WO2021072771A1 - 替加氟共晶体 - Google Patents

替加氟共晶体 Download PDF

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WO2021072771A1
WO2021072771A1 PCT/CN2019/112026 CN2019112026W WO2021072771A1 WO 2021072771 A1 WO2021072771 A1 WO 2021072771A1 CN 2019112026 W CN2019112026 W CN 2019112026W WO 2021072771 A1 WO2021072771 A1 WO 2021072771A1
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tegafur
eutectic
pyridyl
bis
ethylene
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PCT/CN2019/112026
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English (en)
French (fr)
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翟立海
卢元圣
马超
谢印杰
刘云娜
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山东新时代药业有限公司
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Priority to CN201980042572.7A priority Critical patent/CN114502550B/zh
Priority to PCT/CN2019/112026 priority patent/WO2021072771A1/zh
Publication of WO2021072771A1 publication Critical patent/WO2021072771A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and specifically relates to a tegafur-1,2-bis(4-pyridyl)ethylene co-crystal, a preparation method thereof, and use in preparing medicines for treating diseases.
  • Tegafur whose chemical name is 1-(tetrahydro-2-furyl)-5-fluoro-2,4(1H,3H)-pyrimidinedione, is white or off-white crystalline powder ,
  • the molecular formula is C 8 H 9 FN 2 O 3 , the molecular weight is 200, and its structural formula is as follows:
  • Tegafur is a derivative of fluorouracil.
  • Dr. Hiller a former Soviet scientist, successfully synthesized TF.
  • TF works by being degraded into fluorouracil by liver drug metabolizing enzymes and cytochrome P-450 system in the body, and its effect is the same as fluorouracil.
  • TF has the advantages of high chemotherapeutic activity (twice the 5-FU) and low toxicity (5-6 times lower than 5-FU), and is widely used in the treatment of breast cancer and gastrointestinal cancer.
  • Patent No. 855121 describes the existence of 2'R and 2'S racemic isomers of tegafur, but studies have shown that the two isomers have the same biological activity and toxicity ( YasumotoM . etal. ,” J. Med. Chem. ", 1977 , vol.41 , No. 9 , 1632-1635 ); Uchida T et al. studied the crystal form of tegafur and successfully obtained four crystal forms of ⁇ , ⁇ , ⁇ , and ⁇ ( " Chem .
  • the above four crystal forms can be obtained by simpler methods, such as: adding tegafluoride in acetone for hot melt and cold precipitation to obtain the ⁇ crystal form; the saturated methanol solution of tegafluoride can be obtained by rotary evaporation. Obtain ⁇ crystal form; ⁇ crystal form can be transformed to obtain ⁇ crystal form at 130°C; recrystallize tegafur in methanol solution and slowly evaporate at room temperature to obtain ⁇ crystal form. Although four crystal forms were successfully prepared, these four crystal forms did not significantly improve the physical and chemical properties of tegafur, nor did it greatly improve its therapeutic effect.
  • the configuration or crystal form screening does not improve the efficacy of tegafur or reduce its toxicity.
  • Tegafur is currently used in combination with uracil.
  • Kagawa Y. et al. confirmed that tegafur and uracil Mixing with a molar ratio of 1:4 can effectively improve the curative effect of tegafur ( " Cancer Investigation " , Vol.13, No.5, 470-474 ); Sanchiz F et al. invented a combination of tegafur, folic acid and uracil Compound ( " Jpn . Journal Clin. Oncol. " , 1994, vol. 24, No. 6, 322-326 ) to improve the bioavailability of tegafur.
  • one aspect of the present invention provides a tegafur-1,2-bis(4-pyridyl)ethylene co-crystal with high stability and solubility.
  • the co-crystal has exact crystallographic main parameters and Atomic space position; another aspect of the present invention provides a method for preparing the co-crystal.
  • the present invention provides a tegafluoride-1,2-bis(4-pyridyl)ethylene co-crystal, in which tegafluoride and 1,2-bis(4-pyridyl) The molar ratio of ethylene is 1:1.
  • One tegafluoride molecule and one 1,2-bis(4-pyridyl)ethylene molecule constitute the basic structural unit of the eutectic. The specific structure is shown in Formula I:
  • the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal uses Cu-K ⁇ radiation, and the X-ray diffraction spectrum expressed in 2 ⁇ is at 6.26 ⁇ 0.2, 9.30 ⁇ 0.2°, 11.89 ⁇ 0.2°, 12.60 ⁇ 0.2°, 14.79 ⁇ 0.2°, 20.28 ⁇ 0.2°, 23.98 ⁇ 0.2° have characteristic peaks.
  • the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal uses Cu-K ⁇ radiation, and the X-ray diffraction spectrum expressed in 2 ⁇ is at 6.26 ⁇ 0.2°, 9.30 ⁇ 0.2° , 10.59 ⁇ 0.2°, 11.89 ⁇ 0.2°, 12.60 ⁇ 0.2°, 14.79 ⁇ 0.2°, 18.74 ⁇ 0.2°, 19.14 ⁇ 0.2°, 20.28 ⁇ 0.2°, 21.39 ⁇ 0.2°, 22.32 ⁇ 0.2°, 23.98 ⁇ 0.2° , 26.43 ⁇ 0.2° has a characteristic peak.
  • the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal uses Cu-K ⁇ radiation, and its characteristic peaks conform to the X-ray powder diffraction pattern shown in FIG. 1.
  • the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal has an endothermic peak in the differential scanning calorimetry curve (DSC), and the corresponding temperature range is 133.55 ⁇ 153.13°C , Preferably 142.73°C.
  • DSC differential scanning calorimetry curve
  • the present invention provides a method for preparing tegafur-1,2-bis(4-pyridyl)ethylene co-crystal, and the specific preparation steps include:
  • the preparation step includes: adding tegafluoride and 1,2-bis(4-pyridyl)ethylene into the organic solvent A, heating and stirring to dissolve, and then continuing the heat preservation reaction, the reaction is over, filtering, and the filtrate is slowly reduced to room temperature ; Place the filtrate in a beaker, seal with a parafilm, puncture the holes, volatilize, crystallize, filter, and dry under reduced pressure to obtain tegafluoro-1,2-bis(4-pyridyl)ethylene co-crystal.
  • the molar ratio of the tegafur to 1,2-bis(4-pyridyl)ethylene is 1:1 to 1.5, preferably 1:1.1.
  • the organic solvent A is one or two of acetonitrile, acetone, methanol, and ethanol, preferably methanol.
  • the mass-volume ratio of the tegafur and the organic solvent A is 1:80 ⁇ 120, g/ml.
  • the heating and dissolving temperature is 30-50°C.
  • the heat preservation reaction time is 1 to 3 hours; the heat preservation reaction temperature is 30-50°C.
  • the slow cooling method of the filtrate is program cooling, and preferably, the cooling rate is 0.5° C./min.
  • the present invention provides a pharmaceutical composition containing the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal of the present invention and other pharmaceutically acceptable components.
  • the other pharmaceutically acceptable components include other active ingredients, excipients, fillers and the like that can be used in combination.
  • the pharmaceutical composition of the present invention can be prepared using the following method: using standard and conventional techniques, the compound of the present invention is combined with a pharmacologically acceptable solid or liquid carrier, and arbitrarily combined with a pharmacologically acceptable The adjuvants and excipients are combined to prepare usable dosage forms.
  • the pharmaceutical composition is spray, tablet, capsule, powder injection, liquid injection and the like.
  • the present invention provides an application of tegafur-1,2-bis(4-pyridyl)ethylene co-crystal as an active ingredient in the preparation of an antitumor drug.
  • the X-ray crystal data was collected on a Rigaku XtaLAB Synergy model instrument at a test temperature of 293(2) K, and CuKa radiation was used to collect the data in an ⁇ scan mode and perform L p correction.
  • the structure is analyzed by the direct method, and the difference Fourier method is used to find all non-hydrogen atoms. All hydrogen atoms on carbon and nitrogen are obtained by theoretical hydrogenation, and the structure is refined by the least square method.
  • the crystallographic data obtained by testing and analyzing the tegafur crystals prepared by the present invention are (Table 1):
  • the molecular formula is: C 20 H 19 FN 4 O 3 , and the molecular weight is: 382.28.
  • FIG. 3 The packing diagram of the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal of the present invention is shown in FIG. 3.
  • the ORTEP diagram of the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal of the present invention ( Figure 4) shows that the co-crystal of the present invention consists of a molecule of active pharmaceutical ingredient tegafur and a molecule of co-crystal ligand 1 ,2-bis(4-pyridyl)ethylene is combined under the force of NH...N hydrogen bond.
  • X-ray powder diffraction test instrument and test conditions of the present invention X-ray powder diffractometer: PANalytical E; Cu-K ⁇ ; sample stage: flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kv, current 40mA; divergence Slit: 1/4; Anti-scattering slit: 1; Sola slit: 0.04 rad; Step length: 0.5s; Scan range: 3 ⁇ 50°.
  • the samples prepared by the scheme of the present invention have the same crystallographic parameters and X-ray powder diffraction spectrum.
  • TGA/DSC thermal analysis tester and test conditions of the present invention TGA/DSC thermal analyzer: METTLER TOLEDO TGA/DSC3+; dynamic temperature section: 30 ⁇ 300°C; heating rate: 10°C/min; program gas N 2 ; Gas flow rate: 50mL/min; crucible: aluminum crucible 40 ⁇ l.
  • the DSC/TGA chart result of the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal prepared by the method of the present invention is shown in Figure 2.
  • the differential scanning calorimetry (DSC) only contains An endothermic peak with a temperature range of 133.55 ⁇ 153.13°C and a peak value of 142.73°C.
  • the present invention provides a new tegafur-1,2-bis(4-pyridyl)ethylene co-crystal, which has certain crystallographic main parameters and exact atomic spatial positions; the present invention provides the The preparation method of the co-crystal is simple to operate, and the obtained crystal yield and purity are relatively high; the tegafluoro-1,2-bis(4-pyridyl)ethylene co-crystal of the present invention has good stability and high Solubility and dissolution rate can increase the bioavailability of tegafur and improve the efficacy, which is suitable for large-scale promotion and application.
  • Figure 1 X-ray powder diffraction pattern of tegafur co-crystal.
  • Figure 3 Single crystal diffraction stacking pattern of tegafur eutectic.
  • FIG. 4 ORTEP diagram of tegafur eutectic.
  • CN104496972A was prepared by the method of Example 1 disclosed in CN104496972A.
  • solubility of the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal of the present invention is significantly better than that of tegafur ⁇ crystal form and tegafur-isonicotinamide co-crystal.
  • Examples 1 to 6 of the present invention have similar solubility test results.
  • the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal provided by the present invention effectively improves the physicochemical properties of tegafur, provides for reducing the toxic and side effects of tegafur and improving its biological activity. It's possible.

Abstract

提供一种替加氟-1，2-二(4-吡啶基)乙烯共晶，涉及晶型药物分子技术领域。该替加氟共晶使用Cu-Kα辐射，以2θ表示的X射线衍射谱图在6.26±0.2°，9.30±0.2°，11.89±0.2°，12.60±0.2°，14.79±0.2°，20.28±0.2°，23.98±0.2°，26.43±0.2°有特征峰；晶体学测量参数是：三斜晶系，手性空间群为P-1；晶胞参数为：a=5.1391（4）Å，b=9.7392（7）Å，c=13.9658（10）Å，α＝96.008(6)°，β＝92.368(7)°，γ＝103.481(7)°，晶胞体积 V=674.44（9）Å3 并提供了相关制备方法和应用。所述替加氟-1，2-二(4-吡啶基)乙烯共晶的稳定性好，并且具有较高的溶解度及溶出速率。

Description

替加氟共晶体 技术领域
本发明属于药物化学的技术领域，具体涉及一种替加氟-1,2-二(4-吡啶基)乙烯共晶体及其制备方法与在制备治疗疾病药物中的用途。
 背景技术
替加氟(Tegafur，TF)，其化学名为1-(四氢-2-呋喃基)-5-氟-2,4(1H,3H)-嘧啶二酮，为白色或类白色结晶性粉末，分子式为C 8H 9FN 2O 3，分子量为200，其结构式如下所示：
Figure 279380dest_path_image001
。
替加氟属于氟尿嘧啶衍生物，1968年，前苏联科学家Hiller博士成功合成TF。TF是通过在体内被肝脏药物代谢酶及细胞色素P-450***所降解转变为氟尿嘧啶而起作用，其作用与氟尿嘧啶相同。TF具有高化学治疗活性（5-FU的两倍）和低毒性（比5-FU低5-6倍）等优点，并且广泛用于乳腺癌和胃肠道癌的治疗。
替加氟虽然在抗肿瘤治疗中被广泛应用，但其仍然存在着比较严重的骨髓抑制，损伤人体等副作用，因此研究者仍然在不断的研究寻找降低其毒性或提高其生物利用度方式。专利No.855121中描述了替加氟存在2’R和2’S的消旋异构体，但有研究表明两种异构体生物活性、毒性一样( YasumotoM . etal. ，” J. Med. Chem. ”， 1977 ， vol.41 ， No.9 ， 1632-1635)；Uchida T等人对替加氟的晶型进行了研究并成功得到了其α、β、γ、δ四种晶型( “ Chem. Pharm. Bull. ”， Vol.41 ， No.9 ， 1623-1625)。上述4种晶型均可以通过较简便的方法获得，比如：将在替加氟加入在丙酮中进行热溶冷析即可获得α晶型；将饱和的替加氟甲醇溶液通过旋转蒸发即可以获得β晶型；β晶型在130℃下可以转晶获得γ晶型；将替加氟在甲醇溶液中重结晶并室温下缓慢蒸发可获得δ晶型。虽然成功制备了四种晶型，但是这四种晶型并未显著的改善替加氟的理化性质，也并未对其治疗效果有很大的提升。
综上，构型或晶型筛选并没有较好的提高替加氟的疗效或降低其毒性，替加氟目前被用于与尿嘧啶联合应用，例如，KagawaY.等证实替加氟与尿嘧啶以摩尔比1:4混合后能有效提高替加氟的疗效( “ Cancer Investigation ” , Vol.13, No.5, 470-474) ；Sanchiz F等发明了替加氟、叶酸及尿嘧啶组成的复方( “ Jpn . Journal Clin.Oncol. ” ,1994,vol.24,No.6,322-326)，以提高替加氟的生物利用度。由于尿嘧啶本身具有一定的毒性，Fujita H等指出替加氟与胸腺嘧啶、腺苷、胸苷等联合使用时毒性降低更明显( Experimental and Clinical Pharmacotherapy ， Issue 12 ， Riga ， 1983 ， p.205)。美国专利US6,538,001报道当替加氟与甲基尿嘧啶以1:2或1:1形成分子配合物后能提高替加氟的溶解性与生物利用度。Srinivasulu A.等人报道了替加氟与烟酰胺、异烟酰胺、邻苯二酚、茶碱、对-羟基苯甲酸的共晶体的研究，虽然成功制备了共晶体，但是并没有表现出令人惊喜的理化性质（ Crystal Growth&Design 2014,14,12,6557-6569）。目前，联合用药是一种提高替加氟的生物利用度的有效方法，因此需要发展寻求替加氟的复方共用方案，以此提高替加氟的溶出（dissolution）、溶解度和/或增加其生物利用度，以期降低替加氟的毒副作用。
技术问题
针对现有技术的问题，本发明一方面提供一种稳定性及溶解度高的替加氟-1,2-二(4-吡啶基)乙烯共晶体，该共晶具有确切的晶体学主要参数及原子空间位置；本发明另一方面提供了该共晶的制备方法。
 技术解决方案
本发明的具体技术内容如下：
第一方面，本发明提供了一种替加氟-1,2-二(4-吡啶基)乙烯共晶体，所述共晶体中，替加氟与1,2-二(4-吡啶基)乙烯的摩尔比为1:1，一个替加氟分子和一个1,2-二(4-吡啶基)乙烯分子构成共晶的基本结构单元，具体结构如式I：
Figure 855855dest_path_image002
。
优选地，所述的替加氟-1,2-二(4-吡啶基)乙烯共晶体，使用Cu-Kα辐射，以2θ表示的X射线衍射谱图在6.26±0.2，9.30±0.2°，11.89±0.2°，12.60±0.2°，14.79±0.2°，20.28±0.2°，23.98±0.2°有特征峰。
优选地，所述的替加氟-1,2-二(4-吡啶基)乙烯共晶体，使用Cu-Kα辐射，以2θ表示的X射线衍射谱图在6.26±0.2°，9.30±0.2°，10.59±0.2°，11.89±0.2°，12.60±0.2°，14.79±0.2°，18.74±0.2°，19.14±0.2°，20.28±0.2°，21.39±0.2°，22.32±0.2°，23.98±0.2°，26.43±0.2°有特征峰。
优选地，所述的替加氟-1,2-二(4-吡啶基)乙烯共晶体，使用Cu-Kα辐射，其特征峰符合如图1所示的X射线粉末衍射图谱。
优选地，所述的替加氟-1,2-二(4-吡啶基)乙烯共晶体，其在差示扫描量热曲线(DSC)中存在吸热峰，对应温度范围为133.55~153.13℃，优选为142.73℃。
优选地，所述的替加氟-1,2-二(4-吡啶基)乙烯共晶体，其晶体学参数是：三斜晶系，手性空间群为P-1；晶胞参数为：a=5.1391(4)Å，b=9.7392(7)Å，c=13.9658(10)Å，α=96.008(6)°，β=92.368(7)°，γ=103.481(7)°，晶胞体积V=674.44(9)Å 3。
第二方面，本发明提供一种替加氟-1,2-二(4-吡啶基)乙烯共晶的制备方法，具体制备步骤包括：
将替加氟、1,2-二(4-吡啶基)乙烯加入有机溶剂A中，加热搅拌溶清后，继续保温反应，反应结束，过滤，挥发，结晶，过滤，干燥得替加氟-1,2-二(4-吡啶基)乙烯共晶。
优选地，制备步骤包括：将替加氟、1,2-二(4-吡啶基)乙烯加入有机溶剂A中，加热搅拌溶清后，继续保温反应，反应结束，过滤，滤液缓慢降至室温；将滤液置于烧杯中，封口膜封口，扎孔，挥发，结晶，过滤，减压干燥得替加氟-1,2-二(4-吡啶基)乙烯共晶。
优选地，所述替加氟与1,2-二(4-吡啶基)乙烯的投料摩尔比为1：1~1.5，优选1:1.1。
优选地，所述有机溶剂A为乙腈、丙酮、甲醇、乙醇中的一种或两种，优选甲醇。
优选地，所述替加氟与有机溶剂A的质量体积比为1:80~120，g/ml。
优选地，所述加热溶解温度为30~50℃。
优选地，所述保温反应时间为1~3小时；所述保温反应温度为30~50℃。
在一优选方案中，所述的滤液缓慢降温方式为程序降温，优选地，降温速率为0.5℃/min。
第三方面，本发明提供一种药物组合物，该组合物含本发明所述的替加氟-1,2-二(4-吡啶基)乙烯共晶和其它药学上接受的组分。
优选地，所述的其它药学上接受的组分包括可联合使用的其它活性成分、赋形剂、填充剂等。
优选地，本发明的药物组合物可使用如下方法制备：使用标准和常规的技术，使本发明化合物与制剂学上可接受的固体或液体载体结合，以及使之任意地与制剂学上可接受的辅助剂和赋形剂结合制备成可用剂型。
优选地，所述的药物组合物为喷雾剂、片剂、胶囊剂、粉针剂、液体注射剂等。
第四方面，本发明提供一种替加氟-1,2-二(4-吡啶基)乙烯共晶作为活性成分制备治疗抗肿瘤药物中的应用。
晶体结构的确认
X射线晶体数据在日本理学XtaLAB Synergy型号仪器上收集，测试温度293(2) K，用CuKa辐射，以ω扫描方式收集数据并进行 Lp校正。用直接法解析结构，差值傅里叶法找出全部非氢原子，所有碳及氮上的氢原子采用理论加氢得到，采用最小二乘法对结构进行精修。
测试及解析本发明制备的替加氟晶体所得晶体学数据是(表1):其晶体学参数是：三斜晶系，手性空间群为P-1；晶胞参数为：a=5.1391(4)Å，b=9.7392(7)Å，c=13.9658(10)Å，α=96.008(6)°，β=92.368(7)°，γ=103.481(7)°，晶胞体积V=674.44(9)Å 3。分子式是：C 20H 19FN 4O 3，分子量是：382.28。本发明的替加氟-1,2-二(4-吡啶基)乙烯共晶体的堆积图如附图3所示。本发明的替加氟-1,2-二(4-吡啶基)乙烯共晶的ORTEP图(图4)表明本发明共晶由一分子活性药物成分替加氟与一分子共晶配体1,2-二(4-吡啶基)乙烯在N-H…N氢键作用力下结合而成。
Figure 47802dest_path_image003
本发明中X-射线粉末衍射测试仪器及测试条件：X-射线粉末衍射仪:PANalytical E；Cu-Kα；样品台：平板；入射光路:BBHD；衍射光路：PLXCEL；电压45kv，电流40mA；发散狭缝:1/4； 防散射狭缝:1；索拉狭缝:0.04 rad；步长：0.5s；扫描范围：3～50°。
依据晶体学数据，其对应的X射线粉末衍射图（Cu-Kα）中特征峰详见附图1及表2。
Figure 393333dest_path_image004
本发明方案制备的样品具有相同的晶体学参数及X射线粉末衍射谱图。
本发明中TGA/DSC热分析测试仪及测试条件：TGA/DSC热分析仪:METTLER TOLEDO TGA/DSC3+；动态温度段：30~300℃；加热速率：10℃/min；程序段气体N 2；气体流量：50mL/min；坩埚：铝坩埚40μl。
本发明所述方法制备的替加氟-1,2-二(4-吡啶基)乙烯共晶体，其DSC/TGA图谱结果如附图2所示，差示扫描量热曲线(DSC)中只有一个吸热峰，其温度范围为133.55~153.13°C，峰值为142.73°C。
 有益效果
本发明提供了一种新的的替加氟-1,2-二(4-吡啶基)乙烯共晶，该共晶体具有确定的晶体学主要参数及确切的原子空间位置；本发明提供的该共晶的制备方法操作简单，制得的晶体收率及纯度较高；本发明的替加氟-1,2-二(4-吡啶基)乙烯共晶的稳定性好，并且具有较高的溶解度及溶出速率，进而可增加替加氟的生物利用度，提高药效，适于大规模推广应用。
 附图说明
图1 替加氟共晶的X射线粉末衍射图谱。
图2 替加氟共晶的差示扫描量热曲线(DSC)及热分析（TGA）图。
图3 替加氟共晶的单晶衍射堆积图。
图4 替加氟共晶的ORTEP图。
 本发明的实施方式
下面通过实施例来进一步说明本发明，应该正确理解的是：本发明的实施例仅仅是用于说明本发明，而不是对本发明的限制，所以，在本发明的方法前提下对本发明的简单改进均属本发明要求保护的范围。
本发明实验中所使用的替加氟原料（β晶型，纯度99.91%）、1,2-二(4-吡啶基)乙烯均为市售产品，替加氟-异烟酰胺共晶根据专利CN104496972A公开的实施例1的方法制备获得。
实施例 1
将替加氟(2.02 g)、1,2-二(4-吡啶基)乙烯(2.01 g)加入甲醇(200 ml)中，40℃加热搅拌溶清后，继续保持40℃反应1小时，反应结束，过滤，滤液以0.5℃/min的速率降至室温；将滤液置于烧杯中，封口膜封口，扎孔，挥发，结晶1天，过滤，减压干燥得替加氟-1,2-二(4-吡啶基)乙烯共晶，收率95%，纯度：99.94%。
实施例 2
将替加氟(2.04 g)、1,2-二(4-吡啶基)乙烯(1.82 g)加入甲醇(200 ml)中，40℃加热搅拌溶清后，继续保持40℃反应1小时，反应结束，过滤，滤液以0.5℃/min的速率降至室温；将滤液置于烧杯中，封口膜封口，扎孔，挥发，结晶1天，过滤，减压干燥得替加氟-1,2-二(4-吡啶基)乙烯共晶，收率87%，纯度：99.86%。
实施例 3:
将替加氟(2.05 g)、1,2-二(4-吡啶基)乙烯(2.73 g)加入甲醇(240 ml)中，40℃加热搅拌溶清后，继续保持40℃反应1小时，反应结束，过滤，滤液以0.5℃/min的速率降至室温；将滤液置于烧杯中，封口膜封口，扎孔，挥发，结晶1天，过滤，减压干燥得替加氟-1,2-二(4-吡啶基)乙烯共晶，收率90%，纯度：99.88%。
实施例 4
将替加氟(2.03 g)、1,2-二(4-吡啶基)乙烯(2.01 g)加入丙酮(160 ml)中，30℃加热搅拌溶清后，继续保持30℃反应1小时，反应结束，过滤，滤液以0.5℃/min的速率降至室温；将滤液置于烧杯中，封口膜封口，扎孔，挥发，结晶1天，过滤，减压干燥得替加氟-1,2-二(4-吡啶基)乙烯共晶，收率92%，纯度：99.91%。
实施例 5
将替加氟(2.02 g)、1,2-二(4-吡啶基)乙烯(2.02 g)加入乙醇(220 ml)中，45℃加热搅拌溶清后，继续保持45℃反应2小时，反应结束，过滤，滤液以0.5℃/min的速率降至室温；将滤液置于烧杯中，封口膜封口，扎孔，挥发，结晶2天，过滤，减压干燥得替加氟-1,2-二(4-吡啶基)乙烯共晶，收率91%，纯度：99.92%。
实施例 6
将替加氟(2.04 g)、1,2-二(4-吡啶基)乙烯(2.03 g)加入乙腈(240 ml)中，50℃加热搅拌溶清后，继续保持50℃反应3小时，反应结束，过滤，滤液以0.5℃/min的速率降至室温；将滤液置于烧杯中，封口膜封口，扎孔，挥发，结晶3天，过滤，减压干燥得替加氟-1,2-二(4-吡啶基)乙烯共晶，收率89%，纯度：99.90%。
 工业实用性
稳定性实验
具体的稳定性试验方法参照中国药典2015版第四部规定的稳定性考察的指导方法进行，具体的实验条件及结果见表3。
Figure 746954dest_path_image005
通过实验结果可以看出，本发明制备得到的替加氟-1,2-二(4-吡啶基)乙烯共晶体在光照、高温及高湿的条件下其纯度、外观均未发生比较明显的变化，表现出较好的稳定性；而现有技术的β晶型及替加氟-异烟酰胺共晶在相同的实验条件下其纯度都有相对的大幅降低，其杂质含量都有较明显的升高。本发明实施例1~6具有类似的稳定性试验结果。
溶解度测试
溶解度测试方法具体为：分别量取10ml的介质(水、0.01mol/L HCl溶液和pH=6.8的磷酸盐缓冲液)于西林瓶中，加入过量的待测样品，将西林瓶密封置于25℃恒温水浴中搅拌1小时，经0.45μm滤膜过滤，取滤液；在271nm的波长处分别测定吸光度，通过HPLC测试标准对照品的吸光度来计算其溶解度，结果见表4。
Figure 545146dest_path_image006
通过溶解度测试结果看出，本发明的替加氟-1,2-二(4-吡啶基)乙烯共晶的溶解度明显优于替加氟β晶型及替加氟-异烟酰胺共晶。本发明实施例1~6具有类似的溶解度试验结果。
溶出速率测试
本实验在装备有VK750D的加热循环器的VK7010（美国瓦里安公司）溶出仪中进行，大约500mg的样品被压缩进0.5cm 2的圆盘中，采用美国药典认证的电动旋转盘内溶模，在压力为5吨的液压机上工作5分钟。在整个实验过程中，只有磁盘的一面被暴露于溶媒中，圆盘的表面是恒量的。将本样品放入装有900mL磷酸盐缓冲液(pH 6.8)的罐中，37℃预热，50rpm搅拌。每隔一定时间，手动抽取2 mL样品。采集的样品经过0.4μm尼龙膜过滤，使用HPLC对各品的校准曲线进行分析。在PH=6.8的磷酸盐缓冲液中，在271nm的波长处测定吸光度。
Figure 275204dest_path_image007
通过溶出速率测试实验可以看出，本发明制备的替加氟-1,2-二(4-吡啶基)乙烯共晶相较于现有技术公开的替加氟β晶型和替加氟-异烟酰胺共晶溶出快。本发明实施例1~6具有类似溶出速率试验结果。
综上，本发明提供的替加氟-1,2-二(4-吡啶基)乙烯共晶有效的改善了替加氟的理化性质，为降低替加氟的毒副作用及提高其生物活性提供了可能。

Claims (10)

  1. 一种替加氟共晶，其特征在于，所述共晶由活性药物成分替加氟与共晶配体1,2-二(4-吡啶基)乙烯构成。
  2. 如权利要求1所述的替加氟共晶，其特征在于，所述共晶基本单元由一个替加氟分子和一个1,2-二(4-吡啶基)乙烯分子构成，其晶体学参数是：三斜晶系，手性空间群为P-1；晶胞参数为：a=5.1391(4)Å，b=9.7392(7)Å，c=13.9658(10)Å，α=96.008(6)°，β=92.368(7)°，γ=103.481(7)°，晶胞体积V=674.44(9)Å 3，结构如下所示：
    Figure 836875dest_path_image001
    。
  3. 如权利要求1所述的替加氟共晶，其特征在于，所述共晶使用Cu-Kα辐射，以2θ表示的X射线衍射谱图在6.26±0.2°，9.30±0.2°，11.89±0.2°，12.60±0.2°，14.79±0.2°，20.28±0.2°，23.98±0.2°有特征峰。
  4. 如权利要求1所述的替加氟共晶，其特征在于，所述共晶使用Cu-Kα辐射，以2θ表示的X射线衍射谱图在6.26±0.2°，9.30±0.2°，10.59±0.2°，11.89±0.2°，12.60±0.2°，14.79±0.2°，18.74±0.2°，19.14±0.2°，20.28±0.2°，21.39±0.2°，22.32±0.2°，23.98±0.2°，26.43±0.2°有特征峰。
  5. 如权利要求1所述的替加氟共晶，其特征在于，所述共晶具有如图1所示的X-射线粉末衍射图谱。
  6. 一种制备权利要求1-5任一项所述的替加氟共晶的方法，其特征在于，所述方法包括以下步骤：将替加氟、1,2-二(4-吡啶基)乙烯加入有机溶剂A中，加热搅拌溶清后，继续保温反应，反应结束，过滤，滤液挥发结晶，过滤，干燥得替加氟-1,2-二(4-吡啶基)乙烯共晶。
  7. 根据权利要求6所述的替加氟共晶的制备方法，其特征在于，所述替加氟与1,2-二(4-吡啶基)乙烯的投料摩尔比为1：1~1.5。
  8. 根据权利要求6所述的替加氟共晶的制备方法，其特征在于，所述有机溶剂A为乙腈、丙酮、甲醇、乙醇中的一种或两种；所述替加氟与有机溶剂A的质量体积比为1:80~120，g/ml。
  9. 根据权利要求6所述的替加氟共晶的制备方法，其特征在于，所述加热溶解温度为30~50℃；所述保温反应温度为30~50℃。
  10. 权利要求1-5任一项所述的替加氟共晶作为活性成分制备抗肿瘤药物的应用。
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