WO2021129651A1 - 2-[4-[(e)-(2-酮环己烯基)甲基]苯基]丙酸的晶型及其制备方法 - Google Patents

2-[4-[(e)-(2-酮环己烯基)甲基]苯基]丙酸的晶型及其制备方法 Download PDF

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WO2021129651A1
WO2021129651A1 PCT/CN2020/138563 CN2020138563W WO2021129651A1 WO 2021129651 A1 WO2021129651 A1 WO 2021129651A1 CN 2020138563 W CN2020138563 W CN 2020138563W WO 2021129651 A1 WO2021129651 A1 WO 2021129651A1
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methyl
crystal form
ketocyclohexenyl
phenyl
propionic acid
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PCT/CN2020/138563
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French (fr)
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袁威冠
宁虎林
谭军华
王谦志
肖稳定
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湖南九典制药股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/38—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups having unsaturation outside the aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention belongs to the field of medical synthesis, and specifically relates to the crystal form of 2-[4-[(E)-(2-ketocyclohexenyl)methyl]phenyl]propionic acid and a preparation method thereof.
  • Pebiprofen also known as Pelubiprofen
  • the chemical name is 2-[4-[(E)-(2-ketocyclohexenyl)methyl]phenyl]propionic acid, CAS number: 69956-77-0
  • the molecular formula is C 16 H 18 O 3
  • the molecular weight is 258.32
  • the structural formula is shown in the following formula
  • Pebiprofen is a non-steroidal analgesic and anti-inflammatory agent (NSAIDs), derived from 2-phenylpropionic acid intermediates, so it is a member of the 2-arylpropionic acid family, which is also a racemic Prodrug has analgesic and anti-inflammatory effects. According to reports, Pebiprofen has higher pharmacological effects and tolerability than other non-steroidal anti-inflammatory, analgesic and antipyretic drugs such as loxoprofen, ketoprofen, ibuprofen and naproxen.
  • NSAIDs non-steroidal analgesic and anti-inflammatory agent
  • Pebiprofen is a non-steroidal anti-inflammatory drug (NSAIDs), a prodrug of 2-arylpropionic acid, and has a relatively selective effect on cyclooxygenase-2 activity.
  • NSAIDs non-steroidal anti-inflammatory drug
  • the four metabolites of Pebiprofen include saturated ketones (M-A), unsaturated alcohols (M-B), cis alcohols (M-C) and trans alcohols (M-D).
  • M-A saturated ketones
  • M-B unsaturated alcohols
  • M-C cis alcohols
  • M-D trans alcohols
  • the main metabolites in human plasma are M-B, M-C and M-D, with half-lives (t1/2) of 0.9, 2.6 and 1.2h, respectively.
  • the total recovery rate of urine was 26% of the dose, but the change of CS-670 was less than 2% within 48 hours.
  • the absolute configuration of the metabolites was detected by HPLC. The results showed that Pebiprofen can easily pass the chiral transformation of the 2-arylpropionic acid moiety and the ⁇ , ⁇ -unsaturated ketone moiety in humans. The stereoselective reduction of biotransformation.
  • Pebiprofen compounds were first disclosed in Japanese Patent Registration No. 1167548 (Japanese Patent Application No. 1977-98121) and Japanese Patent Registration No. 1637767 (Japanese Patent Application No. 1984-14257). There are many reports on the synthetic route of pebbiprofen compounds in the literature, but there are no relevant reports on the crystal form of pebbiprofen and its preparation method. The preparation method of the original compound of Pebiprofen also does not mention the related technology in the patent US4254274A, but white crystals are obtained in the examples, and the solidification temperature is 106 ⁇ 108°C. There is no relevant powder diffraction pattern disclosed.
  • the main purpose of this application is to provide the crystal form of 2-[4-[(E)-(2-ketocyclohexenyl)methyl]phenyl]propionic acid, because there is no related to Pebiprofen in the prior art.
  • crystal form I the crystal form of the present invention. After research, our inventors found that this crystal form meets various requirements in the field of preparations and is a crystalline substance with advantageous properties.
  • pharmaceutical active substances should have high stability, and this stability should be ensured even in different environments.
  • This stability includes the stability of the pharmaceutical composition during the process and the stability of the final storage form of the pharmaceutical composition Sex.
  • the moisture absorption effect will reduce the content of pharmaceutical active substances. Therefore, moisture absorption should be paid attention to during storage.
  • the active substance is exposed to an environment that is not protected from moisture in any way, moisture absorption will reduce its content.
  • This crystal form I uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed in 2 ⁇ angles is at 8.4 ⁇ 0.2°, 12.0 ⁇ 0.2°, 15.7 ⁇ 0.2°, 19.8 ⁇ 0.2°, 24.2 ⁇ 0.2°, 26.7 ⁇ There are characteristic peaks at 0.2°, 29.3 ⁇ 0.2°.
  • this crystal form I uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed in 2 ⁇ angles is at 8.4 ⁇ 0.2°, 12.0 ⁇ 0.2°, 15.7 ⁇ 0.2°, 19.8 ⁇ 0.2°, 24.2 ⁇ 0.2° , 26.7 ⁇ 0.2°, 29.3 ⁇ 0.2°, 13.0 ⁇ 0.2°, 16.3 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.1 ⁇ 0.2°, 22.1 ⁇ 0.2°, 25.5 ⁇ 0.2°, 27.7 ⁇ 0.2°, 28.5 ⁇ 0.2° There are characteristic peaks everywhere.
  • this crystal form I uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed in 2 ⁇ angles is at 8.4 ⁇ 0.2°, 12.0 ⁇ 0.2°, 15.7 ⁇ 0.2°, 19.8 ⁇ 0.2°, 24.2 ⁇ 0.2 °, 26.7 ⁇ 0.2°, 29.3 ⁇ 0.2°, 13.0 ⁇ 0.2°, 16.3 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.1 ⁇ 0.2°, 22.1 ⁇ 0.2°, 25.5 ⁇ 0.2°, 27.7 ⁇ 0.2°, 28.5 ⁇ 0.2 °, 23.0 ⁇ 0.2°, 23.7 ⁇ 0.2°, 25.8 ⁇ 0.2°, 27.1 ⁇ 0.2°, 28.2 ⁇ 0.2°, 33.6 ⁇ 0.2°, 39.2 ⁇ 0.2°, 40.2 ⁇ 0.2°, 40.6 ⁇ 0.2°, there are characteristic peaks .
  • This crystal form I uses Cu-K ⁇ radiation, and the relative intensities of the characteristic peaks of X-ray powder diffraction expressed in 2 ⁇ angles are shown in the following table:
  • the X-ray powder diffraction pattern of the crystal form I is shown in Fig. 1, and the differential scanning thermal analysis of the crystal form I is used.
  • the obtained DSC-TGA pattern is shown in Fig. 3, and its melting point is 122.9°C.
  • the moisture content of this crystalline form I ranges from 0.01 to 0.5%, and the purity is greater than or equal to 95% by weight, preferably greater than 98% by weight, and most preferably greater than 99% by weight.
  • Another object of the present application is to provide a method for preparing the crystal form I of Pebiprofen.
  • at least one of the following solvents is selected: (i) acetone, (ii) tetrahydrofuran , (Iii) ethyl acetate, (iv) dichloromethane, (v) methyl tert-butyl ether, (vi) ethanol, (vii) toluene, (viii) acetonitrile.
  • the preparation method specifically includes the following steps: mixing powdered Pebiprofen with a solvent, then heating and stirring, then cooling for crystallization, filtering, and vacuum drying to obtain Pebiprofen crystals in a light yellow or yellow-like solid state.
  • the temperature during the stirring is 18-60°C, and the stirring time is 4-5h.
  • the crystallization temperature is -5°C-0°C.
  • Another object of the application is to provide a pharmaceutical composition prepared by this compound, which comprises Pebiprofen crystal form I and a pharmaceutically acceptable carrier.
  • the composition can be prepared into any pharmaceutically acceptable dosage form, including tablets, capsules, cataplasms and the like.
  • This application uses commercially available amorphous pebbiprofen as the starting material.
  • the crystal form I is obtained by dissolving it and recrystallizing it.
  • the X-ray powder diffraction pattern expressed at an angle of 2 ⁇ 0.2° is at 8.4°
  • the solubility and stability of the prepared crystalline form of Pebiprofen were investigated. The experiment proved that the crystalline form of Pebiprofen I has high solubility in organic solvents such as acetone and ethyl acetate, is not easy to absorb moisture, and has good stability.
  • the DSC-TGA and elemental analysis showed that the crystal form does not contain water of crystallization and is an anhydrate crystal form.
  • the new crystal form of 2-[4-[(E)-(2-ketocyclohexenyl)methyl]phenyl]propionic acid prepared in this application fills the gap of no crystal form report at present.
  • this crystal form is not easy to absorb moisture and is also very stable under high temperature and high humidity conditions, so that the safety of the drug is further improved, and the subsequent preparation process is convenient.
  • Figure 1 is an X-ray powder diffraction pattern of the crystal form I prepared in Example 1;
  • Example 2 is an X-ray powder diffraction pattern of the crystal form I prepared in Example 2;
  • Fig. 3 is a DSC-TGA chart of crystal form I prepared in Example 1;
  • Fig. 5 is a detection pattern of related substances of the crystal form I prepared in Example 1 after 10 days of high humidity;
  • Fig. 6 is a detection pattern of related substances of the crystal form I prepared in Example 1 after 10 days of irradiation.
  • the instrument model and reagent test conditions are as follows:
  • Reagent acetone, purity 99.5%, manufacturer: Hunan Huihong Reagent Co., Ltd.; reagent: ethyl acetate grade: AR, manufacturer: Hunan Huihong Reagent Co., Ltd.
  • XRD The powder X-ray diffraction patterns of various polycrystalline substances are measured by a D/MAX-RB X-ray diffractometer using a Cu-K ⁇ beam (2 ⁇ °).
  • TG/DSC Shimadzu DSC-40M (model); heating rate 10°C/min, nitrogen atmosphere, flow rate 40ml/min.
  • XRD-Powder Diffraction Test Unit The Key Laboratory of Non-ferrous Metal Materials of Ministry of Education, Central South University;
  • the DSC-TGA testing unit is: the Key Laboratory of Non-ferrous Metal Materials of the Ministry of Education, Central South University;
  • Pebiprofen crystal form I was subjected to DSC-TGA test, and it was found that there was a single peak at 122.9°C, which was a melting endothermic peak; TGA: Pebiprofen crystal form I was stable at a temperature of ⁇ 230°C. It starts to decompose at 230°C to 250°C, and decomposes rapidly above 250°C.
  • the concrete DSC test and TGA test result are shown as in Fig. 3. Perform elemental analysis on the obtained crystal form I of Pebiprofen:
  • the molecular formula of Pebiprofen is C 16 H 18 O 3 , the calculated value: H: 6.98%; C: 74.42%; O: 18.60%; The measured value of the precipitated crystal powder of Pebiprofen: H: 7.02%; C: 74.40%; O: 15.58%.
  • Example 2 The experimental equipment and conditions were the same as in Example 1, and the solvent was changed to ethyl acetate.
  • the obtained crystal form I of Pebiprofen was subjected to XRD-powder diffraction test and DSC-TGA test. The test result is shown in FIG. 2 and it is found that the crystal form obtained in Example 1 is the same crystal form.
  • the obtained crystal form I of Pebiprofen was subjected to XRD-powder diffraction test and DSC-TGA test, and it was found that the crystal form obtained in Example 1 was the same crystal form.
  • the obtained crystal form I of Pebiprofen was subjected to XRD-powder diffraction test and DSC-TGA test, and it was found that the crystal form obtained in Example 1 was the same crystal form.
  • Example 2 The experimental equipment and conditions were the same as in Example 1, and the solvent was changed to ethanol.
  • the obtained crystal form I of Pebiprofen was subjected to XRD-powder diffraction test and DSC-TGA test, and it was found that the crystal form obtained in Example 1 was the same crystal form.
  • the obtained crystal form I of Pebiprofen was subjected to XRD-powder diffraction test and DSC-TGA test, and it was found that the crystal form obtained in Example 1 was the same crystal form.
  • Example 2 The experimental equipment and conditions are the same as in Example 1, and the solvent is replaced with methyl tert-butyl ether.
  • the obtained crystal form I of Pebiprofen was subjected to XRD-powder diffraction test and DSC-TGA test, and it was found that the crystal form obtained in Example 1 was the same crystal form.
  • Example 2 The experimental equipment and conditions were the same as in Example 1, and the solvent was changed to acetonitrile.
  • the obtained crystal form I of Pebiprofen was subjected to XRD-powder diffraction test and DSC-TGA test, and it was found that the crystal form obtained in Example 1 was the same crystal form.
  • High temperature conditions 60°C, placed in an open area.
  • Illumination conditions total illuminance 1.2 ⁇ 106Lux, 25°C, near ultraviolet energy not less than 200w ⁇ hr/m, RH 60%, open.
  • Pebiprofen crystal I is not easy to be stable under ultraviolet light and may easily undergo configuration conversion. Exposure to strong light should be avoided. The specific detection spectrum is shown in Figure 6.
  • the Pebiprofen crystal I obtained in Example 1 is easily soluble in ethanol, N,N-dimethylformamide, acetonitrile and acetone, slightly soluble in absolute ethanol and ether, and almost insoluble in water. Dissolve in 0.1mol/L sodium hydroxide (4.3g is configured to 1000ml) solution.

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Abstract

本发明公开了一种新的2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸的晶型，填补了目前无晶型报道的空白。且此晶型不易吸湿、在高温、高湿条件下也很稳定，使得药物的安全性进一步得到了提高，方便了后续的制剂过程。

Description

2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸的晶型及其制备方法 【技术领域】
本发明属于医药合成领域，具体涉及2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸的晶型及其制备方法。
【背景技术】
培比洛芬(Pelubiprofen)，也有称培鲁比洛芬，化学名为2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸，CAS号：69956-77-0，分子式为C 16H 18O 3，分子量为258.32，结构式如下式所示
Figure PCTCN2020138563-appb-000001
培比洛芬是非甾体镇痛和抗炎剂(NSAIDs)，是由2-苯基丙酸中间体衍生而来，因此是2-芳基丙酸家族的成员，其也是一种外消旋前药，具有镇痛、抗炎的功效。据报道，培比洛芬比其他非甾体类抗炎镇痛解热药如洛索洛芬、酮洛芬、布洛芬和萘普生具有更高的药理作用和耐受性。培比洛芬与塞来昔布在类风湿性关节炎患者中的疗效和安全性比较的III期临床试验结果表明，培比洛芬在减轻疼痛和缓解类风湿性关节炎患者僵硬方面与塞来昔布效果相当。
培比洛芬是一种非甾体类抗炎药(NSAIDs)，是2-芳基丙酸的前药，对环氧合酶-2活性具有相对选择性的作用。LPS诱导的巨噬细胞和角叉菜胶诱导的急性炎症大鼠模型中的炎症介质的分子机制研究表明，培比洛芬参与COX活性和TAK1-IKK-NF-kB途径的双重抑制，揭示了培比洛芬的抗炎特性的分子基础。
培比洛芬4种代谢物包括饱和酮(M-A)、不饱和醇(M-B)、顺式醇(M-C)和反式醇(M-D)。人血浆中的主要代谢物是M-B，M-C和M-D，半衰期(t1/2)分别为0.9，2.6和1.2h。尿液的总回收率为剂量的26％，但在48小时内CS-670的变化不到2％。此外，用手性试剂衍生化后，通过HPLC检测代谢物的绝对构型，结果表明培比洛芬易于通过2-芳基丙酸部分的手性转化和人体中α，β-不饱和酮部分的立体选择性还原进行生物转化。
培比洛芬化合物最早公开于日本专利登记号1167548(日本专利申请号1977-98121)和日本专利登记号1637767(日本专利申请号1984-142567)中。培比洛芬化合物的合成路线文献报道很多，但是关于培比洛芬的晶型及其制备方法则没有相关报道。培比洛芬原研化合物的制备方法专利US4254274A中也没有提及到相关的技术，只是在实施例中得到了白色晶体，固化成晶温度在106～108℃，并未有公开相关的粉末衍射图谱，且国内的迄今为止的专利和文献都未有公开过培比洛芬晶型的有关数据以及其晶型的制备方法，考虑到不同晶型对化合物的理化性质等存在着重要影响，为了得到更加有效的晶型，需要对培比洛芬的结晶行为进行全面的考察，以得到满足制剂等生产要求的有利晶型。
【发明内容】
本申请的主要目的是提供2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸的晶型，由于现有技术中未有关于培比洛芬晶型的相关记载，我们称本发明的晶型为晶型I，我方发明人经过研究后发现此晶型满足在制剂领域方面的各种要求，是具有有利性质的晶体物质。
在药物制剂领域而言，药物活性物质应该具有高稳定性，即使在不同环境下亦应确保此稳定性，这个稳定性包括有药物组合物过程中的稳定性以及药物组合物最终储存形式的稳定性。另外，由于水分的吸收会引起重量增加，所以吸湿作用会降低医药活性物质的含量。因此，对于易吸湿药品在贮存过程中应该注意防潮，在生产过程中，若活性物质暴露于未以任何方式防潮的环境中，则吸湿会降低其含量。
本申请提供了2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸的晶型I，也可以称之为培比洛芬的晶型I，其结构式为：
Figure PCTCN2020138563-appb-000002
此晶型I使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图中在8.4±0.2°，12.0±0.2°，15.7±0.2°，19.8±0.2°，24.2±0.2°，26.7±0.2°，29.3±0.2°处有特征峰。
进一步的，此晶型I使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图中在8.4±0.2°，12.0±0.2°，15.7±0.2°，19.8±0.2°，24.2±0.2°，26.7±0.2°，29.3±0.2°，13.0±0.2°，16.3±0.2°，20.3±0.2°，21.1±0.2°，22.1±0.2°，25.5±0.2°，27.7±0.2°，28.5±0.2°处有特征峰。
更进一步的，此晶型I使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图中在8.4±0.2°，12.0±0.2°，15.7±0.2°，19.8±0.2°，24.2±0.2°，26.7±0.2°，29.3±0.2°，13.0±0.2°， 16.3±0.2°，20.3±0.2°，21.1±0.2°，22.1±0.2°，25.5±0.2°，27.7±0.2°，28.5±0.2°，23.0±0.2°，23.7±0.2°，25.8±0.2°，27.1±0.2°，28.2±0.2°，33.6±0.2°，39.2±0.2°，40.2±0.2°，40.6±0.2°处有特征峰。
此晶型I使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射的特征峰的相对强度如下表所示：
2θ角 相对强度I(％)
8.4±0.2° 27.0
12.0±0.2° 100.0
13.0±0.2° 14.9
15.7±0.2° 77.8
16.3±0.2° 11.3
19.8±0.2° 37.0
20.3±0.2° 18.5
21.1±0.2° 27.1
22.1±0.2° 18.6
23.0±0.2° 4.1
23.7±0.2° 7.0
24.2±0.2° 39.3
25.5±0.2° 12.7
25.8±0.2° 7.7
26.7±0.2° 37.3
27.1±0.2° 5.4
27.7±0.2° 13.7
28.2±0.2° 6.5
28.5±0.2° 16.1
29.3±0.2° 35.6
33.6±0.2° 4.4
39.2±0.2° 8.0
40.2±0.2° 5.9
40.6±0.2° 3.9
对晶型I进行X-射线粉末衍射的图谱列于图1，对晶型I使用差示扫描热分析，所得的DSC-TGA图谱列于图3，其熔点为122.9℃。
此晶型I的水分含量范围在0.01～0.5％，纯度大于或等于95％重量，优选大于98％重量，最优选大于99％重量。
本申请的另一个目的是提供此培比洛芬晶型I的制备方法，所述培比洛芬晶型I的重结晶过程中选用以下至少一种溶剂：(i)丙酮，(ii)四氢呋喃，(iii)乙酸乙酯，(iv)二氯甲烷，(v)甲基叔丁基醚，(vi)乙醇，(vii)甲苯，(viii)乙腈。
作为对上述技术方案的进一步改进：
制备方法具体包括以下步骤：将粉末状培比洛芬与溶剂混合在一起，然后升温搅拌，再降温析晶、过滤，并真空干燥得到微浅黄色或类黄色固体状态的培比洛芬晶体。
所述搅拌时的温度为18-60℃，搅拌的时间为4-5h。
所述析晶的温度为-5℃-0℃。
本申请的另一个目的是提供了此化合物制备的药物组合物，该药物组合物包括了培比洛芬晶型I和药学上可接受的载体。所述组合物可以制备成药学上可接受的任何剂型，包括有片剂、胶囊、巴布膏等。
本申请使用市售的无定型培比洛芬作为起始原料，通过对其进行溶解并重新析晶得到了晶型I，以2θ±0.2°角度表示的X-射线粉末衍射图中在8.4°，12.0°，15.7°，19.8°，24.2°，26.7°，29.3°处有特征峰，其中12.0°和15.7°两处的特征峰是强峰。对制得的培比洛芬晶型进行溶解度和稳定性的考察实验，实验证明，培比洛芬晶型I的在丙酮和乙酸乙酯等有机溶剂中溶解度大，不易吸湿，稳定性好，其DSC-TGA和元素分析表明，该晶型不含有结晶水，为无水物晶型。
本申请的有益效果在于：
本申请制备得到的2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸新晶型，填补了目前无晶型报道的空白。且此晶型具有不易吸湿、在高温、高湿条件下也很稳定，使得药物的安全性进一步得到了提高，方便了后续的制剂过程。
【附图说明】
图1是实施例1制备得到的晶型I的X-射线粉末衍射图谱；
图2是实施例2制备得到的晶型I的X-射线粉末衍射图谱；
图3是实施例1制备得到的晶型I的DSC-TGA图谱；
图4是实施例1制备得到的晶型I高温10天后的有关物质检测图谱；
图5是实施例1制备得到的晶型I高湿10天后的有关物质检测图谱；
图6是实施例1制备得到的晶型I光照10天后的有关物质检测图谱。
【具体实施方式】
下面通过具体实施例和附图对本申请作进一步详细说明。以下实施例仅对本申请进行进一步说明，不应理解为对本申请的限制。
实施例1培比洛芬的晶型I的制备
仪器型号与试剂测试条件如下：
试剂：丙酮，纯度99.5％，厂家：湖南汇虹试剂有限公司；试剂：乙酸乙酯级别：AR，厂家：湖南汇虹试剂有限公司
仪器：液相色谱仪，型号Acquity Arc System，厂家Waters；电子分析天平，型号Ms205Du，厂家：梅特勒。
XRD：各种多晶体物的粉末X-射线衍射图用Cu-Kα线束(2θ°)，通过D/MAX-RB型X射线衍射仪测得。
TG/DSC：日本岛津DSC-40M(型号)；升温速率10℃/min，氮气气氛，流量40ml/min。
XRD-粉末衍射测试单位为：中南大学有色金属材料教育部重点实验室；
DSC-TGA测试单位为：中南大学有色金属材料教育部重点实验室；
制备方法：
向反应釜中加入培比洛芬粉末100g，再加入丙酮200g，升温至40℃下搅拌4h，然后0℃下析晶搅拌12h，过滤，30℃真空干燥得到产品70g。
将获得的培比洛芬晶型I进行XRD-粉末衍射测试，以2θ角度表示的X-射线粉末衍射的特征峰的相对强度如下表所示：
2θ角 相对强度I(％)
8.4±0.2° 27.0
12.0±0.2° 100.0
13.0±0.2° 14.9
15.7±0.2° 77.8
16.3±0.2° 11.3
19.8±0.2° 37.0
20.3±0.2° 18.5
21.1±0.2° 27.1
22.1±0.2° 18.6
23.0±0.2° 4.1
23.7±0.2° 7.0
24.2±0.2° 39.3
25.5±0.2° 12.7
25.8±0.2° 7.7
26.7±0.2° 37.3
27.1±0.2° 5.4
27.7±0.2° 13.7
28.2±0.2° 6.5
28.5±0.2° 16.1
29.3±0.2° 35.6
33.6±0.2° 4.4
39.2±0.2° 8.0
40.2±0.2° 5.9
40.6±0.2° 3.9
具体如图1所示。
将获得的培比洛芬晶型I进行DSC-TGA测试，发现其存在122.9℃的单峰，是熔化吸热峰；TGA：培比洛芬晶型I在温度＜230℃阶段晶型稳定，在230℃至250℃开始分解，超过250℃快速分解。具体的DSC测试和TGA测试结果如图3所示。将获得的培比洛芬晶型I进行元素分析：
元素分析：C 16H 18O 3
培比洛芬的分子式为C 16H 18O 3，计算值：H：6.98％；C：74.42％；O：18.60％；培比 洛芬析出晶体粉末的测量值：H：7.02％；C：74.40％；O：15.58％。
实施例2培比洛芬的晶型I的制备
实验仪器和条件与实施例1相同，将溶剂换成乙酸乙酯。
制备方法：
向反应釜中加入培比洛芬粉末100g，再加入乙酸乙酯200g，升温至40℃下搅拌4h，然后-2℃下析晶搅拌12h，过滤，30℃真空干燥得到产品75g。
将获得的培比洛芬晶型I进行XRD-粉末衍射测试以及DSC-TGA测试，检测结果如图2所示，发现与实施例1所得的晶型为同一种晶型。
实施例3培比洛芬的晶型I的制备
实验仪器和条件与实施例1相同，将溶剂换成二氯甲烷。
制备方法：
向反应釜中加入培比洛芬粉末100g，再加入二氯甲烷200g，升温至33℃下搅拌4h，然后-3℃下析晶搅拌12h，过滤，30℃真空干燥得到产品80g。
将获得的培比洛芬晶型I进行XRD-粉末衍射测试以及DSC-TGA测试，发现与实施例1所得的晶型为同一种晶型。
实施例4培比洛芬的晶型I的制备
实验仪器和条件与实施例1相同，将溶剂换成四氢呋喃。
制备方法：
向反应釜中加入培比洛芬粉末100g，再加入四氢呋喃200g，升温至18℃下搅拌4h，然后-5℃下析晶搅拌12h，过滤，30℃真空干燥得到产品60g。
将获得的培比洛芬晶型I进行XRD-粉末衍射测试以及DSC-TGA测试，发现与实施例1所得的晶型为同一种晶型。
实施例5培比洛芬的晶型I的制备
实验仪器和条件与实施例1相同，将溶剂换成乙醇。
制备方法：
向反应釜中加入培比洛芬粉末100g，再加入乙醇200g，升温至50℃下搅拌4h，然后-4℃下析晶搅拌12h，过滤，30℃真空干燥得到产品68g。
将获得的培比洛芬晶型I进行XRD-粉末衍射测试以及DSC-TGA测试，发现与实施例1所得的晶型为同一种晶型。
实施例6培比洛芬的晶型I的制备
实验仪器和条件与实施例1相同，将溶剂换成甲苯。
制备方法：
向反应釜中加入培比洛芬粉末100g，再加入甲苯200g，升温至60℃下搅拌4h，然后-3℃下析晶搅拌12h，过滤，30℃真空干燥得到产品85g。
将获得的培比洛芬晶型I进行XRD-粉末衍射测试以及DSC-TGA测试，发现与实施例1所得的晶型为同一种晶型。
实施例7培比洛芬的晶型I的制备
实验仪器和条件与实施例1相同，将溶剂换成甲基叔丁基醚。
制备方法：
向反应釜中加入培比洛芬粉末100g，再加入甲基叔丁基醚200g，升温至55℃下搅拌4h，然后-5℃下析晶搅拌12h，过滤，30℃真空干燥得到产品82g。
将获得的培比洛芬晶型I进行XRD-粉末衍射测试以及DSC-TGA测试，发现与实施例1所得的晶型为同一种晶型。
实施例8培比洛芬的晶型I的制备
实验仪器和条件与实施例1相同，将溶剂换成乙腈。
制备方法：
向反应釜中加入培比洛芬粉末100g，再加入乙腈200g，升温至40℃下搅拌4h，然后-5℃下析晶搅拌12h，过滤，30℃真空干燥得到产品78g。
将获得的培比洛芬晶型I进行XRD-粉末衍射测试以及DSC-TGA测试，发现与实施例1所得的晶型为同一种晶型。
实施例9培比洛芬晶型I性质测定
1.培比洛芬晶体I化学稳定性实验
试验用样品：晶体I
A、高温试验
高温条件：60℃，敞口放置。
结果如下：
时间 培比洛芬纯度 总杂 含量
0天 99.70％ 0.30％ 99.54％
5天 99.68％ 0.32％ 100.28％
10天 99.67％ 0.33％ 100.69％
B、高湿试验
高湿条件：RH 75％，敞口放置。
结果如下：
时间 培比洛芬纯度 总杂 含量
0天 99.66％ 0.34％ 99.54％
5天 99.58％ 0.42％ 100.18％
10天 99.65％ 0.35％ 100.86％
从上述各指标变化率比较可以看出，在高温或高湿条件下，晶体都比较稳定，具体检测图谱如图4～图5所示。
C、光照试验
光照条件：总照度1.2×106Lux，25℃，近紫外能量不低于200w·hr/m，RH 60％，敞口放置。
时间 培比洛芬纯度 总杂 含量
0天 99.66％ 0.34％ 99.54％
5天 99.45％ 0.55％ 98.77％
10天 98.28％ 1.72％ 99.54％
在光照条件下，杂质增加，培比洛芬晶体I在紫外光下，不易稳定，可能易发生构型的转换，应该避免暴露在强光下，具体检测图谱如图6所示。
D、培比洛芬溶解度评价
经测试，实施例1所得到的培比洛芬晶体I在乙醇、N，N-二甲基甲酰胺、乙腈及丙酮中易溶，在无水乙醇、乙醚中微溶，在水中几乎不溶，在0.1mol/L氢氧化钠(4.3g配置成1000ml)溶液中溶解。
以上内容是结合具体的实施方式对本申请所作的进一步详细说明，不能认定本申请的具体实施只局限于这些说明。对于本申请所属技术领域的普通技术人员来说，在不脱离本申请构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本申请的保护范围。

Claims (12)

  1. 2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸的晶型，所述晶型为晶型I，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图中在8.4±0.2°，12.0±0.2°，15.7±0.2°，19.8±0.2°，24.2±0.2°，26.7±0.2°，29.3±0.2°处有特征峰。
  2. 如权利要求1所述的晶型，其特征在于，以2θ角度表示的X-射线粉末衍射图中在13.0±0.2°，16.3±0.2°，20.3±0.2°，21.1±0.2°，22.1±0.2°，25.5±0.2°，27.7±0.2°，28.5±0.2°处有特征峰。
  3. 如权利要求1或2所述的晶型，其特征在于，以2θ角度表示的X-射线粉末衍射图中在23.0±0.2°，23.7±0.2°，25.8±0.2°，27.1±0.2°，28.2±0.2°，33.6±0.2°，39.2±0.2°，40.2±0.2°，40.6±0.2°处有特征峰。
  4. 如权利要求1所述的晶型，其特征在于，衍射角2θ为12.0±0.2°的峰的相对强度大于99.5％。
  5. 如权利要求1所述的晶型，其特征在于，DSC图中的熔点是122.9℃。
  6. 一种如权利要求1至5中任一项所述2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸的晶型I的制备方法，其特征在于，所述2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸的晶型I的重结晶过程中选用以下至少一种溶剂：(i)丙酮，(ii)四氢呋喃，(iii)乙酸乙酯，(iv)二氯甲烷，(v)甲基叔丁基醚，(vi)乙醇，(vii)甲苯，(viii)乙腈。
  7. 如权利要求6所述的制备方法，其特征在于，包括以下步骤：将粉末状培比洛芬与溶剂混合，升温至18-60℃，搅拌，降温至-5℃-0℃，析晶，过滤，真空干燥，得到晶型为晶型I的2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸。
  8. 如权利要求7所述的制备方法，其特征在于，所述搅拌的时间为4-5h。
  9. 一种药物组合物，其特征在于，所述药物组合物包括2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸和药学上可接受的载体，所述2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸为如权利要求1至5中任一项所述的晶型为晶型I的2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸或者如权利要求6至8任一项所述的制备方法制备得到的晶型为晶型I的2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸。
  10. 一种2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸的组合物的制备方法，其特征在于，所述组合物中至少一部分2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸作为晶型I的形态存在，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图中在8.4±0.2°，12.0±0.2°，15.7±0.2°，19.8±0.2°，24.2±0.2°，26.7±0.2°，29.3±0.2°处有特征峰，该方法包括使2-[4-[(E) -(2-酮环己烯基)甲基]苯基]丙酸从选自以下的溶剂系统结晶：(i)丙酮，(ii)四氢呋喃，(iii)乙酸乙酯，(iv)二氯甲烷，(v)甲基叔丁基醚，(vi)乙醇，(vii)甲苯，(viii)乙腈。
  11. 一种2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸的组合物的制备方法，其特征在于，所述组合物中至少一部分2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸作为晶型I的形态存在，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图中在13.0±0.2°，16.3±0.2°，20.3±0.2°，21.1±0.2°，22.1±0.2°，25.5±0.2°，27.7±0.2°，28.5±0.2°处有特征峰，该方法包括使2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸从选自以下的溶剂系统结晶：(i)丙酮，(ii)四氢呋喃，(iii)乙酸乙酯，(iv)二氯甲烷，(v)甲基叔丁基醚，(vi)乙醇，(vii)甲苯，(viii)乙腈。
  12. 一种2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸的组合物的制备方法，其特征在于，所述组合物中至少一部分2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸作为晶型I的形态存在，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图中在23.0±0.2°，23.7±0.2°，25.8±0.2°，27.1±0.2°，28.2±0.2°，33.6±0.2°，39.2±0.2°，40.2±0.2°，40.6±0.2°处有特征峰，该方法包括使2-[4-[(E)-(2-酮环己烯基)甲基]苯基]丙酸从选自以下的溶剂系统结晶：(i)丙酮，(ii)四氢呋喃，(iii)乙酸乙酯，(iv)二氯甲烷，(v)甲基叔丁基醚，(vi)乙醇，(vii)甲苯，(viii)乙腈。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4673761A (en) * 1984-07-10 1987-06-16 Sankyo Company, Limited Process for preparing anti-inflammatory cycloalkylidenemethylphenylacetic acid derivatives
CN110041191A (zh) * 2019-04-30 2019-07-23 湖南九典宏阳制药有限公司 一种培比洛芬的纯化方法
CN111039782A (zh) * 2019-12-26 2020-04-21 湖南九典制药股份有限公司 2-[4-[（e）-（2-酮环己烯基）甲基]苯基]丙酸的晶型及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4673761A (en) * 1984-07-10 1987-06-16 Sankyo Company, Limited Process for preparing anti-inflammatory cycloalkylidenemethylphenylacetic acid derivatives
CN110041191A (zh) * 2019-04-30 2019-07-23 湖南九典宏阳制药有限公司 一种培比洛芬的纯化方法
CN111039782A (zh) * 2019-12-26 2020-04-21 湖南九典制药股份有限公司 2-[4-[（e）-（2-酮环己烯基）甲基]苯基]丙酸的晶型及其制备方法

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