CN114208825A

CN114208825A - Preparation process of niclosamide ethanolamine salt granules

Info

Publication number: CN114208825A
Application number: CN202111619082.4A
Authority: CN
Inventors: 黄梅; 李文新
Original assignee: Hengcheng Pharmaceutical Group Huainan Co ltd
Current assignee: Hengcheng Pharmaceutical Group Huainan Co ltd
Priority date: 2021-12-21
Filing date: 2021-12-27
Publication date: 2022-03-22

Abstract

The invention discloses a preparation process of niclosamide ethanolamine salt granules, belonging to the technical field of pesticides and comprising the following steps: firstly, mixing styrene-maleic anhydride copolymer, p-toluenesulfonic acid and THF, adding THF solution of hydroxyl quaternary ammonium salt compound and THF solution of benzotriazole polyhydroxy compound, and reacting at 65 ℃ for 6 hours to obtain a stabilizer; secondly, preparing the following raw materials in percentage by mass: 0.5-10% of niclosamide ethanolamine salt raw material, 10-15% of water, 2-6% of wetting agent, 2-3% of stabilizing agent, 2-5% of disintegrating agent and the balance of filler; and thirdly, mixing the 98% niclosamide ethanolamine salt raw drug, the wetting agent, the stabilizer, the disintegrating agent and the filler, performing air flow crushing, adding water for kneading, then granulating, drying, subpackaging and warehousing to obtain the niclosamide ethanolamine salt granules.

Description

Preparation process of niclosamide ethanolamine salt granules

Technical Field

The invention belongs to the technical field of pesticides, and particularly relates to a preparation process of niclosamide ethanolamine salt granules.

Background art

The molluscicide is a field-used molluscicide, and is generally prepared into molluscicide ethanolamine salt because the molluscicide is insoluble in water and influences molluscicidal effect. The niclosamide ethanolamine salt is an amide compound with the chemical name of N- (2-chloro-4-nitrophenyl) -2-hydroxy-5-chlorobenzoyl ethanolamine and the CAS of 1420-04-8. The pure product of the niclosamide ethanolamine salt is yellow crystal, is the most widely used molluscicide at present, has higher stability to heat, is a molluscicide with stronger contact poisoning and stomach poisoning effects, has stronger killing effects on adult snails, snail eggs, schistosome cercaria, phalaenopsis amabilis and the like, and has quick action and lasting drug effect.

The main preparation forms of the niclosamide ethanolamine salt comprise wettable powder and suspending agent, and the main specifications comprise 50% and 70% wettable powder; 25% aqueous suspending agent. The wettable powder has the problems of dust flying during production and use and uneven particle size distribution of the product; the suspending agent is a thermodynamically unstable system, cannot be prepared into a high-content preparation, and has poor stability after long-term storage. The granules serving as a conventional pesticide formulation have a remarkable complementary effect on a spray preparation diluted by water, can be directly spread on the soil surface, are not attached to stems and leaves of plants, avoid the phytotoxicity caused by direct contact, save time and labor, but the niclosamide ethanolamine salt needs to be stored in a dark place, the pesticide effect of the niclosamide ethanolamine salt can be reduced by long-time illumination, and the niclosamide ethanolamine salt has small molecules, poor dispersibility and easy aggregation, so that the technical problem to be solved at present is to provide the niclosamide ethanolamine salt granules with good storage property and high pesticide effect.

Disclosure of Invention

In order to solve the technical problems mentioned in the background technology, the invention provides a preparation process of niclosamide ethanolamine salt granules.

The purpose of the invention can be realized by the following technical scheme:

a preparation process of niclosamide ethanolamine salt granules comprises the following steps:

firstly, preparing the following raw materials in percentage by mass: 0.5-10% of niclosamide ethanolamine salt raw material, 10-15% of water, 2-6% of wetting agent, 2-3% of stabilizing agent, 2-5% of disintegrating agent and the balance of filler;

secondly, adding 98% of niclosamide ethanolamine salt raw drug, a wetting agent, a stabilizer, a disintegrating agent and a filler into a two-dimensional or three-dimensional mixer, and mixing for 0.5-1h at the rotating speed of 15-30r/min to obtain a mixed material;

and thirdly, crushing the mixed materials by air flow until D90 is less than or equal to 75 microns, adding water, kneading for 5-30min in a groove type mixer, granulating in a rotary granulator, finally drying for 0.5-2h at 70-90 ℃, subpackaging and warehousing to obtain the niclosamide ethanolamine salt granules.

Further, the stabilizer is prepared by the following steps:

step B1, dissolving maleic anhydride and AIBN in toluene, placing the mixture in a three-neck flask, dropwise adding styrene into the flask, heating to 70 ℃ after dropwise adding, stirring and reacting for 6 hours, after the reaction is finished, carrying out suction filtration on a reaction product, dissolving the suction-filtered solid product in acetone, precipitating and separating out the product by using absolute ethyl alcohol, and repeatedly operating for three times to purify the product to obtain a white solid, thereby obtaining a styrene-maleic anhydride copolymer;

wherein the dosage ratio of the maleic anhydride, the AIBN, the toluene and the styrene is 1.18 g: 0.25 g: 35-45 g: 1.04g, AIBN is taken as an initiator, maleic anhydride and styrene are subjected to copolymerization reaction to obtain a styrene-maleic anhydride copolymer, and the structural formula is as follows:

step B2, adding styrene-maleic anhydride copolymer, p-toluenesulfonic acid and THF into a three-neck flask with a condenser, stirring for 20-30min, adding THF solution of hydroxyl quaternary ammonium salt compound and THF solution of benzotriazole polyhydroxy compound into the three-neck flask, keeping the temperature at 65 ℃ for reaction for 6h, removing THF by rotary evaporation after the reaction is finished, washing a rotary evaporation product with deionized water, and drying at 60 ℃ to constant weight to obtain a stabilizer;

wherein the dosage ratio of the styrene-maleic anhydride copolymer, THF solution of hydroxyl quaternary ammonium salt compound and THF solution of benzotriazole polyhydroxy compound is 6.8-7.4 g: 80-100 mL: 5mL of: 7mL, the dosage of the p-toluenesulfonic acid is 3-5% of the mass of the styrene-maleic anhydride copolymer, and the THF solution of the hydroxyl quaternary ammonium salt compound is prepared from the hydroxyl quaternary ammonium salt compound and THF according to the proportion of 1.3-1.5 g: 5mL of a mixture, and a THF solution of benzotriazole polyol was prepared by mixing benzotriazole polyol and THF in an amount of 2.1 to 2.3 g: 7mL of the stabilizer is mixed, and the styrene-maleic anhydride copolymer, the hydroxyl quaternary ammonium salt compound and the benzotriazole polyhydroxy compound are subjected to chemical reaction under the catalytic action of p-toluenesulfonic acid to obtain the stabilizer, wherein the structural formula of the stabilizer is as follows:

the stabilizer is added into a preparation system of the niclosamide ethanolamine salt granules, belongs to a high molecular compound, is adsorbed on the surface of the niclosamide ethanolamine salt and is distributed in a comb shape, and charges are carried on the surface of the niclosamide ethanolamine salt, so that steric hindrance and electrostatic repulsion are generated among the molecules of the niclosamide ethanolamine salt, the aggregation of particles is prevented, and the dispersion effect of the particles is improved.

Further, the hydroxy quaternary ammonium salt compound is prepared by the following steps:

sequentially adding N-butanol, epichlorohydrin, N-dimethylpropionamide and concentrated hydrochloric acid into a reaction bottle provided with a magnetic stirrer and a condenser tube, heating, refluxing for 8h, concentrating the reaction solution, recrystallizing with acetone for 3 times, and vacuum drying at 60 ℃ to constant weight to obtain a hydroxyl quaternary ammonium salt compound;

wherein the dosage ratio of the N-butyl alcohol, the epichlorohydrin, the N, N-dimethylpropionamide and the concentrated hydrochloric acid is 80-100 mL: 0.05 mol: 0.025 mol: 1.7-2.4mL of concentrated hydrochloric acid, wherein the mass fraction of the concentrated hydrochloric acid is 37%, under an acidic condition, epoxy chloropropane and N, N-dimethylpropionamide are subjected to quaternization reaction to obtain a hydroxyl quaternary ammonium salt compound, and the structural formula of the compound is as follows:

further, the benzotriazole polyol is prepared by the steps of:

step C1, dissolving an ultraviolet absorbent UV-P in THF, then adding chloroacetyl chloride and triethylamine, heating to reflux reaction for 4-8h, after the reaction is finished, adding ice water for precipitation, filtering, washing a filter cake with a saturated sodium bicarbonate solution, and then drying at 80 ℃ to constant weight to obtain an intermediate product 1;

wherein the dosage ratio of the ultraviolet absorbent UV-P, THF to the chloracetyl chloride to the triethylamine is 0.1 mol: 40-60 mL: 20 g: 12-14mL, taking triethylamine as an acid-binding agent, and enabling phenolic hydroxyl of an ultraviolet absorbent UV-P and chloroacetyl chloride to generate an HCl elimination reaction to obtain an intermediate product 1;

step C2, adding the intermediate product 1 and anhydrous aluminum chloride into a three-neck flask, heating to 120 ℃, violently stirring, adding nitrobenzene, stirring for reacting for 4-6 hours, adding ice water for precipitating after the reaction is finished, performing suction filtration, washing a filter cake for 3-5 times by using a hydrochloric acid solution with the mass fraction of 15%, placing the filter cake in toluene for recrystallization, and drying to obtain chlorinated benzotriazole;

wherein the dosage ratio of the intermediate product 1, the anhydrous aluminum chloride and the nitrobenzene is 0.05 mol: 0.06 mol: 80-100mL, taking nitrobenzene as a solvent and anhydrous aluminum chloride as a catalyst, and carrying out Fries rearrangement reaction on the intermediate product 1 to obtain benzotriazole chloride, wherein the structural formula of the benzotriazole chloride is as follows:

step C3, dissolving benzotriazole chloride in DMF, adding aqueous solution of potassium carbonate and tris (hydroxymethyl) aminomethane, heating to reflux for 5-8h, adjusting pH to 7-8 by using hydrochloric acid solution with the mass fraction of 10% after the reaction is finished, and carrying out reduced pressure distillation to obtain benzotriazole polyol;

wherein the dosage ratio of the water solution of the benzotriazole chloride, DMF, potassium carbonate and tris (hydroxymethyl) aminomethane is 0.05 mol: 120-150 mL: 6.8-7.2 g: 6.1g, under the alkaline condition, the halogen atom of the benzotriazole chloride and the amino group of the trihydroxymethyl aminomethane are subjected to elimination of HCl reaction to obtain the benzotriazole polyhydroxy compound, which has the following structural formula:

further, the wetting agent is selected from at least one of sodium dodecyl sulfate, sodium dodecyl benzene sulfonate, sodium lignin sulfonate, sodium alkyl naphthalene sulfonate and fatty acid ester sulfate.

Further, the disintegrating agent is at least one selected from the group consisting of ammonium sulfate, potassium sulfate, urea, diammonium phosphate, sodium sulfate, sodium chloride, sodium methylcellulose and ammonium nitrate.

Further, the filler is at least one selected from kaolin, light calcium carbonate, bentonite, corn starch, white carbon black and anhydrous sodium sulfate.

The invention has the beneficial effects that:

the invention provides a process for preparing niclosamide ethanolamine salt granules, which comprises the steps of uniformly mixing 98% of niclosamide ethanolamine salt raw drug, water, a wetting agent, a stabilizer, a disintegrating agent and a filler, granulating and drying to obtain the niclosamide ethanolamine salt granules, and solves the problems of poor storage property and poor drug effect of the existing niclosamide ethanolamine salt granules. The stabilizer has higher molecular weight, not only can improve the dispersibility of the niclosamide ethanolamine salt in a system, but also has higher viscosity of an aqueous solution, and can form a physical or chemical combination by utilizing the high viscosity of the solution per se and the action of other substances such as the niclosamide ethanolamine salt, a filler, a high-molecular auxiliary agent and the like to cause the viscosity of the system to be increased and have a thickening effect, and a layer of 'protective cover' is formed on the surface of the niclosamide ethanolamine salt, the heat resistance and light resistance of the granules are improved, so that the niclosamide ethanolamine salt granules prepared by the invention have the characteristics of high drug effect and good storage property.

Drawings

The invention will be further described with reference to the accompanying drawings.

FIG. 1 is a flow chart of a process for preparing niclosamide ethanolamine salt granules.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

This example provides a stabilizer made by the steps of:

step B1, dissolving 1.18g of maleic anhydride and 0.25g of AIBN in 35g of toluene, placing the mixture into a three-neck flask, dropwise adding 1.04g of styrene into the flask, heating to 70 ℃ after dropwise adding, stirring and reacting for 6 hours, after the reaction is finished, carrying out suction filtration on a reaction product, dissolving the suction-filtered solid product into acetone, precipitating and separating out the solution by using absolute ethyl alcohol, repeatedly operating for three times, and purifying the product to obtain a white solid, thus obtaining the styrene-maleic anhydride copolymer;

step B2, adding 6.8g of styrene-maleic anhydride copolymer, p-toluenesulfonic acid and 80mL of THF into a three-neck flask with a condenser, stirring for 20min, adding 5mL of THF solution of hydroxyl quaternary ammonium salt compound and 7mL of THF solution of benzotriazole polyhydroxy compound into the three-neck flask, keeping the temperature at 65 ℃ for reaction for 6h, after the reaction is finished, performing rotary evaporation to remove THF, washing the rotary evaporation product with deionized water, drying at 60 ℃ to constant weight to obtain a stabilizer, wherein the dosage of the p-toluenesulfonic acid is 3% of the mass of the styrene-maleic anhydride copolymer, and the THF solution of the hydroxyl quaternary ammonium salt compound is prepared from the hydroxyl quaternary ammonium salt compound and the THF according to 1.3 g: 5mL of a mixture, and a THF solution of benzotriazole polyol was prepared from benzotriazole polyol and THF in an amount of 2.1 g: 7mL of the mixture was mixed.

Wherein, the hydroxyl quaternary ammonium salt compound is prepared by the following steps:

adding 80mL of N-butanol, 0.05mol of epoxy chloropropane, 0.025mol of N, N-dimethylpropionamide and 1.7mL of concentrated hydrochloric acid into a reaction bottle provided with a magnetic stirrer and a condenser tube in sequence, heating, refluxing, reacting for 8 hours, concentrating the reaction solution, recrystallizing with acetone for 3 times, and drying in vacuum at 60 ℃ to constant weight to obtain the hydroxyl quaternary ammonium salt compound, wherein the mass fraction of the concentrated hydrochloric acid is 37%.

Wherein the benzotriazole polyol is prepared by the following steps:

step C1, dissolving 0.1mol of ultraviolet absorbent UV-P in 40mL of THF, then adding 20g of chloroacetyl chloride and 12mL of triethylamine, heating to reflux for reaction for 4 hours, adding ice water for precipitation after the reaction is finished, filtering, washing a filter cake with a saturated sodium bicarbonate solution, and then drying at 80 ℃ to constant weight to obtain an intermediate product 1;

step C2, adding 0.05mol of intermediate product 1 and 0.06mol of anhydrous aluminum chloride into a three-neck flask, heating to 120 ℃, violently stirring, then adding 80mL of nitrobenzene, stirring for reaction for 4 hours, after the reaction is finished, adding ice water for precipitation, performing suction filtration, washing a filter cake for 3 times by using a hydrochloric acid solution with the mass fraction of 15%, then placing the filter cake into toluene for recrystallization, and drying to obtain benzotriazole chloride;

and step C3, dissolving 0.05mol of benzotriazole chloride in 120mL of DMF, adding 6.8g of potassium carbonate and 6.1g of aqueous solution of tris (hydroxymethyl) aminomethane, heating to reflux for 5 hours, adjusting the pH to 7 by using a hydrochloric acid solution with the mass fraction of 10% after the reaction is finished, and carrying out reduced pressure distillation to obtain the benzotriazole polyol.

Example 2

This example provides a stabilizer made by the steps of:

step B1, dissolving 1.18g of maleic anhydride and 0.25g of AIBN in 39g of toluene, placing the mixture into a three-neck flask, dropwise adding 1.04g of styrene into the flask, heating to 70 ℃ after dropwise adding, stirring and reacting for 6 hours, after the reaction is finished, carrying out suction filtration on a reaction product, dissolving the suction-filtered solid product into acetone, precipitating and separating out the solution by using absolute ethyl alcohol, repeatedly operating for three times, and purifying the product to obtain a white solid, thus obtaining the styrene-maleic anhydride copolymer;

step B2, adding 7.0g of styrene-maleic anhydride copolymer, p-toluenesulfonic acid and 90mL of THF into a three-neck flask with a condenser, stirring for 25min, adding 5mL of THF solution of hydroxyl quaternary ammonium salt compound and 7mL of THF solution of benzotriazole polyhydroxy compound into the three-neck flask, keeping the temperature at 65 ℃ for reaction for 6h, after the reaction is finished, performing rotary evaporation to remove THF, washing the rotary evaporation product with deionized water, drying at 60 ℃ to constant weight to obtain a stabilizer, wherein the dosage of the p-toluenesulfonic acid is 4% of the mass of the styrene-maleic anhydride copolymer, and the THF solution of the hydroxyl quaternary ammonium salt compound is prepared from the hydroxyl quaternary ammonium salt compound and the THF according to 1.4 g: 5mL of a mixture, and a THF solution of benzotriazole polyol was prepared from benzotriazole polyol and THF in an amount of 2.2 g: 7mL of the mixture was mixed.

adding 90mL of N-butanol, 0.05mol of epoxy chloropropane, 0.025mol of N, N-dimethylpropionamide and 1.9mL of concentrated hydrochloric acid into a reaction bottle provided with a magnetic stirrer and a condenser tube in sequence, heating, refluxing, reacting for 8 hours, concentrating the reaction solution, recrystallizing with acetone for 3 times, and drying in vacuum at 60 ℃ to constant weight to obtain the hydroxyl quaternary ammonium salt compound, wherein the mass fraction of the concentrated hydrochloric acid is 37%.

Wherein the benzotriazole polyol is prepared by the following steps:

step C1, dissolving 0.1mol of ultraviolet absorbent UV-P in 50mL of THF, then adding 20g of chloroacetyl chloride and 13mL of triethylamine, heating to reflux for reaction for 6h, adding ice water for precipitation after the reaction is finished, filtering, washing a filter cake with a saturated sodium bicarbonate solution, and then drying at 80 ℃ to constant weight to obtain an intermediate product 1;

step C2, adding 0.05mol of intermediate product 1 and 0.06mol of anhydrous aluminum chloride into a three-neck flask, heating to 120 ℃, violently stirring, then adding 90mL of nitrobenzene, stirring for reaction for 5 hours, after the reaction is finished, adding ice water for precipitation, performing suction filtration, washing a filter cake for 4 times by using a hydrochloric acid solution with the mass fraction of 15%, then placing the filter cake into toluene for recrystallization, and drying to obtain benzotriazole chloride;

and step C3, dissolving 0.05mol of benzotriazole chloride in 140mL of DMF, adding 7.0g of potassium carbonate and 6.1g of aqueous solution of tris (hydroxymethyl) aminomethane, heating to reflux for reaction for 7h, adjusting the pH to 7 by using a hydrochloric acid solution with the mass fraction of 10% after the reaction is finished, and carrying out reduced pressure distillation to obtain the benzotriazole polyol.

Example 3

This example provides a stabilizer made by the steps of:

step B1, dissolving 1.18g of maleic anhydride and 0.25g of AIBN in 45g of toluene, placing the mixture into a three-neck flask, dropwise adding 1.04g of styrene into the flask, heating to 70 ℃ after dropwise adding, stirring and reacting for 6 hours, after the reaction is finished, carrying out suction filtration on a reaction product, dissolving the suction-filtered solid product into acetone, precipitating and separating out the solution by using absolute ethyl alcohol, repeatedly operating for three times, and purifying the product to obtain a white solid, thus obtaining the styrene-maleic anhydride copolymer;

step B2, adding 7.4g of styrene-maleic anhydride copolymer, p-toluenesulfonic acid and 100mL of THF into a three-neck flask with a condenser, stirring for 30min, adding 5mL of THF solution of hydroxyl quaternary ammonium salt compound and 7mL of THF solution of benzotriazole polyhydroxy compound into the three-neck flask, keeping the temperature at 65 ℃ for reaction for 6h, after the reaction is finished, performing rotary evaporation to remove THF, washing the rotary evaporation product with deionized water, drying at 60 ℃ to constant weight to obtain a stabilizer, wherein the dosage of the p-toluenesulfonic acid is 5% of the mass of the styrene-maleic anhydride copolymer, and the THF solution of the hydroxyl quaternary ammonium salt compound is prepared from the hydroxyl quaternary ammonium salt compound and the THF according to 1.5 g: 5mL of a mixture, and a THF solution of benzotriazole polyol was prepared from benzotriazole polyol and THF in an amount of 2.3 g: 7mL of the mixture was mixed.

adding 100mL of N-butanol, 0.05mol of epoxy chloropropane, 0.025mol of N, N-dimethylpropionamide and 2.4mL of concentrated hydrochloric acid into a reaction bottle provided with a magnetic stirrer and a condenser tube in sequence, heating, refluxing, reacting for 8 hours, concentrating the reaction solution, recrystallizing with acetone for 3 times, and drying in vacuum at 60 ℃ to constant weight to obtain the hydroxyl quaternary ammonium salt compound, wherein the mass fraction of the concentrated hydrochloric acid is 37%.

Wherein the benzotriazole polyol is prepared by the following steps:

step C1, dissolving 0.1mol of ultraviolet absorbent UV-P in 60mL of THF, then adding 20g of chloroacetyl chloride and 14mL of triethylamine, heating to reflux for reaction for 8h, adding ice water for precipitation after the reaction is finished, filtering, washing a filter cake with a saturated sodium bicarbonate solution, and then drying at 80 ℃ to constant weight to obtain an intermediate product 1;

step C2, adding 0.05mol of intermediate product 1 and 0.06mol of anhydrous aluminum chloride into a three-neck flask, heating to 120 ℃, violently stirring, then adding 100mL of nitrobenzene, stirring for reacting for 6 hours, after the reaction is finished, adding ice water for precipitation, performing suction filtration, washing a filter cake for 5 times by using a hydrochloric acid solution with the mass fraction of 15%, then placing the filter cake into toluene for recrystallization, and drying to obtain benzotriazole chloride;

and step C3, dissolving 0.05mol of benzotriazole chloride in 150mL of DMF, adding 7.2g of potassium carbonate and 6.1g of aqueous solution of tris (hydroxymethyl) aminomethane, heating to reflux for 8 hours, adjusting the pH to 8 by using a hydrochloric acid solution with the mass fraction of 10% after the reaction is finished, and carrying out reduced pressure distillation to obtain the benzotriazole polyol.

Comparative example 1

This example provides a stabilizer made by the steps of:

dissolving 1.18g of maleic anhydride and 0.25g of AIBN in 45g of toluene, placing the mixture into a three-neck flask, dropwise adding 1.04g of styrene into the flask, heating to 70 ℃ after dropwise adding, stirring and reacting for 6 hours, after the reaction is finished, carrying out suction filtration on a reaction product, dissolving a suction-filtered solid product into acetone, precipitating and separating out by using absolute ethyl alcohol, and repeatedly operating for three times to purify the product to obtain a white solid, thereby obtaining the styrene-maleic anhydride copolymer.

The stabilizers of examples 1 to 3 and comparative example 1 were subjected to surface activity measurement, stabilizer solutions of different mass concentrations ρ were prepared with double redistilled water, and the temperature was maintained at (25. + -. 1) ° C for 24 hours. The surface tension γ of solutions of different mass concentrations was measured at (25. + -. 1) ° C using a K100 surface tensiometer manufactured by KRUSS, Germany, and the surface tension isotherm was obtained by plotting γ against lg ρ. The critical micelle concentration of phosphorus (CMC) was determined from the γ -lg ρ curve and the results are shown in Table 1:

TABLE 1

As can be seen from Table 1, the stabilizers prepared in examples 1-3 have lower critical micelle concentrations, indicating that the stabilizers prepared according to the present invention have better dispersing, emulsifying and thickening effects.

Example 4

Referring to fig. 1, a process for preparing niclosamide ethanolamine salt granules includes the following steps:

firstly, preparing the following raw materials in percentage by mass: 0.5% of niclosamide ethanolamine salt raw material with the concentration of 98%, 10% of water, 2% of sodium dodecyl sulfate, 2% of the stabilizing agent in the embodiment 1, 2% of ammonium sulfate and the balance of kaolin;

secondly, adding 98% of niclosamide ethanolamine salt raw drug, sodium dodecyl sulfate, a stabilizer, ammonium sulfate and kaolin into a two-dimensional or three-dimensional mixer, and mixing for 1h at the rotating speed of 15r/min to obtain a mixed material;

and thirdly, crushing the mixed material by air flow until D90 is less than or equal to 75 microns, adding water, kneading for 5min in a groove type mixer, granulating in a rotary granulator, drying for 2h at 70 ℃, subpackaging and warehousing to obtain the niclosamide ethanolamine salt granules.

Example 5

firstly, preparing the following raw materials in percentage by mass: 5% of a 98% niclosamide ethanolamine salt raw material, 12% of water, 4% of sodium dodecyl benzene sulfonate, 2.5% of a stabilizer in example 2, 4% of potassium sulfate and the balance of bentonite;

secondly, adding 98% of niclosamide ethanolamine salt raw material, sodium dodecyl benzene sulfonate, a stabilizer, potassium sulfate and bentonite into a two-dimensional or three-dimensional mixer, and mixing for 0.8h at the rotating speed of 20r/min to obtain a mixed material;

and thirdly, crushing the mixed material by air flow until D90 is less than or equal to 75 microns, adding water, kneading for 20min in a groove type mixer, granulating in a rotary granulator, drying for 0.5h at 90 ℃, subpackaging and warehousing to obtain the niclosamide ethanolamine salt granules.

Example 6

firstly, preparing the following raw materials in percentage by mass: 10% of a 98% niclosamide ethanolamine salt raw material, 15% of water, 6% of sodium lignosulfonate, 3% of a stabilizer in example 3, 5% of urea and the balance of corn starch;

secondly, adding 98% of niclosamide ethanolamine salt raw material, sodium lignosulfonate, a stabilizer, urea and corn starch into a two-dimensional or three-dimensional mixer, and mixing for 1h at the rotating speed of 30r/min to obtain a mixed material;

and thirdly, crushing the mixed material by air flow until D90 is less than or equal to 75 microns, adding water, kneading for 30min in a groove type mixer, granulating in a rotary granulator, drying for 0.5h at 90 ℃, subpackaging and warehousing to obtain the niclosamide ethanolamine salt granules.

Comparative example 2

The stabilizer in example 4 was removed and the remaining preparation process steps were unchanged.

Comparative example 3

The stabilizer in example 4 was replaced by the same amount of dispersant NNO sold by shinjiang leap soil gmbh.

Comparative example 4

The comparative example is niclosamide ethanolamine salt granules sold by Shanghai Hulian biological medicine (Xiaxi) GmbH.

The niclosamide ethanolamine salt granules of examples 4 to 6 and comparative examples 2 to 4 were tested as follows:

(I) thermal storage stability: drying 10g of each group of granules at 80 ℃ to constant weight, then placing the granules in a penicillin bottle to enable the granules to be spread smoothly and uniformly, placing the granules in a thermostat at 55 ℃ for 14 days, taking out the granules, placing the granules in a dryer, cooling the granules to room temperature, and respectively preparing absolute ethyl alcohol solutions. Preparing an absolute ethanol solution by using each group of L naturally placed samples as a control group, and performing qualitative and quantitative analysis on the absolute ethanol solution by using an ultraviolet-visible spectrophotometer to determine the decomposition rate of the effective components.

(II) light storage stability: drying 10g of each group of granules at 80 ℃ to constant weight, then placing the granules in a transparent glass bottle to enable the granules to be spread smoothly and uniformly, airing the granules for 14 days in the sunlight, taking out the granules, placing the granules in a dryer, and cooling the granules to room temperature to respectively prepare absolute ethyl alcohol solutions. Preparing absolute ethanol solution as a control group by using each group of naturally placed samples, and performing qualitative and quantitative analysis on the absolute ethanol solution by using an ultraviolet-visible spectrophotometer to determine the decomposition rate of the effective components.

The test results are shown in table 2:

TABLE 2

As can be seen from Table 2, the granules of niclosamide ethanolamine salts obtained in examples 4 to 6 are superior in light resistance and heat resistance and have superior storage stability.

(III) drug effect: the drug effect detection of the drugs of the examples and the comparative examples is carried out by referring to agricultural industry standard NY/T1617-:

1. indoor dusting test: selecting 6-8-turn adult live snails collected on site in the Yangxin and the county of Dangdu as test objects, and weighing by an electronic balance with the weighing precision of 1mg according to the ratio of 2g/m²Weighing corresponding medicaments according to the dosage, and mixing the medicaments with the fine river sand according to the mass ratio of 1: 4, uniformly spreading the mixture to each test group. Each test group treated 100 oncomelania at a time and examined the oncomelania for viability at 1d, 3d and 7d post-application. The indoor test is repeated for three times, and the mortality rate is calculated by taking the average value;

2. and (3) field dusting test: the field test area is located in a river beach of the country of yellow country of the heart of the country of Dandu province of Anhui province. The density of the oncomelania in the test area is low, and the density of the oncomelania in the test area is improved to about 10 oncomelania per frame by a method of manually capturing, throwing and supplementing the oncomelania. Field test about 100m per test cell². According to 10g/m²Weighing corresponding medicaments according to the dosage, and mixing each group of test medicaments with the fine river sand according to the ratio of 1: 4, mixing evenly and spreading evenly. After 1d, 3d and 7d after application, the oncomelania were investigated by checkerboard sampling, 10 boxes were extracted in each test area, all oncomelania in the boxes were captured, wrapped with paper bags in units of boxes, numbered, and the death rate was determined and recorded.

The test results are shown in table 3:

TABLE 3

As can be seen from table 3, the niclosamide ethanolamine salt granules obtained in examples 4 to 6 have high drug efficacy and can rapidly kill oncomelania, and in conclusion, the niclosamide ethanolamine salt granules prepared by the invention have good storage performance and high medicinal activity.

It is noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims

1. A preparation process of niclosamide ethanolamine salt granules is characterized by comprising the following steps:

firstly, mixing styrene-maleic anhydride copolymer, p-toluenesulfonic acid and THF, adding THF solution of hydroxyl quaternary ammonium salt compound and THF solution of benzotriazole polyhydroxy compound, reacting at 65 ℃ for 6 hours, and after the reaction is finished, performing rotary evaporation, washing and drying to obtain a stabilizer;

secondly, preparing the following raw materials in percentage by mass: 0.5-10% of niclosamide ethanolamine salt raw material, 10-15% of water, 2-6% of wetting agent, 2-3% of stabilizing agent, 2-5% of disintegrating agent and the balance of filler;

and thirdly, mixing 98% of niclosamide ethanolamine salt raw drug, a wetting agent, a stabilizer, a disintegrating agent and a filler to obtain a mixed material, performing airflow crushing on the mixed material to obtain D90 of which the diameter is less than or equal to 75 microns, adding water, kneading for 5-30min, then granulating, drying, subpackaging and warehousing to obtain the niclosamide ethanolamine salt granules.

2. A process for the preparation of niclosamide ethanolamine salt granules according to claim 1, wherein the ratio of the amount of styrene-maleic anhydride copolymer, THF solution of a hydroxy quaternary ammonium salt compound and THF solution of a benzotriazole polyol is 6.8 to 7.4 g: 80-100 mL: 5mL of: 7mL, and the dosage of the p-toluenesulfonic acid is 3-5% of the mass of the styrene-maleic anhydride copolymer.

3. A process for the preparation of niclosamide ethanolamine salt granules according to claim 1, wherein the THF solution of the hydroxy quaternary ammonium salt compound is prepared from the hydroxy quaternary ammonium salt compound and THF according to a ratio of 1.3-1.5 g: 5mL of a mixture, and a THF solution of benzotriazole polyol was prepared by mixing benzotriazole polyol and THF in an amount of 2.1 to 2.3 g: 7mL of the mixture was mixed.

4. The process for preparing niclosamide ethanolamine salt granules according to claim 1, wherein the hydroxy quaternary ammonium salt compound is prepared by the following steps:

mixing N-butanol, epichlorohydrin, N-dimethylpropionamide and concentrated hydrochloric acid, refluxing for 8h, concentrating the reaction solution, recrystallizing with acetone for 3 times, and vacuum drying at 60 deg.C to constant weight to obtain hydroxy quaternary ammonium salt compound.

5. The process for preparing niclosamide ethanolamine salt granules according to claim 4, wherein the dosage ratio of N-butanol, epichlorohydrin, N-dimethylpropionamide and concentrated hydrochloric acid is 80-100 mL: 0.05 mol: 0.025 mol: 1.7-2.4mL, and the mass fraction of concentrated hydrochloric acid is 37%.

6. The process for preparing niclosamide ethanolamine salt granules according to claim 1, wherein the benzotriazole polyol is prepared by the following steps:

dissolving benzotriazole chloride in DMF, adding aqueous solution of potassium carbonate and tris (hydroxymethyl) aminomethane, refluxing for 5-8h, adjusting pH to 7-8 after the reaction is finished, and distilling under reduced pressure to obtain benzotriazole polyhydroxy compound.

7. The preparation process of niclosamide ethanolamine salt granules according to claim 6, wherein the benzotriazole chloride is prepared by the following steps:

step C1, dissolving an ultraviolet absorbent UV-P in THF, adding chloroacetyl chloride and triethylamine, carrying out reflux reaction for 4-8h, adding ice water for precipitation after the reaction is finished, filtering, washing a filter cake, and drying to obtain an intermediate product 1;

and step C2, mixing the intermediate product 1 with anhydrous aluminum chloride, heating to 120 ℃, violently stirring, then adding nitrobenzene, stirring for reacting for 4-6 hours, adding ice water for precipitation after the reaction is finished, performing suction filtration, washing a filter cake, and drying to obtain the benzotriazol chloride.

8. The process for preparing niclosamide ethanolamine salt granules according to claim 7, wherein the dosage ratio of the ultraviolet absorbent UV-P, THF, chloroacetyl chloride and triethylamine in the step C1 is 0.1 mol: 40-60 mL: 20 g: 12-14 mL.

9. The process for preparing niclosamide ethanolamine salt granules according to claim 7, wherein the dosage ratio of the intermediate product 1, the anhydrous aluminum chloride and the nitrobenzene in the step C2 is 0.05 mol: 0.06 mol: 80-100 mL.