CN115057814A - Milrinone malate crystal - Google Patents
Milrinone malate crystal Download PDFInfo
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- CN115057814A CN115057814A CN202111484233.XA CN202111484233A CN115057814A CN 115057814 A CN115057814 A CN 115057814A CN 202111484233 A CN202111484233 A CN 202111484233A CN 115057814 A CN115057814 A CN 115057814A
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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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- 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
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- 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
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
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- 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 provides a milrinone-malate crystal which uses Cu-Kalpha radiation, and an X-ray diffraction spectrogram expressed by 2 theta at least has characteristic peaks at 10.4 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.3 +/-0.2 degrees, 20.9 +/-0.2 degrees and 25.5 +/-0.2 degrees. The milrinone-malate crystal has the characteristics of high solubility and good stability; the crystal form provides an ideal raw material for a milrinone preparation product, and the use of a large amount of auxiliary materials and auxiliary agents in the prior art can be avoided by using the crystal form to prepare the preparation product, so that the production cost is reduced, and the potential safety hazard of clinical medication is reduced.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and relates to a new milrinone crystal form, in particular to a milrinone and malic acid crystal, and a preparation method and application thereof.
Background
Milrinone (milrinone) with the chemical name of 1, 6-dihydro-2-methyl-6-oxo- [3, 4-bipyridine]-5-carbonitrile of the formula C 12 H 9 N 3 O, with a molecular weight of 211.22, is white or off-white crystalline powder and has a structural formula:
milrinone was first developed as a successful anti-heart failure drug by Sterling corporation in the United states, was first approved by the FDA in the United states in 1987, was officially marketed in the United states in 1992, and was subsequently marketed in successive countries such as the United kingdom, France, Germany, the Netherlands, Belgium, and the like.
Milrinone is a phosphodiesterase inhibitor and is a derivative of amrinone, and the action mechanism of milrinone is the same as that of amrinone. It is effective for oral administration and intravenous injection, and has positive inotropic effect and vasodilatation effect. The traditional Chinese medicine composition is suitable for short-term treatment of severe congestive heart failure patients with ineffective conventional maintenance treatment, the curative effect is 10-30 times stronger than that of amrinone, the tolerance is better, and the adverse reaction is less. The positive inotropic effect of the product is mainly achieved by inhibiting phosphodiesterase, so that adenosine Cyclophosphate (CAMP) concentration in myocardial cells is increased, intracellular calcium is increased, myocardial contractility is strengthened, and cardiac output is increased. Generally, the medicine is a heart-strengthening medicine with high efficiency, low toxicity, no digitalis and no sympathomimetic effect, has obvious effects on serious heart failure and pulmonary edema caused by ischemic heart disease, dilated cardiomyopathy and the like, is superior to dopamine, has few adverse reactions and does not increase heart rate. Therefore, the medicine plays an increasingly important role in treating Congestive Heart Failure (CHF), peripheral vascular dilatation and the like.
However, milrinone is hardly soluble in water, so that in the preparation of a milrinone preparation product, a special adjuvant needs to be added to improve the solubility. The existing preparation method generally adopts the addition of cosolvent and pH regulator to improve the water solubility, and the dosage is larger. Therefore, the safety and solubilizing effect of the cosolvent are particularly important. For example, patent CN9151919A discloses a method for preparing a lyophilized preparation by salifying with inorganic acids such as hydrochloric acid, phosphoric acid, and sulfuric acid; patent CN106361710A discloses a method for preparing a preparation by precipitating crystals in a solvent of ethanol + acetone + water and then using lactic acid as a pH adjuster. But still can not completely solve the problems of poor solubility and poor stability of milrinone, such as adopting inorganic acid as cosolvent and Cl brought by hydrochloric acid - May cause hyperchloremia, and phosphoric acid,Sulfuric acid and the like have poor dissolution assisting effect; among organic acids, lactic acid has a good solubilizing effect, but lactic acid is a racemate and consists of L-lactic acid and D-lactic acid, and because only L-lactic acid metabolizing enzymes exist in a human body and the metabolizing capacity is limited, metabolic disturbance and even acidosis can be caused if excessive D-lactic acid is taken.
Moreover, it is known from the disclosure of patent CN105663034A that milrinone is hardly soluble in water, and in the process of mass production, the problems of long dissolution time, incomplete dissolution and excessive insoluble particles are caused. In the existing preparation technology of the milrinone injection, a pyrogen removal method adopts activated carbon adsorption, the adsorption capacity of the activated carbon to the milrinone is large, the milrinone can be adsorbed by about 14 percent when the usage amount of the activated carbon is 0.05 percent, and the content of the milrinone injection can be ensured to meet the specification only by adding excessive materials. And excessive feeding causes a great increase in production cost, and when the activated carbon adsorbs pyrogen, excessive unidentified substances are introduced to influence the product quality.
Based on the problems, the problems of poor solubility and poor stability of milrinone are solved only by a preparation technology, and the potential safety hazard of clinical medication caused by excessive use of auxiliary materials and auxiliaries can be avoided. Therefore, it is an urgent problem to be solved by those skilled in the art to provide a new crystalline form of milrinone with good solubility, stability and safety.
Disclosure of Invention
Aiming at the problems of the existing milrinone, the invention aims to provide a novel milrinone crystal form with better solubility and stability, namely a milrinone-malate crystal. In addition, the invention provides a method for preparing the milrinone-malate crystals, which is simple, convenient and suitable for industrial production.
The specific technical content of the invention is as follows:
in one aspect, the invention provides a milrinone-malate crystal, wherein the mol ratio of milrinone, malic acid and water molecules in a crystal unit structure is 1: 1:1.
preferably, the milrinone-malate crystal has an X-ray diffraction pattern expressed in 2 theta using Cu-Kalpha radiation and has characteristic peaks at least at 10.4 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.3 +/-0.2 degrees, 20.9 +/-0.2 degrees and 25.5 +/-0.2 degrees.
Preferably, the milrinone-malate crystal has an X-ray diffraction pattern expressed in 2 theta using Cu-Kalpha radiation having characteristic peaks at least at 10.4 + -0.2 °, 11.1 + -0.2 °, 13.3 + -0.2 °, 13.6 + -0.2 °, 15.3 + -0.2 °, 20.9 + -0.2 °, 23.6 + -0.2 °, 25.1 + -0.2 °, 25.5 + -0.2 °, 27.3 + -0.2 °, 31.5 + -0.2 °, 37.2 + -0.2 °, and 42.1 + -0.2 °.
Preferably, the milrinone-malate crystal is irradiated by Cu-Ka, and the characteristic peak of the milrinone-malate crystal accords with an X-ray powder diffraction pattern shown in figure 1.
Preferably, the milrinone-malate crystal has a molecular formula of C 16 H 17 N 3 O 7 The crystallographic parameters are: triclinic, space group P-1, cell parameters:
a is 77.4810(10) °, β is 82.8690(10) °, γ is 86.3840(10) °, unit cell volume
In another aspect, the present invention provides a method of preparing milrinone-malate crystals, comprising the steps of:
dissolving milrinone and malic acid in a mixed solvent, heating and stirring, filtering, cooling, standing for crystallization, filtering and drying to obtain milrinone-malate crystals.
Preferably, the mixed solvent is a combination of an organic solvent and water, and the organic solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone and trifluoroethanol; one or two of trifluoroethanol, methanol and acetone are particularly preferable.
Further preferably, when the volume ratio of the organic solvent to the water in the mixed solvent is 1:1.
preferably, the mass-volume ratio of the milrinone to the mixed solvent is 21.1: 1-4, mg/ml; more preferably 21.1: 1.5-3 mg/ml.
Preferably, the mol ratio of milrinone to malic acid is 1: 0.8 to 2.0; more preferably 1: 1.1 to 1.5.
Preferably, the heating temperature is 50-70 ℃.
Preferably, the temperature for cooling and crystallizing is 0-30 ℃; more preferably 10 to 15 ℃.
Preferably, the crystallization time is 8-72 hours.
Preferably, the drying temperature is 45-65 ℃, and the drying time is 8-12 hours.
Finally, the invention provides a pharmaceutical composition comprising the milrinone-malate crystals of the invention and other pharmaceutically acceptable components.
Preferably, the other pharmaceutically acceptable components can be combined pharmaceutical active ingredients and/or pharmaceutically acceptable auxiliary ingredients.
Confirmation of the Crystal Structure
X-ray crystal data in the milrinone-malate crystal test are collected on an instrument of a Japan XtaLAB Synergy model, the test temperature is 293(2) K, Cu-Ka radiation is used, data are collected in an omega scanning mode, and Lp correction is carried out. Analyzing the structure by a direct method, finding out all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and refining the structure by a least square method.
The crystallographic data (as shown in Table 1) for testing and analyzing the crystalline form of the milrinone-malate crystal prepared by the invention is that the crystal is a triclinic system, the space group is P-1, and the unit cell parameters are as follows:
a is 77.4810(10) °, β is 82.8690(10) °, γ is 86.3840(10) °, unit cell volume
TABLE 1 Milrinone-malate Crystal principal crystallography data
The ORTEP plot (shown in figure 2) of the milrinone-malate salt crystal of the present invention shows that the crystalline form contains one molecule of milrinone, one molecule of malic acid and one molecule of water. The hydrogen bond diagram of the milrinone-malate crystal of the present invention (shown in fig. 3). According to the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are detailed in FIG. 1 and Table 2.
TABLE 2 PXRD peaks for milrinone-malate crystals
Compared with the prior art, the invention has the following technical effects:
firstly, the invention provides a milrinone-malate crystal which has the characteristics of high solubility and good stability; the crystal form provides an ideal raw material for a milrinone preparation product, and the use of a large amount of auxiliary materials and auxiliary agents in the prior art can be avoided by using the crystal form to prepare the preparation product, so that the production cost is reduced, and the potential safety hazard of clinical medication is reduced.
Secondly, the invention provides a preparation method of the milrinone-malate crystal, which has the advantages of simple operation, easy control of the crystallization process and good reproducibility.
Drawings
FIG. 1 is a PXRD spectrum of milrinone-malate crystals.
FIG. 2 ORTEP diagram of Milrinone-malate crystals.
FIG. 3 is a hydrogen bond diagram of the milrinone-malate crystals.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
The materials used in the examples were prepared according to the methods known in the art or purchased from commercial products, the milrinone crystals being prepared according to patent CN106361710A and the milrinone hydrochloride and milrinone mesylate being prepared according to patent CN 1951919A.
Example 1
Dissolving 211mg of milrinone and 148mg of malic acid in a mixed solvent of 10mL of methanol and 10mL of purified water, heating in a water bath at 50 ℃, stirring until the materials are completely dissolved, filtering, standing at 10-15 ℃ for crystallization for 48 hours, filtering, and drying at 50 ℃ for 12 hours to obtain a milrinone-malate crystal, wherein the yield is as follows: 94%, purity: 99.92 percent.
Example 2
Dissolving 110mg of milrinone and 76mg of malic acid in a mixed solvent of 10mL of acetone and 10mL of purified water, heating in a water bath at 50 ℃, stirring until the materials are completely dissolved, filtering, standing at 10-15 ℃ for crystallization for 48 hours, filtering, and drying at 50 ℃ for 12 hours to obtain a milrinone-malate crystal, wherein the yield is as follows: 93%, purity: 99.90 percent.
Example 3
Dissolving 211mg of milrinone and 148mg of malic acid in a mixed solvent of 15mL of trifluoroethanol and 15mL of purified water, heating in a water bath at 50 ℃, stirring until the materials are completely dissolved, filtering, standing at 10-15 ℃ for crystallization for 48 hours, filtering, and drying at 50 ℃ for 12 hours to obtain a milrinone-malate crystal, wherein the yield is as follows: 91%, purity: 99.89 percent.
Example 4
Dissolving 211mg of milrinone and 148mg of malic acid in a mixed solvent of 10mL of ethanol and 10mL of purified water, heating in a water bath at 60 ℃, stirring until the materials are completely dissolved, filtering, standing at 5-10 ℃ for crystallization for 48h, filtering, and drying at 45 ℃ for 12h to obtain a milrinone-malate crystal, wherein the yield is as follows: 86%, purity: 99.91 percent.
Example 5
Dissolving 211mg of milrinone and 148mg of malic acid in a mixed solvent of 10mL of trifluoroethanol and 10mL of purified water, heating in a water bath at 60 ℃, stirring until the milrinone and the malic acid are completely dissolved, filtering, standing at 20-25 ℃ for crystallization for 72h, filtering, and drying at 65 ℃ for 8h to obtain a milrinone-malate crystal, wherein the yield is as follows: 82%, purity: 99.92 percent.
Example 6
Dissolving 211mg of milrinone and 148mg of malic acid in a mixed solvent of 25mL of acetonitrile and 25mL of purified water, heating in a water bath at 45 ℃, stirring until the materials are completely dissolved, filtering, standing at 25-30 ℃ for crystallization for 72h, filtering, and drying at 50 ℃ for 12h to obtain a milrinone-malate crystal, wherein the yield is as follows: 74%, purity: 99.87 percent.
Stability test
The specific stability test method is carried out according to the guidance method related to stability investigation in the fourth part of the Chinese pharmacopoeia, the purity detection is carried out by an HPLC method, and the specific detection result is shown in Table 3.
TABLE 3 stability test results for milrinone-malate crystals
Solubility test
The method comprises the following steps: respectively measuring 10ml of medium (water and 0.01mol/LHCl solution) into penicillin bottles, adding excessive samples to be detected, sealing the penicillin bottles, stirring in a constant-temperature water bath at 25 ℃ for 1 hour, filtering by a filter membrane, and taking filtrate; and (4) detecting by HPLC, and calculating the concentration of the saturated solution according to an external standard method.
TABLE 4 solubility of Milrinone-malate crystals (mg/mL)
Claims (10)
1. A milrinone-malate crystal is characterized in that the mol ratio of milrinone to malic acid to water molecules in a crystal unit structure is 1: 1:1.
2. the crystal of claim 1, having an X-ray diffraction pattern expressed in terms of 2 Θ using Cu-ka radiation with characteristic peaks at least 10.4 ± 0.2 °, 13.6 ± 0.2 °, 15.3 ± 0.2 °, 20.9 ± 0.2 °, 25.5 ± 0.2 °.
3. The crystal of claim 1, wherein an X-ray diffraction pattern, expressed in terms of 2 Θ, using Cu-ka radiation has characteristic peaks at least at 10.4 ± 0.2 °, 11.1 ± 0.2 °, 13.3 ± 0.2 °, 13.6 ± 0.2 °, 15.3 ± 0.2 °, 20.9 ± 0.2 °, 23.6 ± 0.2 °, 25.1 ± 0.2 °, 25.5 ± 0.2 °, 27.3 ± 0.2 °, 31.5 ± 0.2 °, 37.2 ± 0.2 °, 42.1 ± 0.2 °.
4. The crystal of claim 1, wherein the Cu-ka radiation is used with characteristic peaks according to the X-ray powder diffraction pattern shown in figure 1.
5. The crystal of claim 1 having the formula C 16 H 17 N 3 O 7 The crystallographic parameters are: triclinic, space group P-1, cell parameters:
a is 77.4810(10) °, β is 82.8690(10) °, γ is 86.3840(10) °, unit cell volume
6. A method for producing a crystal according to any one of claims 1 to 5, comprising the steps of:
dissolving milrinone and malic acid in a mixed solvent, heating and stirring, filtering, cooling, standing for crystallization, filtering and drying to obtain milrinone-malate crystals.
7. The preparation method according to claim 6, wherein the mixed solvent is a combination of an organic solvent and water, and the organic solvent is one or more selected from methanol, ethanol, acetonitrile, acetone and trifluoroethanol.
8. The preparation method according to claim 6, wherein the temperature reduction and crystallization temperature is 0-30 ℃.
9. A pharmaceutical composition comprising the milrinone-malate crystal according to any one of claims 1-5 and other pharmaceutically acceptable components.
10. The pharmaceutical composition of claim 9, wherein the other pharmaceutically acceptable component is a pharmaceutically active ingredient and/or a pharmaceutically acceptable excipient ingredient in combination.
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| CN106361710A (en) * | 2016-08-29 | 2017-02-01 | 海南合瑞制药股份有限公司 | Milrinone lactate composition |
| CN112156067A (en) * | 2020-10-10 | 2021-01-01 | 上海旭东海普药业有限公司 | Pharmaceutical composition containing milrinone and preparation method thereof |
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2021
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