Milrinone and ketorolac cocrystal and preparation method thereof

Abstract

The present invention relates to the technical field of pharmaceutical cocrystals, and in particular to a milrinone-ketorolac cocrystal and a preparation method thereof. The cocrystal is formed by combining milrinone and ketorolac in a molar ratio of 1:1. Using Cu-Kα radiation, an X-ray diffraction spectrum represented by 2θ has characteristic peaks at 7.9±0.2°, 13.3±0.2°, 15.7±0.2°, 15.8±0.2°, and 17.8±0.2°. The milrinone-ketorolac cocrystal provided by the present invention has good stability and high solubility, and the preparation method is simple and easy, low in cost, and convenient for large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug co-crystals, and in particular to a milrinone-ketorolac drug co-crystal and a preparation method thereof. Background Art

[0002] Milrinone, 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 is a cardiotonic drug that enhances myocardial contractility and directly dilates blood vessels. Its mechanism of action is similar to that of amrinone and is well tolerated. It dilates vascular smooth muscle, reduces cardiac workload, and significantly improves blood supply to the kidneys and muscles, without serious adverse reactions. It is suitable for acute and chronic refractory congestive heart failure caused by various reasons that are ineffective or ineffective with digitalis, diuretics, and vasodilators. However, milrinone is virtually insoluble in water, so when preparing milrinone formulations, special excipients are required to improve its solubility. Existing formulation methods typically use cosolvents and pH regulators to improve its water solubility, and these agents require high dosages, which can easily lead to toxic side effects. For example, patent CN106361710B discloses a method for preparing a formulation by first precipitating crystals in an ethanol+acetone+water solvent and then using lactic acid as a pH regulator. However, lactic acid is a racemic compound composed of L-lactic acid and D-lactic acid. Since the human body only has enzymes capable of metabolizing L-lactic acid and its metabolic capacity is limited, excessive intake of D-lactic acid can cause metabolic disorders and even acidosis. Patent CN9151919A discloses a method for preparing a freeze-dried formulation using inorganic acids such as hydrochloric acid, phosphoric acid, and sulfuric acid after salt formation. However, using inorganic acids as cosolvents can introduce chlorine into the formulation, potentially leading to hyperchloremia, while phosphoric acid and sulfuric acid are less effective as cosolvents. Furthermore, since milrinone is virtually insoluble in water, large-scale production can result in long dissolution times, incomplete dissolution, and excessive insoluble particulate matter, impacting product quality.

[0005] In summary, the existing technology still fails to completely solve the problem of poor solubility and stability of milrinone itself. Summary of the Invention

[0006] In view of the deficiencies in the prior art, the present application aims to provide a new milrinone crystal form with high solubility and good stability, specifically providing a milrinone-ketorolac cocrystal and a preparation method thereof.

[0007] Ketorolac is a nonsteroidal anti-inflammatory drug with strong analgesic and moderate anti-inflammatory effects. Its analgesic effect is comparable to that of morphine and stronger than aspirin, indomethacin, and naproxen. Chemical name: (+ / -)-5-benzoyl-2,3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid, molecular formula: C 15 H 13 NO3, the structural formula is:

[0008]

[0009] The specific technical contents of the present invention are as follows:

[0010] In a first aspect, the present invention provides a milrinone-ketorolac cocrystal, wherein the molar ratio of milrinone to ketorolac in a crystal unit of the cocrystal is 1:1.

[0011] Preferably, the milrinone-ketorolac cocrystal has characteristic peaks at 7.9±0.2°, 13.3±0.2°, 15.7±0.2°, 15.8±0.2°, and 17.8±0.2° in an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0012] Preferably, the milrinone-ketorolac cocrystal, using Cu-Kα radiation, has an X-ray diffraction spectrum expressed in 2θ having characteristic peaks at 2θ values ​​of 7.9±0.2°, 8.9±0.2°, 10.2±0.2°, 13.3±0.2°, 15.4±0.2°, 15.7±0.2°, 15.8±0.2°, 17.6±0.2°, 17.8±0.2°, 30.0±0.2°, and 31.3±0.2°.

[0013] Preferably, the characteristic peaks of the milrinone-ketorolac cocrystal, when irradiated with Cu-Kα, conform to Figure 1 The X-ray powder diffraction pattern is shown.

[0014] Preferably, the milrinone-ketorolac drug cocrystal has a molecular formula of C 27 H 22 N4O4, crystallographic parameters are: monoclinic system, space group is P21 / c, unit cell parameters are: α=90°、β=107.2010(10)°、γ=90°,unit cell volume

[0015] In a second aspect, the present invention provides a method for preparing a milrinone-ketorolac cocrystal, the specific steps of which include: adding milrinone and ketorolac to solvent A, heating to dissolve, clarifying the solution, cooling to crystallize, filtering and drying to obtain the milrinone-ketorolac cocrystal.

[0016] Preferably, the solvent A is selected from one or two of methanol, acetone, acetonitrile and water.

[0017] Preferably, the molar ratio of milrinone to ketorolac is 1:0.8-1.2; more preferably 1:1.

[0018] Preferably, the mass-to-volume ratio of milrinone to solvent A is 3-6:1, wherein the mass is measured in mg and the volume is measured in mL.

[0019] Preferably, the dissolving and heating temperature is 40-60°C, more preferably 50°C.

[0020] Preferably, the temperature of the cooling crystallization is 10-20°C.

[0021] Preferably, the crystallization time is 48 to 72 hours.

[0022] In a third aspect of the present application, a pharmaceutical composition is provided, comprising the milrinone-ketorolac cocrystal of the present invention and other pharmaceutically acceptable components.

[0023] Preferably, the pharmaceutical composition can be prepared using standard and conventional techniques by combining the compound of the present invention with a pharmaceutically acceptable solid or liquid carrier, and optionally with pharmaceutically acceptable adjuvants and excipients.

[0024] The fourth aspect of the present invention further provides the use of milrinone and ketorolac drug co-crystal in the preparation of anti-inflammatory and analgesic drugs and in the treatment of heart failure.

[0025] Confirmation of crystal structure

[0026] X-ray crystallography data were collected on a Rigaku XtaLAB Synergy instrument at 293(2)K using CuKa radiation, using ω scanning mode and Lp correction. The structure was solved by direct analysis, with the difference Fourier transform method identifying all non-hydrogen atoms. All hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation, and the structure was refined by the least squares method.

[0027] The crystallographic data of the milrinone-ketorolac cocrystal prepared by the present invention were tested and analyzed (as shown in Table 1). The crystallographic parameters are: monoclinic system, space group P21 / c, and unit cell parameters are: α=90°、β=107.2010(10)°、γ=90°,unit cell volume

[0028] Table 1 Main crystallographic data of milrinone and ketorolac cocrystal

[0029]

[0030]

[0031] The ORTEP diagram of the milrinone-ketorolac cocrystal provided by the present invention shows that one molecule of milrinone is bound to one molecule of ketorolac in the crystalline form, as shown in the attached diagram. Figure 3 The hydrogen bond diagram of the milrinone-ketorolac cocrystal of the present invention is shown in the attached Figure 4 According to the above crystallographic data, the corresponding characteristic peaks in the X-ray powder diffraction pattern (Cu-Kα) are shown in the attached Figure 1 And Table 2.

[0032] Table 2 PXRD peaks of milrinone and ketorolac cocrystal

[0033]

[0034] The TGA / DSC thermal analysis tester and test conditions in the present invention are as follows: TGA / DSC thermal analyzer: METTLER TOLEDO TGA / DSC3+; dynamic temperature range: 30-300°C; heating rate: 10°C / min; program gas N2; gas flow rate: 50 mL / min; crucible: aluminum crucible 40 μl.

[0035] The TGA / DSC test results of the milrinone and ketorolac drug cocrystal prepared by the present invention are as follows: Figure 2 As shown, the DSC spectrum shows an endothermic peak in the range of 175.78-210.57°C, and the peak value of the endothermic peak is 193.22°C; its thermogravimetric analysis (TGA) has only one weight loss step, indicating that the milrinone and ketorolac cocrystal does not contain a solvent and has a stable structure.

[0036] The milrinone and ketorolac drug co-crystal prepared by the method of the present invention has the following advantages over the currently reported milrinone crystal form:

[0037] (1) High stability. The milrinone-ketorolac drug cocrystal has high stability in the solid state. After high temperature testing and storage in a high humidity environment, the HPLC purity is still higher than 99.9%. Compared with the existing milrinone crystal form, its solid state stability is better.

[0038] (2) High solubility. Milrinone-ketorolac cocrystal has significantly higher solubility than other milrinone crystals.

[0039] (3) The preparation method of the drug cocrystal provided by the present invention is simple to operate, the crystallization process is easy to control, and has good reproducibility, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 .PXRD pattern of milrinone and ketorolac drug cocrystal.

[0041] Figure 2 .TGA / DSC diagram of milrinone and ketorolac drug co-crystal.

[0042] Figure 3 .ORTEP diagram of the cocrystal of milrinone and ketorolac.

[0043] Figure 4 .Hydrogen bond diagram of milrinone and ketorolac drug 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] The materials used in the examples can be prepared according to any method in the prior art or purchased from commercial products.

[0046] Example 1

[0047] 211.2 mg of milrinone and 204.2 mg of ketorolac were added to 40 mL of acetone and heated in a 40°C water bath with stirring to dissolve. After the solution was clarified, it was filtered. The filtrate was allowed to stand at 10-15°C for 48 hours to crystallize, filtered, and dried to obtain milrinone-ketorolac cocrystals with a yield of 92.6% and an HPLC analysis of 99.92%.

[0048] Example 2

[0049] 211.2 mg of milrinone and 255.2 mg of ketorolac were added to 70 mL of acetonitrile and heated in a 60°C water bath with stirring to dissolve. After the solution was clarified, it was filtered. The filtrate was allowed to stand at 10-15°C for 72 hours to crystallize, filtered, and dried to obtain milrinone-ketorolac cocrystals with a yield of 96.1% and an HPLC analysis of 99.96%.

[0050] Example 3

[0051] 211.2 mg of milrinone and 255.2 mg of ketorolac were added to 35 mL of acetone and heated in a 50°C water bath with stirring to dissolve. After the solution was clarified, it was filtered. The filtrate was allowed to stand at 15-20°C for 48 hours to crystallize, filtered, and dried to obtain milrinone-ketorolac cocrystals with a yield of 93.5% and an HPLC analysis of 99.90%.

[0052] Example 4

[0053] 211.2 mg of milrinone and 306.2 mg of ketorolac were added to a mixed solvent of 20 mL of water and 40 mL of methanol, and the mixture was heated in a water bath at 60°C with stirring to dissolve. After the solution was clarified, it was filtered. The filtrate was allowed to stand at 10-15°C for 48 hours to crystallize, filtered, and dried to obtain milrinone-ketorolac cocrystals with a yield of 94.2% and an HPLC analysis of 99.94%.

[0054] Example 5

[0055] 211.2 mg of milrinone and 255.2 mg of ketorolac were added to 40 mL of ethanol and heated in a 50°C water bath with stirring to dissolve. After the solution was clarified, it was filtered. The filtrate was allowed to stand at 15-20°C for 48 hours to crystallize, filtered, and dried to obtain milrinone-ketorolac cocrystals with a yield of 85.5% and an HPLC analysis of 99.90%.

[0056] Example 6

[0057] 140.8 mg of milrinone and 255.2 mg of ketorolac were added to 60 mL of tetrahydrofuran and heated in a 50°C water bath with stirring to dissolve. After the solution was clarified, it was filtered. The filtrate was allowed to stand at room temperature for 48 hours to crystallize, filtered, and dried to obtain milrinone-ketorolac cocrystals with a yield of 80.3% and an HPLC analysis of 99.90%.

[0058] Example 7

[0059] 211.2 mg of milrinone and 255.2 mg of ketorolac were added to 30 mL of acetonitrile and heated in a 50°C water bath with stirring to dissolve. After the solution was clarified, it was filtered. The filtrate was allowed to stand at 0-5°C for 24 h to crystallize, filtered, and dried to obtain milrinone-ketorolac cocrystals with a yield of 82.8% and an HPLC analysis of 99.89%.

[0060] Comparative Example 1

[0061] Milrinone crystals were prepared with reference to Example 1 of Chinese patent CN106361710B.

[0062] Comparative Example 2

[0063] Referring to the method described in Example 1 of Chinese Patent CN104387320B, milrinone was recrystallized in an ethanol-water system to obtain white milrinone crystals.

[0064] Comparative Example 3

[0065] Milrinone crystals were prepared according to the method of Chinese patent CN102558044A specification

[0013] .

[0066] Comparative Example 4

[0067] Milrinone sodium salt was prepared according to the method of Example 1 of Chinese Patent CN1951919A.

[0068] Comparative Example 5

[0069] Milrinone hydrochloride was prepared according to the method of Example 3 of Chinese Patent CN1951919A.

[0070] Verification Example

[0071] 1. Stability test

[0072] (1) Test materials: Milrinone-ketorolac cocrystal prepared in Example 2, milrinone crystals prepared in Comparative Examples 1-3, milrinone sodium salt prepared in Comparative Example 4, and milrinone hydrochloride prepared in Comparative Example 5.

[0073] (2) Test method: The test was conducted in accordance with the method in Appendix 9001, Part IV, "Guidelines for Stability Testing of Active Pharmaceutical Ingredients and Preparations" of the Chinese Pharmacopoeia (2020 edition). The high temperature test conditions were: 60°C; the strong light irradiation test conditions were: 4500lx±500lx; and the high humidity test conditions were: 25°C, relative humidity 90%±5%. Purity was determined by HPLC. Three parallel tests were performed, and the results were averaged.

[0074] (3) Test results: The test results are shown in Table 3.

[0075] Table 3 Stability test results

[0076]

[0077] The experimental results show that the milrinone-ketorolac cocrystal prepared in the embodiment of the present invention has high purity, and the purity of the sample changes little under high temperature, high humidity and strong light conditions, and has good stability.

[0078] 2. Solubility test

[0079] Milrinone-ketorolac cocrystal, milrinone crystals from Comparative Examples 1-3, milrinone sodium salt, and milrinone hydrochloride were placed in a constant temperature medium (0.01 mol / L HCl and water) at 37°C and stirred to supersaturate. The saturated solution was filtered, and the filtrate was measured. The concentration of the saturated solution was calculated by the external standard method. The results are shown in Table 4.

[0080] Table 4 Solubility test results

[0081]

[0082] The test results show that the solubility of the milrinone-ketorolac cocrystal in 0.01 mol / L HCl and water is significantly improved compared with other crystalline forms of milrinone, which helps to improve its bioavailability.

Claims

1. A milrinone-ketorolac cocrystal, characterized in that The co-crystal uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 7.9±0.2°, 13.3±0.2°, 15.7±0.2°, 15.8±0.2°, and 17.8±0.2°. The molecular formula of the co-crystal is C 27 H 22 N4O4, crystallographic parameters are: monoclinic system, space group is P21 / c, unit cell parameters are: a=20.9830(2)Å, b=4.98570(10)Å, c=23.3993(3)Å, α=90°, β=107.2010(10)°, γ=90°, unit cell volume V=2338.43(6)Å 3 .

2. The milrinone-ketorolac cocrystal according to claim 1, wherein The co-crystal uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 2θ values ​​of 7.9±0.2°, 8.9±0.2°, 10.2±0.2°, 13.3±0.2°, 15.4±0.2°, 15.7±0.2°, 15.8±0.2°, 17.6±0.2°, 17.8±0.2°, 30.0±0.2°, and 31.3±0.2°.

3. The milrinone-ketorolac cocrystal according to claim 1, wherein The co-crystal was subjected to Cu-Kα radiation and its characteristic peaks were consistent with the X-ray powder diffraction pattern shown in FIG1 .

4. The milrinone-ketorolac cocrystal according to claim 1, wherein In the crystal unit of the co-crystal, the molar ratio of milrinone to ketorolac is 1:

1.

5. A method for preparing the milrinone-ketorolac cocrystal according to any one of claims 1 to 4, characterized in that: The specific steps include: adding milrinone and ketorolac into solvent A, heating to dissolve, cooling the solution after the solution is clarified, crystallizing, filtering and drying to obtain milrinone-ketorolac cocrystal.

6. The preparation method according to claim 5, characterized in that The solvent A is selected from one or two of methanol, acetone, acetonitrile and water.

7. The preparation method according to claim 5, characterized in that The molar ratio of milrinone to ketorolac is 1:0.8-1.

2.

8. The preparation method according to claim 5, characterized in that The mass-to-volume ratio of milrinone to solvent A is 3-6:1, where the mass is in mg and the volume is in mL.

9. The preparation method according to claim 5, characterized in that The temperature of the cooling crystallization is 10-20°C, and the crystallization time is 48-72h.

10. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises the co-crystal according to claim 1 and other pharmaceutically acceptable components.

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