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WO2018214877A1 - 一种地佐辛晶型及其制备方法 - Google Patents

一种地佐辛晶型及其制备方法 Download PDF

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WO2018214877A1
WO2018214877A1 PCT/CN2018/087856 CN2018087856W WO2018214877A1 WO 2018214877 A1 WO2018214877 A1 WO 2018214877A1 CN 2018087856 W CN2018087856 W CN 2018087856W WO 2018214877 A1 WO2018214877 A1 WO 2018214877A1
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dextrozine
crystal form
solvent
present application
preparation
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PCT/CN2018/087856
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English (en)
French (fr)
Inventor
黄翔
徐镜人
蔡伟
王庆辉
肖志超
要世伟
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扬子江药业集团有限公司
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Priority to US16/611,629 priority Critical patent/US10947185B2/en
Publication of WO2018214877A1 publication Critical patent/WO2018214877A1/zh

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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
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
    • C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings

Definitions

  • the present application relates to, but is not limited to, the field of medicine, and in particular relates to a new crystal form of dizocine and a preparation method thereof.
  • Dizocine is developed by the Swiss company Astrazeneca (US4001331) and belongs to a typical opioid alkaloid analgesic. It is a ⁇ receptor agonist and a ⁇ receptor antagonist. These drugs have the effect of both agonists and antagonists, showing different characteristics by different receptor subtype affinity than other opioids.
  • U.S. Patent No. 4,001,331 discloses the preparation of dizocine and its various analogs and various salt forms;
  • Chinese patent CN102503840A is a patent for the preparation of compounds, and compared with the patent US4001331, the environmental friendliness and economy of the oxidant used for the preparation of intermediate II are environmentally friendly. Preferably, the preparation process of the intermediate III is safer, the separation efficiency is higher, and the process is simple and efficient.
  • Patent CN101671269B discloses a preparation method of a key intermediate of dizocine, which has a simpler operation method and a mild reaction condition, high safety and low cost.
  • Chinese patent CN104910002A discloses a preparation method of dizocine intermediate V.
  • Patent DE 2159324 discloses a preparation method of dizocine injection
  • Chinese patent 201510080325.X reports an oral preparation of dizocine and a preparation method thereof, which are in substantive examination
  • Chinese patent 201410405193.9 discloses a freeze-dried dizocine The powder injection and the preparation method thereof have lower safety risks and better stability than the injection, and are in substantive examination
  • Chinese Patent 201410470463.4 discloses a dexamethasone frozen pharmaceutical composition and a preparation method thereof.
  • Chinese Patent 201410405193.9 its impurity content is low, and there is no organic solvent, and its clinical application is safer. It is currently under substantive examination; Chinese Patent 201410804930.2 discloses a preparation method of dizocine injection, which is currently under substantive examination.
  • the analgesic effect of dizocine is stronger than that of pentazocine, which is less addictive, has good safety and tolerability, and is suitable for treating pain in patients with moderate to severe pain, visceral colic and advanced cancer after surgery. Its analgesic intensity, onset time and duration of action and maximum analgesic effect are comparable to those of morphine, 5-9 times stronger than that of dulantin, with mild side effects.
  • the raw materials and preparations of dizocine have been marketed in China, and the recognition of the market and medical institutions has been continuously improved, so the clinical demand is also increasing.
  • the inventors have developed a new crystal form of dextrozine, which has a fast dissolution, a fast absorption by the human body, a better stability, and a lower content of related substances during storage, in particular, which does not contain impurities B (chemical Structural formula II); Moreover, the preparation method of the new crystal form has the advantages of simple operation, good reproducibility, and suitable for industrial large-scale production.
  • the present application provides a novel crystalline form of dextrozine.
  • the present application provides a method of preparing the novel crystalline form.
  • the present application provides a pharmaceutical composition comprising the above novel dextrozine crystalline form.
  • the present application provides the use of the above novel dextrozine crystalline form or a pharmaceutical composition thereof for analgesic drugs.
  • Figure 1a shows the XRD pattern of the new dextrozine crystal form of Example 1 of the present application.
  • Figure 1b shows the XRD pattern of the sample obtained in Example 1 of the patent CN102503840A.
  • Figure 2a shows the DSC pattern of the new dextrozine crystal form of Example 1 of the present application.
  • Figure 2b shows the DSC pattern of the sample obtained in Example 1 of the patent CN102503840A.
  • Figure 3 is a graph showing the IR spectrum of the new dextrozine crystal form of Example 1 of the present application.
  • Fig. 4 is a view showing the TGA spectrum of the new dextrozine crystal form of Example 1 of the present application.
  • the present application provides a novel crystalline form of dextrozine having an X-ray powder diffraction pattern determined using Cu/K- ⁇ 1 at 2 ⁇ values of 9.1 ⁇ 0.2 and 12.2 ⁇ 0.2. There are diffraction peaks, and the height % of these diffraction peaks are all greater than 20.
  • the present application provides a novel crystalline form of dextrozine having an X-ray powder diffraction pattern measured using Cu/K- ⁇ 1 at a value of 2 ⁇ of 9.1 ⁇ 0.2, 12.2 ⁇ 0.2,
  • the diffraction peaks may be at 13.6 ⁇ 0.2, and 23.1 ⁇ 0.2, and the height % of these diffraction peaks may be greater than 20.
  • the present application provides a novel crystalline form of dextrozine having an X-ray powder diffraction pattern measured using Cu/K- ⁇ 1 at a value of 2 ⁇ of 9.1 ⁇ 0.2, 12.2 ⁇ 0.2, 13.0 ⁇ 0.2, 13.6 ⁇ 0.2, 14.0 ⁇ 0.2, 14.7 ⁇ 0.2, 15.2 ⁇ 0.2, 19.6 ⁇ 0.2, 23.1 ⁇ 0.2, 24.4 ⁇ 0.2, and 27.2 ⁇ 0.2 may have diffraction peaks, and the height % of these diffraction peaks Can be greater than 20.
  • the present application provides a novel crystalline form of dextrozine having an X-ray powder diffraction pattern determined using Cu/K- ⁇ 1, and the diffraction peak condition may be:
  • Peak number 2 ⁇ d value height% area% FWHM 1 9.100 9.7102 51.4 66.1 0.460 2 12.161 7.2716 100.00 100.0 0.358 3 13.008 6.8003 23.0 9.2 0.143 4 13.556 6.5265 41.8 22.3 0.191 5 13.973 6.3329 52.2 26.2 0.179 6 14.743 6.0038 98.7 72.5 0.263 7 15.197 5.8252 56.3 44.9 0.285 8 16.656 5.3183 4.2 2.5 0.208 9 17.051 5.1958 7.7 3.9 0.183 10 18.118 4.8923 12.1 9.2 0.271 11 18.452 4.8043 14.7 17.4 0.424 12 19.186 4.6222 13.0 9.7 0.266 13 19.598 4.5259 19.8 12.8 0.231 14 21.808 4.0720 14.8 8.4 0.202 15 22.675 3.9182 8.1 6.2 0.273 16 23.111 3.8452 74.9 42.2 0.201 17 23.444 3.7914 8.9 7.9 0.318 18 24.355 3.6516 25.5 22.9
  • the present application provides a novel crystalline form of dextrozine having an X-ray powder diffraction pattern determined using Cu/K- ⁇ 1, substantially as shown in Figure 1a.
  • the present application provides a novel dextrozine crystal form having a DSC detection having an endothermic peak near 168.40 ° C.
  • the present application provides a novel crystalline form of dexrazin having a DSC pattern characteristic substantially as shown in Figure 2a.
  • the present application provides a novel dextrozine crystal form having IR data characteristics substantially as shown in FIG.
  • the present application provides a novel dextrozine crystal form having a TGA data characteristic substantially as shown in FIG.
  • the present application provides a method for preparing the above novel dextrozine crystal form, which is prepared as follows:
  • Crystals are precipitated by cooling and heat preservation, and the crystals are collected after filtration and dried.
  • Solvent A having a relatively high solubility of dextrozine is dissolved, and another solvent B having a small solubility to terrazzo with respect to solvent A is added, and then a subsequent step is carried out to precipitate a new dextrozine crystal form as claimed in the present application.
  • solvent A having a higher solubility to dextrozine may be a solvent which dissolves more than 0.1 g of dextrozine per ml of solvent A
  • solvent B having a small solubility may be a solvent which dissolves less than 0.03 g of dextrozine per ml of the solvent B.
  • the method for preparing a new crystal form of dextrozine provided by the present application wherein the solvent A having a higher solubility to dextrozine in the step 1) may be selected from the group consisting of dioxane and ethyl acetate One or two of the esters.
  • the method for preparing a new crystal form of dextrozine provided by the present application, wherein the solvent A having a higher solubility to essoxine in the step 1) may be dioxane.
  • the method for preparing a novel crystal form of dextrozine provided by the present application wherein the solvent B having a small solubility to dexrazin in the step 1) may be selected from the group consisting of acetonitrile, toluene and petroleum ether. One or more.
  • the method for preparing a novel crystal form of dextrozine provided by the present application, wherein the solvent B having a small solubility to dexrazin in the step 1) may be petroleum ether.
  • the method for preparing a new crystal form of dextrozine provided by the present application wherein the ratio of the amount of the solvent A to the dose of dextrozine in the step 1) may be: per gram of dextrozine dissolved In 1 ml to 30 ml of solvent A.
  • the method for preparing a new crystal form of dextrozine provided by the present application wherein the ratio of the amount of the solvent A to the dose of dextrozine in the step 1) may be: per gram of dextrozine dissolved In 2 ml to 10 ml of solvent A.
  • the present invention provides a novel method for preparing a crystal form of dextrozine, wherein the volume ratio of solvent A to solvent B in step 1) may be 1:0.3 to 1:10.
  • the method for preparing a new crystal form of dextrozine provided by the present application wherein the volume ratio of solvent A to solvent B in step 1) may be 1:0.4 to 1:10.
  • the present invention provides a novel method for preparing a crystal form of dextrozine, wherein the volume ratio of solvent A to solvent B in step 1) may be 1:0.5 to 1:10.
  • the present invention provides a novel method for preparing a crystalline form of dextrozine, wherein the volume ratio of solvent A to solvent B in step 1) may be from 1:1 to 1:2.5.
  • the method for preparing a new crystal form of dextrozine provided by the present application wherein the temperature of the heat dissolution in the step 1) may be from 30 ° C to 100 ° C.
  • the novel method for preparing a crystal form of dextrozine provided by the present application, wherein the temperature of the heat dissolution in the step 1) may be from 70 ° C to 80 ° C.
  • the method for preparing a new crystal form of dextrozine provided by the present application wherein the temperature of the temperature-lowering crystallization in the step 2) may be 0 ° C to 20 ° C.
  • the method for preparing a new crystal form of dextrozine provided by the present application wherein the temperature of the temperature-lowering crystallization in the step 2) may be 0 ° C to 10 ° C.
  • the present invention provides a novel method for preparing a crystal form of dextrozine, wherein the drying in step 2) is vacuum (-0.1 MPa) drying, and the drying temperature may be 60 ° C to 90 ° C.
  • the present invention provides a novel method for preparing a crystal form of dextrozine, wherein the drying in step 2) is vacuum (-0.1 MPa) drying, and the drying temperature may be 60 ° C to 80 ° C.
  • the method for preparing a novel dextrozine crystal form provided by the present application wherein the dextrozine used in the step 1) can be prepared by the method in the patent CN102503840A.
  • the present application provides a pharmaceutical composition comprising the above novel dextrozine crystalline form.
  • the administration mode, administration dose, and the like of the pharmaceutical composition can be referred to the teaching of US4001331.
  • the present application provides the use of the above novel dextrozine crystalline form or a pharmaceutical composition thereof for analgesic drugs.
  • the dizocine used in the examples was prepared according to the method of Example 1 in the patent CN102503840A.
  • Equipment model TA Q200; equilibrium temperature 25 ° C; heating conditions: temperature rise to 250 ° C at a rate of 10 ° C / min; nitrogen flow rate of 40 ml / min; aluminum plate, capping;
  • Equipment model Bruker Tensor 27; KBr tablet; scanning range: 4000-400cm -1 ;
  • Equipment model NETZSCH TG 209; heating rate: 10 ° C / min; temperature range: 30-250 ° C; ⁇ material: Al 2 O 3 .
  • FIG. 1a A typical XRD pattern of the dextrozine crystal form obtained in the examples of the present application is shown in Fig. 1a, the DSC spectrum is shown in Fig. 2a, the IR spectrum is shown in Fig. 3, and the TGA spectrum is shown in Fig. 4.
  • the present application detects the dextrozine crystal obtained by the patent CN102503840A (hereinafter referred to as the dextrozine I crystal form), and measures the X-ray powder diffraction pattern thereof using Cu/K- ⁇ 1, as shown in FIG. 1b, the diffraction peak is as follows :
  • dexozin II crystal form novel dextrozine crystal form
  • the new crystal form of dextrozine in the present application has better solubility in a 0.1 mol/L hydrochloric acid solution, and the solubility is improved by about 32%, as shown in the following table:
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 5 relative substance 0.08% 0.06% 0.07% 0.04% 0.06% 0.04%
  • Example 1 0.06% 0.07% 0.10% 0.13%
  • Example 2 0.07% 0.09% 0.10% 0.12%
  • Example 3 0.04% 0.05% 0.8% 0.10%
  • Example 4 0.06% 0.08% 0.10% 0.12%
  • Example 5 0.04% 0.06% 0.07% 0.09%
  • the new crystalline form of dextrozine prepared in the present application has better stability, and the impurity B content of the 6-month change is as follows:
  • Dizocine crystal form I One refinement Secondary refining Three refinements Impurity B content 0.03% 0.03% 0.03% 0.03% 0.03% 0.03%
  • the new crystal form of dizoxin provided by the present application has better solubility, is favorable for drug dissolution and absorption by the human body; has better stability, and has lower content of related substances during storage; meanwhile, preparation of the new crystal form
  • the method has the advantages of simple operation, good reproducibility, and suitable for industrialized large production.

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Abstract

公开了一种地佐辛晶型，使用Cu/K-α1测定其X射线粉末(XRD)衍射图，在2θ值为9.1±0.2和12.2±0.2处具有衍射峰，并且这些衍射峰的高度％均大于20，还公开了该晶型的制备方法、药物组合物和用途。该地佐辛晶型溶解性好，制备方法操作简单，重现性好，适合工业化生产等。

Description

一种地佐辛晶型及其制备方法 技术领域
本申请涉及但不限于医药领域，具体涉及一种地佐辛新晶型及其制备方法。
背景技术
地佐辛，英文名Dezocine，CAS No.：32619-42-4，化学名为(-)-[5R-(5α,11α,13S*)]-13-氨基-5,6,7,8,9,10,11,12-八氢-5-甲基-5,11-甲撑苯并环癸烯-3-醇，化学结构式为
Figure PCTCN2018087856-appb-000001
地佐辛是由瑞士Astrazeneca公司开发(US4001331)，属于一种典型的阿片生物碱类镇痛药，是κ受体激动剂，也是μ受体拮抗剂。该类药物兼有激动剂和拮抗剂的作用，通过对受体亚型亲和力与其他阿片类药物不同而显示了不同的特点。
美国专利US4001331公开了地佐辛及其多种类似物、各种盐型的制备方法；中国专利CN102503840A为化合物制备专利，相比于专利US4001331，制备中间体Ⅱ所用氧化剂的环境友好性、经济性较好，中间体Ⅲ的制备过程安全性更高，拆分效率更高，工艺简单高效。专利CN101671269B公布了一种地佐辛关键中间体的制备方法，其合成方法操作更加简便，且反应其条件温和，安全性高，成本低。中国专利CN104910002A公布了一种地佐辛中间体V的制备方法，相比较于专利CN102503840A，其合成方法更加简便、条件温和，以7-甲氧基-2-萘满酮为原料，成本较低；专利DE2159324公开了地佐辛注射液制备方法；中国专利201510080325.X报道了一种地佐辛口服制剂及其制备方法，处于实质性审查中；中国专利201410405193.9公布了一种地佐辛冻干粉针剂及其制备方法，相比较于注射剂，其安全隐患更低，稳定 性更好，处于实质性审查中；中国专利201410470463.4公开了一种地佐辛冻药物组合物及其制备方法，相比较于中国专利201410405193.9，其杂质含量低，且无有机溶剂，临床应用更安全，目前处于实质性审查中；中国专利201410804930.2公开了一种地佐辛注射液的制备方法，目前处于实质性审查中。
发明概述
以下是对本文详细描述的主题的概述。本概述并非是为了限制权利要求的保护范围。
地佐辛的镇痛作用强于喷他佐辛，成瘾性小，具有良好的安全性和耐受性，适用于治疗手术后中等至剧烈疼痛、内脏绞痛及晚期癌症患者的疼痛。其镇痛强度、起效时间和作用持续时间及最大镇痛效果与吗啡相当，比杜冷丁强5-9倍，副作用轻微。目前地佐辛原料和制剂已在国内上市销售，并且市场和医疗机构认可度不断提高，因此临床需求也不断加大。
关于“背景技术”部分中提及的专利只涉及到地佐辛及类似物的合成工艺、中间体制备、制剂等方面，未涉及化合物晶型方面。多晶型现象在药物中广泛存在。同一药物的不同晶型在溶解度、熔点、密度、稳定性等方面有显著的差异，从而不同程度地影响药物的稳定性、均一性、生物利用度、疗效和安全性。尤其是溶解度方面，目前的地佐辛药品溶解度极差，不利于制剂的开发及药物在人体内的吸收。因此，对地佐辛进行全面系统地多晶型筛选，选择溶解度高、稳定性好的晶型是不可忽视的重要研究内容之一。因此，开发溶解度更好的地佐辛新晶型对于相关制剂的开发及提高地佐辛的生物利用度具有重要意义。
本发明人开发了一种新的地佐辛晶型，具有溶解快，人体吸收快，具有更好的稳定性，在贮存过程中有关物质含量更低，特别的，其中不含杂质B(化学结构式II)；而且，该新晶型的制备方法，具有操作简单、重现性好、适合工业化大生产等优点。
Figure PCTCN2018087856-appb-000002
在本申请的一种实施方案中，本申请提供了一种新的地佐辛晶型。
在本申请的另一种实施方案中，本申请提供了提供该新晶型的制备方法。
在本申请的另一种实施方案中，本申请提供了包含上述新的地佐辛晶型的药物组合物。
在本申请的另一种实施方案中，本申请提供了上述新的地佐辛晶型或其药物组合物在止痛药物中的应用。
附图概述
图1a表示的是本申请实施例1新的地佐辛晶型的XRD图谱。
图1b表示的是专利CN102503840A实施例1得到的样品的XRD图谱。
图2a表示的是本申请实施例1新的地佐辛晶型的DSC图谱。
图2b表示的是专利CN102503840A实施例1得到的样品的DSC图谱。
图3表示的是本申请实施例1新的地佐辛晶型的IR图谱。
图4表示的是本申请实施例1新的地佐辛晶型的TGA图谱。
详述
在本申请的一种实施方案中，本申请提供了一种新的地佐辛晶型，使用Cu/K-α1测定其X射线粉末衍射图，在2θ值为9.1±0.2和12.2±0.2处具有衍射峰，并且这些衍射峰的高度％均大于20。
在本申请的一种实施方案中，本申请提供了一种新的地佐辛晶型，使用Cu/K-α1测定其X射线粉末衍射图，在2θ值为9.1±0.2、12.2±0.2、13.6±0.2、和23.1±0.2处可以具有衍射峰，并且这些衍射峰的高度％均可以大于20。在 本申请的一种实施方案中，本申请提供了一种新的地佐辛晶型，使用Cu/K-α1测定其X射线粉末衍射图，在2θ值为9.1±0.2、12.2±0.2、13.0±0.2、13.6±0.2、14.0±0.2、14.7±0.2、15.2±0.2、19.6±0.2、23.1±0.2、24.4±0.2、和27.2±0.2处可以具有衍射峰，并且这些衍射峰的高度％均可以大于20。
在本申请的一种实施方案中，本申请提供了一种新的地佐辛晶型，使用Cu/K-α1测定其X射线粉末衍射图，衍射峰情况可以为：
峰编号 2θ d值 高度％ 面积％ FWHM
1 9.100 9.7102 51.4 66.1 0.460
2 12.161 7.2716 100.00 100.0 0.358
3 13.008 6.8003 23.0 9.2 0.143
4 13.556 6.5265 41.8 22.3 0.191
5 13.973 6.3329 52.2 26.2 0.179
6 14.743 6.0038 98.7 72.5 0.263
7 15.197 5.8252 56.3 44.9 0.285
8 16.656 5.3183 4.2 2.5 0.208
9 17.051 5.1958 7.7 3.9 0.183
10 18.118 4.8923 12.1 9.2 0.271
11 18.452 4.8043 14.7 17.4 0.424
12 19.186 4.6222 13.0 9.7 0.266
13 19.598 4.5259 19.8 12.8 0.231
14 21.808 4.0720 14.8 8.4 0.202
15 22.675 3.9182 8.1 6.2 0.273
16 23.111 3.8452 74.9 42.2 0.201
17 23.444 3.7914 8.9 7.9 0.318
18 24.355 3.6516 25.5 22.9 0.321
19 24.865 3.5779 6.9 5.9 0.307
20 25.580 3.4794 6.0 4.7 0.276
21 27.159 3.2807 19.9 12.4 0.223
22 27.549 3.2351 3.0 3.6 0.425
23 28.043 3.1792 4.5 4.2 0.337
24 28.281 3.1530 5.6 3.7 0.236
25 29.859 2.9899 1.8 1.1 0.215
26 30.274 2.9498 5.9 5.1 0.311
27 30.773 2.9031 2.6 2.1 0.281
28 31.635 2.8259 1.2 0.6 0.178
29 32.467 2.7554 2.7 2.1 0.275
30 33.201 2.6962 1.6 0.5 0.108
31 33.865 2.6448 3.7 2.2 0.215
32 34.519 2.5962 1.1 0.8 0.271
33 36.000 2.4927 5.6 4.5 0.286
34 37.715 2.3832 5.4 4.6 0.310
35 39.298 2.2908 3.3 1.5 0.158
在本申请的一种实施方案中，本申请提供了一种新的地佐辛晶型，使用Cu/K-α1测定其X射线粉末衍射图，基本上可以如图1a所示。
在本申请的一种实施方案中，本申请提供了一种新的地佐辛晶型，其DSC检测在168.40℃附近可以有吸热峰，
在本申请的一种实施方案中，本申请提供了一种新的地佐辛晶型的，其DSC图谱特征基本上可以如图2a所示。
在本申请的一种实施方案中，本申请提供了一种新的地佐辛晶型，其IR数据特征基本上可以如图3所示。
在本申请的一种实施方案中，本申请提供了一种新的地佐辛晶型，其TGA数据特征基本上可以如图4所示。
另一方面，在本申请的另一种实施方案中，本申请提供了上述新的地佐辛晶型的制备方法，其制备过程如下：
1)加热下，将地佐辛溶解于一种对地佐辛溶解度较大的溶剂A中，搅拌下，再加入另一种对地佐辛溶解度小的溶剂B；
2)经降温、保温方式析出晶体，过滤后收集晶体，干燥后制得。
在本申请中，“将地佐辛溶解于一种对地佐辛溶解度较大的溶剂A中，搅拌下，再加入另一种对地佐辛溶解度小的溶剂B”(或“将地佐辛溶解于一种对地佐辛易溶的溶剂A中，搅拌下，再加入另一种对地佐辛难溶的溶剂B”)指的是可选取两种对地佐辛溶解度不同的溶剂，首先使用对地佐辛溶解度较大的溶剂A进行溶解，再加入相对于溶剂A另一种对地佐辛溶解度小的溶剂B后再经后续步骤，析出本申请要求保护的新的地佐辛晶型。
具体地，“对地佐辛溶解度较大的溶剂A”(或“对地佐辛易溶的溶剂A”)可以是每毫升溶剂A中溶解超过0.1g的地佐辛的溶剂；“对地佐辛溶解度小的溶剂B”(或“对地佐辛难溶的溶剂B”)可以是每毫升溶剂B中溶解低于0.03g的地佐辛的溶剂。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中步骤1)中所述对地佐辛溶解度较大的溶剂A可以选自二氧六环和乙酸乙酯中的一种或两种。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中步骤1)中所述对地佐辛溶解度较大的溶剂A可以为二氧六环。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中步骤1)中所述对地佐辛溶解度小的溶剂B可以选自乙腈、甲苯和石油醚中的一种或更多种。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中步骤1)中所述对地佐辛溶解度小的溶剂B可以为石油醚。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中步骤1)中所述溶剂A的用量与地佐辛的用量比可以为：每克地佐辛溶解于1ml至30ml溶剂A中。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中步骤1)中所述溶剂A的用量与地佐辛的用量比可以为：每克地佐辛溶解于2ml至10ml溶剂A中。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中步骤1)中溶剂A与溶剂B的体积比可以为1:0.3至1:10。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中步骤1)中溶剂A与溶剂B的体积比可以为1:0.4至1:10。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中步骤1)中溶剂A与溶剂B的体积比可以为1:0.5至1:10。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中步骤1)中溶剂A与溶剂B的体积比可以为1:1至1:2.5。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中步骤1)中加热溶解的温度可以为30℃至100℃。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其 中步骤1)中加热溶解的温度可以为70℃至80℃。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中步骤2)中降温析晶的温度可以为0℃至20℃。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中步骤2)中降温析晶的温度可以为0℃至10℃。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中步骤2)中所述干燥为真空(-0.1MPa)干燥，干燥温度可以为60℃至90℃。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中步骤2)中所述干燥为真空(-0.1MPa)干燥，干燥温度可以为60℃至80℃。
在本申请的实施方案中，本申请提供的新的地佐辛晶型的制备方法，其中，步骤1)所用的地佐辛，可以采用专利CN102503840A中的方法制备。
第三方面，本申请提供了包含上述新的地佐辛晶型的药物组合物。该药物组合物的给药方式和给药剂量等，可以参考US4001331教导。
第四方面，本申请提供了上述新的地佐辛晶型或其药物组合物在止痛药物中的应用。
下面以具体实施实例对本申请的技术方案做进一步说明，可以使本领域的技术人员更好的理解本申请，但本申请的保护范围不限于此。
实施例中所用的地佐辛是按照专利CN102503840A中的实施例1方法制备的。
XRD检测条件：
设备型号：德国BrukerD8advance；X射线管：Cu管；使用的放射物：K(α1)；发生器的电压和电流：40kV和40mA；步长：0.02°；扫描速度：0.5s/次；扫描范围：3°-40°；
DSC检测条件：
设备型号：TA Q200；平衡温度25℃；升温条件：以10℃/min的速率升温至250℃；氮气流速为40ml/min；铝盘、加盖；
IR检测条件：
设备型号：Bruker Tensor 27；KBr压片；扫描范围：4000-400cm -1；
TGA检测条件：
设备型号：NETZSCH TG 209；升温速率：10℃/min；温度范围：30-250℃；坩埚材质：Al 2O 3。
实施例1
在干净的50ml反应瓶中加入地佐辛2g，加入二氧六环7.5ml，搅拌加热至80℃全溶后，加入7.5ml乙腈，降温至5℃左右析晶2h，过滤，得到固体，80℃下真空干燥，得干品地佐辛1.7g，收率85％。测定该地佐辛晶型的XRD图谱如图1a所示，DSC图谱如图2a所示，IR图谱如图3所示，TGA图谱如图4所示。
实施例2
在干净的50ml反应瓶中加入地佐辛2g，加入二氧六环9ml，搅拌加热至60℃全溶后，加入6ml石油醚，降温至5℃左右析晶2h，过滤，得到固体，60℃下真空干燥，得干品地佐辛1.9g，收率95％。
实施例3
在干净的50ml反应瓶中加入地佐辛2g，加入乙酸乙酯15ml，搅拌加热至60℃全溶后，加入6ml石油醚，降温至15℃左右析晶2h，过滤，得到固体，80℃下真空干燥，得干品地佐辛1.3g，收率65％。
实施例4
在干净的50ml反应瓶中加入地佐辛2g，加入乙酸乙酯15ml，搅拌加热至65℃全溶后，加入10ml甲苯，降温至10℃左右析晶2h，过滤，得到固体，70℃下真空干燥，得干品地佐辛1.6g，收率80％。
实施例5
在干净的50ml反应瓶中加入地佐辛2g，加入二氧六环9ml，搅拌加热至75℃全溶后，加入15ml甲苯，降温至5℃左右析晶2h，过滤，得到固体，90℃下真空干燥，得干品地佐辛1.4g，收率70％。
本申请实施例得到的地佐辛晶型典型的XRD图谱如图1a所示，DSC图 谱如图2a所示，IR图谱如图3所示，TGA图谱如图4所示。
本申请检测了专利CN102503840A得到的地佐辛结晶(以下称作地佐辛I晶型)，使用Cu/K-α1测定其X射线粉末衍射图，如图1b所示，其衍射峰的情况如下：
峰编号 2θ d值 高度％ 面积％ FWHM
1 9.750 9.0639 3.5 3.6 0.148
2 10.398 8.5007 8.4 8.4 0.147
3 11.585 7.6319 16.4 17.0 0.152
4 13.008 6.8000 75.1 74.6 0.145
5 14.150 6.2537 100.0 100.0 0.146
6 14.604 6.0606 5.9 6.6 0.164
7 15.688 5.6439 38.6 28.7 0.109
8 16.615 5.3313 6.6 9.7 0.215
9 17.188 5.1548 4.5 3.8 0.122
10 17.938 4.9408 3.8 5.4 0.212
11 18.200 4.8704 5.5 6.3 0.166
12 18.888 4.6945 9.4 11.8 0.185
13 19.403 4.5710 3.7 4.3 0.173
14 19.773 4.4863 19.7 26.4 0.196
15 20.918 4.2433 27.1 31.8 0.172
16 21.531 4.1238 27.1 32.5 0.175
17 22.399 3.9659 7.9 6.6 0.122
18 23.798 3.7358 26.4 48.9 0.271
19 24.173 3.6787 4.3 5.9 0.202
20 24.828 3.5831 2.6 2.6 0.150
21 25.302 3.5171 4.9 7.5 0.222
22 25.950 3.4307 4.9 13.8 0.410
23 26.286 3.3876 16.2 25.6 0.231
24 26.564 3.3528 4.3 8.1 0.273
25 27.827 3.2034 3.2 3.9 0.179
26 29.958 2.9802 4.3 7.9 0.272
27 31.024 2.8802 11.4 19.0 0.244
28 31.657 2.8240 8.6 10.9 0.187
29 32.818 2.7267 5.4 6.2 0.168
30 33.548 2.6691 0.7 1.5 0.304
31 34.615 2.5892 2.2 2.7 0.180
32 35.029 2.5595 2.1 3.5 0.240
33 35.526 2.5248 5.3 5.2 0.143
34 36.431 2.4642 2.1 2.9 0.208
35 36.851 2.4371 0.8 1.1 0.203
36 37.850 2.3750 2.9 7.1 0.359
37 38.362 2.3444 2.2 5.3 0.348
38 39.471 2.2811 1.7 1.8 0.154
经溶解度和稳定性试验，本发明人惊奇地发现，本申请的新的地佐辛晶型(以下简称地佐辛II晶型)的溶解度和稳定性都显著地优于地佐辛I晶型。
i.对比地佐辛I晶型的样品，本申请中的地佐辛新晶型在0.1mol/L的盐酸溶液中溶解性更好，溶解度提高约32％，见下表：
样品 样品量 溶剂量 溶解度
地佐辛II晶型 50mg 1.5ml 0.033g/ml
地佐辛I晶型 50mg 2.0ml 0.025g/ml
ii.对比地佐辛I晶型的样品，本申请中的地佐辛新晶型的有关物质含量更低，具体如下表所示：
样品 I晶型 实施例1 实施例2 实施例3 实施例4 实施例5
有关物质 0.08％ 0.06％ 0.07％ 0.04％ 0.06％ 0.04％
iii.对比地佐辛I晶型的样品，本申请中的所制备的地佐辛新晶型的稳定性更好，其6个月有关物质变化如下：
样品 0天 1个月 3个月 6个月
地佐辛I晶型 0.08％ 0.15％ 0.21％ 0.28％
实施例1 0.06％ 0.07％ 0.10％ 0.13％
实施例2 0.07％ 0.09％ 0.10％ 0.12％
实施例3 0.04％ 0.05％ 0.8％ 0.10％
实施例4 0.06％ 0.08％ 0.10％ 0.12％
实施例5 0.04％ 0.06％ 0.07％ 0.09％
iv.对比地佐辛I晶型的样品，本申请中的所制备的地佐辛新晶型的稳定性更好，其6个月杂质B含量变化如下：
样品 0天 1个月 3个月 6个月
地佐辛I晶型 0.03％ 0.04％ 0.04％ 0.05％
实施例1 未检出 未检出 未检出 未检出
实施例2 未检出 未检出 未检出 未检出
实施例3 未检出 未检出 未检出 未检出
实施例4 未检出 未检出 未检出 未检出
实施例5 未检出 未检出 未检出 未检出
v.按专利CN102503840A对地佐辛晶型I进行了多次精制，其杂质B含量都相同，如下表所示：
  地佐辛晶型I 一次精制 二次精制 三次精制
杂质B含量 0.03％ 0.03％ 0.03％ 0.03％
因此，本申请提供的地佐辛新晶型具有更好的溶解性，有利于药物溶出及人体吸收；具有更好的稳定性，在贮存过程中有关物质含量更低；同时，该新晶型的制备方法，具有操作简单、重现性好、适合工业化大生产等优点。

Claims (13)

  1. 一种地佐辛晶型，使用Cu/K-α1测定其X射线粉末(XRD)衍射图，在2θ值为9.1±0.2和12.2±0.2处具有衍射峰，并且这些衍射峰的高度％均大于20。
  2. 根据权利要求1所述的地佐辛晶型，其中，使用Cu/K-α1测定其X射线粉末衍射图，在2θ值为9.1±0.2、12.2±0.2、13.0±0.2、13.6±0.2、14.0±0.2、14.7±0.2、15.2±0.2、19.6±0.2、23.1±0.2、24.4±0.2、和27.2±0.2处具有衍射峰，并且这些衍射峰的高度％均大于20。
  3. 根据权利要求1所述的地佐辛晶型，其中，使用Cu/K-α1测定其X射线粉末衍射图，衍射峰情况为：
    Figure PCTCN2018087856-appb-100001
    Figure PCTCN2018087856-appb-100002
  4. 根据权利要求1所述的地佐辛晶型，其DSC检测在168.40℃附近有吸热峰。
  5. 根据权利要求1所述的地佐辛晶型，其IR数据特征基本上如图3所示。
  6. 根据权利要求1所述的地佐辛晶型，其TGA数据特征基本上如图4所示。
  7. 权利要求1-6中任一项所述的地佐辛晶型的制备方法，包括如下步骤：
    1)加热下，将地佐辛溶解于一种对地佐辛易溶的溶剂A中，搅拌下，再加入另一种对地佐辛难溶的溶剂B；
    2)经降温、保温方式析出晶体，过滤后收集晶体，干燥后制得。
  8. 根据权利要求7所述的制备方法，其中，所述溶剂A选自二氧六环和乙酸乙酯中的一种或两种，可选地为二氧六环。
  9. 根据权利要求7所述的制备方法，其中，所述溶剂B选自乙腈、甲苯、石油醚和乙醚中的一种或更多种，可选地为石油醚。
  10. 根据权利要求7所述的制备方法，其中，步骤1)中所述溶剂A的用量与地佐辛的用量比为：每克地佐辛溶解于1ml至30ml溶剂A中，可选地2ml至10ml；溶剂A与溶剂B的体积比为1:0.3至1:10，可选地为1:1至1:2.5。
  11. 根据权利要求7所述的制备方法，其中，步骤1)中加热溶解的温度为30℃至100℃，可选地为70℃至80℃。
  12. 根据权利要求7所述的制备方法，其中，步骤2)中降温析晶温度为0℃至20℃，可选地为0℃至10℃。
  13. 根据权利要求7所述的制备方法，其中，步骤2)中干燥为真空干燥，干燥温度为60℃至90℃，可选地为60℃至80℃。
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