A mirin and citric acid dihydrate co-crystal

Abstract

The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a milrinone-citric acid dihydrate co-crystal. The application provides a new milrinone-citric acid dihydrate 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] This invention belongs to the field of medicinal chemistry technology, specifically relating to a new crystal form of milrinone, specifically a milrinone and citric acid dihydrate cocrystal. Background Technology

[0002] Milrinone, chemically named 1,6-dihydro-2-methyl-6-oxo-[3,4-bispyridine]-5-carboxynitrile, has the molecular formula C2. 12 H9N3O, with a molecular weight of 211.22, is a white or off-white crystalline powder with the following structural formula:

[0003]

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

[0005] Milrinone is a phosphodiesterase inhibitor, a derivative of amrinone, with the same mechanism of action. It is effective both orally and intravenously, exhibiting both positive inotropic and vasodilatory effects. It is suitable for short-term treatment of severe congestive heart failure unresponsive to conventional maintenance therapy, with efficacy 10-30 times stronger than amrinone, better tolerability, and fewer adverse reactions. Its positive inotropic effect is mainly achieved by inhibiting phosphodiesterase, increasing intracellular cyclic adenosine monophosphate (cAMP) concentration, intracellular calcium, myocardial contractility, and cardiac output. It is generally considered a highly effective, low-toxicity, non-digitalis, non-sympathomimetic cardiotonic drug, showing significant efficacy against severe heart failure and pulmonary edema caused by ischemic heart disease and dilated cardiomyopathy, superior to dopamine derivatives, with fewer adverse reactions and no increase in heart rate. Therefore, this 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 are needed to improve its solubility when preparing milrinone formulations. Existing formulation methods typically use solubilizers and pH adjusters to improve water solubility, and these are used in large quantities. Therefore, the safety and solubilizing effect of solubilizers are particularly important. For example, patent CN9151919A discloses a method for preparing lyophilized formulations by first precipitating crystals in a solvent of ethanol + acetone + water, and then using lactic acid as a pH adjuster. However, the problems of poor solubility and stability of milrinone itself have not been completely solved. For example, when inorganic acids are used as cosolvents, the Cl- brought in by hydrochloric acid may cause hyperchloremia, while phosphoric acid and sulfuric acid are not good cosolvents. Among organic acids, lactic acid has a better cosolvent effect, but lactic acid is a racemic mixture composed of L-lactic acid and D-lactic acid. Since the human body only has enzymes that metabolize L-lactic acid and their metabolic capacity is limited, excessive intake of D-lactic acid can also cause metabolic disorders or even acidosis.

[0007] Furthermore, according to the disclosure of patent CN105663034A, because milrinone is almost insoluble in water, large-scale production can lead to problems such as long dissolution time, incomplete dissolution, and excessive levels of insoluble particles. Current milrinone injection preparation technology uses activated carbon adsorption to remove pyrogens. Activated carbon has a large adsorption capacity for milrinone; with 0.05% activated carbon, it can adsorb approximately 14% milrinone, requiring excessive addition to ensure the milrinone injection content meets regulations. However, excessive addition significantly increases production costs, and while adsorbing pyrogens, activated carbon itself can introduce excessive amounts of unknown substances, affecting product quality.

[0008] Based on the above problems, relying solely on formulation technology to solve the issues of poor solubility and stability of milrinone inevitably leads to potential clinical safety risks due to excessive use of excipients and auxiliaries. Therefore, providing a new crystalline form of milrinone with good solubility, stability, and safety remains a problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0009] To address the safety concerns arising from the need for large amounts of adjuvants and pH adjusters in existing technologies to improve the solubility of milrinone, this invention aims to provide a milrinone-citric acid dihydrate cocrystal with high solubility and safety. This fundamentally solves the solubility problem of milrinone, reduces the use of excipients in later formulation preparations, and improves medication safety.

[0010] The specific technical content of this invention is as follows:

[0011] In a first aspect, the present invention provides a milrinone-citric acid dihydrate eutectic, characterized in that the molar ratio of milrinone, citric acid and water in the eutectic unit structure is 1:1:2.

[0012] Preferably, the milrinone and citric acid dihydrate cocrystal, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 10.6±0.2°, 15.3±0.2°, 16.5±0.2°, 24.7±0.2°, 24.9±0.2°, 25.0±0.2°, 31.2±0.2°, and 37.8±0.2°.

[0013] Preferably, the milrinone and citric acid dihydrate eutectic crystal, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 6.0±0.2°, 10.6±0.2°, 13.3±0.2°, 15.3±0.2°, 16.5±0.2°, 17.6±0.2°, 18.0±0.2°, 20.7±0.2°, 21.1±0.2°, 24.7±0.2°, 24.9±0.2°, 25.0±0.2°, 26.2±0.2°, 31.2±0.2°, 37.8±0.2°, and 42.1±0.2°.

[0014] Preferably, the milrinone and citric acid dihydrate eutectic crystal is subjected to Cu-Kα radiation, and its characteristic peaks have... Figure 1 The X-ray powder diffraction pattern shown is shown.

[0015] Preferably, the milrinone and citric acid dihydrate cocrystal has the molecular formula C2. 18 H 21 N3O 10 The crystallographic parameters are: triclinic crystal system, space group P-1, and unit cell parameters are: α = 81.8880(10)°, β = 85.9210(10)°, γ = 77.1430(10)°, cell volume

[0016] In a second aspect, the present invention provides a method for preparing milrinone-citric acid dihydrate eutectic, comprising the following steps:

[0017] Milrinone and citric acid were dissolved in a mixed solvent, heated and stirred, filtered, cooled and allowed to stand, volatilized and crystallized, filtered and dried to obtain milrinone-citric acid dihydrate eutectic.

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

[0019] Preferably, the mass-to-volume ratio of milrinone to the mixed solvent is 21.1:2 to 6; more preferably, it is 21.1:3.5 to 4.5.

[0020] Preferably, the molar ratio of milrinone to citric acid is 1:1 to 2.3, more preferably 1:1.3.

[0021] Preferably, the heating temperature is 35-55°C, and more preferably 45°C.

[0022] Preferably, the cooling and crystallization temperature is -5 to 20°C, more preferably 0 to 5°C.

[0023] The crystallization time is 1 to 4 days.

[0024] The drying temperature is 40–55°C, and the drying time is 6–11 hours.

[0025] Preferably, a method for preparing milrinone-citric acid dihydrate eutectic comprises the following steps:

[0026] Milrinone and citric acid were dissolved in a mixed solvent, heated to 35-55°C and stirred, filtered, cooled to -5-20°C and allowed to stand for 1-4 days to volatilize and crystallize, filtered, and dried at 40-55°C for 6-11 hours to obtain milrinone-citric acid dihydrate eutectic crystals.

[0027] Milrinone, the raw material 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 invention provides the use of milrinone-citric acid dihydrate cocrystal in the preparation of drugs for treating heart failure.

[0029] Finally, the present invention provides a pharmaceutical composition comprising the milrinone-citric acid dihydrate cocrystal described herein and other pharmaceutically feasible components.

[0030] Preferably, the other pharmaceutically feasible components may be co-operable active pharmaceutical ingredients and / or pharmaceutically acceptable excipients.

[0031] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0032] This invention provides for the first time a milrinone-citric acid dihydrate cocrystal, which can significantly enhance the solubility and stability of milrinone, improve oral bioavailability, and has strong pharmaceutical value; moreover, its preparation method is simple to operate, the crystallization process is easy to control, has good reproducibility, and is suitable for industrial production. Attached Figure Description

[0033] Figure 1 PXRD pattern of milrinone and citric acid dihydrate cocrystal.

[0034] Figure 2 ORTEP diagram of milrinone and citric acid dihydrate cocrystal.

[0035] Figure 3 Hydrogen bond diagram of milrinone and citric acid dihydrate cocrystal. Detailed Implementation

[0036] Confirmation of crystal structure

[0037] X-ray crystallography data for the Milrinone and citric acid dihydrate eutectic prepared according to this invention were collected using a Rigaku XtaLABSynergy instrument at a test temperature of 293(2) K. Cu-Ka radiation was used, and data were collected via ω-scan and Lp correction was performed. The structure was resolved using a direct method, and all non-hydrogen atoms were identified using the difference Fourier method. Hydrogen atoms on all carbon and nitrogen atoms were obtained through theoretical hydrogenation, and the structure was refined using the least squares method. The crystallographic data for the crystalline form of the Milrinone and citric acid dihydrate eutectic prepared according to this invention are shown in Table 1.

[0038] Table 1. Main crystallographic data of milrinone-citric acid dihydrate eutectic

[0039]

[0040]

[0041] The ORTEP diagram of the milrinone-citric acid dihydrate eutectic of this invention shows that the crystalline form contains one molecule of milrinone, one molecule of citric acid, and two molecules of water, as shown in the attached diagram. Figure 2 As shown. The hydrogen bond diagram of the milrinone-citric acid dihydrate eutectic of the present invention is attached. Figure 3 As shown. Based on the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are detailed in the appendix. Figure 1 And Table 2.

[0042] Table 2 PXRD peaks of milrinone-citric acid dihydrate eutectic

[0043]

[0044]

[0045] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0046] The materials used in the examples can be prepared according to any method in the prior art or purchased from commercially available products. Milrinone crystals are prepared according to patent CN106361710A, and milrinone hydrochloride, milrinone methanesulfonate, milrinone phosphate and milrinone sulfate are prepared according to CN1951919A.

[0047] Example 1

[0048] 211.2 mg milrinone and 249.8 mg citric acid were dissolved in a mixed solvent of 30 mL acetonitrile, 10 mL acetone and 10 mL water. The solution was heated and stirred at 45 °C until completely dissolved. The solution was filtered, and the mixture was allowed to stand at 0–5 °C for 2–3 days to allow volatilization and crystallization. The filtered solution was then filtered again, and the filter cake was dried in a vacuum drying oven at 50 °C for 8–9 hours to obtain milrinone-citric acid dihydrate eutectic crystals. The yield was 91.8% and the purity was 99.93%.

[0049] Example 2

[0050] 211.2 mg milrinone and 192.0 mg citric acid were dissolved in a mixed solvent of 20 mL methanol, 15 mL trifluoroethanol and 5 mL water. The solution was heated and stirred at 55 °C until completely dissolved. The solution was filtered and allowed to stand at -5 to 0 °C for 1 to 2 days to allow volatilization and crystallization. The filtered solution was then dried in a vacuum drying oven at 55 °C for 6 to 8 hours to obtain milrinone-citric acid dihydrate eutectic crystals. The yield was 89.9% and the purity was 99.90%.

[0051] Example 3

[0052] 211.2 mg milrinone and 441.8 mg citric acid were dissolved in a mixed solvent of 20 mL methanol, 40 mL acetonitrile and 8 mL water. The solution was heated and stirred at 35 °C until completely dissolved. The solution was filtered, and the mixture was allowed to stand at 5–10 °C for about 2 days to allow volatilization and crystallization. The solution was then filtered again, and the filter cake was dried in a vacuum drying oven at 40 °C for 11 hours to obtain milrinone-citric acid dihydrate eutectic crystals. The yield was 91.2% and the purity was 99.92%.

[0053] Example 4

[0054] 211.2 mg milrinone and 384.3 mg citric acid were dissolved in a mixed solvent of 45 mL ethanol and 10 mL water. The solution was heated and stirred at 50 °C until completely dissolved. The solution was filtered, and the mixture was allowed to stand at 10–15 °C for 2–3 days to allow volatilization and crystallization. The solution was then filtered again, and the filter cake was dried in a vacuum drying oven at 50 °C for 9–10 hours to obtain milrinone-citric acid dihydrate eutectic crystals. The yield was 92.0%, and the purity was 99.91%.

[0055] Example 5

[0056] 211.2 mg milrinone and 249.8 mg citric acid were dissolved in a mixed solvent of 20 mL methanol and 12 mL water. The solution was heated and stirred at 55 °C until completely dissolved. The solution was filtered, and the mixture was allowed to stand at 15–20 °C for 3–4 days to allow volatilization and crystallization. The solution was then filtered again, and the filter cake was dried in a vacuum drying oven at 55 °C for 8–9 hours to obtain milrinone-citric acid dihydrate eutectic crystals. The yield was 90.5%, and the purity was 99.90%.

[0057] Stability test

[0058] The specific stability test methods were carried out in accordance with the guidelines for stability studies in Part IV of the Chinese Pharmacopoeia. Purity was determined by HPLC, and the specific test results are shown in Table 3.

[0059] Table 3. Stability test results of Milrinone-citric acid dihydrate eutectic under light, high temperature and high humidity conditions.

[0060]

[0061] Solubility test

[0062] Method: Measure 10 ml of medium (water, 0.01 mol / L HCl solution) into a vial, add excess sample to be tested, seal the vial and place it in a 25℃ constant temperature water bath and stir for 1 hour. Filter through a filter membrane and collect the filtrate. Calculate the solubility by measuring the absorbance of the standard reference.

[0063] Table 4. Solubility of Milrinone-Citrate-Water Cocrystal in Different Media (mg / mL)

[0064]

[0065]

Claims

1. A milrinone-citric acid dihydrate eutectic, characterized in that, The molar ratio of milrinone, citric acid, and water in the eutectic unit structure is 1:1:

2. Using Cu-Kα radiation, the X-ray diffraction pattern (represented by 2θ) shows characteristic peaks at 10.6±0.2 °, 15.3±0.2 °, 16.5±0.2 °, 24.7±0.2 °, 24.9±0.2 °, 25.0±0.2 °, 31.2±0.2 °, and 37.8±0.2 °. The milrinone-citric acid dihydrate eutectic has the molecular formula C2. 18 H 21 N3O 10 The crystal structure parameters are: triclinic system, space group P-1, cell parameters: a=7.41510(10)Å, b=10.58790(10)Å, c=12.9829(2)Å, α=81.8880(10)°, β=85.9210(10)°, γ=77.1430(10)°, cell volume V=982.96(2)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 6.0±0.2°2, 10.6±0.2°, 13.3±0.2°, 15.3±0.2°, 16.5±0.2°, 17.6±0.2°, 18.0±0.2°, 20.7±0.2°, 21.1±0.2°, 24.7±0.2°, 24.9±0.2°, 25.0±0.2°, 26.2±0.2°, 31.2±0.2°, 37.8±0.2°, and 42.1±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 dihydrate eutectic according to any one of claims 1-3, characterized in that, The process includes the following steps: dissolving milrinone and citric acid in a mixed solvent, heating and stirring, filtering, cooling and allowing to stand, evaporating and crystallizing, filtering and drying to obtain milrinone-citric acid dihydrate eutectic crystals.

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

6. The preparation method according to claim 4, characterized in that, The mass-to-volume ratio of milrinone to the mixed solvent is 21.1:2-6.

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

3.

8. The preparation method according to claim 4, characterized in that, The specific steps are as follows: Milrinone and citric acid are dissolved in a mixed solvent, heated to 35-55℃ and stirred, filtered, cooled to -5-20℃ and left to stand for 1-4 days to volatilize and crystallize, filtered, and dried at 40-55℃ for 6-11 hours to obtain milrinone-citric acid dihydrate cocrystal.

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

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