CN117105854A - Milrinone-nicotinic acid crystal and preparation method thereof - Google Patents

Milrinone-nicotinic acid crystal and preparation method thereof Download PDF

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Publication number
CN117105854A
CN117105854A CN202210779324.4A CN202210779324A CN117105854A CN 117105854 A CN117105854 A CN 117105854A CN 202210779324 A CN202210779324 A CN 202210779324A CN 117105854 A CN117105854 A CN 117105854A
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milrinone
nicotinic acid
crystal
degrees
niacin
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翟立海
张明明
路来菊
刘玉婷
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Shandong New Time Pharmaceutical Co Ltd
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Shandong New Time Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

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

Description

Milrinone-nicotinic acid crystal and preparation method thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to milrinone-nicotinic acid crystals and a preparation method thereof.
Background
Heart Failure (HF) is a global epidemic that affects about 2.6 tens of millions of people worldwide. It is the fastest growing cardiovascular disorder worldwide, with very high morbidity, mortality, and cost burden on the health care system. HF is the most common cause of hospitalization for patients over 65 years old. Five years after HF hospitalization have a mortality rate of about 42%, comparable to many cancers.
Milrinone (milrinone) is a phosphodiesterase inhibitor, is a derivative of amirinone, and has the same action mechanism as amirinone. It is effective for oral administration and intravenous injection, and has positive muscle strength and vasodilatation effects. Is suitable for short-term treatment of patients with severe congestive heart failure, the curative effect of which is 10-30 times stronger than that of amrinone, the tolerance is better, and the adverse reaction is less. The positive inotropic effect is mainly to increase the concentration of Cyclic Adenosine Monophosphate (CAMP) in myocardial cells by inhibiting phosphodiesterase, increase intracellular calcium, strengthen myocardial contractility and increase cardiac output. It is considered to be a high-efficiency, low-toxicity, non-digitalis and non-sympathomimetic cardiotonic, and has remarkable effects on severe heart failure and pulmonary edema caused by ischemic heart disease, dilated cardiomyopathy, etc., and is superior to dopamine, less in adverse reaction and not increasing heart rate. Therefore, the medicine plays an increasingly important role in treating Congestive Heart Failure (CHF), peripheral vascular dilation and the like.
In reality, due to poor water solubility of milrinone and heavy adverse reaction during oral administration, although the prior art discloses some methods for attempting to improve the solubility or stability of milrinone, no ideal effect is obtained, and the defects of poor absorption and the like are overcome. For example, patent CN1951919a discloses that the inorganic acid salts of milrinone series are used for preparing freeze-dried formulations for injection, and although the solubility of milrinone can be improved, stability problems still exist generally; for example, patent CN102558044a discloses a crystallization method of milrinone, and the milrinone obtained by the method has high purity and good crystal form, but the physicochemical properties of milrinone are not improved yet; in addition, patent CN106361710a describes that, in order to solve the problems of poor stability of milrinone lactate, easy degradation and obvious increase of related substances in the prior art, the stability of injection is increased by adding a certain amount of vitamin E and glutathione in the prescription and using a new crystal form, and the degradation reaction is reduced, but the problem of poor solubility of milrinone is not overcome by using a new crystal form. Therefore, the crystal form of milrinone with good solubility, high stability and good patent medicine prospect is provided, and the problem to be solved by the person skilled in the art is urgent.
The pharmaceutical co-crystal can combine the co-crystal formation into the same crystal lattice through non-covalent bonds, and the physicochemical properties of the medicine, including stability, solubility, bioavailability and the like, are changed on the premise of not changing the covalent structure and pharmacological behavior of the molecules. Because of the capabilities and advantages in the modification and optimization of bulk drugs, the development of pharmaceutical co-crystals has received more attention and attention from industry, academia and regulatory authorities. Probably due to the presence of stable cyclic lactam homodimers, very few studies have been reported to date on milrinone co-crystals. Niacin, also known as vitamin B3, is one of the water-soluble B vitamins. Niacin in its highly bioavailable form NAD and NADP are naturally found in many animal foods such as poultry, beef and fish. Vegetable foods such as nuts, beans and grains are mainly present in the form of niacin. Natural niacin is naturally found in some cereal products. Nicotinic acid is in a free form with high bioavailability, and thus milrinone and niacin are of great significance as viable co-crystal formations in the field of pharmaceutical co-crystallization.
Disclosure of Invention
Aiming at the defects of poor solubility and low stability of milrinone provided by the prior art, the invention aims to provide a novel crystal form of milrinone with higher solubility and stability, namely a milrinone-nicotinic acid crystal. In addition, the invention provides a method for preparing milrinone-nicotinic acid crystals, which is simple, convenient and suitable for industrial production.
The specific technical content of the invention is as follows:
in one aspect, the present invention provides a high purity milrinone-niacin crystal.
Preferably, the milrinone-nicotinic acid crystal uses Cu-K alpha radiation and Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 6.8+/-0.2 DEG, 10.5+/-0.2 DEG, 15.2+/-0.2 DEG, 15.3+/-0.2 DEG, 26.9+/-0.2 DEG and 27.0+/-0.2 deg.
Preferably, the milrinone-nicotinic acid crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 6.8+/-0.2 degrees, 10.5+/-0.2 degrees, 15.2+/-0.2 degrees, 15.3+/-0.2 degrees, 20.1+/-0.2 degrees, 21.4+/-0.2 degrees, 24.3+/-0.2 degrees, 25.7+/-0.2 degrees, 26.9+/-0.2 degrees and 27.0+/-0.2 degrees.
Preferably, the milrinone-nicotinic acid crystals use Cu-ka radiation, the characteristic peaks of which correspond to the X-ray powder diffraction pattern shown in figure 1.
PreferablyThe molecular formula of the milrinone-nicotinic acid crystal is C 12 H 12 N 4 O 4 S, the crystallographic parameters are: the triclinic system has a space group of P-1 and unit cell parameters of:α= 86.5320 (10) °, β= 82.0760 (10) °, γ= 76.9770 (10) °, unit cell volume +.>
In another aspect, the present invention provides a method for preparing the milrinone-niacin crystal, comprising the steps of:
and dissolving milrinone and nicotinic acid in a solvent, heating, stirring, performing heat preservation reaction, cooling, crystallizing, filtering, washing and drying to obtain milrinone-nicotinic acid crystals.
Preferably, the solvent is selected from one or a combination of trifluoroethanol, methanol, ethanol and acetone solvents, and particularly preferably trifluoroethanol.
Preferably, the mass-volume ratio of the milrinone to the organic solvent is 10:0.7-1.5; preferably 10:0.9 to 1.2, wherein the mass is in mg and the volume is in mL.
Preferably, the molar ratio of milrinone to nicotinic acid is 1:0.85-1.8, preferably 1:0.9-1.5.
Preferably, the heating temperature is 50 to 65 ℃, preferably 55 ℃.
Preferably, the temperature-reducing crystallization temperature is 15-30 ℃, and more preferably, the temperature-reducing crystallization temperature is 20-25 ℃.
Preferably, the crystallization time is 10-36 h.
Preferably, the drying temperature is 50-55 ℃ and the drying time is 8-10 h.
In yet another aspect, the present invention provides a pharmaceutical composition comprising milrinone-niacin crystals of the present invention and other pharmaceutically acceptable components.
Preferably, the other pharmaceutically acceptable components may be pharmaceutically active ingredients that may be combined and/or pharmaceutically acceptable auxiliary ingredients.
Compared with the prior art, the invention has the technical effects that:
the milrinone-nicotinic acid crystal provided by the invention has the advantages of simple operation, easy control of crystallization process and good reproducibility. The milrinone-nicotinic acid crystal phase has obviously enhanced stability and solubility compared with the free alkali and the crystal form thereof, thereby being beneficial to the storage, transportation and application of the product in preparation, effectively playing the advantages of in-vivo pharmacokinetics behavior, shortening the peak time, improving the plasma drug concentration, prolonging the half-life and improving the bioavailability. The pharmaceutical polycrystal provided by the invention has good physicochemical properties, provides good pharmaceutical raw materials for treating diseases in clinic, and has great clinical research and development values.
Drawings
Fig. 1: x-ray powder diffraction pattern of milrinone-niacin.
Fig. 2: ORTEP diagram of milrinone-niacin.
Fig. 3: milrinone-niacin stacking diagram.
Fig. 4: differential Scanning Calorimetry (DSC) plot of milrinone-niacin.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
Example 1
Milrinone (22.0 mg) and nicotinic acid (13.4 mg) are dissolved in trifluoroethanol (2 mL) solvent, heated in a water bath at 55 ℃ and stirred until the milrinone and the nicotinic acid are completely dissolved, the temperature is kept for 4h for reaction, after the temperature is slowly reduced to 20-25 ℃, the temperature is controlled for standing and crystallization for 24h, the filtration is carried out, the filter cake is washed by the trifluoroethanol, the vacuum drying is carried out for 8h at 50 ℃ to obtain the milrinone-nicotinic acid eutectic, the yield is: 98.5%, purity: 99.95%.
Example 2
Milrinone (26.0 mg) and nicotinic acid (15.8 mg) are dissolved in methanol (3 mL) solvent, heated and stirred in a water bath at 55 ℃ until the milrinone and the nicotinic acid are completely dissolved, the temperature is kept for 4h, the reaction is slowly reduced to 20-25 ℃, then the temperature is controlled to be static for crystallization for 28h, the filtration is carried out, a filter cake is washed by methanol, the vacuum drying is carried out for 10h at 50 ℃ to obtain the milrinone-nicotinic acid eutectic, the yield is: 97.4%, purity: 99.92%.
Example 3
Milrinone (44.2 mg) and nicotinic acid (25.1 mg) are dissolved in ethanol (3.5 mL) solvent, heated and stirred in water bath at 50 ℃ until the milrinone and the nicotinic acid are completely dissolved, the temperature is kept for 4h, the reaction is slowly reduced to 15-20 ℃, then the temperature is controlled to be static for crystallization for 30h, the filtration is carried out, a filter cake is washed by methanol, the vacuum drying is carried out for 8h at 55 ℃ to obtain milrinone-nicotinic acid eutectic, and the yield is: 96.2%, purity: 99.91%.
Example 4
Milrinone (50.0 mg) and nicotinic acid (24.8 mg) are dissolved in acetone (4.5 mL) solvent, heated and stirred in a water bath at 65 ℃ until the milrinone and the nicotinic acid are completely dissolved, the reaction is kept at the temperature for 4 hours, after the temperature is slowly reduced to 30 ℃, the temperature is controlled to be static for crystallization for 25 hours, the filtration is carried out, a filter cake is washed by acetone, the vacuum drying is carried out for 10 hours at 50 ℃ to obtain the milrinone-nicotinic acid eutectic, and the yield is: 95.1 percent of purity: 99.90%.
Confirmation of Crystal Structure
In the drug crystal test of milrinone, X-ray crystal data are collected on a Japanese science XtaLAB Synergy model instrument, the test temperature 293 (2) K is measured, cu-Ka radiation is used, and data are collected in an omega scanning mode and are subjected to Lp correction. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
The crystallography data (as in table 1) for testing and resolving crystalline forms of milrinone-niacin crystals prepared in accordance with the present invention are: the triclinic system has a space group of P-1 and unit cell parameters of:α= 86.5320 (10) °, β= 82.0760 (10) °, γ= 76.9770 (10) °, unit cell volume +.>
TABLE 1 Milrinon-nicotinic acid Crystal principal crystallographic data
The ORTEP diagram of milrinone-niacin crystals of the present invention shows that the crystalline form contains two molecules of milrinone and one molecule of niacin, as shown in figure 2. The stacking diagram of milrinone-nicotinic acid crystals of the invention is shown in figure 3. According to the crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in the accompanying figures 1 and 2.
TABLE 2 PXRD peaks for milrinone-nicotinic acid crystals
Comparative example 1
Into a 1000mL three-necked flask, 93.0g of 4-methylpyridine and 500mL of chloroform were added, and the mixture was placed in an ice-water bath to control the temperature below 50 ℃ and 80.0g of acetyl chloride was added dropwise, and after the dropwise addition was completed, the mixture was heated to 55 ℃ and reacted for 2.5 hours. After the reaction, saturated sodium carbonate aqueous solution is added dropwise into the system under ice bath cooling to adjust the pH to 5-7, 30.0g sodium hydroxide solution (30 wt%) is added, and the mixture is stirred at 30-50 ℃ for 2.5h. After the reaction, the layers are separated, the water layer is removed, the anhydrous sodium sulfate is dried, and after the solvent is recovered, the fraction of 100-105 ℃/217kPa, namely 1- (4-pyridyl) -2-acetone is collected by reduced pressure distillation.
60.0g of 1- (4-pyridyl) -2-acetone is added into a 500mL round bottom flask, 40.5g of triethyl orthoformate, 92.2g of acetic anhydride and 80.0g of glacial acetic acid are added into a reaction flask under stirring, and the reaction is carried out for 4 hours under stirring at 35-45 ℃ to finish the reaction of the raw materials. The solvent was removed by concentration under reduced pressure at 80℃to give a dark red oil which was used directly in the next reaction without purification.
600mL of absolute methanol and the above oil were added to 5000mL of the mixture, and then 64.0g of α -cyanoacetamide and 210g of 50% sodium hydroxide solution were added with stirring, and the reaction time was 1.5 hours. And after the reaction is finished, regulating the pH to 6.5-7.2 by using an acetic acid solution to separate out solids, and filtering to obtain a milrinone crude product. Recrystallizing the solid by an ethanol-water system to obtain the white milrinone crystal.
Comparative example 2
Placing 10g milrinone in a 500mL beaker, dropwise adding 0.1N sodium hydroxide aqueous solution, stirring to dissolve the solution until the pH value is 7-8, adding acetone with the volume of 5 times of the solution, cooling, precipitating white precipitate, filtering, washing a filter cake with acetone for 2 times, air-drying, and then drying at 105 ℃ for 2 hours to obtain milrinone sodium salt.
Comparative example 3
Placing 10g milrinone in a 500mL beaker, dropwise adding 0.1N hydrochloric acid solution, stirring to dissolve the solution to enable the pH value of the solution to be 4-4.5, adding acetone with the volume of 5 times of the solution, cooling, precipitating white precipitate, filtering, washing a filter cake with acetone for 2 times, airing, and then drying at 105 ℃ for 2 hours to obtain milrinone hydrochloride.
Comparative example 4
Mirinone (169.0 mg) and gallic acid (136.1 mg) were mixed uniformly in equimolar ratio, 50. Mu.L of water was gradually added and sufficiently ground in mortar for 45 minutes. Dissolving the ground powder sample in a minimum amount of methanol/acetonitrile/H 2 In O-mixed solvent (v) Methanol ：v Acetonitrile ：v Water and its preparation method =2:1:1), rapidly vigorously stirred at 60 ℃ for about 3h. After cooling to room temperature, the resulting reaction mixture was filtered. The above powder sample was added to the filtrate as seed crystal, and the solution was allowed to stand for slow evaporation for 1 day to obtain colorless crystals.
Stability test
The specific stability test method is carried out by referring to the guidance method of the fourth section of the Chinese pharmacopoeia on stability investigation.
High temperature test: placing the sample in a clean container, standing at 60deg.C for 10 days, sampling at 5 th and 10 th days, and detecting purity by HPLC;
high humidity test: placing the sample in a constant humidity closed container at 25 ℃ under the conditions of 90% and 5% relative humidity for 10 days, sampling on the 5 th day and the 10 th day, and detecting the purity by using an HPLC method;
strong light irradiation test: the sample was placed in an illumination device equipped with a fluorescent lamp, and left for 10 days under the condition of an illuminance of 4500lx and 500lx, and samples were taken on days 5 and 10, and the purity was measured by HPLC.
TABLE 3 stability test results of milrinone-nicotinic acid crystals
Solubility test
The method comprises the following steps: respectively weighing 10ml of medium (water and 0.01mol/L HCl solution) in a penicillin bottle, adding excessive sample to be tested, sealing the penicillin bottle, placing in a constant-temperature water bath at 25 ℃ for stirring for 1 hour, filtering by a filter membrane, and taking filtrate; the absorbance was measured at a wavelength of 270nm, and the solubility was calculated by measuring the absorbance of the standard control.
TABLE 4 solubility of milrinone-nicotinic acid crystals in various media (mg/mL)
Test results show that the solubility of the milrinone-nicotinic acid crystal provided by the invention in 0.01mol/L HCl and water is obviously improved compared with other crystal forms of milrinone, and the milrinone-nicotinic acid crystal is beneficial to the application of the milrinone-nicotinic acid crystal in oral preparations.
Pharmacokinetic studies
The method comprises the following steps: in vivo PK test was carried out by single dose oral administration, male SD rats (220-260 g) were fed in a quiet atmosphere of 0% -60% constant humidity at 25+ -1deg.C, with rhythmic light from 7 in the morning to 7 in the evening. PK experiments were strictly performed according to the laboratory management guidelines issued by the chinese institute of technology. Prior to the experiment, the rats tested were randomly divided into three groups (n=5 per group) and allowed to drink water freely, and fasted overnight. All samples tested were suspended in vegetable oil and then orally administered in a single dose of 10mg/kg milrinone or its equivalent. After administration, 0.5mL blood samples were collected at the designed time points according to the administration conditions, and the concentration of milrinone in blood was measured according to the literature method.
TABLE 5 pharmacokinetic experiment results of milrinone-nicotinic acid crystals
Test results show that compared with other milrinone crystal forms, the milrinone-nicotinic acid crystal form provided by the invention has higher peak concentration, has the same dissolution trend as that of the milrinone-nicotinic acid crystal form, and provides conditions for rapid absorption of the milrinone and a large amount of medicines into blood. The prolonged half-life of milrinone-niacin forms provides longer residence time of the drug in the body compared to other forms of milrinone, thereby providing the possibility of achieving long-term therapeutic effects.

Claims (10)

1. Milrinone-nicotinic acid crystal is characterized in that Cu-K alpha radiation is used, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 6.8+/-0.2 degrees, 10.5+/-0.2 degrees, 15.2+/-0.2 degrees, 15.3+/-0.2 degrees, 26.9+/-0.2 degrees and 27.0+/-0.2 degrees.
2. Milrinone-niacin crystal according to claim 1, characterized in that the X-ray diffraction pattern expressed in 2Θ 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 °, 25.7 ± 0.2 °, 26.9 ± 0.2 °, 27.0 ± 0.2 ° using Cu-ka radiation.
3. Milrinone-niacin crystal according to claim 1, characterized in that Cu-ka radiation is used, the characteristic peaks of which correspond to the X-ray powder diffraction pattern as shown in figure 1.
4. The preparation method of the milrinone-nicotinic acid crystal is characterized by comprising the following specific preparation steps: and dissolving milrinone and nicotinic acid in a solvent, heating, stirring, performing heat preservation reaction, cooling, crystallizing, filtering, washing and drying to obtain milrinone-nicotinic acid crystals.
5. The method for preparing milrinone-nicotinic acid crystals as defined in claim 4, wherein the solvent is selected from one or a combination of trifluoroethanol, methanol, ethanol and acetone solvents, preferably trifluoroethanol.
6. The method for preparing milrinone-nicotinic acid crystals as defined in claim 4, wherein the mass-to-volume ratio of milrinone to solvent is 10:0.7-1.5; preferably 10:0.9 to 1.2, wherein the mass is in mg and the volume is in mL.
7. The method for preparing milrinone-nicotinic acid crystals according to claim 4, wherein the molar ratio of milrinone to nicotinic acid is 1:0.85-1.8, preferably 1:0.9-1.5.
8. The method for preparing milrinone-nicotinic acid crystals as claimed in claim 4, wherein the temperature is 15-30 ℃, preferably 20-25 ℃.
9. The method for preparing milrinone-nicotinic acid crystals as defined in claim 4, wherein the drying temperature is 50-55 ℃ and the drying time is 8-10 hours.
10. A pharmaceutical composition comprising milrinone-niacin crystals according to any one of claims 1-4 in combination with other ingredients.
CN202210779324.4A 2022-07-01 2022-07-01 Milrinone-nicotinic acid crystal and preparation method thereof Pending CN117105854A (en)

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