Method for preparing phenazino-1-carboxylic acid compound suspending agent through acidification and melt dispersion

Abstract

The invention discloses a method for preparing a phenazino-1-carboxylic acid compound suspending agent by acidification and melt dispersion, which comprises the following steps: (1) carrying out primary alkali regulation and flocculation on phenazino-1-carboxylic acid fermentation liquor, filtering out solid matters, carrying out ultrafiltration on filtrate to remove macromolecular organic matters, directly carrying out acidification to prepare the phenazino-1-carboxylic acid suspending agent, and if the content of effective components in the filtrate is insufficient, carrying out secondary alkali regulation and flocculation on the filtrate; the filtrate concentration can be adjusted through MVR multi-effect evaporation; and (2) hot-melting condensation: adding a high-boiling-point emulsifier into the low-melting-point bactericide to participate in compounding, enabling a mixed system of the low-melting-point bactericide and the emulsifier to be in a homogeneous-phase molten state, enabling the temperature of the system to be higher than the melting point of the bactericide by 10 DEG C or more, and then adding the mixture into the phenazino-1-carboxylic acid suspending agent which is sheared at a high speed to prepare the product. The production cost is effectively reduced, the environmental pollution is reduced, and double response of economic benefits and social benefits is achieved.

Description

Technical Field

[0001] The invention relates to a method for preparing a shinamicin compound suspension. Background Art

[0002] Shenqinmycin is a new type of biogenic agricultural fungicide jointly developed by the School of Life Sciences of Shanghai Jiao Tong University and Shanghai Nong Le Biological Products Co., Ltd. Its chemical component is phenazine-1-carboxylic acid, which is a secondary metabolite produced by the microorganism Pseudomonas fluorescens through biological culture and fermentation. Since then, Shenqinmycin has entered my country's agricultural production field as a new type of broad-spectrum biogenic pesticide. After more than ten years of field application, its broad-spectrum and high-efficiency characteristics have been registered in my country's field crops and economic crops. The registered diseases for prevention and control include: wilt, vine blight, blight, sheath blight, rice false smut, downy mildew, stripe rust, sclerotinia, fusarium head blight, anthracnose, gray mold, black spot, leaf spot, bacterial wilt, ulcer and other soil-borne diseases. At the same time, it was found during use that it has the effect of promoting plant growth.

[0003] As a new broad-spectrum agricultural fungicide, the dosage forms of sinocycline currently developed in the market are relatively single, mainly 1% suspension products. Jiangsu Good Harvest Wayne Agrochemical Co., Ltd. registered a compound suspension of 6% sinocycline and 24% thiophanate-methyl in 2018. There are many combinations of sinocycline and various agricultural fungicides in other articles or patents, but the research and development of dosage forms may not be synchronized with production. In recent years, no new products have been registered and launched.

[0004] From the initial small-scale trials in the development of sinocycline to the current industrial production, the extraction and purification of the active ingredient raw material has always been a major difficulty in the process production. Since sinocycline is a heterocyclic organic acid, its solubility in most organic solvents is very small and cannot be extracted with solvents. Due to the nature of organic acids, the process adopts the alkali separation method, but filtration under alkaline conditions is simply impossible. The alkaline fermentation broth must be flocculated before filtration, and the requirements for flocculation are also relatively high. The flocculation and filtration process has a great impact on the yield of the active ingredient, especially the yield of the refining process is relatively low, and the waste is serious, resulting in high costs for the raw material, which may be a major reason for hindering market promotion and application.

[0005] After the fermentation broth of styraxine is filtered and deslagging is removed by a single flocculation, the crude mother liquor is directly filtered by modern membrane filtration technology to separate and remove organic and inorganic substances with a molecular weight greater than 10,000 Daltons as impurities. The styraxine technical drug obtained by acid filtration of the filtrate basically meets the index requirements of the technical drug, and there is almost no loss of effective ingredients in the membrane filtration process, which is nearly doubled compared with the old process of secondary alkaline dissolution flocculation. The filtrate can be made into an aqueous solution, a suspension, a water-dispersible granule, a dry suspension and a compound preparation by adding the technical drug or MVR high-efficiency concentration method.

[0006] Acid precipitation is the process of converting a dissolved or colloidal system into a suspended state. The size of the suspended particles can be controlled by different conditions, such as the concentration of the crystalline suspension in the system, the amplitude of temperature change, the speed of acid addition, and the intensity of system stirring or shearing. By controlling the relevant acid precipitation crystallization conditions and in the presence of relevant additives, the suspension system produced by acid precipitation is a stable suspended dispersion system.

[0007] The basic principle of hot melt coagulation is similar to that of melt dispersion and hot melt dispersion, that is, a molten pesticide liquid meets water or oil under high-speed stirring. Its system consists of technical drug, emulsifier, dispersant, wetting agent, solvent, thickener, defoamer, preservative and pH regulator, etc. Its essence is the process of phase transfer and recrystallization. This process is easy to prepare SC dispersions with ultrafine particle size, easy to transform the crystal size through the auxiliary agent system, easy to process SC dispersions of low melting point technical drugs, easy to achieve stability of cold storage and hot storage, and prepare stable SC dispersion system. At the same time, for technical drug manufacturers, there is no need to dry and crush the technical drugs, which is easy to improve production efficiency and reduce energy consumption. Summary of the invention

[0008] The object of the present invention is to provide a method for preparing a sinocycline compound suspension by acid precipitation and melt dispersion, which can effectively reduce production costs and environmental pollution.

[0009] The technical solution of the present invention is:

[0010] A method for preparing a shinazomib compound suspension concentrate by acid precipitation and melt dispersion, characterized in that it comprises the following steps:

[0011] (1) The fermentation broth of sinocycline is subjected to primary alkali adjustment and flocculation, solids are filtered out, the filtrate is subjected to ultrafiltration to remove macromolecular organic matter, and acid precipitation is directly performed to prepare sinocycline suspension. If the content of active ingredient in the filtrate is insufficient, the concentration of the filtrate can be adjusted by MVR multi-effect evaporation;

[0012] (2) Hot melt coagulation: Add a high boiling point emulsifier to the low melting point fungicide to be compounded, so that the mixed system of the low melting point fungicide and the emulsifier is in a homogeneous molten state, and the system temperature is higher than the melting point of the fungicide by more than 10°C. Then add it to the high-speed shearing sinocycline suspension to obtain the product.

[0013] The ultrafiltration in step (1) uses a ceramic membrane or an organic membrane with a molecular weight of 10,000 Daltons for filtration.

[0014] The method for preparing the shinazomib suspension by acid precipitation in step (1) is as follows: adding a wetting agent, a dispersant and a defoaming agent to the filtrate, stirring evenly, controlling the system temperature at 25°C to 30°C, turning on high-speed shearing, and when the rotation speed reaches 3000rp / s, slowly adding 50% H2SO4 solution until the pH of the system drops from 9 to 10 to 4.5 to 5.5, continuing shearing for 5-15 minutes, stopping shearing, and detecting the particle size for standby use; if the particle size is too large and does not meet the standard, sand grinding is used to remedy the condition and meet the standard.

[0015] The wetting agent includes one or a combination of two of butyl naphthalene sulfonate sodium salt BX, sodium dodecyl sulfate, condensate of fatty alcohol and ethylene oxide JFC, NP-10, Quick T, RS, T-1004, Morwet EFW, YUS-LXC, SXC, Igebel BC / 10, W-2001, KDS95, and DF95; the dispersant includes one or a combination of two of lignin sulfonate, naphthalene sulfonate, alkyl naphthalene sulfonate formaldehyde condensate, alkylphenol polyoxyethylene ether, fatty alcohol polyoxyethylene ether, polyarylphenol polyoxyethylene ether, EO-PO block copolymer, high molecular weight polycarboxylic acid comb copolymer, HLN-9501, and Soprophor SC; the defoamer includes one of silicone, fatty alcohol, polyether, mineral oil, and composite defoamer.

[0016] The specific steps of step (2) are as follows: adding a high boiling point emulsifier to the low melting point fungicide to be compounded, heating and stirring, so that the mixed system of the low melting point fungicide and the emulsifier is in a homogeneous molten state, the system temperature is higher than the melting point of the fungicide by more than 10°C, and then dripping into the suspension system of the first high-speed shearing process, keeping the temperature of the suspension system between 25°C and 30°C, after the dripping is completed, continuing the high-speed shearing for 10 to 15 minutes, stopping the shearing and sampling to detect the fineness of the dispersed particles, if the test is qualified, adding a thickener, an antifreeze agent, a preservative, adjusting the pH value, stirring and mixing evenly, and then sampling for inspection, if the particle size test is unqualified, sand grinding is required for remediation.

[0017] The emulsifier includes one of castor oil polyoxyethylene ether, calcium dodecylbenzene sulfonate, styrylphenyl polyoxyethylene ether, alkylphenol formaldehyde resin polyoxyethylene ether, Ningru 700#, Ningru 33#34#37#, Nongru 0201, Nongru 0202, and LAE-9; the thickener includes one of xanthan gum, magnesium aluminum silicate, sodium carboxymethyl starch (CMS), gelatin, alginic acid, sodium alginate, propylene glycol alginate, carrageenan, pectin, gum arabic, hydroxypropyl starch, hydroxyethyl starch, dextrin, cyclodextrin, and carboxymethyl cellulose, or a combination of two; the antifreeze includes one of ethylene glycol, propylene glycol, glycerol, and polyethylene glycol; the preservative includes one of phenol, sodium sorbate, potassium sorbate, and isothiazolinone.

[0018] Shenqinmycin is a biosynthetic agricultural fungicide, an organic compound of microbial secondary metabolism synthesized through fermentation engineering. At present, the fermentation titer achieved in production and scientific research reported at home and abroad is between 0.4‰ and 1.08‰, and the actual production titer is basically around 0.4‰. Due to the physical and chemical properties of shenqinmycin, its extraction process must be carried out in a water-based state. It needs to go through the process of secondary alkaline dissolution, secondary flocculation, secondary acid precipitation, and four filtrations to obtain basically qualified raw materials. The raw materials are dried and crushed before being made into suspension concentrates. The secondary flocculation in this process has a great influence on the extraction yield, resulting in high production costs.

[0019] The production process of the present invention greatly simplifies the above-mentioned complex extraction process. The fermentation broth is subjected to alkali adjustment and flocculation, solids are filtered out, the filtrate is subjected to ultrafiltration to remove macromolecular organic matter, and acid precipitation is directly performed to prepare the sinocycline suspension. If the content of the active ingredient in the filtrate is insufficient, the concentration of the filtrate can be adjusted by MVR multi-effect evaporation.

[0020] The production process of the invention solves the problem of low yield of effective components caused by secondary flocculation. Calculated based on effective original medicine, the total yield is increased from the original 40% to 50% to 85% to 90%, which is increased by nearly 1 times.

[0021] The production process of the present invention solves a very thorny problem in fermentation engineering, the wastewater problem. In the original production process, the wastewater after the original drug is extracted has very high COD, ammonia nitrogen and chloride ions, and the processing cost is very high. In the production process of the present invention, no wastewater is generated, and the water filtered by the ultrafiltration membrane directly enters the water suspension, and a small amount of MVR concentrated distilled water can be recycled for production, so as to achieve zero discharge of production wastewater.

[0022] Low-melting-point agricultural fungicides and fungicides with slightly higher solubility in water are difficult to prepare in the pesticide suspension. Like other agricultural fungicides, the compounding is not easy to select auxiliary agents, the sand grinding fineness cannot be achieved, and the stability is poor.

[0023] The production process of the present invention uses the hot melt condensation method for the compound production process, so that the low melting point fungicide undergoes phase transfer and recrystallization in the suspension system of sinocycline, thereby avoiding the phenomenon of poor efficiency in the sand milling process and unstable crystal structure.

[0024] The production process of the invention provides a convenient channel for preparation processing for manufacturers of sinocycline technical, reduces production costs, reduces environmental pollution, and has both economic and social benefits.

[0025] The present invention will be further described below in conjunction with the embodiments. DETAILED DESCRIPTION

[0026] Take 20L of shinazomib fermentation liquid, adjust the pH value to 9.0-10.0, use calcium salt as flocculant, add orthophosphate to precipitate excess calcium ions, filter with filter cloth, treat the filter residue as waste, concentrate the filtrate to a shinazomib content of about 1%-5%, directly use ultrafiltration ceramic membrane or organic membrane to filter out impurities and macromolecular organic matter with a molecular weight greater than 10,000 Daltons, and use the ultrafiltrate for standby use.

[0027] According to the requirements of the concentration of the suspension, the measured wetting agent, dispersant and defoamer are added to the ultrafiltrate, and the above-mentioned additives are dissolved under low-speed shearing or stirring. At the same time, the system is heated to about 30°C, the shear speed is increased to 3000rp / s, and 50% sulfuric acid concentrate is added dropwise. At this time, a light yellow emulsion is produced in the system, which is the microparticles of styrene formed by acid precipitation. The pH value of the system continues to decrease. When the pH of the system drops to about 5.5, the addition of sulfuric acid concentrate is stopped, and the particle size distribution is sampled and tested. If it meets the particle size fineness requirements of the pesticide suspension (if it does not meet the particle fineness, it needs to be remedied by sand grinding), then the corresponding thickener and other additives are added, and the shearing is uniform to complete the production process of the agricultural suspension. The following are the particle fineness test data and suspension test data of the three tests:

[0028] Table 1: Particle size distribution of three different concentration tests

[0029]

[0030] Table 2: Performance test results of 3 formulation samples

[0031]

[0032] Starting from the acid precipitation suspension system of the above scheme, a hot melt coagulation method test was carried out, and pyraclostrobin was used as the compound agent. The scheme implemented this time used 0.5%, 1%, and 1.5% of shinazomib and 19.5%, 19%, and 18.5% of pyraclostrobin for corresponding compounding, and the total effective content was 20%. First, the shinazomib acid precipitation was made into corresponding suspension systems, and the amount of pyraclostrobin was calculated according to the amount to be prepared in the experimental plan. The emulsifier was added to the melting pot with stirring and mixed and heated. The melting point of pyraclostrobin is low, and it is completely melted at about 65°C. The temperature was raised to 75°C-80°C, and high-speed In the sheared shinazomib suspension system, the temperature of the shinazomib suspension system is controlled at 25℃~30℃. At this time, the molten pyraclostrobin mixed solution contacts the low-temperature dynamic water suspension, quickly disperses and enters the water phase from the emulsifier to crystallize, forming tiny particles. After the dropwise addition is completed, high-speed shearing is continued for 15~20 minutes, and the temperature is lowered to room temperature. The particle fineness is sampled and tested. If it meets the particle size and fineness requirements of the pesticide suspension (if it does not meet the particle fineness, it needs to be remedied by sand grinding), then the corresponding thickener and other additives are added, and the shearing is uniform to complete the production process of the agricultural suspension. The following are the particle fineness test data and suspension test data of the three tests:

[0033] Table 3: Particle size distribution of three different concentration compounding tests

[0034]

[0035] Table 4: Performance test results of 3 compound preparation samples

[0036]

[0037] This shows the excellent technical effect of the present invention.

Claims

1. A method for preparing a shinazomib compound suspension concentrate by acid precipitation and melt dispersion, characterized in that: The following steps are involved: (1) The fermentation broth of sinocycline is subjected to flocculation by adjusting the base once, and the solids are filtered out. The filtrate is subjected to ultrafiltration to remove the macromolecular organic matter, and then directly subjected to acid precipitation to prepare the sinocycline suspension. If the content of the active ingredient in the filtrate is insufficient, the concentration of the filtrate can be adjusted by MVR multi-effect evaporation; (2) Hot melt coagulation: Add a high boiling point emulsifier to the low melting point fungicide to be compounded, so that the mixed system of the low melting point fungicide and the emulsifier is in a homogeneous molten state, and the system temperature is more than 10°C higher than the melting point of the fungicide. Then add it to the high-speed shearing sinocycline suspension to obtain the product.

2. The method for preparing a composite suspension concentrate of sinocycline by acid precipitation and melt dispersion according to claim 1, characterized in that: The ultrafiltration in step (1) uses a ceramic membrane or an organic membrane with a molecular weight of 10,000 Daltons for filtration.

3. A method for preparing a shinazomib composite suspension concentrate by acid precipitation and melt dispersion according to claim 1 or 2, characterized in that: The method for preparing the shinazomib suspension by acid precipitation in step (1) is as follows: adding a wetting agent, a dispersant and a defoaming agent to the filtrate, stirring evenly, controlling the system temperature at 25°C to 30°C, turning on high-speed shearing, and when the speed reaches 3000rp / s, slowly adding 50% H2SO4 solution until the pH of the system drops from 9 to 10 to 4.5 to 5.5, continuing shearing for 5 to 15 minutes, stopping shearing, and detecting the particle size for later use; if the particle size is too large and does not meet the standard, sand milling is used to remedy the condition.

4. A method for preparing a sinocycline composite suspension concentrate by acid precipitation and melt dispersion according to claim 3, characterized in that: The wetting agent includes one or a combination of two of butyl naphthalene sulfonate sodium salt BX, sodium dodecyl sulfate, condensate of fatty alcohol and ethylene oxide JFC, NP-10, Quick T, RS, T-1004, Morwet EFW, YUS-LXC, SXC, Igebel BC / 10, W-2001, KDS95, and DF95; the dispersant includes one or a combination of two of lignin sulfonate, naphthalene sulfonate, alkyl naphthalene sulfonate formaldehyde condensate, alkylphenol polyoxyethylene ether, fatty alcohol polyoxyethylene ether, polyarylphenol polyoxyethylene ether, EO-PO block copolymer, high molecular weight polycarboxylic acid comb copolymer, HLN-9501, and Soprophor SC; the defoamer includes one of silicone, fatty alcohol, polyether, mineral oil, and composite defoamer.

5. A method for preparing a composite suspension concentrate of shinazomib by acid precipitation and melt dispersion according to claim 1 or 2, characterized in that: The specific steps of step (2) are as follows: adding a high boiling point emulsifier to the low melting point fungicide to be compounded, heating and stirring, so that the mixed system of the low melting point fungicide and the emulsifier is in a homogeneous molten state, and the system temperature is higher than the melting point of the fungicide by more than 10°C, and then dripping it into the suspension system of the first high-speed shearing process, maintaining the temperature of the suspension system between 25°C and 30°C, and after the dripping is completed, continuing the high-speed shearing for 10 to 15 minutes, stopping the shearing and taking samples to detect the fineness of the dispersed particles. If the test is qualified, add a thickener, an antifreeze agent, a preservative, adjust the pH value, stir and mix evenly, and then take samples for inspection. If the particle size test is unqualified, sand grinding is required for remediation.

6. The method for preparing a composite suspension concentrate of shinazomib by acid precipitation and melt dispersion according to claim 5, characterized in that: The emulsifier includes one of castor oil polyoxyethylene ether, calcium dodecylbenzene sulfonate, styrylphenyl polyoxyethylene ether, alkylphenol formaldehyde resin polyoxyethylene ether, Ningru 700#, Ningru 33#34#37#, Nongru 0201, Nongru 0202, and LAE-9; the thickener includes one of xanthan gum, magnesium aluminum silicate, sodium carboxymethyl starch (CMS), gelatin, alginic acid, sodium alginate, propylene glycol alginate, carrageenan, pectin, gum arabic, hydroxypropyl starch, hydroxyethyl starch, dextrin, cyclodextrin, and carboxymethyl cellulose, or a combination of two; the antifreeze includes one of ethylene glycol, propylene glycol, glycerol, and polyethylene glycol; the preservative includes one of phenol, sodium sorbate, potassium sorbate, and isothiazolinone.

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