阅读说明：本技术 一种双甲脒晶型及其制备方法 (Crystal form of amitraz and preparation method thereof ) 是由 李亚玲 吴燕子 刘爱玲 李守军 张瑞 于 2019-09-20 设计创作，主要内容包括：本发明涉及一种双甲脒晶型及其制备方法,所述晶型物可以通过将双甲脒溶解在良性有机溶剂中,再加入不良溶剂析出结晶,降温后,过滤,干燥而得。本发明所制备的双甲脒晶型具有以下优良特性：理化性质稳定、耐潮湿,制备方法简单易操作,适合工业化生产。(The invention relates to a amitraz crystal form and a preparation method thereof, wherein the amitraz crystal form can be obtained by dissolving amitraz in a benign organic solvent, adding a poor solvent to separate out crystals, cooling, filtering and drying. The amitraz crystal form prepared by the invention has the following excellent characteristics: stable physicochemical property, moisture resistance, simple preparation method and easy operation, and is suitable for industrial production.)

1. A amitraz crystal form is characterized in that in an X-ray powder diffraction pattern obtained by using CuKa rays for measurement, the crystal form comprises characteristic peaks of 4.52 +/-0.2 degrees, 6.83 +/-0.2 degrees, 7.09 +/-0.2 degrees, 8.48 +/-0.2 degrees, 9.20 +/-0.2 degrees, 11.96 +/-0.2 degrees, 13.90 +/-0.2 degrees, 15.05 +/-0.2 degrees, 15.45 +/-0.2 degrees, 16.21 +/-0.2 degrees, 17.50 +/-0.2 degrees, 17.71 +/-0.2 degrees, 18.64 +/-0.2 degrees, 19.37 +/-0.2 degrees, 20.49 +/-0.2 degrees, 21.11 +/-0.2 degrees, 23.02 +/-0.2 degrees, 23.38 +/-0.2 degrees, 23.90 +/-0.2 degrees, 24.14 +/-0.2 degrees, 24.29 +/-0.2 degrees, 26.00 +/-0.2 degrees, 27.46 +/-0.2 degrees, 23.27.2 degrees, 23.3 +/-0.2 degrees, 3.3 +/-0.2 degrees, 3 degrees, 3.3 degrees, 3.2 degrees, 3 +/-0.2 degrees, 3 degrees, 3.2.

2. The crystalline form of amitraz of claim 1, which has an X-ray powder diffraction pattern as shown in figure 1.

3. A process for the preparation of the crystalline form of amitraz according to claim 1, which comprises the steps of:

(1) dissolving amitraz in an organic good solvent, and filtering to obtain a filtrate;

(2) and (2) adding a poor solvent into the filtrate obtained in the step (1), concentrating under reduced pressure, remaining a certain volume of solvent, cooling, crystallizing, filtering and drying to obtain the amitraz crystal form.

4. The method for preparing the crystal form of amitraz according to claim 3, wherein the good organic solvent in the step (1) is one or more selected from halogenated hydrocarbons, alcohols, esters, ketones and tetrahydrofuran.

5. The method for preparing the crystal form of amitraz according to claim 4, wherein the good organic solvent in the step (1) is one or more selected from tetrahydrofuran, dichloromethane, chloroform, ethyl acetate and acetone.

6. The method for preparing the crystalline form of amitraz according to claim 3, wherein the poor solvent in step (2) is one or more of acetonitrile, n-hexane, n-heptane, petroleum ether and purified water.

7. The method for preparing the amitraz crystal form according to claim 3, wherein the weight volume ratio of the amitraz to the good solvent in the step (1) is 1: 0.5-2; the temperature of the thermal dissolution is 20-60 ℃.

8. The method for preparing the crystalline amitraz according to claim 3, wherein the weight-to-volume ratio of the amitraz to the poor solvent in the step (2) is 1: 1-5; the volume of the remaining solvent was 0.5 times the mass of amitraz.

9. The method for preparing the crystalline amitraz according to claim 8, wherein the weight-to-volume ratio of the amitraz to the poor solvent in the step (2) is 1: 1-2.

10. The method for preparing the crystal form of amitraz according to claim 3, wherein the temperature reduction temperature in the step (2) is-5-15 ℃, and the drying temperature is 30-80 ℃.

Technical Field

The invention belongs to the technical field of crystallization of veterinary medicines and chemical engineering, and particularly relates to a amitraz crystal form and a preparation method thereof.

Background

Amitraz, commonly known by the generic name Amitraz, and the chemical name N, N-bis (2, 4-dimethylphenyliminomethyl) methylamine, was independently developed by the british company, and was produced since 1974. The amitraz is a broad-spectrum acaricide, belongs to an acaricide for both agriculture and animal husbandry, is a high-efficiency low-toxicity organic nitrogen acaricide insecticide, and has obvious contact-killing and fumigating effects. The pesticide is mainly used for mite damage of crops such as fruit trees, vegetables, camellia, cotton, soybeans and the like in the aspect of agriculture, and has good poisoning effect on other pests. In the field of animal husbandry, it can be used for treating acarid, scabies, bee mite, chigger and environmental pest mite of animals such as cattle, sheep, dog, pig, etc. The amitraz is safe to human and livestock, has almost no residue in agricultural products, can be degraded in animal bodies and then discharged out of the bodies of the animals, has no accumulation, has wide application in the market and has huge market potential.

Amitraz is readily soluble in organic solvents such as dichloromethane, acetone, chloroform, ethyl acetate, and the like, and is practically insoluble in water. Is stable to temperature and light under anhydrous conditions, but is unstable under acidic and aqueous conditions, and is easily decomposed and deteriorated in humid regions when stored for a long period of time.

At present, the commercial amitraz mainly has drop, solution and collar dosage forms, and has low bioavailability due to the limitation of administration modes. In the process of acaricide development and application, delaying the drug resistance or cross resistance of harmful mites is a key factor for prolonging the service life of products, and the reasonable use of acaricides is particularly important for controlling the use times and the dosage. Therefore, the method for crystallizing the amitraz with simple and easy operation and the amitraz with stable crystal form are developed, so that the problem of poor long-term storage stability can be solved, more choices are provided for developing new preparation formulations, and the requirements of the veterinary drug market are further met.

Disclosure of Invention

The invention aims to provide a amitraz crystal form and a preparation method thereof, and the obtained crystal form has strong stability and good fluidity; the preparation process has short heating time and simple operation, is suitable for industrial production, overcomes the defects of the prior art, and provides more choices for the development of new formulations of amitraz.

In a first aspect of the invention, there is provided a crystalline form of amitraz.

The X-ray powder diffraction pattern (figure 1) of the crystal form has special characteristic absorption peaks at 2 theta of 4.52, 6.83, 7.09, 8.48, 9.20, 11.96, 13.90, 15.05, 15.45, 16.21, 17.50, 17.71, 18.64, 19.37, 20.49, 21.11, 23.02, 23.38, 23.90, 24.14, 24.29, 26.00, 27.46, 27.77, 28.22, 30.12 and 42.10 (+ -0.2 degrees).

Preferably, the crystal form of amitraz provided by the invention has an X-ray powder diffraction pattern as shown in figure 1.

On the other hand, the invention also provides a preparation method of the amitraz crystal form, which comprises the following steps:

(1) putting amitraz into a good solvent, thermally dissolving, and filtering to obtain a filtrate;

(2) and (2) adding a poor solvent into the filtrate obtained in the step (1), concentrating under reduced pressure, remaining a certain volume of solvent, cooling, crystallizing, filtering and drying to obtain the amitraz crystal.

The crystallization equipment is selected from a conventional crystallization kettle with stirring effect in the field.

The following steps are explained in one step:

the good solvent in the step (1) is selected from one or more of halogenated hydrocarbon, alcohol, ester, ketone or tetrahydrofuran and other organic solvents.

Preferably, the good solvent in step (1) is one or more selected from tetrahydrofuran, dichloromethane, chloroform, ethyl acetate and acetone.

The mass volume ratio of the amitraz in the step (1) to the good solvent is 1:0.5-2 (g/ml).

The thermal dissolution temperature in the step (1) is 20-60 ℃.

The ratio of the volume of the poor solvent added in the step (2) to the mass of the amitraz solid is 1-5:1(ml/g), and the optimal ratio is 1-2: 1.

The poor solvent for preparing the crystal form in the step (2) is selected from one or more of acetonitrile, n-hexane, n-heptane, petroleum ether and purified water.

The volume of the residual solvent in the step (2) is 0.5 times (ml/g) of the mass of the amitraz solid.

The temperature reduction range of the step (2) is-5-15 ℃, and the drying temperature is 30-80 ℃.

Has the advantages that:

1. the refining process is simple, easy to operate and suitable for industrial production.

2. The amitraz crystal form obtained by the crystallization process has good stability and does not have the risk of crystal form transformation. And the coating is easy to store and can not be decomposed under a high-humidity environment.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of a crystalline form of amitraz prepared in example 1 of the invention;

FIG. 2 is an X-ray powder diffraction pattern of a crystalline form of amitraz prepared according to comparative example 1 of the present invention;

FIG. 3 is an X-ray powder diffraction pattern of amitraz prepared according to example 1 of the present invention and comparative example 1;

FIG. 4 is an FTIR spectrum of a crystalline form of amitraz prepared in example 1 of the present invention;

FIG. 5 is an FTIR spectrum of a crystalline form of amitraz prepared according to comparative example 1 of the present invention.

Detailed Description

For further illustration of the invention, preferred embodiments of the invention are described below in conjunction with the examples, but it should be understood that these descriptions are only intended to further illustrate the features and advantages of the invention, and not to limit the claims of the invention.

The general test method comprises the following steps:

x-ray powder diffraction (XRD) instrument: japanese Rigaku D/Max-2500 type: radiation source: copper target scanning at room temperature: scanning range: 2.0-50.0 DEG, scanning rate: 8 °/min, step size: 0.02 degree;