CN108276308A - A kind of hydrochloric acid leonurine beta crystal and its preparation method and application - Google Patents
A kind of hydrochloric acid leonurine beta crystal and its preparation method and application Download PDFInfo
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- CN108276308A CN108276308A CN201810047133.2A CN201810047133A CN108276308A CN 108276308 A CN108276308 A CN 108276308A CN 201810047133 A CN201810047133 A CN 201810047133A CN 108276308 A CN108276308 A CN 108276308A
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- hydrochloric acid
- leonurine
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- beta crystal
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
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- 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
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Abstract
The invention discloses a kind of hydrochloric acid leonurine beta crystal and its preparation method and application, the stronger diffraction maximum shown in the x-ray diffractogram of powder which is indicated with 2 θ of the angle of diffraction is 11.630 (54%), 11.990 (21%), 14.420 (18%), 22.430 (21%), 23.330 (19%), 24.710 (16%), 25.670 (100%).The hydrochloric acid leonurine beta crystal that the present invention prepares has the characteristics that stability is good, can keep stablizing under bloom photograph, high temperature, high humidity and long-time storage condition, can be used for preparing pharmaceutical composition.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, and in particular to a kind of hydrochloric acid leonurine beta crystal and preparation method thereof
And application.
Background technology
Motherwort is the fresh of labiate motherwort (Leonurus Japonicus Houtt) or dry ground
Part, original name motherwort, first recorded in《Sheng Nong's herbal classic》, the female Chinese mugwort of alias benefit, eel grass, female grass etc., acrid flavour hardship, slight bitter, cold nature,
Return liver, pericardium channel；The effect of active tune stasis of blood, inducing diuresis to remove edema, is clinically used for irregular menstruation, postpartum stasis caused pain, blood disease, the heart
The treatment of cranial vascular disease is known as the title of " blood man panacea " " through producing good recipe ".
Leonurine (Leonurine) is one of main active substances of motherwort, has significant directly expansion periphery
Blood vessel increases the effects that blood flow, platelet aggregation-against, can effectively reduce blood viscosity and improve the deformation energy of red blood cell
Power, can also regulating menstruation, hemostasis, Ischemic myocardium reperfusion injury.Content of the leonurine in crude drug be only 0.02~
0.12%, and extraction process is more complex, and sample cleanup is difficult, and environmental pollution is more serious, and the method for passing through biological concentration
Enough products are not only hardly resulted in meet production and living needs, and may under the driving of interests to relevant ecological and
Environment causes damage difficult to the appraisal.
The structural formula of hydrochloric acid leonurine is as follows：
Currently, the research in terms of hydrochloric acid leonurine synthesis is many, such as：
(Structure and synthesis of leonurine, Tetrahedron 25 such as Sugiura S:5155,
1969) structure and synthetic method of leonurine are disclosed；(Leonurine, an improved such as K.F.Cheng
Synthesis, Experientia, 1979, Vol35, pp571-714) disclose a kind of Improved synthesis method of leonurine.
Application publication number is that the application for a patent for invention document of CN 1415602A discloses a kind of synthesis side of leonurine
Method, this method is using syringic acid as starting material, successively through carbonylation, acyl chloride reaction, and after esterification and aminating reaction,
Intermediate motherwort amine is prepared, is finally synthesized to obtain leonurine with methyl isothiourea by intermediate motherwort amine.
The application for a patent for invention document that application publication number is CN 1415603A discloses a kind of leonurine salt and its system
Agent, with inorganic acid, either the acid salt of organic acid or polyacid is anti-by leonurine that is extracting or synthesizing for the leonurine salt
The soluble salt that should be generated, pH are 4~7；The leonurine salt can be processed into several formulations.
But the research of the crystal form of hydrochloric acid leonurine is but had not been reported.In addition, the polymorphic of solid chemical is existing
As if a kind of natural phenomena existing for universal substance.Although its chemical nature of allomorphous solid matter is identical, its
Physicochemical property may be different.For physicochemical property different " allomorph drug ", can also clinically show not
The effect of with disease preventing and treating, directly affects application and the clinical effectiveness of drug.Therefore, the allomorph of solid chemical is studied
Phenomenon is highly important content in drug research.
Invention content
The present invention provides the preparation method and application of a kind of beta crystal that hydrochloric acid leonurine is new and beta crystal, the hydrochloric acid
Leonurine beta crystal can be used for preparing pharmaceutical composition, and have preferable dissolubility and stability.
Particular content is as follows：
A kind of hydrochloric acid leonurine beta crystal has following diffraction maximum with the X-ray powder diffraction that 2 θ angles indicate：
The X-ray powder diffraction uses Cu KβRadioactivity measures.
The X-ray powder diffraction figure of the hydrochloric acid leonurine beta crystal is as shown in Figure 1.
The present invention also provides a kind of preparation methods of hydrochloric acid leonurine beta crystal, include the following steps：Hydrochloric acid benefit is female
Potash is successively dissolved in ethyl alcohol and acetone, is heated to reflux and is made it completely dissolved, and filters obtain filtrate while hot, control filtrate cooling speed
Degree enables it slowly cool to 0~5 DEG C, and standing precipitates crystal, and after crystal is precipitated completely, crystal is obtained after filtering, true through depressurizing
Sky is dry, obtains the hydrochloric acid leonurine beta crystal.
The hydrochloric acid leonurine refers to commercially available in the prior art or can be synthesized according to synthetic method is disclosed
The hydrochloric acid leonurine of the various non-crystalline states obtained.
The concentration of hydrochloric acid leonurine and the ingredient of solvent and ratio all can be to the hydrochloric acid leonurine beta crystals of preparation
Yield and purity have an impact.Preferably, the amount ratio of the hydrochloric acid leonurine and ethyl alcohol, acetone is 1g:5~20：15~
60mL。
In the present invention, filtrate cooling rate has an impact the precipitation of crystal and the purity of hydrochloric acid leonurine beta crystal,
Preferably, the cooling rate is 0.5~2 DEG C/min.
Preferably, the time of the standing is 1~10h；It is further preferred that the time is 4~8h.Suitable time of repose can shadow
Ring the yield and purity of hydrochloric acid leonurine beta crystal.
In order to remove the coloration of product hydrochloric acid leonurine beta crystal, preferably, it is molten that hydrochloric acid leonurine is dissolved in mixing
In agent and then activated carbon is added, is then heated.
Preferably, the mass ratio of the hydrochloric acid leonurine and activated carbon is 1:0.01~0.05；It is further preferred that mass ratio
It is 1:0.02.
The hydrochloric acid leonurine beta crystal can also be used to prepare pharmaceutical composition, which includes effective active
Ingredient and at least one inert non-toxic carrier, the effective active composition are containing the as described in claim 1 of effective therapeutic dose
Hydrochloric acid leonurine beta crystal.
The inert non-toxic carrier includes diluent, flavouring agent, solubilizer, lubricant and package pharmaceutically used
Agent etc., such as magnesium phosphate, smoothers sugar, lactose, pectin, starch and gelatin etc..
Compared with prior art, the invention has the advantages that：
The hydrochloric acid leonurine beta crystal that the present invention prepares has the characteristics that stability is good, can be shone in bloom, is high
It keeps stablizing under temperature, high humidity and long-time storage condition, can be used for preparing pharmaceutical composition.
Description of the drawings
Fig. 1 is the XRPD collection of illustrative plates of hydrochloric acid leonurine beta crystal made from embodiment 1；
Wherein, abscissa is the angle of diffraction, and ordinate is diffracted intensity.
Fig. 2 is the DSC collection of illustrative plates of hydrochloric acid leonurine beta crystal made from embodiment 1；
Wherein, abscissa is temperature, and ordinate is the hot-fluid numerical value for flowing to sample.
Fig. 3 is the IR collection of illustrative plates of hydrochloric acid leonurine beta crystal made from embodiment 1；
Wherein, abscissa is wavelength, and ordinate is light transmittance.
Specific implementation mode
The present invention is described in further detail with reference to specific implementation case.
Experiment condition：
XRPD spectrograms：Determining instrument is X ' Pert PRO type diffractometers, PHILIPS；Determination condition is：Continuous scanning, 0-2θLinkage, start angle are 0 °, and termination point is 60 °, and sweep speed is 0.02 °/sec, and the sampling time is 1 second, target Cu, wave
Long value is 1.54056, tube voltage 40KV, tube current 200mA, and divergent slit is 1 degree.
IR spectrograms：Use instrument for Nicolet 8700, Thermo Scientific Instrument Co.U.S.A,
Scanning range is 400~4000cm-1；Assay method is：Take sample appropriate, with reference to having for Chinese Pharmacopoeia version annex IVC in 2015
It closes and requires, using pressing potassium bromide troche, the infrared spectrum of determination sample.
DSC spectrograms：Use instrument for Shimadzu DTG-60 TG-DTA analysis instrument, environmental gas is nitrogen, and heating rate is
10.00℃/min。
The preparation of 1 hydrochloric acid leonurine beta crystal of embodiment
10g hydrochloric acid leonurines are added in 100ml ethyl alcohol, is dissolved by heating, is added 0.2g activated carbons and be heated to reflux
It 0.5 hour, filters while hot, filtrate adds the acetone of 300ml to dilute, and 5 DEG C are cooled to 1 DEG C/min speed, stands 6h and precipitates crystal,
It is filtered after crystallization is complete, filtrate recovery, merges gained crystallization, dried in 60 DEG C of reduced vacuums, obtain white solid, i.e.,
For hydrochloric acid leonurine beta crystal, weight 8.3g, yield 83%.
X-ray powder diffraction, infrared spectrum and DSC characterizations are carried out to hydrochloric acid leonurine beta crystal.As a result such as Fig. 1~3
Shown in table 1.
The X- diffraction analysis datas of 1 hydrochloric acid leonurine beta crystal of table
| Serial number | Angle | D values | Half-peak breadth | Intensity | Intensity ratio |
| 01 | 11.630 | 7.6087 | 0.27 | 1604 | 54 |
| 02 | 11.990 | 7.3810 | 0.23 | 636 | 21 |
| 03 | 13.490 | 6.5635 | 0.36 | 318 | 11 |
| 04 | 14.420 | 6.1422 | 0.41 | 551 | 18 |
| 05 | 14.720 | 6.0177 | 0.14 | 446 | 15 |
| 06 | 15.740 | 5.6299 | 0.23 | 430 | 14 |
| 07 | 16.820 | 5.2708 | 0.27 | 424 | 14 |
| 08 | 20.990 | 4.2331 | 0.32 | 355 | 12 |
| 09 | 22.430 | 3.9636 | 0.27 | 621 | 21 |
| 10 | 23.330 | 3.8127 | 0.36 | 561 | 19 |
| 11 | 24.710 | 3.6028 | 0.50 | 475 | 16 |
| 12 | 25.040 | 3.5560 | 0.14 | 350 | 12 |
| 13 | 25.670 | 3.2329 | 0.32 | 2987 | 100 |
| 14 | 26.480 | 3.3658 | 0.27 | 361 | 12 |
| 15 | 27.590 | 3.2329 | 0.00 | 327 | 11 |
| 16 | 29.060 | 3.0726 | 0.18 | 311 | 10 |
| 17 | 30.230 | 2.9563 | 0.00 | 247 | 8 |
| 18 | 31.400 | 2.8488 | 0.00 | 233 | 8 |
| 19 | 32.690 | 2.7392 | 0.23 | 248 | 8 |
| 20 | 37.250 | 2.4137 | 0.23 | 214 | 7 |
As shown in Fig. 2, the absorption peak of hydrochloric acid leonurine beta crystal changes about at 194 DEG C or so.
Beta crystal hydrochloric acid leonurine solid matter as shown in Figure 3, when being analyzed using the KBr tablettings of infrared spectrum
3357cm-1、3178m-1、2971cm-1、2943m-1、1701cm-1、1667cm-1、1615cm-1、1514cm-1、1472cm-1、
1425cm-1、1342cm-1、1272cm-1、1233cm-1、1207m-1、1115cm-1、988m-1And 760cm-1Place has absorption peak to deposit
In wherein 3357m-1、3178cm-1、2971cm-1、2943cm-1、1667cm-1、1615cm-1、1472cm-1、1207m-1、
1115cm-1And 982cm-1Peak is the absorption position that crystal form feature is presented in beta crystal hydrochloric acid leonurine solid matter.
Probing into terms of doing dissolubility and stability to the above-mentioned hydrochloric acid leonurine beta crystal prepared.
1, solubility test：(the results are shown in Table 2)
The dissolubility result of 2 hydrochloric acid leonurine beta crystal of table
2, stability test：Specific method reference《Chinese Pharmacopoeia (four)》9001 material medicine of general rule and preparation stability
Test direction principle.
(1) investigation of strong illumination (4500lx ± 500lx) stability
The stability result of hydrochloric acid leonurine beta crystal under the conditions of 3 strong illumination of table
(2) investigation of high temperature (60 DEG C) stability
The stability result of hydrochloric acid leonurine beta crystal under 4 hot conditions of table
(3) investigation of high humidity (RH92.5%) stability
The stability result of hydrochloric acid leonurine beta crystal under 5 super-humid conditions of table
(4) stability test
Hydrochloric acid leonurine beta crystal is placed in plate, under the conditions of 40 DEG C/relative humidity 75%, 6 are stored in sealing state
With 12 months, the results are shown in Table 6.
The stability result of 6 hydrochloric acid leonurine beta crystal of table
Conclusion：By above-mentioned experimental result it is found that hydrochloric acid leonurine beta crystal is in high temperature, high humidity, bloom photograph and long-time
X-ray powder diffraction result does not change under storage condition, still keeps script crystal form, has preferable stability.
Claims (8)
1. a kind of hydrochloric acid leonurine beta crystal, which is characterized in that the X-ray powder diffraction indicated with 2 θ angles has spreads out as follows
Penetrate peak：
The X-ray powder diffraction uses Cu KβRadioactivity measures.
2. a kind of preparation method of hydrochloric acid leonurine beta crystal as described in claim 1, which is characterized in that including following step
Suddenly：Hydrochloric acid leonurine is successively dissolved in ethyl alcohol and acetone, is heated to reflux and makes it completely dissolved, filters obtain filtrate while hot,
Control filtrate cooling rate enables it slowly cool to 0~5 DEG C, and standing precipitates crystal, and after crystal is precipitated completely, is obtained after filtering
Crystal is dried through reduced vacuum, obtains the hydrochloric acid leonurine beta crystal.
3. preparation method as claimed in claim 2, which is characterized in that the dosage of the hydrochloric acid leonurine and ethyl alcohol, acetone
Than for 1g:5~20：15~60mL.
4. preparation method as claimed in claim 2, which is characterized in that the cooling rate is 0.5~2 DEG C/min.
5. preparation method as claimed in claim 2, which is characterized in that the time of the standing is 1~10h.
6. preparation method as claimed in claim 2, which is characterized in that after hydrochloric acid leonurine is dissolved in the mixed solvent,
Activated carbon is added again, is then heated.
7. preparation method as claimed in claim 6, which is characterized in that the mass ratio of the hydrochloric acid leonurine and activated carbon is
1:0.01~0.05.
8. a kind of pharmaceutical composition, including effective active composition and at least one inert non-toxic carrier, which is characterized in that described to have
Effect active constituent is the hydrochloric acid leonurine beta crystal as described in claim 1 containing effective therapeutic dose.
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| CN201810047133.2A CN108276308A (en) | 2018-01-18 | 2018-01-18 | A kind of hydrochloric acid leonurine beta crystal and its preparation method and application |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3685834A4 (en) * | 2017-10-23 | 2020-12-09 | Zhuhai Hengqin New District Zhongzhu Zhengtai Medical Management Co. Ltd. | Leonurine crystal and use thereof in preparation of insulin sensitizer, hypoglycemic drug and lipid-lowering drug |
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2018
- 2018-01-18 CN CN201810047133.2A patent/CN108276308A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3685834A4 (en) * | 2017-10-23 | 2020-12-09 | Zhuhai Hengqin New District Zhongzhu Zhengtai Medical Management Co. Ltd. | Leonurine crystal and use thereof in preparation of insulin sensitizer, hypoglycemic drug and lipid-lowering drug |
| US11446270B2 (en) | 2017-10-23 | 2022-09-20 | Zhuhai Hengqin New District Zhongzhu Zhengtai Medical Management Co., Ltd. | Leonurine crystal and use thereof in preparation of insulin sensitizer, hypoglycemic drug and lipid-lowering drug |
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Application publication date: 20180713 |
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