CN113121419A - Acipimox-1, 2-di (4-pyridyl) ethylene eutectic crystal - Google Patents
Acipimox-1, 2-di (4-pyridyl) ethylene eutectic crystal Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 73
- 230000005496 eutectics Effects 0.000 title claims abstract description 61
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- 238000002360 preparation method Methods 0.000 claims abstract description 15
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 7
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- MGFJDEHFNMWYBD-OWOJBTEDSA-N 4-[(e)-2-pyridin-4-ylethenyl]pyridine Chemical group C=1C=NC=CC=1/C=C/C1=CC=NC=C1 MGFJDEHFNMWYBD-OWOJBTEDSA-N 0.000 claims description 19
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- 239000004475 Arginine Substances 0.000 description 11
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- 238000002425 crystallisation Methods 0.000 description 11
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- OQZRYEKQMSJDPM-UHFFFAOYSA-N 1-pyridin-4-ylethenol Chemical compound OC(=C)C1=CC=NC=C1 OQZRYEKQMSJDPM-UHFFFAOYSA-N 0.000 description 4
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- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- KFDVPJUYSDEJTH-UHFFFAOYSA-N 4-ethenylpyridine Chemical group C=CC1=CC=NC=C1 KFDVPJUYSDEJTH-UHFFFAOYSA-N 0.000 description 1
- RBYJWCRKFLGNDB-UHFFFAOYSA-N 5-methylpyrazine-2-carboxylic acid Chemical compound CC1=CN=C(C(O)=O)C=N1 RBYJWCRKFLGNDB-UHFFFAOYSA-N 0.000 description 1
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- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
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- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
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- 125000000627 niacin group Chemical group 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 1
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- 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
- C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention belongs to the technical field of medicines, and particularly provides an acipimox-1, 2-di (4-pyridyl) ethylene eutectic crystal, a preparation method thereof and application thereof in preparing a blood fat reducing medicine. The acipimox-1, 2-di (4-pyridyl) ethylene eutectic prepared by the invention uses Cu-Kalpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at least at 5.79 +/-0.2 degrees, 8.67 +/-0.2 degrees, 12.00 +/-0.2 degrees and 16.40 +/-0.2 degrees. The acipimox-1, 2-di (4-pyridyl) ethylene eutectic prepared by the invention has high solubility, moderate dissolution rate, good stability and better industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of organic pharmaceutical co-crystals, and particularly relates to an acipimox-1, 2-di (4-pyridyl) ethylene co-crystal.
Background
Pharmaceutical co-crystals are based on the supramolecular chemistry principle, i.e. molecular recognition and supramolecular self-assembly by intermolecular interactions. The pharmaceutical active ingredient (API) is self-assembled with a suitable co-crystal former (CCF) through hydrogen bonds, or non-covalent bonds with saturation and directionality (such as Van der Waals force of aromatic hydrocarbon or benzene ring, pi-pi conjugation and halogen bonds), to form a novel structure, namely, the pharmaceutical co-crystal. The method is based on hydrogen bonds, does not need to form new covalent bonds or destroy existing covalent bonds, can modify the physicochemical properties of the medicament while retaining the pharmacological action of the medicament, such as improving the stability of the medicament, reducing the hygroscopicity of the medicament, improving the solubility, improving the bioavailability and the like, and provides a wide development prospect for the application of pharmaceutical co-crystals in the aspect of pharmaceutical industry. In recent years, pharmaceutical co-crystal research has received increasing attention. At the present stage, the research on pharmaceutical co-crystals in foreign countries is gradually increased and deepened; and domestic research on the method is relatively less. For the imitation drugs, the research on the pharmaceutical co-crystal can also break the patent protection of the original research pharmaceutical company on the pharmaceutical crystal form, and is beneficial to the market of the imitation drugs. Therefore, it is of great practical significance to obtain more novel, practical and inventive pharmaceutical co-crystals, especially some water-insoluble drugs.
Acipimox is a nicotinic acid derivative, is a broad-spectrum long-acting lipid regulating drug, is used for various primary and secondary hyperlipidemias, mainly acts on adipose tissues, reduces the synthesis of plasma low-density lipoprotein and very low-density lipoprotein by inhibiting the release of free fatty acid from the adipose tissues, thereby reducing the levels of the plasma low-density lipoprotein and the very low-density lipoprotein in the plasma and simultaneously increasing the level of plasma HDL by inhibiting the activity of liver lipase. Acipimox was developed by Farmitalia caro Erba company of italy, marketed in italy in 1985, and then, by virtue of its high safety and remarkable therapeutic effect, it was marketed successively in many countries and regions of germany, chile, switzerland, hong kong, china, etc.
The pharmaceutical co-crystal can affect the physicochemical properties of the medicine, directly affect the dissolution and absorption efficiency of the medicine under physiological conditions, and further affect the bioavailability, clinical efficacy and the like of the medicine. By means of drug co-crystallization, the advantages of co-crystallization can be well applied, which has very important effect on understanding and mastering the space arrangement and physicochemical properties of effective molecules of drugs.
At present, a lot of reports about acipimox exist, but reports about preparation, physicochemical properties, pharmacology and other properties of the acipimox are mainly about, reports about a crystal eutectic structure of the acipimox are less, the patent US2005239803A1, the patent CN 103508963A and the like report a preparation method of the acipimox, and the patent CN86103304-2 obtains an acipimox precipitate with a crystal property, which is acipimox hydrate, and has low yield. In the previous reports, the reports of the acipimox eutectic crystal are less, and the characterization parameters of the acipimox eutectic crystal are not mentioned.
Patent CN 109438371A reports that an acipimox arginine hydrate is prepared by dissolving acipimox and arginine in a mixed solution of an organic solvent and water, heating for dissolving, cooling for crystallization after the solution is clarified, filtering and drying to obtain the crystal form of the acipimox arginine hydrate.
Patent CN 109369546A reports that acipimox theophylline dihydrate is obtained by adding acipimox and theophylline into a mixed solution of an organic solvent and water, heating for dissolving, stirring for reaction, cooling for crystallization, filtering and drying.
Disclosure of Invention
In view of the defects of the prior art, the invention provides an acipimox-1, 2-di (4-pyridyl) ethylene eutectic crystal.
The acipimox serving as the medicinal component of the invention has the chemical name of 5-methylpyrazine-2-carboxylic acid-4-oxide, and is white or off-white crystalline powder. CAS number: 51037-30-0 molecular formula C6H6N2O3The structural formula is shown as a, the selected eutectic formation substance is 1, 2-di (4-pyridyl) ethylene, and the molecular formula is C12H10N2The structural formula is shown as b:
in a first aspect of the invention, a cocrystal of acipimox-1, 2-bis (4-pyridyl) ethene is provided. In the cocrystal, the molar ratio of the acipimox to the 1, 2-bis (4-pyridyl) ethylene is 2: 1.
The acipimox-1, 2-di (4-pyridyl) ethylene eutectic crystal uses Cu-Kalpha radiation, and has an X-ray diffraction spectrum expressed by 2 theta with characteristic peaks at least at 5.79 +/-0.2 degrees, 8.67 +/-0.2 degrees, 12.00 +/-0.2 degrees and 16.40 +/-0.2 degrees.
Preferably, the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic crystal has an X-ray diffraction spectrum expressed by 2 theta by using Cu-Ka radiation and has characteristic peaks at least at 5.79 +/-0.2 degrees, 8.67 +/-0.2 degrees, 12.00 +/-0.2 degrees, 16.40 +/-0.2 degrees, 17.49 +/-0.2 degrees, 19.46 +/-0.2 degrees, 22.18 +/-0.2 degrees, 26.14 +/-0.2 degrees, 27.22 +/-0.2 degrees and 27.60 +/-0.2 degrees.
Preferably, the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic crystal uses Cu-Ka radiation, and the characteristic peak of the eutectic crystal accords with an X-ray powder diffraction pattern shown in figure 1.
Preferably, the acipimox-1, 2-di (4-pyridyl) ethylene eutectic crystal has an endothermic peak in a Differential Scanning Calorimetry (DSC) curve at the temperature range of 210.85-231.74 ℃.
Preferably, the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic crystal has the following crystallographic parameters: triclinic system with space group P
The unit cell parameters are:
a is 117.673(4) °, β is 100.534(3) °, γ is 94.828(3) °, unit cell volume
The second aspect of the invention provides a preparation method of acipimox-1, 2-di (4-pyridyl) ethylene eutectic, which comprises the following specific preparation steps: adding the acipimox and the 1, 2-di (4-pyridyl) ethylene into an organic solvent A, heating and refluxing for reaction, cooling and crystallizing, filtering and drying to obtain the acipimox-1, 2-di (4-pyridyl) ethylene eutectic crystal.
The organic solvent A is selected from one or more of methanol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, ethanol and isopropanol.
Preferably, the organic solvent A is selected from one or two of methanol, ethanol and ethyl acetate.
The molar ratio of the acipimox to the 1, 2-bis (4-pyridyl) ethylene is 2.05-2.35: 1.
Preferably, the molar ratio of the acipimox to the 1, 2-bis (4-pyridyl) ethylene is 2.10-2.20: 1.
The mass-volume ratio of the 1, 2-bis (4-pyridyl) ethylene to the organic solvent A in the system is 4-6: 1, wherein the mass is mg, and the volume is mL.
The cooling crystallization temperature is 0-15 ℃.
Preferably, the temperature reduction and crystallization temperature is 5-10 ℃.
The crystallization time is 40-62 hours.
Further preferably, the preparation method comprises the following steps:
dissolving acipimox and 1, 2-bis (4-pyridyl) ethylene in an organic solvent A, heating to dissolve at 45-75 ℃, stirring, refluxing, reacting for 7-12 hours, cooling to 0-15 ℃, crystallizing for 40-62 hours, filtering, washing a filter cake, and drying to obtain the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic crystal.
The solvent for washing the filter cake is selected from one of ethanol, ethyl acetate and acetone.
The drying temperature is 50-70 ℃, and the drying time is 8-12 hours.
In a third aspect, the invention provides the use of the acipimox-1, 2-di (4-pyridyl) ethylene cocrystal as an active ingredient in the preparation of a medicament for treating hypolipidemia.
Confirmation of the Crystal Structure
X-ray crystal data were collected on a jtaab Synergy model instrument, japan, testing temperature 293(2) K, irradiating with CuKa, collecting data in an omega scan fashion and Lp correction. The crystal structure is calculated by a ShelXT program in olex2 software, the ShelXL program is adopted to correct the structure parameters and judge the atom species by a least square method, the positions of all hydrogen atoms are obtained by a geometric calculation method and a difference Fourier method, the goodness of fit (GooF value) is 1.123 and is close to 1.0, and the weight scheme is proper and the structure is accurate.
Testing and analyzing the acipimox crystal prepared by the inventionThe crystallographic data are (Table 1) and the crystallographic parameters are: triclinic system with space group P
The unit cell parameters are:
a is 117.673(4) °, β is 100.534(3) °, γ is 94.828(3) °, unit cell volume
The molecular formula is: c24H22N6O6The molecular weight is: 490.47. the ORTEP chart of the eutectic crystal of acipimox-1, 2-bis (4-pyridyl) ethylene of the present invention shows that acipimox and 1, 2-bis (4-pyridyl) ethylene are bonded together by intramolecular hydrogen bonds, wherein H4 of the carboxyl group of acipimox forms a hydrogen bond with N4 of 1, 2-bis (4-pyridyl) ethylene, and H3 of the other acipimox molecule carboxyl group forms an intramolecular hydrogen bond with N3 of 1, 2-bis (4-pyridyl) ethylene, as shown in FIG. 3. The stacking diagram of the acipimox-1, 2-bi (4-pyridyl) ethylene eutectic crystal is shown in the attached figure 2.
TABLE 1 Acipimox-1, 2-bis (4-pyridyl) ethenol eutectic Primary crystallography data
X-ray powder diffraction test instrument and test conditions: x-ray powder diffractometer PANalytical Empyrean; Cu-K alpha; a sample stage: a flat plate; the incident light path is BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40 mA; a diverging slot 1/4; an anti-scatter slit 1; 0.04rad of cable pull slit; step length: 0.5 s; scanning range: 3 to 50 degrees.
According to the above crystallographic data, the characteristic peak of the corresponding X-ray powder diffraction pattern (Cu-Ka) is detailed in figure 1 and table 2.
TABLE 2 PXRD peaks for Acipimox-1, 2-bis (4-pyridyl) ethenol cocrystal
All samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction patterns.
The test result of the eutectic TGA/DSC of acipimox-1, 2-bis (4-pyridyl) ethylene prepared by the method is shown in figure 4, the DSC test result has an endothermic peak at the temperature range of 210.85-231.74 ℃, and the corresponding peak temperature is 210.85 ℃. According to the TGA detection result, a weight loss step exists, and the DSC/TGA detection result shows that the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic crystal prepared by the invention does not contain other solvents.
Compared with the currently reported acipimox crystal form, the acipimox-1, 2-di (4-pyridyl) ethylene eutectic prepared by the method has the following advantages:
(1) the stability is high. The acipimox-1, 2-di (4-pyridyl) ethylene eutectic crystal is placed in an environment of 40 ℃/75 percent RH (open small bottle) for 7 days, and XRD data of the eutectic crystal is not obviously changed, which indicates that the eutectic crystal has good solid state stability.
(2) The dissolution rate is high and the dissolution concentration is high. The acipimox-1, 2-di (4-pyridyl) ethylene eutectic is dissolved out quickly in water, hydrochloric acid buffer solution with the pH value being 1.2 and phosphate buffer solution with the pH value being 6.8, and the dissolution rate is still kept high along with the prolonging of the dissolution time.
Drawings
FIG. 1: an X-ray powder diffraction pattern of the acipimox-1, 2-di (4-pyridyl) ethylene eutectic;
FIG. 2: stacking diagram of Acipimox-1, 2-bis (4-pyridyl) ethylene eutectic crystal;
FIG. 3: an ORTEP diagram of the acipimox-1, 2-bis (4-pyridyl) ethene eutectic;
FIG. 4: differential Scanning Calorimetry (DSC) chart of the acipimox-1, 2-di (4-pyridyl) ethylene eutectic;
FIG. 5: superposition graph of X-ray powder diffraction of Acipimox-1, 2-bis (4-pyridyl) ethylene eutectic after placement at 40 ℃/75% RH and before placement.
Detailed Description
The advantageous effects of the present invention will now be further described by the following examples, which are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications apparent to those of ordinary skill in the art according to the present invention are also included in the scope of the present invention.
Example 1:
adding 154.1mg of acipimox (1mmol,2.15eq) and 84.4mg of 1, 2-bis (4-pyridyl) ethylene (0.465mmol) into 17mL of methanol, heating to 45 ℃, stirring for dissolving, carrying out reflux reaction for 7 hours, slowly cooling to 5-10 ℃, standing for crystallization for 48 hours at controlled temperature, filtering, washing a filter cake with acetone, and carrying out vacuum drying at 50 ℃ for 12 hours to obtain the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic crystal, wherein the yield is 97.33%, and the purity is 99.97%.
Example 2:
154.1mg of acipimox (2.1eq) and 86.8mg of 1, 2-bis (4-pyridyl) ethylene are added into 15mL of mixed solvent (10mL of methanol and 5mL of ethyl acetate), heated to 75 ℃, stirred and dissolved, refluxed for reaction for 9 hours, slowly cooled to 0-5 ℃, kept at a controlled temperature for crystallization for 40 hours, filtered, washed with ethanol to obtain a filter cake, and dried in vacuum at 70 ℃ for 8 hours to obtain the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic crystal, wherein the yield is 96.56%, and the purity is 99.98%.
Example 3:
154.1mg of acipimox (2.2eq) and 82.8mg of 1, 2-bis (4-pyridyl) ethylene are added into 21mL of ethyl acetate, heated to 60 ℃, stirred and dissolved, refluxed for 12 hours, slowly cooled to 10-15 ℃, kept at a controlled temperature for standing and crystallized for 62 hours, filtered, washed by ethyl acetate, and vacuum-dried for 10 hours at 60 ℃ to obtain the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic with the yield of 96.28% and the purity of 99.95%.
Example 4:
154.1mg of acipimox (2.05eq) and 88.9mg of 1, 2-bis (4-pyridyl) ethylene are added into 12ml of acetonitrile, heated to 55 ℃, stirred and dissolved, refluxed for 10 hours, slowly cooled to-5-0 ℃, kept at a controlled temperature for standing and crystallized for 35 hours, filtered, washed by acetone, and dried in vacuum for 10 hours at 50 ℃ to obtain the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic crystal with the yield of 94.51 percent and the purity of 99.88 percent.
Example 5:
154.0mg of acipimox (1mmol,2.35eq) and 77.5mg of 1, 2-bis (4-pyridyl) ethylene are added into 26mL of tetrahydrofuran, heated to 65 ℃, stirred and dissolved, refluxed for 10 hours, slowly cooled to 15-20 ℃, kept at a controlled temperature for crystallization for 48 hours, filtered, washed by ethanol, and vacuum-dried at 50 ℃ for 12 hours to obtain the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic crystal, wherein the yield is 93.73%, and the purity is 99.85%.
Example 6
154.1mg of acipimox (1mmol,2.5eq) and 72.9mg of 1, 2-bis (4-pyridyl) ethylene are added into 10mL of acetone, heated to 35 ℃, stirred and dissolved, refluxed for 15 hours, slowly cooled to-5-0 ℃, kept at a controlled temperature for crystallization for 48 hours, filtered, washed by acetone, and vacuum-dried at 50 ℃ for 10 hours to obtain the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic with the yield of 92.35% and the purity of 99.82%.
Comparative example 1:
dissolving 5.0g (32.4mmol) of acipimox and 5.6g (32.4mmol) of arginine in methanol water solution (50mL of methanol and 0.5mL of water), heating to 60 ℃ for dissolution, cooling to 20 ℃ after the solution is clarified, standing for crystallization for 52 hours, filtering and drying to obtain the acipimox arginine hydrate, wherein the yield is 96.80%, and the HPLC: 99.92 percent.
Comparative example 2:
adding 61.6mg (0.4mmol) of acipimox and 288.3mg (1.6mmol) of theophylline into 12mL of mixed solvent (10.0 mL of acetonitrile and 2.0mL of purified water), heating to 60 ℃, stirring for reaction for 10 hours, slowly cooling to 5-10 ℃, standing at controlled temperature for crystallization for 50 hours, filtering, leaching a filter cake with acetonitrile, and vacuum drying at 50 ℃ for 10 hours to obtain acipimox theophylline dihydrate, wherein the yield is 96.53%, and the purity is 99.94%.
Comparative example 3:
330mg (1mmol) of Na2WO4·2H2O was placed in a 50mL flask, dissolved in 16mL of water and fitted with mechanical stirring, reflux cooler and thermometer. 3.75mL of 40% w/v (400g/L) (44mmol) hydrogen peroxide was added to the solution with dilute H2SO4The pH was adjusted to 1.5 and 5.52g (40mmol) of 2-carboxy-5-methylpyrazine were then added.
The suspension of water produced by the reaction was heated to 70 ℃ with stirring and maintained at this temperature for 2.5 hours. Thus a gradually solubilised suspension is obtained. Finally, some product was found to precipitate. The mixture was allowed to stand at room temperature overnight to cause precipitation of the reaction product in a crystal form. This product was filtered, washed with ice water and dried on a bisque-fired plate to give 4.68g of partially hydrated (2.83%) 2-carboxy-5-methylpyrazine-4-oxide, corresponding to 4.54g of anhydrous product, 73.01% yield, HPLC purity: 95.15 percent.
1. Stability test
The acipimox-1, 2-bis (4-pyridyl) ethylene eutectic prepared by the invention is stored at 40 ℃/75% RH (open vial). Any possible change in the crystal structure was analyzed by XRD over 7 days and the results are shown in figure 5.
Tests prove that the acipimox-1, 2-di (4-pyridyl) ethylene eutectic crystal prepared by the invention is placed at 40 ℃/75% RH (open small bottle), XRD data is not changed, and the stability is better.
2. Dissolution Rate test
(1) Selection of dissolution method
According to a dissolution rate determination rule specified in 'Chinese pharmacopoeia' of 2015 edition, the determination method of the selected dissolution rate is a slurry method, the volume of a dissolution medium is 900mL and the rotating speed is 50 revolutions per minute during the dissolution rate determination recommended by the pharmacopoeia, the method is operated, 15mL of solution is taken after 15 minutes, the solution is filtered, 2mL of subsequent filtrate is precisely taken, the subsequent filtrate is placed in a 50mL measuring flask, and water is added to dilute the solution to a scale; in addition, an appropriate amount of the acipimox reference substance is precisely weighed, dissolved by adding water and quantitatively diluted into 1mL of solution containing 10 mu g, the absorbance is measured by the same method, and the dissolution amount is calculated. In order to save the crystal form, the volume of the dissolution medium is set to be 90 mL.
Water, a hydrochloric acid buffer solution having a pH of 1.2, and a phosphoric acid buffer solution having a pH of 6.8 were selected as dissolution media.
(2) Establishment of HPLC analytical method
Octadecylsilane chemically bonded silica is used as a filling agent; methanol-0.0 lmol/L tetrabutylammonium hydroxide solution (15:85) (pH adjusted to 6.0 with phosphoric acid) as mobile phase, with a detection wavelength of 264 nm. Taking the reference solution and the blank solution as system adaptability solutions, taking 20 mu L of the system adaptability solutions, and injecting into a liquid chromatograph.
(3) Determination of Acipimox-1, 2-bis (4-pyridyl) ethylene eutectic crystal and comparative Acipimox crystal form dissolution rate
The acipimox-1, 2-di (4-pyridyl) ethylene eutectic and the comparative acipimox crystal are sieved by a 60-mesh sieve, so that the interference of the particle size difference of different crystal forms on the determination of the dissolution rate is reduced.
Dissolution test: by adopting a slurry method, 90mL of dissolution medium water is transferred into a crystallizer, the rotating speed of a stirring paddle is adjusted to be 50rpm/min, and the temperature is stabilized at 37 +/-0.5 ℃ by a super constant temperature water bath. Adding excessive Acipimox-1, 2-bis (4-pyridyl) ethylene eutectic into a crystallizer, stirring at a constant rotating speed under the condition of constant temperature, simultaneously timing, precisely sampling 5mL through an injector at six time points of 5min, 10 min, 20 min, 45min, 90min and 150min, quickly filtering by using a filter membrane, and simultaneously supplementing a dissolution medium with the same volume. The filtered supernatant was measured accurately with a pipette gun and diluted to 250mL with dissolution medium. Each set of experiments was performed in parallel 2 times. The above procedure was repeated for the other comparative example acipimox crystalline form dissolution test procedures.
Similarly, the dissolution medium was changed to a hydrochloric acid buffer solution having a pH of 1.2 or a phosphate buffer solution having a pH of 6.8, and these were run in parallel 2 times.
(4) Determination of dissolution: the standard solution and the sample solution obtained by the test are injected respectively, and the dissolution concentration (calculated by the acipimox) of the acipimox-1, 2-di (4-pyridyl) ethylene eutectic and the dissolution concentration of the acipimox crystal form of the comparative examples 1-3 in 5, 10, 20, 45, 90 and 150min are calculated according to an external standard method, and the results are shown in a table 3.
TABLE 3 dissolution concentration of Acipimox-1, 2-bis (4-pyridyl) ethenol cocrystal and comparative examples 1-3 crystalline forms in water
All the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic samples prepared in the examples of the present invention have the same dissolution property.
The acipimox-1, 2-di (4-pyridyl) ethylene eutectic prepared by the invention is quickly dissolved out in water, and keeps higher dissolution concentration along with the prolonging of time, so that the acipimox-1, 2-di (4-pyridyl) ethylene eutectic is suitable for being prepared into a preparation. The acipimox arginine hydrate (the crystal form of the comparative example 1) is quickly dissolved out in water, but the duration of high concentration is short, and the dissolution concentration of the acipimox is quickly reduced along with the time; the acipimox theophylline dihydrate (the crystal form in the comparative example 2) is slowly dissolved out in water, and after the maximum dissolution concentration is reached, the dissolution concentration is rapidly reduced; the dissolution properties of the acipimox arginine hydrate and the acipimox theophylline dihydrate are not suitable for preparing preparations on a large scale. The acipimox crystal form prepared according to patent CN86103304-2 (the crystal form of comparative example 3) is slowly dissolved in water, and the maximum dissolution concentration is low.
Table 4 dissolution concentrations of acipimox-1, 2-bis (4-pyridyl) etheno-cocrystal and comparative examples 1-3 crystalline form in hydrochloric acid buffer at pH 1.2
All the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic samples prepared in the examples of the present invention have the same dissolution property.
The acipimox-1, 2-di (4-pyridyl) ethylene eutectic prepared by the invention is quickly dissolved out in a hydrochloric acid buffer solution with the pH value of 1.2, and still keeps higher dissolution concentration along with the prolonging of time, so that the acipimox-1, 2-di (4-pyridyl) ethylene eutectic is suitable for being prepared into a preparation. The acipimox arginine hydrate (the crystal form of the comparative example 1) is quickly dissolved out in a hydrochloric acid buffer solution with the pH value of 1.2, but the high concentration lasts for a short time, and the dissolution concentration of the acipimox is quickly reduced along with the time; the acipimox theophylline dihydrate (the crystal form in the comparative example 2) is slowly dissolved in a hydrochloric acid buffer solution with the pH value of 1.2, and after the maximum dissolution concentration is reached, the dissolution concentration is rapidly reduced; the dissolution properties of the acipimox arginine hydrate and the acipimox theophylline dihydrate are not suitable for preparing preparations on a large scale. The crystalline form of acipimox prepared with reference to patent CN86103304-2 (crystalline form of comparative example 3) was slowly dissolved in a hydrochloric acid buffer at pH 1.2 with a low maximum dissolution concentration.
TABLE 5 dissolution concentration of Acipimox-1, 2-bis (4-pyridyl) ethenol cocrystal and comparative examples 1-3 in phosphate buffer solution at pH 6.8
All the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic samples prepared in the examples of the present invention have the same dissolution property.
The acipimox-1, 2-di (4-pyridyl) ethylene eutectic prepared by the invention is slowly dissolved in a phosphate buffer solution with the pH value of 6.8, reaches a dissolution peak value at 90min, still keeps higher dissolution concentration along with the prolonging of time, and is suitable for being prepared into a preparation. The acipimox arginine hydrate (the crystal form of the comparative example 1) is quickly dissolved in a phosphate buffer solution with the pH value of 6.8, the dissolution peak value is reached within 45min, but the high concentration duration is short, and the dissolution concentration of the acipimox is rapidly reduced along with the time extension; the acipimox theophylline dihydrate (the crystal form in the comparative example 2) is slowly dissolved in a phosphate buffer solution with the pH value of 6.8, and after the maximum dissolution concentration is reached, the dissolution concentration is rapidly reduced; the dissolution properties of the acipimox arginine hydrate and the acipimox theophylline dihydrate are not suitable for preparing preparations on a large scale. The crystalline form of acipimox prepared with reference to patent CN86103304-2 (crystalline form of comparative example 3) slowly dissolved in phosphate buffer solution at pH 6.8 with low maximum dissolution concentration.
The results of the previous dissolution rate studies (tables 3, 4, 5) show that the solubility of the co-crystal of acipimox-1, 2-bis (4-pyridyl) ethene is higher than that of the reported crystalline form of acipimox. The dissolution rate of the acipimox-1, 2-di (4-pyridyl) ethylene eutectic is high, the high dissolution concentration can be kept along with the time extension, and the solubility and the dissolution property of the acipimox eutectic are obviously better than those of the existing acipimox crystal form.
Claims (10)
1. The acipimox-1, 2-di (4-pyridyl) ethylene eutectic crystal is characterized by comprising the following components in percentage by weight: 1, 2-bis (4-pyridyl) ethylene is combined in a molar ratio of 2: 1.
2. The acipimox-1, 2-bis (4-pyridyl) etheno-cocrystal of claim 1, wherein the X-ray diffraction pattern, in terms of 2 Θ, using Cu-ka radiation has characteristic peaks at least at 5.79 ± 0.2 °, 8.67 ± 0.2 °, 12.00 ± 0.2 °, 16.40 ± 0.2 °.
3. The acipimox-1, 2-bis (4-pyridyl) etheno-cocrystal of claim 2, wherein the X-ray diffraction pattern, in terms of 2 θ, using Cu-ka radiation has characteristic peaks at least at 5.79 ± 0.2 °, 8.67 ± 0.2 °, 12.00 ± 0.2 °, 16.40 ± 0.2 °, 17.49 ± 0.2 °, 19.46 ± 0.2 °, 22.18 ± 0.2 °, 26.14 ± 0.2, 27.22 ± 0.2 °, 27.60 ± 0.2 °.
4. The co-crystal of acipimox-1, 2-bis (4-pyridyl) ethene of claim 3 wherein the characteristic peaks using Cu-Ka radiation follow the X-ray powder diffraction pattern of figure 1.
5. Acipimox-1, 2-bis (4-pyridyl) etheno co-crystal as claimed in any one of claims 1 to 4 having the crystallographic parameters: triclinic system, space group of
The unit cell parameters are:
a is 117.673(4) °, β is 100.534(3) °, γ is 94.828(3) °, unit cell volume
6. A preparation method of acipimox-1, 2-di (4-pyridyl) ethylene eutectic crystal is characterized by comprising the following specific preparation steps: adding the acipimox and the 1, 2-di (4-pyridyl) ethylene into an organic solvent A, heating and refluxing for reaction, cooling and crystallizing, filtering and drying to obtain the acipimox-1, 2-di (4-pyridyl) ethylene eutectic crystal.
7. The method for preparing the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic crystal according to claim 6, wherein the organic solvent A is one or more selected from methanol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, ethanol and isopropanol, preferably one or two selected from methanol, ethanol and ethyl acetate.
8. The method for preparing the acipimox-1, 2-bis (4-pyridyl) ethylene eutectic crystal according to claim 6, wherein the molar ratio of the acipimox to the 1, 2-bis (4-pyridyl) ethylene is 2.05-2.35: 1.
9. A pharmaceutical composition comprising the acipimox-1, 2-bis (4-pyridyl) etheno co-crystal of any one of claims 1 to 4 and a pharmaceutically acceptable further excipient component.
10. Use of a co-crystal of acipimox-1, 2-bis (4-pyridyl) ethene as claimed in any one of claims 1 to 4 in the manufacture of a medicament for lowering blood lipid.
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| CN117466784A (en) * | 2023-09-28 | 2024-01-30 | 青岛市市立医院 | Co-crystals of probenecid and 1, 2-di (4-pyridyl) ethylene, and preparation method and application thereof |
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| CN1651417A (en) * | 2004-12-15 | 2005-08-10 | 鲁南制药股份有限公司 | Preparation method of acymose |
| CN101863780A (en) * | 2009-04-15 | 2010-10-20 | 北京利乐生制药科技有限公司 | Choline salt of hypolipidemic drug and preparation method and pharmaceutical use thereof |
| CN109438369A (en) * | 2018-11-04 | 2019-03-08 | 鲁南制药集团股份有限公司 | A kind of preparation method of Acipimox |
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| CN1651417A (en) * | 2004-12-15 | 2005-08-10 | 鲁南制药股份有限公司 | Preparation method of acymose |
| CN101863780A (en) * | 2009-04-15 | 2010-10-20 | 北京利乐生制药科技有限公司 | Choline salt of hypolipidemic drug and preparation method and pharmaceutical use thereof |
| CN109438369A (en) * | 2018-11-04 | 2019-03-08 | 鲁南制药集团股份有限公司 | A kind of preparation method of Acipimox |
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| CN117466784A (en) * | 2023-09-28 | 2024-01-30 | 青岛市市立医院 | Co-crystals of probenecid and 1, 2-di (4-pyridyl) ethylene, and preparation method and application thereof |
| CN117466784B (en) * | 2023-09-28 | 2024-10-25 | 青岛市市立医院 | Co-crystals of probenecid and 1, 2-di (4-pyridyl) ethylene, and preparation method and application thereof |
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