CN116813543A - Milrinone eutectic solvate - Google Patents

Milrinone eutectic solvate Download PDF

Info

Publication number
CN116813543A
CN116813543A CN202210281666.3A CN202210281666A CN116813543A CN 116813543 A CN116813543 A CN 116813543A CN 202210281666 A CN202210281666 A CN 202210281666A CN 116813543 A CN116813543 A CN 116813543A
Authority
CN
China
Prior art keywords
milrinone
crystal
acid
degrees
methanol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202210281666.3A
Other languages
Chinese (zh)
Inventor
张贵民
翟立海
李玲
夏祥来
郑家芳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shandong New Time Pharmaceutical Co Ltd
Original Assignee
Shandong New Time Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong New Time Pharmaceutical Co Ltd filed Critical Shandong New Time Pharmaceutical Co Ltd
Priority to CN202210281666.3A priority Critical patent/CN116813543A/en
Publication of CN116813543A publication Critical patent/CN116813543A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • C07D213/85—Nitriles in position 3
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
    • C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
    • C07C29/78—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by condensation or crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/02—Monohydroxylic acyclic alcohols
    • C07C31/04—Methanol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/34—Halogenated alcohols
    • C07C31/38—Halogenated alcohols containing only fluorine as halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a milrinone eutectic solvate, in particular to milrinone-4-hydroxy cinnamic acid-3H 2 O-methanol co-crystal and milrinone-4-hydroxy benzeneMethanolic formate solvate crystals, milrinone-vanillic acid-trifluoroethanol co-crystals, milrinone-2, 6-dihydroxybenzoic acid hydrate crystals; compared with the existing crystal forms of milrinone, the eutectic solvate provided by the invention has better stability and higher solubility, thereby being beneficial to the storage and transportation of products and the application in preparation; the preparation method is simple to operate, the crystallization process is easy to control, and the reproducibility is good.

Description

Milrinone eutectic solvate
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a pharmaceutical eutectic solvate crystal of milrinone, and a preparation method and application thereof.
Background
Milrinone (milrinone) with chemical name 1, 6-dihydro-2-methyl-6-oxo- [3, 4-bipyridine]-5-carbonitrile of formula C 12 H 9 N 3 O, molecular weight 211.22, is white or white-like crystalline powder, and has the structural formula:
milrinone was first developed by Sterling corporation in the united states to successfully produce an anti-heart failure drug, which was first approved by the FDA in the united states in 1987, formally marketed in the united states in 1992, and subsequently marketed in the united kingdom, france, germany, the netherlands, belgium, etc.
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.
Researches show that milrinone has poor water solubility, is almost insoluble in water, has poor in vivo dissolution and absorption effects, and has adverse reaction when orally taken; the existing milrinone injection has the problems of poor stability and easy degradation. Although the prior art discloses some methods of attempting to improve the solubility or stability of milrinone, none of them achieve the desired effect, nor do they improve the disadvantages of poor absorption. 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 preparation method provides the milrinone medicinal crystal with good solubility, high stability and good application prospect, provides a solution for developing the preparation with the effect of improving in vivo absorption, and is still a problem to be solved in the field.
Disclosure of Invention
In view of the deficiencies of the prior art, the present invention aims to provide novel crystalline forms of milrinone with higher solubility and good stability.
Specifically, the specific technical content of the invention is as follows:
the invention provides a milrinone eutectic solvate crystal, wherein the eutectic solvate is milrinone-4-hydroxy cinnamic acid-3H 2 O-methanol co-crystals, milrinone-4-hydroxybenzoic acid-methanol solvate crystals, milrinone-vanillic acid-trifluoroethanol co-crystals, milrinone-2, 6-dihydroxybenzoic acid hydrate crystals.
Preferably, the milrinone-4-hydroxycinnamic acid-3H 2 The O-methanol co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 14.6+/-0.2 degrees, 18.9+/-0.2 degrees, 19.9+/-0.2 degrees, 25.3+/-0.2 degrees and 31.6+/-0.2 degrees.
Preferably, the milrinone-4-hydroxycinnamic acid-3H 2 O-methanol co-crystal, usingThe X-ray diffraction pattern expressed by 2 theta of Cu-K alpha radiation has characteristic peaks at least at 11.0+/-0.2 degrees, 12.3+/-0.2 degrees, 14.6+/-0.2 degrees, 15.8+/-0.2 degrees, 18.9+/-0.2 degrees, 19.9+/-0.2 degrees, 24.3+/-0.2 degrees, 25.3+/-0.2 degrees, 27.4+/-0.2 degrees, 27.5+/-0.2 degrees, 29.0+/-0.2 degrees, 29.9+/-0.2 degrees and 31.6+/-0.2 degrees and 37.4+/-0.2 degrees.
Preferably, the milrinone-4-hydroxycinnamic acid-3H 2 The O-methanol co-crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 1.
Preferably, the milrinone-4-hydroxycinnamic acid-3H 2 O-methanol co-crystal with molecular formula of C 22 H 27 N 3 O 8 The crystallographic parameters were: the triclinic system has a space group of P-1 and unit cell parameters of: α= 79.815 (2) °, β= 72.953 (2) °, γ= 78.588 (2) °, unit cell volume
Preferably, the milrinone-4-hydroxybenzoic acid methanol solvate crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 9.9+/-0.2 degrees, 13.7+/-0.2 degrees, 14.4+/-0.2 degrees, 17.5+/-0.2 degrees, 19.7+/-0.2 degrees, 23.1+/-0.2 degrees, 24.2+/-0.2 degrees, 24.6+/-0.2 degrees, 24.9+/-0.2 degrees, 25.1+/-0.2 degrees and 26.1+/-0.2 degrees.
Preferably, the milrinone-4-hydroxybenzoic acid methanol solvate crystals are characterized by an X-ray diffraction pattern expressed in terms of 2θ using Cu-ka radiation at least at 9.9±0.2°, 10.4±0.2°, 12.2±0.2°, 13.1±0.2°, 13.7±0.2°, 14.4±0.2°, 17.3±0.2 °, 17.5±0.2 °, 17.7±0.2°, 19.0±0.2 °, 19.7±0.2 °, 21.2±0.2 °, 22.3±0.2°, 22.8±0.2°, 23.1±0.2 °, 24.2±0.2±0.2 °, 24.6±0.2±0.2 °, 25.0±0.2°, 25.1±0.2°, 25.2±0.2°, 25.7±0.2°, 26.1±0.2°, 27.2±0.2° 0.30°.2°.
Preferably, the milrinone-4-hydroxybenzoic acid methanol solvate crystals are irradiated with Cu-K alpha, and have characteristic peaks corresponding to the X-ray powder diffraction pattern shown in FIG. 4.
Preferably, the milrinone-4-hydroxybenzoic acid methanol solvate crystal has a molecular formula of C 20 H 19 N 3 O 5 The crystallographic parameters were: monoclinic system, space group C2/C, unit cell parameters: α=90 °, β= 90.538 (8) °, γ=90°, unit cell volume +.>
Preferably, the milrinone-vanillic acid-trifluoroethanol co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 8.9+/-0.2 degrees, 10.0+/-0.2 degrees, 12.0+/-0.2 degrees, 13.7+/-0.2 degrees, 14.3+/-0.2 degrees, 21.7+/-0.2 degrees and 24.0+/-0.2 degrees.
Preferably, the milrinone-vanillic acid-trifluoroethanol co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 5.0+/-0.2 degrees, 8.9+/-0.2 degrees, 10.0+/-0.2 degrees, 12.0+/-0.2 degrees, 12.8+/-0.2 degrees, 13.7+/-0.2 degrees, 14.3+/-0.2 degrees, 20.2+/-0.2 degrees, 20.9+/-0.2 degrees, 21.7+/-0.2 degrees, 24.0+/-0.2 degrees, 24.9+/-0.2 degrees, 26.9+/-0.2 degrees and 27.8+/-0.2 degrees.
Preferably, the milrinone-vanillic acid-trifluoroethanol co-crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 7.
Preferably, the milrinone-vanillic acid-trifluoroethanol co-crystal has a molecular formula of C 22 H 20 F 3 N 3 O 6 The crystallographic parameters were: monoclinic system, space group P21/n, unit cell parameters:α=90 °, β= 100.5630 (10) °, γ=90°, unit cell volume +.>
Preferably, the milrinone-2, 6-dihydroxybenzoic acid hydrate crystal has characteristic peaks at least at 10.9+/-0.2 degrees, 12.6+/-0.2 degrees, 15.0+/-0.2 degrees, 26.4+/-0.2 degrees and 27.6+/-0.2 degrees in an X-ray diffraction spectrum expressed in terms of 2 theta by using Cu-K alpha radiation.
Preferably, the milrinone-2, 6-dihydroxybenzoic acid hydrate crystal has characteristic peaks at least at 10.0+/-0.2 °, 10.9+/-0.2 °, 12.6+/-0.2 °, 15.0+/-0.2 °, 17.8+/-0.2 °, 24.9+/-0.2 °, 26.4+/-0.2 °, 27.6+/-0.2 °, 29.2+/-0.2 °, 30.2+/-0.2 °, 31.7+/-0.2 °, 32.7+/-0.2 ° and 34.1+/-0.2 ° in an X-ray diffraction spectrum expressed in 2θ using Cu-kα radiation.
Preferably, the milrinone-2, 6-dihydroxybenzoic acid hydrate crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 10.
Preferably, the milrinone-2, 6-dihydroxybenzoic acid hydrate crystal form has a molecular formula of C 19 H 17 N 3 O 6 The crystallographic parameters were: triclinic crystal system, space group is P-1, unit cell parameters are: α= 94.111 (4) °, β= 95.347 (4) °, γ= 112.273 (5) °, unit cell volume
In another aspect, the invention provides a method of preparing a milrinone eutectic solvate crystal: the method comprises the following steps: dissolving milrinone and ligand in a mixed solvent, heating and stirring, filtering, cooling, standing, volatilizing, crystallizing, filtering and drying to obtain medicine crystals; the ligand is 4-hydroxy cinnamic acid, 4-hydroxy benzoic acid, vanillic acid and 2, 6-dihydroxy benzoic acid.
Preferably, the mixed solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, acetone, trifluoroethanol, and water.
Preferably, the molar ratio of milrinone to ligand is 0.5-1.5.
Preferably, the heating temperature is 40 to 70 ℃.
Preferably, the crystallization temperature is between-5 and 30 ℃ and the crystallization time is between 8 and 84 hours.
Preferably, the drying temperature is 40-65 ℃ and the drying time is 6-12h.
Further preferably, the present invention provides milrinone-4-hydroxycinnamic acid-3H 2 The preparation method of the O-methanol eutectic comprises the following steps: dissolving milrinone and 4-hydroxy cinnamic acid in mixed solvent, heating and stirring, filtering, cooling, standing, volatilizing, crystallizing, filtering, and drying to obtain milrinone-4-hydroxy cinnamic acid-3H 2 An O-methanol co-crystal;
the mixed solvent is a mixed solvent of methanol and water, and can also contain one of ethanol, acetonitrile, acetone and trifluoroethanol, preferably the mixed solvent of methanol and water, and the volume ratio of the methanol to the water is 4-5: 1, a step of;
the mass volume ratio of the milrinone to the mixed solvent is 21.1:3-8, wherein the mass is calculated in mg and the volume is calculated in ml; preferably 21.1:5-6, wherein the mass is in mg and the volume is in ml;
the molar ratio of milrinone to 4-hydroxy cinnamic acid is 1:0.5 to 1.2, preferably 1:1, a step of;
the heating temperature is 40-60 ℃, preferably 50 ℃;
the temperature of the cooling, standing and crystallization is 0-30 ℃, preferably 20-25 ℃;
the crystallization time is 16-72 hours;
the drying temperature is 45-65 ℃ and the drying time is 8-12 hours.
Further preferably, the present invention provides a method for preparing milrinone-4-hydroxybenzoic acid methanol solvate crystals, comprising the steps of: dissolving milrinone and 4-hydroxybenzoic acid in a mixed solvent, heating and stirring, filtering, cooling, standing, volatilizing, crystallizing, filtering and drying to obtain a milrinone-4-hydroxybenzoic acid methanol solvate;
the mixed solvent is a combination of methanol and other solvents, wherein the other solvents are selected from one or two of ethanol, acetonitrile, water, acetone and trifluoroethanol; the mixed solvent is preferably a mixed solvent of methanol and trifluoroethanol or a mixed solvent of methanol and acetone; preferably, the volume ratio of the methanol to the trifluoroethanol or the acetone is 1:1, a step of;
the mass-volume ratio of the milrinone to the mixed solvent is 21.1:1-3, preferably 21.1:1.5-2.5, wherein the mass is calculated in mg and the volume is calculated in ml;
the molar ratio of milrinone to 4-hydroxybenzoic acid is 1:0.8 to 1.1; preferably 1:1, a step of;
the heating temperature is 50-70 ℃, preferably 60 ℃;
the temperature reduction crystallization temperature is 0-30 ℃, preferably 10-15 ℃; the crystallization time is 8-72 hours;
the drying temperature is 45-65 ℃ and the drying time is 8-12 hours.
Further preferably, the present invention provides a method for preparing milrinone-vanillic acid-trifluoroethanol co-crystal, comprising the steps of: dissolving milrinone and vanilla acid in a mixed solvent, heating and stirring, filtering, cooling, standing, volatilizing, crystallizing, filtering and drying to obtain milrinone-vanillic acid-trifluoroethanol crystal;
the mixed solvent is a combination of trifluoroethanol and other solvents; the other solvent is selected from one or more of methanol, ethanol, acetonitrile and acetone; the mixed solvent is preferably a combination of trifluoroethanol and methanol or ethanol or acetone;
the mass volume ratio of the milrinone to the mixed solvent is 21.1:2-6, preferably 21.1:3-4, wherein the mass is calculated in mg and the volume is calculated in ml;
the molar ratio of milrinone to vanillic acid is 1:0.5 to 1.5, preferably 1:1, a step of;
the heating temperature is 40-60 ℃, preferably 55 ℃;
the temperature of the cooling crystallization is 10-30 ℃, preferably 10-15 ℃; the crystallization time is 8-72 hours;
the drying temperature is 45-65 ℃ and the drying time is 8-12 hours.
Further preferably, the present invention provides a method for preparing milrinone-2, 6-dihydroxybenzoic acid hydrate crystals, comprising the steps of: dissolving milrinone and 2, 6-dihydroxybenzoic acid in a mixed solvent, heating and stirring, filtering, cooling, standing, volatilizing, crystallizing, filtering and drying to obtain milrinone-2, 6-dihydroxybenzoic acid hydrate crystals;
the mixed solvent is selected from the combination of methanol or ethanol or isopropanol or acetone or trifluoroethanol and water, preferably the mixed solvent of ethanol and water;
the mass-volume ratio of the milrinone to the mixed solvent is 16-8:1, preferably 10-12:1, wherein the mass is calculated in mg and the volume is calculated in ml;
the molar ratio of milrinone to 2, 6-dihydroxybenzoic acid is 1:0.9 to 1.2, preferably 1:1.1;
the heating temperature is 40-60 ℃, preferably 55 ℃;
the temperature reduction crystallization temperature is-5-10 ℃, preferably 0-5 ℃; the crystallization time is 60-84 hours;
the drying temperature is 40-50 ℃ and the drying time is 6-10 hours.
Finally, the present invention provides a pharmaceutical composition comprising the milrinone co-crystal solvate of the present invention and other pharmaceutically acceptable ingredients; the other pharmaceutically acceptable components may be pharmaceutically active ingredients which may be used in combination and/or pharmaceutically acceptable auxiliary ingredients.
Compared with the prior art, the invention has the technical effects that:
the milrinone eutectic solvate provided by the invention has the advantages of simple operation, easy control of crystallization process and good reproducibility. Milrinone-4-hydroxycinnamic acid-3H 2 O-methanol eutectic and milrinone-The 4-hydroxybenzoic acid methanol solvate crystal, the milrinone-vanillic acid-trifluoroethanol eutectic and the milrinone-2, 6-dihydroxybenzoic acid hydrate crystal have better stability and higher solubility compared with the existing crystal forms of milrinone, thereby being beneficial to the storage and transportation of products and the application in preparation of preparations.
Drawings
FIG. 1 Milrinon-4-hydroxycinnamic acid-3H 2 PXRD pattern of O-methanol co-crystal.
FIG. 2 Milrinon-4-hydroxycinnamic acid-3H 2 ORTEP diagram of O-methanol co-crystal.
FIG. 3 Milrinon-4-hydroxycinnamic acid-3H 2 Hydrogen bonding diagram of O-methanol co-crystal.
FIG. 4 PXRD spectra of milrinone-4-hydroxybenzoic acid methanol solvate crystals.
FIG. 5 ORTEP diagram of milrinone-4-hydroxybenzoic acid methanol solvate crystals.
FIG. 6 shows a hydrogen bonding diagram of a milrinone-4-hydroxybenzoic acid methanol solvate crystal.
FIG. 7 PXRD spectra of milrinone-vanillic acid-trifluoroethanol co-crystals.
FIG. 8 ORTEP diagram of milrinone-vanillic acid-trifluoroethanol co-crystal.
FIG. 9 shows hydrogen bonding diagrams of milrinone-vanillic acid-trifluoroethanol co-crystals.
FIG. 10 PXRD spectra of milrinone-2, 6-dihydroxybenzoic acid hydrate crystals.
FIG. 11 ORTEP diagram of milrinone-2, 6-dihydroxybenzoic acid hydrate crystals.
FIG. 12 shows hydrogen bonding diagrams of milrinone-2, 6-dihydroxybenzoic acid hydrate crystals.
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.
The materials used in the examples may be prepared according to methods known in the art or purchased from commercial products.
Example 1 Milrinone-4-hydroxycinnamic acid-3H 2 O-methanol co-crystal
Preparation example 1
Dissolving 21.1mg milrinone and 16.4mg 4-hydroxy cinnamic acid in a mixed solvent of 4mL methanol and 1mL water, heating in water bath at 50deg.C, stirring to dissolve completely, filtering, standing at 20-25deg.C for volatilizing and crystallizing for 48 hr, filtering, and drying at 50deg.C for 10 hr to obtain milrinone-4-hydroxy cinnamic acid-3H 2 Co-crystal of O-methanol, yield: 96.0% purity: 99.92%.
Preparation example 2
Heating and stirring 21.1mg milrinone and 16.4mg 4-hydroxy cinnamic acid 5mL methanol and 1mL water in water bath at 40 ℃ until completely dissolved, filtering, standing at 25-30 ℃ for volatilizing and crystallizing for 72H, filtering, drying at 45 ℃ for 12H to obtain milrinone-4-hydroxy cinnamic acid-3H 2 Co-crystal of O-methanol, yield: 92.3% of purity: 99.93%.
Preparation example 3
Heating 21.1mg milrinone and 19.7mg 4-hydroxy cinnamic acid in a mixed solvent of 6mL methanol and 2mL water in a water bath at 40 ℃ and stirring until the mixture is completely dissolved, filtering, standing at 20-25 ℃ for volatilizing and crystallizing for 48H, filtering, and drying at 65 ℃ for 8H to obtain milrinone-4-hydroxy cinnamic acid-3H 2 Co-crystal of O-methanol, yield: 88.6% of purity: 99.69%.
Preparation example 4
Heating 21.1mg milrinone and 8.2mg 4-hydroxy cinnamic acid in a mixed solvent of 2.5mL methanol and 0.5mL water at 60deg.C under heating and stirring to dissolve completely, filtering, cooling to 0-5deg.C, crystallizing for 36H, filtering, and drying at 50deg.C for 10H to obtain milrinone-4-hydroxy cinnamic acid-3H 2 Co-crystal of O-methanol, yield: 86.5%, purity: 99.74%.
Confirmation of Crystal Structure
The invention relates to milrinone-4-hydroxy cinnamic acid-3H 2 X-ray crystal data in the O-methanol co-crystal test were collected on a Japanese national Phantom XtaLAB Synergy model instrument, temperature 293 (2) K was tested, data were collected in an omega scan mode using Cu-Ka radiation and Lp correction was performed. Resolving structure by direct methodAnd (3) finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by adopting theoretical hydrogenation, and finishing the structure by adopting a least square method.
Testing and resolving Mirinone-4-hydroxy cinnamic acid-3H prepared by the invention 2 The crystallographic data (see Table 1) of the O-methanol co-crystal form are that the triclinic system, the space group is P-1, and the unit cell parameters are: α= 79.815 (2) °, β= 72.953 (2) °, γ= 78.588 (2) °, unit cell volume +.>
TABLE 1 milrinone-4-hydroxycinnamic acid-3H 2 Data on primary crystallography of O-methanol co-crystals
The milrinone-4-hydroxy cinnamic acid co-crystal-3H 2 The ORTEP diagram of O-methanol shows that two molecules of milrinone bind to two molecules of 4-hydroxy cinnamic acid, three molecules of water and one molecule of methanol in this crystalline form, as shown in FIG. 2. Milrinone-4-hydroxy cinnamic acid-3H of the invention 2 The hydrogen bond diagram of the O-methanol eutectic 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 milrinone-4-hydroxycinnamic acid-3H 2 PXRD peak of O-methanol eutectic
Example 2 Milrinone-4-hydroxybenzoic acid methanol solvate
Preparation example 1
211.1mg of milrinone and 138.1mg of 4-hydroxybenzoic acid are added into a mixed solvent of 10mL of methanol and 10mL of trifluoroethanol, the mixture is heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, the mixture is filtered, and the mixture is subjected to standing volatilization crystallization at 10-15 ℃ for 48 hours, is filtered and is dried at 50 ℃ for 10 hours, thus obtaining the milrinone-4-hydroxybenzoic acid methanol solvate with the yield: 95.2%, purity: 99.92%.
Preparation example 2
211.1mg of milrinone and 151.9mg of 4-hydroxybenzoic acid are added into a mixed solvent of 15mL of methanol and 15mL of acetone, the mixture is heated in a water bath at 50 ℃ and stirred until the mixture is completely dissolved, the mixture is filtered, the mixture is stood at room temperature for volatilizing and crystallizing for 72 hours, the mixture is filtered, and the mixture is dried at 45 ℃ for 12 hours to obtain the milrinone-4-hydroxybenzoic acid methanol solvate, and the yield is: 92.6%, purity: 99.91%.
Preparation example 3
211.1mg of milrinone and 110.5mg of 4-hydroxybenzoic acid are added into a mixed solvent of 20mL of methanol and 20mL of ethanol, the mixture is heated and stirred in a water bath at 50 ℃ until the mixture is completely dissolved, the mixture is filtered, the mixture is stood and volatilized for crystallization for 72 hours at 5-10 ℃, the mixture is filtered, and the mixture is dried at 50 ℃ for 10 hours to obtain the milrinone-4-hydroxybenzoic acid methanol solvate, and the yield is: 86.3%, purity: 99.85%.
Preparation example 4
211.1mg of milrinone and 138.1mg of 4-hydroxybenzoic acid are added into a mixed solvent of 5mL of methanol and 5mL of acetonitrile, the mixture is heated in a water bath at 70 ℃ and stirred until the mixture is completely dissolved, the mixture is filtered, the mixture is stood at room temperature for volatilizing and crystallizing for 72 hours, the mixture is filtered, and the mixture is dried at 50 ℃ for 10 hours to obtain the milrinone-4-hydroxybenzoic acid methanol solvate, and the yield is: 90.4%, purity: 99.89%.
Confirmation of Crystal Structure
In the milrinone-4-hydroxybenzoic acid methanol solvate test, 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 the data are collected in an omega scanning mode and are corrected by Lp. 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.
Testing and analysis of the crystallographic data (as in Table 3) of the crystalline form of the methanol solvate of milrinone-4-hydroxybenzoic acid prepared according to the present invention is that the monoclinic system, the space group is C2/C, the unit cell parameters are: α=90 °, β= 90.538 (8) °, γ=90°, unit cell volume +.>
TABLE 3 data on major crystallography of milrinone-4-hydroxybenzoic acid methanol solvate
The ORTEP pattern of the milrinone-4-hydroxybenzoic acid methanol solvate of the present invention shows that one molecule of milrinone binds to one molecule of 4-hydroxybenzoic acid and one molecule of methanol in the crystalline form, as shown in fig. 5. The hydrogen bond diagram of the milrinone-4-hydroxybenzoic acid methanol solvate is shown in figure 6. Based on the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in FIG. 4 and Table 4.
TABLE 4 PXRD peak of milrinone-4-hydroxybenzoic acid methanol solvate
Example 3 Co-crystals of milrinone-vanillic acid-trifluoroethanol
Preparation example 1
Adding 21.3 mg milrinone and 16.9mg vanilla acid into a mixed solvent of 1.5mL trifluoroethanol and 1.5mL ethanol, heating and stirring in a water bath at 55 ℃ until the mixture is completely dissolved, filtering, standing and volatilizing at 10-15 ℃ for crystallization for 60 hours, filtering, and drying at 50 ℃ for 10 hours to obtain a milrinone-vanillic acid-trifluoroethanol eutectic, wherein the yield is: 96.0% purity: 99.92%.
Preparation example 2
Adding 21.2mg milrinone and 25.2mg vanilla acid into a mixed solvent of 2mL trifluoroethanol and 2mL acetone, heating in a water bath at 45 ℃ and stirring until the mixture is completely dissolved, filtering, standing at 10-15 ℃ for volatilizing and crystallizing for 72h, filtering, drying at 50 ℃ for 10h to obtain a milrinone-vanillic acid-trifluoroethanol eutectic, and obtaining the yield: 93.5%, purity: 99.91%.
Preparation example 3
21.1mg milrinone and 17.1mg vanilla acid are added into a mixed solvent of 3mL trifluoroethanol and 3mL methanol, the mixture is heated in a water bath at 45 ℃ and stirred until the mixture is completely dissolved, the mixture is filtered, the mixture is stood at room temperature for volatilizing and crystallizing for 72 hours, the mixture is filtered, and the mixture is dried at 50 ℃ for 10 hours to obtain the milrinone-vanillic acid-trifluoroethanol eutectic, the yield is: 88.2% purity: 99.81%.
Preparation example 4
21.0mg milrinone and 8.4mg vanillic acid are heated in a water bath at 60 ℃ and stirred into a mixed solvent of 1mL trifluoroethanol and 1mL acetonitrile until the mixture is completely dissolved, the mixture is filtered, the mixture is stood at room temperature for volatilizing and crystallizing for 48 hours, the filtered mixture is dried at 50 ℃ for 10 hours, and the milrinone-vanillic acid-trifluoroethanol eutectic is obtained, and the yield is: 83.4% of purity: 99.75%.
Confirmation of Crystal Structure
In the milrinone-vanillic acid-trifluoroethanol co-crystal test, 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 the 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.
Testing and analyzing the crystallographic data (as shown in Table 5) of the milrinone-vanillic acid-trifluoroethanol co-crystal form prepared by the invention, wherein the space group is P21/n, and the unit cell parameters are as follows:α=90°, β= 100.5630 (10) °, γ=90°, and unit cell volume v= 2250.19 (5).
TABLE 5 data on primary crystallography of milrinone-vanillic acid-trifluoroethanol co-crystals
The ORTEP diagram of the milrinone-vanillic acid-trifluoroethanol co-crystal of the invention shows that one molecule of milrinone in the crystalline form combines one molecule of vanillic acid and one molecule of trifluoroethanol, as shown in fig. 8. The hydrogen bond diagram of the milrinone-vanillic acid-trifluoroethanol eutectic is shown in figure 9. Based on the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in FIG. 7 and Table 6.
TABLE 6 PXRD peak of the milrinone-vanillic acid-trifluoroethanol co-crystal
Example 4 milrinone-2, 6-dihydroxybenzoic acid hydrate
Preparation example 1
422.4mg milrinone and 369.84mg 2, 6-dihydroxybenzoic acid are added into a mixed solvent of 35mL methanol and 5mL purified water, heated and stirred in a water bath at 55 ℃ until the mixture is completely dissolved, filtered, cooled, stood and crystallized at 0-5 ℃ for 60 hours, filtered and dried at 45 ℃ for 10 hours, thus obtaining milrinone-2, 6-dihydroxybenzoic acid hydrate with the yield: 94.4%, purity: 99.84%.
Preparation example 2
211.1mg milrinone and 165.2mg 2, 6-dihydroxybenzoic acid are added into a mixed solvent of 18mL ethanol and 2mL purified water, the mixture is heated and stirred in a water bath at 55 ℃ until the mixture is completely dissolved, the mixture is filtered, the mixture is cooled, kept stand and crystallized for 72 hours at 0-5 ℃, the mixture is filtered, and the mixture is dried for 10 hours at 45 ℃ to obtain milrinone-2, 6-dihydroxybenzoic acid hydrate with the yield: 98.7%, purity: 99.89%.
Preparation example 3
211.1mg milrinone and 131.0mg 2, 6-dihydroxybenzoic acid are added into a mixed solvent of 11mL isopropyl alcohol and 2mL purified water, the mixture is heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, the mixture is filtered, the mixture is cooled and kept stand for crystallization for 84 hours at 5-10 ℃, the mixture is filtered, and the mixture is dried for 10 hours at 45 ℃ to obtain milrinone-2, 6-dihydroxybenzoic acid hydrate with the yield: 87.1%, purity: 99.79%.
Confirmation of Crystal Structure
In the milrinone-2, 6-dihydroxybenzoic acid hydrate crystal form test, X-ray crystal data are collected on a Japanese science XtaLAB Synergy model instrument, the test temperature 293 (2) K is radiated by Cu-Ka, and the 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 shown in table 7) for testing and analyzing the crystal form of the milrinone-2, 6-dihydroxybenzoic acid hydrate prepared by the invention are as follows: triclinic crystal system, space group is P-1, unit cell parameters are: α= 94.111 (4) °, β= 95.347 (4) °, γ= 112.273 (5) °, unit cell volume +.>
TABLE 7 major crystallographic data for the crystalline form of milrinone-2, 6-dihydroxybenzoic acid hydrate
The ORTEP diagram of the crystalline form of milrinone-2, 6-dihydroxybenzoic acid hydrate of the present invention shows that one molecule of milrinone binds one molecule of 2, 6-dihydroxybenzoic acid and one molecule of free water in the crystalline form, as shown in fig. 11. The hydrogen bond diagram of milrinone-2, 6-dihydroxybenzoic acid hydrate is shown in figure 12. Based on the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in FIG. 10 and Table 8.
TABLE 8 PXRD peaks for crystalline form of milrinone-2, 6-dihydroxybenzoic acid hydrate
Comparative example 1
Milrinone crystals were prepared with reference to example 1 of chinese patent CN 106361710B.
Comparative example 2
Milrinone was recrystallized from an ethanol-water system as described in example 1 of chinese patent CN104387320B to give white crystals of milrinone.
Comparative example 3
The milrinone crystal is prepared by the method of Chinese patent CN102558044A specification [0013 ].
Comparative example 4
Referring to the method of example 1 of chinese patent CN1951919a, milrinone sodium salt was prepared.
Comparative example 5
Referring to the method of example 3 of chinese patent CN1951919a, milrinone hydrochloride was prepared.
Verification embodiment
1. Stability test
(1) Test materials: milrinone-4-hydroxycinnamic acid-3H 2 O-methanol co-crystal (preparation 2), milrinone-4-hydroxybenzoic acid methanol solvate crystal (preparation 1), milrinone-vanillic acid-trifluoroethanol co-crystal (preparation 1), milrinone-2, 6-dihydroxybenzoic acid hydrate (preparation 2), milrinone crystal prepared in comparative examples 1 to 3, milrinone sodium salt prepared in comparative example 4, milrinone hydrochloride prepared in comparative example 5.
(2) The test method comprises the following steps: test is carried out by referring to the method of annex <9001 drug substance and preparation stability test guidelines > of the fourth part of Chinese pharmacopoeia (2020 edition), high-temperature test conditions: 60 ℃; strong light irradiation test conditions: 4500lx±500lx; high humidity test conditions: the temperature is 25 ℃, and the relative humidity is 90% +/-5%. Purity was measured by HPLC, and three replicates were performed, respectively, and the results averaged.
(3) Test results: the test results are shown in Table 9.
TABLE 9 stability test determination results
Experimental results show that the milrinone eutectic solvate prepared by the embodiment of the invention has high purity, small sample purity change under high temperature, high humidity and strong light conditions and good stability.
2. Solubility test
Mirinone-4-hydroxycinnamic acid-3H 2 The O-methanol eutectic, milrinone-4-hydroxybenzoic acid methanol solvate crystal, milrinone-vanillic acid-trifluoroethanol eutectic, milrinone-2, 6-dihydroxybenzoic acid hydrate, comparative examples 1-3 milrinone crystal, milrinone sodium salt and milrinone hydrochloride are respectively placed in a medium (0.01 mol/L HCl and water) with constant temperature at 37 ℃ and stirred so as to be oversaturated, a saturated solution is taken and filtered, the concentration of the saturated solution is calculated according to an external standard method by measuring the subsequent filtrate, and the result is shown in table 10.
Table 10 solubility test results
Test results show that the solubility of the milrinone eutectic solvate in 0.01mol/L HCl and water is obviously improved compared with other crystal forms of milrinone, and the application of the milrinone eutectic solvate in oral preparations is facilitated.

Claims (10)

1. Milrinone-4-hydroxycinnamic acid-3H 2 An O-methanol co-crystal characterized by having characteristic peaks at least at 14.6±0.2°, 18.9±0.2°, 19.9±0.2°, 25.3±0.2°, 31.6±0.2° in an X-ray diffraction pattern expressed in 2θ using Cu-kα radiation.
2. The crystal of claim 1, wherein the X-ray diffraction pattern expressed in 2Θ has characteristic peaks at least at 11.0±0.2°, 12.3±0.2°, 14.6±0.2°, 15.8±0.2°, 18.9±0.2°, 19.9±0.2°, 24.3±0.2°, 25.3±0.2°, 27.4±0.2°, 27.5±0.2°, 29.0±0.2°, 29.9±0.2°, 31.6±0.2°, 37.4±0.2°, using Cu-ka radiation.
3. A milrinone-4-hydroxybenzoic acid methanol solvate crystal characterized by having characteristic peaks at least at 9.9±0.2°, 13.7±0.2°, 14.4±0.2°, 17.5±0.2°, 19.7±0.2°, 23.1±0.2°, 24.2±0.2°, 24.6±0.2°, 24.9±0.2°, 25.1±0.2°, 26.1±0.2° using Cu-kα radiation.
4. A crystal according to claim 3, wherein the X-ray diffraction pattern expressed in 2Θ has characteristic peaks at least at 9.9±0.2 °, 10.4±0.2 °, 12.2±0.2 °, 13.1±0.2 °, 13.7±0.2 °, 14.4±0.2 °, 17.3±0.2 °, 17.5±0.2 °, 17.7±0.2 °, 19.0±0.2 °, 19.7±0.2 °, 21.2±0.2 °, 22.3±0.2 °, 22.8±0.2 °, 23.1±0.2 °, 24.2±0.2 °, 24.6±0.2 °, 24.9±0.2 °, 25.0±0.2 °, 25.1±0.2 °, 25.2±0.2±0.2°, 26.1±0.2°, 27.2±0.2° 0.2° 30.2°.
5. The milrinone-vanillic acid-trifluoroethanol co-crystal is characterized in that Cu-K alpha radiation is used, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at least at 8.9+/-0.2 degrees, 10.0+/-0.2 degrees, 12.0+/-0.2 degrees, 13.7+/-0.2 degrees, 14.3+/-0.2 degrees, 21.7+/-0.2 degrees and 24.0+/-0.2 degrees.
6. The crystal according to claim 5, wherein the X-ray diffraction pattern expressed in 2Θ has characteristic peaks at least at 5.0±0.2°, 8.9±0.2°, 10.0±0.2°, 12.0±0.2°, 12.8±0.2°, 13.7±0.2°, 14.3±0.2°, 20.2±0.2°, 20.9±0.2°, 21.7±0.2°, 24.0±0.2°, 24.9±0.2°, 26.9±0.2°, 27.8±0.2°, using Cu-ka radiation.
7. Milrinone-2, 6-dihydroxybenzoic acid hydrate crystal, characterized in that the X-ray diffraction pattern expressed in 2θ has characteristic peaks at least at 10.9±0.2°, 12.6±0.2°, 15.0±0.2°, 26.4±0.2°, 27.6±0.2° using Cu-kα radiation.
8. The crystal of claim 7, wherein the X-ray diffraction pattern expressed in 2Θ has characteristic peaks at least at 10.0±0.2°, 10.9±0.2°, 12.6±0.2°, 15.0±0.2°, 17.8±0.2°, 24.9±0.2°, 26.4±0.2°, 27.6±0.2°, 29.2±0.2°, 30.2±0.2°, 31.7±0.2°, 32.7±0.2°, 34.1±0.2°, using Cu-ka radiation.
9. A process for preparing a milrinone eutectic solvate crystal according to any one of claims 1 to 8, comprising the steps of: dissolving milrinone and ligand in a mixed solvent, heating and stirring, filtering, cooling, standing, volatilizing, crystallizing, filtering and drying to obtain medicine crystals; the ligand is 4-hydroxy cinnamic acid, 4-hydroxy benzoic acid, vanillic acid and 2, 6-dihydroxy benzoic acid.
10. The method of claim 9, wherein the mixed solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, acetone, trifluoroethanol, and water.
CN202210281666.3A 2022-03-21 2022-03-21 Milrinone eutectic solvate Pending CN116813543A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210281666.3A CN116813543A (en) 2022-03-21 2022-03-21 Milrinone eutectic solvate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210281666.3A CN116813543A (en) 2022-03-21 2022-03-21 Milrinone eutectic solvate

Publications (1)

Publication Number Publication Date
CN116813543A true CN116813543A (en) 2023-09-29

Family

ID=88115406

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210281666.3A Pending CN116813543A (en) 2022-03-21 2022-03-21 Milrinone eutectic solvate

Country Status (1)

Country Link
CN (1) CN116813543A (en)

Similar Documents

Publication Publication Date Title
NO335103B1 (en) Compound, pharmaceutical composition containing the compound, use of the compound and method of preparation thereof
CN112142679A (en) Gefitinib and vanillic acid eutectic methanol solvate and preparation method thereof
TWI819502B (en) Triethylenetetramine tetrahydrochloride and its preparation method and composition
JP2023509242A (en) Co-crystals of novel empagliflozin
CN112538123B (en) Shugansu sodium crystal form M
CN116813543A (en) Milrinone eutectic solvate
US9388113B2 (en) Salts of sitagliptin, process from the preparation and pharmaceutical composition therefore
WO2022005928A1 (en) Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin -1-yl]ethyl pyridine-3-carboxylate and methods of synthesis
CN111518040B (en) Methylpyrazine derivative-piperazine eutectic
CN109438372B (en) Methyl pyrazine derivative methanol compound
CN112390792A (en) Puerarin-proline eutectic crystal and preparation method thereof
CN116253680A (en) Milrinone and ketorolac eutectic crystal and preparation method thereof
KR102150825B1 (en) Novel sglt-2 inhibitors cocrystal
CN116813542A (en) Pharmaceutical polycrystals of milrinone
KR102207319B1 (en) New Empagliflozin cocrystal
CN116239520A (en) Milrinone-tartaric acid eutectic
CN116239522A (en) Milrinone-succinic acid co-crystal
CN115073368B (en) Milrinone-5-sulfosalicylic acid crystal form
CN116239525A (en) Milrinone-baicalein co-crystal
CN116813541A (en) Co-crystal for milriness pesticide and preparation method thereof
CN117069653A (en) Milrinone gallic acid eutectic
CN116239527A (en) Milrinon-citric acid monohydrate co-crystal
AU2018298154A1 (en) Salt and polymorph of benzopyrimidinone compound and pharmaceutical composition and use thereof
CN113929630B (en) Gefitinib drug co-crystal
CN117105855A (en) Milrinone-saccharin crystal form

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication