A mirinemonocitrate monohydrate co-crystal

Abstract

The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a milrinone-citric acid monohydrate co-crystal. The application provides a new milrinone-citric acid monohydrate co-crystal and a preparation method thereof. The co-crystal has excellent properties, can significantly enhance the solubility and stability of milrinone, is helpful to improve the oral bioavailability, improve the clinical curative effect, has strong drug-making value, the preparation method is simple in operation and easy to control, and is suitable for industrial amplification.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a milrinone-citric acid monohydrate co-crystal. BACKGROUND

[0002] Milrinone, with a chemical name of 1,6-dihydro-2-methyl-6-oxo-[3,4-bipyridine]-5-carbonitrile, a molecular formula of C 12 H9N3O, a molecular weight of 211.22, and a white or white-like crystalline powder, has a structural formula as follows:

[0003]

[0004] Milrinone was first developed by the American Sterling Company as an anti-heart failure drug, and was first approved by the FDA in the United States in 1987, officially launched in the United States in 1992, and then successively launched and sold in the United Kingdom, France, Germany, the Netherlands, Belgium and other countries.

[0005] Milrinone is a phosphodiesterase inhibitor, a derivative of amirinone, and has the same mechanism of action as amirinone. It is effective for oral and intravenous administration, has positive inotropic effect and vasodilating effect, is suitable for short-term treatment of severe congestive heart failure patients who are ineffective for conventional maintenance treatment, has 10-30 times stronger efficacy than amirinone, has better tolerance, and has fewer adverse reactions. The positive inotropic effect of the product is mainly through the inhibition of phosphodiesterase, so that the concentration of cyclic adenosine monophosphate (CAMP) in the myocardial cell is increased, the intracellular calcium is increased, the myocardial contractility is strengthened, and the cardiac output is increased. It is generally considered to be a high-efficiency, low-toxicity, non-digitalis, non-pseudo-steroidal inotropic drug, which has a significant effect on severe heart failure, pulmonary edema caused by ischemic heart disease, dilated cardiomyopathy, etc., is superior to dopamine, has fewer adverse reactions, and does not increase heart rate. Therefore, the drug plays an increasingly important role in the treatment of congestive heart failure (CHF) and peripheral vasodilation.

[0006] However, milrinone is almost insoluble in water, so special excipients need to be added to improve its solubility when preparing milrinone preparation products. The existing preparation method usually uses a large amount of a solubilizing agent and a pH regulator to improve its water solubility. Therefore, the safety and solubilizing effect of the solubilizing agent are particularly important. For example, patent CN9151919A discloses a method of preparing a freeze-dried preparation by salting with inorganic acids such as hydrochloric acid, phosphoric acid and sulfuric acid; and patent CN106361710A discloses a method of preparing a preparation by first precipitating crystals in a solvent of ethanol + acetone + water, and then using lactic acid as a pH regulator. However, the problems of poor solubility and poor stability of milrinone itself have not been completely solved, for example, the chloride brought by hydrochloric acid may cause hyperchloridemia, and the solubilizing effect of phosphoric acid and sulfuric acid is poor; among organic acids, the solubilizing effect of lactic acid is good, but lactic acid is a racemate composed of L-lactic acid and D-lactic acid, and only the enzyme that metabolizes L-lactic acid in the human body has limited metabolic capacity. If excessive D-lactic acid is ingested, it may cause metabolic disorders and even acidosis.

[0007] Moreover, according to the disclosure of patent CN105663034A, because milrinone is almost insoluble in water, the problems of long dissolution time, incomplete dissolution and excessive insoluble particles may occur during mass production. In the existing preparation technology of milrinone injection, activated carbon adsorption is used to remove pyrogens, and the adsorption amount of activated carbon for milrinone is large. When the amount of activated carbon used is 0.05%, the adsorption of milrinone can reach about 14%, and excessive feeding is required to ensure that the content of milrinone injection meets the requirements. Excessive feeding leads to a large increase in production cost, and activated carbon also introduces excessive unknown substances when adsorbing pyrogens, which affects the quality of the product.

[0008] Based on the above problems, it is inevitable that the use of excessive amounts of excipients and solubilizing agents will cause safety hazards in clinical medication when only relying on preparation technology to solve the problems of poor solubility and poor stability of milrinone. Therefore, it has become a problem to be solved for those skilled in the art to provide a new crystal form of milrinone with good solubility, good stability and high safety. SUMMARY

[0009] In view of the safety hazards caused by the use of a large amount of solubilizing agents and pH regulators to improve the solubility of milrinone in the prior art, the present application aims to provide a milrinone-citric acid monohydrate co-crystal with high solubility and safety, which fundamentally solves the solubility problem of milrinone and reduces the use of excipients in the preparation of the product in the later stage, thereby improving the safety of the drug.

[0010] The specific technical content of the present application is as follows:

[0011] In a first aspect, the present application provides a mirin-citric acid monohydrate co-crystal, characterized in that the molar ratio of mirin, citric acid and water in the co-crystal unit structure is 1:1:1.

[0012] Preferably, the mirin-citric acid monohydrate co-crystal has an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation, which has characteristic peaks at least at 8.5±0.2°, 15.1±0.2°, 17.6±0.2°, 20.5±0.2°, 25.1±0.2°, 26.8±0.2°, 26.9±0.2°.

[0013] Preferably, the mirin-citric acid monohydrate co-crystal has an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation, which has characteristic peaks at least at 6.7±0.2°, 8.5±0.2°, 9.9±0.2°, 15.1±0.2°, 16.2±0.2°, 17.6±0.2°, 18.6±0.2°, 20.5±0.2°, 21.5±0.2°, 25.1±0.2°, 26.8±0.2°, 26.9±0.2°, 35.8±0.2°, 39.9±0.2°, 43.4±0.2°.

[0014] Preferably, the mirin-citric acid monohydrate co-crystal has the following crystallographic parameters: triclinic system, space group P-1, and cell parameters: α=75.286(2)°, β=78.2560(4)°, γ=80.871(2)°, cell volume

[0015] Preferably, the mirin-citric acid monohydrate co-crystal has characteristic peaks with Figure 1 the X-ray powder diffraction spectrum shown.

[0016] In a second aspect, the present application provides a method for preparing a mirin-citric acid monohydrate co-crystal, comprising the following steps:

[0017] The mirin and citric acid monohydrate are dissolved in a mixed solvent, heated and stirred, filtered, cooled and placed, volatilized and crystallized, filtered and dried to obtain the mirin-citric acid monohydrate co-crystal.

[0018] Preferably, the mixed solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, trifluoroethanol, water, preferably a mixed solvent of trifluoroethanol, acetonitrile and water.

[0019] Preferably, the mass / volume ratio of mirin to mixed solvent is 21.1:1-3; preferably 21.1:1.5-2.5.

[0020] Preferably, the molar ratio of the milrinone to citric acid monohydrate is 1:0.8-2.0, preferably 1:1.

[0021] Preferably, the heating temperature is 50-70℃, preferably 60℃.

[0022] Preferably, the cooling and crystallization temperature is 0-30℃, preferably 10-15℃.

[0023] The crystallization time is 1-3 days.

[0024] Preferably, the drying temperature is 45-65℃, and the drying time is 8-12 hours.

[0025] Preferably, the method for preparing the milrinone-citric acid monohydrate co-crystal comprises the following steps:

[0026] The milrinone and citric acid monohydrate are dissolved in a mixed solvent, heated to 50-70℃ and stirred, filtered, cooled to 0-30℃ and left standing for 1-3 days, volatilized and crystallized, filtered, dried at 45-65℃ for 8-12 hours to obtain the milrinone-citric acid monohydrate co-crystal.

[0027] The raw material milrinone used in the preparation method can be prepared according to any method in the prior art or purchased from commercially available products.

[0028] In a third aspect, the present application provides a use of the milrinone-citric acid monohydrate co-crystal in the preparation of an anti-heart failure drug.

[0029] Finally, the present application provides a pharmaceutical composition comprising the milrinone-citric acid monohydrate co-crystal and other pharmaceutically acceptable components.

[0030] Preferably, the other pharmaceutically acceptable components can be a combination of a pharmaceutically active ingredient and / or a pharmaceutically acceptable excipient.

[0031] Compared with the prior art, the present application has the following beneficial effects:

[0032] The present application first provides the milrinone-citric acid monohydrate co-crystal. The milrinone and citric acid form a co-crystal, which can significantly enhance the solubility and stability of the milrinone, improve the oral bioavailability, and has a strong pharmaceutical value. The preparation method is simple to operate, the crystallization process is easy to control, the reproducibility is good, and is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 . PXRD spectrum of the milrinone-citric acid monohydrate co-crystal.

[0034] Figure 2 . ORTEP diagram of the milrinone-citric acid monohydrate co-crystal.

[0035] Figure 3 Hydrogen bonding scheme of the milrinone and citric acid monohydrate co-crystal. DETAILED DESCRIPTION

[0036] Confirmation of the crystal structure

[0037] The X-ray crystal data of the milrinone and citric acid monohydrate co-crystal tested in the present application were collected on a Rigaku XtaLAB Synergy model instrument at a temperature of 293(2) K, with Cu-Ka radiation, in an omega scan mode, and Lp correction was performed. The structure was solved by direct methods, and all non-hydrogen atoms were found by difference Fourier methods, with hydrogen atoms on all carbons and nitrogens being placed in calculated positions. The structure was refined by least squares methods. The crystallographic data of the milrinone and citric acid monohydrate co-crystal crystalline form prepared in the present application were tested and analyzed, as shown in Table 1.

[0038] Table 1 Main crystallographic data of the milrinone and citric acid monohydrate co-crystal

[0039]

[0040]

[0041] The ORTEP diagram of the milrinone and citric acid monohydrate co-crystal of the present application shows that the crystalline form contains one molecule of milrinone, one molecule of citric acid and one molecule of water, as shown in Figure 1. The hydrogen bonding scheme of the milrinone and citric acid monohydrate co-crystal of the present application is shown in Figure 2. According to the above crystallographic data, the characteristic peaks in the X-ray powder diffraction pattern (Cu-Ka) corresponding thereto are shown in Figure 3 and Table 2. Figure 2 Figure 3 Figure 1

[0042] Table 2 PXRD peaks of the milrinone and citric acid monohydrate co-crystal

[0043]

[0044]

[0045] The present application will be further described by way of examples. It should be understood that the examples of the present application are only used to illustrate the present application, and are not intended to limit the present application. Therefore, simple improvements of the present application under the premise of the method of the present application are within the scope of the present application.

[0046] ​​​The materials used in the examples can be prepared according to any method in the prior art or purchased from commercially available products, wherein the mirin crystal is prepared with reference to patent CN106361710A, and the mirin hydrochloride, mirin methanesulfonate, mirin phosphate and mirin sulfate are prepared with reference to CN1951919A.

[0047] Example 1

[0048] Dissolve 211.2 mg of mirin and 210.1 mg of citric acid monohydrate in 10 mL of methanol, heat and stir at 60°C until completely dissolved, filter, and let stand at 5-10°C for 2-3 days, volatilize and crystallize, filter, and dry the filter cake in a vacuum drying oven at 50°C for 8-10 hours to obtain mirin-citric acid monohydrate eutectic, yield: 91.0%, purity: 99.94%.

[0049] Example 2

[0050] Dissolve 211.1 mg of mirin and 168.1 mg of citric acid monohydrate in 5 mL of methanol and 10 mL of acetonitrile mixed solvent, heat and stir at 50°C until completely dissolved, filter, and let stand at 0-5°C for 1-2 days, volatilize and crystallize, filter, and dry the filter cake in a vacuum drying oven at 60°C for 8-10 hours to obtain mirin-citric acid eutectic, yield: 93.5%, purity: 99.95%.

[0051] Example 3

[0052] Dissolve 211.2 mg of mirin and 210.0 mg of citric acid monohydrate in 10 mL of trifluoroethanol, 5 mL of acetonitrile and 5 mL of water mixed solvent, heat and stir at 60°C until completely dissolved, filter, and let stand at 10-15°C for 2-3 days, volatilize and crystallize, filter, and dry the filter cake in a vacuum drying oven at 60°C for 8-10 hours to obtain mirin-citric acid monohydrate eutectic, yield: 95.3%, purity: 99.97%.

[0053] Example 4

[0054] Dissolve 211.0 mg of mirin and 420.3 mg of citric acid monohydrate in 5 mL of ethanol, 10 mL of acetone and 15 mL of acetonitrile mixed solvent, heat and stir at 60°C until completely dissolved, filter, and let stand at room temperature for 2-3 days, volatilize and crystallize, filter, and dry the filter cake in a vacuum drying oven at 45°C for 10-12 hours to obtain mirin-citric acid monohydrate eutectic, yield: 89.2%, purity: 99.92%.

[0055] Example 5

[0056] Dissolve 211.2 mg milrinone and 210.0 mg citric acid monohydrate in 15 mL of a mixed solvent of methanol and water, heat and stir at 70°C until completely dissolved, filter, and let stand at 15-20°C for 2-3 days. Evaporate to crystallize, filter, and dry the filter cake in a vacuum drying oven at 65°C for 8-10 hours to obtain milrinone-citric acid monohydrate eutectics, yield: 94.3%, purity: 99.93%.

[0057] Stability experiment

[0058] The specific stability test method refers to the guidance method for stability investigation in the fourth part of Chinese Pharmacopoeia 2020 edition. The purity is detected by HPLC method, 3 parallel experiments are carried out, and the average value is taken. The specific detection results are shown in Table 3.

[0059] Table 3 Stability test results of milrinone-citric acid monohydrate eutectics under light, high temperature and high humidity conditions

[0060]

[0061] Solubility experiment

[0062] Method: 10 ml of medium (water, 0.01 mol / L HCl solution) was weighed into a vial, and an excess of the sample to be tested was added. The vial was sealed and placed in a 25°C constant temperature water bath for stirring for 1 hour, filtered through a filter membrane, and the filtrate was taken. The solubility was calculated by testing the absorbance of the standard control.

[0063] Table 4 Solubility of milrinone-citric acid monohydrate eutectics in different media (mg / mL)

[0064]

[0065]

Claims

1. A milrinone-citric acid monohydrate eutectic, characterized in that, The molar ratio of milrinone, citric acid, and water in the eutectic unit structure is 1:1:1; using Cu-Kα radiation, the X-ray diffraction pattern represented by 2θ has characteristic peaks at 8.5±0.2°, 15.1±0.2°, 17.6±0.2°, 20.5±0.2°, 25.1±0.2°, 26.8±0.2°, and 26.9±0.2°; its crystallographic parameters are: triclinic system, space group P-1, a=7.41510(10)Å, b=8.7041(2)Å, c=15.3795(3)Å, α=75.286(2)°, β=78.2560(4)°, γ=80.871(2)°, and cell volume V=933.38(3)Å. 3 .

2. The eutectic according to claim 1, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, has characteristic peaks at 6.7±0.2°2, 8.5±0.2°, 9.9±0.2°, 15.1±0.2°, 16.2±0.2°, 17.6±0.2°, 18.6±0.2°, 20.5±0.2°, 21.5±0.2°, 25.1±0.2°, 26.8±0.2°, 26.9±0.2°, 35.8±0.2°, 39.9±0.2°, and 43.4±0.2°.

3. The eutectic according to claim 1, characterized in that, Its characteristic peaks have the X-ray powder diffraction pattern shown in Figure 1.

4. A method for preparing the milrinone-citric acid monohydrate eutectic according to any one of claims 1-3, characterized in that, The process includes the following steps: dissolving milrinone and citric acid monohydrate in a solvent, heating and stirring, filtering, cooling and allowing to stand, evaporating and crystallizing, filtering and drying to obtain milrinone-citric acid monohydrate eutectic crystals.

5. The preparation method according to claim 4, characterized in that, The solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, trifluoroethanol, and water.

6. The preparation method according to claim 4, characterized in that, The mass-to-volume ratio of milrinone to solvent is 21.1:1 to 3.

7. The method according to claim 4, characterized in that, The molar ratio of milrinone to citric acid monohydrate is 1:0.8 to 2.

0.

8. The preparation method according to claim 4, characterized in that, The specific steps are as follows: Milrinone and citric acid monohydrate are dissolved in a solvent, heated to 50-70℃ and stirred, filtered, cooled to 0-30℃ and allowed to stand for 1-3 days to volatilize and crystallize, filtered, and dried at 45-65℃ for 8-12 hours to obtain milrinone-citric acid monohydrate eutectic crystals.

9. Use of the milrinone-citric acid monohydrate eutectic according to any one of claims 1-3 in the preparation of an anti-heart failure drug.

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