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CN-121990988-A - Novel crystal form of milrinone lactate and preparation method and application thereof

CN121990988ACN 121990988 ACN121990988 ACN 121990988ACN-121990988-A

Abstract

The application relates to the technical field of pharmaceutical chemistry crystallization, and particularly discloses a novel crystal form of milrinone lactate, and a preparation method and application thereof. The novel crystal form of milrinone lactate disclosed by the application comprises characteristic diffraction peaks at diffraction angles 2 theta of 10.48+/-0.2, 11.25+/-0.2, 16.39+/-0.2, 17.861 +/-0.2, 24.88 +/-0.2 and 26.07+/-0.2, wherein the X-ray powder diffraction pattern is generated by using CuK alpha 1 rays. The application also discloses a preparation method of the lactic acid milrinone, which comprises the steps of dissolving lactic acid and milrinone at high temperature, crystallizing at low temperature, and adding an antisolvent to precipitate solids to obtain a new crystal form. By utilizing the technical scheme provided by the application, the prepared novel crystal form of the milrinone lactate has good stability and can be kept stable at high temperature, high humidity and strong light.

Inventors

  • CHEN XIAODONG
  • WANG JIAYONG
  • SUN XUEWEI

Assignees

  • 北京汇康博源医药科技有限公司

Dates

Publication Date
20260508
Application Date
20260320

Claims (10)

  1. 1. A novel crystal form of milrinone lactate, characterized in that the X-ray powder diffraction pattern of the novel crystal form of milrinone lactate comprises characteristic diffraction peaks at diffraction angles 2Θ at 10.48 ± 0.2, 11.25 ± 0.2, 16.39 ± 0.2, 17.861 ± 0.2, 24.88 ± 0.2, 26.07 ± 0.2, wherein the X-ray powder diffraction is generated using cukα1 rays.
  2. 2. The novel crystalline form of milrinone lactate according to claim 1, characterized in that the X-ray powder diffraction pattern of the novel crystalline form of milrinone lactate comprises a characteristic diffraction peak at angle 2Θ of diffraction at 10.48±0.2、11.25±0.2、12.36±0.2、12.99±0.2、13.83±0.2、14.76±0.2、15.83±0.2、16.39±0.2、16.67±0.2、17.861±0.2、18.99±0.2、20.85±0.2、21.36±0.2、22.37±0.2、23.45±0.2、24.88±0.2、26.07±0.2、28.23±0.2.
  3. 3. A lactic acid milrinone with a new crystal form, characterized in that the lactic acid milrinone has the new crystal form according to any one of claims 1-2.
  4. 4. A process for the preparation of a novel crystalline form of milrinone lactate according to any one of claims 1-2, characterized in that it comprises the following steps, in particular in sequence: (1) Dissolving milrinone in lactic acid, and heating to dissolve; (2) Cooling the solution to-10-25 ℃, adding a ketone solvent into the solution, and separating out a white solid; (3) Adding an ether antisolvent into the solution to completely crystallize; (4) Filtering the solution, collecting the crystallized solid, and drying at 10-50 ℃.
  5. 5. The preparation method of the novel crystal form of milrinone lactate, which is characterized in that in the step (1), the weight ratio of milrinone to lactic acid is 1:2-10, and the heating temperature is 80-150 ℃.
  6. 6. The preparation method of the novel crystal form of milrinone lactate according to claim 4, wherein in the step (2), the temperature of the solution is reduced to-10-0 ℃, the ketone solvent is one or more selected from acetone, butanone and tetramethyl-dipentamethylenedione, and the use amount of the ketone solvent is 3-5 times of the weight of milrinone.
  7. 7. The preparation method of the novel crystal form of milrinone lactate according to claim 4, wherein in the step (3), the ether antisolvent is one or more selected from diethyl ether, isopropyl ether, methyl tertiary butyl ether and petroleum ether, and the use amount of the ether antisolvent is 7-9 times of the weight of milrinone.
  8. 8. The method for preparing a novel crystal form of milrinone lactate according to claim 4, wherein in the step (4), the drying temperature is 20-50 ℃.
  9. 9. A pharmaceutical composition comprising the novel crystalline form of any one of claims 1-2 or the milrinone lactate having the novel crystalline form of claim 3.
  10. 10. Use of the novel crystalline form of any one of claims 1-2 or the milrinone lactate having the novel crystalline form of claim 3 or the pharmaceutical composition of claim 9 in the preparation of a cardiotonic agent.

Description

Novel crystal form of milrinone lactate and preparation method and application thereof Technical Field The application relates to the technical field of pharmaceutical chemistry crystallization, in particular to a novel crystal form of milrinone lactate, and a preparation method and application thereof. Background Milrinone lactate is a novel cardiac agent which is not cardiac glycoside or catecholamine and is a congestive heart failure therapeutic agent developed by Sterling corporation in the united states, which is approved for the first time by 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. The chemical name of the milrinone lactate is 2-methyl-6-oxo-1, 6-dihydro-3, 4 bipyridine-5-carbonitrile lactate, is a phosphodiesterase inhibitor, is a similar medicine of the milrinone, has the same action mechanism as the milrinone, is effective by oral administration and intravenous injection, has positive myogenic action and vasodilation action, and has the action which is 10-30 times stronger than the milrinone. Has effects in treating congestive heart failure and dilating peripheral blood vessel. The milrinone lactate is mainly suitable for short-term intravenous administration of congestive heart failure, researches show that the milrinone can also be used for treating cardiac surgery extracorporeal circulation hypocardiac discharge syndrome, relieving bypass vasospasm, improving cardiac function of heart in situ transplantation, resisting inflammatory reaction, improving visceral blood flow perfusion and the like, the cardiovascular effect of the milrinone is related to dosage, the milrinone mainly shows gray positive inotropic effect when the dosage is small, when the dosage is large, the maximum positive inotropic effect of steady state is gradually reached, the vasodilating effect of the milrinone can be gradually enhanced along with the increase of the dosage, the milrinone is safer for patients with conduction block, and the milrinone is clinically suitable for acute and chronic intractable congestive heart failure caused by various reasons of invalidism, vasodilators and poor effects. Researches show that the milrinone lactate injection has poor stability and is easy to degrade and increase related substances. Therefore, the novel crystal form of the milrinone lactate with high stability is provided, the novel crystal form of the milrinone lactate is more beneficial to storage, and a novel solution can be provided for developing safe and stable preparations. Disclosure of Invention In order to solve the technical problems, the application provides a novel crystal form of milrinone lactate, and a preparation method and application thereof. In a first aspect, the application provides a novel crystal form of milrinone lactate, the X-ray powder diffraction pattern of the novel crystal form of milrinone lactate comprises characteristic diffraction peaks at 10.48+/-0.2, 11.25+/-0.2, 16.39+/-0.2, 17.861 +/-0.2, 24.88 +/-0.2 and 26.07+/-0.2 at a diffraction angle 2 theta, wherein the X-ray powder diffraction is generated by CuK alpha 1 rays. In the process of researching the crystal form of the milrinone lactate, the application prepares a brand new crystal form which has stable chemical property and is easy to store. The chemical name of the milrinone lactate is 6-methyl l-2-oxo-5- (pyridine-4-yl) -1, 2-dihydropyridine-3 cyano lactate, and the chemical structural formula is shown as the formula (1); formula (1). Specifically, the intensity of the X-ray powder diffraction pattern of the novel crystal form of the milrinone lactate at the diffraction angle 2 theta is more than 50%. Preferably, the X-ray powder diffraction pattern of the novel crystalline form of milrinone lactate comprises a characteristic diffraction peak at 10.48±0.2、11.25±0.2、12.36±0.2、12.99±0.2、13.83±0.2、14.76±0.2、15.83±0.2、16.39±0.2、16.67±0.2、17.861±0.2、18.99±0.2、20.85±0.2、21.36±0.2、22.37±0.2、23.45±0.2、24.88±0.2、26.07±0.2、28.23±0.2 at diffraction angle 2θ. Specifically, the intensity of the X-ray powder diffraction pattern of the novel crystal form of the milrinone lactate at the diffraction angle 2 theta is more than 10%. In a second aspect, the application provides milrinone lactate having a novel crystalline form as described above. In a third aspect, the application provides a preparation method of the novel crystal form of milrinone lactate, which specifically comprises the following steps in sequence: (1) Dissolving milrinone in lactic acid, and heating to dissolve; (2) Cooling the solution to-10-25 ℃, adding a ketone solvent into the solution, and separating out a white solid; (3) Adding an ether antisolvent into the solution to completely crystallize; (4) Filtering the solution, collecting the crystallized solid, and drying at 10-50 ℃. Preferably, in the step (1), the weight ratio of milrinone to lactic