CN111454187A - Lutein ethanol solvate crystal and preparation method thereof - Google Patents
Lutein ethanol solvate crystal and preparation method thereof Download PDFInfo
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- CN111454187A CN111454187A CN202010280120.7A CN202010280120A CN111454187A CN 111454187 A CN111454187 A CN 111454187A CN 202010280120 A CN202010280120 A CN 202010280120A CN 111454187 A CN111454187 A CN 111454187A
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 358
- 229960005375 lutein Drugs 0.000 title claims abstract description 231
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 title claims abstract description 231
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 title claims abstract description 231
- KBPHJBAIARWVSC-RGZFRNHPSA-N lutein Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=C[C@H](O)CC1(C)C KBPHJBAIARWVSC-RGZFRNHPSA-N 0.000 title claims abstract description 227
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- 239000013078 crystal Substances 0.000 title claims abstract description 123
- 239000012453 solvate Substances 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
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- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 230000003834 intracellular effect Effects 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
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- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
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- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
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- 235000003903 alpha-carotene Nutrition 0.000 description 1
- ANVAOWXLWRTKGA-HLLMEWEMSA-N alpha-carotene Natural products C(=C\C=C\C=C(/C=C/C=C(\C=C\C=1C(C)(C)CCCC=1C)/C)\C)(\C=C\C=C(/C=C/[C@H]1C(C)=CCCC1(C)C)\C)/C ANVAOWXLWRTKGA-HLLMEWEMSA-N 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
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- SWGJCIMEBVHMTA-UHFFFAOYSA-K trisodium;6-oxido-4-sulfo-5-[(4-sulfonatonaphthalen-1-yl)diazenyl]naphthalene-2-sulfonate Chemical compound [Na+].[Na+].[Na+].C1=CC=C2C(N=NC3=C4C(=CC(=CC4=CC=C3O)S([O-])(=O)=O)S([O-])(=O)=O)=CC=C(S([O-])(=O)=O)C2=C1 SWGJCIMEBVHMTA-UHFFFAOYSA-K 0.000 description 1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/24—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by six-membered non-aromatic rings, e.g. beta-carotene
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a lutein ethanol solvent compound crystal and a preparation method thereof. One-molecule xanthophyll solvent compound crystal contains one-molecule xanthophyll and two-molecule ethanol, and the molecular formula is [ C40H56O2]2C2H6And O. Single crystal unit cell parameter
c＝13.108(3)A，α＝94.10(3)°，β＝108.09(3)°，γ＝101.65(3)°，
The number of intracellular molecules is 1. Triclinic, P (1) space group. Compared with solvent-free lutein crystals, the lutein ethanol solvate of the invention has determined crystal form, and the prepared crystals have regular and complete crystal form, good fluidity and small hygroscopicity, and simultaneously participate inLess impurity, higher purity and higher chemical stability compared with solvent-free lutein crystal.
Description
Technical Field
The invention belongs to the technical field of medical crystallization, and particularly relates to a lutein ethanol solvent compound crystal and a preparation method thereof.
Background
The lutein belongs to carotenoid substances, has a chemical name of 3 s-3's-dihydroxy- α -carotene, is widely present in leaves, flowers and fruits of plants, has vitamin A activity and higher antioxidant activity, and has good application value in the aspects of biological medicines, food additives, electronic materials and the like.
Due to the existence of polyunsaturated double bonds, the lutein is unstable in property, is easily influenced by factors such as oxygen, illumination, temperature and the like, is oxidized, and the application range of the lutein is greatly limited. Lutein is easy to form needle-shaped or flaky crystals, and crystals with regular crystal forms are difficult to generate in the production process. On one hand, needle-shaped or thin-sheet crystals are easy to be broken under crystallization conditions, secondary nucleation occurs, the final control of the product granularity and the crystal form is directly influenced, and certain difficulty is brought to the downstream operation of production and manufacturing. On the other hand, lattice defects are easy to form in the preparation process of the product, and impurities are easy to be doped into the lattice, which is also one of the factors that the purity of the lutein is difficult to be improved by a crystallization mode. The nature of crystal growth of carotenoids makes it extremely difficult to grow single crystals, and although there are more than about 600 members of the carotenoid family, only single crystal structures of about 32 carotenoids (including carotenoid derivatives, carotenoid solvates) are presently disclosed. However, as for lutein, no literature and patent reports of lutein and lutein solvate single crystal structures exist at present. The preparation method of the lutein crystal or lutein solvate with complete crystal form can effectively improve the physicochemical property of the lutein crystal, and has important value for producing lutein products with good fluidity, stability and higher purity.
Although some patent documents report the preparation method of lutein crystal, for example, chinese patent CN107445878B, the method is to mix and stir lutein grease and alkaline ionic liquid ethanol solution for ester exchange to obtain ester exchange product; cooling and crystallizing the ester exchange product, filtering to obtain a filter cake which is a crude product of the lutein, and recrystallizing with acetone to obtain a lutein crystal, wherein the purity of the lutein is only 82.45-85.64%. Chinese patent CN 108191730A, marigold extract is added into supercritical CO2In the extraction tank, extracting and separating to obtain stock solution; saponifying the stock solution, centrifuging to collect the material, finally adding a certain amount of absolute ethyl alcohol into the material, recrystallizing at the low temperature of 5-15 ℃ to collect lutein crystals, drying to obtain the lutein crystals with total carotenoid of 99.15% and lutein content of 95.23%, and indicating that the solvent-free lutein crystals are prepared by the method. The us patent USRE40931E adopts a solvent system of dichloromethane/n-hexane to prepare lutein crystal by means of elution crystallization, and the content of lutein in the final product can reach 94.79%. However, these patents are mainly concerned with the process technology and the purity of lutein in the final product, and do not concern the crystal form and crystal habit of lutein. The control of the crystal form and the crystal habit of crystal products is a key technology of industrial crystallization process.
The crystal form of the lutein ethanol solvate is determined, and the prepared lutein ethanol solvate has the advantages of complete crystal form, good fluidity, small hygroscopicity, less impurity, higher purity and higher chemical stability compared with a solvent-free lutein crystal.
Disclosure of Invention
The invention aims to research the crystal form of a lutein solvent compound and provides a crystallization method of a novel lutein solvent compound.
The present invention provides a crystal structure of a solvent compound of lutein and a crystallization method thereof. The method solves the problems of the prior art that the lutein is in a flaky crystal habit, poor in fluidity, extremely unstable, difficult to improve the purity only by a crystallization mode and the like, and provides a novel lutein compound.
The technical scheme of the invention is as follows:
a crystal of xanthophyll solvent compound has a crystal structure of xanthophyll ethanol solvent compound, wherein one-molecule xanthophyll solvent compound crystal contains one-molecule xanthophyll and two-molecule ethanol, and the molecular formula is [ C ]40H56O2]2C2H6And O. The molar ratio of xanthophyll molecules to ethanol solvent molecules is 1:2, molecular formula C40H56O2·2C2H6O, characterization of the single crystal structure of the xanthophyll ethanol solvent compound, with the following results:
single crystal unit cell parameters:
c＝13.108(3)A，α＝94.10(3)°，β＝108.09(3)°，γ＝101.65(3)°，
the number of intracellular molecules is 1. Triclinic, P (1) space group.
The structure diagram of the single crystal molecule of the crystal of the xanthophyll ethanol solvent compound of the invention is shown in figure 1.
The lutein ethanol solvent compound crystal has characteristic peaks at 2 theta angles of 2.38 +/-0.2 degrees, 3.88 +/-0.2 degrees, 6.86 +/-0.2 degrees, 10.9 +/-0.2 degrees, 14.9 +/-0.2 degrees, 15.3 +/-0.2 degrees, 17.32 +/-0.2 degrees, 19.9 +/-0.2 degrees, 20.5 +/-0.2 degrees, 21.08 +/-0.2 degrees, 21.64 +/-0.2 degrees, 21.68 +/-0.2 degrees, 21.98 +/-0.2 degrees, 22.7 +/-0.2 degrees, 24.36 +/-0.2 degrees and 24.88 +/-0.2 degrees by using Cu-Ka radiation, and the X-ray powder diffraction pattern is shown in figure 2.
The thermogravimetric analysis showed 11.86% weight loss before 120 ℃ and the thermogravimetric analysis pattern is shown in FIG. 3.
The crystallization method of the lutein ethanol solvent compound crystal is characterized in that a lutein crude product is dissolved in dichloromethane or tetrahydrofuran under the stirring action, the mass ratio of lutein to dichloromethane or tetrahydrofuran is 1: 5-50, the solution is heated to be dissolved and filtered, the filtrate is placed in a reaction kettle, ethanol is supplemented at the speed of 0.1-10m L/min under the protection of nitrogen until a mauve crystal appears, and the lutein ethanol solvent compound is obtained after filtering and drying.
The dosage of the ethanol is 1 to 20 times of the volume of the solvent.
The lutein ethanol solvent compound can be prepared by suspending and crystallizing at the constant temperature of 20-40 ℃: adding a lutein raw material into an ethanol solvent with constant temperature, wherein the mass ratio of lutein to ethanol is 1: stirring for 1-48h for 10-50 h, and carrying out ethanol-mediated crystal transformation to obtain the lutein ethanol compound.
The lutein ethanol solvent compound is used for preparing the lutein solvent-free compound, and the prepared lutein ethanol solvent compound is dried for 1-72h at the temperature of 60-100 ℃ and under the vacuum condition of 0.05-0.2 Mpa, so that the high-purity lutein solvent-free compound is obtained.
The crystal of the xanthophyll ethanol solvent compound is regular wedge-shaped crystal, and the microscopic morphology observation is shown in figure 4 b. The lutein ethanol solvate is a regular wedge-shaped crystal, has regular edge, good transparency, particle size of 0.2-1mm and good crystal habit.
The lutein ethanol solvate has better fluidity. The fluidity of the crystals of the xanthophyll solvent compound was analyzed by injection. The angle of repose of the xanthophyll ethanol solvate is 42 degrees, the angle of repose of the solvent-free xanthophyll crystal raw material is 53 degrees, which shows that the xanthophyll ethanol solvate crystal has better fluidity compared with the solvent-free xanthophyll crystal.
Compared with the lutein crystal without solvent, the lutein ethanol solvate of the present invention has smaller hygroscopicity, and the hygroscopicity analysis is shown in fig. 6a and fig. 6 b. The weight of the lutein ethanol solvate is increased by about 0.1 percent, while the weight of the lutein solvent-free crystal powder is increased by 2 percent, and compared with the solvent-free lutein crystal powder, the lutein ethanol solvate has smaller hygroscopicity and better stability.
After the lutein ethanol solvate is desolventized, the purity of the lutein is higher, and the analysis of the purity of TG/DSC is shown in figure 7a and figure 7 b. After desolvation of the ethanol solvate, the sample has only one sharp melting peak, and the raw material has two obvious impurity absorption peaks at 50 ℃. Combining the structure of the lutein solvate crystal and the results of TGA thermogravimetric analysis shows that the main components in the lutein ethanol solvate crystal are lutein and solvent ethanol. By preparing the lutein ethanol solvate and then desolventizing the solvate, the lutein solid with higher purity can be obtained.
The lutein ethanol solvate of the present invention has higher stability compared to solvent free crystals as shown in figure 5. After the ultraviolet irradiation condition for 96 hours, the characteristic peak absorption value of the lutein in the solvent-free lutein crystal is reduced from 1.4 to 1.0, which indicates that the lutein residual quantity of the solvent-free lutein crystal is 71.4%. Under the same conditions, the characteristic peak absorption value of the lutein ethanol solvate is basically kept at 1.45, and the later characteristic absorption peak is slightly increased due to desolvation of the solvate and slightly increased relative content of lutein. This indicates that the residual amount of lutein in the lutein solvate is essentially unchanged under uv irradiation within 96h, and that the lutein ethanol solvate is more uv stable than the lutein solvent-free crystals. Under the high temperature condition of 65 ℃, the characteristic peak absorption value of the lutein after 96 hours of solvent-free crystal is reduced to 0.2 from the initial 1.4, and the lutein residue is about 14.28%. The peak absorption of lutein ethanol solvate is reduced from 1.4 to 0.3, and the residual amount of lutein is about 21.42%. Under both accelerated conditions, the lutein residual amount of the lutein ethanol solvate crystals is relatively high, indicating that the lutein methanol solvate is relatively more stable.
The crystal form of the lutein ethanol solvate is determined, and the prepared crystal is regular and complete in crystal form, good in fluidity, small in hygroscopicity, less in doped impurities, higher in purity and higher in chemical stability compared with a solvent-free lutein crystal.
Drawings
Figure 1 is a schematic single crystal structure of a xanthophyll ethanol solvate.
FIG. 2 is a powder x-ray diffraction pattern of a xanthophyll ethanol solvate. The ordinate represents diffraction intensity, and the abscissa represents diffraction angle.
Fig. 3 is a thermogravimetric analysis of lutein ethanol solvate.
Figure 4a is a microscopic view of a xanthophyll ethanol solvate.
Figure 4b is a microscopic view of the xanthophyll ethanol solvate.
FIG. 5a is a graph of the residual amount of lutein in the solvent-free crystals of lutein at various time points of the stability analysis.
FIG. 5b is a graph of the residual amount of lutein in the xanthophyll ethanol solvate at various time points of the stability analysis.
FIG. 6a is an analysis of hygroscopicity of lutein solvent-free crystalline powder
FIG. 6b is the hygroscopicity analysis of crystalline powder of xanthophyll ethanol solvent compound.
FIG. 7a is TG/DSC purity analysis of lutein solvent free crystals.
FIG. 7b is TG/DSC purity analysis of xanthophyll ethanol solvate after desolvation.
Detailed Description
The foregoing and other objects of the present invention will be more fully understood from the following detailed description of the embodiments, taken in conjunction with the accompanying drawings, which are included to illustrate, but are not to be construed as the limit of the invention. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1
Preparation of xanthophyll ethanol solvent compound
Dissolving a lutein crude product in dichloromethane, mixing 20g of lutein with 100g of dichloromethane (the mass ratio is 1:5), heating and stirring the solution until the solution is dissolved, filtering, placing the filtrate in a reaction kettle, replacing air in the reaction kettle with nitrogen, supplementing 75m L ethanol at the rate of 0.1ml/min, generating purple red crystals, filtering solids, and drying to obtain the lutein ethanol solvent compound, wherein the lutein ethanol solvent compound is obtained by performing X-ray powder diffraction analysis on the product, and the spectrum is shown as the attached figure 2, and has characteristic absorption peaks at 2 theta (2 theta), 2.38 degrees, 3.88 degrees, 6.86 degrees, 10.9 degrees, 14.9 degrees, 15.3 degrees, 17.32 degrees, 19.9 degrees, 20.5 degrees, 21.08 degrees, 21.64 degrees, 21.68 degrees, 21.98 degrees, 22.7 degrees, 24.36 degrees and 24.88 degrees, and the specific data are as follows:
TGA thermogravimetric analysis is carried out on the product, the environment is purged by nitrogen, the heating rate is 10 ℃/min, the analysis result is shown in figure 3, an obvious desolvation peak is formed, and the weight loss percentage of the desolvation is 11.86%. The product was observed by microscope as shown in FIG. 4, which is wedge-shaped with regular edges and uniform particle size.
Example 2
Preparation of xanthophyll ethanol solvent compound
Dissolving the crude product of lutein in dichloromethane, mixing 10g of lutein with 100g of dichloromethane (mass ratio of 1:10), heating and stirring the solution until the solution is dissolved, filtering, placing the filtrate in a reaction kettle, replacing air in the reaction kettle with nitrogen, supplementing ethanol 750m L at the speed of 5m L/min, generating mauve crystals, filtering the solid, drying to obtain the ethanol solvent compound of lutein, and carrying out X-ray powder diffraction analysis on the product, wherein the spectrum is shown as attached figure 2.
Example 3
Preparation of xanthophyll ethanol solvent compound
Dissolving the lutein crude product in dichloromethane, mixing 2g of lutein with 100g of dichloromethane (mass ratio is 1:50), heating and stirring the solution until the solution is dissolved, filtering, placing the filtrate in a reaction kettle, replacing air in the reaction kettle with nitrogen, supplementing ethanol 1500m L at the speed of 10m L/min, generating mauve crystals, filtering the solid, drying to obtain the lutein ethanol solvent compound, and carrying out X-ray powder diffraction analysis on the product, wherein the spectrum is shown as attached figure 2.
Example 4
Dissolving the lutein crude product in tetrahydrofuran, mixing 20g of lutein with 100g of tetrahydrofuran (mass ratio of 1:5), heating and stirring the solution until the solution is dissolved, filtering, placing the filtrate in a reaction kettle, replacing air in the reaction kettle with nitrogen, supplementing ethanol 112m L at the speed of 0.1m L/min, generating mauve crystals, filtering the solid, and drying to obtain the lutein ethanol solvent compound.
Example 5
Preparation of xanthophyll ethanol solvent compound
Dissolving the lutein crude product in tetrahydrofuran, mixing 5g of lutein with 100g of tetrahydrofuran (mass ratio of 1:20), heating and stirring the solution until the solution is dissolved, filtering, placing the filtrate in a reaction kettle, replacing air in the reaction kettle with nitrogen, supplementing ethanol 1120m L at the speed of 5m L/min, generating mauve crystals, filtering the solid, drying to obtain the lutein ethanol solvent compound, and carrying out X-ray powder diffraction analysis on the product, wherein the spectrum is shown as attached figure 2.
Example 6
Preparation of xanthophyll ethanol solvent compound
Dissolving the lutein crude product in tetrahydrofuran, mixing 2g of lutein with 100g of tetrahydrofuran (mass ratio of 1:50), heating and stirring the solution until the solution is dissolved, filtering, placing the filtrate in a reaction kettle, replacing air in the reaction kettle with nitrogen, supplementing ethanol 2240m L at the speed of 10m L/min, generating mauve crystals, filtering solids, drying to obtain the lutein ethanol solvent compound, and carrying out X-ray powder diffraction analysis on the product, wherein the spectrum is shown as the attached figure 2.
Example 7
Preparation of xanthophyll ethanol solvent compound
The preparation method of the lutein ethanol solvate comprises the steps of suspending 10g of lutein raw materials in 100g of ethanol (mass ratio is 1:10), stirring at a constant temperature of 20 ℃ to enable the lutein to be in a uniform suspension state, filtering after 48 hours, and drying to obtain the lutein ethanol solvate. The product was subjected to X-ray powder diffraction analysis, and the spectrum is shown in FIG. 2.
Example 8
Preparation of xanthophyll ethanol solvent compound
The preparation method of the lutein ethanol solvate comprises the steps of suspending 20g of lutein raw materials in 500g of ethanol (mass ratio is 1:25), stirring at the constant temperature of 30 ℃ to enable the lutein to be in a uniform suspension state, filtering after 24 hours, and drying to obtain the lutein ethanol solvate. The product was subjected to X-ray powder diffraction analysis, and the spectrum is shown in FIG. 2.
Example 9
Preparation of xanthophyll ethanol solvent compound
The preparation method of the lutein ethanol solvate comprises the steps of suspending 20g of lutein raw materials in 1000g of ethanol (mass ratio is 1:50), stirring at the constant temperature of 40 ℃ to enable the lutein to be in a uniform suspension state, filtering after 1 hour, and drying to obtain the lutein ethanol solvate. The product was subjected to X-ray powder diffraction analysis, and the spectrum is shown in FIG. 2.
Example 10
Sample preparation of xanthophyll ethanol solvate desolventization
Spreading 1g xanthophyll ethanol solvate in a glass plate, and drying at 60 deg.C and 0.05MP for 72h to obtain xanthophyll solvent-free amorphous solid.
Example 11
Sample preparation of xanthophyll ethanol solvate desolventization
Spreading 1g xanthophyll ethanol solvate in a glass plate, and drying at 80 deg.C and 0.1MP for 36h to obtain xanthophyll solvent-free amorphous solid.
Example 12
Sample preparation of xanthophyll ethanol solvate desolventization
Spreading 1g xanthophyll ethanol solvate in a glass plate, and drying at 100 deg.C and 0.2MP for 1h to obtain xanthophyll solvent-free amorphous solid.
The product performance obtained in the examples of the present invention was analyzed as follows:
morphology analysis of lutein ethanol solvate crystals
The inventors have analysed the crystal habit of the xanthophyll ethanol solvate and the micrograph is shown in figure 4 b. The lutein solvent-free crystal is irregular flaky crystal (fig. 4a), rough edge, incomplete crystal form and poor crystal habit. The lutein ethanol solvate is a regular wedge-shaped crystal, has regular edge, good transparency, particle size of 0.2-1mm and good crystal habit.
Lutein ethanolate crystal flowability analysis
The fluidity of the crystals of the xanthophyll solvent compound was analyzed by injection. With funnel vertical fixation on the iron stand platform, place the sample collection platform apart from funnel bottom export 3cm level, pour the lutein crystal powder of 2g into the funnel at the uniform velocity, the material powder is flowed by the funnel, falls on the sample collection platform and forms the cone, cone generating line and the contained angle of base plane be the angle of repose of sample. The repose angle of the lutein ethanol solvate measured by the method is 42 degrees, and the repose angle of the solvent-free lutein crystal raw material is 53 degrees, which shows that the fluidity of the lutein ethanol solvate crystal is better than that of the solvent-free lutein crystal.
Hygroscopicity analysis of lutein ethanol solvate crystals
The hygroscopicity of the lutein ethanol solvate crystal powder was compared with that of lutein solvent-free crystal powder by dynamic moisture sorption spectrometry (DVS). The temperature was 25 ℃, nitrogen flow, 500ml/min, relative humidity was increased from 0% to 95% in 5% humidity changes, each humidity was equilibrated for 60min, and the time interval for automatic recording of sample mass was 1min, with the results shown in fig. 6a and 6 b. The lutein ethanol solvate gained about 0.1% (fig. 6b) and 2% (fig. 6a) of the lutein solvent-free crystal powder, and the research result shows that the lutein ethanol solvate has less hygroscopicity and thus better stability compared with the solvent-free lutein crystal powder.
Purity identification of lutein ethanol solvate desolventizing sample TG/DSC
The purity of the lutein solvate desolventizing samples and lutein starting material obtained in example 10, example 11 and example 12 were analyzed by Mettler TGA/DSC 1 star system with nitrogen flow of 20ml-50ml/min and temperature rise rate of 10K/min, and the results are shown in fig. 7a and 7 b. After desolvation of the ethanol solvate, the sample had only one sharp melting peak (fig. 7b), while the feedstock had two distinct impurity absorption peaks at 50 ℃ (fig. 7 a). Combining the structure of the lutein solvate crystal and the results of TGA thermogravimetric analysis shows that the main components in the lutein ethanol solvate crystal are lutein and solvent ethanol. By preparing the lutein ethanol solvate and then desolventizing the solvate, the lutein solid with higher purity can be obtained.
Lutein ethanol solvate crystal stability study
Respectively placing the lutein ethanol solvate crystal and the solvent-free lutein crystal at 65 ℃ for treatment for 120 hours, then sampling and analyzing the lutein content of a sample, and judging the stability of the crystal.
And (3) placing the lutein ethanol solvate crystal and the solvent-free lutein crystal under ultraviolet irradiation for treatment for 120 hours, then sampling and analyzing the lutein content in a sample, and judging the stability of the crystal.
The results of this experiment show the profile of the lutein content at different time points in the accelerated test as shown in FIG. 5.
According to fig. 5, after the ultraviolet irradiation condition for 96 hours, the characteristic peak absorption value of lutein in the solvent-free lutein crystal is reduced from 1.4 to 1.0, which indicates that the lutein residual amount of the solvent-free lutein crystal is 71.4%. Under the same conditions, the characteristic peak absorption value of the lutein ethanol solvate is basically kept at 1.45, and the later characteristic absorption peak is slightly increased due to desolvation of the solvate and slightly increased relative content of lutein. This indicates that the residual amount of lutein in the lutein solvate is essentially unchanged under uv irradiation within 96h, and that the lutein ethanol solvate is more uv stable than the lutein solvent-free crystals. Under the high temperature condition of 65 ℃, the characteristic peak absorption value of the lutein after 96 hours of solvent-free crystal is reduced to 0.2 from the initial 1.4, and the lutein residue is about 14.28%. The peak absorption of lutein ethanol solvate is reduced from 1.4 to 0.3, and the residual amount of lutein is about 21.42%. Under both accelerated conditions, the lutein residual amount of the lutein ethanol solvate crystals is relatively high, indicating that the lutein methanol solvate is relatively more stable.
The experimental results show that: under the conditions of high temperature and ultraviolet irradiation, the lutein content of the lutein ethanol solvate crystal is relatively higher compared with that of the solvent-free lutein crystal, which indicates that the lutein ethanol solvate is relatively more stable.
Although the method and process of the present invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations and modifications of the method and process described herein can be made without departing from the spirit and scope of the invention to achieve the final product. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and content of the invention.
Claims (6)
1. A xanthophyll ethanol solvent compound crystal, which is characterized in that the single crystal is characterized as follows: the molar ratio of xanthophyll molecules to ethanol solvent molecules is 1:2, molecular formula C40H56O2·2C2H6O, single crystal unit cell parameters:
c＝13.108(3)A，α＝94.10(3)°，β＝108.09(3)°，γ＝101.65(3)°，
the number of intracellular molecules is 1, triclinic, P (1) space group.
2. The xanthophyll ethanol solvate according to claim 1, characterized by a characteristic peak in terms of 2 Θ at 2 Θ -2.38 ± 0.2 °, 3.88 ± 0.2 °, 6.86 ± 0.2 °, 10.9 ± 0.2 °, 14.9 ± 0.2 °, 15.3 ± 0.2 °, 17.32 ± 0.2 °, 19.9 ± 0.2 °, 20.5 ± 0.2 °, 21.08 ± 0.2 °, 21.64 ± 0.2 °, 21.68 ± 0.2 °, 21.98 ± 0.2 °, 22.7 ± 0.2 °, 24.36 ± 0.2 °, 24.88 ± 0.2 ° by X-ray powder diffraction; there was a weight loss of 11.86% before 120 ℃ in thermogravimetric analysis.
3. The method for preparing the xanthophyll ethanol solvent compound as claimed in claim 1, wherein the preparation method comprises the steps of dissolving a xanthophyll crude product in dichloromethane or tetrahydrofuran at a mass ratio of 1: 5-50, heating the solution to dissolve, filtering, placing the filtrate in a reaction kettle, under the protection of nitrogen, supplementing ethanol at a rate of 0.1-10m L/min until a mauve crystal appears, filtering the solid, and drying to obtain the xanthophyll ethanol solvent compound.
4. The method as set forth in claim 2, wherein the amount of ethanol is 1 to 20 times the volume of the solvent.
5. The process for the preparation of the xanthophyll ethanol solvent compound as claimed in claim 1, characterized by the fact that it is prepared by suspension crystallization at a constant temperature of 20-40 ℃: adding a lutein raw material into an ethanol solvent with constant temperature, wherein the mass ratio of lutein to ethanol is 1: stirring for 1-48h for 10-50 h, and obtaining the lutein solvent compound through ethanol mediated crystal transformation.
6. The xanthophyll ethanol solvent compound as claimed in claim 1, which is used for preparing the xanthophyll solvent-free compound, characterized in that the xanthophyll ethanol solvent compound is dried at 60-100 ℃ and 0.05-0.2 Mpa vacuum condition for 1-72h to obtain the xanthophyll solvent-free compound with high purity.
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| CN108191730A (en) * | 2018-01-16 | 2018-06-22 | 邯郸市美康生物科技有限公司 | A kind of production method that high purity lutein crystal is prepared by marigold extractum |
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| CN105708799A (en) * | 2016-01-27 | 2016-06-29 | 金银秀 | Nano-structural lipid carrier pharmaceutical composition and preparation method thereof |
| CN108191730A (en) * | 2018-01-16 | 2018-06-22 | 邯郸市美康生物科技有限公司 | A kind of production method that high purity lutein crystal is prepared by marigold extractum |
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