A mirinoglycoside gallate co-crystal

Abstract

The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a new crystal form of milrinone, and particularly to a co-crystal of milrinone and gallic acid, and a preparation method and application thereof. The present application provides a new crystal form of milrinone with high solubility and stability, i.e. a milrinone gallic acid co-crystal hemihydrate. In addition, the present application provides a method for preparing the milrinone gallic acid co-crystal hemihydrate, which is simple, convenient and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the technical field of medicinal chemistry, specifically relating to a milrinone-gallic acid eutectic, 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] In reality, due to the poor water solubility of milrinone and the severe adverse reactions when taken orally, providing a crystalline form of milrinone with good solubility, high stability, and promising drug development prospects has become an urgent problem for those skilled in the art.

[0007] Gallic acid, also known as gallic acid or gallnut acid, is an organic acid found in plants such as gallnut, lacquer tree, and tea. It has antibacterial, antiviral, antioxidant, anti-atherosclerotic, antithrombotic, anti-angiogenic, and anti-inflammatory effects.

[0008] Drug co-crystallization refers to the formation of crystals in which drug molecules are bonded to other physiologically acceptable acids, bases, salts, and nonionic compounds within the same crystal lattice through non-covalent interactions such as hydrogen bonds, π-π stacking, and van der Waals forces. Without disrupting the covalent bonds of the drugs, the formation of co-crystallization can alter the physicochemical properties of the drugs, including stability, solubility, and bioavailability. When two drugs form a co-crystallization, their physicochemical properties and pharmacokinetic parameters can be improved, achieving the goal of combined drug administration. Summary of the Invention

[0009] To address the shortcomings of existing milrinone technologies, such as poor solubility and low stability, this invention aims to provide a new crystalline form of milrinone with higher solubility and stability: milrinone-gallic acid eutectic hemihydrate. Furthermore, this invention provides a simple, convenient method for preparing milrinone-gallic acid eutectic hemihydrate, 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-gallic acid eutectic hemihydrate, wherein the molar ratio of milrinone, gallic acid and water in the eutectic is 2:2:1, and two molecules of milrinone, two molecules of gallic acid and one molecule of water constitute the basic unit of the crystal form.

[0012] Preferably, the milrinone-gallic acid eutectic hemihydrate is characterized by having characteristic peaks at at least 9.2±0.2°, 15.0±0.2°, 23.7±0.2°, and 27.0±0.2° in its X-ray diffraction pattern expressed as 2θ using Cu-Kα radiation.

[0013] Preferably, the milrinone-gallic acid eutectic hemihydrate, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 9.2±0.2°, 10.6±0.2°, 15.0±0.2°, 16.4±0.2°, 22.3±0.2°, 23.7±0.2°, 24.9±0.2°, 27.0±0.2°, 28.0±0.2°, and 28.3±0.2°.

[0014] Preferably, the milrinone-gallic acid eutectic hemihydrate, when subjected to Cu-Kα radiation, exhibits characteristic peaks consistent with... Figure 1 The X-ray powder diffraction pattern shown is shown.

[0015] Preferably, the milrinone-gallic acid eutectic hemihydrate has the molecular formula C2. 38 H 32 N6O 13The crystallographic parameters are: triclinic system, space group P-1, cell parameters are: a=10.3716(2), b=11.1089(2), c=17.5817(2), α=80.4750(10), β=83.7000(10), γ=62.256(2), cell volume V=1766.87(6).

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

[0017] Milrinone and gallic acid were dissolved in a mixed solvent, heated and stirred, filtered, cooled to crystallize, filtered and dried to obtain milrinone-gallic acid eutectic hemihydrate.

[0018] Preferably, the solvent is selected from two organic solvents selected from methanol, ethanol, acetonitrile, acetone and trifluoroethanol and water, and is particularly preferred as a mixture of trifluoroethanol, ethanol and water.

[0019] Preferably, the mass-to-volume ratio of milrinone to organic solvent is 21.1:3 to 6; more preferably 21.1:4 to 5; wherein the mass of milrinone is expressed in mg and the volume of the mixed solvent is expressed in ml.

[0020] Preferably, the molar ratio of milrinone to gallic acid is 1:0.8 to 1.2, more preferably 1:1.

[0021] Preferably, the heating temperature is 40-60°C, and more preferably 50°C.

[0022] The cooling and crystallization temperature is 0–30°C, preferably 20–25°C.

[0023] The crystallization time is 16 to 72 hours, preferably 48 to 72 hours.

[0024] The drying temperature is 45–65°C, and the drying time is 8–12 hours.

[0025] 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.

[0026] Finally, the present invention provides a pharmaceutical composition comprising the milrinone-gallic acid co-crystal hemihydrate described herein and its pharmaceutically feasible components.

[0027] Preferably, the pharmaceutically feasible component may be a combination of a pharmaceutically active ingredient and / or a pharmaceutically acceptable excipient.

[0028] Confirmation of crystal structure

[0029] The X-ray crystal data for the milrinone-gallic acid eutectic hemihydrate test described in this invention were collected using a Rigaku XtaLAB Synergy instrument at a test temperature of 293(2) K. Cu-Ka radiation was used, and data were collected via ω-scan mode 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 (as shown in Table 1) of the crystal form of the milrinone gallic acid eutectic hemihydrate prepared by the present invention were tested and analyzed. The crystal system is triclinic, space group is P-1, and the cell parameters are: a = 10.3716 (2), b = 11.1089 (2), c = 17.5817 (2), α = 80.4750 (10), β = 83.7000 (10), γ = 62.256 (2), and the cell volume V = 1766.87 (6).

[0031] Table 1. Main crystallographic data of milrinone-gallic acid eutectic hemihydrate

[0032]

[0033]

[0034] The ORTEP diagram of the milrinone-gallic acid eutectic hemihydrate of the present invention shows that this crystalline form contains two molecules of milrinone, two molecules of gallic acid, and one molecule of water, as shown in the attached diagram. Figure 2 As shown in the attached diagram. This is a packing diagram of the milrinone-gallic acid eutectic hemihydrate of the present invention. 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.

[0035] Table 2. PXRD peaks of milrinone-gallic acid cocrystal hemihydrate

[0036]

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

[0038] This invention provides a novel milrinone-gallic acid co-crystal hemihydrate, which is simple to prepare, easy to control during crystallization, and has good reproducibility. The co-crystal formation of the two 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 gallic acid eutectic hemihydrate.

[0040] Figure 2 ORTEP diagram of milrinone gallic acid eutectic hemihydrate.

[0041] Figure 3 Packing diagram of milrinone gallic acid eutectic hemihydrate.

[0042] Figure 4 Comparative analysis of ORTEP diagram and key crystallographic data of Example 1 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] Example 1

[0045] 21.2 mg milrinone and 17.2 mg gallic acid were dissolved in a mixed solvent of 2 mL trifluoroethanol, 2 mL ethanol and 0.5 mL water. The solution was heated in a water bath at 50 °C and stirred until completely dissolved. The solution was filtered, cooled to 20–25 °C and allowed to stand to crystallize. After crystallization, the solution was filtered and dried to obtain milrinone-gallic acid co-crystal hemihydrate. Yield: 95%, purity: 99.93%.

[0046] Example 2

[0047] 21.3 mg milrinone and 17.0 mg gallic acid were dissolved in a mixed solvent of 3 mL trifluoroethanol, 2 mL methanol and 1 mL water. The solution was heated in a water bath at 40 °C and stirred until completely dissolved. The solution was filtered, cooled to 0–10 °C and allowed to stand to crystallize. After crystallization, the solution was filtered and dried to obtain milrinone-gallic acid co-crystal hemihydrate. Yield: 92%, purity: 99.88%.

[0048] Example 3

[0049] 21.2 mg milrinone and 17.2 mg gallic acid were dissolved in a mixed solvent of 2 mL trifluoroethanol, 1.5 mL ethanol and 0.5 mL water. The solution was heated in a water bath at 60 °C and stirred until completely dissolved. The solution was filtered, cooled to 10–15 °C and allowed to stand to crystallize. After crystallization, the solution was filtered and dried to obtain milrinone-gallic acid co-crystal hemihydrate. Yield: 91%, purity: 99.89%.

[0050] Example 4

[0051] 21.2 mg milrinone and 17.1 mg gallic acid were dissolved in a mixed solvent of 2 mL methanol, 2 mL acetonitrile and 0.5 mL water. The solution was heated in a water bath at 50 °C and stirred until completely dissolved. The solution was filtered, cooled to 25–30 °C and allowed to stand to crystallize. After crystallization, the solution was filtered and dried to obtain milrinone-gallic acid co-crystal hemihydrate. Yield: 93%, purity: 99.83%.

[0052] Example 5

[0053] 21.0 mg milrinone and 17.2 mg gallic acid were dissolved in a mixed solvent of 2 mL acetone, 2 mL ethanol and 0.5 mL water. The solution was heated in a water bath at 50 °C and stirred until completely dissolved. The solution was filtered, cooled to 20–25 °C and allowed to stand to crystallize. After crystallization, the solution was filtered and dried to obtain milrinone-gallic acid co-crystal hemihydrate. Yield: 94%, purity: 99.86%.

[0054] Example 6

[0055] 21.2 mg milrinone and 17.2 mg gallic acid were dissolved in a mixed solvent of 2 mL trifluoroethanol, 2 mL methanol and 0.5 mL water. The solution was heated in a water bath at 50 °C and stirred until completely dissolved. The solution was filtered, cooled to 10–20 °C and allowed to stand to crystallize. After crystallization, the solution was filtered and dried to obtain milrinone-gallic acid co-crystal hemihydrate. Yield: 91%, purity: 99.82%.

[0056] Comparative Example 1

[0057] Milrinone (169.0 mg) and gallic acid (136.1 mg) were mixed in an equimolar ratio until homogeneous. 50 μl of water was gradually added, and the mixture was thoroughly ground in a slurry for 45 minutes. The ground powder sample was dissolved in a minimum amount of methanol / acetonitrile / H₂O mixed solvent (methanol:acetonitrile:water volume ratio 2:1:1) and rapidly and vigorously stirred at 60 °C for approximately 3 hours. After cooling to room temperature, the resulting reaction mixture was filtered. The powder sample was added to the filtrate as seed crystals, and the solution was allowed to stand for slow evaporation for 1 day to obtain colorless crystals. Yield: 83.5%, Purity: 99.90%.

[0058] Comparative Example 2

[0059] Milrinone crude product, ethanol, acetone, and water were mixed and dissolved in a mass-to-volume ratio of 7 g: 83 ml: 57 ml: 105 ml. The mixture was slowly heated to 94°C and stirred thoroughly until homogeneous. Then, activated charcoal (8% of the mass of the crude milrinone product) was added for decolorization over 4.5 hours. The solution was filtered while hot to remove the activated charcoal. The filtered solution was stirred at a stirring rate of 6 rpm and cooled to 34°C at a cooling rate of 2°C / min. When the filtrate reached room temperature, deionized water was added dropwise under an ultrasonic field until crystals precipitated. The ultrasonic field was then turned off, and the mixture was allowed to stand for 27 hours. The solution was filtered, washed with ethanol, and dried to obtain the milrinone crystals. The yield was 87.5%, and the purity was 99.88%.

[0060] Comparative Example 3

[0061] Place 10g of milrinone in a 500ml beaker, add 0.1N hydrochloric acid solution dropwise and stir to dissolve it, adjusting the pH of the solution to 4-4.5. Add acetone in 5 times the volume of the solution, cool, and a white precipitate will form. Filter, wash the filter cake twice with acetone, air dry, and then dry at 105℃ for 2 hours to obtain 12g of milrinone hydrochloride, with a yield of 93% and a purity of 99.90%.

[0062] Comparative Example 4

[0063] 10g of milrinone was placed in a 500ml beaker, and 0.1N sulfuric acid solution was added dropwise while stirring to dissolve it, adjusting the pH of the solution to 4-5. Acetone, five times the volume of the solution, was added, and the mixture was cooled. A white precipitate was formed, filtered, and the filter cake was washed twice with acetone, dried, and then dried at 105℃ for 2 hours to obtain 14.3g of milrinone sulfate, with a yield of 97% and a purity of 99.89%.

[0064] Comparative Example 5

[0065] 10g of milrinone was placed in a 500ml beaker, and 0.1N methanesulfonic acid solution was added dropwise while stirring to dissolve it, adjusting the pH of the solution to 4-5. Acetone, five times the volume of the solution, was added, and the mixture was cooled. A white precipitate was formed, filtered, and the filter cake was washed twice with acetone, dried, and then dried at 105℃ for 2 hours to obtain 14.0g of milrinone methanesulfonate, with a yield of 96.2% and a purity of 99.91%.

[0066] Stability test

[0067] 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.

[0068] Table 3. Stability test results of different milrinone crystals under light, high temperature and high humidity conditions.

[0069]

[0070] Experimental results show that the milrinone-gallic acid eutectic hemihydrate prepared in the embodiments of the present invention has high purity, and the purity of the sample changes little under high temperature, high humidity, and strong light conditions, indicating good stability. Further investigation revealed similar stability test results for Examples 1-6.

[0071] Solubility test

[0072] Method: Measure 10 ml of medium (water, 0.01 mol / L HCl solution) into a vial, add excess sample, 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. Measure the absorbance at a wavelength of 270 nm. Calculate the solubility by measuring the absorbance of the standard reference.

[0073] Table 4. Solubility of different milrinone crystals in different media

[0074]

[0075] The experimental results show that the solubility of milrinone gallic acid eutectic hemihydrate in 0.01 mol / L HCl and water is significantly improved compared to other crystal forms of milrinone, which helps to improve its bioavailability. Similar solubility test results were found in Examples 1-6.

[0076] Pharmacokinetic parameters of milrinone and its cocrystal

[0077] Methods: In vivo pharmacokinetic (PK) experiments were conducted using a single oral dose. Male SD rats (220-260g) were fed in a quiet environment with constant humidity (0%-60%) and a temperature of 25±1℃, with rhythmic light exposure from 7:00 AM to 7:00 PM. The PK experiment was strictly conducted in accordance with the "Laboratory Management Guidelines" issued by the Ministry of Science and Technology of China. Before the experiment, the rats were randomly divided into three groups (n=5 per group), allowed free access to water, and fasted overnight. All test samples were suspended in vegetable oil and then administered orally at a single dose of 10 mg / kg milrinone or its equivalent. After administration, 0.5 mL blood samples were collected at the designed time points according to the administration status to detect the blood concentration of milrinone. The results are shown in Table 5.

[0078] Table 5. Pharmacokinetic Study Results of Different Milrinone Crystals

[0079]

[0080] These results indicate that milrinone gallic acid eutectic hemihydrate has better bioavailability compared to other milrinone crystals.

Claims

1. A milrinone-gallic acid eutectic hemihydrate, characterized in that, The cocrystal is composed of the active pharmaceutical ingredient milrinone and the cocrystal ligand gallic acid. In the cocrystal, the molar ratio of milrinone, gallic acid and water is 2:2:

1. The basic unit of the cocrystal is composed of two molecules of milrinone, two molecules of gallic acid and one molecule of water. Its crystallographic parameters are: triclinic crystal system, space group P-1, cell parameters are: a=10.3716(2), b=11.1089(2), c=17.5817(2), α=80.4750(10), β=83.7000(10), γ=62.256(2), cell volume V=1766.87(6).

2. The milrinone-gallic acid eutectic hemihydrate as described in claim 1, characterized in that, The eutectic is subjected to Cu-Kα radiation, and its X-ray diffraction pattern, expressed in 2θ, has characteristic peaks at at least 9.2±0.2°, 15.0±0.2°, 23.7±0.2°, and 27.0±0.2°.

3. The milrinone-gallic acid eutectic hemihydrate as described in claim 1, characterized in that, The eutectic exhibits characteristic peaks at at least 9.2±0.2°, 10.6±0.2°, 15.0±0.2°, 16.4±0.2°, 22.3±0.2°, 23.7±0.2°, 24.9±0.2°, 27.0±0.2°, 28.0±0.2°, and 28.3±0.2° in its Cu-Kα radiation X-ray diffraction pattern (expressed as 2θ).

4. The milrinone-gallic acid eutectic hemihydrate as described in claim 1, characterized in that, The eutectic has an X-ray powder diffraction pattern as shown in Figure 1.

5. A method for preparing the milrinone-gallic acid eutectic hemihydrate according to any one of claims 1-4, characterized in that, The method includes the following steps: Milrinone and gallic acid were dissolved in a mixed solvent, heated and stirred, filtered, cooled to crystallize, filtered and dried to obtain milrinone-gallic acid eutectic hemihydrate.

6. The method for preparing milrinone-gallic acid eutectic hemihydrate as described in claim 5, characterized in that, The solvent is selected from two organic solvents selected from methanol, ethanol, acetonitrile, acetone, and trifluoroethanol, and water.

7. The method for preparing milrinone-gallic acid eutectic hemihydrate as described in claim 5, characterized in that, The solvent is a mixture of trifluoroethanol, ethanol and water.

8. The method for preparing milrinone-gallic acid eutectic hemihydrate as described in claim 5, characterized in that, The molar ratio of milrinone to gallic acid is 1:0.8 to 1.

2.

9. The method for preparing milrinone-gallic acid eutectic hemihydrate as described in claim 5, characterized in that, The molar ratio of milrinone to gallic acid is 1:

1.

10. The method for preparing milrinone-gallic acid eutectic hemihydrate as described in claim 5, characterized in that, The cooling and crystallization temperature is 0–30°C.

11. The use of milrinone-gallic acid eutectic hemihydrate as described in any one of claims 1-4, characterized in that, This is used to prepare drugs for the treatment of congestive heart failure (CHF) and peripheral vasodilatory diseases.

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