阅读说明：本技术 一种卡巴匹林钙新晶型及其制备方法 (Novel crystal form of carbasalate calcium and preparation method thereof ) 是由 李雪娇 李亚玲 曹春芳 吴燕子 聂丽娜 刘爱玲 李守军 于 2019-10-28 设计创作，主要内容包括：本发明公开了一种卡巴匹林钙新晶型及其制备方法。制备所得卡巴匹林钙晶型的XRD衍射图谱在2θ为6.997±0.2°、7.720±0.2°、7.959±0.2°、9.020±0.2°、12.118±0.2°、13.560±0.2°、14.201±0.2°、16.959±0.2°、18.300±0.2°、19.681±0.2°、20.721±0.2°、24.518±0.2°、27.698±0.2°、28.919±0.2°、32.279±0.2°处有特征峰。该晶型具有较好的稳定性,不易水解产生水杨酸,有效改善了卡巴匹林钙不耐贮存的问题。该发明制备工艺简单、安全、环保,降低了生产过程中的安全隐患。(The invention discloses a novel crystal form of carbasalate calcium and a preparation method thereof. An XRD diffraction pattern of the prepared carbasalate calcium crystal form has characteristic peaks at the 2 theta of 6.997 +/-0.2 degrees, 7.720 +/-0.2 degrees, 7.959 +/-0.2 degrees, 9.020 +/-0.2 degrees, 12.118 +/-0.2 degrees, 13.560 +/-0.2 degrees, 14.201 +/-0.2 degrees, 16.959 +/-0.2 degrees, 18.300 +/-0.2 degrees, 19.681 +/-0.2 degrees, 20.721 +/-0.2 degrees, 24.518 +/-0.2 degrees, 27.698 +/-0.2 degrees, 28.919 +/-0.2 degrees and 32.279 +/-0.2 degrees. The crystal form has good stability, is not easy to hydrolyze to generate salicylic acid, and effectively solves the problem of intolerance to storage of the carbasalate calcium. The preparation process is simple, safe and environment-friendly, and reduces potential safety hazards in the production process.)

1. A new crystal form of carbasalate calcium, which is characterized in that an X-ray powder diffraction pattern of the new crystal form has characteristic peaks at 6.997 +/-0.2 degrees, 7.720 +/-0.2 degrees, 7.959 +/-0.2 degrees, 9.020 +/-0.2 degrees, 12.118 +/-0.2 degrees, 13.560 +/-0.2 degrees, 14.201 +/-0.2 degrees, 16.959 +/-0.2 degrees, 18.300 +/-0.2 degrees, 19.681 +/-0.2 degrees, 20.721 +/-0.2 degrees, 24.518 +/-0.2 degrees, 27.698 +/-0.2 degrees, 28.919 +/-0.2 degrees and 32.279 +/-0.2 degrees of 2 degrees.

2. The novel crystalline form of carbapenem calcium of claim 1, wherein the novel crystalline form has an X-ray powder diffraction pattern of figure 2.

3. A process for the preparation of a new crystalline form of carbapenem calcium of claim 1 or 2, which comprises the steps of:

(1) adding aspirin and urea into purified water, stirring for dissolving, adding calcium bicarbonate, and reacting at a certain temperature to obtain a reaction solution;

(2) carrying out suction filtration on the reaction solution, and removing precipitates to obtain a filtrate;

(3) adding alcohol to the filtrate, and culturing the crystals to obtain white solid;

(4) filtering and vacuum drying to obtain the carbasalate calcium crystal.

4. The preparation method according to claim 3, wherein the mass ratio of aspirin to urea in step (1) is 1: 0.1-0.3; the mass ratio of the aspirin to the calcium bicarbonate is 1: 2-4; the mass volume ratio of the aspirin to the purified water is 1: 3-6.

5. The method according to claim 3, wherein the reaction temperature in the step (1) is 10 to 20 ℃ and the reaction time is 2 to 5 hours.

6. The production method according to claim 3, wherein the alcohol in the step (3) is isopropyl alcohol;

or, the alcohol in the step (3) is an isopropanol-methanol mixture;

or, the alcohol in the step (3) is an isopropanol-ethanol mixture.

7. The method according to claim 6, wherein the volume ratio of isopropanol to methanol in the isopropanol-methanol mixture is 1: 1; the volume ratio of isopropanol to ethanol in the isopropanol-ethanol mixture is 1: 1.

8. The preparation method according to claim 3, wherein the volume-to-mass ratio of the alcohol in step (3) to the aspirin in step (1) is 3-7.5: 1.

9. The method according to claim 3, wherein the temperature is controlled to 10 to 15 ℃ for 1 to 3 hours and then 1 to 5 ℃ for 2 to 5 hours when the crystals are cultured in the step (3).

10. The method according to claim 3, wherein the vacuum drying temperature in the step (4) is 40 to 45 ℃ and the drying time is 8 to 12 hours.

Technical Field

The invention belongs to the field of chemical veterinary medicines, and particularly relates to a novel crystal form of carbasalate calcium and a preparation method thereof.

Background

Carbasalate calcium (also called acetylsalicylic acid calcium urea), is a complex salt of calcium aspirin and urea, is the only oral antipyretic analgesic approved by the Ministry of agriculture at present for livestock and poultry, belongs to three new veterinary drugs in China, can be used for treating fever and inflammatory reaction of livestock, relieving kidney swelling of chicken and removing urate deposition, can be used for adjuvant therapy of febrile diseases such as avian influenza and Newcastle disease, and is widely applied in veterinary clinical use.

Disclosure of Invention

The invention aims to provide a novel crystal form of carbasalate calcium and a preparation method thereof, the crystal form of the carbasalate calcium has better stability, the preparation process is safe and simple, and the defects of the prior art are overcome.

The X-ray powder diffraction pattern of the new crystal form of the carbasalate calcium has characteristic peaks at 6.997 +/-0.2 degrees, 7.720 +/-0.2 degrees, 7.959 +/-0.2 degrees, 9.020 +/-0.2 degrees, 12.118 +/-0.2 degrees, 13.560 +/-0.2 degrees, 14.201 +/-0.2 degrees, 16.959 +/-0.2 degrees, 18.300 +/-0.2 degrees, 19.681 +/-0.2 degrees, 20.721 +/-0.2 degrees, 24.518 +/-0.2 degrees, 27.698 +/-0.2 degrees, 28.919 +/-0.2 degrees and 32.279 +/-0.2 degrees of 2 degrees.

The X-ray powder diffraction pattern of the new crystal form of the carbasalate calcium is shown in figure 2.

The invention also provides a preparation method of the novel crystal form of the carbasalate calcium, which comprises the following steps:

(1) adding aspirin and urea into purified water, stirring for dissolving, adding calcium bicarbonate, and reacting at a certain temperature to obtain a reaction solution;

(2) carrying out suction filtration on the reaction solution, and removing precipitates to obtain a filtrate;

(3) adding alcohol to the filtrate, and culturing the crystals to obtain white solid;

(4) filtering and vacuum drying to obtain the carbasalate calcium crystal.

The mass ratio of the aspirin to the urea in the step (1) is 1: 0.1-0.3; the mass ratio of aspirin to calcium bicarbonate is 1: 2-4; the mass-volume ratio of aspirin to purified water is 1:3-6(g: ml).

The reaction temperature in the step (1) is 10-20 ℃, and the reaction time is 2-5 hours.

The alcohol in the step (3) is isopropanol, or the alcohol is an isopropanol-methanol mixture, or the alcohol is an isopropanol-ethanol mixture; the volume ratio of isopropanol to methanol in the isopropanol-methanol mixture is 1: 1; the volume ratio of isopropanol to ethanol in the isopropanol-ethanol mixture is 1: 1.

The volume-mass ratio of the alcohol to the aspirin in the step (3) is 3-7.5:1(ml: g).

And (3) when the crystal is cultured, firstly controlling the temperature to be 10-15 ℃ for 1-3 hours, and then controlling the temperature to be 1-5 ℃ for 2-5 hours.

And (4) drying at 40-45 ℃ for 8-12 hours in vacuum.

Has the advantages that:

1. the novel crystal form of the carbasalate calcium prepared by the invention is not easy to hydrolyze to generate salicylic acid, has good stability, and effectively solves the problem of intolerance of storage of the carbasalate calcium.

2. The preparation process is simple, safe and environment-friendly, and reduces potential safety hazards in the production process.

Drawings

FIG. 1 is an infrared spectrum of a carbapenem calcium crystal of the present invention;

FIG. 2 is an X-ray powder diffraction pattern of a crystalline form of carbapenem calcium of the present invention;

FIG. 3 is an infrared spectrum of a carbapenem calcium crystal of comparative example 1;

FIG. 4X-ray powder diffraction pattern of the crystalline form of calcium carbapenem of comparative example 1.

Detailed Description

The technical content of the present invention is further described below with reference to specific embodiments for better understanding of the content of the present invention, but the content of the present invention is not limited thereto.