便、结晶收率高、产品粒径的均匀度高。  A further object of the present invention is to provide a process for the preparation of voglibose hemihydrate crystals which has fewer steps, simple and easy reagents, low contamination, high handling efficiency, high crystallization yield and high uniformity of product particle size.

本发明同时还提供了由这种结晶制备伏格列波糖无水结晶的方法。  The present invention also provides a process for preparing anhydrous crystals of voglibose from such crystallization.

本发明还提供了这种伏格列波糖半水合结晶在药物制剂中的应用，具体地 是含有这种伏格列波糖半水合结晶的药物组合物。  The present invention also provides the use of such voglibose hemihydrate crystals in pharmaceutical preparations, in particular pharmaceutical compositions containing such voglibose hemihydrate crystals.

本发明的研究者在制备伏格列波糖结晶的过程中，对伏格列波糖的结晶条 件进行了研究， 发现使用纯水和短碳链脂肪醇（如甲醇、 乙醇、 正丙醇或异丙 醇）混合溶剂的方法对伏格列波糖进行结晶， 可以获得伏格列波糖的半水合结 晶物， 工艺过程中所用溶剂量少， 结晶迅速完全， 收率和纯度都较高， 结晶的 颗粒均匀性好， 具有良好的稳定性， 适合用于制剂生产。  The inventors of the present invention studied the crystallization conditions of voglibose during the preparation of voglibose crystals, and found that pure water and short carbon chain fatty alcohols (such as methanol, ethanol, n-propanol or Isopropanol) mixed solvent method For the crystallization of voglibose, the hemihydrate crystal of voglibose can be obtained. The amount of solvent used in the process is small, the crystallization is complete and complete, and the yield and purity are high. The crystallized particles have good uniformity, good stability and are suitable for formulation production.

通过对该结晶的粉末 X -射线衍射、 DSC、 单晶 X-射线衍射、 TG、 IR图 谱、 元素分析、 比旋度等检测和分析， 确证获得的结晶是含有 0.5分子结晶水 的一种新型的伏格列波糖结晶， 即伏格列波糖半水合结晶。  Through the detection and analysis of the powdered powder X-ray diffraction, DSC, single crystal X-ray diffraction, TG, IR spectrum, elemental analysis, specific rotation, etc., it is confirmed that the obtained crystal is a new type containing 0.5 molecular water of crystallization. The voglibose crystals, that is, voglibose hemihydrate crystals.

通常， 该结晶可以通过其粉末 X -射线衍射图谱进行表征， 所迷结晶在位 于 2Θ为 9.64±0.2, 16.08±0.2, 18.34±0.2, 19.26±0.2, 21.92±0.2, 22.42±0.2度 处有特征衍射峰； 除上述相对强度大于 25 %的特征峰外， 所述结晶在粉末 X 射线衍射中还可以进一步包含位于 2Θ 为 12.70±0.2, 18.92±0.2, 20.10±0.2, 20.40±0.2, 21.22±0.2, 24.58±0.2, 26.20±0.2, 32.86±0.2度的衍射峰（见图 1 )， 表 1为该结晶的粉末 X -射线衍射数据。  Generally, the crystallization can be characterized by its powder X-ray diffraction pattern, which is characterized by being located at 9.64 ± 0.2, 16.08 ± 0.2, 18.34 ± 0.2, 19.26 ± 0.2, 21.92 ± 0.2, 22.42 ± 0.2 degrees. Diffraction peaks; in addition to the above characteristic peaks having a relative intensity of more than 25%, the crystals may further comprise, in powder X-ray diffraction, at 12.70±0.2, 18.92±0.2, 20.10±0.2, 20.40±0.2, 21.22±0.2. , 24.58 ± 0.2, 26.20 ± 0.2, 32.86 ± 0.2 degrees of diffraction peaks (see Figure 1), Table 1 is the powder X-ray diffraction data of the crystal.

表 1 粉末 X -射线 †射数据  Table 1 Powder X-ray data

2Θ角 d值 强度值 相对强 2Θ角 d值 强度值 相对强 度值 1 1。 度值 M0 2 d angle d value intensity value is relatively strong 2 Θ angle d value intensity value relative intensity value 1 1 . Degree M 0

9.64 9.1672 10685 46 20.40 4.3498 4411 199.64 9.1672 10685 46 20.40 4.3498 4411 19

12.70 6.9645 2859 13 21.22 4.1835 2312 1012.70 6.9645 2859 13 21.22 4.1835 2312 10

16.08 5.5073 10243 44 21.92 4.0515 6746 29 1834 4.8335 7960 35 22.42 3.9622 8319 3616.08 5.5073 10243 44 21.92 4.0515 6746 29 1834 4.8335 7960 35 22.42 3.9622 8319 36

18.92 4.6866 5418 24 24.58 3.6187 1819 8 18.92 4.6866 5418 24 24.58 3.6187 1819 8

19.26 4.6046 23321 100 26.20 3.3985 2322 10 19.26 4.6046 23321 100 26.20 3.3985 2322 10

20.10 4.4140 3415 15 32.86 2.7233 2386 11 20.10 4.4140 3415 15 32.86 2.7233 2386 11

从伏格列波糖半水合结晶的热重分析图线上（见图 2 ) 可以看出， 该结晶 在 85°C开始失水， 到 119°C失水完全， 失重 3.39 % , 代表了失去 0.5分子结晶 水的过程。  From the thermogravimetric analysis line of voglibose hemihydrate crystals (see Figure 2), it can be seen that the crystal began to lose water at 85 °C, and the water loss was completely completed at 119 °C, and the weight loss was 3.39 %, which represented the loss. The process of 0.5 molecules of crystal water.

在伏格列波糖半水合结晶的 DSC图线上（见图 3 ),相应存在两个吸热峰， 一个峰值在 98.9°C， 另一个在 167.3°C。 第一个峰代表了伏格列波糖半水合结 晶失去结晶水的过程， 与该结晶的 TG图线上 85 - 119°C失重 3.39 %的过程是 相对应的； 第二个位于 167.3Ό的峰表明失水后伏格列波糖的熔化过程， 峰值 所在温度与伏格列波糖无水结晶的熔点一致。  On the DSC plot of the voglibose hemihydrate crystal (see Figure 3), there are two endothermic peaks, one at 98.9 °C and the other at 167.3 °C. The first peak represents the process of losing the water of crystallization of the voglibose hemihydrate crystals, corresponding to the process of losing 3% at 85-119 °C on the TG line of the crystal; the second is located at 167.3 Ό. The peak indicates the melting process of voglibose after dehydration, and the peak temperature is consistent with the melting point of the anhydrous crystal of voglibose.

伏格列波糖半水合结晶的元素分析 C10H21NO7O.5H2O(理论值 C, 43.47; H 8.03; 5.07 ) 实验值为 C, 43.50; H 8.04; 5.10; 与理论值符合得很好。 Elemental analysis of voxelose sugar hemihydrate crystals C 10 H 21 NO 7 O.5H 2 O (theoretical C, 43.47; H 8.03; 5.07). Found: C, 43.50; H 8.04; 5.10; Very good.

选取伏格列波糖半水合结晶中的合适大小的单晶进行单晶 X一射线 †射试 验， 结构解析确证该结晶的分子式为： C1()H21NO7*0.5H2O, 该结晶属于正交晶 系， P2(l)2(l)2(l)空间群， 晶胞参数为 a=9.877(2) A, b=9.905(2) A, c=26.760(5) A, α=90°β=90°γ=90°, R值为 0.0324。 该分子的空间立体结构如图 4所示； 分 子在 A方向的晶胞堆积图如图 5所示， 该图中显示分子间通过氢键相连结。 下列表 2〜一表 7分别列出了晶体数据、 原子坐标、 键长、 键角、 扭角、 氢键 键长键角的数据。 A single crystal X-ray ray test is performed on a single crystal of a suitable size in the voglibose hemihydrate crystal. The structural formula confirms that the crystal has the formula: C 1() H 21 NO 7 *0.5H 2 O, The crystal belongs to the orthorhombic system, P2(l)2(l)2(l) space group, the unit cell parameters are a=9.877(2) A, b=9.905(2) A, c=26.760(5) A, α = 90° β = 90° γ = 90°, and the R value was 0.0324. The spatial three-dimensional structure of the molecule is shown in Fig. 4; the cell packing pattern of the molecule in the A direction is shown in Fig. 5, and the figure shows that the molecules are linked by hydrogen bonding. Table 2 to Table 7 below list the crystal data, atomic coordinates, bond length, bond angle, twist angle, and hydrogen bond long bond angle data.

Figure imgf000005_0001
数据收集的 Θ范围 （ Theta range for
Figure imgf000005_0001
The range of data collection (Theta range for

1.52 to 25.00 °  1.52 to 25.00 °

data collection )  Data collection )

指标范围 ( Index ranges ) 0<h<l 1 ,-ll<k<l 1 ,-31<1<31 收集的衍射点数 /独立的衍射点数  Index ranges 0<h<l 1 , -ll<k<l 1 , -31<1<31 Number of diffracted points collected / Independent diffracted points

7954 12547 [R(int) = 0.0400]  7954 12547 [R(int) = 0.0400]

( Reflections collected 1 unique )  ( Reflections collected 1 unique )

完整度  Completion

96.7%  96.7%

( Completeness to theta = 25.00 )  ( Completeness to theta = 25.00 )

吸收校正类型 半经验 ( Semi-empirical from ( Absorption correction ) equivalents )  Absorption correction type semi-empirical ( Semi-empirical from ( Absorption correction ) equivalents )

最大和最小透射  Maximum and minimum transmission

0.9788 and 0.9764  0.9788 and 0.9764

( Max. and min. transmission )  ( Max. and min. transmission )

全矩阵最小二乘法  Full matrix least squares

修正方法 ( Refinement method )  Refinement method

( Full-matrix least-squares on F2 ) 衍射点 限定参¾ /修正参数 ( Data / (Full-matrix least-squares on F 2 ) Diffraction point limit parameter / correction parameter ( Data /

2547 / 0 / 407  2547 / 0 / 407

restraints / parameters )  Restraints / parameters )

拟合值 ( Goodness- of-fit on F2 ) 1.018 Fitness-of-fit on F 2 1.018

最终结构偏离因子 R ( Final R indices  Final structural deviation factor R ( Final R indices

Rl = 0.0324, wR2 = 0.0747  Rl = 0.0324, wR2 = 0.0747

[I>2sigma (I)] )  [I>2sigma (I)] )

全部衍射点修正偏离因子 R  All diffraction point correction deviation factor R

Rl = 0.0393, wR2 = 0.0768 ( R indices (all data) )  Rl = 0.0393, wR2 = 0.0768 ( R indices (all data) )

绝对结构参数  Absolute structural parameter

0(10) '  0(10) '

( Absolute structure parameter )  (Absolute structure parameter )

消光系数 ( Extinction coefficient ) 0.0139 ( 13 )  Extinction coefficient 0.0139 ( 13 )

差值电子密度最大峰和最低峰  Maximum and minimum peaks of difference electron density

0.204 and -0.217 e. A3 ( Largest diff. peak and hole ) 0.204 and -0.217 e. A 3 ( Largest diff. peak and hole )

表 3. 原子坐标和各项异性温度参数 ( Atomic coordinates (χΐθ4 ) and equivalent isotropic displacement parameters ( A2 xlO3 ). U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ) Table 3. Atomic coordinates (χΐθ 4 ) and equivalent isotropic displacement parameters ( A 2 xlO 3 ). U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. )

原子 ( atom ) X y z U(eq)  Atom X y z U(eq)

O(l') 11686(2) 4367(2) 11335(1) 32(1) O(l') 11686(2) 4367(2) 11335(1) 32(1)

O(l) 4335(2) 9694(2) 10457(1) 35(1)O(l) 4335(2) 9694(2) 10457(1) 35(1)

0(2') 13008(2) 1834(2) 11537(1) 33(1)0(2') 13008(2) 1834(2) 11537(1) 33(1)

0(2) 4569(2) 12409(2) 10713(1) 36(1)0(2) 4569(2) 12409(2) 10713(1) 36(1)

0(3*) 15219(2) 3048(2) 12079(1) 32(1)0(3*) 15219(2) 3048(2) 12079(1) 32(1)

0(3) 6877(2) 12334(2) 11351(1) 43(1)0(3) 6877(2) 12334(2) 11351(1) 43(1)

0(4，） 14917(2) 5683(2) 12414(1) 37(1)0(4,) 14917(2) 5683(2) 12414(1) 37(1)

0(4) 8099(2) 9811(2) 11465(1) 48(1)0(4) 8099(2) 9811(2) 11465(1) 48(1)

0(5') 9115(2) 3544(2) 11662(1) 51(D0(5') 9115(2) 3544(2) 11662(1) 51(D

0(5) . 5817(3) 11848(2) 9500(1) 52(1) 0(6') 10656(2) 9094(2) 11194(1) 60(1) 0(5) . 5817(3) 11848(2) 9500(1) 52(1) 0(6') 10656(2) 9094(2) 11194(1) 60(1)

0(6) 8291(3) 6150(3) 11285(1) 104(1) 0(6) 8291(3) 6150(3) 11285(1) 104(1)

0(7) 13389(2) 9377(2) 11953(1) 45(1) 0(7) 13389(2) 9377(2) 11953(1) 45(1)

0(7) 5038(2) 4929(2) 10363(1) 52(1)  0(7) 5038(2) 4929(2) 10363(1) 52(1)

0(8) 6680(2) 14444(2) 9566(1) 46(1)  0(8) 6680(2) 14444(2) 9566(1) 46(1)

Ν(Γ) 12659(2) 6509(2) 11838(1) 27(1)  Ν(Γ) 12659(2) 6509(2) 11838(1) 27(1)

N(l) 6355(2) 8150(2) 10906(1) 38(1)  N(l) 6355(2) 8150(2) 10906(1) 38(1)

C(l') 11509(2) 3676(2) 11802(1) 26(1)  C(l') 11509(2) 3676(2) 11802(1) 26(1)

C(l) 5422(2) 10481(2) 10243(1) 30(1)  C(l) 5422(2) 10481(2) 10243(1) 30(1)

C(2') 12780(2) 2842(2) 11910(1) 25(1)  C(2') 12780(2) 2842(2) 11910(1) 25(1)

C(2) 5771(2) 11654(2) 10596(1) 28(1)  C(2) 5771(2) 11654(2) 10596(1) 28(1)

C(3') 14005(2) 3765(2) 11976(1) 25(1)  C(3') 14005(2) 3765(2) 11976(1) 25(1)

C(3) 6425(2) 11178(2) 11082(1) 28(1)  C(3) 6425(2) 11178(2) 11082(1) 28(1)

C(4') 13763(2) 4818(2) 12384(1) 27(1)  C(4') 13763(2) 4818(2) 12384(1) 27(1)

C(4) 7629(2) 10263(2) 10990(1) 32(1)  C(4) 7629(2) 10263(2) 10990(1) 32(1)

C(5') 12498(2) 5663(2) 12294(1) 26(1)  C(5') 12498(2) 5663(2) 12294(1) 26(1)

C(5) 7290(2) 9080(2) 10645(1) 32(1)  C(5) 7290(2) 9080(2) 10645(1) 32(1)

C(6') 11293(2) 4703(2) 12227(1) 27(1)  C(6') 11293(2) 4703(2) 12227(1) 27(1)

C(6) 6671(3) 9605(2) 10159(1) 32(1)  C(6) 6671(3) 9605(2) 10159(1) 32(1)

C(7) 10282(3) 2752(2) 11747(1) 35(1)  C(7) 10282(3) 2752(2) 11747(1) 35(1)

C(7) 4858(3) 11016(3) 9749(1) 42(1)  C(7) 4858(3) 11016(3) 9749(1) 42(1)

C(8') 11699(2) 7652(2) 11800(1) 30(1)  C(8') 11699(2) 7652(2) 11800(1) 30(1)

C(8) 6435(3) 6716(2) 10741(1) 43(1)  C(8) 6435(3) 6716(2) 10741(1) 43(1)

C(9') 11552(3) 7985(2) 11252(1) 40(1)  C(9') 11552(3) 7985(2) 11252(1) 40(1)

C(9) 6953(4) 5809(3) 11160(2) 69(1) C(9) 6953(4) 5809(3) 11160(2) 69(1)

C(IO') 12117(3) 8863(2) 12111(1) 38(1)C(IO') 12117(3) 8863(2) 12111(1) 38(1)

C(10) 5048(3) 6259(3) 10569(1) 48(1) C(10) 5048(3) 6259(3) 10569(1) 48(1)

表 4.键长（ Bond lengths [A] )  Table 4. Bond lengths (Bin lengths [A])

原予-原子 Original-atomic

长度 长度 ( Atom-atom 原子-原子 长度 原子-原子  Length ( Atom-atom atom - atom length atom - atom

( Length ) (Atom-atom) ( Length ) (Atom-atom) ( Length ) ( Length ) ( Atom-atom ) ( Length ) ( Atom-atom ) ( Length )

) )

0(1')-C(1') 1.437(3) 0(7)-H(7E) 0.80(4) C(5')-C(6') 1.534(3) 0(1')-C(1') 1.437(3) 0(7)-H(7E) 0.80(4) C(5')-C(6') 1.534(3)

O(l')-H(lF) 0.89(4) 0(8)-H(8F) 0.81(6) C(5')~H(5'A) 0.9800O(l')-H(lF) 0.89(4) 0(8)-H(8F) 0.81(6) C(5')~H(5'A) 0.9800

0(1) - C(l) 1.445(3) 0(8)-H(8E) 0.90(5) C(5)-C(6) 1.530(4)0(1) - C(l) 1.445(3) 0(8)-H(8E) 0.90(5) C(5)-C(6) 1.530(4)

0(1)-H(1E) 0.83(3) N(l')-C(8') 1.481(3) C(5)-H(5A) 0.98000(1)-H(1E) 0.83(3) N(l')-C(8') 1.481(3) C(5)-H(5A) 0.9800

0(2')- C(2') 1.430(3) N(l')-C(5') 1.489(3) C(6')-H(6,A) 0.9700 (2')-H(2E') 0.81(4) N(1')-H(1D) 0.83(3) C(6 H(6'B) 0.97000(2')- C(2') 1.430(3) N(l')-C(5') 1.489(3) C(6')-H(6 , A) 0.9700 (2')-H( 2E') 0.81(4) N(1')-H(1D) 0.83(3) C(6 H(6'B) 0.9700

0(2)-C(2) 1.437(3) N(l)-C(5) 1.479(3) C(6)-H(6A) 0.97000(2)-C(2) 1.437(3) N(l)-C(5) 1.479(3) C(6)-H(6A) 0.9700

O(2)— H(2F) 0.89(3) N(l)-C(8) 1.488(3) C(6)-H(6B) 0.9700

Figure imgf000008_0001
O(2)— H(2F) 0.89(3) N(l)-C(8) 1.488(3) C(6)-H(6B) 0.9700
Figure imgf000008_0001

Figure imgf000009_0001
Figure imgf000009_0001

Figure imgf000010_0001
Figure imgf000010_0001

C(2')-C(3')-C(4,)-0(4') -177.69(18) C(2>-C(l)-C(7)-0(5) 60.7(3)C(2')-C(3')-C(4 , )-0(4') -177.69(18) C(2>-C(l)-C(7)-0(5) 60.7(3 )

0(3')-C(3')~C(4'H (5') 178.37(18) C(5')~N(r)~C(8'H:(9') -154.8(2)0(3')-C(3')~C(4'H (5') 178.37(18) C(5')~N(r)~C(8'H:(9') -154.8(2 )

C(2')"C(3'K (4')- C(5') -55.7(2) (^Ήΐ'Η δ'Η ιο') 80.3(3)C(2')"C(3'K (4')- C(5') -55.7(2) (^Ήΐ'Η δ'Η ιο') 80.3(3)

0(3)-C(3)-C(4)-0(4) 64.1(2) C(5)-N(l)-C(8)-C(10) -123.2(3)0(3)-C(3)-C(4)-0(4) 64.1(2) C(5)-N(l)-C(8)-C(10) -123.2(3)

C(2)-C(3)-C(4)-0(4) -176.17(19) C(5)-N(l)-C(8)-C(9) 114.6(3)C(2)-C(3)-C(4)-0(4) -176.17(19) C(5)-N(l)-C(8)-C(9) 114.6(3)

0(3)-C(3)-C(4>-C(5) -172.6(2) N(l')— C(8')~C(9'K)(6') 」 -179.0(2)0(3)-C(3)-C(4>-C(5) -172.6(2) N(l')—C(8')~C(9'K)(6') -179.0( 2)

C(2)-C(3)-C(4)-C(5) -52.9(3) C(10')- C(8')— C(9'H)(6') -53.9(3)C(2)-C(3)-C(4)-C(5) -52.9(3) C(10')- C(8')- C(9'H)(6') -53.9(3 )

C(8')~N(r)~C(5')"C(4') -162.23(18) N(l)-C(8)-C(9)-0(6) -64.5(4)C(8')~N(r)~C(5')"C(4') -162.23(18) N(l)-C(8)-C(9)-0(6) -64.5(4 )

C(8')~N(r)~C(5'H (6') 78.5(2) C(10)-C(8)-C(9>-O(6) 174.1(3)C(8')~N(r)~C(5'H (6') 78.5(2) C(10)-C(8)-C(9>-O(6) 174.1(3)

0(4')—C(4')-C(5')~N(l') 56.0(2) N(l')-C(8*)-C(10')-O(7') 61.2(3)0(4')-C(4')-C(5')~N(l') 56.0(2) N(l')-C(8*)-C(10')-O(7') 61.2(3)

C(3'H (4'H (5')- Ν(Γ) -65.6(2) C(9')— C(8')—C(10'H3(7) -60.6(3)C(3'H (4'H (5')- Ν(Γ) -65.6(2) C(9')- C(8')-C(10'H3(7) -60.6(3)

0(4')-C(4')-C(5'>-C(6') 176.11(18) N(l)-C(8)-C(10)-O(7) 175.0(2)0(4')-C(4')-C(5'>-C(6') 176.11(18) N(l)-C(8)-C(10)-O(7) 175.0(2)

C(3'H 4'H 5')- C(6') 54.5(2) C(9)-C(8>-C(10)-O(7) -62.4(3) 表 7. 氬 ：键长和键角 （ Hydrogen-bond lengths [A ] and angles[°(deg)] ) C(3'H 4'H 5')- C(6') 54.5(2) C(9)-C(8>-C(10)-O(7) -62.4(3) Table 7. Argon: Bond length and bond angle (Hydrogen-bond lengths [A ] and angles[°(deg)] )

Figure imgf000011_0001
Figure imgf000011_0001

因此， 上述特征可以很好地表征这种新型的伏格列波糖半水合结晶。  Therefore, the above features are a good indicator of this novel voglibose hemihydrate crystal.

本发明还提供了一种制备该结晶的方法， 具体地， 将伏格列波糖粗品溶解 在少量热水中， 加入甲醇或乙醇， 加热搅拌下加入活性炭脱色， 过滤， 向滤液 中加入热的曱醇或乙醇或丙醇或异丙醇，搅拌下析出结晶，冷至室温后，过滤， 40°C真空干燥 12小时， 得到白色的伏格列波糖半水合结晶。 The invention also provides a method for preparing the crystal. Specifically, the crude voglibose is dissolved in a small amount of hot water, added with methanol or ethanol, decolorized by adding activated carbon under heating and stirring, filtered, and hot is added to the filtrate. Hydroxide or ethanol or propanol or isopropanol, crystallizing under stirring, cooling to room temperature, filtering, Drying at 40 ° C for 12 hours under vacuum gave a white voglibose hemihydrate crystal.

更进一步地， 该方法是将 1份（重量份）伏格列波糖粗品溶解在 1 - 3倍 份热水中， 优选 2倍份； 加入甲醇或乙醇 1 - 3倍份， 优选 2倍份乙醇， 加入 活性炭在 60°C脱色 30分钟，过滤， 滤液加入 3 - 10倍份的 50― 70 °C甲醇或乙 醇， 或正丙醇， 或异丙醇， 优选 5倍份的 60°C乙醇， 搅拌下析出白色的结晶， 自然冷至室温后， 过滤， 真空干燥后得到伏格列波糖半水合结晶。  Further, the method is to dissolve 1 part by weight of crude voglibose in 1-3 times hot water, preferably 2 times; add 1-3 times, preferably 2 times, of methanol or ethanol. Ethanol, deactivated by adding activated carbon at 60 ° C for 30 minutes, filtered, and adding 3 - 10 parts of 50-70 ° C methanol or ethanol, or n-propanol, or isopropanol, preferably 5 times of 60 ° C ethanol. The white crystals were precipitated under stirring, and then naturally cooled to room temperature, filtered, and dried under vacuum to obtain voglibose hemihydrate crystals.

对这种伏格列波糖半水合结晶进行了稳定性试验， 结果（见试验实施例 1 中表 8 )表明， 该结晶具有很好的稳定性， 在通常情况下可以长期存放。  The stability test of this voglibose hemihydrate crystal was carried out, and the results (see Table 8 in Test Example 1) showed that the crystal had good stability and could be stored for a long period of time under normal conditions.

由于伏格列波糖半水合结晶制备工艺简单， 节省溶剂，稳定性好， 纯度高， 结晶均匀性好， 因此非常适合用于药物制剂的制备。 因此本发明同时还提供了 该伏格列波糖半水合结晶在药物制剂中的应用。具体地是含有伏格列波糖半水 合结晶的药物组合物或药物制剂， 它们可以被制成例如适合口服的各种形式， 用于治疔糖尿病。 优选的药物制剂剂型可以是片剂、 胶嚢、 颗粒剂或混悬剂。  Because of the simple preparation process of voglibose hemihydrate crystal, solvent saving, good stability, high purity and good crystal uniformity, it is very suitable for the preparation of pharmaceutical preparations. The invention therefore also provides for the use of the voglibose hemihydrate crystals in pharmaceutical formulations. Specifically, it is a pharmaceutical composition or a pharmaceutical preparation containing voglibose hemihydrate crystals, which can be formulated into various forms suitable for oral administration, for treating diabetes. Preferred pharmaceutical formulation forms can be tablets, capsules, granules or suspensions.

本发明所涉及的药物制剂配方中， 除了伏格列波糖半水合结晶以外还包括 药学上可接受的载体、赋形剂和 /或稀释剂，代表性的例子包括（但并不限于）： 一种或多种填充剂， 如甘露醇、 淀粉、 改性淀粉、 乳糖、 葡聚糖、 碳酸钙、 yf 又  In the pharmaceutical formulation formulation of the present invention, in addition to voglibose hemihydrate crystals, pharmaceutically acceptable carriers, excipients and/or diluents are included, representative examples include, but are not limited to: One or more fillers, such as mannitol, starch, modified starch, lactose, dextran, calcium carbonate, yf

一种或多种粘合剂， 如乳糖、 淀粉、 改性淀粉、 微晶纤维素、 蔗糖、 羟丙 基纤维素、聚乙烯吡咯浣酮、羟丙基甲基纤维素、羟乙基纤维素、 曱基纤维素、: 羧甲基纤维素、 明胶。  One or more binders, such as lactose, starch, modified starch, microcrystalline cellulose, sucrose, hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxyethyl cellulose , mercapto cellulose, carboxymethyl cellulose, gelatin.

一种或多种崩解剂， 如交联聚乙烯吡咯烷酮、 交联羧甲基淀粉、 微晶纤维 素等。  One or more disintegrants, such as crosslinked polyvinylpyrrolidone, croscarmellose, microcrystalline cellulose, and the like.

根据需要药物组合物的配方中还可以包括矫味剂如柠檬酸、 阿斯帕坦等。 本发明的研究者同时还对这种新型伏格列波糖半水合结晶的失水进行了 研究， 发现伏格列波糖半水合结晶在室温至 70 °C均能保持较好的稳定性， 不 失去结晶水， 在 80 - 100°C则容易失去结晶水， 变成伏格列波糖无水物， 通过 对该伏格列波糖无水物的粉末 X-射线衍射、 TG、 DSC, IR、 元素分析、 比旋 光度等测试发现该无水物也是一种伏格列波糖结晶形态，进一步通过与从无水 乙醇中结晶出来的伏格列波糖无水结晶对比发现两者完全一致，并且相关理化 常数与文献报道的数据也一致。因此本发明同时提供了一种制备伏格列波糖无 水结晶的方法。其特征是将伏格列波糖半水合结晶在一定条件下真空干燥失去 结晶水， 同时发生晶型转变而获得伏格列波糖无水结晶。  Flavoring agents such as citric acid, aspartame and the like may also be included in the formulation of the pharmaceutical composition as needed. The researchers of the present invention also studied the water loss of the novel voglibose hemihydrate crystal, and found that the voglibose hemihydrate crystals can maintain good stability from room temperature to 70 °C. Without losing crystal water, it is easy to lose crystal water at 80 - 100 ° C, and become voglibose anhydrate, by powder X-ray diffraction, TG, DSC of the voglibose anhydrate. IR, elemental analysis, specific optical rotation and other tests found that the anhydrate is also a voglibose crystal form, which is further found by comparison with anhydrous crystals of voglibose crystallized from absolute ethanol. Consistent, and the relevant physicochemical constants are consistent with the data reported in the literature. The invention therefore also provides a process for the preparation of water-free crystals of voglibose. The invention is characterized in that voxelose sugar hemihydrate crystals are dried under vacuum under certain conditions to lose crystal water, and crystal form transformation occurs at the same time to obtain anhydrous crystals of voglibose.

具体地， 该方法是将伏格列波糖半水合结晶在 80 - 100°C真空干燥 4 - 24 小时， 优选温度 85 - 90°C , 干燥时间优选 8小时。  Specifically, the method is to dry voglibose hemihydrate crystals at 80 - 100 ° C for 4 - 24 hours, preferably at a temperature of 85 - 90 ° C, and preferably for 8 hours.

对这种通过伏格列波糖半水合结晶失水获得的伏格列波糖进行了稳定性 试验， 结果（见试验实施例 2中表 9 )表明， 该结晶具有很好的稳定性， 在通 常情况下可以长期存放。  The stability test of voglibose obtained by dehydration of voglibose hemihydrate crystals was carried out, and the results (see Table 9 in Test Example 2) showed that the crystal had good stability. Usually it can be stored for a long time.

本发明的积极效果是： 一种新型伏格列波糖半水合结晶， 该结晶的纯度很 高， 颗粒均匀性好， 具有良好的稳定性， 特别适合用于制剂生产； 并且制备该 结晶的工艺过程简单实用， 所用溶剂量少， 结晶迅速完全， 收率较高； 同时可 以通过将伏格列波糖半水合结晶真空干燥失水制备伏格列波糖无水结晶，方法 简单，获得的伏格列波糖无水结晶同样具有良好的稳定性， 适合应用于药物制 剂的生产。 The positive effect of the invention is: a novel voglibose hemihydrate crystal, the purity of the crystal is very High, good particle uniformity, good stability, especially suitable for formulation production; and the process of preparing the crystal is simple and practical, the amount of solvent used is small, the crystallization is complete and the yield is high; Lapodose hemihydrate crystals are dried under vacuum and dehydrated to prepare anhydrous crystals of voglibose. The method is simple, and the obtained anhydrous crystals of voglibose also have good stability and are suitable for the production of pharmaceutical preparations.

以下结合附图和实施例对本发明作进一步的说明。但是， 实施例不对本发 明构成任何限制。 附图说明  The invention will be further described below in conjunction with the drawings and embodiments. However, the examples do not constitute any limitation to the invention. DRAWINGS

图 1是伏格列波糖半水合结晶粉末的 X -射线衍射图。  Figure 1 is an X-ray diffraction pattern of a voglibose hemihydrate crystalline powder.

图 2是伏格列波糖半水合结晶热重分析图。  Figure 2 is a thermogravimetric analysis of voglibose hemihydrate crystals.

图 3是伏格列波糖半水合结晶的差示扫描量热分析图。  Figure 3 is a differential scanning calorimetry analysis of voglibose hemihydrate crystals.

图 4是伏格列波糖半水合结晶进行单晶 X -射线衍射获得的分子立体图。 图 5是伏格列波糖半水合结晶的晶体中分子晶胞堆积图， 晶体结构中分子 之间通过氢键相连。  Fig. 4 is a molecular perspective view of voglibose hemihydrate crystals obtained by single crystal X-ray diffraction. Figure 5 is a diagram of the molecular unit cell stacking in the crystal of the voglibose hemihydrate crystal, in which the molecules are connected by hydrogen bonds.

图 6是伏格列波糖半水合结晶的红外光谱图。  Figure 6 is an infrared spectrum of voglibose hemihydrate crystals.

图 7是通过伏格列波糖半水合结晶失水获得的伏格列波糖粉末的 X -射线 衍射图。  Figure 7 is an X-ray diffraction pattern of voglibose powder obtained by dehydration of voglibose hemihydrate crystals.

图 8是通过伏格列波糖半水合结晶失氷获得的伏格列波糖的热重分析图。 图 9是通过伏格列波糖半水合结晶失水获得的伏格列波糖的差示扫描量热 分析图。 . .  Fig. 8 is a thermogravimetric analysis diagram of voglibose obtained by deicing of voglibose hemihydrate crystals. Figure 9 is a differential scanning calorimetry analysis of voglibose obtained by dehydration of voglibose hemihydrate crystals. .

图 10是通过伏格列波糖半水合结晶失水获得的伏格列波糖的红外光语图。 图 11 ,是参照文献从无水乙醇中得到的伏格列波糖无水结晶的粉末 X -射 线 †射图。  Figure 10 is an infrared photogram of voglibose obtained by dehydration of voglibose hemihydrate crystals. Figure 11 is a powder X-ray ray diagram of the anhydrous crystals of voglibose obtained from anhydrous ethanol.

图 12是参照文献从无水乙醇中得到的伏格列波糖无水结晶的热重分析图。 图 13是参照文献从无水乙醇中得到的伏格列波糖无水结晶的差示扫描量 热分析图。  Figure 12 is a thermogravimetric analysis of the anhydrous crystals of voglibose obtained from anhydrous ethanol in the reference. Figure 13 is a differential scanning calorimetry diagram of the anhydrous crystals of voglibose obtained from anhydrous ethanol in the reference.

图 14是参照文献从无水乙醇中得到的伏格列波糖无水结晶的红外光语图。 具体实施方式  Figure 14 is an infrared optical map of the anhydrous crystals of voglibose obtained from anhydrous ethanol in the reference. detailed description

检测条件： Detection conditions:

1、 单晶 X -射线衍射  1, single crystal X-ray diffraction

仪器型号： X -射线影^^反系统 AXIS-IV型， 日本理学公司生产。 Instrument model: X-ray shadow ^^ anti-system AXIS-IV type, produced by Nippon Science.

2, 粉末 X - 线衍射 '、 、、 、 ，  2, powder X-ray diffraction ', , , , , ,

X射线发射使用铜靶（ X-Ray tube with Cu target anode )， X-ray tube with Cu target anode,

发散度 ( Divergence slits 1。），接受缝隙（ receiving slit 0.15mm ),散射度 ( Scatter slit l° ), 管压 40千伏（40KV), 管流 50毫安（50mA) Divergence slits (1), receiving slits (receiving slit 0.15mm), scattering (Scatter slit l°), Tube pressure 40 kV (40KV), tube flow 50 mA (50mA)

3、 热重分析法  3, thermogravimetric analysis

热重分析仪是 NETZSCH TG209型， 升温速度 10°C/min。  The thermogravimetric analyzer is a NETZSCH TG209 type with a heating rate of 10 °C/min.

4 、 差示扫描量热法  4, differential scanning calorimetry

差示扫描量热仪是 NETZSCH DSC204型。  The differential scanning calorimeter is a NETZSCH DSC204 type.

进样重量： 2.4mg  Injection weight: 2.4mg

温度范围： 30- 200°C  Temperature range: 30- 200 ° C

加热速度： 10°C/min  Heating rate: 10 ° C / min

5、 红外光 i脊  5, infrared light i ridge

红外光谱仪是 BrukerEQUINOX55型， 采用溴化钾压片法测定。  The infrared spectrometer was Bruker EQUINOX 55 and was measured by potassium bromide tableting.

【实施例 1】（1S) - (1 (羟基）， 2, 4， 5/1， 3) - 5-[ (2—羟基— 1— (羟 甲基） 乙基） ttl- 1-碳-羟甲基- 1， 2, 3, 4-环己烷四醇半水合结晶 （伏 格列波糖半水合结晶）的制备  [Example 1] (1S) - (1 (hydroxy), 2, 4, 5/1, 3) - 5-[(2-hydroxy-1-(hydroxymethyl)ethyl)ttl-1-carbon- Preparation of hydroxymethyl-1,2,3,4-cyclohexanetetraol hemihydrate crystals (voglibose hemihydrate crystals)

将四苄基伏格列波糖（300.0g, 0.48mol)溶解于 90%甲酸 /甲醇（1: 19, 6L) 中， 加入钯黑 （60g), 在氮气保护下于室温反应 12小时， 过滤， 用曱醇 /水（1: 1) 2L洗涤， 滤液浓缩， 残余用强酸性离子交换树脂 （5L)吸附， 水 洗涤， 然后用 0.5N氨水洗脱， 洗脱液蒸除水份后， 加入无水乙醇 2L， 搅拌， 过滤析出的浅灰色结晶， 真空干燥 12小时， 得到 110g伏格列波糖粗品。  Tetrabenzyl voglibose (300.0 g, 0.48 mol) was dissolved in 90% formic acid/methanol (1: 19, 6 L), palladium black (60 g) was added, and reacted under nitrogen for 12 hours at room temperature. Wash with decyl alcohol/water (1:1) 2L, concentrate the filtrate, remove the residue with strong acidic ion exchange resin (5L), wash with water, then elute with 0.5N ammonia water, evaporate the water and add 2 L of absolute ethanol was stirred, and the precipitated pale gray crystals were filtered and dried under vacuum for 12 hours to obtain a crude product of 110 g of voglibose.

将上述伏格列波糖粗品 100g溶于 200g热的纯水中， 加入乙醇 200g, 活 性炭 10g， 60°C加热 30分钟脱色， 过滤， 滤液加入 60°C乙醇 500g， 搅拌下析. 出结晶， 自然冷至室温， 过滤， 40°C真空干燥 12小时， 得到伏格列波糖半水 合结晶 88g。 [a]23 D+26.5°(cl, H20); 元素分析： C10H21O7«0.5H2O,计算值（ % ) C 43.47, H 8.03, N 5.07;实验值（ % ) C 43.50, H 8.04， N 5.10; NMR(D20, 400Hz), δ: 1.47 (IH, dd, J=2.8， 15Hz), 2.01(1H, dd, J=2.8, 15Hz), 2.81 (IH, m), 3.32-3.38 (2H, m), 3.43-3.50(2H, m), 3.53-3.69 (5H, m)， 3.80 (IH, t, J=9.6Hz)。 100 g of the above voglibose was dissolved in 200 g of hot pure water, 200 g of ethanol, 10 g of activated carbon, and heated at 60 ° C for 30 minutes for decolorization, and filtered, and the filtrate was added to 500 g of ethanol at 60 ° C, and the mixture was stirred and crystallized. It was naturally cooled to room temperature, filtered, and dried under vacuum at 40 ° C for 12 hours to obtain 88 g of voglibose hemihydrate crystals. [a] 23 D + 26.5 ° (cl, H 2 0); Elemental analysis: C 10 H 21 O 7 « 0.5H 2 O, Calcd. (%) C 43.47, H 8.03 , N 5.07; Found (%) C 43.50, H 8.04, N 5.10; NMR (D 2 0, 400 Hz), δ: 1.47 (IH, dd, J = 2.8, 15 Hz), 2.01 (1H, dd, J = 2.8, 15 Hz), 2.81 (IH, m), 3.32-3.38 (2H, m), 3.43-3.50 (2H, m), 3.53-3.69 (5H, m), 3.80 (IH, t, J = 9.6 Hz).

该结晶的粉末 X-射线衍射图、 TG、 DSC、 红外图谱分别见图 1-3和 图 6, 该结晶的粉末 X-射线衍射数据如下表;  The crystal powder X-ray diffraction pattern, TG, DSC, and infrared spectrum are shown in Figures 1-3 and Figure 6, respectively. The crystal powder X-ray diffraction data are shown in the following table;

Figure imgf000014_0001
Figure imgf000014_0001

【实施例 2】伏格列波糖半水合结晶的制备  [Example 2] Preparation of voglibose hemihydrate crystal

将伏格列波糖粗品 （制备方法同实施例 1 ) 100g溶于 100g热的纯水中， 加入甲醇 lOOg, 活性炭 10g, 60°C加热 30分钟脱色， 过滤， 滤液加入 50°C曱 醇 1000g， 搅拌下析出结晶， 自然冷至室温， 过滤， 40°C真空干燥 12小时， 得到 85克伏格列波糖半水合结晶。 100 g of crude voglibose (preparation method as in Example 1) was dissolved in 100 g of hot pure water. Add 100 g of methanol, 10 g of activated carbon, decolorize by heating at 60 ° C for 30 minutes, filter, add 1000 g of methanol to 50 ° C, precipitate crystals under stirring, naturally cool to room temperature, filter, and vacuum dry at 40 ° C for 12 hours to obtain 85 g Globose is semi-hydrated and crystallized.

【实施例 3】伏格列波糖半水合结晶的制备  [Example 3] Preparation of voglibose hemihydrate crystal

将伏格列波糖粗品（制备方法同实施例 1 ) 100g溶于 300g热的纯氷中， 加入乙醇 300g, 活性炭 10g, 60°C加热 30分钟脱色， 过滤， 滤液加入 70°C异 丙醇 300g, 搅拌下析出结晶， 自然冷至室温， 过滤， 40°C真空干燥 48小时， 得到 90克伏格列波糖半水合结晶。  100 g of crude voglibose (preparation method as in Example 1) was dissolved in 300 g of hot pure ice, 300 g of ethanol was added, 10 g of activated carbon was added, and the mixture was heated at 60 ° C for 30 minutes, and the mixture was filtered, and the filtrate was added with 70 ° C of isopropanol. 300 g, crystals were precipitated under stirring, naturally cooled to room temperature, filtered, and dried under vacuum at 40 ° C for 48 hours to obtain 90 g of voglibose hemihydrate crystals.

【实施例 4】伏格列波糖无水结晶的制备  [Example 4] Preparation of anhydrous crystal of voglibose

将 10g伏格列波糖半水合结晶置于真空干燥箱中， 保持温度 85°C , 真空 度 0.095Mpa, 真空干燥 8小时，得到 9.65g白色粉末状结晶， 为伏格列波糖无 水结晶，熔点（mp ): 164.2- 165.6 °C ; [a]23 D+27.3°(cl , H20);元素分析： C10H21O7, 计算值（ % ) C 44.93， H 7.92, N 5.24; 实验值（ % ) C 45.25 , H 8.08, N 5.29; 该失水结晶的粉末 X -射线衍射图、 TG、 DSC.红外图谱分别见图 7 - 10。 按照文献（ J. Org. Chem. 1992, 57， 3651 ) 的方法发明人直接制备了伏格列 波糖的无水结晶， 并通过粉末 X-射线衍射、 TG、 DSC, IR、 元素分析、 比旋 光度等对其结晶特征进行了表征，其特征与通过伏格列波糖半水合结晶失水获 得的伏格列波糖结晶完全一致，说明通过伏格列波糖半水合结晶失水可以获得 同文献报道完全一致的伏格列波糖结晶。 10 g of voglibose hemihydrate crystals were placed in a vacuum oven, maintained at a temperature of 85 ° C, a vacuum of 0.095 MPa, and vacuum dried for 8 hours to obtain 9.65 g of white powdery crystals, which were anhydrous crystals of voglibose. , melting point (mp ): 164.2 - 165.6 ° C ; [a] 23 D +27.3° (cl , H 2 0); Elemental analysis: C 10 H 21 O 7 , calculated (%) C 44.93, H 7.92, N 5.24; Experimental value (%) C 45.25 , H 8.08, N 5.29; The X-ray diffraction pattern, TG, DSC. infrared spectrum of the water-depleted crystal are shown in Fig. 7-10, respectively. According to the method of the literature (J. Org. Chem. 1992, 57, 3651), the inventors directly prepared anhydrous crystals of voglibose, and by powder X-ray diffraction, TG, DSC, IR, elemental analysis, ratio Its crystallinity is characterized by optical rotation, etc., and its characteristics are completely consistent with the voglibose crystals obtained by the dehydration of voglibose hemihydrate crystals, indicating that water loss can be obtained by volatilose sugar hemihydrate crystals. The volagliose crystals are completely consistent with the literature.

【实施例 5】伏格列波糖无水结晶的制备  [Example 5] Preparation of anhydrous crystal of voglibose

将 5g伏格列波糖半水合结晶置于真空干燥箱中， 保持温度 80°C , 真空度 0.095Mpa, 真空干燥 24小时， 得到 4.83g白色粉末状结晶， 为伏格列波糖无 水结晶， 熔点 （mp ): 164.1-165.5 °C。  5 g of voglibose hemihydrate crystals were placed in a vacuum oven, maintained at a temperature of 80 ° C, a vacuum of 0.095 MPa, and dried under vacuum for 24 hours to obtain 4.83 g of white powdery crystals, which were anhydrous crystals of voglibose. , melting point (mp): 164.1-165.5 °C.

【实施例 6】伏格列波糖无水结晶的制备  [Example 6] Preparation of anhydrous crystal of voglibose

将 5g伏格列波糖半水合结晶置于真空干燥箱中， 保持温度 100°C , 真空 度 0.095Mpa, 真空干燥 4小时，得到 4.82g白色粉末状结晶， 为伏格列波糖无 水结晶， 熔点 ( mp ): 164.0-165.6°C o 5 g of voglibose hemihydrate crystals were placed in a vacuum oven, kept at a temperature of 100 ° C, a vacuum of 0.095 MPa, and dried under vacuum for 4 hours to obtain 4.82 g of white powdery crystals, which were anhydrous crystals of voglibose. , melting point (mp): 164.0-165.6 °C o

【实施例 7】伏格列波糖无水结晶的制备  [Example 7] Preparation of anhydrous crystal of voglibose

(参照文献 J. Org. Chem. 1992, 57, 3651方法）将 2g伏格列波糖粗品和 200ml无水乙醇混和回流 30分钟 ,稍冷加入活性炭 0.2g, 回流 15分钟， 过滤， 滤液冷至室温， 将生成的白色粉末过滤， 40°C真空干燥 12小时， 得到 1.2g伏 格列波糖无水结晶， 熔点（mp ): 164.1-165.7O ; [a]23 D+27.4°(cl , ¾0)； 元素 分析： CI0H21O7,计算值（ % ) C 44.93 , H 7.92, N 5.24; 实验值（ % ) C 45.24, H 8.06, N 5.32; (Refer to J. Org. Chem. 1992, 57, 3651 method) 2 g of voglibose crude and 200 ml of absolute ethanol were mixed and refluxed for 30 minutes, 0.2 g of activated carbon was added in a little cold, refluxed for 15 minutes, filtered, and the filtrate was cooled to The resulting white powder was filtered at room temperature and dried under vacuum at 40 ° C for 12 hours to obtain 1.2 g of voglibose anhydrous crystals, melting point (mp): 164.1-165.7O; [a] 23 D +27.4° (cl , 3⁄40); Elemental analysis: C I0 H 21 O 7 , calculated (%) C 44.93 , H 7.92, N 5.24; Experimental (%) C 45.24, H 8.06, N 5.32;

该伏格列波糖无水结晶的粉末 X -射线衍射图、 TG、 DSC. 红外图谱分 別见附图 11 - 14。  The powder of the voglibose anhydrous crystal powder X-ray diffraction pattern, TG, DSC. Infrared spectra are shown in Figures 11-14.

【实施例 8】含有伏格列波糖半水合结晶片剂的制备  [Example 8] Preparation of a tablet containing voglibose hemihydrate crystals

组分： 伏格列波糖半水合结晶 0.207g Component: Voglibose Hemihydrate Crystalline 0.207g

甘露醇 70g  Mannitol 70g

微晶纤维素 20g  Microcrystalline cellulose 20g

交联聚维酮 6g  Cross-linked povidone 6g

柠檬酸 3g  Citric acid 3g

阿斯帕坦 ig  Aspartan ig

硬脂酸镁 0.9g  Magnesium stearate 0.9g

按照组分量将伏格列波糖半水合结晶、甘露醇、 微晶纤维素、 柠檬酸、 阿 斯帕坦混合均匀后， 过筛整粒， 加入硬脂酸镆混合均匀， 压片， 制成 1000片 含有伏格列波糖半水合结晶的片剂， 每片含有伏格列波糖（以无水物计） 0.2 亳克。  According to the amount of components, voglibose hemihydrate crystals, mannitol, microcrystalline cellulose, citric acid, and aspartame are uniformly mixed, sieved and sized, added with stearic acid strontium, uniformly mixed, and tableted. 1000 tablets containing voglibose hemihydrate crystals, each containing voglibose (as an anhydride) 0.2 gram.

试验实施例 1 对伏格列波糖半水合结晶的稳定性考察 Test Example 1 Study on the stability of voglibose hemihydrate crystals

将该结晶在 4CTC放置 15、 30天， 该结晶中伏格列波糖含量、 杂质无明显 变化（见表 8 ), 表明该结晶具有较好的稳定性， 在通常情况下可以长期存放。  The crystal was allowed to stand at 4 CTC for 15 or 30 days, and the voglibose content and impurities in the crystal did not change significantly (see Table 8), indicating that the crystal had good stability and could be stored for a long period of time under normal conditions.

表 8 伏格列波糖半水合结晶的 40°C稳定性考察  Table 8 Stability of 40 °C stability of voglibose hemihydrate crystals

Figure imgf000016_0001
Figure imgf000016_0001

试验实施例 2 失水伏格列波糖结晶的稳定性考察 Test Example 2 Stability of dehydrated voglibose crystals

将通过伏格列波糖半水合结晶失水获得的伏格列波糖结晶和按照文献方 法从无水乙醇中得到的伏格列波糖无水结晶在 40°C放置 15、 30天， 两者含量 和杂质均无明显变化， 显示两者具有同样良好的稳定性（试验数据见表 9 ), 该两种结晶无明显区别。  Voglibose crystals obtained by dehydration of voglibose hemihydrate crystals and anhydrous volatilose crystals obtained from anhydrous ethanol according to literature methods are placed at 40 ° C for 15 or 30 days, two There was no significant change in the content and impurities, indicating that both have the same good stability (test data are shown in Table 9), and there is no significant difference between the two crystals.

表 9失水伏格列波糖结晶的 40 °C稳定性考察  Table 9 Stability of 40 °C stability of dehydrated voglibose crystals

时间 0 天 15 天 30 天  Time 0 days 15 days 30 days

最大单 最大单 最大单 含量 含量 含量 样品 一杂质 一杂质 一杂质  Maximum single largest single largest single content content content one impurity one impurity one impurity

( % ) ( % ) ( % )  ( % ) ( % ) ( % )

( % ) ( % ) ( % ) 实施例 4 99.90 0.05 99.91 0.06 99.90 0.04 实施例 5 99.89 0.06 99.90 0.07 99.90 0.07 实施例 6 99.88 0.05 99.90 0.06 99.89 0.06 实施例 7  ( % ) ( % ) ( % ) Example 4 99.90 0.05 99.91 0.06 99.90 0.04 Example 5 99.89 0.06 99.90 0.07 99.90 0.07 Example 6 99.88 0.05 99.90 0.06 99.89 0.06 Example 7

99.86 0.07 99.87 0.06 99.86 0.06  99.86 0.07 99.87 0.06 99.86 0.06

(对照）  (control)

Claims

权利要求书  Claim 1、 一种伏格列波糖半水合结晶， 其特征在于所述结晶中每分子伏格列波 糖含有 0.5分子结晶水， 其分子式为： （^Η^ θ^  A volatilose hemihydrate crystal, characterized in that the voltaose of each molecule in the crystal contains 0.5 molecules of crystal water, and the molecular formula thereof is: (^Η^ θ^ 2、 如权利要求 1所述的伏格列波糖半水合结晶， 其中所述结晶在 Cu X- 射线粉末 f射中，在 2Θ为 9.64±0.2、 16.08±0.2、 18.34±0.2、 19.26±0.2、21.92±0.2、 2. The voglibose hemihydrate crystal according to claim 1, wherein said crystal is in a Cu X-ray powder f at a frequency of 9.64 ± 0.2, 16.08 ± 0.2, 18.34 ± 0.2, 19.26 ± 0.2. , 21.92±0.2, 22.42±0.2度处有特征峰。 There are characteristic peaks at 22.42 ± 0.2 degrees. 3、 如权利要求 2所述的伏格列波糖半水合结晶， 其中所述的结晶进一步 在 2Θ为 12.70±0.2, 18.92±0.2, 20.10±0.2, 20.40士 0.2, 21.22士 0.2， 24.58±0.2, 26.20±0.2, 32.86士0.2度处有特征峰。  3. The voglibose hemihydrate crystal according to claim 2, wherein said crystal further is 12.70 ± 0.2, 18.92 ± 0.2, 20.10 ± 0.2, 20.40 ± 0.2, 21.22 ± 0.2, 24.58 ± 0.2 at 2Θ. , 26.20 ± 0.2, 32.86 ± 0.2 degrees at the characteristic peak. 4、 如权利要求 1所述的伏格列波糖半水合结晶， 其中所述结晶在常压下 于 85±1 °C开始失去结晶水。  The voglibose hemihydrate crystal according to claim 1, wherein the crystal begins to lose crystal water at 85 ± 1 °C under normal pressure. 5、 如权利要求 1所迷的伏格列波糖半水合结晶， 其中所述伏格列波糖半 水合结晶通过差示扫描量热分析， 具有两个吸热峰， 峰值分別位于 98.9±1 °C , 167.3±1 °C。  5. The voglibose hemihydrate crystal of claim 1, wherein said voglibose hemihydrate crystal has two endothermic peaks by differential scanning calorimetry, and the peaks are at 98.9 ± 1 respectively. °C, 167.3 ± 1 °C. 6、 如权利要求 1所迷的伏格列波糖半水合结晶， 所述伏格列波糖半水合 结晶具有如图 6所示的红外光谱图。  The voglibose hemihydrate crystal according to claim 1, wherein the voglibose hemihydrate crystal has an infrared spectrum as shown in Fig. 6. 7、 如权利要求 1所述的伏格列波糖半水合结晶， 其中所述的伏格列波糖 半水合结晶属于正交晶系、 P2(l)2(l.)2(l)空间群、 晶胞参数为 a=9.877 ( 2 ) A， b=9.905(2) A,c=26.760(5) A, a=90, =90,r=90,R值为 0.0324, 空间立体结构如图 4所示。  7. The voglibose hemihydrate crystal according to claim 1, wherein said voglibose hemihydrate crystal belongs to orthorhombic system, P2(l)2(l.)2(l) space The group and unit cell parameters are a=9.877 ( 2 ) A, b=9.905(2) A, c=26.760(5) A, a=90, =90, r=90, R value is 0.0324, spatial stereo structure such as Figure 4 shows. 8、 如权利要求 1所述的伏格列波糖半水合结晶， 其中所迷的仗格列波糖 分子间通过氢键连接。  The voglibose hemihydrate crystal according to claim 1, wherein the ruthenium ribose sugar molecules are linked by hydrogen bonding. 9、 制备权利要求 1所述伏格列波糖半水合结晶的方法， 其特征在于用纯 水和短链脂肪醇混合溶剂对伏格列波糖进行结晶。  A process for producing a vodopolose hemihydrate crystal according to claim 1, which is characterized in that voglibose is crystallized by a mixed solvent of pure water and a short-chain fatty alcohol. 10、 如权利要求 9所述的方法， 其中所述的短链脂肪醇为曱醇、 乙醇、 正丙醇或异丙醇。  10. The method of claim 9, wherein the short chain fatty alcohol is decyl alcohol, ethanol, n-propanol or isopropanol. 11、 如权利要求 9或 10所述的方法， 包括如下步骤：  11. The method of claim 9 or 10, comprising the steps of: 1 )将伏格列波糖粗品溶解在伏格列波糖粗品重量份的 1-3倍份热水中， 加入伏格列波糖粗品重量份的 1-3倍份的短链脂肪醇， 搅拌加入活性碳脱色， 过滤；  1) Dissolving the crude voglibose in 1-3 times of hot water of the weight fraction of voglibose, and adding 1-3 times the short-chain fatty alcohol of the weight fraction of voglibose. Decolorization by adding activated carbon with stirring, filtering; 2 )在滤液中加入 50-70 °C的伏格列波糖粗品重量份的 3-10倍份的短链脂 肪醇， 搅拌析出结晶， 冷却至室温， 过滤；  2) adding 3-10 parts by weight of the short-chain aliphatic alcohol of 50-70 ° C of the crude voglibose in the filtrate, stirring the precipitated crystals, cooling to room temperature, and filtering; 3 )将过滤所得的固体真空干燥， 得伏格列波糖半水合结晶。  3) The solid obtained by filtration is vacuum dried to obtain voglibose hemihydrate crystals. 12、 一种制备伏格列波糖无水结晶的方法， 将权利要求 1 所述伏格列波 糖半水合结晶在 80-100° (真空干燥 4-24小时。  12. A method of preparing anhydrous crystals of voglibose, wherein the voglibose hemihydrate crystal of claim 1 is crystallized at 80-100 (vacuum drying for 4-24 hours). 13、 含有权利要求 1所述的伏格列波糖半水合结晶的药物组合物。  13. A pharmaceutical composition comprising the voglibose hemihydrate crystal of claim 1.
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