A 1,2-di(4-pyridyl)ethane-acemidox eutectic

Abstract

The present invention belongs to the field of medical technology, and specifically provides 1,2-di(4-pyridyl)ethane-acemidox eutectic and its preparation method. The 1,2-di(4-pyridyl)ethane-acemidox eutectic prepared by the present invention is formed by combining acipimox with 1,2-di(4-pyridyl)ethane in a molar ratio of 2:1, and using Cu-Kα radiation, the X-ray diffraction spectrum represented by 2θ has characteristic peaks at: 9.88±0.2°, 13.92±0.2°, 24.56±0.2°, 26.12±0.2°, and 26.86±0.2°. The 1,2-di(4-pyridyl)ethane-acemidox eutectic prepared by the present invention has a high product purity and good stability after being placed in a solid state. The preparation process of the present invention is simple and has good industrial application prospects.

Description

Technical Field

[0001] The invention belongs to the technical field of organic drug co-crystals, and particularly relates to a 1,2-di(4-pyridyl)ethane-acipimox co-crystal. Background Art

[0002] Pharmaceutical cocrystals are based on supramolecular chemistry principles, i.e., molecular recognition and supramolecular self-assembly through the synergistic interaction between molecules. Active pharmaceutical ingredients (API) and suitable cocrystal formers (CCF) self-assemble through hydrogen bonds, or saturated and directional non-covalent bonds (such as van der Waals forces of aromatic hydrocarbons or benzene rings, π-π conjugation and halogen bonds) to form a new type of structure, namely, pharmaceutical cocrystals. Based on hydrogen bonds, it does not require the formation of new covalent bonds, nor does it require the destruction of existing covalent bonds. While retaining the pharmacological effects of the drug itself, it can also modify the physicochemical properties of the drug, such as improving the stability of the drug, reducing its hygroscopicity, improving solubility, and improving bioavailability, etc., providing broad development prospects for the application of pharmaceutical cocrystals in the pharmaceutical industry. In recent years, the research on pharmaceutical cocrystals has attracted more and more attention. At present, the research on pharmaceutical cocrystals abroad has gradually increased and deepened; while the research on pharmaceutical cocrystals in China is still relatively small. For generic drugs, the research on drug co-crystals can also break the patent protection of drug crystal forms by original drug companies, which is conducive to bringing generic drugs to the market. Therefore, it is of great practical significance to obtain more novel, practical and creative drug co-crystals, especially some water-insoluble drugs.

[0003] Acipimox is a nicotinic acid derivative and a broad-spectrum, long-acting lipid-regulating drug used for various primary and secondary hyperlipidemias. 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 levels of plasma low-density lipoprotein and very-low-density lipoprotein in plasma, and increases plasma HDL levels by inhibiting the activity of hepatic lipase. Acipimox was developed by Farmitalia CarloErba of Italy and was launched in Italy in 1985. Later, it was launched in Germany, Chile, Switzerland and other countries and regions due to its high safety and significant efficacy.

[0004] Drug co-crystals will affect the physicochemical properties of drugs, directly affect the dissolution and absorption efficiency of drugs under physiological pH 7.4, and further affect the bioavailability and clinical efficacy of drugs. Through drug co-crystals, the advantages of co-crystals can be well utilized, which plays a very important role in understanding and mastering the spatial arrangement and physicochemical properties of effective drug molecules.

[0005] At present, there are many reports on acipimox, but they are mainly reports on its preparation, formulation, physicochemical properties and pharmacological properties, and there are few reports on its crystal eutectic structure. Patents US2005239803A1 and CN103508963A all report the preparation method of acipimox, and patent CN86103304.3 obtains a crystalline acipimox precipitate, which is acipimox hydrate, with a low yield. In previous reports, there are few reports on acipimox crystal eutectics, and the crystallographic characterization parameters of acipimox eutectics are not mentioned. Summary of the invention

[0006] In view of the deficiencies in the prior art, the present invention provides a 1,2-di(4-pyridyl)ethane-acipimox cocrystal.

[0007] Acipimox, as the drug ingredient of the present invention, has a chemical name of 5-methylpyrazine-2-carboxylic acid-4-oxide, and is a white or off-white crystalline powder. CAS number: 51037-30-0, molecular formula: C6H6N2O3, and its structural formula is shown in a. The eutectic former selected in the present invention is 1,2-di(4-pyridyl)ethane, and its molecular formula is C 12 H 12 N2, whose structural formula is shown in b.

[0008]

[0009] In a first aspect of the present invention, a 1,2-di(4-pyridyl)ethane-acipimox co-crystal is provided. In the co-crystal, the molar ratio of acipimox to 1,2-di(4-pyridyl)ethane is 2:1.

[0010] The 1,2-di(4-pyridyl)ethane-acipimox cocrystal uses Cu-Kα radiation, and the X-ray diffraction spectrum represented by 2θ has characteristic peaks at 9.88±0.2°, 13.92±0.2°, 24.56±0.2°, 26.12±0.2°, and 26.86±0.2°.

[0011] Preferably, the 1,2-di(4-pyridyl)ethane-acipimox cocrystal uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 9.88±0.2°, 13.92±0.2°, 15.38±0.2°, 15.70±0.2°, 24.56±0.2°, 26.12±0.2°, 26.86±0.2°, 29.59±0.2°, and 36.90±0.2°.

[0012] Preferably, the characteristic peaks of the 1,2-di(4-pyridyl)ethane-acipimox cocrystal, when irradiated with Cu-Kα, conform to the following Figure 1The X-ray powder diffraction pattern is shown.

[0013] Preferably, the 1,2-di(4-pyridyl)ethane-acipimox cocrystal has an endothermic peak at 184.43° C. in the differential scanning calorimetry curve DSC.

[0014] Preferably, the crystallographic parameters of the 1,2-di(4-pyridyl)ethane-acipimox cocrystal are: monoclinic system, space group is P21 / c; unit cell parameters are: α=90°,β=99.3338(11)°,γ=90°,unit cell volume

[0015] The second aspect of the present invention provides a method for preparing a 1,2-di(4-pyridyl)ethane-acemidox cocrystal, and the specific preparation steps include: adding acipimox and 1,2-di(4-pyridyl)ethane to an organic solvent A, heating to dissolve, controlling the temperature to reflux after the solution is clarified, reacting, cooling to crystallize, filtering and drying to obtain the 1,2-di(4-pyridyl)ethane-acemidox cocrystal.

[0016] The organic solvent A is selected from one or two of methanol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, ethanol and isopropanol.

[0017] Preferably, the organic solvent A is selected from one or two of methanol, ethanol and ethyl acetate.

[0018] The molar ratio of acipimox to 1,2-di(4-pyridyl)ethane is 1:0.4-0.6.

[0019] Preferably, the molar ratio of acipimox to 1,2-di(4-pyridyl)ethane is 1:0.5.

[0020] The mass-to-volume ratio of 1,2-di(4-pyridyl)ethane to the organic solvent A in the system is 4-6:1, wherein the mass is measured in mg and the volume is measured in ml.

[0021] The cooling and crystallization temperature is 0-10°C.

[0022] Preferably, the crystallization temperature is 5 to 10°C.

[0023] The crystallization time is 30 to 50 hours.

[0024] Further preferably, the preparation method comprises the following steps:

[0025] Acipimox and 1,2-di(4-pyridyl)ethane are dissolved in an organic solvent A, heated to 50-80°C for dissolution, stirred and refluxed for reaction for 7-10 hours, cooled to 0-10°C for crystallization for 30-50 hours, filtered, the filter cake is washed, and dried to obtain 1,2-di(4-pyridyl)ethane-aceimox cocrystal.

[0026] The solvent for washing the filter cake is selected from one of methanol, ethanol and ethyl acetate.

[0027] The drying temperature is 55-75° C., and the drying time is 8-10 hours.

[0028] The third aspect of the present invention provides a use of 1,2-di(4-pyridyl)ethane-acipimox cocrystal as an active ingredient in the preparation of a lipid-lowering drug.

[0029] Confirmation of crystal structure

[0030] X-ray crystallographic data were collected on a Rigaku XtaLAB Synergy instrument at 293(2)K using CuKa radiation, ω scanning mode, and Lp correction. The crystal structure was calculated using the ShelXT program in the olex2 software, and the ShelXL program was used to correct the structural parameters and identify the atomic species by the least squares method. The geometric calculation method and the difference Fourier method were used to obtain the positions of all hydrogen atoms. The goodness of fit (GooF value) was 1.123, close to 1.0, indicating that the weighting scheme was appropriate and the structure was accurate.

[0031] The crystallographic data obtained by testing and analyzing the 1,2-di(4-pyridyl)ethane-acemidox cocrystal prepared by the present invention are (Table 1): Its crystallographic parameters are: monoclinic system, space group is P2 1 / c ; The unit cell parameters are: α=90,β=99.3338(11),γ=90,unit cell volume The molecular formula is: C 24 H 24 N6O6, molecular weight: 492.49. The ORTEP diagram of the 1,2-di(4-pyridyl)ethane-acemidox eutectic of the present invention shows that acipimox and 1,2-di(4-pyridyl)ethane are linked together by intramolecular hydrogen bonds, wherein the carboxyl group H4 of acipimox forms a hydrogen bond with N4 on 1,2-di(4-pyridyl)ethane, and the carboxyl group H3 of another acipimox molecule forms an intramolecular hydrogen bond with N3 on 1,2-di(4-pyridyl)ethane, as shown in the attached figure. Figure 3 The stacking diagram of 1,2-di(4-pyridyl)ethane-acemidox of the present invention is shown in the attached Figure 2 shown.

[0032] Table 1 Main crystallographic data of 1,2-di(4-pyridyl)ethane-acemidox cocrystal

[0033]

[0034] X-ray powder diffraction test instrument and test conditions: X-ray powder diffractometer: PANalyticalE; Cu-Kα; sample stage: flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kv, current 40mA; divergence slit: 1 / 4; anti-scattering slit: 1; Soller slit: 0.04rad; step size: 0.5s; scanning range: 3~50°.

[0035] According to the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are shown in the attached Figure 1 And Table 2.

[0036] Table 2 PXRD peaks of 1,2-di(4-pyridyl)ethane-acemidox cocrystal

[0037]

[0038]

[0039] All samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction spectra.

[0040] The TGA / DSC test results of the 1,2-di(4-pyridyl)ethane-acemidox eutectic prepared by the method of the present invention are as follows: Figure 4 As shown, the DSC test results have an endothermic peak corresponding to a temperature of 184.43° C. According to the TGA test results, it can be seen that there is a weight loss step. Combined with the DSC / TGA test results, it is shown that the 1,2-di(4-pyridyl)ethane-acemidox eutectic prepared by the present invention does not contain other solvents.

[0041] The 1,2-di(4-pyridyl)ethane-acetilimus cocrystal prepared by the method of the present invention has the following advantages over the currently reported acipimus crystal form:

[0042] The stability is high. After the 1,2-di(4-pyridyl)ethane-acemidox cocrystal has been subjected to light irradiation test and placed in a high temperature and high humidity environment, the HPLC purity is still higher than 99.70%, and the solid state stability is good. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 : X-ray powder diffraction pattern of 1,2-di(4-pyridyl)ethane-acemidox cocrystal.

[0044] Figure 2: Packing diagram of 1,2-di(4-pyridyl)ethane-acipimox cocrystal.

[0045] Figure 3 : ORTEP diagram of 1,2-di(4-pyridyl)ethane-acemidox cocrystal.

[0046] Figure 4 : Differential scanning calorimetry (DSC) graph of 1,2-di(4-pyridyl)ethane-acemidox cocrystal. DETAILED DESCRIPTION

[0047] The beneficial effects of the present invention are further described by the following examples. The examples are only for illustrative purposes and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by ordinary technicians in the field according to the present invention are also included in the scope of the present invention. Impurity I is 5-methylpyrazine-2-carboxylic acid.

[0048] Example 1

[0049] 154.12 mg of acipimox and 92.12 mg of 1,2-di(4-pyridyl)ethane were added to 20 ml of methanol, stirred and dissolved, and the temperature was controlled at 65°C. The reaction was refluxed for 8 hours. After the reaction was completed, the temperature was slowly lowered to 5-10°C, and the mixture was allowed to stand for crystallization for 40 hours. After the crystallization was completed, the mixture was filtered, and the filter cake was washed with methanol. The filter cake was vacuum dried at 50°C for 12 hours to obtain 1,2-di(4-pyridyl)ethane acipimox cocrystal with a yield of 98.33% and a purity of 99.95%.

[0050] Example 2

[0051] 154.12 mg of acipimox and 73.70 mg of 1,2-di(4-pyridyl)ethane were added to 15 ml of ethanol, stirred to dissolve, and the temperature was controlled to reflux. The reaction was carried out for 10 hours. After the reaction was completed, the temperature was slowly lowered to 0-5°C, and the mixture was allowed to stand for crystallization for 40 hours. After the crystallization was completed, the mixture was filtered, and the filter cake was washed with ethanol. The mixture was vacuum dried at 55°C for 8 hours to obtain 1,2-di(4-pyridyl)ethane acipimox cocrystal with a yield of 96.56% and a purity of 99.94%.

[0052] Example 3

[0053] 154.12 mg of acipimox and 110.54 mg of 1,2-di(4-pyridyl)ethane were added to 25 ml of ethyl acetate, stirred to dissolve, and the temperature was controlled to reflux for 7 hours. After the reaction was completed, the temperature was slowly lowered to 10-15°C, and the mixture was allowed to stand for crystallization for 48 hours. The mixture was filtered, and the filter cake was washed with methanol. The mixture was vacuum dried at 60°C for 10 hours to obtain 1,2-di(4-pyridyl)ethane acipimox cocrystal with a yield of 96.88% and a purity of 99.90%.

[0054] Example 4

[0055] Add 154.12 mg of acipimox and 64.48 mg of 1,2-di(4-pyridyl)ethane to 10 ml of acetone, stir to dissolve, control the temperature to reflux, react for 8 hours, and after the reaction is completed, slowly cool to -5 to 0°C, stand for crystallization for 35 hours, filter, wash the filter cake with ethyl acetate, and vacuum dry at 50°C for 10 hours to obtain 1,2-di(4-pyridyl)ethane acipimox cocrystal with a yield of 94.51% and a purity of 99.82%.

[0056] Example 5

[0057] 154.12 mg of acipimox and 119.76 mg of 1,2-di(4-pyridyl)ethane were added to 35 ml of acetonitrile, stirred to dissolve, and the temperature was controlled to reflux for 7 hours. After the reaction was completed, the temperature was slowly lowered to 5-10°C, and the mixture was allowed to stand for crystallization for 30 hours. The mixture was filtered, and the filter cake was washed with methanol. The filter cake was vacuum dried at 50°C for 12 hours to obtain 1,2-di(4-pyridyl)ethane acipimox cocrystal with a yield of 94.33% and a purity of 99.84%.

[0058] Example 6

[0059] 154.12 mg of acipimox and 92.12 mg of 1,2-di(4-pyridyl)ethane were added to 20 ml of a mixed solvent (10 ml of methanol + 10 ml of ethanol), the temperature was controlled to reflux, and the reaction was carried out for 8 hours. After the reaction was completed, the temperature was slowly lowered to 5-10°C, and the temperature was controlled to stand for crystallization for 40 hours. The mixture was filtered, and the filter cake was washed with methanol. The filter cake was vacuum dried at 50°C for 10 hours to obtain 1,2-di(4-pyridyl)ethane acipimox cocrystals with a yield of 97.12% and a purity of 99.90%.

[0060] Comparative Example 1:

[0061] 2730 ml of 98% concentrated sulfuric acid was added to a 10L glass reactor, 910.0 g of 5-methylpyrazine-2,3-dicarboxylic acid was added under stirring, heated to 60°C, heated for 1 hour, then 5.5 kg of water, 164.9 g of sodium tungstate (Na2WO4·2H2O), and 623.0 g of 30% hydrogen peroxide were slowly added, and heating and stirring were continued for 8 hours, cooled and crystallized under ice bath conditions for 4 hours, the solid was filtered, and dried at 100°C for 12 hours to prepare 595 g of the product acipimox. The product yield in the reaction was 77.30%, HPLC purity was 96.20%, and impurity I was 2.80%.

[0062] Comparative Example 2:

[0063] Add 200 ml of water to 100 g of crude acipimox, heat to 100°C, stir and dissolve, add 3.0 g of activated carbon, continue to keep warm and stir for 20 minutes, and filter with suction; cool the filtrate to 60°C at 10°C / h, then drop 220 g of acetone therein, cool to 5°C at 10°C / h for crystallization for 7 hours, filter with suction, wash the filter cake with acetone, and dry (0.01 MPa, 80°C) to obtain off-white acipimox, with a yield of 88.60%. HPLC purity: 98.30%, 5-methylpyrazine-2-carboxylic acid (impurity I): 0.50%.

[0064] Comparative Example 3:

[0065] 330 mg (1 mmol) of Na2WO4·2H2O was placed in a 50 ml flask, dissolved in 16 ml of water and equipped with a mechanical stirrer, a reflux cooler and a thermometer. 3.75 ml of 40% weight / volume (400 g / L) (44 mmol) of hydrogen peroxide was added to the solution, the pH was adjusted to 1.5 with dilute H2SO4, and then 5.52 g (40 mmol) of 2-carboxy-5-methylpyrazine was added.

[0066] The suspension of water produced by the reaction was heated to 70°C with stirring and maintained at this temperature for 2.5 hours. Thus, a gradually solubilized suspension was obtained. Finally, part of the product was found to precipitate. The mixture was allowed to stand overnight at room temperature, and a crystalline precipitate of the reaction product was produced. This product was filtered and washed with ice water, and then dried on a bisque plate to obtain 4.68 g of 2-carboxyl-5-methylpyrazine-4-oxide, which was partially in the hydrated form (2.83%), equivalent to 4.54 g of anhydrous product. The yield was 73.01%. HPLC purity: 95.10%, impurity I: 2.30%.

[0067] Comparative Example 4:

[0068] 250 mg (0.75 mg) of Na2WO4·2H2O was placed in a 50 ml flask, dissolved in 13 ml of water and equipped with a mechanical stirrer, a reflux cooler and a thermometer. 3.23 ml of 40% weight / volume (400 g / L) (38 mmol) of hydrogen peroxide was added to the solution, the pH was adjusted to 2.0 with dilute H2SO4, and then 3.76 g of 98% (30 mmol) of 2-carboxy-5-methylpyrazine was added.

[0069] The aqueous suspension produced by the reaction was heated to 80°C with stirring and maintained at this temperature for 2 hours. After 45 minutes, a completely solubilized suspension was obtained. Finally, the solution was allowed to stand overnight at room temperature to produce a crystalline precipitation of the reaction product. The product was filtered and washed with ice water, and then dried on a bisque plate to obtain 3.02 g of 2-carboxy-5-methylpyrazine-4-oxide monohydrate (experimental value H2O-11.35%; calculated value of monohydrate product H2O-11.3%), with a yield of 63.02%. HPLC purity: 94.21%, impurity I: 3.40%.

[0070] Comparative Example 5:

[0071] 2-Carboxyl-5-methylpyrazine 4-oxide (2.5 g) was added to a mixed solution of methanol (60 ml) and ethanolamine (1.1 ml). The mixture was heated to reflux for 20 minutes, then cooled and filtered to obtain 2-carboxyl-5-methylpyrazine 4-oxide ethanolamine salt (2.1 g) after crystallization from methanol, mp. 177-180°C, yield: 60.17%, HPLC purity: 96.81%, impurity I: 2.10%.

[0072] Comparative Example 6:

[0073] Under nitrogen protection, the reaction was carried out in a 500 mL.x.4-necked flask equipped with a mechanical stirrer, a water condenser (with a gas inlet) and a thermocouple. Sodium trimethylsilanol (3.71 g) and THF (90 g) were added to the reactor, followed by 5-methylpyrazinecarboxylic acid-4-oxide ethyl ester (6.00 g), the mixture was stirred at room temperature for 4 hours, the solid was collected by filtration and rinsed with THF (3x45 g). Vacuum drying (25 inches of mercury, 65° C.) gave 5.38 g (yield: 92.50%) of the sodium salt as an off-white solid, HPLC purity: 96.80%, impurity I: 2.41%.

[0074] Stability test

[0075] Temperature, humidity and light test

[0076] The specific stability test method was carried out in accordance with the guidance method for stability investigation in Part 4 of the 2015 edition of the Chinese Pharmacopoeia. The purity test was carried out using HPLC. The specific test results are shown in the table below.

[0077] Table 3 Stability test results of methylpyrazine derivative crystals under light, high temperature and high humidity conditions

[0078]

[0079]

[0080] After testing, all 1,2-di(4-pyridyl)ethanemethyl-acetifloxacin cocrystals prepared by the present invention can achieve similar stability effects. The purity and appearance of the 1,2-di(4-pyridyl)ethane-acetifloxacin cocrystals prepared by the present invention do not undergo significant changes under conditions of light, high temperature and high humidity, while the purity of the crystal forms of Comparative Examples 1 to Comparative Examples 6 is greatly reduced under the same experimental conditions, and the impurity content is significantly increased, that is, deterioration occurs. It can be seen that the 1,2-di(4-pyridyl)ethane-acetifloxacin cocrystals prepared by the present invention have better chemical stability than the existing crystal forms.

Claims

1. 1,2-di(4-pyridyl)ethane-acemidox cocrystal, characterized in that: It is formed by combining acipimox and 1,2-di(4-pyridyl)ethane in a molar ratio of 2:1; The eutectic uses Cu-K α Radiation, the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 9.88±0.2°, 13.92±0.2°, 15.38±0.2°, 15.70±0.2°, 24.56±0.2°, 26.12±0.2°, 26.86±0.2°, 29.59±0.2°, and 36.90±0.2°.

2. The 1,2-di(4-pyridyl)ethane-acipimox cocrystal according to claim 1, characterized in that Using Cu-K α Radiation, its characteristic peaks conform to the X-ray powder diffraction pattern shown in Figure 1.

3. The 1,2-di(4-pyridyl)ethane-acipimox cocrystal according to claim 1, characterized in that: There is an endothermic peak at 184.43°C in the differential scanning calorimetry curve DSC.

4. The 1,2-di(4-pyridyl)ethane-acipimox cocrystal according to any one of claims 1 to 3, characterized in that: Its crystallographic parameters are: monoclinic system, space group is P21 / c; unit cell parameters are: a =7.41451(9)Å, b =24.5306(3)Å, c =12.60172(14)Å, α =90°, β=99.3338(11)°, γ =90°, unit cell volume V =2261.69(5)Å3.

5. The method for preparing the 1,2-di(4-pyridyl)ethane-acipimox cocrystal according to claim 1, characterized in that: The specific preparation steps include: adding acipimox and 1,2-di(4-pyridyl)ethane to an organic solvent A, stirring and dissolving, controlling the temperature to react, refluxing, and after the reaction is completed, cooling and crystallizing, filtering and drying to obtain 1,2-di(4-pyridyl)ethane-aceimox eutectic; the organic solvent A is selected from one or two of methanol, acetonitrile, acetone, ethyl acetate, and ethanol.

6. The method for preparing the 1,2-di(4-pyridyl)ethane-acipimox cocrystal according to claim 5, characterized in that: The molar ratio of acipimox to 1,2-di(4-pyridyl)ethane is 1:0.4-0.

6.

7. Use of the 1,2-di(4-pyridyl)ethane-acipimox cocrystal according to any one of claims 1 to 3 in the preparation of a lipid-lowering drug.

Images