A mirinone-maleic acid co-crystal

Abstract

The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a new mirinol crystal form, and particularly to a mirinol-adipic acid co-crystal and a preparation method and application thereof. The co-crystal has an X-ray diffraction spectrum expressed by 2theta using Cu-Kalpha radiation, and has characteristic peaks at least at 9.0+ / -0.2°, 15.7+ / -0.2°, 18.0+ / -0.2°, 24.0+ / -0.2°, 31.4+ / -0.2°, 31.6+ / -0.2°. The preparation method of the mirinol-adipic acid co-crystal is simple in operation, easy to control in crystallization process, and good in reproducibility.

Description

Technical Field

[0001] This invention belongs to the technical field of medicinal chemistry, specifically relating to a new crystal form of milrinone, specifically a cocrystal of milrinone and adipic acid, its preparation method, and its application. Background Technology

[0002] Milrinone (Formula I), chemically named 1,6-dihydro-2-methyl-6-oxo-[3,4-bispyridine]-5-carboxynitrile, has the molecular formula C1. 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 cosolvents and pH adjusters to improve water solubility, and these are used in large quantities. Therefore, the safety and solubilizing effect of cosolvents are particularly important. For example, patent CN9151919A discloses a method of preparing lyophilized formulations by forming salts from inorganic acids such as hydrochloric acid, phosphoric acid, and sulfuric acid; patent CN106361710A discloses a method of first precipitating crystals in a solvent of ethanol + acetone + water, and then using lactic acid as a pH adjuster to prepare the formulation. However, these methods still do not completely solve the problems of poor solubility and stability of milrinone itself. For example, when using inorganic acids as cosolvents, the Cl- introduced by hydrochloric acid...- It may cause hyperchloremia, while phosphoric acid and sulfuric acid are not good solubilizers. Among organic acids, lactic acid has a better solubilizing effect, but lactic acid is a racemic mixture composed of L-lactic acid and D-lactic acid. Since the human body only has the enzyme to metabolize L-lactic acid and its 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 issues, relying solely on formulation technology to address the solubility and stability problems of milrinone inevitably leads to potential clinical safety risks due to excessive use of excipients and adjuvants. Therefore, providing a new crystalline form of milrinone with good solubility, high stability, and high safety has become a pressing issue for those skilled in the art. Summary of the Invention

[0009] To address the drawback of poor solubility of milrinone in existing technologies, this invention aims to provide a new crystalline form of milrinone with higher solubility and stability, namely, a milrinone-adipic acid co-crystal. Furthermore, this invention provides a simple, convenient method for preparing the milrinone-adipic acid co-crystal, suitable for industrial production.

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

[0011] The present invention provides a milrinone-adipic acid cocrystal, wherein the crystal units of the cocrystal contain milrinone-adipic acid molecules in a molar ratio of 2:1.

[0012] A Milrinone-adipic acid eutectic, characterized by having characteristic peaks at at least 9.0±0.2°, 15.7±0.2°, 18.0±0.2°, 24.0±0.2°, 31.4±0.2°, and 31.6±0.2° in its X-ray diffraction pattern (denoted as 2θ) using Cu-Kα radiation.

[0013] Preferably, the Milrinone-adipic acid eutectic, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 9.0±0.2°, 12.8±0.2°, 15.7±0.2°, 18.0±0.2°, 24.0±0.2°, 25.6±0.2°, 31.4±0.2°, 31.6±0.2°, and 32.9±0.2°.

[0014] Preferably, the Milrinone-adipic acid eutectic is obtained using Cu-Kα radiation, and its characteristic peaks conform to... Figure 1 The X-ray powder diffraction pattern shown is shown.

[0015] Preferably, the milrinone-adipic acid eutectic has the molecular formula C1. 30 H 28 N6O6, crystallographic parameters are: monoclinic system, space group C2 / c, unit cell parameters are: α = 90°, β = 116.580(2)°, γ = 90°, cell volume

[0016] On the other hand, the present invention provides a method for preparing milrinone-adipic acid eutectic, comprising the following steps:

[0017] Milrinone and adipic acid were dissolved in a mixed solvent, heated and stirred, filtered, cooled and allowed to stand to evaporate and crystallize, and then filtered and dried to obtain milrinone-adipic acid crystals.

[0018] Preferably, the mixed solvent is a combination of methanol and solvent A, wherein solvent A is selected from one or more of ethanol, acetonitrile, water, acetone or trifluoroethanol; a mixed solvent of methanol and trifluoroethanol or acetone is particularly preferred.

[0019] Preferably, the volume ratio of methanol to solvent A in the mixed solvent is 1:1 to 2.

[0020] Preferably, the mass-to-volume ratio of milrinone to the mixed solvent is 7–21:1, mg / mL; more preferably, it is 8.5–14:1, mg / mL.

[0021] Preferably, the molar ratio of milrinone to adipic acid is 1:0.9 to 2.0; more preferably, it is 1:1.1.

[0022] Preferably, the heating temperature is 50–70°C.

[0023] Preferably, the cooling crystallization temperature is 0–30°C; more preferably, the cooling crystallization temperature is 10–15°C.

[0024] Preferably, the crystallization time is 6 to 48 hours.

[0025] Preferably, the drying temperature is 50-60°C and the drying time is 5-24 hours.

[0026] 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.

[0027] Finally, the present invention provides a pharmaceutical composition comprising the milrinone-adipic acid eutectic described herein and other pharmaceutically feasible components.

[0028] Preferably, the other pharmaceutically feasible components may be co-operable active pharmaceutical ingredients and / or pharmaceutically acceptable excipients.

[0029] Confirmation of crystal structure

[0030] The X-ray crystal data for the Milrinone-adipic acid eutectic test described in this invention were collected using a Rigaku XtaLABSynergy instrument in Japan at a test temperature of 293(2) K. Cu-Ka radiation was used, and data were collected via ω-scanning and Lp correction was performed. The structure was analyzed using a direct method, and all non-hydrogen atoms were identified using the difference Fourier method. All hydrogen atoms on carbon and nitrogen were obtained through theoretical hydrogenation. The structure was refined using the least squares method.

[0031] The crystallographic data (as shown in Table 1) for testing and analysis of the milrinone-adipic acid eutectic prepared in this invention are: monoclinic system, space group C2 / c, and cell parameters are: α = 90°, β = 116.580(2)°, γ = 90°, cell volume

[0032] Table 1. Major crystallographic data of milrinone-adipic acid eutectic

[0033]

[0034]

[0035] The ORTEP diagram of the milrinone-adipic acid eutectic of this invention shows that this crystalline form contains two molecules of milrinone and one molecule of adipic acid, as shown in the figure. Figure 2 As shown. The hydrogen bond diagram of the milrinone-adipic acid eutectic of the present invention is as follows. 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 below. Figure 1 And Table 2.

[0036] Table 2 PXRD peaks of milrinone-adipic acid eutectic

[0037]

[0038] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0039] This invention provides a milrinone-adipic acid cocrystal, which significantly enhances the solubility of milrinone, helps improve oral bioavailability, and has strong pharmaceutical value. This invention also provides a method for preparing the milrinone-adipic acid cocrystal, which is simple to operate, easy to control during crystallization, and has good reproducibility. Attached Figure Description

[0040] Figure 1 PXRD pattern of Milrinone-adipic acid eutectic.

[0041] Figure 2 ORTEP diagram of Milrinone-adipic acid eutectic.

[0042] Figure 3 Hydrogen bond diagram of Milrinone-adipic acid eutectic. Detailed Implementation

[0043] 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.

[0044] Milrinone crystals, milrinone hydrochloride, and milrinone methanesulfonate used in stability and solubility tests were prepared according to existing literature.

[0045] Example 1

[0046] 211 mg milrinone and 160 mg adipic acid were dissolved in a mixed solvent of 10 mL methanol and 10 mL trifluoroethanol. The mixture was heated and stirred in a water bath at 60 °C. The filtrate was collected by filtration and allowed to stand at 10–15 °C for 36 h to crystallize. After filtration, the crystals were dried at 50 °C for 24 h to obtain milrinone-adipic acid eutectic crystals. The yield was 94% and the purity was 99.91%.

[0047] Example 2

[0048] 211 mg of milrinone and 146 mg of adipic acid were dissolved in a mixed solvent of 15 mL methanol and 15 mL acetone. The mixture was heated and stirred in a water bath at 55 °C. The filtrate was collected by filtration and allowed to stand at 10–15 °C for 24 h to crystallize. After filtration, the crystals were dried at 50 °C for 24 h to obtain milrinone-adipic acid eutectic crystals. Yield: 93%, purity: 99.92%.

[0049] Example 3

[0050] 280 mg milrinone and 194 mg adipic acid were dissolved in a mixed solvent of 10 mL methanol and 10 mL acetone. The mixture was heated and stirred in a water bath at 55 °C. The filtrate was collected by filtration and allowed to stand at 10–15 °C for 48 h to crystallize. After filtration, the milrinone-adipic acid eutectic was obtained by drying at 50 °C for 24 h. The yield was 91% and the purity was 99.92%.

[0051] Example 4

[0052] 106 mg milrinone and 58 mg adipic acid were dissolved in a mixed solvent of 10 mL methanol and 10 mL water. The mixture was heated and stirred in a water bath at 60 °C. The filtrate was collected by filtration and allowed to stand at 15–20 °C for 48 h to crystallize. After filtration, the milrinone-adipic acid eutectic was obtained by drying at 50 °C for 24 h. The yield was 83% and the purity was 99.91%.

[0053] Stability test

[0054] 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.

[0055] Table 3. Stability test results of milrinone-adipic acid eutectic

[0056]

[0057] Solubility test

[0058] 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; detect by HPLC and calculate the concentration of the saturated solution according to the external standard method.

[0059] Table 4. Solubility of Milrinone-Adipic Acid Cocrystal (mg / mL)

[0060]

Claims

1. A milrinone-adipic acid eutectic, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed in 2θ, exhibits characteristic peaks at at least 9.0±0.2°, 15.7±0.2°, 18.0±0.2°, 24.0±0.2°, 31.4±0.2°, and 31.6±0.2°; the milrinone-adipic acid eutectic has the molecular formula C2. 30 H 28 N6O6 has the following crystallographic parameters: monoclinic system, space group C2 / c, cell parameters: a=22.4214(4)Å, b=11.3299(2)Å, c=12.5731(2)Å, α=90°, β=116.580(2)°, γ=90°, and cell volume V=2856.40(10)Å. 3 .

2. The eutectic as described in claim 1, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, has characteristic peaks at at least 9.0±0.2°, 12.8±0.2°, 15.7±0.2°, 18.0±0.2°, 24.0±0.2°, 25.6±0.2°, 31.4±0.2°, 31.6±0.2°, and 32.9±0.2°.

3. The eutectic as described in claim 1, characterized in that, Using Cu-Kα radiation, its characteristic peaks conform to the X-ray powder diffraction pattern shown in Figure 1.

4. A method for preparing the eutectic according to any one of claims 1-3, characterized in that, The method includes: dissolving milrinone and adipic acid in a mixed solvent, heating and stirring, filtering, cooling and allowing to stand to volatilize and crystallize, filtering and drying to obtain milrinone-adipic acid crystals.

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

6. The preparation method according to claim 5, characterized in that, The volume ratio of methanol to solvent A in the mixed solvent is 1:1 to 2.

7. The preparation method according to claim 4, characterized in that, The mass-to-volume ratio of milrinone to the mixed solvent is 7–21:1, mg / ml.

8. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains the milrinone-adipic acid eutectic as described in any one of claims 1-3 and other pharmaceutically feasible components.

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