A mirin-tartaric acid co-crystal

Abstract

This invention belongs to the technical field of medicinal chemistry and provides a milrinone-tartaric acid cocrystal. Using Cu-Kα radiation, its X-ray diffraction pattern (expressed as 2θ) exhibits characteristic peaks at at least 10.0±0.2°, 13.2±0.2°, 20.4±0.2°, 24.7±0.2°, 26.2±0.2°, 26.7±0.2°, and 34.3±0.2°. The cocrystal of this invention has high solubility and good stability. Using this cocrystal to prepare formulations avoids the use of large amounts of excipients and auxiliaries in existing technologies, reducing both production costs and clinical safety risks. The preparation method of the milrinone-tartaric acid cocrystal provided by this invention is simple to operate, the crystallization process is easy to control, and it has good reproducibility.

Description

Technical Field

[0001] This invention belongs to the technical field of medicinal chemistry, and relates to a new crystal form of milrinone, specifically a co-crystal of milrinone and tartaric acid, its preparation method and application. 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 amilorone, 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 amilorone, 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] Given the above problems, relying solely on formulation technology to address the poor solubility and stability of milrinone inevitably leads to excessive use of excipients and auxiliaries, posing potential safety risks in clinical use. Therefore, providing a new crystalline form of milrinone with good solubility, stability, and safety has become a pressing issue for those skilled in the art. Summary of the Invention

[0009] To address the solubility and stability issues of existing milrinone formulations, this invention aims to provide a novel milrinone crystalline form with higher solubility and stability: the milrinone-tartaric acid co-crystal. This invention also provides a simple, convenient method for preparing the milrinone-tartaric acid co-crystal, suitable for industrial production.

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

[0011] On one hand, the present invention provides a milrinone-tartaric acid eutectic, wherein the molar ratio of milrinone, tartaric acid and water molecules in the eutectic unit structure is 1:1:1.

[0012] Preferably, the Milrinone-tartaric acid eutectic, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 10.0±0.2°, 13.2±0.2°, 20.4±0.2°, 24.7±0.2°, 26.2±0.2°, 26.7±0.2°, and 34.3±0.2°.

[0013] Preferably, the Milrinone-tartaric acid eutectic, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 10.0±0.2°, 13.2±0.2°, 14.5±0.2°, 15.2±0.2°, 20.2±0.2°, 22.0±0.2°, 24.3±0.2°, 24.7±0.2°, 26.2±0.2°, 26.7±0.2°, 27.5±0.2°, 34.3±0.2°, 42.8±0.2°, and 44.5±0.2°.

[0014] Preferably, the Milrinone-tartaric 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-tartaric acid eutectic has the molecular formula C2. 16 H 17 N3O8, crystallographic parameters: triclinic system, space group P-1, unit cell parameters: α = 78.638(2)°, β = 84.900(2)°, γ = 83.845(2)°, cell volume

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

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

[0018] Preferably, the mixed solvent is a combination of an organic solvent and water, wherein the organic solvent is selected from methanol, ethanol, acetonitrile, acetone, DMSO or trifluoroethanol; particularly preferred are trifluoroethanol, DMSO or methanol.

[0019] More preferably, the volume ratio of organic solvent to water in the mixed solvent is 1 to 5:1; more preferably 2 to 4:1.

[0020] Preferably, the mass-to-volume ratio of milrinone to the mixed solvent is 21.1:1 to 4, mg / ml; more preferably, it is 21.1:2 to 3, mg / ml.

[0021] Preferably, the molar ratio of milrinone to tartaric acid is 1:1.0 to 2.0; more preferably, it is 1:1.1 to 1.3.

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

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

[0024] The crystallization time is 8 to 72 hours.

[0025] The drying temperature is 45–65°C, and the drying time is 8–12 hours.

[0026] Finally, the present invention provides a pharmaceutical composition containing the milrinone-tartaric acid cocrystal described herein and other pharmaceutically acceptable components.

[0027] Preferably, the other pharmaceutically acceptable components may be co-used active pharmaceutical ingredients and / or pharmaceutically acceptable excipients.

[0028] Confirmation of crystal structure

[0029] The X-ray crystal data for the Milrinone-tartaric 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 with Lp correction. 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.

[0030] The crystallographic data (Table 1) for the crystallization form of the Milrinone-tartaric acid eutectic prepared in this invention are as follows: triclinic system, space group P-1; cell parameters are: α = 78.638(2)°, β = 84.900(2)°, γ = 83.845(2)°, cell volume

[0031] Table 1. Major crystallographic data of the milrinone-tartaric acid eutectic.

[0032]

[0033]

[0034] The ORTEP diagram of the milrinone-tartaric acid eutectic of this invention shows that this crystalline form contains one molecule of milrinone, one molecule of tartaric acid, and one molecule of water, as shown below. Figure 2 As shown. The hydrogen bond diagram of the milrinone-tartaric 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.

[0035] Table 2 PXRD peaks of milrinone-tartaric acid eutectic

[0036]

[0037] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0038] This invention provides, for the first time, a milrinone-tartaric acid cocrystal, which is simple to prepare, easy to control during crystallization, and has good reproducibility. The cocrystal formation significantly enhances the solubility of milrinone and improves its oral bioavailability, thus possessing strong pharmaceutical value. Attached Figure Description

[0039] Figure 1 PXRD pattern of Milrinone-tartaric acid eutectic.

[0040] Figure 2 ORTEP diagram of Milrinone-tartaric acid eutectic.

[0041] Figure 3 Hydrogen bond diagram of Milrinone-tartaric acid eutectic. Detailed Implementation

[0042] 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.

[0043] 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 with reference to patent CN106361710A, and milrinone hydrochloride and milrinone methanesulfonate are prepared with reference to CN1951919A.

[0044] Example 1

[0045] 212.0 mg milrinone and 165 mg tartaric acid were dissolved in a mixed solvent of 5 mL purified water and 15 mL trifluoroethanol. The solution was heated and stirred in a water bath at 60 °C until completely dissolved. The solution was filtered, allowed to stand at 5–10 °C for 48 h to crystallize, filtered again, and dried at 50 °C for 12 h to obtain milrinone-tartaric acid eutectic crystals. Yield: 95%, purity: 99.91%.

[0046] Example 2

[0047] 101.5 mg milrinone and 82.5 mg tartaric acid were dissolved in a mixed solvent of 10 mL methanol and 2.5 mL water. The solution was heated and stirred in a water bath at 60 °C until completely dissolved. The solution was filtered, allowed to stand at 5–10 °C for 48 h to crystallize, filtered again, and dried at 50 °C for 12 h to obtain a milrinone-tartaric acid eutectic. Yield: 94%, Purity: 99.92%.

[0048] Example 3

[0049] 212.0 mg milrinone and 165 mg tartaric acid were dissolved in a mixed solvent of 5 mL purified water and 10 mL DMSO. The mixture was heated and stirred in a water bath at 70 °C until completely dissolved. After filtration, the mixture was allowed to stand at 0–5 °C for 48 h to crystallize. After filtration, the mixture was dried at 65 °C for 12 h to obtain a milrinone-tartaric acid eutectic crystal with a yield of 91% and a purity of 99.91%.

[0050] Example 4

[0051] 212.0 mg milrinone and 300 mg tartaric acid were dissolved in a mixed solvent of 10 mL purified water and 20 mL trifluoroethanol. The solution was heated and stirred in a water bath at 60 °C until completely dissolved. The solution was filtered, allowed to stand at 5–10 °C for 48 h to crystallize, filtered again, and dried at 50 °C for 12 h to obtain milrinone-tartaric acid eutectic crystals. Yield: 90%, purity: 99.90%.

[0052] Example 5

[0053] 212.0 mg milrinone and 151 mg tartaric acid were dissolved in a mixed solvent of 5 mL purified water and 10 mL acetonitrile. The solution was heated and stirred in a water bath at 60 °C until completely dissolved. The solution was filtered, allowed to stand at 5–10 °C for 72 h to crystallize, filtered again, and dried at 50 °C for 12 h to obtain milrinone-tartaric acid eutectic crystals. Yield: 83%, purity: 99.89%.

[0054] Example 6

[0055] 212.0 mg milrinone and 151 mg tartaric acid were dissolved in a mixed solvent of 10 mL purified water and 10 mL trifluoroethanol. The solution was heated and stirred in a water bath at 60 °C until completely dissolved. The solution was filtered, allowed to stand at 5–10 °C for 48 h to crystallize, filtered again, and dried at 50 °C for 12 h to obtain milrinone-tartaric acid eutectic crystals. Yield: 65%, purity: 99.91%.

[0056] Example 7

[0057] 106.0 mg milrinone and 76 mg tartaric acid were dissolved in a mixed solvent of 5 mL purified water and 20 mL trifluoroethanol. The solution was heated and stirred in a water bath at 60 °C until completely dissolved. The solution was filtered, allowed to stand at 5–10 °C for 48 h to crystallize, filtered again, and dried at 50 °C for 12 h to obtain milrinone-tartaric acid eutectic crystals. Yield: 67%, purity: 99.87%.

[0058] Stability test

[0059] 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.

[0060] Table 3. Stability test results of Milrinone-tartaric acid eutectic

[0061]

[0062] Solubility test

[0063] 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 by external standard method.

[0064] Table 4. Solubility of Milrinone-Tartrate Cocrystal (mg / mL)

[0065]

Claims

1. A milrinone-tartaric acid eutectic, characterized in that, The molar ratio of milrinone, tartaric acid, and water molecules in the eutectic unit structure is 1:1:1; using Cu-Kα radiation, the X-ray diffraction pattern, expressed in 2θ, shows characteristic peaks at at least 10.0±0.2°, 13.2±0.2°, 20.4±0.2°, 24.7±0.2°, 26.2±0.2°, 26.7±0.2°, and 34.3±0.2°; the molecular formula of the milrinone-tartaric acid eutectic is C2. 16 H 17 N3O8 has the following crystallographic parameters: triclinic system, space group P-1, cell parameters: a=7.5214(2)Å, b=8.8216(2)Å, c=13.1392(3)Å, α=78.638(2)°, β=84.900(2)°, γ=83.845(2)°, and cell volume V=847.73(4)Å. 3 .

2. The eutectic as described in claim 1, characterized in that, The Milrinone-tartaric acid eutectic, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 10.0±0.2°, 13.2±0.2°, 14.5±0.2°, 15.2±0.2°, 20.2±0.2°, 22.0±0.2°, 24.3±0.2°, 24.7±0.2°, 26.2±0.2°, 26.7±0.2°, 27.5±0.2°, 34.3±0.2°, 42.8±0.2°, and 44.5±0.2°.

3. The eutectic as described in claim 1, characterized in that, The Milrinone-tartaric acid eutectic was subjected to Cu-Kα radiation, and its characteristic peaks conformed 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 process includes the following steps: dissolving milrinone and tartaric acid in a mixed solvent, heating and stirring, filtering, cooling and allowing to stand to crystallize, filtering and drying to obtain milrinone-tartaric acid crystals.

5. The preparation method according to claim 4, characterized in that, The mixed solvent is a combination of an organic solvent and water, wherein the organic solvent is selected from methanol, ethanol, acetonitrile, acetone, DMSO or trifluoroethanol.

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

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

8. The pharmaceutical composition according to claim 7, characterized in that, Other pharmaceutically feasible components may be co-operable active pharmaceutical ingredients and / or pharmaceutically acceptable excipients.

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