CN115399332B - Oxalin clathrate, preparation method thereof and composition containing same - Google Patents
Oxalin clathrate, preparation method thereof and composition containing same Download PDFInfo
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- CN115399332B CN115399332B CN202211050169.9A CN202211050169A CN115399332B CN 115399332 B CN115399332 B CN 115399332B CN 202211050169 A CN202211050169 A CN 202211050169A CN 115399332 B CN115399332 B CN 115399332B
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- cyclodextrin
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000000203 mixture Substances 0.000 title claims abstract description 16
- DXGPLGPVXNBIQZ-UHFFFAOYSA-L copper;2-hydroxybenzoate;methyl n-(1h-benzimidazol-2-yl)carbamate;6-methyl-n-phenyl-2,3-dihydro-1,4-oxathiine-5-carboxamide;quinolin-8-olate Chemical compound [Cu+2].OC1=CC=CC=C1C([O-])=O.C1=CN=C2C([O-])=CC=CC2=C1.C1=CC=C2NC(NC(=O)OC)=NC2=C1.S1CCOC(C)=C1C(=O)NC1=CC=CC=C1 DXGPLGPVXNBIQZ-UHFFFAOYSA-L 0.000 title description 4
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- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 57
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- SOHAVULMGIITDH-ZXPSTKSJSA-N (1S,9R,14E)-14-(1H-imidazol-5-ylmethylidene)-2,11-dimethoxy-9-(2-methylbut-3-en-2-yl)-2,13,16-triazatetracyclo[7.7.0.01,13.03,8]hexadeca-3,5,7,10-tetraene-12,15-dione Chemical compound C([C@]1(C2=CC=CC=C2N([C@@]21NC1=O)OC)C(C)(C)C=C)=C(OC)C(=O)N2\C1=C\C1=CNC=N1 SOHAVULMGIITDH-ZXPSTKSJSA-N 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 17
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- CHNUNORXWHYHNE-UHFFFAOYSA-N Oxadiazon Chemical compound C1=C(Cl)C(OC(C)C)=CC(N2C(OC(=N2)C(C)(C)C)=O)=C1Cl CHNUNORXWHYHNE-UHFFFAOYSA-N 0.000 description 3
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- CELWCAITJAEQNL-UHFFFAOYSA-N oxan-2-ol Chemical compound OC1CCCCO1 CELWCAITJAEQNL-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- IHNSIFFSNUQGQN-UHFFFAOYSA-N tioxazafen Chemical compound C1=CSC(C=2ON=C(N=2)C=2C=CC=CC=2)=C1 IHNSIFFSNUQGQN-UHFFFAOYSA-N 0.000 description 2
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229910007572 Zn-K Inorganic materials 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
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- RKTYLMNFRDHKIL-UHFFFAOYSA-N copper;5,10,15,20-tetraphenylporphyrin-22,24-diide Chemical compound [Cu+2].C1=CC(C(=C2C=CC([N-]2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3[N-]2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 RKTYLMNFRDHKIL-UHFFFAOYSA-N 0.000 description 1
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- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
-
- 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
- A01N25/26—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 in coated particulate form
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P5/00—Nematocides
Abstract
The invention relates to an oxathiolane-cyclodextrin inclusion compound, which comprises an active ingredient of oxathiolane and cyclodextrin as an inclusion material. The invention also relates to a preparation method of the oxairenol-cyclodextrin inclusion compound, which comprises the following steps: dissolving oxadiol in a medium to obtain a medium solution, dissolving cyclodextrin in a solvent to obtain a wall material, dripping the medium solution into the wall material to form an inclusion compound microcapsule, and crystallizing, separating and drying to obtain a solid inclusion compound. The invention further relates to a composition containing the inclusion compound.
Description
Technical Field
The present application relates to an oxalin-cyclodextrin inclusion compound, a method of preparing the same, and a composition containing the same.
Background
3-phenyl-5- (thiophen-2-yl) - [1,2,4] oxadiazole (Tioxazafen, hereinafter referred to as oxazafen) is a nematicide and shows excellent control effects on cyst nematodes, root-knot nematodes, reniform nematodes and the like. However, the medicine has low water solubility (1.24 mg/L), needs a large amount of organic solvents when in use, pollutes the environment and has higher cost; in addition, the medicine has sensitization and skin irritation, and can cause allergy or skin irritation of contact personnel in synthesis and use.
Disclosure of Invention
In view of the above, the present invention relates to an oxathiols-cyclodextrin inclusion compound comprising the active ingredient oxathiols and cyclodextrin as inclusion material. The inclusion compound can improve stability and water solubility of the oxathiols, reduce sensitization and skin irritation of the oxathiols and prolong release time of the oxathiols.
The invention also relates to a method for preparing the oxawire phenol-cyclodextrin inclusion compound and a composition containing the inclusion compound.
In particular, the invention relates to:
(1) An oxathiols-cyclodextrin inclusion compound comprising the active ingredient oxathiols and cyclodextrin as inclusion material.
(2) The oxathiols-cyclodextrin inclusion compound according to (1) above, wherein the cyclodextrin is β -cyclodextrin (β -CD).
(3) The oxathiols-cyclodextrin inclusion compound according to (1) or (2), wherein the amount of the oxathiols as an active ingredient is 10-20 wt%.
(4) The process for producing an oxawire phenol-cyclodextrin inclusion compound according to any one of the above (1) to (3), comprising the steps of: dissolving oxadiol in a medium to obtain a medium solution, dissolving cyclodextrin in a solvent to obtain a wall material, dripping the medium solution into the wall material to form an inclusion compound microcapsule, and crystallizing, separating and drying to obtain a solid inclusion compound.
(5) The production method according to the above (4), wherein the medium solution tube is extended to below the surface of the wall material for dropwise addition at the time of the dropwise addition.
(6) The production method of the above (4) or (5), wherein the medium is methanol, ethanol, acetonitrile, acetone, an ethanol/acetone mixture, a methanol/acetone mixture, an acetone/acetonitrile mixture, or an ethanol/acetonitrile mixture, preferably methanol, more preferably the volume ratio of the two solvents in each of the above mixtures is 1:1.
(7) The production process according to any one of the above (4) to (6), wherein the solvent of the cyclodextrin is water.
(8) The production method of any one of the above (4) to (7), wherein the feeding ratio of cyclodextrin to oxathiols is (1.5 to 2.5) in terms of a molar ratio: 1, more preferably (1.5 to 2.0): 1.
(9) A composition comprising the oxairesinol-cyclodextrin inclusion compound described in any one of (1) to (3) above, and an auxiliary material which is allowed to be used in any pesticide formulation.
Drawings
FIG. 1 is a schematic illustration of the preparation flow of the oxawire phenol-cyclodextrin inclusion compound of the present invention.
FIG. 2 is a DSC curve measured in example 2.
FIG. 3 is a graph of TG curve measured in example 3.
Fig. 4 is an XRD pattern measured in example 4.
Fig. 5 is an SEM image measured in example 5.
Fig. 6 is an SSNMR chart measured in example 6, wherein fig. 6A is an SSNMR chart of β -CD, fig. 6B is an SSNMR chart of oxalin, and fig. 6C is an SSNMR chart of an oxalin-cyclodextrin inclusion compound.
Fig. 7 is a release profile of the inventive oxathiolane-cyclodextrin inclusion compound measured in example 9, in which fig. 7A is a release profile with ultrapure water as a release medium and fig. 7B is a release profile with a 30% aqueous isopropanol solution as a release medium.
Detailed Description
In this application, the term "oxalin-cyclodextrin inclusion compound" refers to a complex formed by the inclusion of an oxalin molecule, in whole or in part, into the cyclodextrin molecular cavity.
The oxathiols have a structure represented by the following formula (1) and can be prepared, for example, by reference to the methods disclosed in chinese patent applications CN101820761a and CN104936451 a:
in some embodiments, beta-cyclodextrin (beta-CD) is used for cyclodextrin because of its moderate molecular holes and low cost of production.
In some embodiments, the active ingredient, the oxathiols, in the oxathiols-cyclodextrin inclusion compound has a drug loading% of 10-20% by weight, the drug loading% calculated as follows:
the preparation method of the oxairenol-cyclodextrin inclusion compound disclosed by the invention is shown in figure 1, and comprises the following steps of: dissolving oxadiol in a medium to obtain a medium solution, dissolving cyclodextrin in water to obtain a wall material, dripping the medium solution into the wall material to form an inclusion compound microcapsule, and then separating and drying to obtain a solid inclusion compound.
The oxaline phenol is a guest molecule with very low water solubility, in the inclusion process, cyclodextrin is firstly dissolved in water, the oxaline phenol needs to be firstly dissolved in a medium to improve the dispersity, and the oxaline phenol cannot be effectively dispersed in an inclusion system without the medium, so that caking can occur or the oxaline phenol is adsorbed on the outer wall of the cyclodextrin to influence the formation of cyclodextrin inclusion compound.
The medium for dissolving the oxathiols needs to meet the following conditions: (1) is mutually dissolved with water to form a homogeneous system. Cyclodextrin inclusion is a process that a hydrophobic part of a medicine enters a cyclodextrin cavity to replace cyclodextrin high-energy water, and if a medium is insoluble in water, the medium cannot be a homogeneous system and cannot enter the cavity; (2) The cyclodextrin has a solubility in the medium that is less than its solubility in water, preferably the cyclodextrin is insoluble or slightly soluble in the medium. If the solubility of the cyclodextrin in the medium is greater than that of the cyclodextrin in water, the cyclodextrin can be preferentially mutually dissolved with the medium in the system, so that the oxaline phenol is separated out, and the inclusion process is influenced; (3) selecting a low boiling point solvent and not lower than the inclusion temperature. If the boiling point of the selected medium solution is very high, the inclusion compound is not easy to thoroughly dry the solvent in the drying process, so that the encapsulation rate is affected; if the boiling point is too low, the medium solvent is gasified directly in the inclusion process, which affects the inclusion process.
In the preparation process of the oxawire phenol-cyclodextrin inclusion compound, when the medium solution of the oxawire phenol is mixed with the cyclodextrin solution serving as a wall material, a medium solution pipe is required to be extended to be below the liquid level of the cyclodextrin solution and then dropwise added. If the solution does not extend below the liquid level and is added dropwise, the solution of the medium is added dropwise at the liquid level of the cyclodextrin solution, and the solution is mutually dissolved to cause that the oxa-line phenol can be instantaneously separated out and float above the liquid level, so that the inclusion process is not facilitated.
In addition, cyclodextrin, particularly β -CD, acts as a slightly tapered hollow cylindrical stereoring structure, and guest molecules can selectively enter the cavity. The stoichiometry of inclusion compound formed by different guest molecules and cyclodextrin is different, and the encapsulation efficiency is affected. In the preparation method of the inclusion compound, the preferable feeding ratio of cyclodextrin to oxadiazon is (1.5-2.5) according to the mole ratio: 1, more preferably (1.5 to 2.0): 1. the feed ratio of the oxathiols is too large, so that more oxathiols are dissociated outside cyclodextrin, and unnecessary waste of the oxathiols is caused; the too small feed ratio of the oxathiols can cause too low relative quantity of the oxathiols participating in the inclusion process, and a large quantity of cyclodextrin cavities remain, so that the encapsulation rate is reduced.
The oxathiols-cyclodextrin inclusion compounds of the invention can be formulated into compositions with any suitable adjuvant that is permissible for use in pesticide formulations. The composition may be formulated into any suitable dosage form for use with oxathiols, including but not limited to seed coatings and the like.
Examples
The present application is described in more detail by the following examples, which are merely illustrative and do not constitute any limitation of the present invention. Any modifications and variations which do not depart from the gist of the invention are intended to be within the scope of the invention.
EXAMPLE 1 preparation of clathrate
Precisely weighing 2.0g of beta-CD, adding the beta-CD into a four-mouth bottle filled with 50mL of distilled water under stirring, and heating until the beta-CD is completely dissolved to prepare a beta-CD saturated solution. Dissolving 0.20g of oxadiol in a medium shown in Table 1, slowly dripping the obtained medium solution into a beta-CD saturated solution through a tetrafluoro tube at 55 ℃, stretching the tetrafluoro tube below the liquid level of the beta-CD saturated solution during dripping, continuing to perform inclusion after white turbidity and white precipitation appear, keeping the temperature and stirring for 3 hours, cooling to below room temperature for crystallization for 4 hours, performing suction filtration, removing supernatant, washing a filter cake with n-hexane for 1-2 minutes, and drying in a blast drying box to obtain the oxadiol-beta-CD inclusion compound.
TABLE 1
The percent encapsulation and the percent drug loading are calculated by the following formulas:
determination of the content of oxa-line phenols in clathrate
Chromatographic conditions
Chromatographic column C18 column (250 mm. Times.4.6 mm,5 um); mobile phase acetonitrile-water (60:40); the flow rate is 1mL/min; the sample injection amount is 20 mu L; the detection wavelength is 254nm; column temperature is 30 ℃.
Preparation of the solution
(1) The reference substance solution is prepared by taking a proper amount of the oxairenol reference substance, precisely weighing, and preparing a solution with a certain concentration by using flow matching.
(2) And (3) weighing a proper amount of the oxairenol-beta-CD inclusion compound, putting the oxairenol-beta-CD inclusion compound into a 25mL volumetric flask, adding a small amount of methanol for ultrasonic treatment to completely dissolve the oxairenol-beta-CD inclusion compound, fixing the volume of the mobile phase to a scale, and filtering the mobile phase with a 0.45 mu m filter membrane to obtain the sample solution.
(3) And (5) weighing a proper amount of beta-CD in the negative sample solution, and operating according to a sample solution preparation method to obtain the negative sample solution.
Drawing of a Standard Curve
Precisely weighing 0.0500g of oxaline phenol, fixing volume to 100mL volumetric flask with mobile phase, shaking, respectively collecting supernatant 1,2, 3, 4, 5, 6, 7, 8, 9mL, filtering, fixing volume to 25mL volumetric flask, preparing into 20, 40, 60, 80, 100, 120, 140, 160, 180 μg/mL solution, sequentially injecting 20 μl into high performance liquid chromatograph, and measuring peak area. The peak area (a) is taken as the ordinate, the concentration (C) is taken as the abscissa, and a standard curve y=1.357×10 is drawn 6 x-5.6×10 5 The linear relationship is good in the range of 20-180 mug/mL.
Determination of the content
Precisely weighing a proper amount of prepared sample, fixing volume with mobile phase, sampling for 3 times in parallel according to chromatographic conditions, recording peak area, substituting into standard curve, and calculating content.
As can be seen from the results in table 1, the use of methanol as the oxathiols dissolution medium in the above solvents can achieve higher% encapsulation efficiency and% drug loading.
EXAMPLE 2 characterization analysis 1-Differential Scanning Calorimetry (DSC)
Taking a blank crucible as a reference, wherein the heating speed is 20 ℃/min, and the temperature is N 2 The flow rate was 20mL/min and the temperature was in the range of 30-500℃and the differential scanning calorimetric curves (DSC curves) of the oxathiols, the beta-CD, the physical mixtures of the two and the inclusion compound obtained in example 1 with methanol as medium were determined respectively.
The DSC curves for beta-CD, oxanol, physical mixtures of the two, and clathrates are shown in FIG. 2. The apparent absorption peaks of beta-CD appear at 90 ℃ and 322 ℃ to indicate that the beta-CD is dehydrated firstly, melted and decomposed after 322 ℃; the oxathiols exhibit a distinct melting absorption peak at 110 ℃; the physical mixture of the oxathiols and the beta-CD respectively shows absorption peaks at 85 ℃, 110 ℃ and 321 ℃, namely dehydration of the beta-CD, melting of the oxathiols and melting decomposition peaks of the beta-CD; the inclusion compound has no melting absorption peak of the oxathiols at 110 ℃; compared with beta-CD, the absorption peaks appear at 69 ℃ and 326 ℃ and the positions of the absorption peaks are shifted, which proves that the beta-CD inclusion compound has residual low-boiling point solvent and no melting decomposition peak of the oxadiol, and the formation of the inclusion compound is proved.
EXAMPLE 3 characterization analysis 2-thermogravimetric analysis (TG)
Under the conditions of nitrogen flow rate of 50mL/min, heating rate of 20 ℃/min and heating interval of 30-500 ℃, the thermogravimetric analysis curve (TG curve) of the oxathiols, beta-CD, physical mixtures of the oxathiols and beta-CD and the inclusion compound obtained by taking methanol as a medium in the embodiment 1 are respectively measured.
TG curves for β -CD, oxanol, physical mixtures of both, and inclusion compounds are shown in fig. 3. The oxathiols thermally decompose after melting at 110 ℃, resulting in significant weight loss. The beta-CD has small weight loss between 0 ℃ and 90 ℃ and corresponds to the loss of adsorbed water and crystallization water; basically no weight loss exists between 90 ℃ and 300 ℃, which indicates that the stability of beta-CD is very high at the temperature until thermal decomposition occurs between 300 ℃ and 350 ℃ to cause obvious weight loss, and the carbon decomposition products in the beta-CD gradually volatilize; the weight after 400℃tends to stabilize, indicating that the beta-CD has been completely decomposed at this time. The physical mixture of the oxathiols and the beta-CD has a small weight loss after 90 ℃, which corresponds to the loss of the adsorption water and the crystallization water in the beta-CD; after 110 ℃, the second weight loss corresponds to the decomposition of the oxathiols; and then substantially corresponds to the TG curve of β -CD. The weight loss of the inclusion compound at about 90 ℃ is attributed to the loss of the adsorbed water and the crystallization water of the beta-CD, the weight loss of the oxathiols is not observed at 110 ℃, the beta-CD is decomposed to cause rapid weight loss until the temperature reaches 295 ℃, and the whole process is similar to the weight loss process of the beta-CD, so that the formation of the inclusion compound is further indicated.
EXAMPLE 4 characterization analytical 3-X-ray diffraction (XRD)
XRD patterns of the oxathiols, beta-CD, physical mixtures of the oxathiols and beta-CD, and inclusion compound obtained by taking methanol as a medium in example 1 were respectively measured under the conditions of Zn-K alpha rays, tube pressure of 30KV, tube flow of 250mA, diffraction angle of 2-50 degrees, step length of 0.02 degrees and scanning frequency of 5 degrees/min.
The XRD patterns of beta-CD, oxanol, physical mixtures of the two, and clathrates are shown in FIG. 4. The X-ray diffraction peak shapes of beta-CD, oxathiols, physical mixtures of the two and inclusion compounds are greatly different. The oxathiols have good crystalline structure and therefore have distinct characteristic peaks. In the inclusion compound, most of the diffraction peaks (2θ= 10.905, 16.058, 21.827, 26.588) of the oxathiols disappeared, whereas the physical mixture is a superposition of the oxathiols and the β -CD peak shape, without any new characteristic peaks appearing, and clearly different from the spectrum of the inclusion compound. The peak shape of the inclusion compound is very different from the characteristic peaks of beta-CD, oxathiols and physical mixtures, and new diffraction peaks (2θ= 5.697, 17.459) appear, probably because oxathiols occupy the beta-CD cavity, and under the shielding of the beta-CD cavity, the shift of the peak position of the X diffraction peak and the change of the peak shape occur, which indicate the formation of the inclusion compound.
EXAMPLE 5 characterization analysis 4-Scanning Electron Microscopy (SEM)
The physical mixture of the proper amount of the oxaphenol, the beta-CD and the physical mixture of the oxaphenol and the beta-CD and the clathrate compound sample obtained by taking methanol as a medium in the embodiment 1 are taken to observe the characteristics under a microscope, and the observation times are 400 times.
Comparison of microscopic images (400 times) of four forms of beta-CD, oxathiols, physical mixtures of the beta-CD and the oxathiols, and inclusion compounds shows that the beta-CD crystals are tetragonal crystals, the oxathiols are needle-shaped crystals, the physical mixtures of the beta-CD and the oxathiols are in a mixed state of irregularly-sized particles and the oxathiols, the inclusion compounds are in a compact and uniform powdery aggregation state, and the forms and the sizes of the particles are greatly different from those of the beta-CD and the physical mixtures thereof, so that the inclusion compounds are formed.
EXAMPLE 6 characterization analysis 5-solid Nuclear magnetic resonance (SSNMR)
Solid nuclear magnetic resonance analysis was performed on beta-CD, oxa-phenol and the clathrate obtained in example 1 with methanol as medium, and the sample was placed in a 7mm solid nuclear magnetic tube with a magnetic field of 400Hz and a probe temperature of 20 ℃. The results are shown in FIG. 6. The peak of beta-CD at 4.327, the peak of oxathiols at 4.434, the peak of inclusion compound at 6.854, the peak position being greatly shifted from beta-CD and the shape being completely different from beta-CD and oxathiols, indicating the formation of inclusion compound.
Example 7 stability test
Reference standard: four parts of Chinese pharmacopoeia 2020 edition-guiding principle for testing stability of raw materials and preparations
1. Thermal stability test
The drug content of the oxathiols, the physical mixtures of the two, and the inclusion compound obtained in example 1 with methanol as medium were determined at high temperature (60 ℃) at different sampling times.
Specifically, weighing a plurality of parts of each of the oxathiols, the physical mixture of the oxathiols and the beta-CD and the inclusion compound, drying the mixture in a drying oven at a constant temperature of 60 ℃ for 10 days, sampling the mixture on days 0, 5 and 10 respectively, and measuring the content by using a high-efficiency liquid phase.
And (3) content measurement:
precisely weighing a proper amount of sample, metering with mobile phase, sampling for 3 times in parallel under chromatographic condition, averaging peak area, and substituting into standard curve (y=1.357×10) 6 x-5.6×10 5 ) And calculating the content.
Chromatographic conditions were the same as in example 1.
The results are shown in Table 2. The results show that at 60 ℃, the relative contents of the inclusion compound on the 5 th day and the 10 th day are 99.54% and 98.72% respectively, and the total trend is gradually declining, but the declining speed is slow; the relative content of the oxairesinol original drug and the physical mixture is obviously reduced compared with that of the inclusion compound, which shows that the thermal stability of the inclusion compound is obviously better than that of the physical mixture and the original drug, the decomposition is slow at 60 ℃, and the stability is improved as a result of inclusion.
TABLE 2
2. Wet stability test
Under the condition of high humidity (95+/-5%), the content of the drugs in the oxathiols, the physical mixture of the oxathiols and the physical mixture and the inclusion compound obtained by taking methanol as a medium in the embodiment 1 at different sampling times are measured.
Specifically, the oxathiols, the physical mixture of the oxathiols and the inclusion compound are weighed and placed under the condition of high humidity (95+/-5%) for 10 days, and samples are taken on days 0, 5 and 10 respectively, and the content is measured through a high-efficiency liquid phase. And (3) content measurement:
precisely weighing a proper amount of sample, metering with mobile phase, sampling for 3 times in parallel under chromatographic condition, averaging peak area, and substituting into standard curve (y=1.357×10) 6 x-5.6×10 5 ) And calculating the content.
Chromatographic conditions were the same as in example 1.
The wet stability test results are shown in Table 3. The results show that under the high humidity condition, the relative contents of the inclusion compound on the 5 th day and the 10 th day are 97.50% and 90.48% respectively, the inclusion compound is gradually declining, but the declining rate is obviously lower than that of the original medicine; the relative content of the physical mixture is obviously reduced, and the reduction degree is even stronger than that of the original medicine, which is probably caused by the intermolecular interaction to decompose the original medicine. It can be seen that the wet stability of the inclusion compound is better than the original drug and physical mixture, and the stability is improved as a result of inclusion.
TABLE 3 Table 3
3. Photolysis resistance test
After 10 days of irradiation with strong light (intensity 4500±500 LX), the drug content of the oxathiols, the physical mixture of the oxathiols and the clathrates obtained in example 1 with methanol as medium was determined at different sampling times.
Specifically, the oxathiols, the physical mixture of the oxathiols and the inclusion compound are weighed and irradiated under strong light (intensity 4500+ -500 LX) for 10 days, and samples are taken on days 0, 5 and 10 respectively, and the content is measured by a high performance liquid phase.
Precisely weighing a proper amount of sample, metering with mobile phase, sampling for 3 times in parallel under chromatographic condition, averaging peak area, and substituting into standard curve (y=1.357×10) 6 x-5.6×10 5 ) And calculating the content.
Chromatographic conditions were the same as in example 1.
The results of the photolysis resistance test are shown in Table 4. The result shows that under the condition of irradiation under strong light for 10 days, the relative contents of the inclusion compound on the 5 th day and the 10 th day are 98.45% and 96.58% respectively, and the inclusion compound tends to gradually decrease; the relative content of the physical mixture is obviously reduced, and the photostability of the oxathiols-beta-CD inclusion compound is better than that of the physical mixture and the original medicine, and the slow decomposition under the irradiation of strong light is the inclusion result.
TABLE 4 Table 4
EXAMPLE 8 solubility
Weighing excessive oxaline phenol-cyclodextrin inclusion compound and oxaline phenol obtained by taking methanol as a medium in the embodiment 1, respectively dissolving the inclusion compound and the oxaline phenol in 30mL of distilled water to form supersaturated solution, placing the solution in a constant-temperature oscillator at 25 ℃ for shaking for 24 hours, taking supernatant, filtering the supernatant by using a 0.45 mu m microporous filter membrane, properly diluting the filtrate, and measuring the content of the oxaline phenol by a high-performance liquid phase method to obtain inclusion compound with the solubility of 34.07mg/L, wherein the solubility is increased by about 27.5 times compared with the solubility (1.24 mg/L) of the bulk drug.
The method for measuring the content of the oxathiols is the same as in example 1.
Example 9 Release test
Reference standard: four-part dissolution and release measurement method of Chinese pharmacopoeia 2020 edition.
Weighing appropriate amount of oxadiazon-beta-CD clathrate (corresponding to oxadiazon 20 mg) obtained in example 1 with methanol as medium, placing into dialysis bag (molecular weight 8000-14000), adding ultrapure water as release medium, adding 2% (w/v) sodium dodecyl sulfate, heating to 37deg.C in 500mL dissolution cup, and regulating rotation speed to 200r.min -1 5mL of the medium to be measured is sampled every 2 hours at the first 6 time points, and 5mL of the medium to be measured is sampled every 12 hours later, and 5mL of the fresh medium stored at the same temperature is supplemented. The sample was filtered through a 0.45 μm microfiltration membrane, assayed using a high performance liquid phase and the cumulative release was calculated. As a result, as shown in FIG. 7A, the cumulative release rate was 95.43% for 192h, and the rising trend was observed between 0 and 192h, indicating that the release rate of the drug substance was reduced by inclusion.
Weighing appropriate amount of oxadiazon-beta-CD clathrate (corresponding to oxadiazon 20 mg) obtained in example 1 with methanol as medium, placing into dialysis bag (molecular weight 8000-14000), placing 30% isopropanol water solution as release medium, placing into 500mL dissolution cup, heating to 37deg.C, and regulating rotation speed to 200r.min -1 5mL of the medium to be measured is sampled every 2 hours at the first 6 time points, and 5mL of the medium to be measured is sampled every 12 hours later, and 5mL of the fresh medium stored at the same temperature is supplemented. Filtering the sample through a 0.45 μm microporous filter membraneHowever, high performance liquid phase measurement was employed, and the cumulative release amount was calculated. As shown in the following graph, the cumulative release rate at 132h was 86.13%, and the rising trend was between 0 and 132h, indicating that the release rate of the drug substance was reduced by inclusion.
The content of oxathiols was determined as in example 1.
Example 10 skin irritation test
Reference standard: GB/T-15670.7-2017 and GB/T-15670.9-2017
Human skin irritation may be characterized by itching, erythema, papules, blisters, fusogenic blisters. Animals respond differently and may only see skin erythema and edema.
1. Skin irritation test with oxathiols
Healthy adult guinea pigs (200-220 g) are selected before the experiment starts, 4 adult guinea pigs (200-220 g) are fed and observed in an animal laboratory for 3 days, ingestion and behaviors are observed, and the adult guinea pigs are randomly divided into two groups according to male and female weight after no abnormality. The haircut agent was used to depilation the sides of the back of the guinea pig without damaging the skin 24 hours before the experiment, the depilation area was 5cm×5cm, and the depilation and sterilized skin was equally divided into left and right areas.
0.5g of oxadiol is diluted by vaseline and smeared on the left dehaired skin, covered by two layers of gauze and fixed by non-irritating adhesive plaster and bandage. The other side was coated with petrolatum as a control and the treatment was the same as the test side except that no oxathiols were added. The application was performed 1 time a day for 7 days. For the group of oxathiols, the skin response after the previous day of oxathiols application was observed first, starting from the next day. If the length of the wool does not influence the continuous test, the oxairesinol can be continuously smeared; otherwise, the hair should be removed in time, and the oxairenol should be smeared 1h after the hair removal.
The results of the experiment are shown in Table 5, and demonstrate that the oxathiols are stimulatory, and the stimulation intensity level is moderate stimulation.
Table 5 statistical table of the multiple skin irritation test for oxathiols
2. Clathrate skin irritation test
Healthy adult guinea pigs (200-220 g) are selected before the experiment starts, 4 adult guinea pigs (200-220 g) are fed and observed in an animal laboratory for 3 days, ingestion and behaviors are observed, and the adult guinea pigs are randomly divided into two groups according to male and female weight after no abnormality. The haircut agent was used to depilation the sides of the back of the guinea pig without damaging the skin 24 hours before the experiment, the depilation area was 5cm×5cm, and the depilation and sterilized skin was equally divided into left and right areas.
Diluting clathrate 0.5g with vaseline, applying on left dehaired skin, covering with two layers of gauze, and fixing with non-irritating adhesive plaster and bandage. The other side was coated with petrolatum as a control and the treatment was the same as the test side except that inclusion compound was not added. The application was performed 1 time a day for 7 days. For the group of oxathiols, the reaction of the skin after the inclusion compound was applied on the previous day was observed first, starting on the next day. If the length of the wool does not influence the continuous test, coating the inclusion compound continuously; otherwise, the hair should be removed in time, and the inclusion compound should be smeared 1h after the hair removal.
The experimental results are shown in table 6, which shows that after the oxairenol is prepared into the cyclodextrin inclusion compound, no skin irritation exists, the irritation intensity is 0, and the inclusion reduces the irritation of the oxairenol.
Table 6 inclusion compound multiple skin irritation test statistics table
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EXAMPLE 11 study of the Effect of the feed ratio
Precisely weighing beta-CD, adding the beta-CD into a 100mL four-mouth bottle filled with distilled water under stirring, and heating until the beta-CD is completely dissolved to prepare a beta-CD saturated solution. Dissolving the oxaline phenol with methanol, slowly dripping the oxaline phenol-methanol solution into the beta-CD saturated solution through a tetrafluoro tube at 50 ℃, stretching the tetrafluoro tube below the liquid level of the beta-CD saturated solution during dripping, continuing to perform heat preservation and stirring for 3 hours for inclusion after white turbidity and white precipitation appear, cooling to the room temperature for crystallization for 0.5 hour, performing suction filtration, discarding supernatant, stirring and washing a filter cake with n-hexane for 1-2min, and drying in a blast drying box to obtain the oxaline phenol-beta-CD inclusion compound. The effect of the feed mole ratio on% encapsulation and% drug loading is shown in table 7.
TABLE 7
From the above results, it was found that the oxalin- β -CD inclusion compound was successfully produced by the method of the present invention. By inclusion, the stability and water solubility of the active component oxathiols are greatly improved, the release of the oxathiols is slowed down, the irritation of the oxathiols is reduced, and the improvement is beneficial to the preparation and the use of the preparation. Meanwhile, it is known that in the preparation process of the inclusion compound, methanol is used as a medium for dissolving the oxathiols, and the molar ratio of beta-CD to the oxathiols reaches 1.5: more than 1 is beneficial to obtaining higher encapsulation efficiency percent or drug loading percent.
Claims (4)
1. The oxaline phenol-cyclodextrin inclusion compound comprises an active ingredient oxaline phenol and inclusion material cyclodextrin, wherein the cyclodextrin is beta-cyclodextrin, the drug loading rate of the active ingredient oxaline phenol is 10-20 wt%, in the preparation of the inclusion compound, the oxaline phenol is dissolved in medium methanol, the cyclodextrin is dissolved in water, and the feeding ratio of the cyclodextrin to the oxaline phenol is (1.5-2.0) in terms of mole ratio: 1.
2. a process for the preparation of an oxawire phenol-cyclodextrin inclusion compound of claim 1, comprising the steps of: dissolving oxairesinol in a medium to be used as a medium solution, dissolving cyclodextrin in a solvent to be used as a wall material, dripping the medium solution into the wall material to form inclusion compound microcapsules, and then crystallizing, separating and drying to obtain a solid inclusion compound; wherein the medium solution pipe is extended to be below the liquid level of the wall material for dropwise adding during the dropwise adding; the medium is methanol; the solvent of the cyclodextrin is water.
3. The preparation method of claim 2, wherein the feeding ratio of the cyclodextrin to the oxathiols is (1.5-2.0) in terms of molar ratio: 1.
4. a composition comprising the oxathiols-cyclodextrin inclusion compound of claim 1, and any excipients permitted for use in pesticide formulations.
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