A milrinone multi-element eutectic

Abstract

The present invention provides a milrinone multinary eutectic, wherein a crystal unit of the multinary eutectic contains milrinone-baicalein-methanol-acetone molecules in a molar ratio of 2:2:2:1; and using Cu-Kα radiation, an X-ray diffraction spectrum expressed in 2θ has characteristic peaks at at least 7.7±0.2°, 8.5±0.2°, 12.9±0.2°, 14.2±0.2°, 25.6±0.2°, and 26.2±0.2°.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a new crystal form of milrinone, specifically a co-crystal of milrinone and baicalein, and a preparation method and application thereof. Background Art

[0002] Milrinone (Formula I), chemical name is 1,6-dihydro-2-methyl-6-oxo-[3,4-bipyridine]-5-carbonitrile, molecular formula is C 12 H9N3O, with a molecular weight of 211.22, is a white or off-white crystalline powder with the structural formula:

[0003]

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

[0005] Milrinone is a phosphodiesterase inhibitor and a derivative of amrinone, with a mechanism of action similar to that of amrinone. It is effective both orally and intravenously, exhibiting both positive inotropic and vasodilatory effects. It is indicated for short-term treatment of patients with severe congestive heart failure who have failed conventional maintenance therapy. It is 10-30 times more effective than amrinone, has good tolerability, and offers fewer adverse reactions. Its positive inotropic effect is primarily achieved through phosphodiesterase inhibition, which increases cyclic adenosine monophosphate (CAMP) concentrations in myocardial cells, increasing intracellular calcium, strengthening myocardial contractility, and increasing cardiac output. It is generally considered a highly effective, low-toxic, non-digitalis, non-sympathomimetic cardiotonic drug. It is significantly effective for severe heart failure and pulmonary edema caused by ischemic heart disease and dilated cardiomyopathy. It is superior to dopamine-based drugs, has fewer adverse reactions, and does not increase heart rate. Therefore, this drug has played an increasingly important role in the treatment of congestive heart failure (CHF) and peripheral vasodilation.

[0006] However, milrinone is almost insoluble in water, so when preparing milrinone preparations, special excipients need to be added to improve its solubility. Existing preparation methods usually use the addition of cosolvents and pH regulators to improve its water solubility, and the dosage is relatively large. Therefore, the safety and solubility-promoting effect of cosolvents are particularly important. For example, patent CN9151919A discloses a method of using inorganic acids such as hydrochloric acid, phosphoric acid, and sulfuric acid to form salts and then preparing them into freeze-dried preparations; patent CN106361710A discloses a method of first precipitating crystals in a solvent of ethanol + acetone + water, and then using lactic acid as a pH regulator to prepare preparations. However, the problem of poor solubility and stability of milrinone itself has not been completely solved. For example, when inorganic acids are used as cosolvents, the Cl introduced by hydrochloric acid- It may cause hyperchloremia, and phosphoric acid, sulfuric acid and other solubilizing agents have poor effects; among organic acids, lactic acid has a better solubilizing effect, but lactic acid is a racemic body, consisting of L-lactic acid and D-lactic acid. Since the human body only has enzymes that metabolize L-lactic acid and its metabolic capacity is limited, if excessive D-lactic acid is ingested, it will also cause metabolic disorders and even acidosis.

[0007] Furthermore, according to the disclosure of patent CN105663034A, since milrinone is virtually insoluble in water, large-scale production processes can lead to long dissolution times, incomplete dissolution, and excessive amounts of insoluble particulate matter. Existing milrinone injection preparation technology uses activated carbon adsorption to remove pyrogens. However, activated carbon has a high adsorption capacity for milrinone: at a 0.05% activated carbon dosage, it can adsorb approximately 14% milrinone. This requires excessive dosing to ensure the milrinone injection content meets regulatory requirements. However, excessive dosing significantly increases production costs, and while the activated carbon adsorbs pyrogens, it also introduces excessive amounts of unidentified substances, impacting product quality.

[0008] Baicalein is a flavonoid compound with multiple pharmacological effects. For example, it reduces cerebral vascular resistance, improves cerebral circulation, increases cerebral blood flow, and inhibits platelet aggregation. It is clinically used to treat paralysis following cerebrovascular disease. Baicalein is the active ingredient in the body. Upon entering the animal body, baicalein is rapidly converted into baicalin and other metabolites in the blood. However, due to its insolubility in water and poor hydrophilicity, baicalein is difficult to absorb. Poor oral absorption significantly limits its clinical application. Consequently, the development of baicalein formulations presents significant challenges.

[0009] Given the above issues, relying solely on formulation technology to address milrinone's solubility and stability inevitably leads to clinical safety risks caused by excessive amounts of excipients and adjuvants. Therefore, providing a new crystalline form of milrinone with good solubility, high stability, and enhanced safety has become an urgent task for those skilled in the art. Summary of the Invention

[0010] To address the above-mentioned issues, the present invention has discovered through research that the low water-soluble milrinone and baicalein can form a stable multicomponent co-crystal. The resulting crystals possess excellent physicochemical properties not possessed by either milrinone or baicalein, such as significantly improved solubility and stability. Furthermore, the present invention provides a simple, convenient method for preparing the milrinone multicomponent co-crystal, which is suitable for industrial production.

[0011] The specific technical contents of the present invention are as follows:

[0012] In one aspect, the present invention provides a milrinone multinary co-crystal, wherein a crystal unit of the multinary co-crystal contains milrinone-baicalein-methanol-acetone molecules in a molar ratio of 2:2:2:1.

[0013] Preferably, the milrinone multi-element cocrystal has characteristic peaks at least at 7.7±0.2°, 8.5±0.2°, 12.9±0.2°, 14.2±0.2°, 25.6±0.2°, and 26.2±0.2° in an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0014] Preferably, the milrinone multi-element cocrystal has an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation, and has characteristic peaks at at least 7.0±0.2°, 7.7±0.2°, 8.5±0.2°, 12.1±0.2°, 12.9±0.2°, 14.2±0.2°, 16.9±0.2°, 17.1±0.2°, 20.8±0.2°, 21.1±0.2°, 23.0±0.2°, 25.6±0.2°, and 26.2±0.2°.

[0015] Preferably, the characteristic peaks of the milrinone multi-element eutectic, when irradiated with Cu-Kα, conform to Figure 1 The X-ray powder diffraction pattern is shown.

[0016] Preferably, the milrinone multi-element eutectic has a molecular formula of C 59 H 52 N6O 15 , the crystallographic parameters are: triclinic system, space group is P-1, unit cell parameters are: α=97.1580(10)°、β=98.9850(10)°、γ=91.7270(10)°,unit cell volume

[0017] In another aspect, the present invention provides a method for preparing a milrinone multi-element co-crystal, comprising the following steps:

[0018] Milrinone and baicalein are dissolved in a mixed solvent of methanol and acetone, heated and stirred, filtered, cooled and allowed to stand for volatilization and crystallization, filtered and dried to obtain a multi-component eutectic consisting of milrinone-baicalein-methanol-acetone.

[0019] Preferably, the mass-to-volume ratio of milrinone to the mixed solvent is 7-20:1, mg / ml; preferably 10-15:1, mg / ml.

[0020] Preferably, the volume ratio of methanol to acetone in the mixed solvent is 1:1-2.

[0021] Preferably, the molar ratio of milrinone to baicalein is 1:0.8-2.0.

[0022] Preferably, the heating temperature is 50-70°C, preferably 60°C.

[0023] Preferably, the heating and stirring time is 1 to 6 hours.

[0024] Preferably, the cooling and crystallization temperature is 0-20°C; more preferably, the cooling and crystallization temperature is 0-5°C.

[0025] Preferably, the crystallization time is 12 to 72 hours.

[0026] Preferably, the drying temperature is 50 to 80° C., and the drying time is 5 to 24 hours.

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

[0028] Finally, the present invention provides a pharmaceutical composition comprising the milrinone multi-element co-crystal of the present invention and other pharmaceutically acceptable components.

[0029] Preferably, the other pharmaceutically acceptable components may be active pharmaceutical ingredients that can be used in combination and / or pharmaceutically acceptable auxiliary ingredients.

[0030] Confirmation of crystal structure

[0031] X-ray crystallographic data for the milrinone-baicalein-methanol-acetone cocrystal described herein were collected on a Rigaku XtaLAB Synergy instrument at a temperature of 293(2)K using Cu-Ka radiation, with data collected in an ω scan mode and Lp correction. The structure was solved using a direct method, with the difference Fourier transform method identifying all non-hydrogen atoms. All hydrogen atoms on carbon and nitrogen were obtained using theoretical hydrogenation, and the structure was refined using the least squares method.

[0032] The crystallographic data of the milrinone-methanol-acetone co-crystal prepared by the present invention (as shown in Table 1) are as follows: triclinic system, space group P-1, unit cell parameters are: α=97.1580(10)°、β=98.9850(10)°、γ=91.7270(10)°,unit cell volume

[0033] Table 1 Main crystallographic data of milrinone multicomponent cocrystals

[0034]

[0035] The ORTEP diagram of the milrinone-baicalein-methanol-acetone co-crystal of the present invention shows that the crystalline form contains two molecules of milrinone, two molecules of baicalein, one molecule of acetone and two molecules of methanol, as shown in FIG. Figure 2 The hydrogen bond diagram of the milrinone-baicalein-methanol-acetone cocrystal of the present invention is shown in FIG. Figure 3 According to the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are shown in Figure 1 And Table 2.

[0036] Table 2 PXRD peaks of milrinone multi-element cocrystals

[0037]

[0038]

[0039] Compared with the prior art, the technical effects achieved by the present invention are:

[0040] The present invention provides, for the first time, a milrinone-baicalein-methanol-acetone co-crystal. Its preparation method is simple, the crystallization process is easily controlled, and reproducibility is excellent. The co-crystal significantly enhances the solubility of milrinone and improves oral bioavailability, thus possessing strong pharmaceutical value. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 .PXRD pattern of milrinone multi-element cocrystal.

[0042] Figure 2 .ORTEP diagram of milrinone multi-element cocrystal.

[0043] Figure 3 .Hydrogen bond diagram of milrinone multicomponent cocrystal. DETAILED DESCRIPTION

[0044] The present invention is further illustrated by the following examples. It should be understood that the examples of the present invention are merely for illustrating the present invention, rather than for limiting the present invention. Therefore, simple improvements to the present invention based on the method of the present invention fall within the scope of protection claimed by the present invention.

[0045] Example 1

[0046] 300.0 mg of milrinone and 422.1 mg of baicalein were dissolved in a mixed solvent of 10 mL of methanol and 10 mL of acetone, heated in a water bath at 55°C with stirring for 5 h, filtered, and the filtrate was allowed to stand at 0-5°C for 72 h for crystallization, filtered, and dried at 65°C for 12 h to obtain milrinone-baicalein-methanol-acetone cocrystals with a yield of 92% and a purity of 99.87%.

[0047] Example 2

[0048] 250.0 mg of milrinone and 352.3 mg of baicalein were dissolved in a mixed solvent of 10 mL of methanol and 15 mL of acetone, heated in a water bath at 55°C with stirring for 6 h, filtered, and the filtrate was allowed to stand at 0-5°C for 72 h for crystallization, filtered, and dried at 65°C for 12 h to obtain milrinone-baicalein-methanol-acetone cocrystals with a yield of 91% and a purity of 99.89%.

[0049] Example 3

[0050] 150.0 mg of milrinone and 211.3 mg of baicalein were dissolved in a mixed solvent of 5 mL of methanol and 10 mL of acetone, heated in a water bath at 50°C with stirring for 1 h, filtered, and the filtrate was allowed to stand at 0-5°C for 48 h for crystallization, filtered, and dried at 65°C for 12 h to obtain milrinone-baicalein-methanol-acetone cocrystals with a yield of 89% and a purity of 99.89%.

[0051] Example 4

[0052] 300.0 mg of milrinone and 422.1 mg of baicalein were dissolved in a mixed solvent of 5 mL of methanol and 10 mL of acetone, heated in a water bath at 50°C with stirring for 5 h, filtered, and the filtrate was allowed to stand at 10-15°C for 72 h for crystallization, filtered, and dried at 60°C for 16 h to obtain milrinone-baicalein-methanol-acetone cocrystals with a yield of 87% and a purity of 99.86%.

[0053] Example 5

[0054] 100.0 mg of milrinone and 128.1 mg of baicalein were dissolved in a mixed solvent of 10 mL of methanol and 5 mL of acetone, heated in a water bath at 50°C with stirring for 5 h, filtered, and the filtrate was allowed to stand at 20-25°C for 72 h for crystallization, filtered, and dried at 65°C for 24 h to obtain milrinone-baicalein-methanol-acetone cocrystals with a yield of 81% and a purity of 99.87%.

[0055] Stability test

[0056] The specific stability test method was carried out in accordance with the guidance method for stability investigation in Part IV of the Chinese Pharmacopoeia. The purity was tested by HPLC. The specific test results are shown in Table 3. The milrinone crystals used in the experiment were prepared according to patent CN106361710A.

[0057] Table 3 Stability test results of milrinone multi-element cocrystal

[0058]

[0059]

[0060] Solubility test

[0061] Method: 10 mL of medium (water, 0.01 mol / L HCl solution) was measured and placed in a vial, and an excess of the sample to be tested was added. The vial was sealed and placed in a constant temperature water bath at 25°C and stirred for 1 hour. The solution was filtered through a filter membrane and the filtrate was collected. The HPLC test was performed and the concentration of the saturated solution was calculated according to the external standard method.

[0062] Table 4 Solubility of Milrinone Multicomponent Cocrystals (mg / mL)

[0063]

Claims

1. A milrinone multi-element eutectic, characterized in that: The crystal unit of the multi-element eutectic contains milrinone-baicalein-methanol-acetone molecules in a molar ratio of 2:2:2:1, and its molecular formula is C 59 H 52 N6O 15 The crystallographic parameters are: triclinic system, space group is P-1, unit cell parameters are: a=11.18750(10)Å, b=12.21810(10)Å, c=19.8012(2)Å, α=97.1580(10)°, β=98.9850(10)°, γ=91.7270(10)°, unit cell volume V=2649.18(4)Å 3 .

2. The eutectic according to claim 1, wherein The milrinone multi-element cocrystal has characteristic peaks at least at 7.7±0.2°, 8.5±0.2°, 12.9±0.2°, 14.2±0.2°, 25.6±0.2°, and 26.2±0.2° in an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

3. The eutectic according to claim 1, wherein Using Cu-Kα radiation, the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at at least 7.0±0.2°, 7.7±0.2°, 8.5±0.2°, 12.1±0.2°, 12.9±0.2°, 14.2±0.2°, 16.9±0.2°, 17.1±0.2°, 20.8±0.2°, 21.1±0.2°, 23.0±0.2°, 25.6±0.2°, and 26.2±0.2°.

4. The eutectic according to claim 1, wherein Using Cu-Kα radiation, its characteristic peaks conform to the X-ray powder diffraction pattern shown in Figure 1.

5. A method for preparing the milrinone multi-element co-crystal according to any one of claims 1 to 4, comprising the following steps: Milrinone and baicalein are dissolved in a mixed solvent of methanol and acetone, heated and stirred, filtered, cooled and allowed to stand for crystallization, filtered and dried to obtain a multi-component eutectic consisting of milrinone-baicalein-methanol-acetone.

6. The preparation method according to claim 5, wherein The mass volume ratio of the milrinone to the mixed solvent is 7-20:1, mg / ml.

7. The preparation method according to claim 5, wherein The volume ratio of methanol to acetone in the mixed solvent is 1:1-2.

8. The preparation method according to claim 5, wherein The heating and stirring time is 1 to 6 hours.

9. The preparation method according to claim 5, wherein The cooling and crystallization temperature is 0-20°C.

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