CN106083792A - The dihydromyricetin hydrate crystallization of dextrorotation - Google Patents
The dihydromyricetin hydrate crystallization of dextrorotation Download PDFInfo
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- CN106083792A CN106083792A CN201610390126.3A CN201610390126A CN106083792A CN 106083792 A CN106083792 A CN 106083792A CN 201610390126 A CN201610390126 A CN 201610390126A CN 106083792 A CN106083792 A CN 106083792A
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- dihydromyricetin
- dextrorotation
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
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Abstract
The invention discloses the dihydromyricetin hydrate crystallization of a kind of dextrorotation.The present invention uses and is characterized dihydromyricetin spatial configuration than rotation method and efficient liquid phase chiral separation.Utilize solid-state analytical technology, including dihydromyricetin crystal formation is characterized by powder x-ray diffraction technology (XRD), difFerential scanning calorimetry (DSC), thermogravimetry (TGA), karl Fischer titration and Fourier Transform Attenuated Total Reflect ion Infrared Spectroscopy (FT ATR), it is the formulation developments such as bulk drug process exploitation, solid pharmaceutical preparation, semisolid, suspending agent and quality control is significant that the present invention has carried out screening polymorph to dihydromyricetin.
Description
Technical field
The present invention relates to pharmaceutical technology field, in particular to the dihydromyricetin hydrate crystallization of a kind of dextrorotation；Its point
Case is in the Chinese invention patent " five kinds of different crystal forms materials of dihydromyricetin " of Application No. 2014107158285.
Background technology
Dihydromyricetin (Dihydromyricelin), also known as ampelopsin (Ampelopsin), first by Kotake and
Kubota in isolated from the leaf of ampelopsis A. Meliaefolia (Ampelopsis meliaefolia) in 1940,
Being a kind of flavanonol flavonoids, chemical constitution is 3,5,7,3', 4', 5'-hexahydroxy-2,3-flavanonol.
Dihydromyricetin is widely present in porcelain ampelopsis section ampelopsis, exists in Myruca ceas, Cuculidae, Guttiferae, the root of Beijing euphorbia
In the section plants such as section, Burseraceae, pulse family, Sapotaceae and Liu Ke.
Dihydromyricetin is white or faint yellow acicular crystal, water-soluble poor (0.2mg/ml, 25 DEG C), is soluble in heat
Water, in ethanol, methyl alcohol, acetone and DMSO.Under aqueous solution heated condition, chemical stability is poor, has preferably under its solid state
Chemical stability.
Dihydromyricetin molecule steric-configuration exists two chiral centres, Pubchem compound database is included
Two kinds of dihydromyricetin configurations, are respectively (2R, 3R) configuration and (2R, 3S) configuration, and its absolute configuration can distinguish corresponding dextrorotation, left
Rotation and racemization dihydromyricetin.Existing most literature report is given tacit consent to and which is (2R, 3R) configuration, as shown in following mechanism type,
The dihydromyricetin structure of (2R, 3R) configuration
Compound spatial configuration particularly chiral centre may affect validity, toxicity and the clinical efficacy of compound, changes
The stability of compound is likely to associated therewith.
Under state of the art, when there is chiral centre in compound, the absolute configuration at compound chirality center frequently with
Single crystal X-ray diffraction and circular dichroism method determine, chiral separation or can distinguish (+) and (±) dihydromyricetin than rotation method
Element.
Have document (1. Yoo S M, Mun S, Kim J H.Recovery and pre-purification of at present
(+)-dihydromyricetin from Hovenia dulcis[J].Process biochemistry,2006,41(3):
567-570.②Du Q,Cai W,Xia M,et al.Purification of(+)-dihydromyricetin from
leaves extract of Ampelopsis grossedentata using high-speed countercurrent
chromatograph with scale-up triple columns[J].Journal of Chromatography A,
2002,973(1):217-220.③Gao J,Liu B,Ning Z,et al.Characterization and
antioxidant activity of flavonoid-rich extracts from leaves of Ampelopsis
Grossedentata [J] .Journal of food biochemistry, 2009,33 (6): 808-820.) etc. two are reported
In the hydrogen myricetin aqueous solution or ethanol water, crystallisation by cooling separates out is racemic product.Many in racemization through measuring commercial samples
Configuration, consistent with document above report result.
According to polycrystalline in Chinese Pharmacopoeia " Quality Control Technology of polymorphic medicine and guide for method principle " exposure draft
The definition of type, hydrate or solvate belong to polymorph in pharmaceuticals category.Polymorph in pharmaceuticals may cause solubility, stability
With the difference of the aspects such as engineering properties, affect clinical drug curative effect and preparation technology, it is therefore desirable to keep a close eye under study for action, but
Present stage has no the report about the screening of dihydromyricetin crystal formation.In multiple commercial samples, dihydromyricetin disappears for having after measured
The crystalline solid of rotation structure dihydrate.
The crystallization water is entirely different with the absorption water of plane of crystal, and adsorption water easily loses, and formed absorption water for point
Son amount is the compound of about 400, and weight changes≤0.5%, has substantially no effect on compound property, adsorbs the reunion to powder for the water
Having a certain impact with mobility tool, too high absorption water content may cause compound deliquescence.And the crystallization water can directly change
Change solvate crystal structure, changes >=2% to the weight of compound, and compound solubility or stability may be caused to occur bigger
Change, it is however generally that, the solubility of hydrate is less than anhydride, and crystal of hydrate stability in aqueous is generally greater than anhydrous
Thing.
At document (Xu, Z., Liu, B., Ning, Z., &Zhang, Y..Racemic dihydromyricetin
dihydrate.Acta Crystallographica Section E:Structure Reports Online,63.11
(2007) obtain dihydromyricetin monocrystalline by crystallisation by cooling legal system in: 4384.), and use Single Crystal X-ray result to show its structure
Dihydrate for racemization.
In the research polymorphous document of dihydromyricetin (Lin Shuying. in ampelopsis grossdentata, the extraction of dihydromyricetin is pure
Change and antioxidation activity research [D]. South China Science & Engineering University, 2004), author has investigated 60% ethanol and aqueous solution crystallisation by cooling obtains
Crystal formation, in the XRD result of displaying, abscissa is that d value is significantly different with the XRD in the present invention, and additionally author thinks and obtains
Two kinds of different crystal formations, but employing microscope is taken pictures, result only can determine whether as crystal habit different, it is impossible to draws " dihydro poplar in this article
There is polymorphic in syphilis " conclusion.
At document (Ruan L P, Yu B Y, Fu G M, et al.Improving the solubility of
ampelopsin by solid dispersions and inclusion complexes[J].Journal of
Pharmaceutical and Biomedical Analysis, 2005,38 (3): 457-464.) the dihydro poplar of use is mentioned in
Syphilis raw material is dihydrate, but does not illustrates with regard to crystal structure and compound spatial configuration.
Document (Li Yingqi. Yao nationality's vine tea quality standard and main active pharmacokinetic study [D]. Shenyang medicine
University of section, 2003.) in, dihydromyricetin is the dihydromyricetin mentioned in this patent, and dihydromyricetin is being tied by author
Have employed multinomial means during structure confirmation, including circular dichroism, it was demonstrated which is (2R, 3R) configuration, but its crystal structure is not given
Going out to illustrate, only explanation which is white, needle-shaped crystals and provides infrared spectrogram.But deposit in dihydromyricetin molecule
At more hydrogen bond, intramolecular and intermolecular hydrogen bonding can be formed, it is also possible to containing the crystallization water, only from compound at 3300cm-1Place deposits
At broad peak, it is impossible to show its crystal structure.
Content of the invention
The technical problem to be solved just there is provided the dihydromyricetin hydrate crystallization of a kind of dextrorotation.
The present invention use the compound structure type to dihydromyricetin than rotation method and chiral reagent fractionation differentiate, respectively
Utilize (+) and (±) dihydromyricetin raw material to carry out screening polymorph, employing solid-state analytical technology such as: powder x-ray diffraction, poor
Show that gained crystal formation is carried out by calorimetric scan, Karl_Fischer method, thermogravimetric analysis and Fourier Transform Attenuated Total Reflect ion Infrared Spectroscopy
Analyze.Through confirmation, at least there are 5 kinds of crystal formations in dihydromyricetin, 5 kinds of crystal formations there are differences in stability and solubility.
For solving above-mentioned technical problem, the dihydromyricetin dihydrate crystallization of a kind of dextrorotation that the present invention provides, use
Polarimeter records its specific rotation [α]D=+32 ° [c 0.20, DMSO, 20 DEG C], uses powder x-ray diffraction (XRD) to analyze, adopts
Use CuKαRadiation, diffraction maximum position 2-Theta (5-45 °), there is following characteristic peak: 6.63 °, 8.07 °, 9.51 °, 11.50 °,
13.26°,16.08°,18.72°,27.20°,28.58°,28.88°。
Further, described dextrorotation dihydromyricetin dihydrate is 3000-3500cm in wave number-1Interval in have with
Lower characteristic peak: the 3375th, the 3334th, 3200cm-1。
Yet further, described dextrorotation dihydromyricetin dihydrate uses Karl_Fischer method to measure wherein moisture and be
10.1 ± 0.3% (n=3, n are experiment number, lower same).
Present invention also offers a kind of dextrorotation dihydromyricetin anhydride crystallization, use polarimeter to record its specific rotation [α]D
=+36 ° [c 0.20, DMSO, 20 DEG C], uses powder x-ray diffraction (XRD) to analyze, uses CuKαRadiation, diffraction maximum position 2-
Theta (5-45 °), has a following characteristic peak: 7.27 °, 9.69 °, 11.07 °, 15.76 °, 22.74 °, 26.97 °.
Further, the dihydromyricetin anhydride crystallization of described dextrorotation is 3000-3500cm in wave number-1Interval in
There is following characteristics peak: the 3581st, the 3399th, 3220cm-1。
Yet further, described dextrorotation dihydromyricetin anhydride moisture uses Karl_Fischer method mensuration to be less than
0.3% (n=3).
Present invention also offers the dihydromyricetin hydrate crystallization of a kind of dextrorotation, use polarimeter to record its specific rotation
[α]D=+34 ° [c 0.20, DMSO, 20 DEG C], uses powder x-ray diffraction (XRD) to analyze, uses CuKαRadiation, diffraction peak
Put 2-Theta (5-45 °), there is following characteristic peak: 9.98 °, 11.36 °, 13.20 °, 14.52 °, 22.74 °, 22.82 °,
28.32°。
Further, described dihydromyricetin hydrate crystallization is 3000-3500cm in wave number-1Interval in have with
Lower characteristic peak: the 3568th, the 3293rd, 3083cm-1。
Yet further, described dextrorotation dihydromyricetin monohydrate uses Karl_Fischer method to measure wherein moisture
5.30 ± 0.2%.
Present invention also offers the dihydromyricetin anhydride crystallization of a kind of racemization, use polarimeter to record its specific rotation
[α]D=0 ° [c 0.20, DMSO, 20 DEG C], uses powder x-ray diffraction (XRD) to analyze, uses CuKαRadiation, diffraction maximum position
2-Theta (5-45 °), has a following characteristic peak: 10.02 °, 13.82 °, 14.50 °, 16.08 °, 21.22 °, 23.54 °,
25.32°,25.85°,26.72°,26.79°。
Further, the dihydromyricetin anhydride crystallization of described racemization is 3000-3500cm in wave number-1Interval in tool
There is a following characteristics peak: the 3581st, the 3399th, 3220cm-1。
Yet further, the dihydromyricetin anhydride crystallization of described racemization uses Karl_Fischer method to measure wherein moisture and contain
Amount is less than 0.4%.
Present invention also offers the dihydromyricetin hydrate crystallization of a kind of racemization, use polarimeter to record its specific rotation
[α]D=0 ° [c 0.20, DMSO, 20 DEG C], uses powder x-ray diffraction (XRD) to analyze, uses CuKαRadiation, diffraction maximum position
2-Theta (5-45 °), has a following characteristic peak: 7.97 °, 10.01 °, 11.17 °, 14.49 °, 16.70 °, 25.82 °,
26.73°。
Further, the dihydromyricetin hydrate crystallization of described racemization is 3000-3500cm in wave number-1Interval in
There is following characteristics peak: the 3568th, the 3293rd, 3083cm-1。
Yet further, moisture 5.31 ± 0.5% in the dihydromyricetin hydrate crystallization of described racemization.
In the present invention, the preparation method of five kinds of different crystal forms materials of dihydromyricetin belongs to prior art,
The method that the present invention prepares dihydromyricetin dihydrate includes crystallisation by cooling method, antisolvent crystallization method, volatilization knot
Crystallization, crystal seed revulsion, solvent rotating crystal method and solid-state rotating crystal method.
Described crystallisation by cooling method is to utilize dihydromyricetin solubility with temperature in a solvent to change greatly and design, profit
With high-temperature digestion, separate out crystallization during cooling and obtain dihydromyricetin crystallization.Crystalline substance can be added by changing solvent during this
Kind or change rate of temperature fall technique be controlled, solvent can be water, ethanol, and one or more the mixing such as methyl alcohol, acetonitrile is molten
Agent.
Described antisolvent crystallization method refers to be dissolved in dihydromyricetin have (dihydro in the A solvent of higher solubility
Myricetin solubility ＞ 1mg/ml), add and have in a large number compared with low solubility and the B solvent (dihydromyricetin miscible with A solvent
Solubility ＜ 0.2mg/ml), dihydromyricetin crystallization can be prepared.This technical process can be by changing solvent orange 2 A and B species or body
Long-pending, change and add the speed of B solvent to be controlled technique.Wherein A solvent can for DMSO, methyl alcohol, acetonitrile, formic acid, ethanol,
In the mixed solvent of DMF and above-mentioned solvent two or more arbitrary proportion thereof, B solvent can be cold water etc..
Described volatilization crystallisation refers to be dissolved in dihydromyricetin have in volatile solvent, and dihydromyricetin exists
Solubility ＞ 1mg/ml in solvent, slowly volatilization prepares dihydromyricetin crystallization.This technical process can be by changing solvent kind
Class and volume, rate of volatilization is controlled, and wherein solvent can be the single solvents such as ethanol, methyl alcohol, acetonitrile or any proportion mixing
Solvent.
Described solvent rotating crystal method refers to take dihydromyricetin raw material, can be anhydride, monohydrate or amorphous state, add
Entering in solvent, keeping solution to be suspension, be stirred continuously, the transformation of crystal being mediated by generation solvent or solvent are analysed after dissolving
Going out, and then obtaining dihydromyricetin crystallization, this technique can be by changing solvent volume, water activity, temperature and mixing speed with
Control technique, solvent can the single or mixed solvent such as water and DMSO, methyl alcohol, acetonitrile, formic acid, ethanol, DMF.
Described solid-state rotating crystal method refers to crystallize dihydromyricetin, can be anhydride and monohydrate, is positioned over certain
Under temperature and humidity environment, solid-state dihydromyricetin is by the moisture in the absorption external world, and hydrone is combined with crystalline state dihydromyricetin
Generate dihydromyricetin dihydrate.This technical process can by change initial feed crystalline structure, environment temperature and humidity,
Standing time is controlled by.
The method that the present invention prepares dihydromyricetin anhydride includes heating and polishing.
Described heating refers to dihydromyricetin raw material, can be dihydrate and monohydrate, heats up compound
To higher temperature, continuing heating after losing the crystallization water, dihydromyricetin anhydride crystalline state changes, owing to dihydromyricetin adds
Heat loses crystallization water continuation heating and can occur to turn crystalline substance, and high temperature should be at about the 180 DEG C anhydrides stable to obtain dihydromyricetin
Crystallization.This technique can change temperature and the heat time is controlled.
The method that the present invention prepares dihydromyricetin monohydrate includes crystallisation by cooling method and volatilization crystallisation
Described volatilization crystallisation refers to dihydromyricetin, can be dihydrate and monohydrate, be dissolved in one and have
In the solvent of higher solubility (dihydromyricetin solubility ＞ 1mg/ml), slowly evaporate into crystallization, it is thus achieved that crystallization.This work
Skill can pass through feed change crystal formation, and solvent species and volume, rate of volatilization is controlled by.Wherein solvent can be the mixed of water and ethanol
Bonding solvent.
According to Chinese Pharmacopoeia " Quality Control Technology of polymorphic medicine and guide for method principle " exposure draft, new medicine
Thing is when exploitation contains the preparation of solid, if drug crystal forms can affect drug quality, it is necessary to carry out the qualitative of crystal formation and quantitative
System.In view of dihydromyricetin cellulose solution after oral absorption in vivo rapid, solid-state dihydromyricetin is probably due to solubility
Less than normal causing bioavilability on the low side, crystal formation often directly affects stability and the solubility of solid-state drug, and the present invention is to dihydro
It is formulation development and the quality such as bulk drug process exploitation, solid pharmaceutical preparation, semisolid, suspending agent that myricetin has carried out screening polymorph
Control significant.
Brief description
Fig. 1 is the liquid chromatogram with commercial samples for the dihydromyricetin dihydrate of dextrorotation；
Fig. 2 is the XRD diffraction pattern of dextrorotation dihydromyricetin dihydrate；
Fig. 3 is the differential calorimetric scan figure of dextrorotation dihydromyricetin dihydrate；
Fig. 4 is the thermogravimetric analysis figure of dextrorotation dihydromyricetin dihydrate；
Fig. 5 is the infrared spectrogram of dextrorotation dihydromyricetin dihydrate；
Fig. 6 is the liquid chromatogram of dextrorotation dihydromyricetin anhydride；
Fig. 7 is the XRD diffraction pattern of dextrorotation dihydromyricetin anhydride；
Fig. 8 is the differential calorimetric scan figure of dextrorotation dihydromyricetin anhydride；
Fig. 9 is the thermogravimetric analysis figure of dextrorotation dihydromyricetin anhydride；
Figure 10 is the infrared spectrogram of dextrorotation dihydromyricetin anhydride；
Figure 11 is the liquid chromatogram of dextrorotation dihydromyricetin monohydrate；
Figure 12 is the XRD diffraction pattern of dextrorotation dihydromyricetin monohydrate；
Figure 13 is the differential calorimetric scan figure of dextrorotation dihydromyricetin monohydrate；
Figure 14 is the thermogravimetric analysis figure of dextrorotation dihydromyricetin monohydrate；
Figure 15 is the infrared spectrogram of dextrorotation dihydromyricetin monohydrate；
Figure 16 is the liquid chromatogram of the dihydromyricetin anhydride of racemization；
Figure 17 is the XRD diffraction pattern of the dihydromyricetin anhydride of racemization；
Figure 18 is the differential calorimetric scan figure of the dihydromyricetin anhydride of racemization；
Figure 19 is the thermogravimetric analysis figure of the dihydromyricetin anhydride of racemization；
Figure 20 is the infrared spectrogram of the dihydromyricetin anhydride of racemization；
Figure 21 is the liquid chromatogram of the dihydromyricetin monohydrate of racemization；
Figure 22 is the XRD diffraction pattern of the dihydromyricetin monohydrate of racemization；
Figure 23 is the differential calorimetric scan figure of the dihydromyricetin monohydrate of racemization；
Figure 24 is the thermogravimetric analysis figure of the dihydromyricetin monohydrate of racemization；
Figure 25 is the infrared spectrogram of the dihydromyricetin monohydrate of racemization；
Detailed description of the invention
It in order to preferably explain the present invention, is further elucidated with the main contents of the present invention below in conjunction with specific embodiment, but
Present disclosure is not limited solely to following example.
The preparation of embodiment 1 dextrorotation dihydromyricetin dihydrate
Take the dextrorotation dihydromyricetin raw material of about 200mg, can be anhydride or monohydrate, be dissolved in 2ml90-100
DEG C the aqueous solution in, insulation is filtered, and removes after filter residue, separates out crystallization, prepare dextrorotation dihydro after solution naturally cools to room temperature
Myricetin dihydrate.
The preparation of embodiment 2 dextrorotation dihydromyricetin anhydride
Take the dextrorotation dihydromyricetin raw material of about 200mg, can be dihydrate and monohydrate, be 160 DEG C in temperature
Lower placement 1h, can obtain dihydromyricetin anhydride.
The preparation of embodiment 3 dextrorotation dihydromyricetin monohydrate
Take the dextrorotation dihydromyricetin raw material of about 200mg, can be dihydrate and anhydride, be dissolved in the second of high concentration
In alcoholic solution, slowly evaporate into crystallization, dextrorotation dihydromyricetin monohydrate can be obtained.
The preparation of the dihydromyricetin anhydride of embodiment 4 racemization
Take the racemization dihydromyricetin raw material of about 200mg, can be dihydrate and monohydrate, be 160 DEG C in temperature
Lower placement 1h, can obtain dihydromyricetin anhydride.
The preparation of the dihydromyricetin monohydrate of embodiment 5 racemization
Take the racemization dihydromyricetin raw material of about 200mg, can be dihydrate and anhydride, be dissolved in the second of high concentration
In alcoholic solution, slowly evaporate into crystallization, dextrorotation dihydromyricetin monohydrate can be obtained.
Five kinds of different crystal forms materials of dihydromyricetin of above-mentioned preparation are carried out performance detection
1st, method is analyzed:
1.1 ratio rotation methods
WZZ-1 indicates polarimeter, Shanghai Physics Optics Instrument Factory automatically.
In the mensuration stage, take dihydromyricetin crystal-form substances 5.00g and be dissolved in 25ml DMSO, measure solution optical activity, can count
Calculate specific rotation.
1.2 Chiral Resolution in High Performance Liquid Chromatography methods
Using Waters e2695 high performance liquid chromatograph, C18 silica gel chromatographic column, with methyl alcohol: beta cyclodextrin solution (wherein β
Cyclodextrin 18g, phosphatase 11 0ml, add water to 1000ml), flow velocity is 1ml/min, column temperature 30 DEG C.Detection wavelength 290nm.
1.3 elemental microanalysis method
CHNSO elemental analyser (Vario EL111)
1.4 karl Fischer aquametries
Instrument: superfinishing science and technology SKF1 (A) karl Fischer moisture teller
In the mensuration stage, taking 100-200mg dihydromyricetin crystal-form substances powder every time, instrument automatic Titration to terminal, is remembered
The amount of moisture of record display, calculates the moisture in powder.
1.5 powder X-ray diffractometry
Instrument: Holland PANalytical company PANalytical B.V.
Target: Cu-K α radiates
Wavelength: 1.5406A
Pipe pressure: 40KV
Guan Liu: 40mA
Step-length: 0.02 °
Sweep limits: 5-45 °
Sweep speed: 8 °/min
In the mensuration stage, after rectifying an instrument, take dihydromyricetin crystal-form substances powder (D50＜ 100 μm) put into sample determination pond
In, after using glass slide pressed powder extremely in plane, put in instrument and be measured.
1.6 difFerential scanning calorimetry
Instrument: platinum-Ai Ermo instrument (Shanghai) Co., Ltd. (PerkinElmer Instruments) Diamond
DSC
Scope 30-270 DEG C
10 DEG C/min of programming rate
N2Flow velocity: 50ml/min
1.7 thermogravimetry
Instrument: platinum-Ai Ermo instrument (Shanghai) Co., Ltd. (PerkinElmer Instruments) model
Pyris1TGA
Scope 30-500 DEG C
10 DEG C/min of programming rate
N2Flow velocity: 50ml/min
1.8 infra-red sepectrometry
Instrument: Germany Bruker company VERTEX 70
Sweep limits: 450cm-1-4000cm-1
Resolution ratio: 4cm-1
2nd, the dihydromyricetin dihydrate of dextrorotation
2.1 ratio rotation methods
Take dihydromyricetin 5.00g, be dissolved in the DMSO solution of 25ml, record self-control sample optical activity be 6.491 ±
0.013 ° (n=5), specific rotation [α]D=+32 °.
2.2 Chiral Resolution in High Performance Liquid Chromatography methods
Commercial samples is bimodal as shown in Figure 1, i.e. shows which is racemic product, the dihydromyricetin dihydrate of dextrorotation in
Unimodal, and show which is dextrorotation dihydromyricetin purity >=98% in dextrorotation dihydromyricetin dihydrate.
2.3 elemental microanalysis method
C:H:O=50.52%:4.50%:44.98% in dextrorotation dihydromyricetin dihydrate, i.e. molecular formula should be
C15H16O10, i.e. C15H12H8·2H2O。
2.4 karl Fischer titrations
Recording moisture in the dihydromyricetin dihydrate of dextrorotation through titration is 10.1 ± 0.3% (n=3), i.e. right
Answer the moisture of 2 molecules.
2.5 powder X-ray diffractometry
The XRD diffraction pattern (as shown in Figure 2) of dextrorotation dihydromyricetin dihydrate and corresponding peak value thereof see table 1
2.6 difFerential scanning calorimetry
Dextrorotation dihydromyricetin dihydrate 109 DEG C (peak values, lower with), 152 DEG C and 252 DEG C there is endothermic peak, 192
DEG C there is exothermic peak.Wherein 252 DEG C is crystalline state fusion process, and 109 DEG C of stages corresponding with 152 DEG C are and lose crystallization water process
(Fig. 3).
2.7 thermogravimetry
Dihydrate i.e. starts to lose the crystallization water at 60 DEG C, loses completely at 150 DEG C of crystallizations water.Reach 252 DEG C dissolve after,
Dihydromyricetin molecule there occurs decomposition (Fig. 4) as temperature raises further.
2.8. infra-red sepectrometry
It is 3000-3500cm owing to intramolecular hydrogen bond and intermolecular hydrogen bonding can be reflected in wave number-1Between, dextrorotation dihydromyricetin
Element dihydrate has following characteristics peak in this interval: the 3375th, the 3334th, 3200cm-1(Fig. 5).
3rd, dextrorotation dihydromyricetin anhydride
3.1 ratio rotation methods
Take dextrorotation dihydromyricetin anhydride 5.00g, be dissolved in the DMSO solution of 25ml, record self-control sample optical activity
It is 7.221 ± 0.015 ° (n=5), specific rotation [α]D=+36 °.
3.2 Chiral Resolution in High Performance Liquid Chromatography methods
Efficient liquid phase chiral resolution is used to show that the dihydromyricetin which is dextrorotation in dextrorotation dihydromyricetin anhydride is pure
Degree >=98% (Fig. 6).
3.3 elemental microanalysis method
Dextrorotation dihydromyricetin anhydride C:H:O=56.26%:3.74%:40.00%, i.e. molecular formula should be C15H12O8。
4. karl Fischer aquametry
Record dextrorotation dihydromyricetin anhydride moisture and be less than 0.3% (n=3).
5. powder X-ray diffractometry
The XRD diffraction pattern (Fig. 7) of dextrorotation dihydromyricetin anhydride and corresponding peak value thereof see table 2
3.6 difFerential scanning calorimetry
Dextrorotation dihydromyricetin anhydride fusing point is 253.9 DEG C (with peak meters), in the process of the heating less than its fusing point
In do not exist any heat absorption and exothermic peak (Fig. 8).
3.7 thermogravimetry
Dextrorotation dihydromyricetin anhydride in the range of 60-240 DEG C, heating will not any weight of less loss, reach 252 DEG C of crystalline substances
Body dissolves, and continues heating dihydromyricetin molecule and there occurs decomposition (Fig. 9).
3.8 infra-red sepectrometry
It is 3000-3500cm owing to intramolecular hydrogen bond and intermolecular hydrogen bonding can be reflected in wave number-1Between, anhydride has following
Characteristic peak: the 3581st, the 3399th, 3220cm-1(Figure 10).
4th, dextrorotation dihydromyricetin monohydrate
4.1 ratio rotation methods
Take dextrorotation dihydromyricetin monohydrate 5.00g, be dissolved in the DMSO solution of 25ml, record dextrorotation dihydromyricetin
Element monohydrate optical activity is 6.835 ± 0.020 ° (n=5), specific rotation [α]D=+34 °.
4.2 Chiral Resolution in High Performance Liquid Chromatography methods
Efficient liquid phase chiral resolution is used to show which is the dihydromyricetin of dextrorotation in dextrorotation dihydromyricetin monohydrate
Purity >=98% (Figure 11).
4.3 elemental microanalysis method
Record dextrorotation dihydromyricetin monohydrate C:H:O=53.25%:4.14%:42.61%, i.e. molecular formula should be
C15H14O9。
4.4 karl Fischer aquametries
Record moisture 5.30 ± 0.2% in dextrorotation dihydromyricetin monohydrate.
4.5 powder X-ray diffractometry
The XRD diffraction pattern (Figure 12) of dextrorotation dihydromyricetin monohydrate and corresponding peak value thereof see table 3
4.6 difFerential scanning calorimetry
Dextrorotation dihydromyricetin monohydrate has 3 endothermic peaks in measuring, peak value corresponding 116.80 DEG C, 146.78 DEG C respectively
With 252.72 DEG C, wherein 116.80 DEG C of correspondences lose a molecular crystalline water, and the change of 146.78 DEG C of corresponding crystalline state, 252.72 DEG C are right
Answer the fusing point (Figure 13) of dihydromyricetin anhydride.
4.7 thermogravimetry
Dextrorotation dihydromyricetin monohydrate is in the range of 60-240 DEG C, and less loss weight is about 5%, an i.e. corresponding molecule knot
Brilliant water, reach 252 DEG C dissolve after, dihydromyricetin molecule there occurs decomposition (Figure 14).
4.8 infra-red sepectrometry
It is 3000-3500cm owing to intramolecular hydrogen bond and intermolecular hydrogen bonding can be reflected in wave number-1Between, dextrorotation dihydromyricetin
Monohydrate has a following characteristics peak: the 3568th, the 3293rd, 3083cm-1(Figure 15).
5th, the dihydromyricetin anhydride of racemization
5.1 ratio rotation method
Cancel rotation dihydromyricetin anhydride 5.00g, be dissolved in the DMSO solution of 25ml, record the dihydromyricetin of racemization
Element anhydride optical activity is 0 °, specific rotation [α]D=0 °.
5.2 Chiral Resolution in High Performance Liquid Chromatography methods
Efficient liquid phase chiral resolution is used to show that racemization dihydromyricetin anhydride exists two peaks, and two peak area bases
This is equal, it is known that records optical activity the reason that be 0, is the dextrorotation dihydromyricetin containing equivalent and left-handed dihydromyricetin
(Figure 16).
5.3 elemental microanalysis method
The dihydromyricetin anhydride C:H:O=56.27%:3.75%:39.98% of racemization, i.e. molecular formula should be
C15H12O8。
5.4 karl Fischer aquametries
Record moisture in the dihydromyricetin anhydride of racemization and be less than 0.4%.
5.5. the XRD diffraction pattern (Figure 17) of the dihydromyricetin monohydrate of powder X-ray diffractometry racemization and correspondence thereof
Peak value see table 4
5.6 difFerential scanning calorimetry
The dihydromyricetin anhydride of racemization only has an endothermic peak, and corresponding crystal melting process, fusing point is 253.9 DEG C
(with peak meter) (Figure 18).
5.7 thermogravimetry
The dihydromyricetin anhydride of racemization in the range of 60-240 DEG C, weight without less loss, reach 252 DEG C dissolve after, two
Hydrogen myricetin molecule there occurs decomposition (Figure 19).
5.8 infra-red sepectrometry
It is 3000-3500cm owing to intramolecular hydrogen bond and intermolecular hydrogen bonding can be reflected in wave number-1Between, anhydride has following
Characteristic peak: the 3581st, the 3399th, 3220cm-1(Figure 20).
6., the dihydromyricetin monohydrate of racemization
6.1 ratio rotation methods
Cancel rotation dihydromyricetin monohydrate 5.00g, be dissolved in the DMSO solution of 25ml, record self-control sample optically-active
Degree is 0 °, specific rotation [α]D=0 °.
6.2 Chiral Resolution in High Performance Liquid Chromatography methods
Efficient liquid phase chiral resolution is used to show that racemization dihydromyricetin monohydrate exists two peaks, and two peak areas
Of substantially equal, it is known that the reason that its optical activity is 0, it is possible contain the dextrorotation dihydromyricetin of equivalent and left-handed dihydromyricetin
Element (Figure 21).
6.3 elemental microanalysis method
The dihydromyricetin monohydrate C:H:O=53.23%:4.15%:42.62% of racemization, i.e. molecular formula should be
C15H14O9, i.e. C15H12O8·H2O。
6.4. karl Fischer aquametry
Record the dihydromyricetin monohydrate moisture 5.31 ± 0.1% of racemization.
6.5 powder X-ray diffractometry
The XRD diffraction pattern (Figure 22) of dextrorotation dihydromyricetin monohydrate and corresponding peak value thereof see table 5
6.6 difFerential scanning calorimetry
After the dihydromyricetin monohydrate thing of racemization loses the crystallization water, fusing point is 253.9 DEG C (with peak meter) (Figure 23).
6.7 thermogravimetry
The dihydromyricetin monohydrate of racemization is in the range of 60-240 DEG C, and less loss weight is about 5%, an i.e. corresponding molecule
The crystallization water, reach 252 DEG C dissolve after, dihydromyricetin molecule there occurs decomposition (Figure 24).
6.8 infra-red sepectrometry
It is 3000-3500cm owing to intramolecular hydrogen bond and intermolecular hydrogen bonding can be reflected in wave number-1Between, monohydrate have with
Lower characteristic peak: the 3568th, the 3293rd, 3083cm-1, basically identical with the dihydromyricetin of dextrorotation (Figure 25).
7th, the hygroscopicity of five kinds of crystal formations of dihydromyricetin compares
Use saturated salt solution sealing in container 25 DEG C of prepared different humidity, be respectively as follows: 11% (lithium chloride), 23%
(potassium oxalate), 33% (magnesium chloride), 43% (potassium carbonate), 52% (magnesium nitrate), 67% (copper chloride), 75% (sodium chloride),
86% (potassium chloride), 93% (magnesium nitrate).Take prepared dihydromyricetin dihydrate, anhydride and monohydrate respectively, often
Planting crystal formation and taking 3 parts, every part of sample is 200-300mg, is positioned in the flat measuring bottle of known weight.Flat measuring bottle is put into sealing
In container, weighing after placing 3 days, can obtaining different crystal forms and start the humidity of water suction after analyzing data, five kinds of crystal formations are respectively as follows: the right side
Rotation dihydromyricetin dihydrate ＞ 93%, dextrorotation dihydromyricetin anhydride and racemization dihydromyricetin anhydride are 23%,
The dihydromyricetin monohydrate of dextrorotation dihydromyricetin monohydrate and racemization is 33%.
Other unspecified parts are prior art.Although above-described embodiment is made that detailed retouching to the present invention
State, but its a part of embodiment that is only the present invention, rather than whole embodiment, people can also according to the present embodiment without
Obtaining other embodiments under the premise of Chuan Zaoxing, these embodiments broadly fall into scope.
Claims (3)
1. the dihydromyricetin hydrate crystallization of a dextrorotation, it is characterised in that: its specific rotation [α]D=+34 ° [c 0.20,
DMSO, 20 DEG C], use powder x-ray diffraction (XRD) to analyze, use CuKαRadiation, diffraction maximum position 2-Theta (5-45 °),
There is following characteristic peak: 9.98 °, 11.36 °, 13.20 °, 14.52 °, 22.74 °, 22.82 °, 28.32 °.
2. the dihydromyricetin hydrate crystallization of dextrorotation according to claim 1, it is characterised in that: described dihydromyricetin
Hydrate crystallization is 3000-3500cm in wave number-1Interval in there is following characteristics peak: the 3568th, the 3293rd, 3083cm-1。
3. the dihydromyricetin hydrate crystallization of dextrorotation according to claim 1 or claim 2, it is characterised in that: described dextrorotation two
Moisture 5.30 ± 0.2% in hydrogen myricetin monohydrate.
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| CN113155882B (en) * | 2021-03-15 | 2022-04-22 | 宁波大学 | Chiral identification method for enantiomer of dihydromyricetin |
| CN114404369B (en) * | 2022-03-08 | 2023-01-03 | 陕西科技大学 | Dihydromyricetin nanocrystal and preparation method and application thereof |
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