CN115894583B - Arbutin solvent compound and crystallization preparation method thereof - Google Patents
Arbutin solvent compound and crystallization preparation method thereof Download PDFInfo
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- CN115894583B CN115894583B CN202310134561.XA CN202310134561A CN115894583B CN 115894583 B CN115894583 B CN 115894583B CN 202310134561 A CN202310134561 A CN 202310134561A CN 115894583 B CN115894583 B CN 115894583B
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- dimethylacetamide
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- BJRNKVDFDLYUGJ-RMPHRYRLSA-N hydroquinone O-beta-D-glucopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-RMPHRYRLSA-N 0.000 title claims abstract description 266
- 239000002904 solvent Substances 0.000 title claims abstract description 160
- BJRNKVDFDLYUGJ-UHFFFAOYSA-N p-hydroxyphenyl beta-D-alloside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-UHFFFAOYSA-N 0.000 title claims abstract description 123
- 229960000271 arbutin Drugs 0.000 title claims abstract description 122
- 150000001875 compounds Chemical class 0.000 title claims abstract description 95
- 238000002425 crystallisation Methods 0.000 title claims abstract description 17
- 230000008025 crystallization Effects 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title abstract description 23
- 239000013078 crystal Substances 0.000 claims abstract description 83
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims abstract description 56
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 48
- 239000007787 solid Substances 0.000 claims abstract description 22
- 238000003756 stirring Methods 0.000 claims abstract description 17
- 238000001291 vacuum drying Methods 0.000 claims abstract description 13
- 238000010907 mechanical stirring Methods 0.000 claims abstract description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- 238000001035 drying Methods 0.000 claims description 31
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 23
- 239000002245 particle Substances 0.000 claims description 18
- 239000012046 mixed solvent Substances 0.000 claims description 17
- 239000000725 suspension Substances 0.000 claims description 15
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 12
- 238000002411 thermogravimetry Methods 0.000 claims description 12
- 230000004580 weight loss Effects 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 8
- 238000004807 desolvation Methods 0.000 claims description 4
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 4
- 230000008018 melting Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 44
- 239000000843 powder Substances 0.000 description 28
- 238000001914 filtration Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000004455 differential thermal analysis Methods 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- VKEQBMCRQDSRET-UHFFFAOYSA-N Methylone Chemical compound CNC(C)C(=O)C1=CC=C2OCOC2=C1 VKEQBMCRQDSRET-UHFFFAOYSA-N 0.000 description 3
- -1 arbutin monohydrate Chemical class 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 241000208838 Asteraceae Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000000913 Kidney Calculi Diseases 0.000 description 1
- 241000940170 Klasea quinquefolia Species 0.000 description 1
- 206010029148 Nephrolithiasis Diseases 0.000 description 1
- 241001464837 Viridiplantae Species 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000000490 cosmetic additive Substances 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides an arbutin solvent compound crystal and a preparation method thereof, wherein the arbutin solvent compound crystal comprises arbutin N, N-dimethylacetamide solvent compound and arbutin N-methylpyrrolidone solvent compound. The preparation method comprises the following steps: pouring the beta-arbutin solid into a crystallization solvent at a constant temperature, and suspending by mechanical stirring to uniformly mix the beta-arbutin solid with the crystallization solvent: stirring to make it be suspended and converted; vacuum drying to obtain final arbutin solvent compound crystal. The two arbutin solvent compounds are simple in preparation operation, stable in preparation process, low in energy consumption, high in reproducibility, larger in granularity, more stable in granularity compared with hydrate, high in product purity up to more than 99%, and short in production period.
Description
Technical Field
The invention belongs to the technical field of crystallization in chemical engineering industry, and particularly relates to an arbutin two-solvent compound (arbutin N, N-dimethylacetamide solvent compound and arbutin N-methylpyrrolidone solvent compound) crystal and a preparation method thereof.
Background
Arbutin (Arbutin) has a chemical name of 4-hydroxyphenyl-beta-D-glucopyranoside, a molecular formula of C 12H16O7, a molecular weight of 272.251, and a white needle-like crystal or powder appearance, and has a structural formula:
Beta-arbutin is a glycoside substance derived from green plants and naturally occurring in plants and fruits, has a whitening effect, has strong antifungal, antiviral and anticancer activities besides being used as a cosmetic additive, and can be used as a diuretic and a medicament for treating diseases such as urinary tract infection, cystitis, kidney stones and the like. In addition, in recent years, arbutin has certain application in the food fields of improving the aroma of wine and the like, so the arbutin has wide development prospect in the aspects of food and health care products.
The price of the beta-arbutin is low, so most of the arbutin sold and used in the market is beta-arbutin. Currently, patent and literature report on a crystal form of beta-arbutin, for example, patent CN104098620a discloses a crystal form v of beta-arbutin and a preparation method thereof, patent CN104098621a discloses a preparation method of a crystal form III of beta-arbutin, and patent CN104098622a discloses a preparation method of a crystal form iv of beta-arbutin. In addition, nycz et al isolated and extracted beta-arbutin hemihydrate from Compositae plants Serratula quinque-folia. However, the beta-arbutin crystals reported in most of the prior patents and documents are in a fine needle shape and have small granularity, so that the problems of easy agglomeration, poor fluidity and the like exist; and the hydrate has a problem of poor stability at high temperature. The problems affect the subsequent processes of filtering, drying, storing and the like of the beta-arbutin, so that the production energy consumption and the production period are increased, and the production efficiency is reduced.
Disclosure of Invention
In view of the above, the present invention aims to provide arbutin solvent compound crystals including arbutin N, N-dimethylacetamide solvent compound crystals, arbutin N-methylpyrrolidone solvent compound crystals, and a preparation method and application thereof.
The invention provides an arbutin solvent compound crystal, which consists of beta-arbutin and a first solvent, wherein the crystal belongs to an orthorhombic system; the mol ratio of the beta-arbutin to the first solvent in the crystal is 2:1; the first solvent is N, N-dimethylacetamide or N-methylpyrrolidone solvent. In the arbutin solvent compound crystal and the preparation method thereof provided by the invention, the arbutin is beta-arbutin.
The arbutin and N, N-dimethylacetamide solvents form a solvent compound crystal, wherein 1 molecule of arbutin N, N-dimethylacetamide solvent compound crystal comprises 2 molecules of arbutin and 1 molecule of N, N-dimethylacetamide, namely the molar ratio is 2:1, and the molecular formula is 2 (C 12H16O7)·C4H9 NO).
In the solvent compound crystal formed by arbutin and N-methyl pyrrolidone solvent, 1 molecule of arbutin N-methyl pyrrolidone solvent compound crystal comprises 2 molecules of arbutin and 1 molecule of N-methyl pyrrolidone, namely the molar ratio is 2:1, molecular formula 2 (C 12H16O7)·C5H9 NO).
Preferably, the first solvent is N, N-dimethylacetamide, the arbutin solvent compound crystal is an arbutin N, N-dimethylacetamide solvent compound crystal, and the molecular formula is: 2 (C 12H16O7)·C4H9 NO, X-ray powder diffraction pattern of the arbutin N, N-dimethylacetamide solvent compound crystal has characteristic peaks at diffraction angle 2θ＝5.7±0.2°,7.6±0.2°,8.7±0.2°,9.2±0.2°,11.4±0.2°,12.2±0.2°,13.2±0.2°,14.3±0.2°,14.9±0.2°,15.3±0.2°,15.9±0.2°,16.4±0.2°,16.7±0.2°,17.3±0.2°,17.9±0.2°,18.5±0.2°,19.1±0.2°,19.9±0.2°,20.3±0.2°,20.7±0.2°,21.1±0.2°,22.5±0.2°,23.1±0.2°,23.5±0.2°,24.1±0.2°,24.8±0.2°,25.7±0.2°,26.4±0.2°,26.9±0.2°,27.4±0.2°,28.0±0.2°,28.4±0.2°,28.8±0.2°,29.3±0.2°,29.9±0.2°,30.5±0.2°,30.8±0.2°,31.4±0.2°,32.1±0.2°,33.1±0.2°,33.7±0.2°,34.4±0.2°,35.2±0.2°,36.5±0.2°,37.4±0.2°,37.8±0.2°,39.5±0.2°.
Any of the above-mentioned preferably, the molecular weight of arbutin N, N-dimethylacetamide solvent compound is 631.62.
Any one of the above preferred materials is that the arbutin N, N-dimethylacetamide solvent crystal belongs to an orthorhombic system, the space group is P2 12121, and the unit cell parameter value isα＝90.00°，β＝90.00°，γ＝90.00°，Z＝4。
Preferably, any one of the above is that the arbutin N, N-dimethylacetamide solvent compound crystal DSC analysis shows desolvation at 105-135 ℃ and melting at 198+ -0.5 ℃.
Preferably, any of the above, the arbutin N, N-dimethylacetamide solvent compound crystal TGA analysis shows that the weight loss is about 13.94% + -0.5% at 105-135 ℃.
Any one of the above-mentioned preferable examples is that the particle diameter D 50 of the arbutin N, N-dimethylacetamide solvent compound crystal is 30-70 μm as measured by a Markov laser particle size analyzer.
Preferably, the first solvent is an N-methylpyrrolidone solvent, the arbutin solvent compound crystal is an arbutin N-methylpyrrolidone solvent compound crystal, and the molecular formula is: 2 (C 12H16O7)·C5H9 NO), the X-ray powder diffraction pattern of the arbutin N-methylpyrrolidone solvent compound crystal has a characteristic peak at a diffraction angle 2θ＝5.6±0.2°,7.4±0.2°,8.6±0.2°,11.3±0.2°,12.0±0.2°,13.3±0.2°,13.9±0.2°,14.1±0.2°,14.9±0.2°,15.6±0.2°,16.2±0.2°,16.6±0.2°,17.5±0.2°,17.8±0.2°,18.3±0.2°,18.7±0.2°,19.2±0.2°,19.7±0.2°,20.3±0.2°,20.8±0.2°,22.1±0.2°,22.7±0.2°,23.3±0.2°,23.7±0.2°,24.1±0.2°,24.8±0.2°,25.5±0.2°,25.8±0.2°,26.8±0.2°,28.0±0.2°,28.2±0.2°,29.6±0.2°,30.3±0.2°,31.2±0.2°,31.9±0.2°,33.1±0.2°,33.7±0.2°,34.3±0.2°,34.9±0.2°,37.3±0.2°,37.8±0.2°,39.0±0.2°.
Any of the above is preferred that the molecular weight of the arbutin N-methylpyrrolidone solvent compound is 643.63.
Any one of the above preferred embodiments wherein the arbutin N-methylpyrrolidone solvent compound crystals are of orthorhombic system, the space group is P2 12121, and the unit cell parameter value isα＝90.00°，β＝90.00°，γ＝90.00°，Z＝4。
Preferably, any one of the above is that DSC analysis of the arbutin N-methylpyrrolidone solvent compound crystals shows desolvation at 120-150 ℃ and melting at 198+ -0.5 ℃.
Preferably, any of the above, TGA analysis of the arbutin N-methylpyrrolidone solvent compound crystals shows a weight loss of about 15.45% ± 0.5% at 120-150 ℃.
Any one of the above-mentioned preferable examples is that the particle diameter D 50 of the arbutin N-methylpyrrolidone solvent compound crystal is 60-100 μm as measured by a Markov laser particle size analyzer.
The invention also provides a preparation method of the arbutin solvent compound crystal, which comprises the following steps:
step 1: pouring the beta-arbutin solid into a crystallization solvent at a constant temperature, and suspending by mechanical stirring to uniformly mix the beta-arbutin solid;
step 2: stirring to make it be suspended and converted;
Step 3: vacuum drying to obtain final arbutin solvent compound crystal;
the crystallization solvent is a first solvent, and the first solvent is an N, N-dimethylacetamide solvent;
Or the solvent is a mixed solvent of a first solvent and a second solvent, wherein the first solvent is an N, N-dimethylacetamide solvent or an N-methylpyrrolidone solvent, and the second solvent is at least one of methanol, isopropanol or acetone. The methanol, isopropanol or acetone has the function of reducing the solution viscosity and is convenient for subsequent operation.
The crystallization solvent is N, N-dimethylacetamide solvent or a mixed solvent of N, N-dimethylacetamide solvent and at least one of methanol, isopropanol or acetone, so as to prepare arbutin N, N-dimethylacetamide solvent compound crystals;
Or the crystallization solvent is a mixed solvent of N-methyl pyrrolidone solvent and at least one of methanol, isopropanol or acetone, and the arbutin N-methyl pyrrolidone solvent compound crystal is prepared.
Any of the above is preferred, step 1, wherein the constant temperature is 20℃to 25 ℃. Further preferably 20, 21, 22, 23, 24, 25 ℃.
In any of the above, it is preferable that the stirring rate in step 2 is 200 to 300rpm. Further preferably 200, 230, 260, 300rpm.
In step 2, the suspension time is preferably 8 to 24 hours, more preferably 8, 10, 15, 20, 24 hours.
In any of the above steps, it is preferable that the drying temperature in step 3 is 30 to 40 ℃. Further preferably 30, 33, 36, 40 ℃.
In any of the above steps, it is preferable that the drying time is 6 to 24 hours in step 3. Further preferably 6, 10, 15, 20, 24 hours.
Any one of the above is preferable that, when the arbutin solvent compound crystal is an arbutin N, N-dimethylacetamide solvent compound crystal, the preparation method thereof is i, comprising the steps of: pouring excessive arbutin solid into a certain amount of N, N-dimethylacetamide solvent or a mixed solvent of N, N-dimethylacetamide and one of methanol, isopropanol or acetone at constant temperature, and suspending by mechanical stirring to uniformly mix the above materials; stirring for 8-24 h at a certain stirring rate to make it be suspended and converted, and drying in vacuum drying oven to obtain the final arbutin N, N-dimethylacetamide solvent compound product. Further preferably, in the preparation method i, the solvent used is an N, N-dimethylacetamide solvent or a mixed solvent of N, N-dimethylacetamide and one of methanol, isopropanol or acetone; further preferably, in the preparation method i, the suspension temperature is 20-25 ℃; the stirring speed is 200-300 rpm, and the suspension time is 8-24 h; further preferably, in the production method i, the drying temperature is 30 to 40℃and the drying time is 6 to 24 hours.
Any one of the above is preferable that, when the arbutin solvent compound crystal is an arbutin N-methylpyrrolidone solvent compound crystal, for the production method ii, comprising the steps of: pouring excessive arbutin solid into a certain amount of mixed solvent of N-methyl pyrrolidone and one of methanol, isopropanol or acetone at constant temperature, and suspending by mechanical stirring to uniformly mix the above materials; stirring for 8-24 h at a certain stirring rate to make it be suspended and converted, and drying in vacuum drying oven to obtain the final arbutin N-methylpyrrolidone solvent compound product. It is further preferred that in the production method ii, the solvent used is a mixed solvent of N-methylpyrrolidone and one of methanol, isopropanol or acetone; it is further preferred that the suspension temperature is 20℃to 25 ℃; further preferably, in the preparation method ii, the stirring rate used is 200 to 300rpm and the suspension time is 8 to 24 hours; it is further preferable that the drying temperature in the production method ii is 30 to 40℃and the drying time is 6 to 24 hours.
In a preferred embodiment of the present invention, the preparation method of the arbutin N, N-dimethylacetamide solvent compound and the crystal thereof is as follows:
(1) Pouring excessive arbutin solid into a certain amount of N, N-dimethylacetamide solvent or a mixed solvent of N, N-dimethylacetamide and one of methanol, isopropanol or acetone at constant temperature, and suspending by mechanical stirring to uniformly mix the above materials;
(2) Stirring for 8-24 h at a certain stirring rate to enable the mixture to be in suspension and conversion;
(3) Filtering the product, washing a filter cake with absolute ethyl alcohol, and carrying out vacuum suction filtration;
(4) Placing the obtained crystal into a vacuum drying oven for drying;
(5) And drying to obtain the final arbutin N, N-dimethylacetamide solvent compound product.
The method comprises the step (1), wherein the solvent is N, N-dimethylacetamide solvent or a mixed solvent of N, N-dimethylacetamide and one of methanol, isopropanol or acetone, and the suspension temperature is 20-25 ℃;
In the step (2) of the method, the stirring speed is 200-300 rpm, and the suspension time is 8-24 h;
in the step (4) of the method, the drying temperature is 30-40 ℃ and the drying time is 6-24 hours;
in the method, the crystallization mode is suspension crystallization.
In a preferred embodiment of the present invention, the preparation method of the arbutin N-methylpyrrolidone solvent compound and the crystal thereof is as follows:
(1) Pouring excessive arbutin solid into a certain amount of mixed solvent of N-methyl pyrrolidone and one of methanol, isopropanol or acetone at constant temperature, and suspending by mechanical stirring to uniformly mix the above materials;
(2) Stirring for 8-24 h at a certain stirring rate to enable the mixture to be in suspension and conversion;
(3) Filtering the product, washing a filter cake with absolute ethyl alcohol, and carrying out vacuum suction filtration;
(4) Placing the obtained crystal into a vacuum drying oven for drying;
(5) And drying to obtain the final arbutin N-methyl pyrrolidone solvent compound product.
In the step (1) of the method, the solvent is a mixed solvent of N-methyl pyrrolidone and one of methanol, isopropanol or acetone, and the suspension temperature is 20-25 ℃;
In the step (2) of the method, the stirring speed is 200-300 rpm, and the suspension time is 8-24 h;
in the step (4) of the method, the drying temperature is 30-40 ℃ and the drying time is 6-24 hours;
in the method, the crystallization mode is suspension crystallization.
In the preparation method provided by the invention, the excessive arbutin refers to the amount of arbutin exceeding the solubility of beta arbutin in a crystallization solvent.
The two arbutin solvent compounds have the advantages of simple preparation operation, stable preparation process, low energy consumption, high reproducibility, short production period, product purity of more than 99 percent and suitability for manufacturing pharmaceutical preparations. The original particle size range of arbutin is 10-50 mu m, the particle size of arbutin N, N-dimethylacetamide solvent compound is 30-70 mu m, and the particle size of arbutin N-methylpyrrolidone solvent compound is 60-100 mu m; the two arbutin solvent compounds have larger crystal particle size and better fluidity than the anhydrous crystal form of arbutin, and have better stability than the hydrate.
Drawings
Fig. 1 is a polarized light microscopic view of arbutin N, N-dimethylacetamide solvent compound of preferred embodiment 1 of the present invention.
FIG. 2 is a polarized light microscopic view of an arbutin N-methylpyrrolidone solvent compound according to preferred embodiment 4 of the present invention.
FIG. 3 is an X-ray powder diffraction pattern of arbutin N, N-dimethylacetamide solvent compound according to preferred embodiment 1 of the present invention.
FIG. 4 is a graph showing a differential thermal analysis of arbutin N, N-dimethylacetamide solvent compound according to preferred embodiment 1 of the present invention.
FIG. 5 is a thermogravimetric analysis of arbutin N, N-dimethylacetamide solvent compound according to preferred embodiment 1 of the present invention.
FIG. 6 is an X-ray powder diffraction pattern of arbutin N-methylpyrrolidone solvent compound of preferred embodiment 4 of the present invention.
FIG. 7 is a graph showing a differential thermal analysis of arbutin N-methylpyrrolidone solvent compound according to preferred embodiment 4 of the present invention.
FIG. 8 is a thermogravimetric analysis of arbutin N-methylpyrrolidone solvent compound according to preferred embodiment 4 of the present invention.
FIG. 9 is a single crystal structure diagram of arbutin N, N-dimethylacetamide solvent according to preferred embodiment 1 of the present invention.
FIG. 10 is a single crystal structure diagram of arbutin N-methylpyrrolidone solvent compound of preferred embodiment 4 of the present invention.
Detailed Description
The above-described aspects of the present invention are described in further detail. It should not be construed that the scope of the above subject matter of the present invention is limited to the following examples. All techniques implemented based on the above description of the invention are within the scope of the invention.
Example 1:
18.7896g of arbutin solid is poured into 20ml of N, N-dimethylacetamide solvent at 20 ℃, mechanically stirred and suspended for 12 hours at constant temperature, so that the solid is completely and uniformly dispersed in the solvent; filtering the product, washing a filter cake by using absolute ethyl alcohol, and carrying out vacuum suction filtration; placing the obtained crystal in a vacuum drying oven at 30 ℃ for drying; and drying to obtain the final arbutin N, N-dimethylacetamide solvent compound product.
The X-ray powder diffraction pattern of the product has a characteristic peak at diffraction angle 2θ＝5.7±0.2°,7.6±0.2°,8.7±0.2°,9.2±0.2°,11.4±0.2°,12.2±0.2°,13.2±0.2°,14.3±0.2°,14.9±0.2°,15.3±0.2°,15.9±0.2°,16.4±0.2°,16.7±0.2°,17.3±0.2°,17.9±0.2°,18.5±0.2°,19.1±0.2°,19.9±0.2°,20.3±0.2°,20.7±0.2°,21.1±0.2°,22.5±0.2°,23.1±0.2°,23.5±0.2°,24.1±0.2°,24.8±0.2°,25.7±0.2°,26.4±0.2°,26.9±0.2°,27.4±0.2°,28.0±0.2°,28.4±0.2°,28.8±0.2°,29.3±0.2°,29.9±0.2°,30.5±0.2°,30.8±0.2°,31.4±0.2°,32.1±0.2°,33.1±0.2°,33.7±0.2°,34.4±0.2°,35.2±0.2°,36.5±0.2°,37.4±0.2°,37.8±0.2°,39.5±0.2°. Differential thermal analysis showed that it desolvated at 105-135 ℃ and melted at 198+ -0.5 ℃. Thermogravimetric analysis showed a weight loss of about 13.94% after heating. The product was white powder in appearance and had a D 50 particle size of 40.3. Mu.m. The purity of the product is 99.6 percent, and the process yield is 76.5 percent.
Example 2:
5.9642g of arbutin solid is poured into 5ml of mixed solvent of N, N-dimethylacetamide and 5ml of methanol at 20 ℃ and mechanically stirred, and suspended for 24 hours at constant temperature, so that the solid is completely and uniformly dispersed in the solvent; filtering the product, washing a filter cake by using absolute ethyl alcohol, and carrying out vacuum suction filtration; placing the obtained crystal in a vacuum drying oven at 30 ℃ for drying; and drying to obtain the final arbutin N, N-dimethylacetamide solvent compound product.
The X-ray powder diffraction pattern of the product has a characteristic peak at diffraction angle 2θ＝5.7±0.2°,7.6±0.2°,8.7±0.2°,9.2±0.2°,11.4±0.2°,12.2±0.2°,13.2±0.2°,14.3±0.2°,14.9±0.2°,15.3±0.2°,15.9±0.2°,16.4±0.2°,16.7±0.2°,17.3±0.2°,17.9±0.2°,18.5±0.2°,19.1±0.2°,19.9±0.2°,20.3±0.2°,20.7±0.2°,21.1±0.2°,22.5±0.2°,23.1±0.2°,23.5±0.2°,24.1±0.2°,24.8±0.2°,25.7±0.2°,26.4±0.2°,26.9±0.2°,27.4±0.2°,28.0±0.2°,28.4±0.2°,28.8±0.2°,29.3±0.2°,29.9±0.2°,30.5±0.2°,30.8±0.2°,31.4±0.2°,32.1±0.2°,33.1±0.2°,33.7±0.2°,34.4±0.2°,35.2±0.2°,36.5±0.2°,37.4±0.2°,37.8±0.2°,39.5±0.2°. Differential thermal analysis showed that it desolvated at 105-135 ℃ and melted at 198+ -0.5 ℃. Thermogravimetric analysis showed a weight loss of about 13.97% after heating. The product was white powder in appearance and had a D 50 particle size of 39.8. Mu.m. The purity of the product is 99.5 percent, and the process yield is 80.7 percent.
Example 3:
5.7633g of arbutin solid is poured into 5ml of mixed solvent of N, N-dimethylacetamide and 10ml of acetone at 20 ℃, mechanically stirred and suspended for 8 hours at constant temperature, so that the solid is completely and uniformly dispersed in the solvent; filtering the product, washing a filter cake by using absolute ethyl alcohol, and carrying out vacuum suction filtration; placing the obtained crystal in a vacuum drying oven at 30 ℃ for drying; and drying to obtain the final arbutin N, N-dimethylacetamide solvent compound product.
The X-ray powder diffraction pattern of the product has a characteristic peak at diffraction angle 2θ＝5.7±0.2°,7.6±0.2°,8.7±0.2°,9.2±0.2°,11.4±0.2°,12.2±0.2°,13.2±0.2°,14.3±0.2°,14.9±0.2°,15.3±0.2°,15.9±0.2°,16.4±0.2°,16.7±0.2°,17.3±0.2°,17.9±0.2°,18.5±0.2°,19.1±0.2°,19.9±0.2°,20.3±0.2°,20.7±0.2°,21.1±0.2°,22.5±0.2°,23.1±0.2°,23.5±0.2°,24.1±0.2°,24.8±0.2°,25.7±0.2°,26.4±0.2°,26.9±0.2°,27.4±0.2°,28.0±0.2°,28.4±0.2°,28.8±0.2°,29.3±0.2°,29.9±0.2°,30.5±0.2°,30.8±0.2°,31.4±0.2°,32.1±0.2°,33.1±0.2°,33.7±0.2°,34.4±0.2°,35.2±0.2°,36.5±0.2°,37.4±0.2°,37.8±0.2°,39.5±0.2°. Differential thermal analysis showed that it desolvated at 105-135 ℃ and melted at 198+ -0.5 ℃. Thermogravimetric analysis showed a weight loss of about 14.02% after heating. The product was white powder in appearance and had a D 50 particle size of 33.4. Mu.m. The purity of the product is 99.6 percent, and the process yield is 81.6 percent.
The properties of the arbutin N, N-dimethylacetamide solvent compound crystals obtained in examples 1 to 3 are consistent, and fig. 1,3, 4, 5, 9 show the product properties of the obtained arbutin N, N-dimethylacetamide solvent compound crystals by taking the product obtained in example 1 as an example.
Table 1 taking the arbutin N, N-dimethylacetamide solvent compound crystal obtained in example 1 as an example, chemical stability thereof was examined, and compared with the chemical stability of arbutin monohydrate of table 3, the arbutin N, N-dimethylacetamide solvent compound crystal has better stability than the hydrate.
Example 4:
4.5064g of arbutin solid is poured into a mixed solvent of 4ml of N-methyl pyrrolidone and 5ml of methanol at 20 ℃ and magnetically stirred, and suspended for 8 hours at constant temperature, so that the solid is completely and uniformly dispersed in the solvent; filtering the product, washing a filter cake by using absolute ethyl alcohol, and carrying out vacuum suction filtration; placing the obtained crystal in a vacuum drying oven at 35 ℃ for drying; and drying to obtain the final arbutin N-methyl pyrrolidone solvent compound product.
The X-ray powder diffraction pattern of the product has a characteristic peak at diffraction angle 2θ＝5.6±0.2°,7.4±0.2°,8.6±0.2°,11.3±0.2°,12.0±0.2°,13.3±0.2°,13.9±0.2°,14.1±0.2°,14.9±0.2°,15.6±0.2°,16.2±0.2°,16.6±0.2°,17.5±0.2°,17.8±0.2°,18.3±0.2°,18.7±0.2°,19.2±0.2°,19.7±0.2°,20.3±0.2°,20.8±0.2°,22.1±0.2°,22.7±0.2°,23.3±0.2°,23.7±0.2°,24.1±0.2°,24.8±0.2°,25.5±0.2°,25.8±0.2°,26.8±0.2°,28.0±0.2°,28.2±0.2°,29.6±0.2°,30.3±0.2°,31.2±0.2°,31.9±0.2°,33.1±0.2°,33.7±0.2°,34.3±0.2°,34.9±0.2°,37.3±0.2°,37.8±0.2°,39.0±0.2°. Differential thermal analysis showed that it desolvated at 120-150 ℃ and melted at 198+ -0.5 ℃. Thermogravimetric analysis showed a weight loss of about 15.45% after heating. The product was white powder in appearance and had a D 50 particle size of 78.9. Mu.m. The purity of the product is 99.8 percent, and the process yield is 83.6 percent.
Example 5:
3.5415g of arbutin solid is poured into a mixed solvent of 4ml of N-methyl pyrrolidone and 8ml of acetone at 20 ℃, mechanically stirred and suspended for 12 hours at constant temperature, so that the solid is completely and uniformly dispersed in the solvent; filtering the product, washing a filter cake by using absolute ethyl alcohol, and carrying out vacuum suction filtration; placing the obtained crystal in a vacuum drying oven at 30 ℃ for drying; and drying to obtain the final arbutin N-methyl pyrrolidone solvent compound product.
The X-ray powder diffraction pattern of the product has a characteristic peak at diffraction angle 2θ＝5.6±0.2°,7.4±0.2°,8.6±0.2°,11.3±0.2°,12.0±0.2°,13.3±0.2°,13.9±0.2°,14.1±0.2°,14.9±0.2°,15.6±0.2°,16.2±0.2°,16.6±0.2°,17.5±0.2°,17.8±0.2°,18.3±0.2°,18.7±0.2°,19.2±0.2°,19.7±0.2°,20.3±0.2°,20.8±0.2°,22.1±0.2°,22.7±0.2°,23.3±0.2°,23.7±0.2°,24.1±0.2°,24.8±0.2°,25.5±0.2°,25.8±0.2°,26.8±0.2°,28.0±0.2°,28.2±0.2°,29.6±0.2°,30.3±0.2°,31.2±0.2°,31.9±0.2°,33.1±0.2°,33.7±0.2°,34.3±0.2°,34.9±0.2°,37.3±0.2°,37.8±0.2°,39.0±0.2°. Differential thermal analysis showed that it desolvated at 120-150 ℃ and melted at 198+ -0.5 ℃. Thermogravimetric analysis showed a weight loss of about 15.45% after heating. The product was white powder in appearance and had a D 50 particle size of 88.7. Mu.m. The purity of the product is 99.7 percent, and the process yield is 81.2 percent.
Example 6:
2.3416g of arbutin solid is poured into a mixed solvent of 4ml of N-methyl pyrrolidone and 6ml of isopropanol at 20 ℃, mechanically stirred and suspended for 12 hours at constant temperature, so that the solid is completely and uniformly dispersed in the solvent; filtering the product, washing a filter cake by using absolute ethyl alcohol, and carrying out vacuum suction filtration; placing the obtained crystal in a vacuum drying oven at 30 ℃ for drying; and drying to obtain the final arbutin N-methyl pyrrolidone solvent compound product.
The X-ray powder diffraction pattern of the product has a characteristic peak at diffraction angle 2θ＝5.6±0.2°,7.4±0.2°,8.6±0.2°,11.3±0.2°,12.0±0.2°,13.3±0.2°,13.9±0.2°,14.1±0.2°,14.9±0.2°,15.6±0.2°,16.2±0.2°,16.6±0.2°,17.5±0.2°,17.8±0.2°,18.3±0.2°,18.7±0.2°,19.2±0.2°,19.7±0.2°,20.3±0.2°,20.8±0.2°,22.1±0.2°,22.7±0.2°,23.3±0.2°,23.7±0.2°,24.1±0.2°,24.8±0.2°,25.5±0.2°,25.8±0.2°,26.8±0.2°,28.0±0.2°,28.2±0.2°,29.6±0.2°,30.3±0.2°,31.2±0.2°,31.9±0.2°,33.1±0.2°,33.7±0.2°,34.3±0.2°,34.9±0.2°,37.3±0.2°,37.8±0.2°,39.0±0.2°. Differential thermal analysis showed that it desolvated at 120-150 ℃ and melted at 198+ -0.5 ℃. Thermogravimetric analysis showed a weight loss of about 15.45% after heating. The product was white powder in appearance and had a D 50 particle size of 72.4. Mu.m. The purity of the product is 99.6 percent, and the process yield is 81.4 percent.
The properties of the arbutin N-methylpyrrolidone solvent compound crystals obtained in examples 4 to 6 are consistent, and the product properties of the obtained arbutin N-methylpyrrolidone solvent compound crystals are shown in FIGS. 2, 6, 7, 8, 10 by taking the product obtained in example 4 as an example.
Table 2 taking the arbutin N-methylpyrrolidone solvent compound crystals obtained in example 4 as an example, the chemical stability thereof was examined, and compared with the chemical stability of arbutin monohydrate of table 3, the arbutin N-methylpyrrolidone solvent compound crystals have better stability than the hydrate.
TABLE 1 chemical stability investigation Table of arbutin N, N-dimethylacetamide solvent compound
| For 1 day | For 3 days | For 6 days | 9 Days | 11 Days | 13 Days | For 15 days | |
| Traits (3) | Powder | Powder | Powder | Powder | Powder | Powder | Powder |
| Color of | White color | White color | White color | White color | White color | White color | White color |
| Purity of | 99.6％ | 99.6％ | 99.5％ | 99.3％ | 99.2％ | 99.1％ | 99.1％ |
TABLE 2 chemical stability investigation Table of arbutin N-methylpyrrolidone solvent Compounds
| For 1 day | For 3 days | For 6 days | 9 Days | 11 Days | 13 Days | For 15 days | |
| Traits (3) | Powder | Powder | Powder | Powder | Powder | Powder | Powder |
| Color of | White color | White color | White color | White color | White color | White color | White color |
| Purity of | 99.7％ | 99.7％ | 99.7％ | 99.6％ | 99.5％ | 99.5％ | 99.4％ |
TABLE 3 chemical stability investigation table of arbutin monohydrate
| For 1 day | For 3 days | For 6 days | 9 Days | 11 Days | 13 Days | For 15 days | |
| Traits (3) | Powder | Powder | Powder | Powder | Powder | Powder | Powder |
| Color of | White color | White color | White color | White color | White color | White color | White color |
| Purity of | 99.6％ | 99.1％ | 98.4％ | 98.3％ | 98.1％ | 98.0％ | 98.0％ |
The invention discloses and proposes two arbutin solvent compounds and a preparation method thereof, and a person skilled in the art can properly change links such as raw materials, process parameters and the like by referring to the content of the invention. While the methods and products of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and modifications can be applied to the methods and products described herein to practice the techniques of this invention without departing from the spirit or scope of the invention. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be included within the spirit, scope and content of the invention.
Claims (9)
1. An arbutin solvent compound crystal, which consists of beta-arbutin and a first solvent, and is characterized in that the crystal belongs to an orthorhombic system; the mol ratio of the beta-arbutin to the first solvent in the crystal is 2:1; the first solvent is N, N-dimethylacetamide, the arbutin solvent compound crystal is an arbutin N, N-dimethylacetamide solvent compound crystal, and the molecular formula is as follows: 2 (C 12H16O7)·C4H9 NO, X-ray powder diffraction pattern of the arbutin N, N-dimethylacetamide solvent compound crystal has characteristic peaks at diffraction angle 2θ＝5.7±0.2°,7.6±0.2°,8.7±0.2°,9.2±0.2°,11.4±0.2°,12.2±0.2°,13.2±0.2°,14.3±0.2°,14.9±0.2°,15.3±0.2°,15.9±0.2°,16.4±0.2°,16.7±0.2°,17.3±0.2°,17.9±0.2°,18.5±0.2°,19.1±0.2°,19.9±0.2°,20.3±0.2°,20.7±0.2°,21.1±0.2°,22.5±0.2°,23.1±0.2°,23.5±0.2°,24.1±0.2°,24.8±0.2°,25.7±0.2°,26.4±0.2°,26.9±0.2°,27.4±0.2°,28.0±0.2°,28.4±0.2°,28.8±0.2°,29.3±0.2°,29.9±0.2°,30.5±0.2°,30.8±0.2°,31.4±0.2°,32.1±0.2°,33.1±0.2°,33.7±0.2°,34.4±0.2°,35.2±0.2°,36.5±0.2°,37.4±0.2°,37.8±0.2°,39.5±0.2°.
2. The crystal of arbutin solvent compound according to claim 1, characterized in that the molecular weight of the arbutin N, N-dimethylacetamide solvent compound is 631.62, belonging to an orthorhombic system, the space group is P2 12121, the unit cell parameter values are a= 6.3532 (4) a, b= 21.0244 (12) a, c= 22.6649 (18) a, α=90.00 °, β=90.00 °, γ=90.00 °, v= 3027.4 (4) a 3, z=4.
3. The crystal of arbutin solvent compound according to claim 1, characterized in that the crystal of arbutin N, N-dimethylacetamide solvent compound shows desolvation at 105-135 ℃ and melting at 198±0.5 ℃ by DSC analysis; TGA analysis shows that the weight loss is 13.94% ± 0.5% at 105-135 ℃; the particle diameter D 50 is 30-70 μm measured by a Markov laser particle size analyzer.
4. An arbutin solvent compound crystal, which consists of beta-arbutin and a first solvent, and is characterized in that the crystal belongs to an orthorhombic system; the mol ratio of the beta-arbutin to the first solvent in the crystal is 2:1; the first solvent is an N-methyl pyrrolidone solvent, and the molecular formula is as follows: 2 (C 12H16O7)·C5H9 NO), the X-ray powder diffraction pattern of the arbutin N-methylpyrrolidone solvent compound crystal has a characteristic peak at a diffraction angle 2θ＝5.6±0.2°,7.4±0.2°,8.6±0.2°,11.3±0.2°,12.0±0.2°,13.3±0.2°,13.9±0.2°,14.1±0.2°,14.9±0.2°,15.6±0.2°,16.2±0.2°,16.6±0.2°,17.5±0.2°,17.8±0.2°,18.3±0.2°,18.7±0.2°,19.2±0.2°,19.7±0.2°,20.3±0.2°,20.8±0.2°,22.1±0.2°,22.7±0.2°,23.3±0.2°,23.7±0.2°,24.1±0.2°,24.8±0.2°,25.5±0.2°,25.8±0.2°,26.8±0.2°,28.0±0.2°,28.2±0.2°,29.6±0.2°,30.3±0.2°,31.2±0.2°,31.9±0.2°,33.1±0.2°,33.7±0.2°,34.3±0.2°,34.9±0.2°,37.3±0.2°,37.8±0.2°,39.0±0.2°.
5. The crystal of arbutin solvent compound according to claim 4, characterized in that the molecular weight of the arbutin N-methylpyrrolidone solvent compound is 643.63, belonging to an orthorhombic system, the space group is P2 12121, the unit cell parameter values are a= 6.3606 (3) a, b= 20.5593 (9) a, c= 23.4018 (9) a, α=90.00 °, β=90.00 °, γ=90.00 °, v= 3060.2 (2) a 3, z=4.
6. The crystal of arbutin solvent compound according to claim 4, characterized in that the crystal of arbutin N-methylpyrrolidone solvent compound shows desolvation at 120-150 ℃ and melting at 198±0.5 ℃ by DSC analysis; TGA analysis shows that the weight loss is 15.45% +/-0.5% at 120-150 ℃; the particle diameter D 50 is 60-100 μm measured by a Markov laser particle size analyzer.
7. The method for preparing an arbutin solvent compound crystal of claim 1 or 4, comprising the steps of:
step 1: pouring the beta-arbutin solid into a crystallization solvent at a constant temperature, and suspending by mechanical stirring to uniformly mix the beta-arbutin solid;
step 2: stirring to make it be suspended and converted; the suspension temperature is 20-25 ℃;
Step 3: vacuum drying to obtain final arbutin solvent compound crystal;
the crystallization solvent is a first solvent, and the first solvent is an N, N-dimethylacetamide solvent;
Or the crystallization solvent is a mixed solvent of a first solvent and a second solvent, wherein the first solvent is an N, N-dimethylacetamide solvent or an N-methylpyrrolidone solvent, and the second solvent is at least one of methanol, isopropanol or acetone.
8. The method according to claim 7, wherein in step 1, the constant temperature is 20 ℃ to 25 ℃; in the step 2, the stirring speed is 200-300 rpm, and the suspension time is 8-24 h.
9. The method according to claim 7, wherein in the step 3, the drying temperature is 30 to 40 ℃ and the drying time is 6 to 24 hours.
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