An acexamate-1,2-di(4-pyridyl)ethene co-crystal

Abstract

The application belongs to the technical field of medicines, and specifically provides an acipimox-1,2-di(4-pyridyl)ethene co-crystal, a preparation method thereof and application thereof in preparation of a blood lipid-lowering drug. The X-ray diffraction spectrum of the acipimox-1,2-di(4-pyridyl)ethene co-crystal prepared by the application, using Cu-Kα radiation, has characteristic peaks at at least 5.79±0.2°, 8.67±0.2°, 12.00±0.2° and 16.40±0.2°. The acipimox-1,2-di(4-pyridyl)ethene co-crystal prepared by the application has high solubility, moderate dissolution rate and good stability, and has a good industrial application prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic pharmaceutical cocrystal, and particularly relates to a acipimox-1,2-di(4-pyridyl)ethene cocrystal. BACKGROUND

[0002] Pharmaceutical cocrystal is based on the principle of supramolecular chemistry, that is, molecular recognition and supramolecular self-assembly through intermolecular synergistic effect. The active pharmaceutical ingredient (API) and the suitable cocrystal former (CCF) are self-assembled through hydrogen bond, or assembled through non-covalent bond with saturation and directionality (such as van der Waals force of aromatic hydrocarbon or benzene ring, π-π conjugation and halogen bond) to form a new structure, that is, pharmaceutical cocrystal. It is based on hydrogen bond, and does not need to form new covalent bond or destroy existing covalent bond, so that the pharmacological effect of the drug itself can be retained while the physical and chemical properties of the drug are modified, such as improving the stability of the drug, reducing its hygroscopicity, improving the solubility, improving the bioavailability, etc., which provides a broad development prospect for the application of pharmaceutical cocrystal in the pharmaceutical industry. In recent years, the research on pharmaceutical cocrystal has attracted more and more attention. At present, the research on pharmaceutical cocrystal abroad has gradually increased and deepened, while the research on pharmaceutical cocrystal in China is relatively less. For generic drugs, the research on pharmaceutical cocrystal can also break the patent protection of the crystal form of the original drug by the original drug company, which is beneficial to the marketing of generic drugs. Therefore, it has important practical significance to obtain more novel, practical and creative pharmaceutical cocrystals, especially for some water-insoluble drugs.

[0003] Acipimox is a nicotinic acid derivative, which is a broad-spectrum long-acting lipid-regulating drug, and is used for various primary and secondary hyperlipidemia. It mainly acts on adipose tissue, inhibits the release of free fatty acids from adipose tissue, reduces the synthesis of plasma low-density lipoprotein and very low-density lipoprotein, thereby reducing the level of plasma low-density lipoprotein and very low-density lipoprotein in plasma, and at the same time, it increases the plasma HDL level by inhibiting the activity of hepatic lipase. Acipimox was developed by Farmitalia CarloErba Company in Italy, and was marketed in Italy in 1985. Subsequently, due to its high safety and significant efficacy, it has been marketed in Germany, Chile, Switzerland, Hong Kong, China and other countries and regions.

[0004] Pharmaceutical cocrystal can affect the physical and chemical properties of the drug, directly affect the dissolution and absorption efficiency of the drug under physiological conditions, and further affect the bioavailability, clinical efficacy, etc. of the drug. Through the way of pharmaceutical cocrystal, the advantages of cocrystal can be well applied, which plays a very important role in understanding and mastering the spatial arrangement of the effective molecules of the drug and the physical and chemical properties.

[0005] At present, there are many reports about acipimox, but most of them are about the preparation, preparation, physicochemical properties and pharmacology of acipimox, and there are few reports about the crystal eutectic structure of acipimox. Patents US2005239803A1, CN103508963A and the like all report the preparation method of acipimox. Patent CN86103304-2 obtains acipimox precipitate with crystal properties, which is acipimox hydrate, and the yield is low. In the previous reports, there are few reports on acipimox crystal eutectic, and the crystallographic characterization parameters of acipimox eutectic are not mentioned.

[0006] Patent CN109438371A reports a kind of acipimox arginine hydrate, by dissolving acipimox and arginine in mixed solution of organic solvent and water, heating and dissolving, after solution clarification, crystallization is carried out by cooling, and acipimox arginine hydrate crystal form is obtained by filtering and drying.

[0007] Patent CN109369546A reports a kind of acipimox theophylline dihydrate, acipimox and theophylline are added to mixed solution of organic solvent and water, heated and dissolved, stirred and reacted, cooled and crystallized, and acipimox theophylline dihydrate is obtained by filtering and drying. SUMMARY

[0008] In view of the deficiencies of the prior art, the present application provides an acipimox-1,2-di(4-pyridyl)ethylene eutectic.

[0009] As a pharmaceutical ingredient of the present application, acipimox is a white or white-like crystalline powder with the chemical name 5-methylpyrazine-2-carboxylic acid-4-oxide. The CAS number is 51037-30-0, the molecular formula is C6H6N2O3, and the structural formula is shown as a. The selected eutectic former in the present application is 1,2-di(4-pyridyl)ethylene with the molecular formula C 12 H 10 N2, and the structural formula is shown as b:

[0010]

[0011] In the first aspect of the present application, an acipimox-1,2-di(4-pyridyl)ethylene eutectic is provided. In the eutectic, the molar ratio of acipimox to 1,2-di(4-pyridyl)ethylene is 2:1.

[0012] The acipimox-1,2-di(4-pyridyl)ethylene eutectic has at least characteristic peaks at 5.79±0.2°, 8.67±0.2°, 12.00±0.2° and 16.40±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0013] Preferably, the X-ray diffraction spectrum of the acipimox-1,2-di(4-pyridyl)ethene co-crystal, using Cu-Kα radiation, has characteristic peaks at at least 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°.

[0014] Preferably, the X-ray diffraction spectrum of the acipimox-1,2-di(4-pyridyl)ethene co-crystal, using Cu-Kα radiation, has characteristic peaks at at least 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°. Figure 1

[0015] Preferably, the differential scanning calorimetry curve DSC of the acipimox-1,2-di(4-pyridyl)ethene co-crystal has an endothermic peak in the temperature range 210.85-231.74°C.

[0016] Preferably, the crystallographic parameters of the acipimox-1,2-di(4-pyridyl)ethene co-crystal are: triclinic crystal system, space group P with the following cell parameters: α = 117.673(4) °, β = 100.534(3) °, γ = 94.828(3) °, volume of the unit cell V = 1 1 1 1. 1 (3) A3.

[0017] The second aspect of the application provides a method for preparing an acipimox-1,2-di(4-pyridyl)ethene co-crystal, comprising the following steps: adding acipimox and 1,2-di(4-pyridyl)ethene to an organic solvent A, heating to reflux, cooling to crystallize, filtering and drying to obtain the acipimox-1,2-di(4-pyridyl)ethene co-crystal.

[0018] The organic solvent A is selected from one or more of the following: methanol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, ethanol, isopropanol.

[0019] Preferably, the organic solvent A is selected from one or two of the following: methanol, ethanol, ethyl acetate.

[0020] The molar ratio of acipimox to 1,2-di(4-pyridyl)ethene is 2.05-2.35:1.

[0021] Preferably, the molar ratio of acipimox to 1,2-di(4-pyridyl)ethene is 2.10-2.20:1.

[0022] The mass-volume ratio of 1,2-di(4-pyridyl)ethene to organic solvent A in the system is 4-6:1, where the mass is in mg and the volume is in mL.​

[0023] The temperature for the temperature-induced crystallization is 0-15℃.

[0024] Preferably, the temperature for the temperature-induced crystallization is 5-10℃.

[0025] The crystallization time is 40-62 hours.

[0026] Further preferably, the preparation method comprises the following steps:

[0027] The acipimox and 1,2-bis(4-pyridyl)ethene are dissolved in an organic solvent A, heated to dissolve at 45-75℃, stirred and refluxed for 7-12 hours, cooled to 0-15℃ for temperature-induced crystallization for 40-62 hours, filtered, the filter cake is washed, and dried to obtain the acipimox-1,2-bis(4-pyridyl)ethene co-crystal.

[0028] The solvent for washing the filter cake is selected from one of ethanol, ethyl acetate and acetone.

[0029] The drying temperature is 50-70℃, and the drying time is 8-12 hours.

[0030] The third aspect of the present application provides a use of the acipimox-1,2-bis(4-pyridyl)ethene co-crystal as an active ingredient in the preparation of a hypolipidemic drug.

[0031] Confirmation of crystal structure

[0032] X-ray crystal data were collected on a Rigaku XtaLAB Synergy model instrument at a test temperature of 293(2) K, using CuKa radiation, with data collected in ω scan mode and Lp correction. The crystal structure was calculated using the ShelXT program in the olex2 software, and the structure parameters were corrected by least squares method and the atomic species were distinguished using the ShelXL program. The positions of all hydrogen atoms were obtained using geometric calculation method and difference Fourier method. The goodness of fit (GooF value) was 1.123, close to 1.0, indicating that the weight scheme was appropriate and the structure was accurate.

[0033] The crystallographic data obtained by testing and analyzing the acipimox crystal prepared in the present application are shown in Table 1: the crystallographic parameters are: triclinic crystal system, space group P The cell parameters are: α = 117.673(4)°, β = 100.534(3)°, γ = 94.828(3)°, cell volume The molecular formula is: C 24 H 22N6O6, with a molecular weight of 490.47. The ORTEP plot of the acipimox-1,2-di(4-pyridyl)ethene co-crystal of the present application shows that acipimox and 1,2-di(4-pyridyl)ethene are linked together by intramolecular hydrogen bonds, in which the carboxyl H4 of acipimox forms a hydrogen bond with N4 on 1,2-di(4-pyridyl)ethene, and the other carboxyl H3 of acipimox forms an intramolecular hydrogen bond with N3 on 1,2-di(4-pyridyl)ethene, as shown in Figure 1. Figure 3 The packing plot of the acipimox-1,2-di(4-pyridyl)ethene co-crystal of the present application is shown in Figure 2. Figure 2

[0034] Table 1 Main crystallographic data of acipimox-1,2-di(4-pyridyl)ethene co-crystal

[0035]

[0036]

[0037] X-ray powder diffraction testing instrument and testing conditions: X-ray powder diffractometer: PANalytical Empyrean; Cu-Ka; sample stage: flat plate; incident light path: BBHD; diffracted light path: PLXCEL; voltage 45kv, current 40mA; divergence slit: 1 / 4; anti-scattering slit: 1; soller slit: 0.04 rad; step size: 0.5s; scanning range: 3-50°.

[0038] According to the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are shown in Figure 3 and Table 2. Figure 1

[0039] Table 2 PXRD peaks of acipimox-1,2-di(4-pyridyl)ethene co-crystal

[0040]

[0041]

[0042] All samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction spectrum.

[0043] The TGA / DSC test results of the acipimox-1,2-di(4-pyridyl)ethene co-crystal prepared by the method of the present application are shown in Figure 4. Figure 4 ​​As shown, the DSC detection result exists an endothermic peak in the temperature range of 210.85-231.74℃, and the corresponding peak temperature is 210.85℃. According to the TGA detection result, it can be seen that there is a weight loss step, and the combination of the DSC / TGA detection results shows that the acsimor-1,2-di(4-pyridyl) ethylene co-crystal prepared by the method does not contain other solvents.

[0044] The acsimor-1,2-di(4-pyridyl) ethylene co-crystal prepared by the method has the following advantages relative to the currently reported acsimor crystal forms:

[0045] (1) High stability. The XRD data of the acsimor-1,2-di(4-pyridyl) ethylene co-crystal does not change obviously after being placed in a 40℃ / 75%RH (open vial) environment for 7 days, indicating that it has good solid state stability.

[0046] (2) Fast dissolution rate and high dissolution concentration. The acsimor-1,2-di(4-pyridyl) ethylene co-crystal dissolves relatively fast in water, pH=1.2 hydrochloric acid buffer and pH=6.8 phosphate buffer, and still maintains a high dissolution rate as the dissolution time prolongs. BRIEF DESCRIPTION OF DRAWINGS

[0047] Figure 1 : X-ray powder diffraction pattern of acsimor-1,2-di(4-pyridyl) ethylene co-crystal;

[0048] Figure 2 : Packing diagram of acsimor-1,2-di(4-pyridyl) ethylene co-crystal;

[0049] Figure 3 : ORTEP diagram of acsimor-1,2-di(4-pyridyl) ethylene co-crystal;

[0050] Figure 4 : Differential scanning calorimetry curve (DSC) of acsimor-1,2-di(4-pyridyl) ethylene co-crystal;

[0051] Figure 5 : X-ray powder diffraction superimposed diagram of acsimor-1,2-di(4-pyridyl) ethylene co-crystal after being placed at 40℃ / 75%RH and before being placed. DETAILED DESCRIPTION

[0052] The beneficial effects of the present application will be further described by the following examples, which are only for illustrative purposes and do not limit the scope of the present application, and the changes and modifications made by the ordinary skilled in the art according to the present application are also included in the scope of the present application.

[0053] Example 1:

[0054] Add 154.1 mg of Acipimox (1 mmol, 2.15 eq), 84.4 mg of 1,2-di(4-pyridyl)ethylene (0.465 mmol) into 17 mL of methanol, heat to 45 °C, stir to dissolve, reflux for 7 hours, slowly cool to 5-10 °C, control the temperature and stand for crystallization for 48 hours, filter, wash the filter cake with acetone, vacuum dry at 50 °C for 12 h to obtain the Acipimox-1,2-di(4-pyridyl)ethylene co-crystal, with a yield of 97.33% and a purity of 99.97%.

[0055] Example 2:

[0056] Add 154.1 mg of Acipimox (2.1 eq), 86.8 mg of 1,2-di(4-pyridyl)ethylene into 15 mL of mixed solvent (10 mL of methanol and 5 mL of ethyl acetate), heat to 75 °C, stir to dissolve, reflux for 9 hours, slowly cool to 0-5 °C, control the temperature and stand for crystallization for 40 hours, filter, wash the filter cake with ethanol, vacuum dry at 70 °C for 8 h to obtain the Acipimox-1,2-di(4-pyridyl)ethylene co-crystal, with a yield of 96.56% and a purity of 99.98%.

[0057] Example 3:

[0058] Add 154.1 mg of Acipimox (2.2 eq), 82.8 mg of 1,2-di(4-pyridyl)ethylene into 21 mL of ethyl acetate, heat to 60 °C, stir to dissolve, reflux for 12 hours, slowly cool to 10-15 °C, control the temperature and stand for crystallization for 62 hours, filter, wash the filter cake with ethyl acetate, vacuum dry at 60 °C for 10 h to obtain the Acipimox-1,2-di(4-pyridyl)ethylene co-crystal, with a yield of 96.28% and a purity of 99.95%.

[0059] Example 4:

[0060] Add 154.1 mg of Acipimox (2.05 eq), 88.9 mg of 1,2-di(4-pyridyl)ethylene into 12 mL of acetonitrile, heat to 55 °C, stir to dissolve, reflux for 10 hours, slowly cool to -5-0 °C, control the temperature and stand for crystallization for 35 hours, filter, wash the filter cake with acetone, vacuum dry at 50 °C for 10 h to obtain the Acipimox-1,2-di(4-pyridyl)ethylene co-crystal, with a yield of 94.51% and a purity of 99.88%.

[0061] Example 5:

[0062] Add 154.0 mg of acipimox (1 mmol, 2.35 eq) and 77.5 mg of 1,2-di(4-pyridyl)ethylene into 26 mL of tetrahydrofuran, heat to 65°C, stir to dissolve, reflux for 10 hours, slowly cool to 15-20°C, control the temperature and stand for crystallization for 48 hours, filter, wash the filter cake with ethanol, and vacuum dry at 50°C for 12 hours to obtain acipimox-1,2-di(4-pyridyl)ethylene co-crystals, with a yield of 93.73% and a purity of 99.85%.

[0063] Example 6

[0064] Add 154.1 mg of acipimox (1 mmol, 2.5 eq) and 72.9 mg of 1,2-di(4-pyridyl)ethylene into 10 mL of acetone, heat to 35°C, stir to dissolve, reflux for 15 hours, slowly cool to -5-0°C, control the temperature and stand for crystallization for 48 hours, filter, wash the filter cake with acetone, and vacuum dry at 50°C for 10 hours to obtain acipimox-1,2-di(4-pyridyl)ethylene co-crystals, with a yield of 92.35% and a purity of 99.82%.

[0065] Comparative Example 1

[0066] Dissolve 5.0 g (32.4 mmol) of acipimox and 5.6 g (32.4 mmol) of arginine in a methanol aqueous solution (50 mL of methanol + 0.5 mL of water), heat to 60°C to dissolve, after the solution is clear, cool to 20°C, stand for crystallization for 52 hours, filter and dry to obtain acipimox arginine hydrate, with a yield of 96.80% and a purity of 99.92% by HPLC.

[0067] Comparative Example 2

[0068] Add 61.6 mg (0.4 mmol) of acipimox and 288.3 mg (1.6 mmol) of theophylline into 12 mL of a mixed solvent (10.0 mL of acetonitrile + 2.0 mL of purified water), heat to 60°C, stir to react for 10 hours, slowly cool to 5-10°C, control the temperature and stand for crystallization for 50 hours, filter, wash the filter cake with acetonitrile, and vacuum dry at 50°C for 10 hours to obtain acipimox theophylline dihydrate, with a yield of 96.53% and a purity of 99.94%.

[0069] Comparative Example 3

[0070] Into a 50 mL flask, 330 mg (1 mmol) of Na2WO4.2H2O was dissolved in 16 mL of water with mechanical stirring, reflux cooler and thermometer. 3.75 mL of 40% weight / volume (400 g / L) (44 mmol) of hydrogen peroxide was added to the solution, which was adjusted to pH 1.5 with dilute H2SO4, and then 5.52 g (40 mmol) of 2-carboxy-5-methylpyrazine was added.

[0071] The suspension of water produced by the reaction was heated to 70°C with stirring and maintained at this temperature for 2.5 hours. A gradually increasing solubility of the suspension was thus obtained. Finally, it was found that part of the product precipitated. The mixture was left to stand overnight at room temperature, producing a precipitate of the reaction product in the form of crystals. This product was filtered and washed with ice water, and then placed on a porcelain plate to dry, obtaining 4.68 g of 2-carboxy-5-methylpyrazine-4-oxide, part of which was in the hydrated form (2.83%), corresponding to 4.54 g of anhydrous product, with a yield of 73.01% and an HPLC purity of 95.15%.

[0072] 1. Stability test

[0073] The co-crystal of acipimox-1,2-di(4-pyridyl)ethene prepared in the present application was stored at 40°C / 75% RH (open vial). Analysis was performed by XRD for any possible changes in the crystal structure over 7 days, with the results shown in the attached Figure 5 .

[0074] The co-crystal of acipimox-1,2-di(4-pyridyl)ethene prepared in the present application was stored at 40°C / 75% RH (open vial). Analysis was performed by XRD for any possible changes in the crystal structure over 7 days, with the results shown in the attached

[0075] 2. Dissolution rate test

[0076] (1) Selection of dissolution method

[0077] According to the dissolution determination method stipulated in the 2015 edition of the Chinese Pharmacopoeia, the determination method for dissolution was selected as the slurry method. The volume of the dissolution medium recommended by the Pharmacopoeia for dissolution determination is 900 mL, and the rotation speed is 50 revolutions / minute. According to the law, after 15 minutes, 15 mL of the solution was taken, filtered, and 2 mL of the filtrate was accurately taken and placed in a 50 mL volumetric flask, diluted to the mark with water; another appropriate amount of acipimox reference substance was accurately weighed, dissolved and quantitatively diluted to 1 mL to obtain a solution containing 10 μg, and the absorbance was determined by the same method to calculate the dissolution amount. In order to save the crystal form, the volume of the dissolution medium was determined as 90 mL.

[0078] Water, pH = 1.2 hydrochloric acid buffer, and pH = 6.8 phosphate buffer solution were selected as the dissolution medium.

[0079] (2)Establishment of HPLC analysis method

[0080] The octadecylsilane-bonded silica gel was used as the filler; the methanol-0.01 mol / L tetrabutylammonium hydroxide solution (15:85) (pH value was adjusted to 6.0 by phosphoric acid) was used as the mobile phase, and the detection wavelength was 264 nm. The control solution and the blank solution were used as the system suitability solution, and 20 μL of the system suitability solution was injected into the liquid chromatograph.

[0081] (3) Dissolution rate determination of acipimox-1,2-di(4-pyridyl)ethene co-crystal and comparative examples acipimox crystal forms

[0082] The acipimox-1,2-di(4-pyridyl)ethene co-crystal and comparative examples acipimox crystal forms were sieved through a 60-mesh sieve to reduce the interference of the size difference of different crystal forms on the dissolution rate determination.

[0083] Dissolution test: The paddle method was used, 90 mL of the dissolution medium water was moved into the crystallizer, the stirring paddle speed was adjusted to 50 rpm / min, and the temperature was stabilized at 37±0.5°C by using a super constant temperature water bath. Excessive acipimox-1,2-di(4-pyridyl)ethene co-crystal was added to the crystallizer, and the temperature was kept constant while stirring at a constant speed, and the time was counted, and 5 mL was precisely sampled at six time points of 5, 10, 20, 45, 90, and 150 min by using a syringe, and then filtered rapidly by using a filter membrane, and at the same time, the same volume of the dissolution medium was supplemented. 0.5 mL of the supernatant after filtration was accurately taken by using a pipette, and diluted to 250 mL with the dissolution medium. Each test was carried out in parallel for 2 times. The dissolution test of other comparative examples acipimox crystal forms also repeated the above steps.

[0084] Similarly, the dissolution medium was replaced with hydrochloric acid buffer solution with pH=1.2 and phosphate buffer solution with pH=6.8, and each was operated in parallel for 2 times.

[0085] (4) Determination of dissolution: The standard solution and the sample solution obtained by the test were injected, and the dissolution concentrations (calculated as acipimox) of acipimox-1,2-di(4-pyridyl)ethene co-crystal and comparative examples 1-3 acipimox crystal forms at 5, 10, 20, 45, 90, and 150 min were calculated by using the external standard method, and the results are shown in Table 3.

[0086] Table 3 Dissolution concentrations of acipimox-1,2-di(4-pyridyl)ethene co-crystal and comparative examples 1-3 crystal forms in water

[0087]

[0088]

[0089] All the prepared samples of acipimox-1,2-di(4-pyridyl)ethene co-crystal in the embodiments of the present application have the same dissolution properties.

[0090] The prepared acipimox-1,2-di(4-pyridyl)ethene co-crystal in the present application is rapidly dissolved in water, and still maintains a high dissolution concentration with the extension of time, and is suitable for preparation into a preparation. The acipimox arginine hydrate (crystal form of comparative example 1) is rapidly dissolved in water, but the high concentration lasts for a short time, and the acipimox dissolution concentration rapidly decreases with the extension of time; the acipimox theophylline dihydrate (crystal form of comparative example 2) is slowly dissolved in water, and the dissolution concentration rapidly decreases after reaching the maximum dissolution concentration; the dissolution properties of the above acipimox arginine hydrate and acipimox theophylline dihydrate are not suitable for large-scale preparation of a preparation. The acipimox crystal form prepared according to the patent CN86103304-2 (crystal form of comparative example 3) is slowly dissolved in water, and the maximum dissolution concentration is low.

[0091] Table 4: Dissolution concentration of acipimox-1,2-di(4-pyridyl)ethene co-crystal and comparative examples 1-3 crystal forms in pH=1.2 hydrochloric acid buffer solution

[0092]

[0093]

[0094] All the prepared samples of acipimox-1,2-di(4-pyridyl)ethene co-crystal in the embodiments of the present application have the same dissolution properties.

[0095] The prepared acipimox-1,2-di(4-pyridyl)ethene co-crystal in the present application is rapidly dissolved in water, and still maintains a high dissolution concentration with the extension of time, and is suitable for preparation into a preparation. The acipimox arginine hydrate (crystal form of comparative example 1) is rapidly dissolved in water, but the high concentration lasts for a short time, and the acipimox dissolution concentration rapidly decreases with the extension of time; the acipimox theophylline dihydrate (crystal form of comparative example 2) is slowly dissolved in water, and the dissolution concentration rapidly decreases after reaching the maximum dissolution concentration; the dissolution properties of the above acipimox arginine hydrate and acipimox theophylline dihydrate are not suitable for large-scale preparation of a preparation. The acipimox crystal form prepared according to the patent CN86103304-2 (crystal form of comparative example 3) is slowly dissolved in water, and the maximum dissolution concentration is low.

[0096] Table 5: Dissolution concentration of acipimox-1,2-di(4-pyridyl)ethene co-crystal and comparative examples 1-3 crystal forms in pH=6.8 phosphate buffer solution

[0097]

[0098]

[0099] All the prepared samples of acipimox-1,2-di(4-pyridyl)ethene co-crystal in the embodiments of the present application have the same dissolution properties.

[0100] The acipimox-1,2-di(4-pyridyl)ethene co-crystal prepared in the present application is slowly dissolved in the phosphate buffer solution at pH = 6.8, reaches the peak of dissolution at 90 min, and still maintains a high dissolution concentration with the extension of time, which is suitable for preparation of a preparation. The acipimox arginine hydrate (crystal form of comparative example 1) is quickly dissolved in the phosphate buffer solution at pH = 6.8, reaches the peak of dissolution at 45 min, but the duration of high concentration is short, and the acipimox dissolution concentration rapidly decreases with the extension of time; the acipimox theophylline dihydrate (crystal form of comparative example 2) is slowly dissolved in the phosphate buffer solution at pH = 6.8, and the dissolution concentration rapidly decreases after reaching the maximum dissolution concentration; the dissolution properties of the above acipimox arginine hydrate and acipimox theophylline dihydrate are not suitable for large-scale preparation of a preparation. The acipimox crystal form prepared according to the patent CN86103304-2 (crystal form of comparative example 3) is slowly dissolved in the phosphate buffer solution at pH = 6.8, and the maximum dissolution concentration is low.

[0101] The previous dissolution rate research results (Tables 3, 4, and 5) show that the solubility of acipimox-1,2-di(4-pyridyl)ethene co-crystal is higher than that of the reported acipimox crystal forms. The dissolution rate of acipimox-1,2-di(4-pyridyl)ethene co-crystal is fast and can maintain a high dissolution concentration with the extension of time, and the solubility and dissolution properties are obviously better than those of the existing acipimox crystal forms.

Claims

1. An acipimox-1,2-di(4-pyridyl)ethene co-crystal, characterized by, is formed by combining acipimox: 1,2-bis(4-pyridyl)ethene in a molar ratio of 2:1; the acipimox-1,2-bis(4-pyridyl)ethene co-crystal is characterized in that the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation has at least characteristic peaks 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°.

2. The aceclidin-1,2-di(4-pyridyl)ethene co-crystal of claim 1, wherein, the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation has at least characteristic peaks 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°.

3. The aceclidin-1,2-di(4-pyridyl)ethene co-crystal of claim 1, wherein, the characteristic peaks are in accordance with the X-ray powder diffraction spectrum as shown in Figure 1 using Cu-Kα radiation.

4. The aceclidin-1,2-di(4-pyridyl)ethene co-crystal of claim 1, wherein, with crystallographic parameters: triclinic, chiral space group P P 1, with unit cell parameters: a = 9.0269(3) A, b = 11.7606(4) A, c = 12.5229(5) A, a = 117.673(4)°, b = 100.534(3)°, g = 94.828(3)°, volume of the unit cell V = 1135.50(8) A 3 .

5. A process for the preparation of the acipimox-1,2-di(4-pyridyl)ethene co-crystal according to any one of claims 1 to 4, characterized in that, The specific preparation steps include: adding acipimox and 1,2-bis(4-pyridyl)ethene into organic solvent A, heating to reflux for reaction, cooling to crystallize, filtering and drying to obtain acipimox-1,2-bis(4-pyridyl)ethene co-crystal.

6. The method of preparing acipimox-1,2-di(4-pyridyl)ethene cocrystal according to claim 5, characterized in that, The organic solvent A is selected from one or more of methanol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, ethanol and isopropanol.

7. The method of producing acipimox-1,2-di(4-pyridyl)ethene cocrystal according to claim 5, characterized in that, The organic solvent A is one or two of methanol, ethanol and ethyl acetate.

8. The method of producing an acipimox-1,2-di(4-pyridyl)ethene co-crystal according to claim 5, characterized in that, The molar ratio of acipimox to 1,2-bis(4-pyridyl)ethene is 2.05-2.35:

1.

9. A pharmaceutical composition comprising the acipimox-1,2-bis(4-pyridyl)ethene co-crystal of any one of claims 1-4, and comprising other pharmaceutically acceptable excipient components.

10. Use of the acipimox-1,2-bis(4-pyridyl)ethene co-crystal of any one of claims 1-4 in the preparation of a hypolipidemic agent.

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