A crystalline mirinone-nicotinic acid and a method of preparation

Abstract

The application belongs to the technical field of pharmaceutical chemistry, and provides a high-purity milrinone-nicotinic acid crystal, a preparation method thereof is simple in operation, a crystallization process is easy to control, and reproducibility is good. The prepared milrinone-nicotinic acid crystal has significantly enhanced stability and solubility compared with free base and crystal forms thereof, thereby being beneficial to storage, transportation and application in preparation of a preparation of a product, and having enhanced bioavailability and absorption performance.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a milrinone-nicotinic acid crystal and a preparation method thereof. BACKGROUND

[0002] Heart failure (HF) is a global epidemic, affecting approximately 26 million people worldwide. It is the fastest growing cardiovascular condition globally, with very high morbidity, mortality, and cost burden on the health care system. HF is the most common cause of hospitalization in patients over 65 years of age. Five-year mortality after HF hospitalization is approximately 42%, comparable to many cancers.

[0003] Milrinone is a phosphodiesterase inhibitor, a derivative of amirinone, and has the same mechanism of action as amirinone. It is effective for oral and intravenous administration, and has both positive inotropic effect and vasodilating effect. It is suitable for short-term treatment of patients with severe congestive heart failure who are ineffective for routine maintenance treatment, and has 10-30 times stronger efficacy than amirinone, better tolerance, and fewer adverse reactions. Its positive inotropic effect is mainly through the inhibition of phosphodiesterase, increasing the concentration of cyclic adenosine monophosphate (CAMP) in myocardial cells, increasing intracellular calcium, strengthening myocardial contractility, and increasing cardiac output. It is generally considered to be a high-efficiency, low-toxicity, non-digitalis, non-pseudo-steroidal inotropic agent, which is superior to dopamine in treating severe heart failure, pulmonary edema caused by ischemic heart disease and dilated cardiomyopathy, and has fewer adverse reactions and does not increase heart rate. Therefore, the drug plays an increasingly important role in the treatment of congestive heart failure (CHF) and peripheral vasodilation.

[0004] In reality, due to the poor water solubility of milrinone and the heavy adverse reactions when taken orally, although some methods for improving the solubility or stability of milrinone are disclosed in the prior art, none of them has achieved ideal results, nor has improved the poor absorption of milrinone. For example, patent CN1951919A discloses a series of inorganic acid salts of milrinone for preparing injection lyophilized preparations, which can improve the solubility of milrinone, but still has the problem of stability; for another example, patent CN102558044A discloses a crystallization method of milrinone, which obtains milrinone with high purity and good crystal form, but still does not improve the physicochemical properties of milrinone; in addition, patent CN106361710A describes that, in order to solve the problems of poor stability, easy degradation and significant increase in related substances of lactic acid milrinone in the prior art, a certain amount of vitamin E and glutathione are added to the prescription, and a new crystal form is used to increase the stability of the injection and reduce the generation of degradation reactions, but the use of the new crystal form still does not overcome the problem of poor solubility of milrinone. Therefore, it has become a problem to be solved by those skilled in the art to provide a crystal form of milrinone with good solubility, high stability, and good prospects for drug development.

[0005] Drug co-crystals can bind co-crystal formers into the same crystal lattice through non-covalent bonds, change the physicochemical properties of drugs including stability, solubility and bioavailability, etc. without changing their molecular covalent structure and pharmacological behavior. Due to the ability and advantage in the modification and optimization of drug substances, the development of drug co-crystals has attracted more attention and attention from industry, academia and regulatory authorities. It is possible that there are stable cyclic lactam homodimers. So far, there have been few reports on the related research of mirin co-crystals. Nicotinic acid, also known as vitamin B3, is one of the water-soluble B vitamins. Nicotinic acid exists in the form of NAD and NADP with high bioavailability in many animal foods such as poultry, beef and fish. The main form in plant foods such as nuts, beans and cereals is nicotinic acid. Natural nicotinic acid naturally exists in some cereal products. Nicotinic acid is in the free form with high bioavailability, and therefore, mirin and nicotinic acid as a feasible co-crystal former in the field of drug co-crystallization are of great significance. SUMMARY

[0006] In view of the poor solubility and low stability of mirin provided by the prior art, the present application aims to provide a new crystal form of mirin with higher solubility and stability, i.e. mirin-nicotinic acid crystal. In addition, the present application provides a method for preparing mirin-nicotinic acid crystal, which is simple, convenient and suitable for industrial production.

[0007] The specific technical content of the present application is as follows:

[0008] In one aspect, the present application provides a high-purity mirin-nicotinic acid crystal.

[0009] Preferably, the mirin-nicotinic acid crystal has characteristic peaks at least at 6.8±0.2°, 10.5±0.2°, 15.2±0.2°, 15.3±0.2°, 26.9±0.2°, 27.0±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0010] Preferably, the mirin-nicotinic acid crystal has characteristic peaks at least at 6.8±0.2°, 10.5±0.2°, 15.2±0.2°, 15.3±0.2°, 20.1±0.2°, 21.4±0.2°, 24.3±0.2°, 25.7±0.2°, 26.9±0.2°, 27.0±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0011] Preferably, the mirin-nicotinic acid crystal has characteristic peaks at least at 6.8±0.2°, 10.5±0.2°, 15.2±0.2°, 15.3±0.2°, 20.1±0.2°, 21.4±0.2°, 24.3±0.2°, 25.7±0.2°, 26.9±0.2°, 27.0±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation. Figure 1 Preferably, the mirin-nicotinic acid crystal has characteristic peaks at least at 6.8±0.2°, 10.5±0.2°, 15.2±0.2°, 15.3±0.2°, 20.1±0.2°, 21.4±0.2°, 24.3±0.2°, 25.7±0.2°, 26.9±0.2°, 27.0±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0012] Preferably, the said Milrinone-Nicotinic acid crystal has a molecular formula of C 12 H 12 N4O4S, and crystallographic parameters are: triclinic system, space group P-1, cell parameters are: α = 86.5320(10)°, β = 82.0760(10)°, γ = 76.9770(10)°, cell volume

[0013] In another aspect, the present application provides a method for preparing the said Milrinone-Nicotinic acid crystal, comprising the following steps:

[0014] dissolving Milrinone and Nicotinic acid in a solvent, heating and stirring, incubating, cooling and crystallizing, filtering, washing, and drying to obtain the Milrinone-Nicotinic acid crystal.

[0015] Preferably, the said solvent is selected from one or a combination of trifluoroethanol, methanol, ethanol, and acetone, and particularly preferably trifluoroethanol.

[0016] Preferably, the mass-volume ratio of the said Milrinone and the organic solvent is 10:0.7-1.5; preferably 10:0.9-1.2, wherein the mass is in mg and the volume is in mL.

[0017] Preferably, the molar ratio of the said Milrinone and Nicotinic acid is 1:0.85-1.8, preferably 1:0.9-1.5.

[0018] Preferably, the heating temperature is 50-65°C, preferably 55°C.

[0019] Preferably, the cooling and crystallizing temperature is 15-30°C, and the cooling and crystallizing temperature is further preferably 20-25°C.

[0020] Preferably, the crystallization time is 10-36h.

[0021] Preferably, the drying temperature is 50-55°C, and the drying time is 8-10h.

[0022] In still another aspect, the present application provides a pharmaceutical composition containing the said Milrinone-Nicotinic acid crystal and other pharmaceutically acceptable components.

[0023] Preferably, the said other pharmaceutically acceptable components can be a combination of pharmaceutically active ingredients and / or pharmaceutically acceptable excipient ingredients.

[0024] Compared with the prior art, the present application has the following technical effects:

[0025] The milrinone-nicotinic acid crystals provided by this invention have a simple preparation method, easy-to-control crystallization process, and good reproducibility. Compared with free alkali and its crystal form, milrinone-nicotinic acid crystals exhibit significantly enhanced stability and solubility, thus facilitating product storage, transportation, and application in formulation preparation. Furthermore, they can effectively leverage the advantages of in vivo pharmacokinetic behavior, shortening peak time, increasing plasma drug concentration, prolonging half-life, and improving bioavailability. The superior physicochemical properties of the polycrystalline drug provided by this invention offer a better pharmaceutical raw material for clinical treatment of diseases, possessing significant clinical research and development value. Attached Figure Description

[0026] Figure 1 X-ray powder diffraction pattern of milrinone-nicotinic acid.

[0027] Figure 2 ORTEP plot of Milrinone-nicotinic acid.

[0028] Figure 3 : Stacking diagram of Milrinone-nicotinic acid.

[0029] Figure 4 Differential scanning calorimetry (DSC) curve of milrinone-nicotinic acid. Detailed Implementation

[0030] 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.

[0031] Example 1

[0032] Milrinone (22.0 mg) and nicotinic acid (13.4 mg) were dissolved in trifluoroethanol (2 mL) and heated in a water bath at 55 °C with stirring until completely dissolved. The reaction was maintained at this temperature for 4 h, then slowly cooled to 20–25 °C and allowed to stand for crystallization for 24 h. The mixture was filtered, the filter cake was washed with trifluoroethanol, and dried under vacuum at 50 °C for 8 h to obtain a milrinone-nicotinic acid eutectic with a yield of 98.5% and a purity of 99.95%.

[0033] Example 2

[0034] Milrinone (26.0 mg) and nicotinic acid (15.8 mg) were dissolved in methanol (3 mL) and heated in a water bath at 55 °C with stirring until completely dissolved. The reaction was maintained at this temperature for 4 h, then slowly cooled to 20–25 °C and allowed to stand for crystallization for 28 h. The crystals were filtered, washed with methanol, and dried under vacuum at 50 °C for 10 h to obtain a milrinone-nicotinic acid eutectic with a yield of 97.4% and a purity of 99.92%.

[0035] Example 3

[0036] Milrinone (44.2 mg) and nicotinic acid (25.1 mg) were dissolved in ethanol (3.5 mL) solvent, heated and stirred in a 50°C water bath until completely dissolved, incubated for 4h, slowly cooled to 15-20°C, and then controlled temperature was maintained for crystallization for 30h, filtered, the filter cake was washed with methanol, and vacuum dried at 55°C for 8h to obtain the co-crystal of milrinone-nicotinic acid, yield: 96.2%, purity: 99.91%.

[0037] Example 4

[0038] Milrinone (50.0 mg) and nicotinic acid (24.8 mg) were dissolved in acetone (4.5 mL) solvent, heated and stirred in a 65°C water bath until completely dissolved, incubated for 4h, slowly cooled to 30°C, and then controlled temperature was maintained for crystallization for 25h, filtered, the filter cake was washed with acetone, and vacuum dried at 50°C for 10h to obtain the co-crystal of milrinone-nicotinic acid, yield: 95.1%, purity: 99.90%.

[0039] Confirmation of crystal structure

[0040] The X-ray crystal data of the pharmaceutical crystal of the milrinone described in the present application was collected on a Japan Rigaku XtaLAB Synergy model instrument, the test temperature was 293(2) K, Cu-Ka radiation was used, the data was collected in an omega scan mode and Lp correction was performed. The structure was solved by direct method, all non-hydrogen atoms were found by difference Fourier method, and all hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation. The structure was refined by least squares method.

[0041] The crystallographic data of the milrinone-nicotinic acid crystal form prepared in the present application (as shown in Table 1) is as follows: triclinic crystal system, space group P-1, cell parameters are as follows: α = 86.5320(10)°, β = 82.0760(10)°, γ = 76.9770(10)°, cell volume

[0042] Table 1 Main crystallographic data of milrinone-nicotinic acid crystal

[0043]

[0044]

[0045] The ORTEP diagram of the milrinone-nicotinic acid crystal of the present application shows that two molecules of milrinone and one molecule of nicotinic acid are contained in the crystal form, as shown in the attached Figure 2 The packing diagram of the milrinone-nicotinic acid crystal of the present application is shown in the attached Figure 3 According to the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are shown in the attached Figure 1 and Table 2.

[0046] Table 2 PXRD peaks of milrinone-nicotinic acid crystals

[0047]

[0048] Comparative Example 1

[0049] In a 1000 mL three-necked flask, 4-methylpyridine 93.0 g, chloroform 500 mL, was placed in an ice water bath to control the temperature below 50°C, acetyl chloride 80.0 g was added dropwise, after the addition was completed, the temperature was raised to 55°C and the reaction was carried out for 2.5 h. After the reaction was completed, the system was cooled in an ice bath, saturated sodium carbonate aqueous solution was added dropwise to adjust the pH to 5-7, then 30.0 g of sodium hydroxide solution (30 wt%) was added, and the reaction was carried out at 30-50°C for 2.5 h. After the reaction was completed, the layers were separated, the water layer was removed, dried with anhydrous sodium sulfate, and after recovery of the solvent, the fraction at 100-105°C / 217 kPa was collected by distillation to obtain 1-(4-pyridyl)-2-propanone.

[0050] In a 500 mL round-bottom flask, 1-(4-pyridyl)-2-propanone 60.0 g was added, and under stirring, 40.5 g of triethyl orthoformate, 92.2 g of acetic anhydride, and 80.0 g of glacial acetic acid were added to the reaction flask, and the reaction was carried out at 35-45°C for 4 h. After the raw material was completely reacted, the solvent was removed by concentration under reduced pressure at 80°C to obtain a dark red oil, which was directly used in the next step without purification.

[0051] In a 5000 mL flask, 600 mL of anhydrous methanol and the above oil were added, and under stirring, 64.0 g of α-cyanacetamide and 210 g of 50% sodium hydroxide solution were added, and the reaction was carried out for 1.5 h. After the reaction was completed, the pH was adjusted to 6.5-7.2 with acetic acid solution to precipitate a solid, which was filtered to obtain crude milrinone. The solid was recrystallized from an ethanol-water system to obtain white milrinone crystals.

[0052] Comparative Example 2

[0053] In a 500 mL beaker, 10 g of milrinone was dissolved by dropwise addition of 0.1 N sodium hydroxide aqueous solution while stirring, and the pH was adjusted to 7-8. A solution having a volume 5 times that of the milrinone solution was added, and the mixture was cooled to precipitate a white solid. The solid was filtered, the filter cake was washed twice with acetone, and then dried at 105°C for 2 h to obtain milrinone sodium salt.

[0054] Comparative Example 3

[0055] In a 500 mL beaker, 10 g of milrinone was dissolved by dropwise addition of 0.1 N hydrochloric acid solution while stirring, and the pH of the solution was adjusted to 4-4.5. A solution having a volume 5 times that of the milrinone solution was added, and the mixture was cooled to precipitate a white solid. The solid was filtered, the filter cake was washed twice with acetone, and then dried at 105°C for 2 h to obtain milrinone hydrochloride.

[0056] Comparative Example 4

[0057] Milrinone (169.0 mg) and gallic acid (136.1 mg) were mixed in equimolar ratio and 50 μL of water was added gradually and ground thoroughly in a mortar for 45 minutes. The ground powder sample was dissolved in a minimum amount of a mixed solvent of methanol / acetonitrile / H2O (v 甲醇 : v 乙腈 : v 水 = 2:1:1) at 60°C with rapid and vigorous stirring for about 3 h. After cooling to room temperature, the resulting reaction mixture was filtered. To the filtrate, the above-mentioned powder sample was added as a seed crystal and the solution was allowed to stand for slow evaporation for 1 day to obtain colorless crystals.

[0058] Stability Test

[0059] The specific stability test method was performed according to the guidance method for stability test in the fourth part of Chinese Pharmacopoeia.

[0060] High temperature test: the test sample was placed in an appropriate clean container at a temperature of 60°C for 10 days, and samples were taken on the 5th day and the 10th day, and the purity was detected by HPLC method;

[0061] High humidity test: the test sample was placed in a constant humidity airtight container at 25°C under the condition of relative humidity 90%±5% for 10 days, and samples were taken on the 5th day and the 10th day, and the purity was detected by HPLC method;

[0062] Strong light irradiation test: the test sample was placed in a light irradiation device equipped with a daylight lamp under the condition of irradiance 4500 lx±500 lx for 10 days, and samples were taken on the 5th day and the 10th day, and the purity was detected by HPLC method.

[0063] Table 3 Stability test results of milrinone-nicotinic acid crystal

[0064]

[0065]

[0066] Solubility Test

[0067] Method: 10 ml of medium (water, 0.01 mol / L HCl solution) was respectively taken in a vial, and an excess amount of the sample to be tested was added, and the vial was sealed and placed in a 25°C constant temperature water bath for stirring for 1 hour, and then filtered through a filter membrane, and the filtrate was taken; the absorbance was measured at a wavelength of 270 nm, and the solubility was calculated by testing the absorbance of the standard control.

[0068] Table 4 Solubility of milrinone-nicotinic acid crystal in different media (mg / mL)

[0069]

[0070] The test results show that the solubility of the milrinone-nicotinic acid crystal provided by the application in 0.01 mol / L HCl and water is significantly improved compared to other crystal forms of milrinone, which is beneficial to the application of the milrinone-nicotinic acid crystal in oral preparations.

[0071] Pharmacokinetic study

[0072] Methods: The in vivo PK test was performed by using a single-dose oral administration method. Male SD rats (220-260 g) were fed in a constant humidity of 0%-60% in a quiet environment, and the temperature was 25±1℃. The light was regularly illuminated from 7 am to 7 pm. The PK test was strictly performed according to the Laboratory Management Guide issued by the Ministry of Science and Technology of China. Before the experiment, the test rats were randomly divided into three groups (n=5 each), and they were allowed to drink water freely and fast overnight. All the test samples were suspended in vegetable oil, and then a single dose of 10 mg / kg of milrinone or its equivalent was orally administered. After administration, 0.5 mL of blood samples were collected at the designed time points according to the administration, and the blood drug concentration of milrinone was detected according to the literature method.

[0073] Table 5 Pharmacokinetic test results of the milrinone-nicotinic acid crystal

[0074]

[0075]

[0076] The test results show that the milrinone-nicotinic acid crystal provided by the application reaches a higher peak concentration at a faster speed compared to other crystal forms of milrinone, which is the same as their solubility trend, and provides conditions for the rapid absorption of milrinone and a large amount of drugs into the blood. Compared to other crystal forms of milrinone, the extension of the half-life of the milrinone-nicotinic acid crystal makes the drug stay in the body for a longer time, thereby providing the possibility of obtaining a long-term therapeutic effect.

Claims

1. A crystalline mirinone-nicotinic acid characterized in that, X-ray diffraction spectrum using Cu-Kα radiation has characteristic peaks at at least 6.8±0.2°, 10.5±0.2°, 15.2±0.2°, 15.3±0.2°, 26.9±0.2°, 27.0±0.2° in terms of 2θ; the mirinol-nicotinic acid crystal has a molecular formula of C 12 H 12 N4O4S, and crystallographic parameters are: triclinic system, space group P-1, cell parameters are: a = 7.16950(10) Å, b = 9.63080(10) Å, c = 19.9056(2) Å, α = 86.5320(10) °, β = 82.0760(10) °, γ = 76.9770(10) °, cell volume V = 1325.69(3) Å 3 .

2. The mifonine-nicotinic acid crystal of claim 1, wherein X-ray diffraction spectrum using Cu-Kα radiation has characteristic peaks at at least 6.8±0.2°, 10.5±0.2°, 15.2±0.2°, 15.3±0.2°, 20.1±0.2°, 21.4±0.2°, 25.7±0.2°, 26.9±0.2°, 27.0±0.2° in terms of 2θ.

3. The mifonine-nicotinic acid crystal of claim 1, wherein X-ray powder diffraction spectrum using Cu-Kα radiation has characteristic peaks as shown in Figure 1.

4. A process for preparing the crystalline mirinone-nicotinic acid of claim 1, characterized by, The specific preparation steps include: dissolving milrinone and nicotinic acid in a solvent, heating and stirring, incubating, cooling and crystallizing, filtering, washing, and drying to obtain milrinone-nicotinic acid crystals.

5. The method of preparing a mirinol-nicotinic acid crystal according to claim 4, wherein The solvent is selected from one or a combination of trifluoroethanol, methanol, ethanol, and acetone.

6. The method of preparing a mirinol-nicotinic acid crystal according to claim 4, wherein The solvent is trifluoroethanol.

7. The method of preparing a mirinol-nicotinic acid crystal according to claim 4, wherein the step of crystallizing the mirinol-nicotinic acid crystal is performed at a temperature of 20 to 30°C. The mass-volume ratio of milrinone to solvent is 10:0.7~1.5; wherein the mass is in mg and the volume is in mL.

8. The method of preparing a mirinol-nicotinic acid crystal according to claim 4, wherein The mass-volume ratio of milrinone to solvent is 10:0.9~1.2; wherein the mass is in mg and the volume is in mL.

9. The method of preparing a mirinol-nicotinic acid crystal according to claim 4, wherein The molar ratio of milrinone to nicotinic acid is 1:0.85~1.

8.

10. The method of preparing mirinone-nicotinic acid crystals according to claim 4, wherein the step of crystallizing is performed at a temperature of 20 to 30°C. The molar ratio of milrinone to nicotinic acid is 1:0.9~1.

5.

11. The method of preparing mirinone-nicotinic acid crystals according to claim 4, wherein The cooling and crystallization temperature is 15~30℃.

12. The method of preparing mirinone-nicotinic acid crystals according to claim 4, wherein The cooling and crystallization temperature is 20~25℃.

13. The method of preparing mirinone-nicotinic acid crystals according to claim 4, wherein the step of crystallizing is performed at a temperature of 20 to 30°C. The drying temperature is 50~55℃, and the drying time is 8~10h.

14. A pharmaceutical composition, characterized by, The composition contains the milrinone-nicotinic acid crystals of any one of claims 1-3 and other pharmaceutically acceptable components, which can be a combination of a pharmaceutically active ingredient and / or a pharmaceutically acceptable excipient.

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