CN107853319B - 10% Prochloraz oxazole fluosilicate micro emulsion and preparation method thereof - Google Patents
10% Prochloraz oxazole fluosilicate micro emulsion and preparation method thereof Download PDFInfo
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- CN107853319B CN107853319B CN201711327502.5A CN201711327502A CN107853319B CN 107853319 B CN107853319 B CN 107853319B CN 201711327502 A CN201711327502 A CN 201711327502A CN 107853319 B CN107853319 B CN 107853319B
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- prochloraz
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- ethyl alcohol
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N55/00—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
- A01N25/04—Dispersions, emulsions, suspoemulsions, suspension concentrates or gels
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
- A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
- A01N47/38—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the group >N—CO—N< where at least one nitrogen atom is part of a heterocyclic ring; Thio analogues thereof
Abstract
The invention discloses a kind of 10% Prochloraz oxazole fluosilicate micro emulsions and preparation method thereof.The microemulsion by following mass percentages material composition: Prochloraz 2%, Flusilazole 8%, n,N-Dimethylformamide 10%, ethyl alcohol 8%-10%, agriculture breast 602#20%-25%, water are supplemented to 100%.The preparation method is as follows: Prochloraz and Flusilazole are dissolved in n,N-Dimethylformamide and the ethyl alcohol, it is mixed evenly later with agriculture breast 602#, is prepared into uniform solution；Then water is added under stiring, is initially formed the emulsion of Water-In-Oil, further by heating stirring, is inverted to the solution of oil-in-water type, is finally cooled to the light yellow transparent solution that room temperature spontaneously forms O/W.
Description
Technical field
The present invention relates to a kind of 10% Prochloraz oxazole fluosilicate micro emulsions and preparation method thereof.
Background technique
Pesticide as an indispensable ring in agricultural production at this stage, exploitation, using for farming production and
Economic development has direct influence, and China has even more reached surprising as traditional large agricultural country, the use of annual various pesticides
Tonnage.However the use of pesticide also brings problems while bringing economic benefit, especially environmental problem is [old
Luxuriant woods, Han Mouguo, the Anhui exploitation [J] the chemical industry of Wen Jiajun environment friendly agricultural novel form, 2004,128 (02): 2-5.].Many institute's weeks
Know, in modern production, pesticide is few direct using raw medicine, needs to add related auxiliaries, and according to a certain percentage and work
Sequence makes corresponding dosage form, so that agricultural facility be cooperated rationally efficiently to use.At this stage, relevant law prohibits all already
Production [the Henan present condition and developing tendency [J] of the China Ai Xiaokai, Zhu Zhongfeng formulations of pesticide of more high poison high residue raw medicines
Work, 2007,24 (08): 7-9.], so, the case where causing environmental pollution is more medicament improper use, medicament drift, medicine
Caused by auxiliary agent contained by agent itself, the abuse problem of auxiliary agent contained by Chinese medicine itself has become extremely serious [Wheeler
WB.Role of research and regulation in 50 years of pest management in
agriculture[J].J Agric Food Chem,2002,50(15),4151-4155.].Therefore, how to reduce in medicament
The dosage and exploitation environment friendly agricultural dosage form of auxiliary agent, have become the primary problems faced in formulation development.And it is compatible with the environment
Property good, low toxicity, efficient environment friendly agricultural dosage form --- water baseization preparation more enters the sight of people.
Existing water baseization preparation mainly includes the dosage forms such as suspending agent, microemulsion, aqueous emulsion, aqua.Suspending agent refer to by
Water-soluble general solid raw medicine is by being added suitable auxiliary agent, and manufactured raw medicine is uniform with 5 μm of partial size after pulverizing
The preparation being dispersed in water.Aqueous emulsion is similar to its, is the condition using high-speed stirred, cooperates a small amount of solvent, add suitable
Suitable emulsifier, by pesticide particle with the 0.1-50 μm of evenly dispersed preparation into water.The above two are as common water baseization system
Agent, the development cycle is low, easy to use, and extensive research and development have been obtained and utilize, such as 50% iprodione suspending agent, 6% is big
Allicin aqueous emulsion.But disadvantage is not suitable for it is also obvious that the product of the two obtained after processing is thermodynamic unstable system
It is used in long-term storage and more harsh environment, storage at normal temperature all must can be inevitably layered, in some extreme
Irreversible variation can even occur for situation, and [Feng Jianguo, Zhang little Jun, Zhao Zhewei wait the application of pesticide emulsion in water emulsifier
Present Research [J] pesticide, 2012,51 (10): 706- 709+723.], and processing conditions needed for the two is higher, needs certain
Equipment as support.The requirement of aqua is comparatively more harsh, prepare the raw medicine needed for it just need first its
Possess higher solubility in water, greatly limits the raw medicine type that can be applied.At this stage, in addition to a small number of raw medicines are extremely close
Water, most of is all slightly soluble raw medicine even not soluble in water, therefore widely applied aqua type is few, such as 10% grass is sweet
Phosphine aqua etc..
In conclusion in comparison, microemulsion physicochemical properties are relatively stable, the physicochemical property of raw medicine is wanted in preparation
Ask not high, general microemulsion formulation belongs to thermodynamic stable system [Zhang Chun in 0.1-0.01 μm of particle diameter of pesticide middle peasant's medicine
China, Wang Zhongwei, Huang Qiliang, wait microemulsion superiority and its current situation [J] pesticide science and management, 2006,27
(1):35-37+6.].As long as microemulsion formula is proper, it will be able to which completely, pesticide particle is evenly dispersed for dispersion rapidly in water
Everywhere to solution, the microemulsion for the excellent for substantially increasing the utilization efficiency of pesticide active ingredient, and being successfully prepared exists
It can keep for a long time being not in layering under room temperature.Simultaneously because microemulsion is the uniform system of thermodynamics, as long as theoretically matching
Side is proper, or slightly stirring or its thermoplastic polymer, can form the transparent or semitransparent solution of stable uniform, also just mean
, requirement of the preparation of microemulsion for equipment is lower, and hand operated mixing or general magnetic stirring apparatus can complete solution
Configuration.Certain microemulsion is also not without disadvantage, the still immature of theoretical side, effective component hydrolysis and adaptation for a long time
The problems such as temperature range is narrow is still problem urgently to be resolved, and [Gao Yangfan, Wang Jianhua, Wang Zhenhe wait the development of microemulsion existing
Shape and its preparation Study on influencing factors [J] Henan Science and Technology College's journal (natural science edition), 2007,35 (04): 44-46.].Cause
During this configuration microemulsion, formula, temperature, time and the agitating mode of preparation are required to by testing constantly adjustment,
It can determine that optimal preparation method.
Prochloraz selected by the present invention and Flusilazole, wherein Prochloraz belongs to imidazoles wide-spectrum bactericide, by inhibiting steroid
The biosynthesis of alcohol and work, no systemic action, it is splendid for multiple diseases preventive effect caused by sac fungus and Fungi Imperfecti [
Prompt dragon, Zhang Wanchang, Li Chuncong wait green syt [J] chemical reagent of bactericide prochloraz, 2010,32 (09): 856-
858.].And Flusilazole belongs to triazole bactericidal agent, by inhibiting sterol demethylation generation effect, has interior suction particularly with height
Equal fungies such as Ascomycetes, Basidiomycetes and Fungi Imperfecti fungi have the higher preventive effect [study on the synthesis of Li Jing's Flusilazole
The Tianjin [D] Hebei University of Technology, 2013.].The characteristics of the two compounding, medicament has both the two, bactericidal activity is higher, acts on machine
Reason is unique, is not easy to produce resistance, while having interior suction, protection, treatment, eradicant action.Though having the heat of the two compounding at this stage
The application of mist agent and aqueous emulsion, such as [Wang Shuming, Yang Yongzhi, Lan Ming wait .20% fluorine silicon to 20% Prochloraz Flusilazole thermal fog
Azoles Prochloraz thermal fog prevents and treats rubber tree powdery mildew Preliminary Report on Experiment [J] tropical agriculture science and technology, 2008,31 (01): 9+22.]
[Hu Min, Zhang Qiang .20% Flusilazole prochloraz aqueous emulsion prevent and treat cucumber anthracnose with 20% Prochloraz Flusilazole aqueous emulsion
[J] pesticide, 2006,45 (01): 64-65.].But there is no relevant reports in terms of microemulsion.
Summary of the invention
The object of the present invention is to provide a kind of 10% Prochloraz oxazole fluosilicate micro emulsions and preparation method thereof.
10% Prochloraz oxazole fluosilicate micro emulsion provided by the present invention, by the material composition of following mass percentages:
Prochloraz 2%, Flusilazole 8%, n,N-Dimethylformamide (DMF) 10%, ethyl alcohol 8%-10%, agriculture breast 602# (i.e. styrene
Base phenol polyoxyethylene ether 602#) 20%-25%, water is supplemented to 100%.
Preferably, the 10% Prochloraz oxazole fluosilicate micro emulsion, by the material composition of following mass percentages: miaow is fresh
Amine 2%, Flusilazole 8%, n,N-Dimethylformamide (DMF) 10%, ethyl alcohol 8%, agriculture breast 602# (i.e. styrylphenol polyoxy
Vinethene 602#) 25%, water is supplemented to 100%.
The water can be deionized water, standard hard water or tap water, preferably tap water.
10% Prochloraz oxazole fluosilicate micro emulsion provided by the present invention is prepared according to phase conversion method, including following steps
It is rapid: the Prochloraz and Flusilazole being dissolved in solvent (n,N-Dimethylformamide and ethyl alcohol), mixed later with agriculture breast 602#
It stirs evenly, is prepared into uniform solution；Then water is added under stiring, is initially formed the emulsion of Water-In-Oil, further leads to
Heating stirring is crossed, the solution of oil-in-water type is inverted to, is finally cooled to the pale yellow transparent that room temperature spontaneously forms O/W
Solution.
The stirring carries out in magnetic stirring apparatus.The revolving speed of the stirring is 100-200rpm.
The heating temperature of the heating stirring is 40-55 DEG C.
The present invention utilizes the property of Prochloraz and flusilazole, finds Flusilazole: Prochloraz=8 by early-stage study:
2 compounding has good control efficiency to mango anthracnose, and coefficient of synergism reaches 2.63.And also have in terms of delaying drug resistance
Certain effect.This research selects Flusilazole: Prochloraz=8:2 compound proportion, to 10% Prochloraz as exploitation point
Research and discovery is unfolded in oxazole fluosilicate micro emulsion preparation process.According to the general preparation method of microemulsion, simultaneously contrived experiment side is determined
Case.From solvent, single emulsifier screening screens to composite emulsifier, then arrives the optimization of formula and the measurement of correlated quality index,
The optimum proportioning of successive optimization pharmaceutical formulation and proportion, the final microemulsion for determining 10% Prochloraz Flusilazole is as follows: miaow is fresh
Amine 2%, Flusilazole 8%, DMF10%, ethyl alcohol 8%, emulsifier 25%, tap water is supplemented to 100%.
Detailed description of the invention
Fig. 1 is the preparation technology figure of 10% Prochloraz oxazole fluosilicate micro emulsion of the invention.
Fig. 2 is Flusilazole and Prochloraz standard items HPLC spectrogram.
Fig. 3 is Flusilazole standard items HPLC spectrogram.
Fig. 4 is Prochloraz standard items HPLC spectrogram.
Specific embodiment
Method of the invention is illustrated below by specific embodiment, but the present invention is not limited thereto, it is all at this
Any modifications, equivalent replacements, and improvements etc. done within the spirit and principle of invention, should be included in protection model of the invention
Within enclosing.
Experimental method used in following embodiments is conventional method unless otherwise specified.
The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.
Following percentage compositions as described in the examples are mass percentage unless otherwise specified.
Material
1. material installation
Electronic analytical balance, magnetic heating stirrer, high performance liquid chromatograph (Hitachi's electronics), electric heating constant temperature forced air drying
Case, digital control constant temperature water-bath, ultrasonic washing instrument.
2, primary drug
96% flusilazole (Shenzhen Nuopuxin Agricultural Chemical Co., Ltd), 97% Prochloraz (Jiangsu Hui Feng agrochemical stock
Part Co., Ltd production).
3, test solvent
Toluene, dimethylbenzene, acetone, n,N-Dimethylformamide (DMF), cyclohexanone, dimethyl sulfoxide, normal propyl alcohol, ethyl alcohol
(being AR).
4, emulsifier
Compound (2201), the castor oil of alkyl phenol polyoxyethylene ether (OP-10), anion and cationic surfactant
With ethylene oxide condensate (EL-20 and EL-12), nonylphenol polyoxyethylene ether (NP-10), alkyl phenol polyoxyethylene ether (TX-10
With TX-4), styrylphenol polyoxyethylene ether (500#, 602# and 604#), condensation compound of alkyl phenol and epoxy ethane (JFC-
II), secondary alcohol polyoxyethylene ether (S-15), fatty alcohol and ethylene oxide condensate (O-15), each emulsifier detailed nature see the table below
1。
The type and HLB value of 1 surfactant of table
Embodiment,
1.1 experimental method
1.1.1 the preparation process of 10% Prochloraz oxazole fluosilicate micro emulsion
The preparation of 10% Prochloraz oxazole fluosilicate micro emulsion uses phase conversion method (see Fig. 1).Raw medicine is completely dissolved in first molten
It in agent, is mixed evenly later with emulsifier, is prepared into uniform solution, be stirred continuously (revolving speed in magnetic stirring apparatus
Under 100rpm), it is slowly added into deionized water, is initially formed the emulsion of Water-In-Oil, further passes through the (heating of continuous heating stirring
Temperature 45 C, speed of agitator 100rpm), it is inverted to the solution of oil-in-water type, room temperature is finally cooled to and spontaneously forms O/W
Light yellow transparent solution.
1.1.2 the selection method of solvent
According to two kinds of raw medicine properties, first select 8 kinds of solvents, then take a certain amount of raw medicine in tool plug test tube, successively plus
Enter 8 kinds of different solvents, under equal conditions, observes respective dissolution situation, record dosage is few and dissolves complete type.It connects
Will dissolve complete solvent and be respectively put into 0 DEG C of refrigerator and 54 DEG C of temperature control boxs and place, whether there is or not precipitatings for observation after 24 hours
Or layering, if mobility is still preferable after cold and hot storage, the solvent that no precipitated crystal washes out is selected as target solvent.
1.1.3 the selection method of surfactant
The screening of surfactant is the important link of microemulsion preparation, to the oily mutually stabilization in water phase of microemulsion
All play the role of with phase reversal vital.This experiment first using HLB value as refer to, to 13 kinds of common emulsifiers into
Gone screening, on the basis of filtering out effect and preferably emulsifying single dose, by calculating HLB value, the single dose that will be singled out into
Composite emulsifier, is then compared, so that it is determined that the optimal emulsifier of effect out by row compounding with single dose.Since microemulsion holds
Phase inversion easily occurs and precipitates crystal, microemulsion is often needed using the surfactant for being equivalent to 2-5 times of active compound content, preliminary true
Determine surface-active contents and is unified for 20% to carry out further experiment.
1.1.4 the selection of different quality
Condition of water quality has larger impact for the stability of preparation and phase reversal, respectively with tap water, deionization
Best water quality needed for water, three kinds of standard hard water different water quality carry out 10% Prochloraz oxazole fluosilicate micro emulsion of Research on configuration.
The quality analysis and detection of 1.2 10% Prochloraz oxazole fluosilicate micro emulsions
1.2.1 appearance detects
According in GB/T 19378-2003, clarification transparent and homogeneous is presented or translucent for qualification in solution.
1.2.2 the measurement of 10% Prochloraz Flusilazole content
(1) preparation of sample
The preparation of 100g sample: after capacity is placed zero on an electronic balance for the 200ml beaker for being placed with magnetic rotor,
It weighs 97% Prochloraz raw medicine 2.0619g (folding hundred), 96% Flusilazole 8.3333g (folding hundred), ethyl alcohol 10g, DMF 8g are put into burning
In cup, beaker is then placed on magnetic stirring apparatus heating stirring and dissolves to raw medicine and is sufficiently uniformly mixed with solvent, then
It weighs 25g 602# and is added in beaker and continue to stir, be eventually adding 47g tap water and stirred evenly into beaker, is cooled to room temperature standby
With.
(2) preparation of standard solution
Weigh Prochloraz, Flusilazole standard items 0.01g (is accurately dissolved dilute to 0.0002g) in 10ml volumetric flask with methanol
Graduation mark is released and be settled to, is shaken up, stands, then takes the solution 1ml after constant volume in 10ml volumetric flask, with methanol constant volume again
Afterwards, it shakes up, it is to be measured.
(3) preparation of sample solution
After preparing sample solution, sample 0.01g is weighed (accurately to 0.0002g) in 10ml volumetric flask.Take a small amount of third
Ketone dissolution, again with methanol is settled to graduation mark, shakes up, then takes the solution 1ml after constant volume in 10ml volumetric flask, again with methanol
After constant volume, shake up, it is to be measured finally with 0.22 μm of filtering with microporous membrane.
(4) chromatographic condition of the measurement of sample
Chromatographic column: Amethyst C18-H (4.6mm × 250mm, 5 μm)；Detector: UV detector；Column temperature: 30 DEG C,
Flow velocity: 1.0ml/min；Sample volume: 20 μ l.Mobile phase: methanol-water (volume ratio 85:15), Prochloraz Detection wavelength: 230nm,
Flusilazole Detection wavelength: 220nm, retention time: Flusilazole about 5.5min, Prochloraz about 7.2min (Fig. 2,3,4).
(5) method of Specimen Determination
Under above-mentioned chromatographic condition, after waiting instrumental baseline steady, without obvious miscellaneous peak, continuously into three needle standard solution, to
When the response of the opposite variation of adjacent two needle is less than 1.5%, carried out according to the sequence of standard solution, sample solution, standard solution
Measurement.Flusilazole, Prochloraz standard specimen and Flusilazole Prochloraz confection liquid chromatogram are shown in figure.
1.2.3pH it is worth the measuring method of range
It is carried out according to GB/T 1601-1993, calibrates pH meter using standard solution, then take 1g sample in 100ml beaker,
100ml water is added, acutely vibrates 1min, stands 1min.The glass electrode rinsed well and calomel electrode are inserted into sample solution
Middle measurement pH value, parallel to repeat three times, the absolute error of measurement result is less than 0.1, and taking its arithmetic average is the pH of sample
Value.Respectively take a sample again, be continuously added acetic acid and ammonium hydroxide respectively, until occur it is muddy, in triplicate, record as a result, this when
The pH value at quarter is critical pH value.
1.2.4 the measuring method of pesticidal emulsion stability
It is carried out according to GB/T 1603-2001, under the conditions of 30 DEG C, takes 1g sample in 250ml beaker, 100ml is added
Standard hard water, and after being stirred continuously and being made into 100ml emulsion, 100ml graduated cylinder is moved it to, 30 DEG C of ± 2 DEG C of waters bath with thermostatic control are put in
In pot, stand 1h, on without oil slick, lower no precipitating, i.e. judgement lotion is qualified.
1.2.5 low-temperature stability
It is carried out according to GB/T 19137-2003, takes 80ml sample to be placed in 100ml centrifuge tube, be cooled in refrigerator
0 ± 2 DEG C, primary every 15min stirring, each 15s keeps 1h, and after recording cosmetic variation situation, continuation is placed in refrigerator
After 7 days, 7 days, the centrifuge tube place of taking is restored out to room temperature, 15min is centrifuged, the volume of solution bottom precipitate is observed, through over vibration
Without being precipitated without layering after swinging, for qualification.
1.2.6 high-temperature stability
It is carried out according to GB/T 19136-2003, (will avoid trying in the clean ampoule bottle of 30ml sample injection with syringe
Sample contacts bottleneck), it is placed in canister after ampoule bottle is sealed by thermal-flame, then canister is put into 54 ± 2
In DEG C water-bath, after placing 14 days, taking-up is cooled to room temperature, and the measurement of active constituent content is completed in for 24 hours, and heat storage requires
Effective resolution ratio < 5%.
1.2.7 persistent foamability
It is carried out according to GB/T 28137-2011, has stiffened water in plug graduated cylinder to 250ml and be weighed into 1g to 180ml graduation mark
Sample, then stiffened water is at away from graduated cylinder plug bottom 9 ± 0.1cm graduation mark, centered on graduated cylinder bottom, after turning upside down 30 times
(each 2s) stands 1min, records foam volume.
2. result and analysis
2.1 solvent screening results
It is related to waiting according to Prochloraz, the physical property of Flusilazole, solubility by consulting pertinent literature combination preliminary experiment
Characteristic has determined that 8 kinds of Alternative solvents are as follows, takes a certain amount of raw medicine in proportion, under identical condition, uses this 8 kinds of difference
The raw medicine of equivalent is dissolved, record dissolution situation the results are shown in Table 2.
Dissolution situation of 2 different solvents of table to raw medicine
According to the dissolution of upper table as a result, showing that acetone is best to raw medicine effect solute effect, but acetone is due to its flash-point mistake
It is low, only -20 DEG C, therefore the similar ethyl alcohol of dissolved efficiency is paid the utmost attention to, however the flash-point of ethyl alcohol is relatively low, comprehensively considers DMF
Alternately solvent uses.The above-mentioned solvent filtered out is first being carried out cold and hot storage experiment by the influence in view of temperature to solvent
Later, solvent for use is further screened, concrete condition is shown in Table 3.
3 different solvents of table are under the conditions of cold and hot storage to the dissolution situation of raw medicine
Note: √ is clear, ↓ it is that crystallization is precipitated ,-indicate unqualified
After cold and hot storage, in addition to toluene and dimethylbenzene make two groups of solvent, there is raw medicine crystallization to be precipitated in cold storage, other
Group dissolves situation and the state of good qualification is all presented in mobility either under normal temperature conditions or under the conditions of cold and hot storage.Cause
This is according to the data judging of upper table, and using ethyl alcohol as primary solvent, DMF is as spare solvent.Next respectively with different
Emulsifier attempts both solvents, higher according to moisture content in microemulsion, the few feature of solvent content, in conjunction with pre- reality
It tests, the solvent content in microemulsion is uniformly set as 15% carry out follow-up test.
The determination of 2.2 emulsifiers
2.2.1 the screening of single emulsifier
According to the requirement in GB/T 1603-2001 (agricultural-chemical emulsion 4stability determination), first to single emulsifier into
Row selection.Referring to the method in GB/T 1603-2001, Prochloraz raw medicine 0.4124g, flusilazole 1.6667g are weighed,
Add ethyl alcohol or DMF 2g to be dissolved, then weigh 4g emulsifier and solution is added, is stirred uniformly.Under 30 DEG C of ± 2 DEG C of environment,
1ml solution is drawn at water surface 2cm height, to be added drop-wise to dropwise equipped with dilution observation in 200ml standard hard water.Every kind of cream
Agent is repeated 3 times, assessment grade such as the following table 4, and the above are qualification, next emulsibility gradings to use table 4 as foundation for second level.
The oil of table 4 mutually dispersity in water, the relationship between emulsified state and assessment grade
Using ethyl alcohol as solvent, selecting for single emulsifier is carried out, according to the grading of 4 emulsified state of table, is as a result detailed in down
Table 5, emulsifier effect only have 602# and NP-10 up to standard, still keep good emulsified state, and 602# after 24h
Emulsifying effectiveness be better than NP-10, therefore think that the emulsifying effectiveness of 602# is best when ethyl alcohol is as solvent.
Emulsification situation of 5 different emulsifiers of table to Prochloraz Flusilazole
Note: ↓ indicate precipitating, × indicating unqualified, * indicates that no Precipitation, √ indicate qualified
Using DMF as solvent, selecting for single emulsifier is carried out, according to the grading of 4 emulsified state of table, the results are shown in Table 6, together
Sample discovery emulsifier effect only has 602# and NP-10 up to standard, and still keeps good emulsified state after 24h, and
The emulsifying effectiveness of 602# is better than NP-10, therefore thinks that the emulsifying effectiveness of 602# is best when DMF is as solvent.
Emulsification situation of 6 different emulsifiers of table to Prochloraz Flusilazole
Note: ↓ indicate precipitating, × indicating unqualified, * indicates that no Precipitation, √ indicate qualified
According to ethyl alcohol and DMF respectively as solvent, in the selection result of single emulsifier, it can be seen that 602# and NP-
There is good emulsifying effectiveness at normal temperature when 10 pairs of two kinds of reagents are as solvent.Therefore setting solvent dosage is 15%, emulsification
When agent dosage is 20%, remaining is supplied with water, is carried out the experiment of further cold and hot storage, is further looked at 602#'s and NP-10
Emulsifiability.
When using ethyl alcohol as solvent, in the microemulsion for preparing single emulsifier, 602# can be well by antiphase method
Make preparation.Right NP-10 cannot attempt oil emulsion and add under existing ratio by antiphase method successful formulation, at the same time
Water law and emulsified water oiling are prepared with oil emulsion water feeding method containing NP-10's finally, finding by the trial repeatedly to NP-10
Preparation is only lower than the preparation that 30% Shi Caineng is successfully prepared, and is successfully prepared in water content, and emulsifying effectiveness can only achieve three
Grade (table 4), it is ineffective, Precipitation is had after stirring.Therefore 602# has only been carried out to cold and hot storage experiment in proportion.As a result see
Table 7, using ethyl alcohol as solvent, 602# single dose shows stabilization under cold and hot storage state, further can be tested.
The cold and hot storage situation of 7 602# single dose of table
When using DMF as solvent, in the microemulsion for preparing single emulsifier, same problem, 602# are also encountered
By antiphase method can well according to and certainty ratio with preparing preparation, and NP-10 cannot, as a result make with ethyl alcohol is used
Similar when for solvent, for single dose NP-10 when being successfully prepared with oil emulsion water feeding method, water content therein is lower than 30%, and preparation
Emulsibility is poor, is not able to satisfy the standard of second level (table 4), and have Precipitation after stirring.Therefore only 602# is carried out in proportion
Cold and hot storage experiment.The results are shown in Table 8, using DMF as solvent, 602# single dose shows stabilization under cold and hot storage state, can do into
The experiment of one step.
The cold and hot storage situation of 8 602# single dose of table
By above-mentioned two groups of experiments, as solvent, 602# can play emulsification well and make either ethyl alcohol or DMF
With, table 7 and table 8 are compared, it can be found that when DMF makees solvent, through when thermal stability it is more preferable.So two kinds of solvents can be selected
As solvent complex, ratio optimization experiment, observing effect are carried out.But [Gao Yangfan, Wang Jianhua, Wang Zhenhe wait to Wang Jianhua etc.
Microemulsion current situation and its preparation Study on influencing factors [J] Henan Science and Technology College's journal (natural science edition), 2007,
35 (04): 44-46.] people to microemulsion research shows that: single nonionic emulsifier is highly prone to the influence of temperature change,
In prolonged place, with the rising of temperature, easily there is turbid phenomenon；And compound emulsifier, it can be for greater flexibility
The surface tension for changing water, adapts to different environmental conditions.Especially anionic surfactant and nonionic surfactant
Compounding, when the temperature rises, anionic surfactant hydrophily will increase, nonionic surface active agent hydrophobicity meeting
Increase, conversely,.Comprehensively consider, is next answered nonionic surfactant 602# and other anion emulsifiers
Match, after filtering out more preferable more stable emulsifier ratio, then carries out ratio optimization experiment.
2.2.2 compound screening is carried out using HLB value, the property of emulsifier
By consulting literatures and preliminary experiment, when preparing oil-in-water microemulsion, the HLB value of emulsifier is generally 12~15
Between effect it is best, comprehensive literature, often select lipophilic anionic surfactant and 12 or more strongly hydrophilic of HLB value it is non-from
Son compound use [development [J] modern of Li Hong, Zhang Leilei .15% azoles phosphorus chlorpyrifos micro emulsion, 2012,11 (02):
23-27.].By the screening experiment of single emulsifier, it can be seen that single dose can effect preferably there was only 602#, but due to NP-
10 emulsified state at normal temperature is not bad, it is possible that after being compounded with the anionic surfactant of lipophilic, preparation
Emulsifying property is significantly improved.According to the HLB value for each emulsifier chosen in experiment and type (table 1), anion table
Face property agent 500# belongs to the emulsifier of lipophilic, can be compounded with nonionic surfactant 602#, NP-10, be combined into HLB
The composite emulsifier being worth between 12~15.
Using ethyl alcohol as solvent, according to the calculating of HLB value, when accounting is higher than 80% to 602# and NP-10 in emulsifier total amount
When, the HLB value of mixed emulsifier is just able to satisfy the interval range 12~15.By 602# and 500# respectively with 4:1,6:1,8:
1, it prepares mixed emulsifier and carries out stability of emulsion test；Equally, by NP-10 and 500# respectively with 4:1,6:1,8:1, preparation
Mixed emulsifier carries out stability of emulsion test out, and opinion rating is shown in Table 4.It the results are shown in Table 9, using ethyl alcohol as solvent, two kinds mixed
Result with mode is undesirable, and emulsifying effectiveness is poor, cannot use as the emulsifier of preparation.
The emulsification situation of the mixed emulsifier of table 9
Note: ↓ indicate precipitating, × indicating unqualified, * indicates no Precipitation
Using DMF as solvent, after the calculating of HLB value, by 602# and 500# respectively with 4:1,6:1,8:1, preparation
Mixed emulsifier carries out stability of emulsion test out；By NP-10 and 500# respectively with 4:1,6:1,8:1, mixed emulsification is prepared
Agent carries out stability of emulsion test.It the results are shown in Table 10, using DMF as solvent, the result of two kinds of mixed modes is undesirable, emulsification
Effect is poor, cannot use as the emulsifier of preparation.
The emulsification situation of the mixed solvent of table 10
Note: ↓ indicate precipitating, × indicating unqualified, * indicates no Precipitation
In table 9 and table 10 as the result is shown: using ethyl alcohol or DMF as solvent, respectively with 602# and 500#, NP-10 and
For 500# mixture as emulsifier, emulsifying effectiveness is bad, cannot reach the standard of preparation stability of emulsion, and compared to list
The stability of emulsion of agent, gap are larger.Comprehensively consider, determines the screening examination for carrying out optimum formula using 602# single dose as emulsifier
It tests.
The screening of 2.3 optimum proportionings
Using the ethyl alcohol and DMF picked out as solvent, 602# carries out Orthogonal Experiment and Design as emulsifier, to determine most
Good proportion.It is influenced with the selection of the type of solvent, the ratio of different solvents, the ratio of emulsifier, different quality on preparation is prepared
Biggish four factors design the horizontal Orthogonal Experiment and Design of four factor three, are shown in Table 11, and use L9 (34) orthogonal arrage,
Under the conditions of 54 DEG C and 0 DEG C, cold and hot storage experiment is carried out respectively, using layering ratio as standard, probes into the optimum proportioning of preparation.By right
The very poor comparison of each factor in table 12, the primary and secondary sequence being discharged by very poor size are as follows: C > A > B > D, the wherein amount of emulsifier
(C) it is maximum to illustrate that the amount (C) of emulsifier influences the layering ratio of preparation in heat storage for maximum.The very poor of each factor is analyzed,
When heat storage layering ratio minimum, the formula of preparation are as follows: DMF (A3) 10%, ethyl alcohol (B2) 8%, 602# (C3) 25%, tap water (D3)
When；By being compared to the very poor of factor in table 13, the primary and secondary sequence that is discharged by very poor size are as follows: C > B > A=D, explanation
The amount (C) of emulsifier is also that influence is maximum on the layering ratio of preparation in cold storage.Analyze the very poor of each factor, cold storage layering
When rate minimum, the formula of preparation are as follows: DMF (A3) 10%, ethyl alcohol (B2) 8% or ethyl alcohol (B3) 10%, 602# (C2) 20% or
Person 602# (C3) 25%, tap water (D2)；Thermal Synthetic storage and cold storage are as a result, the amount (C) of emulsifier is to influence the main effect of layering ratio
It answers, the type (D) of water influences minimum to layering ratio, therefore selection process is A3B2C3D3, i.e. DMF (A3) 10%, ethyl alcohol (B2)
8%, 602# (C3) 25%, tap water (D3)。
11 10% Prochloraz Flusilazole factor level table of table
12 10% Prochloraz Flusilazole heat of table stores orthogonal test layering ratio result
The cold storage orthogonal test layering ratio result of 13 10% Prochloraz Flusilazole of table
The quality analysis and detection of 2.4 optimum proportionings
2.4.1 appearance
When dosage form proportion is Prochloraz 2%, Flusilazole 8%, DMF10%, ethyl alcohol 8%, emulsifier 25%, tap water supplement
When to 100%, under 10% Prochloraz oxazole fluosilicate micro emulsion room temperature, faint yellow clear state is presented, can with tap water with
Arbitrary proportion is miscible.
2.4.2 the stability of emulsion of optimum proportioning
It is carried out according in national standard (GB/T 1603-2001), after sample is added dropwise to standard hard water, can disperse automatically, stir
Form clear transparent solutions after mixing, place for 24 hours, on without oil slick, lower no precipitating, sample stability of emulsion is qualified.2.4.3 cold storage
Stability Determination result
Sample is deposited under the conditions of 0 DEG C according to the measuring method of low-temperature stability in national standard (GB/T 19137-2003)
It is centrifuged after putting 7 days, no layering and crystalline polamer occur, and meet national standard, illustrate that the cold storage of sample is qualified.
2.4.4 heat storage stability measurement result
According to the measuring method of national standard (GB/T19136-2003) high temperature stability, under the conditions of 54 DEG C, by sample heat
After storage 14 days, 14 are shown in Table, Prochloraz and Flusilazole resolution ratio are respectively less than 5%, illustrate that the storage of sample heat is qualified.
14 10% Prochloraz Flusilazole heat of table stores resolution ratio
2.4.5 the measurement of persistent foamability
It is carried out according to national standard (GB/T 28137-2011), after oscillation tool plug graduated cylinder, stands 1min, measuring foam volume is
32ml.There is not definite regulation to microemulsion bubble content in view of in national standard, and in recent years, Li Hong[17]The micro emulsion of equal production
After agent is compared, belong to normal range (NR).
2.4.6pH the measurement of value
It is carried out according to national standard (GB/T 1601-1993), after calibrating pH meter, is measured in parallel three times, the results are shown in Table 15.
2.4.7pH it is worth the measurement of range
It is carried out according to national standard (GB/T 1601-1993), after calibrating pH meter, by being continuously added weak acid-base accommodation pH value,
Observation discovery sample is more sensitive to alkalinity, and when pH value is greater than 10, sample will appear the phenomenon that lotion is precipitated, in measurement pH value
While also the emulsified state of sample is determined, in pH5.0~7.6, sample is not in precipitation phenomenon, and cream
It is best to change effect.
The determination of 2.5 optimum proportioning formulas and every quality index
The optimum proportioning of 10% Prochloraz oxazole fluosilicate micro emulsion: Prochloraz 2%, Flusilazole 8%, DMF10%, ethyl alcohol
8%, emulsifier 25%, tap water is supplemented to 100%.10% Prochloraz Flusilazole indices are shown in Table 16.
16 10% Prochloraz Flusilazole items quality index of table
In recent years, since people are for the appearance of the continuous enhancing and relevant laws and regulations of environmental protection consciousness, many works
Limited for the organic solvent that formulation uses and use and produce so that the high dosage form of part organic solvent content accounting also by
Limitation application, such as missible oil.Water baseization preparation becomes to be concerned, as the microemulsion of wherein one of representative, moisture content
It is general higher, prepare that organic solvent used is less, and preparation effective component dispersibility itself is high, it is easy to use, it is compatible with the environment
Property is good, and the requirement to production equipment is relatively low.It can protect environment to a certain extent in this way and reduce the cost of business men, it is special
It is not to be prepared into microemulsion using corresponding pesticidal properties mixture, on the one hand, can in new pesticide R&D cycle extended today
To play the role of expansion preventive effect, delaying drug resistance using the interaction between different raw medicines；On the other hand, microemulsion is effective
The high property with easy processing of ingredient dispersibility, can be effectively reduced production cost.
The present invention utilizes the property of Prochloraz and flusilazole, according to the known mix ratio with good preventive effect, according to
The general preparation method of microemulsion determines simultaneously contrived experiment scheme.From solvent, single emulsifier screening is sieved to composite emulsifier
Choosing, then to the optimization of formula and the measurement of correlated quality index, successive optimization pharmaceutical formulation and proportion, final determining 10% miaow are fresh
The optimum proportioning of the microemulsion of amine Flusilazole is as follows: Prochloraz 2%, Flusilazole 8%, DMF10%, ethyl alcohol 8%, emulsifier
25%, tap water is supplemented to 100%.
Claims (6)
1. a kind of 10% Prochloraz oxazole fluosilicate micro emulsion, by the material composition of following mass percentages: Prochloraz 2%, fluorine
Silicon azoles 8%, n,N-Dimethylformamide 10%, ethyl alcohol 8%-10%, agriculture breast 602#20%-25%, water are supplemented to 100%.
2. 10% Prochloraz oxazole fluosilicate micro emulsion according to claim 1, it is characterised in that: 10% Prochloraz
Oxazole fluosilicate micro emulsion, by the material composition of following mass percentages: Prochloraz 2%, Flusilazole 8%, N, N- dimethyl formyl
Amine 10%, ethyl alcohol 8%, agriculture breast 602#25%, water are supplemented to 100%.
3. 10% Prochloraz oxazole fluosilicate micro emulsion according to claim 1 or 2, it is characterised in that: the water be go from
Sub- water, standard hard water or tap water.
4. the preparation method of the described in any item 10% Prochloraz oxazole fluosilicate micro emulsions of claim 1-3, includes the following steps:
The Prochloraz and the Flusilazole are dissolved in the n,N-Dimethylformamide and the ethyl alcohol, later with the agriculture breast
602# is mixed evenly, and is prepared into uniform solution；Then water is added under stiring, is initially formed the emulsion of Water-In-Oil, then
Further by heating stirring, it is inverted to the solution of oil-in-water type, room temperature is finally cooled to and spontaneously forms the yellowish of O/W
Color clear solution.
5. the preparation method according to claim 4, it is characterised in that: the stirring carries out in magnetic stirring apparatus；It is described
The revolving speed of stirring is 100-200rpm.
6. preparation method according to claim 4 or 5, it is characterised in that: the heating temperature of the heating stirring is 40-55
℃。
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