WO2018196681A1 - 硝苯地平与异烟酰胺的共晶 - Google Patents

硝苯地平与异烟酰胺的共晶 Download PDF

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WO2018196681A1
WO2018196681A1 PCT/CN2018/083815 CN2018083815W WO2018196681A1 WO 2018196681 A1 WO2018196681 A1 WO 2018196681A1 CN 2018083815 W CN2018083815 W CN 2018083815W WO 2018196681 A1 WO2018196681 A1 WO 2018196681A1
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nifedipine
acid amide
isonicotinic acid
eutectic
isonicotinic
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PCT/CN2018/083815
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French (fr)
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梅雪锋
余琦慧
王建荣
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中国科学院上海药物研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • 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

Definitions

  • the invention relates to the technical field of medicinal chemistry and crystallization technology, in particular to a eutectic of nifedipine and isonicotinic acid amide, a preparation method and application thereof.
  • Nifedipine 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester
  • the chemical structural formula is as follows:
  • Nifedipine is the first antihypertensive drug for dihydropyridine calcium blockers marketed in 1975. It inhibits extracellular calcium influx by blocking calcium channels on the membrane of myocardial and vascular smooth muscle cells. , so that the intracellular calcium ion concentration is lowered, thereby achieving the effect of lowering blood pressure.
  • the dihydropyridine ring in the structure of the drug is easily oxidized to a pyridine ring to form impurities, and such impurities have a certain harmful effect on the skin.
  • Drug eutectic refers to the formation of a drug active molecule (API) with one or more ligand molecules (Co-crystal Co-formers, CCF) under weak interactions such as hydrogen bonding, van der Waals force, ⁇ - ⁇ stacking, and halogen bonding. , having a fixed ratio of co-crystals, and API, CCF, co-crystals are all solid at room temperature. As a new solid form, drug eutectic has an indispensable effect on improving the solubility, stability and mechanical properties of drugs.
  • API drug active molecule
  • CCF Co-crystal Co-formers
  • Drug eutectics have a greater advantage than other solid forms of the drug, such as polymorphs and salts.
  • the polymorphic form of the drug means that there are two or more crystal forms of the active molecule in the drug, and the solubility of the different crystal forms of the drug is generally not too different, and the eutectic is compared with the API due to the introduction of the ligand. , its solubility may increase by a dozen times.
  • a salt is a compound composed of a positive ion and a negative ion.
  • each component in the eutectic may be a neutral molecule, and the range of molecules capable of forming a eutectic is greatly expanded, and may be a food additive.
  • Preservatives, excipients, vitamins, minerals, amino acids, etc., and even other drugs, provide a diverse range of solid forms for the lack of ionizable functional groups.
  • the inventors of the present application designed and synthesized a new eutectic of nifedipine and isonicotinic acid amide, and the illumination stability of the eutectic was significantly improved compared with nifedipine, and the preparation method was simple and easy. It has good reproducibility and provides a practical means to improve the light stability of nifedipine.
  • One of the objects of the present invention is to provide a co-crystal of nifedipine and isonicotinic acid amide having improved photostability.
  • Another object of the present invention is to provide a method for preparing a cocrystal of nifedipine and isonicotinic acid amide.
  • a third object of the present invention is to provide a pharmaceutical composition comprising the above-described cocrystal of nifedipine and isonicotinic acid amide and a pharmaceutically acceptable carrier.
  • a fourth object of the present invention is to provide a use of a eutectic of nifedipine and isonicotinic acid amide for the preparation of a medicament for treating cardiovascular and cerebrovascular diseases.
  • a eutectic of nifedipine and isonicotinic acid amide wherein a molar ratio of nifedipine to isonicotinic acid amide in the eutectic of nifedipine and isonicotinic acid amide is 1 :1.
  • the X-ray powder diffraction pattern (XRPD) of the eutectic of nifedipine and isonicotinic acid amide is about 7.94° ⁇ 0.2°, 9.77° ⁇ 0.2°, 11.77° ⁇ 0.2°, 13.14° ⁇ 0.2 at 2 ⁇ angle.
  • the X-ray powder diffraction pattern of the eutectic of nifedipine and isonicotinic acid amide has an XRPD pattern substantially as shown in FIG.
  • the 2 ⁇ angle and relative intensity of each peak on the XRPD diffraction pattern may vary. Generally, the 2 ⁇ angle change is within ⁇ 0.2°, but the range may be slightly exceeded. Those skilled in the art should understand that the relative of diffraction The strength may depend, for example, on the sample preparation or the equipment used.
  • the differential scanning calorimetry spectrum of the eutectic of nifedipine and isonicotinic acid amide has a characteristic melting peak at about 157.86 ⁇ 0.2 ° C, and the eutectic of nifedipine and isonicotinic acid amide has a basic pattern.
  • Differential Scanning Calorimetry (DSC) map as shown in 4.
  • the infrared spectrum of the eutectic of nifedipine and isonicotinic acid amide is at least about 3408 cm -1 , 3291 cm -1 , 3227 cm -1 , 3093 cm -1 , 2944 cm -1 , 1693 cm -1 , 1672 cm -1 , 1523 cm - 1, 1480cm -1, 1427cm -1, 1379cm -1, 1358cm -1, 1309cm -1, 1240cm -1, 1202cm -1, 1112cm -1, 1091cm -1, 1011cm -1, 856cm -1, 829cm -1, There are characteristic peaks at 776 cm -1 , 749 cm -1 , 717 cm -1 , 626 cm -1 , and 588 cm -1 .
  • the eutectic nifedipine nicotinamide different Raman spectra at least at about 3166cm -1, 3074cm -1, 2996cm -1 , 2955cm -1, 2936cm -1, 2840cm -1, 1696cm -1, 1673cm - 1, 1641cm -1, 1577cm -1, 1503cm -1, 1362cm -1, 1215cm -1, 1055cm -1, with characteristic peaks at 1004cm -1.
  • a process for preparing a cocrystal of nifedipine and isonicotinic acid amide which is one of the following preparation methods:
  • Method one includes the following steps:
  • step (c) separating the nifedipine formed by the step (b) and the isonicotinamide to obtain a eutectic of nifedipine and isonicotinic acid amide;
  • the method 2 includes the following steps:
  • the method three includes the following steps:
  • nifedipine formed by the separation step (h) is co-crystallized with the isonicotinamide to obtain a eutectic of nifedipine and isonicotinic acid amide.
  • the organic solvent is selected from one or more of methyl isobutyl ketone, methanol, ethyl acetate, nitromethane, ethanol, and isopropyl acetate;
  • step (c) and step (f) are identical in step (c).
  • the separation includes:
  • step (c3) after separating the eutectic of nifedipine and isonicotinic acid amide by the step (c1) or (c2), further evaporating and removing the liquid solution obtained by the separation in the step (c1) or (c2), thereby obtaining nifedipine a eutectic of the ground and isonicotinic acid amide;
  • step (h)
  • the weight-to-volume ratio of the nifedipine to the organic solvent is 1 kg: (8 to 10) mL; more preferably 1 kg: (8.5 to 10) mL.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the above-described co-crystal of nifedipine and isonicotinic acid amide and a pharmaceutically acceptable carrier.
  • Another aspect of the invention relates to a eutectic of nifedipine and isonicotinic acid amide or a pharmaceutical composition comprising the co-crystal of nifedipine and isonicotinic acid amide and a pharmaceutically acceptable carrier in the preparation of a therapeutic heart
  • a eutectic of nifedipine and isonicotinic acid amide or a pharmaceutical composition comprising the co-crystal of nifedipine and isonicotinic acid amide and a pharmaceutically acceptable carrier in the preparation of a therapeutic heart
  • a pharmaceutical composition comprising the co-crystal of nifedipine and isonicotinic acid amide and a pharmaceutically acceptable carrier in the preparation of a therapeutic heart
  • the invention provides a eutectic of nifedipine and isonicotinic acid amide, the preparation method is simple, the crystallization process is easy to control, and the reproducibility is good. Compared with nifedipine itself, it not only has the medicinal activity of nifedipine, Moreover, the light stability is greatly improved, which provides a practical and feasible technical means for the storage and transportation of nifedipine.
  • SCXRD X-ray single crystal diffraction
  • Figure 2 is a X-ray powder diffraction (XRPD) diagram of the eutectic of nifedipine and isonicotinic acid amide according to Example 1 of the present invention
  • FIG. 3 is a thermogravimetric analysis (TG) diagram of the eutectic of nifedipine and isonicotinic acid amide according to Example 1 of the present invention
  • Figure 4 is a differential scanning calorimetry (DSC) chart of the eutectic of nifedipine and isonicotinic acid amide according to Example 1 of the present invention
  • Figure 5 is an infrared spectrum (IR) diagram of a eutectic of nifedipine and isonicotinic acid amide according to Example 1 of the present invention
  • Figure 6 is a Raman spectrum diagram of a eutectic of nifedipine and isonicotinic acid amide according to Example 1 of the present invention.
  • Fig. 7 is a graph showing the residual content of the light stability test of the eutectic of nifedipine and isonicotinic acid amide according to Example 1 of the present invention.
  • the instrument used for X-ray single crystal diffraction was a Bruker Smart Apex II X-ray single crystal diffractometer from Bruker Instruments.
  • the measurement conditions are graphite monochromator, Mo–K ⁇ ray
  • the test was carried out at room temperature with a test voltage of 50 kV and a current of 30 mA.
  • the data reduction and structural analysis of all single crystal structures were performed by the SAINT–5.0 and SHELXTL–97 procedures, respectively, and the absorption correction was performed by the SADABS program.
  • the non-hydrogen atom coordinates are obtained by the difference function method and the least squares method, and the hydrogen atoms are added to the appropriate positions by theoretical calculation.
  • the instrument used for X-ray powder diffraction is the Bruker D8 Advance diffractometer, which uses K ⁇ ray for Cu (line ), the voltage is 40 kV and the current is 40 mA.
  • the instrument is used to correct the peak position with the standard sample supplied with the instrument before use.
  • the acquisition software is Diffrac Plus XRD Commander and the analysis software is MDI Jade 6.0.
  • the sample is tested at room temperature and the sample to be tested is placed on an organic slide.
  • the detailed detection conditions are as follows: 2 ⁇ angle range: 3 to 40°; step size: 0.02°; speed: 0.1 second/step. Samples were not ground prior to testing unless otherwise stated.
  • thermogravimetric analysis (TGA) data was obtained from TG20F3 type of German Benz Scientific Instrument Co., Ltd., the instrument control software is NETZSCH-Proteus-6, and the analysis software is Proteus Analysis.
  • the sample was raised from room temperature to 400 ° C under the protection of 50 mL/min dry dry nitrogen at a temperature increase rate of 10 ° C/min, while software recorded the change in weight of the sample during the temperature increase.
  • the differential thermal analysis (DSC) data was obtained from the TA Instruments Q2000 Differential Scanning Calorimeter from TA Instruments, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis.
  • the sample was raised from room temperature to 200 ° C under the protection of 50 mL/min dry nitrogen at a temperature increase rate of 10 ° C/min, while the TA software recorded the change in heat of the sample during the temperature increase.
  • IR Infrared analysis
  • Raman spectroscopy was performed at room temperature using a DXR micro-Raman spectrometer from Thermo Scientific, USA, and the detection range was: 3500-50 cm -1 Raman shift.
  • the reagents such as isonicotinic acid amide, methyl isobutyl ketone and methanol are all analytically pure and provided by Sinopharm Chemical Reagent Co., Ltd.
  • the reagents and solvents used are not specially treated unless otherwise specified.
  • Nifedipine bulk drug was purchased from Adamas Reagent, with a purity greater than 99%.
  • isonicotinic acid amide (12.2 g) was formed into a saturated solution in 200 mL of methyl isobutyl ketone solution, and the supernatant was taken out by filtration, and nifedipine (46.1 g) powder was added thereto, and suspended until formation. Supersaturated, centrifuged and filtered to obtain a eutectic (33.6 g) of nifedipine and isonicotinic acid amide. The prepared eutectic was characterized by X-ray single crystal diffraction. The X-ray single crystal diffraction structure of the eutectic of nifedipine and isonicotinic acid amide is shown in Fig. 1.
  • the results of X-ray single crystal diffraction show that the nitrate The molar ratio of fendipine to isonicotinic acid amide was 1:1.
  • the prepared eutectic of nifedipine and isonicotinic acid amide is also subjected to X-ray powder diffraction (XRPD), thermogravimetric analysis (TG), differential scanning calorimetry (DSC), infrared (IR) and Raman ( Raman) spectra were characterized.
  • XRPD X-ray powder diffraction
  • TG thermogravimetric analysis
  • DSC differential scanning calorimetry
  • IR infrared
  • Raman Raman
  • nifedipine (34.6 g) was formed into a saturated solution in 200 mL of methyl isobutyl ketone solution, and the supernatant was taken out by filtration, and isonicotinamide (12.2 g) powder was added thereto, and suspended until formation. Supersaturated, centrifuged and filtered to obtain a eutectic (35.1 g) of nifedipine and isonicotinic acid amide.
  • isonicotinic acid amide (30.5 g) was formed into a saturated solution in 250 mL of methanol solution, and the supernatant was taken out by filtration, and nifedipine (86.5 g) powder was added thereto, suspended until supersaturation was formed, and centrifuged. And filtration to obtain a eutectic (90.6 g) of nifedipine and isonicotinic acid amide.
  • isonicotinic acid amide (12.2 g) and nifedipine (34.6 g) were placed in a mortar at a molar ratio of 1:1, and 300 ⁇ L of a methanol solvent was added dropwise thereto, followed by grinding for 8 minutes to obtain nifedipine.
  • Eutectic with isonicotinic acid amide (40.3 g).
  • Nifedipine (34.6 g) and isonicotinic acid amide (12.2 g) were placed in a mortar at a molar ratio of 1:1 at room temperature, and 300 ⁇ L of methyl isobutyl ketone solvent was added dropwise thereto, followed by grinding for 8 minutes.
  • a eutectic (42.1 g) of nifedipine and isonicotinic acid amide was obtained.
  • Example 2 The liquid obtained by obtaining the eutectic of nifedipine and isonicotinic acid amide in Example 2 was evaporated at room temperature to obtain a eutectic (11.2 g) of nifedipine and isonicotinic acid amide.
  • Test sample sources co-crystals of nifedipine and isonicotinic acid amide prepared in Example 1, and nifedipine bulk drug purchased from Adamas Reagent.
  • the eutectic of nifedipine and isonicotinic acid amide prepared by the present invention has higher light stability than the eutectic of nifedipine and isonicotinic acid under the same illumination condition as compared with nifedipine. Sex.

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Abstract

本发明涉及了一种硝苯地平与异烟酰胺的共晶，其制备方法和应用。运用X-射线单晶衍射分析、X-射线粉末衍射分析、热重分析、差示扫描量热分析、红外光谱分析等手段对硝苯地平与异烟酰胺的共晶进行了全面表征，发现该共晶相比于硝苯地平具有更高的光照稳定性的优点。该硝苯地平与异烟酰胺的共晶的制备方法简单，容易控制，重现性好，可以获得稳定的硝苯地平与异烟酰胺的共晶。

Description

硝苯地平与异烟酰胺的共晶 技术领域
本发明涉及药物化学及结晶工艺技术领域，具体地，涉及硝苯地平与异烟酰胺的共晶及其制备方法和应用。
背景技术
硝苯地平(Nifedipine)的化学名为:1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-3,5-吡啶二羧酸二甲酯(1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylic acid dimethyl ester)，其化学结构式如下：
Figure PCTCN2018083815-appb-000001
硝苯地平是1975年第一个上市的二氢吡啶类钙离子阻滞剂抗高血压药物，该药物主要是通过阻断心肌和血管平滑肌细胞膜上的钙离子通道，抑制细胞外钙离子内流，使得细胞内钙离子浓度降低，从而达到降低血压的效果。但是随着研究的深入，发现该类药物结构中的二氢吡啶环容易被氧化成吡啶环，生成杂质，此类杂质对皮肤具有一定的伤害作用。
药物共晶是指药物活性分子(API)同一个或者多个配体分子(Co-crystal Co-formers,CCF)在氢键，范德华力，π-π堆积，卤键等弱相互作用下形成的，具有固定计量比的共结晶物，并且API，CCF，共结晶物在室温条件下均为固体。药物共晶作为一种新型的固体形态，对改善药物的溶解度，稳定性，机械性质等方面具有不容小觑的作用。
药物共晶与药物的其他固体形态，如多晶型和盐相比具有更大的优势。药物多晶型是指药物中活性分子存在两种或两种以上的晶体形态，药物的不同晶型溶解度一般相差不会太大，而共晶中由于配体的引入，共晶相比于API，其溶解度可能提高十几倍。盐则是由正离子和负离子组成的化合物，要求化合物至少有一个离子化中心，而共晶中的各个组分可以是中性分子，将可形成共晶的分子范围扩大许多，可以是食品添加剂，防腐剂，辅料，维生素，矿物质，氨基酸等，甚至是其他药物，为缺乏可电离官能团分子提供了多样化的固体形态。
本申请发明人通过研究，设计并合成了一种新的硝苯地平与异烟酰胺的共晶，并且该共晶的光照稳定性相比硝苯地平有明显提高，而且制备方法简便易行，重现性很好，为改善硝苯地平的光稳定性提供了一种切实可行的手段。
发明内容
本发明的目的之一在于提供了一种光稳定性有所提高的硝苯地平与异烟酰胺的共晶。
本发明的目的之二在于提供一种硝苯地平与异烟酰胺的共晶的制备方法。
本发明的目的之三在于提供一种药物组合物，所述药物组合物包含上述硝苯地平与异烟酰胺的共晶以及药学上可接受的载体。
本发明的目的之四在于提供一种硝苯地平与异烟酰胺的共晶在制备用于治疗心脑血管疾病的药物中的用途。
根据本发明的第一方面，提供一类硝苯地平与异烟酰胺的共晶，其中，所述硝苯地平与异烟酰胺的共晶中，硝苯地平和异烟酰胺的摩尔比为1:1。
所述硝苯地平与异烟酰胺的共晶的晶型为单斜晶系，空间群为P2 1/n，晶胞参数为：
Figure PCTCN2018083815-appb-000002
α＝90°；β＝90.080(5)°；γ＝90°，晶胞体积为
Figure PCTCN2018083815-appb-000003
。
所述硝苯地平与异烟酰胺的共晶的X-射线粉末衍射图谱(XRPD)中在2θ角度约为7.94°±0.2°，9.77°±0.2°，11.77°±0.2°，13.14°±0.2°，13.38°±0.2°，13.77°±0.2°，15.24°±0.2°，15.85°±0.2°，17.59°±0.2°，17.86°±0.2°，18.32°±0.2°，19.48°±0.2°，19.64°±0.2°，21.04°±0.2°，21.30°±0.2°，22.38°±0.2°，22.86°±0.2°，23.63°±0.2°，24.11°±0.2°，24.96°±0.2°，26.32°±0.2°，26.72°±0.2°，27.27°±0.2°，27.68°±0.2°，29.11°±0.2°，31.92°±0.2°，35.01°±0.2°，36.54°±0.2°处具有特征峰。
特别地，所述的硝苯地平与异烟酰胺的共晶的X-射线粉末衍射图谱，具有基本上如附图2所示的XRPD图谱。
由于测量条件的不同，XRPD衍射图上各峰2θ角和相对强度会有所变动，一般2θ角变化在±0.2°以内，但也能稍溢出该范围，本领域技术人员应理解，衍射的相对强度可取决于，例如，样品制剂或所用设备。
所述的硝苯地平与异烟酰胺的共晶的差示扫描量热分析谱图在约157.86±0.2℃处有特征熔融峰，所述硝苯地平与异烟酰胺的共晶具有基本如图4所示的差示扫描量热分析(DSC)图谱。
所述的硝苯地平与异烟酰胺的共晶的红外谱图至少在约3408cm -1、3291cm -1、3227cm -1、3093cm -1、2944cm -1、1693cm -1、1672cm -1、1523cm -1、1480cm -1、1427cm -1、1379cm -1、1358cm -1、1309cm -1、1240cm -1、1202cm -1、1112cm -1、1091cm -1、1011cm -1、856cm -1、829cm -1、776cm -1、749cm -1、717cm -1、626cm -1、588cm -1处具有特征峰。
所述的硝苯地平与异烟酰胺的共晶的拉曼图谱至少在约3166cm -1、3074cm -1、2996cm -1、2955cm -1、2936cm -1、2840cm -1、1696cm -1、1673cm -1、1641cm -1、1577cm -1、1503cm -1、1362cm -1、1215cm -1、1055cm -1、1004cm -1处具有特征峰。
根据本发明的另一方面，提供了一种制备硝苯地平与异烟酰胺的共晶的方法，所述制备方法为以下制备方法之一：
方法一：
方法一包括以下步骤：
(a)在室温条件下，将异烟酰胺溶于有机溶剂，配制成异烟酰胺饱和溶液；
(b)往异烟酰胺的饱和溶液中加入硝苯地平粉末，混悬直至形成过饱和状态，析晶，从而形成硝苯地平与异烟酰胺的共晶；
(c)分离步骤(b)所形成的硝苯地平与异烟酰胺共晶，得到硝苯地平与异烟酰胺的共晶；
方法二：
所述方法二包括以下步骤：
(d)在室温条件下，将硝苯地平溶于有机溶剂，配制成硝苯地平饱和溶液；
(e)往硝苯地平的饱和溶液中加入异烟酰胺粉末，混悬直至形成过饱和状态，析晶，从而形成硝苯地平与异烟酰胺的共晶；
(f)分离步骤(e)所形成的硝苯地平与异烟酰胺共晶，得到硝苯地平与异烟酰胺的共晶；
方法三：
所述方法三包括以下步骤：
(g)在室温条件下，按照摩尔比1:1称取硝苯地平和异烟酰胺，得硝苯地平和异烟酰胺的混合物；
(h)往硝苯地平和异烟酰胺的混合物中滴加有机溶剂，进行研磨，以在固相中形成硝苯地平与异烟酰胺的共晶；
(i)分离步骤(h)所形成的硝苯地平与异烟酰胺额共晶，得到硝苯地平与异烟酰胺的共晶。
优选地，
所述有机溶剂选自甲基异丁基酮，甲醇，乙酸乙酯，硝基甲烷，乙醇，乙酸异丙酯中的一种或多种；
在步骤(c)和步骤(f)中，
所述的分离包括：
(c1)通过过滤，从而获得硝苯地平与异烟酰胺的共晶；或
(c2)通过离心和过滤，从而获得硝苯地平与异烟酰胺的共晶；或
(c3)在采用(c1)或者(c2)步骤分离了硝苯地平与异烟酰胺的共晶后，进一步蒸发去除(c1)或者(c2)步骤中的分离得到的液体溶液，从而获得硝苯地平与异烟酰胺的共晶；
在步骤(h)中，
所述硝苯地平与有机溶剂的重量体积比为1Kg:(8～10)mL；进一步优选为1Kg:(8.5～10)mL。
本发明的另一方面涉及一种药物组合物，所述药物组合物包含上述硝苯地平与异烟酰胺的共晶以及药学上可接受的载体。
本发明的另一方面涉及一种硝苯地平与异烟酰胺的共晶或所述包含硝苯地平与异烟酰胺的共晶以及药学上可接受的载体的药物组合物在制备用于治疗心脑血管疾病的药物中的用途，所述的心脑血管疾病包括高血压等。
有益效果
本发明提供的一种硝苯地平与异烟酰胺的共晶，其制备方法简单，结晶过程容易控制，重现性好，相比于硝苯地平本身，其不仅具有硝苯地平的药物活性，而且光照稳定性有很大提高，为硝苯地平贮存运输，临床运用提供了一种切实可行的技术手段。
附图说明
图1是本发明实施例1的硝苯地平与异烟酰胺的共晶的X-射线单晶衍射(SCXRD)结构图；
图2是本发明实施例1的硝苯地平与异烟酰胺的共晶的X-射线粉末衍射(XRPD)图；
图3是本发明实施例1的硝苯地平与异烟酰胺的共晶的热重分析(TG)图；
图4是本发明实施例1的硝苯地平与异烟酰胺的共晶的差示扫描量热分析(DSC)图；
图5是本发明实施例1的硝苯地平与异烟酰胺的共晶的红外光谱(IR)图；
图6是本发明实施例1的硝苯地平与异烟酰胺的共晶的拉曼光谱(Raman)图；
图7是本发明实施例1的硝苯地平与异烟酰胺的共晶的光照稳定性实验剩余含量图。
具体实施方式
下面结合具体实施例对本发明作进一步阐述，但不限制本发明。
检测仪器及方法：
X-射线单晶衍射(SCXRD)所使用的仪器为布鲁克仪器有限公司Bruker Smart Apex II型X射线单晶衍射仪。测定条件为石墨单色器，Mo–Kα射线
Figure PCTCN2018083815-appb-000004
在室温下进行测试，测试电压为50kV，电流为30mA。所有单晶结构的数据还原和结构解析工作分别由SAINT–5.0和SHELXTL–97程序完成，吸收校正由SADABS程序完成。非氢原子坐标由差值函数法和最小二乘法求出，氢原子通过理论计算加在合适的位置。
X-射线粉末衍射(XRPD)所使用的仪器为Bruker D8 Advance diffractometer，采用Cu用Kα射线(线用
Figure PCTCN2018083815-appb-000005
)，电压为40千伏，电流为40毫安。仪器在使用前用仪器自带的标准样品校正峰位。采集软件是Diffrac Plus XRD Commander，分析软件是MDI Jade 6.0。样品在室温条件下测试，把需要检测的样品放在有机玻片上。详细检测条件如下：2θ角度范围：3～40°；步长：0.02°；速度：0.1秒/步。除非特别说明，样品在检测前未经研磨。
热重分析(TGA)数据采自于德国耐驰科学仪器有限公司TG20F3型，仪器控制软件是NETZSCH-Proteus-6，分析软件是Proteus Analysis。以10℃/min的升温速度在50mL/min干干燥氮气的保护下将样品从室温升至400℃，同时软件记录样品在升温过程中的重量变化。
差热分析(DSC)数据采自于美国TA仪器公司DSC Q2000差示扫描量热仪，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。以10℃/min的升温速度在50mL/min干燥氮气的保护下将样品从室温升至200℃，同时TA软件记录样品在升温过程中的热量变化。
红外分析(IR)采用美国尼高力公司的Nicolet-Magna FT-IR 750红外光谱分析仪于室温检测，检测范围为：4000-350cm -1波数。
拉曼光谱分析采用美国热电公司的DXR显微拉曼光谱仪于室温检测，检测范围为：3500-50cm -1拉曼位移。
异烟酰胺，甲基异丁基酮，甲醇等试剂均为分析纯，由国药集团化学试剂有限公司提供，所用试剂和溶剂除特别说明外，均未经特别处理。硝苯地平原料药购买自阿达玛斯试剂公司，纯度大于99％。
实施例1
硝苯地平与异烟酰胺的共晶
在室温条件下，将异烟酰胺(12.2g)在200mL甲基异丁基酮溶液中形成饱和溶液，过滤将上清液取出，往其中加入硝苯地平(46.1g)粉末，混悬直至形成过饱和状态， 离心和过滤，得到硝苯地平与异烟酰胺的共晶(33.6g)。将制备得到的共晶采用X-射线单晶衍射进行了表征，硝苯地平与异烟酰胺的共晶的X-射线单晶衍射结构图见图1，X-射线单晶衍射的结果显示硝苯地平和异烟酰胺的摩尔比为1:1。硝苯地平与异烟酰胺的共晶的晶型为单斜晶系，空间群为P2 1/n，晶胞参数为：
Figure PCTCN2018083815-appb-000006
Figure PCTCN2018083815-appb-000007
α＝90°；β＝90.080(5)°；γ＝90°，晶胞体积为
Figure PCTCN2018083815-appb-000008
。
对制得的硝苯地平与异烟酰胺的共晶还采用X-射线粉末衍射(XRPD)、热重分析(TG)、差示扫描量热分析(DSC)、红外(IR)以及拉曼(Raman)光谱进行了表征。X-射线粉末衍射分析结果见附图2，热重分析结果见附图3，差示扫描量热分析结果见附图4，红外分析结果见附图5，拉曼光谱分析结果见附图6。
实施例2
硝苯地平与异烟酰胺的共晶
在室温条件下，将硝苯地平(34.6g)在200mL甲基异丁基酮溶液中形成饱和溶液，过滤将上清液取出，往其中加入异烟酰胺(12.2g)粉末，混悬直至形成过饱和状态，离心和过滤，得到硝苯地平与异烟酰胺的共晶(35.1g)。
实施例3
硝苯地平与异烟酰胺的共晶
在室温条件下，将异烟酰胺(30.5g)在250mL甲醇溶液中形成饱和溶液，过滤将上清液取出，往其中加入硝苯地平(86.5g)粉末，混悬直至形成过饱和状态，离心和过滤，得到硝苯地平与异烟酰胺的共晶(90.6g)。
实施例4
硝苯地平与异烟酰胺的共晶
在室温条件下，将异烟酰胺(12.2g)和硝苯地平(34.6g)按照摩尔比1:1放入研钵中，滴加300μL的甲醇溶剂，进行研磨8分钟后，得到硝苯地平与异烟酰胺的共晶(40.3g)。
实施例5
硝苯地平与异烟酰胺的共晶
在室温条件下，将硝苯地平(34.6g)和异烟酰胺(12.2g)按照摩尔比1:1放入研钵中，滴加300μL的甲基异丁基酮溶剂，进行研磨8分钟后，得到硝苯地平与异烟酰胺的共晶(42.1g)。
实施例6
硝苯地平与异烟酰胺的共晶
在室温条件下，蒸发去除实施例2中得到硝苯地平与异烟酰胺的共晶之后的液体，得到硝苯地平与异烟酰胺的共晶(11.2g)。
实施例2、3、4、5和6中的制备的硝苯地平与异烟酰胺的共晶，通过X-射线粉末衍射(XRPD)、热重分析(TG)、差示扫描量热分析(DSC)、红外(IR)以及拉曼(Raman)光谱等固体化学方法表征后，其结果同实施例1制备的硝苯地平与异烟酰胺的共晶基本一致。
实施例7
硝苯地平与异烟酰胺的共晶与硝苯地平本身的光照稳定性比较
受试样品来源：实施例1制备的硝苯地平与异烟酰胺的共晶和购买自阿达玛斯试剂公司的硝苯地平原料药。
实验方法：将硝苯地平与异烟酰胺的共晶和硝苯地平原料药粉末研磨后，分别称取约15毫克样品，平铺于玻璃板上，并用称量纸轻压，铺平。放入药品强光照射试验箱中。样品距离光源约为20cm，光照间隔一段时间后对样品进行取样。用高效液相色谱方法检测各个取样点的剩余样品含量，最终得到硝苯地平与异烟酰胺共晶以及硝苯地平原料药的光照稳定性曲线。
光照条件：
仪器：药品强光照射试验箱
光照强度：4000lux
光照温度：25摄氏度
取样时间：0小时，2小时，4小时，6小时，8小时，10小时
高效液相色谱测定条件条件：
仪器：安捷伦1260
色谱紫外检测仪型号：安捷伦G1315D
色谱双相泵型号：安捷伦G1331C
色谱柱:Agilent Zorbax Eclipse Plus C18柱(4.6×150mm,5μm)
流动相：0.1％，v/v三氟乙酸和乙腈，洗脱梯度如下：
时间(分钟) 0.1％三氟乙酸(体积占比，％) 乙腈(体积占比，％)
0.00 70 30
2.00 70 30
14.00 10 90
16.00 70 30
柱温：35℃
流速：1mL/min
进样量：20μL
检测波长：236nm
实验结果：
硝苯地平与异烟酰胺的共晶和硝苯地平本身相比剩余含量见图7。
如图7所示，本发明所制备的硝苯地平与异烟酰胺的共晶与硝苯地平相比，在相同光照条件下，硝苯地平与异烟酰胺的共晶具有更高的光稳定性。
以上所述仅为本发明的最佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种硝苯地平与异烟酰胺的共晶，其特征在于，所述的共晶中，硝苯地平和异烟酰胺的摩尔比为1:1。
  2. 一种硝苯地平与异烟酰胺的共晶，其特征在于，所述的硝苯地平与异烟酰胺的共晶的X-射线粉末衍射图谱中在2θ角度约为7.94°±0.2°，9.77°±0.2°，11.77°±0.2°，13.14°±0.2°，13.38°±0.2°，13.77°±0.2°，15.24°±0.2°，15.85°±0.2°，17.59°±0.2°，17.86°±0.2°，18.32°±0.2°，19.48°±0.2°，19.64°±0.2°，21.04°±0.2°，21.30°±0.2°，22.38°±0.2°，22.86°±0.2°，23.63°±0.2°，24.11°±0.2°，24.96°±0.2°，26.32°±0.2°，26.72°±0.2°，27.27°±0.2°，27.68°±0.2°，29.11°±0.2°，31.92°±0.2°，35.01°±0.2°，36.54°±0.2°处具有特征峰。
  3. 如权利要求1或2所述的硝苯地平与异烟酰胺的共晶，其特征在于，所述的硝苯地平与异烟酰胺的共晶的X-射线粉末衍射图谱，具有基本上如附图2所示的X-射线粉末衍射图谱。
  4. 如权利要求1或2所述的硝苯地平与异烟酰胺的共晶，其特征在于，所述的硝苯地平与异烟酰胺的共晶的晶型为单斜晶系，空间群为P2 1/n，晶胞参数为：
    Figure PCTCN2018083815-appb-100001
    Figure PCTCN2018083815-appb-100002
    α＝90°；β＝90.080(5)°；γ＝90°，晶胞体积为
    Figure PCTCN2018083815-appb-100003
    Figure PCTCN2018083815-appb-100004
  5. 如权利要求1或2所述的硝苯地平与异烟酰胺的共晶，其特征在于，所述的硝苯地平与异烟酰胺的共晶的差示扫描量热分析谱图在约157.86±0.2℃处有特征熔融峰。
  6. 一种制备如权利要求1～5任一项所述的硝苯地平与异烟酰胺的共晶的方法，所述方法为以下方法之一：
    方法一：
    方法一包括以下步骤：
    (a)将异烟酰胺溶于有机溶剂，配制成异烟酰胺饱和溶液；
    (b)往异烟酰胺的饱和溶液中加入硝苯地平粉末，混悬直至形成过饱和状态，析晶，从而形成硝苯地平与异烟酰胺的共晶；
    (c)分离步骤(b)所形成的硝苯地平与异烟酰胺共晶，得硝苯地平与异烟酰胺的共晶；
    方法二：
    所述方法二包括以下步骤：
    (d)将硝苯地平溶于有机溶剂，配制成硝苯地平饱和溶液；
    (e)往硝苯地平的饱和溶液中加入异烟酰胺粉末，混悬直至形成过饱和状态，析晶，从而形成硝苯地平与异烟酰胺的共晶；
    (f)分离步骤(e)所形成的硝苯地平与异烟酰胺共晶，得硝苯地平与异烟酰胺的共晶；
    方法三：
    所述方法三包括以下步骤：
    (g)按照摩尔比1:1称取硝苯地平和异烟酰胺，得硝苯地平和异烟酰胺的混合物；
    (h)往硝苯地平和异烟酰胺的混合物中滴加有机溶剂，进行研磨，以在固相中形成硝苯地平与异烟酰胺的共晶；
    (i)分离步骤(h)所形成的硝苯地平与异烟酰胺的共晶，得到硝苯地平与异烟酰胺的共晶。
  7. 如权利要求6所述的硝苯地平与异烟酰胺的共晶的方法，其特征在于，所述的有机溶剂选自甲基异丁基酮，甲醇，乙酸乙酯，硝基甲烷，乙醇，乙酸异丙酯中的一种或多种；
    在步骤(c)和步骤(f)中，
    所述的分离包括：
    (c1)通过过滤，从而获得硝苯地平与异烟酰胺的共晶；或
    (c2)通过离心和过滤，从而获得硝苯地平与异烟酰胺的共晶；或
    (c3)在采用(c1)或者(c2)步骤分离了硝苯地平与异烟酰胺的共晶后，进一步蒸发去除(c1)或者(c2)步骤中的分离得到的液体溶液，从而获得硝苯地平与异烟酰胺的共晶。
  8. 如权利要求6所述的硝苯地平与异烟酰胺的共晶的方法，其特征在于，在步骤(h)中，所述硝苯地平与有机溶剂的重量体积比为1Kg:(8～10)mL；进一步优选为1Kg:(8.5～10)mL。
  9. 一种药物组合物，所述药物组合物包含权利要求1～5中任一项所述的硝苯地平与异烟酰胺的共晶以及药学上可接受的载体。
  10. 如权利要求1～5中任一项所述硝苯地平与异烟酰胺的共晶或如权利要求9所述的药物组合物在制备用于治疗心脑血管疾病的药物中的用途。
PCT/CN2018/083815 2017-04-26 2018-04-20 硝苯地平与异烟酰胺的共晶 WO2018196681A1 (zh)

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