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WO2016155334A1 - 一种奥美拉唑钠半水合物及其制剂和制备方法 - Google Patents

一种奥美拉唑钠半水合物及其制剂和制备方法 Download PDF

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WO2016155334A1
WO2016155334A1 PCT/CN2015/095230 CN2015095230W WO2016155334A1 WO 2016155334 A1 WO2016155334 A1 WO 2016155334A1 CN 2015095230 W CN2015095230 W CN 2015095230W WO 2016155334 A1 WO2016155334 A1 WO 2016155334A1
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Prior art keywords
omeprazole sodium
omeprazole
hemihydrate
sodium hemihydrate
preparation
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PCT/CN2015/095230
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English (en)
French (fr)
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鲍颖
陶灵刚
李龙
郝红勋
吕军
侯宝红
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天津大学
海南灵康制药有限公司
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Application filed by 天津大学, 海南灵康制药有限公司 filed Critical 天津大学
Priority to US15/305,653 priority Critical patent/US9834540B2/en
Publication of WO2016155334A1 publication Critical patent/WO2016155334A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the invention belongs to the technical field of chemical engineering medicine crystallization, and relates to an omeprazole sodium hemihydrate and a preparation method thereof.
  • Omeprazole Sodium is chemically known as 5-methoxy-2- ⁇ [(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl ⁇ - 1H-benzimidazole sodium salt, molecular formula C 17 H 18 N 3 NaO 3 S, relative molecular mass 367.4, the structural formula is as follows:
  • Omeprazole sodium is a racemic mixture of a pair of active optical antipodes, which is a special inhibitor of acid pumps in gastric parietal cells by a highly targeted action to reduce gastric acid secretion.
  • Omeprazole is fat-soluble and can be concentrated around the secretory tube of parietal cells and converted into an active sulfenamide derivative.
  • omeprazole sodium has a significant curative effect, a high cure rate and a low recurrence rate. This indicates that omeprazole sodium has a wide application and great market potential.
  • Patent US 4,397,794 A reports and prepares omeprazole sodium hydrate containing 1 to 2 water molecules.
  • the hydrate has poor stability and is hygroscopic, and the increase in water content is obviously inconvenient for quantitative filling in the downstream formulation process, and thus is not convenient for industrial applications.
  • the patent adopts the preparation method of omeprazole and alkali reaction, dissolution and cooling crystallization. Since the supersaturation process is large and the precipitation rate is fast, the omeprazole sodium hydrate and the amorphous mixture are obtained.
  • the type is low in purity; and it is operated overnight and takes a long time.
  • Patented WO1999000380A1 reports omeprazole sodium monohydrate (currently commercially available crystalline form).
  • the monohydrate has poor stability and a low thermal decomposition temperature of 209.0 °C.
  • the patent adopts a preparation method for crystallization reaction of omeprazole with a base, and two mixed solvents must be used, and the crystallization operation takes a long time, requiring 10 to 24 hours, and the efficiency is low.
  • the invention discloses a new solvate of omeprazole sodium, more specifically omeprazole sodium hemihydrate, that is, 0.5 mole of water per mole of omeprazole sodium hemihydrate, the structural formula is as follows (I ) shown:
  • the Karl Fischer method is one of the most specific and accurate methods for determining the moisture content of various substances. It has been listed as the standard method for moisture determination in many substances, especially for organic compounds, and the results are accurate and reliable.
  • the omeprazole sodium hemihydrate disclosed in the present invention is washed with acetone and dried, and the water weight content is determined by the Karl Fischer method to be between 2.28 and 2.45%, which is consistent with the moisture content without acetone washing.
  • the theoretical water content of omeprazole sodium hemihydrate is 2.39%, and it can be confirmed that each of the omeprazole sodium hemihydrates of the present invention contains 0.5 crystal water.
  • the powder X-ray diffraction pattern of the omeprazole sodium hemihydrate of the present invention is 6.26 ⁇ 0.1, 11.10 ⁇ 0.1, 12.20 ⁇ 0.1, 15.58 ⁇ 0.1, 16.02 ⁇ 0.1, 17.12 ⁇ 0.1, 19.08 at the diffraction angle 2 ⁇ .
  • X-ray powder diffraction test conditions Rigaku D/max 2500X-ray powder diffractometer, CuK ⁇ radiation, tube voltage 40kV, filament current 300mA, continuous scanning, step size 0.02°, scanning speed 8°/min, scanning range It is 2 to 50 °.
  • the omeprazole sodium hemihydrate of the present invention has a Fourier transform infrared spectrum with a wave number of 3413.5 ⁇ 2, 3131.9 ⁇ 2, 2969.3 ⁇ 2, 2938.8 ⁇ 2, 2847.4 ⁇ 2, 2755.5 ⁇ 2, 1606.7 ⁇ 2,1571.1 ⁇ 2,1473.9 ⁇ 2,1440.5 ⁇ 2,1376.3 ⁇ 2,1266.5 ⁇ 2,1147.0 ⁇ 2,1111.5 ⁇ 2,1073.8 ⁇ 2,1032.3 ⁇ 2,942.3 ⁇ 2,830.2 ⁇ 2,802.6 ⁇ 2,750.6 ⁇ 2 and 672.7 ⁇ 2cm - There is a characteristic absorption peak at 1 as shown in Fig. 2.
  • Fourier transform infrared spectroscopy test conditions Nicolet, Nexus 470, potassium bromide tablet.
  • the DSC analysis of the omeprazole sodium hemihydrate of the present invention showed a liberation heat peak at 228.5 ⁇ 1 ° C, as shown in FIG. DSC data by differential scanning calorimeter (DSC1/500, Mettler Toledo, Switzerland)
  • the analysis conditions are as follows: the sample 5-10 mg sample is placed in 40 ⁇ L aluminum crucible, and the high purity nitrogen gas is used as the reaction gas and the shielding gas, and the flow rates are 50 mL/min and 20 mL/min, respectively.
  • the heating rate is 10 ° C / min, and the temperature range is 25 to 300 ° C.
  • the omeprazole sodium hemihydrate has a rod shape and a main particle size of about 100 ⁇ m, as shown in the micrograph of Fig. 4.
  • the microscope photograph was observed and recorded by a polarizing microscope (OLYMPUS BX51, MicroPublisher 5.0 RTU).
  • the preparation method of the omeprazole sodium hemihydrate of the invention comprises adding the raw material omeprazole sodium hydrate to an organic solvent, stirring at a constant temperature of 25 to 60 ° C for 2 to 9 hours, filtering and drying, and obtaining the Austrian Melazodazole sodium hemihydrate.
  • the organic solvent is selected from the group consisting of n-propanol, n-butanol, sec-butanol, formamide, N,N-dimethylformamide, methyl acetate, ethyl acetate, butyl acetate, n-heptane, trichloro
  • the initial concentration of the raw material omeprazole sodium hydrate is 0.015 to 0.12 g/mL.
  • the stirring form and the stirring speed had no significant effect on the crystal transformation results.
  • Omeprazole sodium readily forms hydrates, possibly with oxygen on the sulfinyl group forming hydrogen bonds with water molecules.
  • the specific organic solvent used in the present invention can interact with water molecules in the raw material omeprazole sodium hydrate to remove part of the water, and connect two omeprazole sodium to one water molecule; Among the specific organic solvents, the solubility of the raw material omeprazole sodium hydrate is large, and the solubility of the omeprazole sodium hemihydrate is small. Therefore, the present invention prepares a high yield and good morphology of omeprazole sodium hemihydrate by using a suitable solvent, at a suitable concentration, temperature and time, by the raw material omeprazole sodium hydrate.
  • the preparation method of the omeprazole sodium hemihydrate provided by the invention has the advantages that the operation is simple, the obtained filter cake does not need to be washed, the solvent consumption is small, the crystallization, the filtration and the drying rate are fast, the time is short, the efficiency is high; Low; high molar yield, not less than 95%; prepared omeprazole sodium hemihydrate high performance liquid chromatography (HPLC) content of 100% (as anhydrous), in line with the European Pharmacopoeia 98 ⁇ 101.0% Provisions.
  • HPLC high performance liquid chromatography
  • the omeprazole sodium hemihydrate provided by the invention has excellent crystal morphology: block crystal, smooth surface, unique crystal form, not easy to coalesce, the Karl index is less than 15%, and the fluidity is good; the applicant has experimentally determined the document of WO1999000380A1.
  • the fluidity of the reported monohydrate has a Karl index of more than 41% and poor fluidity.
  • the omeprazole sodium hemihydrate provided by the invention has good thermal stability: DSC analysis shows that the thermal decomposition temperature is 228.5 ° C, which is significantly higher than the thermal decomposition temperature of omeprazole sodium monohydrate 209.0 ° C (as shown in Fig. 5 Shown).
  • the results of the 60 ° C thermal stability test showed that the crystal form of the omeprazole sodium hemihydrate provided by the present invention was stable and did not change significantly (X-ray diffraction pattern as shown in Fig. 6), and the weight change rate in 10 days was 2.2%. Within, the weight change rate of omeprazole sodium monohydrate was 4.8%, and the stability was better (see Table 1).
  • Ogilvy provided by the present invention Sodium azole sodium hemihydrate is less hygroscopic than omeprazole sodium monohydrate (see Table 2). Therefore, the omeprazole sodium hemihydrate provided by the invention is superior to omeprazole sodium monohydrate in terms of heat stability, fluidity and moisture resistance, and has wider application prospects.
  • the toxicity of the omeprazole sodium hemihydrate obtained by the present invention indicates that the toxicity is improved compared with the existing omeprazole sodium or its monohydrate, and the drug mutation test and the reproductive toxicity test result are all negative and carcinogenic. No cancer metastasis was seen in the trial.
  • Figure 2 is a Fourier transform infrared spectroscopy (FT-IR) image of omeprazole sodium hemihydrate;
  • Figure 3 is a differential thermal analysis (DSC) chart of omeprazole sodium hemihydrate
  • Figure 4 is a micrograph of omeprazole sodium hemihydrate
  • Figure 5 is a differential thermal analysis (DSC) chart of omeprazole sodium monohydrate
  • Figure 6 is a comparison of powder X-ray diffraction spectra of omeprazole sodium hemihydrate at 60 ° C for ten days.
  • omeprazole sodium monohydrate 20 mL of ethyl acetate and 10 mL of sec-butanol were added, and the mixture was stirred at 35 ° C and a magnet speed of 200 r/min for 2 hours, filtered and dried to obtain omeprazole.
  • the sodium hemihydrate was 0.42 g, the molar yield was 95.6%, and the HPLC content was 99.8%.
  • the X-ray powder diffraction pattern of the product is consistent with Figure 1, and the solid Fourier transform infrared spectrum is identical to Figure 2 with a DSC decomposition temperature of 227.5 °C (see Figure 3).
  • the crystal has a primary particle size of 92 ⁇ m and does not coalesce (see Figure 4).
  • the Carr index is 14.3%, indicating good fluidity.
  • the X-ray diffraction spectrum (see Figure 6) has not changed significantly.
  • the thermal stability test at 60 °C shows that the weight change rate of 2.4 days is 2.4%. Thermal stability it is good. At 40 ° C and 75% relative humidity for 3 days, the weight change rate was 0.68%, indicating that the product is not easy to absorb moisture.
  • omeprazole sodium monohydrate 2.40 g of omeprazole sodium monohydrate and 20 mL of methyl isobutyl ketone were added to the crystallizer, and the mixture was stirred at 60 ° C for 30 hours under mechanical stirring speed of 300 r/min, filtered, and dried at 35 ° C under a vacuum of 0.05 MPa.
  • the omeprazole sodium hemihydrate was 2.27 g, the molar yield was 96.8%, and the HPLC content was 100.2%.
  • the X-ray powder diffraction pattern of the product has characteristic peaks at diffraction angles 2 ⁇ of 6.34, 11.18, 12.26, 15.58, 16.02, 17.06, 19.12, 21.04, 22.66, 23.52, 24.10, 26.44 and 28.04 degrees, solid Fourier transform infrared
  • the spectra are at 3414.5, 3132.1, 2969.9, 2939.8, 2846.9, 2756.5, 1607.7, 1571.9, 1474.5, 1441.5, 1377.3, 1266.0, 1147.8, 1112.3, 1072.8, 1032.9, 941.3, 830.7, 803.4, 751.1 and 673.2 cm -1
  • the characteristic peak, DSC decomposition temperature was 229.2 °C.
  • the crystal has a primary particle size of 95 ⁇ m, does not coalesce, and has a Karl index of 13.9%, indicating good fluidity. After being placed at a high temperature of 60 ° C for ten days, it was still white crystal, and the X-ray diffraction pattern did not change significantly. The thermal stability test at 60 ° C showed that the weight change rate of the 10-day was 2.5%, and the thermal stability was good.
  • omeprazole sodium hydrate water content: 7.02%
  • 10 mL of tetrahydrofuran 10 mL of formamide
  • 10 mL of methyl ethyl ketone 10 mL
  • the mixture was stirred at 25 ° C for 9 hours under a mechanical stirring speed of 600 r / min.
  • the mixture was filtered, dried at 30 ° C and a vacuum of 0.1 MPa to obtain 2.78 g of omeprazole sodium hemihydrate, the molar yield was 97.4%, and the HPLC content was 100.0%.
  • the X-ray powder diffraction pattern of the product has characteristic peaks at diffraction angles 2 ⁇ of 6.28, 11.16, 12.16, 15.62, 16.02, 17.02, 19.10, 21.00, 22.60, 23.44, 24.16, 26.42 and 28.02 degrees, solid Fourier transform infrared
  • the spectra are at 3413.0, 3132.3, 2968.7, 2938.1, 2846.8, 2754.6, 1605.4, 1572.1, 1474.6, 1441.5, 1375.8, 1266.2, 1146.8, 1111.0, 1074.2, 1032.9, 942.8, 831.2, 803.6, 751.5 and 671.7 cm -1
  • Characteristic peak, DSC decomposition temperature was 229.5 °C.
  • the crystal has a primary particle size of 100 ⁇ m and does not coalesce.
  • the Carr index is 14.7%, indicating good fluidity. After being placed at 60 ° C for 10 days, it was still white crystal, and the X-ray diffraction pattern did not change significantly. The thermal stability test at 60 ° C showed that the weight change rate of 2.4 days was 2.4%, and the thermal stability was good.
  • the omeprazole sodium hemihydrate obtained by the present invention was subjected to a toxicity test, a drug mutation test, a reproductive toxicity test, and a carcinogenic test (for example, the omeprazole sodium hemihydrate obtained in Example 1).
  • omeprazole In the long-term administration of omeprazole in rats, gastric ECL cell enlargement and benign tumors were observed, which was the result of persistent hypergastrinemia due to gastric acid suppression.
  • Intravenous administration of LDLo (lowest lethal dose) was 500 mg/kg in dogs, and LD 50 (half lethal dose) in rats was 302 mg/kg.
  • the LD 50 of the intravenous administration of mice was 82.8 mg/kg, and the LD 50 >2000 mg/kg was orally administered.
  • Oral doses of 138 mg/kg/day had no effect on the reproductive performance of male and female rats.
  • liver and kidney weight was observed in the long-term toxicity test of rats administered continuously from 140 mg/kg/day for 1-6 months, but no biochemical changes were observed.
  • Rats with a 24-month carcinogenicity test found that hypergastrinemia caused intestinal chromoblast-like cell proliferation in the gastric mucosa and showed carcinogenesis, but no cancer metastasis.
  • omeprazole sodium hemihydrate and the preparation method thereof disclosed and proposed by the invention can be passed by a person skilled in the art After learning from the content of this article, appropriate changes in raw materials, process parameters and other links.
  • the method and product of the present invention have been described by way of a preferred embodiment, and it is obvious that those skilled in the art can make modifications or appropriate changes and combinations of the methods and products described herein without departing from the scope of the invention.
  • the technology of the present invention It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the spirit, scope and content of the invention.

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Abstract

本发明公开一种奥美拉唑钠半水合物及其制备方法，每摩尔奥美拉唑钠半水物含0.5摩尔水，其X-射线衍射图谱衍射角2θ为6.26±0.1，11.10±0.1，12.20±0.1，15.58±0.1，16.02±0.1，17.12±0.1，19.08±0.1，21.00±0.1，22.68±0.1，23.48±0.1，24.08±0.1，26.52±0.1和28.08±0.1度处有特征峰。将原料奥美拉唑钠水合物加入到有机溶剂中，25～60℃恒温搅拌2～9小时，过滤干燥，得到奥美拉唑钠半水物。本发明的奥美拉唑钠半水合物纯度高、稳定性好、不易聚结、流动性好，具有更广泛的应用前景。

Description

一种奥美拉唑钠半水合物及其制剂和制备方法 技术领域
本发明属于化学工程医药结晶技术领域，涉及一种奥美拉唑钠半水合物及其制备方法。
背景技术
奥美拉唑钠(Omeprazole Sodium)化学名为5-甲氧基-2-{[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基]亚磺酰基}-1H-苯并咪唑钠盐，分子式C17H18N3NaO3S，相对分子质量367.4，结构式如下：
Figure PCTCN2015095230-appb-000001
奥美拉唑钠是一对活性旋光对映体的消旋混合物，籍由高目标性的作用来降低胃酸的分泌，是胃壁细胞中酸泵的特殊抑制剂。奥美拉唑为脂溶性，可浓集于壁细胞分泌小管周围，转变为有活性的次磺酰胺衍生物。与H2受体阻断剂相比，奥美拉唑钠疗效显著，治愈率高，复发率低。这表明奥美拉唑钠的应用广、市场潜力大。
专利US4738974A报道并制备了含有1到2个水分子的奥美拉唑钠水合物。该水合物稳定性差，易吸湿，其水含量的增加明显不便于下游制剂工艺中的定量装填，因而不便于工业应用。该专利采用奥美拉唑与碱反应、溶析、冷却结晶的制备方法，由于溶析过程过饱和度大，沉淀速率快，得到的是奥美拉唑钠水合物和无定型的混合物，晶型纯度低；而且操作过夜，时间长。
专利WO1999000380A1报道了奥美拉唑钠一水合物(目前市售晶型)。该一水合物稳定性差，热分解温度低，为209.0℃。该专利采用奥美拉唑与碱反应结晶的制备方法，必须使用两种混合溶剂，且结晶操作耗时长，要求10～24小时，效率低。
因此，有必要发明一种优势明显，包括制备过程简单、收率高；热稳定性好、流动性好、不易吸湿的奥美拉唑钠水合物。
发明内容
本发明公开了奥美拉唑钠的一种新的溶剂化物，更具体的为奥美拉唑钠半水合物，即每摩尔奥美拉唑钠半水合物含0.5摩尔水，结构式如(I)所示：
Figure PCTCN2015095230-appb-000002
卡尔费休法是各种测定物质中水分方法中最为专一、准确的方法之一，已被列为许多物质中水分测定的标准方法，尤其对有机化合物，结果准确可靠。本发明公开的奥美拉唑钠半水合物用丙酮洗涤、干燥后，用卡尔费休法测定水分重量含量在2.28～2.45％之间，与未经丙酮洗涤的水分含量一致。奥美拉唑钠半水合物理论水含量为2.39％，可确定本发明每个奥美拉唑钠半水合物含有0.5个结晶水。
本发明所述的奥美拉唑钠半水合物的粉末X-射线衍射图谱在衍射角2θ为6.26±0.1,11.10±0.1,12.20±0.1,15.58±0.1,16.02±0.1,17.12±0.1,19.08±0.1,21.00±0.1,22.68±0.1,23.48±0.1,24.08±0.1,26.52±0.1和28.08±0.1度处有特征衍射峰，如附图1所示。X-射线粉末衍射测试条件：日本理学Rigaku D/max 2500X-射线粉末衍射仪，CuKα辐射，光管电压40kV，灯丝电流300mA，连续扫描，步长0.02°，扫描速度8°/min，扫描范围为2～50°。
文献多有报道相同物质的不同晶型、相同物质的不同溶剂化物有相同的粉末X-射线衍射谱图或者有部分相同的粉末X-射线衍射谱图，所以有必要根据《多晶型药品的质量控制技术与方法指导原则》，给出其他的鉴别方法证明本专利报道的是新的水合物。
本发明所述的奥美拉唑钠半水合物，其傅里叶变换红外光谱在波数为3413.5±2,3131.9±2,2969.3±2,2938.8±2,2847.4±2,2755.5±2,1606.7±2,1571.1±2,1473.9±2,1440.5±2,1376.3±2,1266.5±2,1147.0±2,1111.5±2,1073.8±2,1032.3±2,942.3±2,830.2±2,802.6±2,750.6±2和672.7±2cm-1处有特征吸收峰，如附图2所示。傅里叶变换红外光谱测试条件：Nicolet,Nexus470，溴化钾压片。
本发明所述的奥美拉唑钠半水合物，其DSC分析结果显示，在228.5±1℃有分解放热峰，如附图3所示。DSC数据由差示扫描量热仪(DSC1/500，瑞士Mettler Toledo公 司)分析得到，分析条件为：样品5～10mg样品置于40μL铝坩埚内，高纯氮气做反应气和保护气，流量分别为50mL/min和20mL/min。升温速率10℃/min，温度范围25～300℃。
所述奥美拉唑钠半水合物的外形棒状，主粒度100μm左右，如附图4显微镜照片所示。显微镜照片由偏光显微镜(OLYMPUS BX51,MicroPublisher5.0RTU)观察并记录得到。
本发明所述的奥美拉唑钠半水合物的制备方法，将原料奥美拉唑钠水合物加入到有机溶剂中，25～60℃恒温搅拌2～9小时，经过滤、干燥，得到奥美拉唑钠半水物。
所述的有机溶剂选自正丙醇、正丁醇、仲丁醇、甲酰胺、N,N-二甲基甲酰胺、乙酸甲酯、乙酸乙酯、乙酸丁酯、正庚烷、三氯甲烷、乙腈、四氢呋喃、丙酮、丁酮或甲基异丁基甲酮中的一种或几种的混合溶剂。
所述原料奥美拉唑钠水合物初始浓度为0.015～0.12g/mL。
搅拌形式以及搅拌速度对转晶结果无明显影响。
奥美拉唑钠容易形成水合物，可能是亚硫酰基上的氧与水分子形成氢键。本发明采用的特定有机溶剂，可与原料奥美拉唑钠水合物中的水分子形成相互作用，脱去其部分水，使两个奥美拉唑钠与一个水分子连接；而且，在这些特定的有机溶剂中，原料奥美拉唑钠水合物的溶解度大，奥美拉唑钠半水物的溶解度小。因此，本发明使用适宜的溶剂、在适宜的浓度、温度和时间下，通过原料奥美拉唑钠水合物制备出收率高、形态好的奥美拉唑钠半水合物。
本发明提供的奥美拉唑钠半水合物的制备方法优点为操作简单，所得滤饼无需洗涤，溶剂消耗少；结晶、过滤和干燥速率快，耗时短，效率高；无需蒸发，能耗低；摩尔收率高，不小于95％；所制备的奥美拉唑钠半水合物高效液相色谱(HPLC)含量在100％(以无水物计)左右，符合欧洲药典98～101.0％的规定。
本发明更为有益的效果还体现在晶体形态和稳定性。本发明提供的奥美拉唑钠半水合物具有优异的晶体形态：块状晶体、表面光洁、晶型唯一、不易聚结，卡尔指数小于15％，流动性好；申请人实验测定了WO1999000380A1文献报道的一水合物的流动性，其卡尔指数大于41％，流动性差。本发明提供的奥美拉唑钠半水合物热稳定性好：DSC分析表明其热分解温度为228.5℃，明显高于奥美拉唑钠一水合物的热分解温度209.0℃(如附图5所示)。60℃热稳定性试验结果显示，本发明提供的奥美拉唑钠半水合物晶型稳定，未发生明显变化(X-射线衍射图谱如附图6)，10天的重量变化率在2.2％以内，比奥美拉唑钠一水合物重量变化率4.8％更小，稳定性更好(见表1)。本发明提供的奥美拉 唑钠半水物与奥美拉唑钠一水合物相比更不易吸湿(见表2)。因此，本发明提供的奥美拉唑钠半水合物在热稳定性、流动性、抗湿性方面均优于奥美拉唑钠一水合物，具有更广泛的应用前景。
表1本发明奥美拉唑钠半水合物与奥美拉唑钠一水合物60℃下稳定性对比
Figure PCTCN2015095230-appb-000003
注：按照《化学药物稳定性研究技术指导原则》，将样品置于密闭洁净容器中60℃下十天，定期称重。
表2本发明奥美拉唑钠半水合物与奥美拉唑钠一水合物40℃下吸湿性对比
Figure PCTCN2015095230-appb-000004
注：将样品置于动态蒸汽吸附仪中40℃下，记录3hr内质量变化小于0.01g时的重量。
本发明获得的奥美拉唑钠半水合物的毒性反应表明，其毒性比现有的奥美拉唑钠或其一水合物有所改善，药物突变试验及生殖毒性试验结果均为阴性，致癌试验未见癌转移。
附图说明
图1奥美拉唑钠半水合物的X-射线粉末衍射谱图；
图2奥美拉唑钠半水合物的傅里叶变换红外光谱(FT-IR)图；
图3奥美拉唑钠半水合物的差热分析(DSC)图；
图4奥美拉唑钠半水合物的显微镜图；
图5奥美拉唑钠一水合物的差热分析(DSC)图；
图6奥美拉唑钠半水合物在60℃下放置十天前后粉末X-射线衍射谱对比图。
具体实施方式
以下将通过实施例形式的具体实施方式，对本发明的上述内容进一步的详细说明，但不应该将此理解为本发明上述主体的范围仅局限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1：
向结晶器中加入0.45g奥美拉唑钠一水合物、20mL乙酸乙酯和10mL仲丁醇，在35℃、磁子转速200r/min下搅拌2小时，过滤、干燥，得到奥美拉唑钠半水物0.42g，摩尔收率95.6％，HPLC含量99.8％。产品的X-射线粉末衍射图谱与附图1一致，固体傅里叶变换红外光谱和附图2一致，DSC分解温度为227.5℃(可参见图3)。晶体主粒度92μm，不聚结(可参见图4)，卡尔指数为14.3％，表明其流动性好。60℃高温下放置十天，仍为白色晶体，X-射线衍射图谱(可参见图6)未发生明显变化，60℃热稳定性试验结果显示，10天的重量变化率2.4％，热稳定性好。40℃、相对湿度75％的条件下3天，重量变化率0.68％，表明产品不易吸湿。
实施例2：
向结晶器中加入2.40g奥美拉唑钠一水合物、20mL甲基异丁基甲酮，60℃、机械搅拌转速300r/min下搅拌7小时、过滤、35℃、真空度0.05MPa下干燥，得到奥美拉唑钠半水物2.27g，摩尔收率96.8％，HPLC含量100.2％。产品的X-射线粉末衍射图谱在衍射角2θ为6.34,11.18,12.26,15.58,16.02,17.06,19.12,21.04,22.66,23.52,24.10,26.44和28.04度处有特征峰，固体傅里叶变换红外光谱在波数为3414.5,3132.1,2969.9,2939.8,2846.9,2756.5,1607.7,1571.9,1474.5,1441.5,1377.3,1266.0,1147.8,1112.3,1072.8,1032.9,941.3,830.7,803.4,751.1和673.2cm-1处有特征峰，DSC分解温度为229.2℃。晶体主粒度95μm，不聚结，卡尔指数为13.9％，表明其流动性好。60℃高温下放置十天，仍为白色晶体，X-射线衍射图谱未发生明显变化，60℃热稳定性试验结果显示，10天的 重量变化率2.5％，热稳定性好。
实施例3：
向结晶器中加入3.00g奥美拉唑钠水合物(水含量7.02％)、10mL四氢呋喃、10mL甲酰胺和10mL丁酮，25℃、机械搅拌转速600r/min下搅拌9小时。过滤，30℃、真空度0.1MPa下干燥，得到奥美拉唑钠半水物2.78g，摩尔收率97.4％，HPLC含量100.0％。产品的X-射线粉末衍射图谱在衍射角2θ为6.28,11.16,12.16,15.62,16.02,17.02,19.10,21.00,22.60,23.44,24.16,26.42和28.02度处有特征峰，固体傅里叶变换红外光谱在波数为3413.0,3132.3,2968.7,2938.1,2846.8,2754.6,1605.4,1572.1,1474.6,1441.5,1375.8,1266.2,1146.8,1111.0,1074.2,1032.9,942.8,831.2,803.6,751.5和671.7cm-1处有特征峰，DSC分解温度为229.5℃。晶体主粒度100μm，不聚结，卡尔指数为14.7％，表明其流动性好。60℃高温下放置十天，仍为白色晶体，X-射线衍射图谱未发生明显变化，60℃热稳定性试验结果显示，10天的重量变化率2.4％，热稳定性好。
毒性实验：
对本发明获得的奥美拉唑钠半水物进行毒性反应实验、药物突变实验、生殖毒性实验和致癌试验(以实施例1获得的奥美拉唑钠半水物为例)。
在大鼠长期给予奥美拉唑的研究中，观察到胃ECL细胞增大和良性肿瘤，这是持续性高胃泌素血症因胃酸抑制的结果。犬静脉给药LDLo(公布的最低致死剂量)是500mg/kg，大鼠静脉给药LD50(半数致死量)是302mg/kg。小鼠静脉给药LD50为82.8mg/kg，经口给药LD50>2000mg/kg。
口服剂量138mg/kg/day(约为基于体表面积的人类剂量40mg/day的34倍)时对雌雄大鼠的生殖表现无影响。
对大鼠进行1-6个月的从140mg/kg/日剂量连续给药的长期毒性试验时可见肝肾重量增加，但无生化组织学变化。
对大鼠及犬以14-140mg/kg/日剂量连续3个月给药，可致高胃泌素血症(1000-5000pg/ml)，这是胃酸分泌减少引起的反馈反应，停药后可恢复。
药物突变实验及生殖毒性实验结果均为阴性。
大鼠24个月致癌试验(连续给药)发现高胃泌素血症引起胃粘膜肠嗜铬样细胞增生，并出现类癌变，但未见癌转移。
本发明公开和提出的一种奥美拉唑钠半水合物及其制备方法，本领域技术人员可通 过借鉴本文内容，适当改变原料、工艺参数等环节实现。本发明的方法与产品已通过较佳实施例子进行了描述，相关技术人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和产品进行改动或适当变更与组合，来实现本发明技术。特别需要指出的是，所有相类似的替换和改动对本领域技术人员来说是显而易见的，他们都被视为包括在本发明精神、范围和内容中。

Claims (7)

  1. 一种奥美拉唑钠半水合物，其特征为每摩尔奥美拉唑钠半水合物中含0.5摩尔水，结构式如下：
    Figure PCTCN2015095230-appb-100001
  2. 如权利要求1所述的奥美拉唑钠半水合物，其特征是，粉末X-射线衍射图谱在衍射角2θ为6.26±0.1,11.10±0.1,12.20±0.1,15.58±0.1,16.02±0.1,17.12±0.1,19.08±0.1,21.00±0.1,22.68±0.1,23.48±0.1,24.08±0.1,26.52±0.1和28.08±0.1度处有特征衍射峰。
  3. 如权利要求1所述的奥美拉唑钠半水合物，其特征是红外光谱在波数为3413.5±2,3131.9±2,2969.3±2,2938.8±2,2847.4±2,2755.5±2,1606.7±2,1571.1±2,1473.9±2,1440.5±2,1376.3±2,1266.5±2,1147.0±2,1111.5±2,1073.8±2,1032.3±2,942.3±2,830.2±2,802.6±2,750.6±2和672.7±2cm-1处有特征吸收峰。
  4. 如权利要求1所述的奥美拉唑钠半水合物，其特征是其DSC在228.5±1℃有分解放热峰。
  5. 如权利要求1所述的奥美拉唑钠半水合物的制备方法，其特征是：将原料奥美拉唑钠水合物加入到有机溶剂中，25～60℃恒温搅拌2～9小时，经过滤干燥，得到奥美拉唑钠半水物。
  6. 如权利要求5所述的方法，其特征是所述的有机溶剂选自正丙醇、正丁醇、仲丁醇、甲酰胺、N,N-二甲基甲酰胺、乙酸甲酯、乙酸乙酯、乙酸丁酯、正庚烷、三氯甲烷、乙腈、四氢呋喃、丙酮、丁酮或甲基异丁基甲酮中的一种或几种的混合溶剂。
  7. 如权利要求5所述的方法，其特征为所述原料奥美拉唑钠水合物初始浓度为0.015～0.12g/mL。
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