CN116199729B - Avermectin crystal form B and preparation method thereof - Google Patents

Abstract

The invention discloses an acetaminophen polymorphism, and in particular relates to an acetaminophen crystal form A, an acetaminophen crystal form B, an acetaminophen amorphous and a preparation method thereof. The crystal form A and the amorphous can be obtained by dissolving the acetamiprid in benign organic solvent, adding poor solvent to precipitate crystals, cooling, filtering and drying. Form B may be prepared by crystallization from amorphous suspension in a mixture. The acetamiprid polymorphs of the present invention have the following advantageous properties: stable physical and chemical properties, good fluidity, simple and easy operation preparation method, and suitability for industrial production.

Description

Avermectin crystal form B and preparation method thereof

This invention patent application is a divisional application of the invention patent application with Chinese patent application number CN201911049186.9 and application date October 31, 2019.

Technical Field

The invention belongs to the field of veterinary drugs and chemical engineering crystal technology, and specifically relates to avermectin crystal form A, crystal form B, amorphous form and a preparation method thereof.

Background technique

Avermectin is a macrolide antibiotic developed by Merck in the United States in 1996. It has high biological activity and low toxicity (to mammals and aquatic organisms). It is a highly effective, broad-spectrum, low-residue veterinary antiparasitic drug that has a strong killing effect on most nematodes and arthropods. Due to its extremely high activity against various parasites inside and outside livestock, and its extremely low distribution coefficient in dairy products, it has become the first insecticide that can be used in any growth period of various livestock, and is a preferred agent for preventing and controlling various parasites inside and outside livestock.

Avermectin is easily soluble in organic solvents, such as methanol, ethanol, acetone, chloroform, ethyl acetate, etc., but almost insoluble in water. Due to the unstable amide bond in the chemical structure of Avermectin itself, the product is very easy to oxidize and is easily degraded in water, light conditions and aerobic environments. The problems of strong hygroscopicity and poor stability have always existed.

In the prior art, the purification method of avermectin mainly adopts acetonitrile recrystallization, and its main defect is that the residual amount of solvent is large, does not meet the requirements of the veterinary pharmacopoeia, and is difficult to be configured into an injection formulation. Chinese patent CN105001289A provides a purification method of avermectin, which solves the problems of low product purity and high residual amount of solvent. However, the process operation is complicated. First, the wet powder of acetonitrile crystallization is pulped in solvent A, then dissolved in solvent B for crystallization, and finally pulped in solvent C. Several steps are complicated, and ether is also used as solvent in the last step, which has a large safety hazard. Even if the problem of acetonitrile exceeding the standard is solved, the problem of poor stability and easy oxidation and degradation is still not solved. CN109303049A discloses a method for improving stability, that is, adding an antioxidant to avermectin to improve drug stability, but it is not clear that the potential risk of introducing antioxidants in API to clinical medication is brought.

At present, the commercially available avermectin is mainly in the form of pour-on for external use and injection for internal use, both of which have limitations. The pour-on is a surface-targeted preparation, and due to the limitations of the administration method, the bioavailability is low. The avermectin injection is an oily clear liquid with good insecticidal effects. In addition to the high requirements for the residual organic solvent of the original drug, the selection of amorphous original drugs will shorten the dissolution and configuration time of the preparation, thereby reducing the generation of degradation impurities. Therefore, the development of an avermectin or amorphous substance with a simple crystallization process, easy operation, low organic solvent residue, weak hygroscopicity, and stable crystal form can not only solve the problem of complex crystallization process, but also provide more options for the development of new preparations in the future, so as to further meet the needs of the veterinary drug market.

Summary of the invention

The present invention provides a new crystal form of avermectin and a preparation method thereof. The new crystal form is a polymorphic form, including crystal form A, crystal form B and amorphous form. The preparation method of the polymorphic form is simple, the process heating time is short, and it is suitable for industrial production. The residual organic solvent content in the obtained crystal is low, which not only overcomes the defects of the prior art, but also provides more options for the development of new dosage forms and optimization of the preparation process of avermectin.

In a first aspect of the present invention, two avermectin crystal forms, crystal form A and crystal form B, are provided.

The X-ray powder diffraction pattern of the crystalline form A (Figure 1) has exclusive characteristic absorption peaks at 2θ of 6.40°, 6.92°, 8.30°, 9.40°, 10.38°, 10.74°, 11.46°, 13.10°, 14.12°, 14.60°, 15.85°, 16.88°, 17.28°, 17.96°, 18.30°, 21.18°, 21.55°, 21.91°, 23.24°, 25.48°, 25.75°, and 27.18° (±0.2).

The X-ray powder diffraction pattern of the crystalline form B ( FIG. 4 ) has exclusive characteristic absorption peaks at 2θ of 7.5°, 7.7°, 8.8°, 9.3°, 10.4°, 11.3°, 12.0°, 13.0°, 14.4°, 15.2°, 15.5°, 16.0°, 16.6°, 18.1°, 19.4°, 19.8°, 21.4°, 22.1°, 22.8°, 23.6°, 25.0°, 25.5°, and 26.1° (±0.2).

Preferably, the avermectin crystal form A provided by the present invention has an X-ray powder diffraction pattern as shown in FIG1 .

Preferably, the avermectin crystal form B provided by the present invention has an X-ray powder diffraction pattern as shown in FIG4 .

The second aspect of the present invention provides a method for preparing avermectin crystal form A and crystal form B.

The preparation steps of Form A are as follows:

(1) Dissolve avermectin in a good organic solvent by heating and filter.

(2) The filtrate is concentrated under reduced pressure to remove a portion of the good solvent, and then a poor solvent is added, and the concentration is continued until crystals are precipitated. After cooling, the crystals are filtered and dried to obtain avermectin crystal form A.

The organic good solvent in step (1) is selected from one or more organic solvents such as heterocyclics, halogenated hydrocarbons, esters, ketones, alcohols, etc. Preferably, the good solvent in step (1) is selected from one or more of tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ethyl butyrate, acetone, methanol, and ethanol.

The dosage ratio (m:v) of avermectin to good solvent in step (1) is 1:1-5 (g:mL).

The poor solvent for preparing the crystal form A in step (2) is one or more of aliphatic hydrocarbons, alcohols, ketones, and aromatic hydrocarbons. Preferably, the poor solvent for preparing the crystal form A in step (2) is one or more selected from n-hexane, isopropanol, n-butanol, butanone, and toluene solvents. More preferably, the poor solvent for preparing the crystal form A in step (2) is one or more selected from n-hexane, isopropanol, and n-butanol.

The volume weight ratio of the good solvent concentrated under reduced pressure in step (2) to the avermectin solid is 0.5-3:1 (ml:g), preferably 1-2:1; the volume weight ratio of the added poor solvent to the avermectin solid is 0.5-3:1 (ml:g), preferably 1-2:1.

The thermal dissolution temperature in step (1) is 20-60°C.

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

The preparation steps of Form B are as follows:

The amorphous material is placed in a certain ratio of suspension and stirred at 20-50°C for 5-10 hours for crystallization.

The suspension is a mixture of one or more organic solvents selected from acetone, methanol, and ethanol and water, wherein the volume ratio of the organic solvent to water in the mixture is 1:8-15; or, the suspension is water.

The volume weight ratio of the suspension to the non-crystal is 1-10:1 (ml:g).

Preferably, the volume weight ratio of the suspension to the amorphous substance is 2-5:1 (ml:g), and the volume ratio of the organic solvent in the suspension to purified water is 1:8-10.

The third aspect of the present invention provides a method for preparing amorphous avermectin.

The steps for preparing amorphous materials are as follows:

(1) Dissolve avermectin in a good organic solvent and filter.

(2) slowly adding a poor solvent dropwise to the filtrate, stirring to precipitate a solid, filtering and drying to obtain a non-crystalline avermectin.

The organic good solvent in step (1) is selected from one or more organic solvents such as heterocyclics, halogenated hydrocarbons, esters, ketones, alcohols, etc. Preferably, the organic good solvent in step (1) is selected from one or more of tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ethyl butyrate, acetone, methanol, and ethanol.

The dosage ratio (m:v) of avermectin to good solvent in step (1) is 1:0.5-5 (g:ml).

The poor solvent for preparing the amorphous substance in step (2) is one or more of n-hexane, cyclohexane, n-heptane, dimethyl ether, diisopropyl ether, petroleum ether, and methyl tert-butyl ether. Preferably, the poor solvent for preparing the amorphous substance in step (2) is one or more of n-hexane, n-heptane, and petroleum ether.

The volume weight ratio of the poor solvent to the avermectin solid in step (2) is 1-8:1 (ml:g), preferably 2-5:1.

The drying temperature in step (2) is 30-80°C.

The crystallization equipment used can be a conventional crystallization kettle with stirring effect in the art.

Beneficial effects:

1. The refining process of the present invention is simple, easy to operate, suitable for industrial production, and the residual amount of organic solvent in the obtained crystal and amorphous substance meets the VICH requirements.

2. The polymorph obtained by this crystallization process has good stability, no crystal transformation and no moisture absorption.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is an X-ray powder diffraction pattern of avermectin crystalline form A prepared in Example 1 of the present invention;

FIG2 is an X-ray powder diffraction pattern of avermectin crystalline form A prepared in Example 2 of the present invention;

FIG3 is an X-ray powder diffraction pattern of amorphous avermectin prepared in Example 3 of the present invention;

FIG4 is an X-ray powder diffraction pattern of avermectin crystal form B prepared in Example 4 of the present invention;

FIG5 is an X-ray powder diffraction pattern of the acetaminophen crystal prepared in Comparative Example 1 of the present invention;

FIG6 is an X-ray powder diffraction pattern of the acetaminophen crystal prepared in Comparative Example 2 of the present invention.

Detailed ways

In order to further illustrate the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

General test method:

X-ray powder diffraction (XRD) instrument: Japanese Rigaku D/Max-2500: Radiation source: copper target scanning at room temperature: scanning range: 2.0~50.0°, scanning rate: 8°/min, step size: 0.02°.

Example 1

Take 10g of avermectin, add 10ml of dichloromethane, heat to 35℃, concentrate under reduced pressure until 5ml remains, add 10ml of isopropanol, continue to concentrate under reduced pressure until 10ml remains. Cool to 0-5℃, filter, and dry the filter cake at 40-50℃ to obtain avermectin crystals. XRD test results:

Fig. 1 is the X-ray powder diffraction pattern of the acetaminophen avermectin crystal form obtained in Example 1. As can be seen from Fig. 1, the XRD diffraction angle (2θ) has exclusive characteristic absorption peaks at 6.40°, 6.92°, 8.30°, 9.40°, 10.38°, 10.74°, 11.46°, 13.10°, 14.12°, 14.60°, 15.85°, 16.88°, 17.28°, 17.96°, 18.30°, 21.18°, 21.55°, 21.91°, 23.24°, 25.48°, 25.75°, and 27.18°. It can be seen that the obtained acetaminophen avermectin is crystal form A.

Example 2

Take 10g of avermectin, add 10ml of ethyl acetate, heat to 40℃ to dissolve, concentrate to 5ml remaining, add 10ml of n-hexane, continue to concentrate to 10ml remaining, crystallize out, cool to 10℃, filter, and dry the filter cake at 60-80℃ to obtain avermectin crystals.

The obtained avermectin crystals were subjected to XRD test, and the results are shown in Figure 2:

XRD diffraction 2θ value = 6.46°, 6.88°, 8.32°, 9.26°, 10.34°, 10.60°, 11.48°, 13.20°, 14.08°, 14.88°, 15.70°, 16.94°, 17.52°, 18.26°, 18.48°, 20.02°, 20.69°, 21.80°, 22.18°, 23.40°, 23.82°, 25.27°, 25.53°, 27.30° have exclusive characteristic absorption peaks. It can be seen that the obtained avermectin is crystal form A.

Example 3

Take 10 g of avermectin, add 10 ml of ethyl acetate, dissolve, slowly add 20 ml of n-heptane, stir until solid precipitates, filter, and dry the filter cake at 50-60°C to obtain avermectin.

The obtained avermectin was subjected to XRD test, and the results were as follows:

Fig. 3 is an X-ray powder diffraction pattern of avermectin obtained in Example 3. As can be seen from Fig. 3, the obtained avermectin is amorphous.

Example 4

Take 10 g of avermectin, add 5 ml of acetone, slowly add 10 ml of petroleum ether after dissolving, stir until solid precipitates, filter, and dry the filter cake at 50-60°C to obtain avermectin.

The obtained avermectin was subjected to XRD test, and the result showed that the obtained avermectin was amorphous.

Example 5

Take 5 g of amorphous material, place it in a mixture of 1 ml of acetone and 10 ml of purified water, stir for 7 hours and then filter, and dry the filter cake at 45-60°C to obtain avermectin.

The obtained avermectin crystals were subjected to XRD test, and the results are shown in Figure 4:

XRD diffraction angle (2θ) has diffraction peaks at 7.5°, 7.7°, 8.8°, 9.3°, 10.4°, 11.3°, 12.0°, 13.0°, 14.4°, 15.2°, 15.5°, 16.0°, 16.6°, 18.1°, 19.4°, 19.8°, 21.4°, 22.1°, 22.8°, 23.6°, 25.0°, 25.5°, and 26.1°. It can be seen that the obtained avermectin is Form B.

Comparative Example 1

According to the crystallization method of CN105968154A, 10 g of avermectin was added to 50 ml of acetonitrile, heated to dissolve, and then cooled to precipitate a large amount of crystals. The filter cake was filtered and vacuum dried at 65°C to obtain avermectin crystals.

The obtained avermectin crystals were subjected to XRD test, and the results are shown in Figure 5:

XRD diffraction 2θ values have exclusive characteristic absorption peaks at 4.38°, 5.02°, 5.48°, 8.98°, 9.68°, 10.34°, 11.12°, 12.81°, 14.32°, 16.80°, and 19.48°.

Comparative Example 2

According to the crystallization method of CN105001289A, 10 g of avermectin was added with 8 ml of ethanol, 10 ml of acetone and 2 ml of purified water, stirred and heated to dissolve, and then the temperature was lowered to room temperature after adding seed crystals, and a large amount of crystals were precipitated and filtered. The filter cake was added into a mixed solvent consisting of 35 ml of ether and 35 ml of purified water, stirred thoroughly, filtered, and the filter cake was vacuum dried at 65°C to obtain avermectin crystals.

The obtained avermectin crystals were subjected to XRD test, and the results are shown in Figure 6:

The XRD diffraction 2θ values have exclusive characteristic absorption peaks at 7.9°, 8.7°, 8.9°, 9.5°, 10.7°, 11.7°, 12.1°, 12.8°, 13.1°, 14.6°, 15.4°, 15.7°, 16.1°, 16.8°, 17.3°, 18.3°, 18.7°, 19.3°, 19.7°, 20.1°, 21.5°, 23.1°, 23.7°, 25.1°, and 26.5°.

Example 6 Residual Solvent Analysis

The crystals obtained in Examples 1-5 of the present invention and the comparative example were tested for residual gas phase organic solvents, and the results were as follows:

Table 1 Analysis of residual solvents in avermectin crystal forms

Experimental results show that:

Under the experimental conditions in the above table, the residual organic solvent content of the avermectin crystal forms A, B and amorphous form obtained by the present invention all meet the VICH residual solvent limit standard, can be fully applied to pharmaceutical preparations, and the crystallization process is simple and easy to industrialize.

Example 7 Stability Study

The stability study of this polymorph was conducted and the results are as follows:

Table 2 Study on the stability of avermectin crystals

Experimental results show that:

Under the experimental conditions in the above table, the avermectin crystal obtained by the present invention has no significant changes in content, appearance and crystal form, has good stability, and is non-hygroscopic, and can be better applied to pharmaceutical preparations.

The preparation methods of the avermectin crystalline form A, crystalline form B and amorphous form proposed in the present invention have been described by way of examples. It is obvious that the relevant technical personnel can modify or appropriately change and combine the avermectin polymorphs and the preparation methods thereof described herein without departing from the content, spirit and scope of the present invention to implement the technology of the present invention. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all deemed to be included in the spirit, scope and content of the present invention.

Claims (5)

1. An avermectin crystal form B, characterized in that the X-ray powder diffraction pattern of the crystal form B measured using CuKa ray is 7.5±0.2°, 7.7±0.2°, 8.8±0.2°, 9.3±0.2°, 10.4±0.2°, 11.3±0.2°, 12.0±0.2°, 13.0±0.2°, 14.4±0.2°, 15. There are characteristic peaks at 2±0.2°, 15.5±0.2°, 16.0±0.2°, 16.6±0.2°, 18.1±0.2°, 19.4±0.2°, 19.8±0.2°, 21.4±0.2°, 22.1±0.2°, 22.8±0.2°, 23.6±0.2°, 25.0±0.2°, 25.5±0.2°, and 26.1±0.2°. 2. A method for preparing avermectin crystal form B as claimed in claim 1, characterized in that the preparation steps are: placing avermectin amorphous material in a suspension of a certain ratio, stirring for 5-10 hours at 20-50° C. for crystallization; the suspension is a mixture of one or more of acetone, methanol, and ethanol and water, and the volume ratio of the organic solvent to water in the mixture is 1:8-15; or the suspension is water. 3. The preparation method of avermectin crystal form B according to claim 2, wherein the volume weight ratio of the suspension to the amorphous phase is 1-10:1. 4. The method for preparing the amorphous avermectin according to claim 2, wherein the preparation steps are: (1) dissolving avermectin in an organic good solvent and filtering; (2) slowly adding a poor solvent dropwise to the obtained filtrate, stirring to precipitate a solid, filtering and drying to obtain an amorphous form of avermectin; The organic good solvent in step (1) is selected from one or more of tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ethyl butyrate, acetone, methanol, and ethanol; the poor solvent in step (2) is selected from one or more of n-hexane, n-heptane, and petroleum ether. 5. The method for preparing amorphous avermectin according to claim 4, characterized in that the weight-to-volume ratio of avermectin to good solvent in step (1) is 1:0.5-5; the volume-to-weight ratio of poor solvent to avermectin solid in step (2) is 1-8:1, and the drying temperature is 30-80°C.