CN106967139A - A kind of lamp-dish flower acetic crystal formation and preparation method thereof - Google Patents
A kind of lamp-dish flower acetic crystal formation and preparation method thereof Download PDFInfo
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/06—Benzopyran radicals
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- C07H17/07—Benzo[b]pyran-4-ones
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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Abstract
The invention belongs to field of pharmaceutical chemistry technology.Lamp-dish flower acetic crystal formation of the present invention, is named as lamp-dish flower acetic crystal formation III.Using Cu K α radiations, λ=1.5405A, diffraction peak intensity is that 100%, SC analysis endothermic transition temperature be 107 137 DEG C at the θ positions 16.18 of X ray powder diffractions 2, and fusion and decomposition temperature is 195 201 DEG C.Its preparation method comprises the following steps：First, lamp-dish flower acetic is added in organic solvent, is completely dissolved lamp-dish flower acetic, then the solution of dissolving is slowly added in the aqueous solvent of 5 12 times of liquor capacity, and be stirred, lamp-dish flower acetic is separated out and is dispersed in aqueous solvent immediately；2nd, filter, isolate solid, be dried under reduced pressure, produce the lamp-dish flower acetic crystal formation III of micronizing.It is an advantage of the invention that improving dissolution velocity and reducing impurity.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, the system of more particularly to a kind of new lamp-dish flower acetic crystal formation and the crystal formation
Preparation Method.
Background technology
Fleabane flower is complete for feverfew Erigeron breviscapus Erigeron breviscapus (Vant.) Hand-Mazz drying
Grass, is distributed mainly on Yunnan Province, first recorded in《The southern regions of the Yunnan Province book on Chinese herbal medicine》, for treating the diseases such as apoplexy sequelae, rheumatism, the obstruction of qi in the chest.20 generation
Discipline the seventies study the lamp-dish flower acetic therefrom separated through scholar, and (i.e. No. CAS is 27740- by scutellarin, scutellarin
It is 01-8) active ingredient for the treatment of apoplexy.
Due to the intrinsic face type molecular structure of lamp-dish flower acetic, cause the compound water soluble and fat-soluble poor.
In daily injection production process, using the carboxyl on glucuronic acid in alkaline aqueous solution and lamp-dish flower acetic molecule into salt,
Finally it is dissolved into the aqueous solution.Small size prepares lamp-dish flower acetic aqueous solution process because of the poor solubility of lamp-dish flower acetic and dissolving speed
Also injection product quality will not be constituted a threat to for the slow physicochemical property of degree and production process causes inconvenience.But, industrialization
On a large scale with liquid production breviscapine B injection agent during, because lamp-dish flower acetic poor solubility and dissolution velocity will cause slowly
Whole liquid preparation time significantly extends, and therefore brings lamp-dish flower acetic to produce catabolite in alkaline aqueous solution for a long time, finally
It is reflected in product quality that relevant material is higher, production process is longer.It is necessary a kind of new scutellarin crystal shape of research
Formula, can make enhanced dissolution rate of the lamp-dish flower acetic in alkaline aqueous solution.
Chinese patent CN200910164855.7 discloses scutellarin crystal I and preparation method thereof, and there is provided crystallization
Quantity of solvent is few, and production cost is low, easy industrialized production, scutellarin crystal I of high income and preparation method thereof.Obtained knot
The lamp-dish flower acetic of crystalline form state is high with purity compared with existing Breviscapinun, using safer, mass produce or is configured to
Performance required for therapeutic preparation, it is stable to light, wet, hot etc., more stablize in alkaline solution, be easy to industrialized production,
Storage.CN201410269593.1 discloses lamp-dish flower acetic dihydrate crystal II and preparation method thereof and closed there is provided one kind
Into high-purity scutellarin dihydrate crystallization II, with the plant extract lamp-dish flower acetic without the crystallization water and it has been reported that
Scutellarin crystal I compare with purity is high, stability is good, it is low draw dissolubility moist, in water and ethanol it is good, will not
There is deliquescence phenomenon.The related crystal formation patent of above-mentioned lamp-dish flower acetic does not refer to that lamp-dish flower acetic is molten in alkaline aqueous solution
The problem of solution speed is lifted.
Oral administration solid medicine by body absorption and play a role depending on active constituents of medicine water solubility and penetrate internal organ
Viscous permeability of the membrane, wherein being dissolved as the rate-determining steps of absorption process.Its active component of about 90% medicine in pharmacy industry
Included in solid particle, it is water insoluble in these solid drugs compounds to there are about 1/3rd.Water-insoluble drug due to
Gastro-intestinal Fluid can not be effectively dissolved in, therefore, its performance acted in human body is limited.Improve solubility and the dissolving of medicine
Speed, has become a major challenge of pharmacy industry development.According to Noyes-Whitney equations, cause because grain diameter reduces
Specific surface area increase and high wettability, can promote particle quick dissolving (Chen Peng, Zhang little Gang micronization technologies improve water
Insoluble drugs solubility [J] chemistry circulates a notice of .2007,10：766-771).
The method of conventional reduction drug particles granularity mainly has low-temperature airflow comminuting method, ball-milling method, solid dispersion method etc..
First two method generally there are that energy consumption is big, efficiency is low, Granularity Distribution is wide, easily make thermally labile medicine structure destroy with
The shortcomings of environment is polluted due to dust from flying in degraded, crushing process.And though solid dispersion method improves medicine to a certain extent
The result of extraction of thing, but operating process is more complicated, and cost is higher, and (Zhou Minyi, Chen Jianfeng, Liu Xiao woods recrystallization methods prepare micro mist
Change desk study [J] the chemical industry progress .2003 of brufen, 22 (5)：524-527).
Micropowder crystallization process is another important method for preparing micronized medicine, is the appearance of solid matter under certain condition
The technical method for promoting it to be micronized in product during crystallization, this method is without special disintegrating apparatus, the grain size of micropowder overwhelming majority
Below 50 microns, and granularity uniformity is good, changes in amplitude it is smaller (micronizing of Zhang Gengyuan ticagrelors and its crystal formation,
And preparation method and medicinal application [P] Chinese patents：201410033754.7,2014-01-24).
Up to the present, do not disclose still both at home and abroad and the rapidly-soluble lamp-dish flower acetic knot of energy is obtained by micronizing approach
Brilliant report.
The content of the invention
The purpose of the present invention is to overcome the defect of prior art there is provided a kind of new, faster fleabane flower second of dissolution velocity
Plain crystal formation.
It is a further object of the present invention to provide the preparation method of this lamp-dish flower acetic crystal formation.
Lamp-dish flower acetic crystal formation of the present invention, is named as lamp-dish flower acetic crystal formation III.
Lamp-dish flower acetic crystal formation III of the present invention, is radiated, λ=1.5405A using Cu-K α, is represented with 2 θ angles
X-ray powder diffraction spectral signature is as follows：
| 2θ | I/I0% |
| 8.02 | 73.14 |
| 9.51 | 13.27 |
| 10.18 | 36.85 |
| 14.34 | 37.46 |
| 16.18 | 100 |
| 19.13 | 10 |
| 21.18 | 13.86 |
| 25.89 | 24.74 |
| 26.83 | 27.63 |
| 29.06 | 15.95 |
| 38.73 | 15.01 |
| 46.56 | 11.09 |
Diffraction peak intensity is at lamp-dish flower acetic crystal formation III of the present invention, the θ positions 16.18 of X-ray powder diffraction 2
100%.
The dsc analysis endothermic transition temperature of lamp-dish flower acetic crystal formation III of the present invention is 107-137 DEG C.
The fusion and decomposition temperature of lamp-dish flower acetic crystal formation III of the present invention is 195-201 DEG C.
Lamp-dish flower acetic crystal formation III provided by the present invention, is a kind of crystal formation of lamp-dish flower acetic micronizing, and its particle diameter exists
Less than 50 microns, preferable particle size is below 30 microns, and preferable particle size is at 1-20 microns, more preferably 1-10 microns, and its powder
X-ray diffracting spectrum and existing scutellarin crystal powder X-ray diffracting spectrum it is significantly different.
The preparation method of lamp-dish flower acetic crystal formation III of the present invention comprises the following steps：
First, lamp-dish flower acetic is added in organic solvent, the addition of organic solvent is in room temperature to solvent reflux temperature
Under be completely dissolved lamp-dish flower acetic, then the solution of dissolving is slowly added in the aqueous solvent of 5-12 times of liquor capacity, gone forward side by side
Row stirring, makes lamp-dish flower acetic separate out and be dispersed in aqueous solvent immediately；
2nd, filter, isolate solid, be dried under reduced pressure, produce the lamp-dish flower acetic crystal formation III of micronizing.
Wherein, the speed of stirring is 500-1500r/min, and described organic solvent is methanol, ethanol, isopropanol, N, N-
One or more in dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide.
Described aqueous solvent is the mixed solvent of water and above-mentioned organic solvent, for example methanol aqueous solution, ethanol water
Or isopropanol water solution etc..Described aqueous solvent reclaimed water and the consumption volume ratio of organic solvent are 100：0~40.
It should be noted that in above-mentioned preparation method, aqueous solvent can be water or the mixed solvent containing water, when water with
The consumption volume ratio of organic solvent is 100:When 0, it is meant that aqueous solvent now is water.The water includes pure water, distillation
Water, deionized water or water for injection.
Described is dried under reduced pressure the drying being included under the arbitrary temp of room temperature~60 DEG C.
Lamp-dish flower acetic crystal formation III of the present invention is not compared with being micronized sample, with methanol, ethanol, alkaline water
The faster advantage of dissolution velocity in solution equal solvent, dissolution velocity lifting becomes apparent especially in alkaline aqueous solution.This
Outside, compared with not being micronized sample, impurity is less.Improve dissolution velocity and reduce impurity, perhaps had little significance in some fields,
But in pharmaceutical field, improve dissolution velocity even less numerical value can all bring more important result, reduce impurity even
It is that less numerical value can all greatly improve the security of medicine.Lamp-dish flower acetic as injection bulk drug, the two numerical value
Improve, time cost can be greatlyd save, product quality is improved, extraordinary clinical effectiveness is brought.
Dissolution velocity is tested：
Precision weighs lamp-dish flower acetic highly finished product (not being micronized) and each 3 parts of lamp-dish flower acetic crystal formation III (micronizing), often
Part 10mg, under the conditions of 25 DEG C, is separately added into alkaline aqueous solution (pH6-8), methanol, appropriate amount of ethanol, ultrasound dissolves it, records
Dissolution time.It the results are shown in Table 1, table 2, table 3.
Dissolution time (min) of the different lamp-dish flower acetic samples of table 1 in 100ml different solvents
Shown from table 1, lamp-dish flower acetic crystal formation III is compared with lamp-dish flower acetic highly finished product (not being micronized), with faster
Dissolution velocity.
The different lamp-dish flower acetic sample preparation 200L breviscapine B injection preparation dissolution times (h) of table 2
| Sample ID | Alkaline aqueous solution (pH6-8) |
| Lamp-dish flower acetic highly finished product (are not micronized) | 3.0 |
| Scutellarin crystal III (embodiment 1) | 2.5 |
| Scutellarin crystal III (embodiment 2) | 2.8 |
| Scutellarin crystal III (embodiment 3) | 2.7 |
| Scutellarin crystal III (embodiment 4) | 2.8 |
It has been shown that, when producing breviscapine B injection agent with liquid on a large scale, dissolution time substantially increases, and pass through micro- from table 2
The lamp-dish flower acetic crystal formation III of efflorescence can significantly shorten liquid preparation time.
Table 3 is with a collection of lamp-dish flower acetic sample is through micronizing and is not micronized preparation 200L lamp-dish flower acetic notes
Penetrate the relevant material testing result of preparation
| Sample ID | Impurity (%) |
| Lamp-dish flower acetic highly finished product (are not micronized) | 1.4 |
| Scutellarin crystal III (embodiment 1) | 1.2 |
Shown from table 3, lamp-dish flower acetic crystal formation III is compared with lamp-dish flower acetic highly finished product (not being micronized), and impurity substantially subtracts
It is few.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction figure of scutellarin crystal III of the present invention.
Fig. 2 schemes for the DSC of scutellarin crystal III of the present invention.
Fig. 3 schemes for the TG-DTA of scutellarin crystal III of the present invention.
Fig. 4 schemes for the HPLC of scutellarin crystal III of the present invention.
Embodiment
Embodiment 1：
Lamp-dish flower acetic highly finished product 1g is taken to add in 50ml methanol, being heated to reflux 20~25min is completely dissolved it, slowly
(or dropwise addition) is added into 300ml distilled water, side is added dropwise, side stirring, mixing speed is 800r/min, and lamp-dish flower acetic is analysed immediately
Go out and be dispersed in water.Filtering, is stirred with distilled water and washes or rinse 2-4 times, is filtered, and is dried under reduced pressure to constant weight, is produced micro- at 30 DEG C
The scutellarin crystal III of efflorescence, yield 90%.Above-mentioned powder is taken to carry out powder diameter detection, powder average particle size is 4-7
Micron.
Embodiment 2：
Lamp-dish flower acetic highly finished product 1g is taken to add in 45ml methanol, being heated to reflux 30min is completely dissolved it, is slowly added to
(or dropwise addition) arrives the mixed solution (V of 400ml distilled water and ethanol:V=360:40) in, side is added dropwise, side stirring, and mixing speed is
750r/min, lamp-dish flower acetic is separated out and is dispersed in water immediately.Filtering, is stirred with distilled water and washes or rinse 2-4 times, is filtered, 50
It is dried under reduced pressure at DEG C to constant weight, produces the scutellarin crystal III of micronizing, yield 92%.Above-mentioned powder is taken to carry out powder grain
Detect that powder average particle size is 6-8 microns in footpath.
Embodiment 3：
Lamp-dish flower acetic highly finished product 1g is taken to add the mixed solvent (V of 60ml methanol and isopropanol:V=8:2) in, heat back
30~35min of stream is completely dissolved it, is slowly added to (or dropwise addition) into 800ml distilled water, side is added dropwise, side stirring, stirring speed
Spend for 800r/min, lamp-dish flower acetic is separated out and is dispersed in water immediately.Filtering, is stirred with distilled water and washes or rinse 2-4 times, mistake
Filter, be dried under reduced pressure at 60 DEG C to constant weight, produce the scutellarin crystal III of micronizing, yield 89%.Above-mentioned powder is taken to carry out
Powder diameter detects that powder average particle size is 6-9 microns.
Embodiment 4：
Lamp-dish flower acetic highly finished product 1g is taken to add in 60ml ethanol, being heated to reflux 30~35min is completely dissolved it, slowly
(or dropwise addition) is added to 600ml distilled water and the mixed solution (V of isopropanol:V=550:50) in, side is added dropwise, side stirring, stirring
Speed is 900r/min, and lamp-dish flower acetic is separated out and is dispersed in the mixed solution immediately.Filtering, is stirred with distilled water and washes or rinse
2-4 times, filter, be dried under reduced pressure at 45 DEG C to constant weight, produce the scutellarin crystal III of micronizing, yield 87%.Take above-mentioned
Powder carries out powder diameter detection, and powder average particle size is 3-7 microns.
The purity testing of lamp-dish flower acetic in scutellarin crystal III：
Chromatographic condition and system suitability：Using octadecylsilane chemically bonded silica as filler；With methanol -0.1%
Phosphoric acid solution (40:60) it is mobile phase；Flow velocity is 1.0ml per minute；40 DEG C of column temperature；Detection wavelength 335nm.Number of theoretical plate is by open country
Scutelloside, which is calculated, should be not less than 5000.
The preparation of reference substance solution takes scutellarin reference substance 10mg, accurately weighed, puts in 100ml measuring bottles, plus methanol
70ml, ultrasonically treated (power 300W, frequency 50kHz) 45 minutes takes out, places room temperature, plus methanol dilution is to scale, shakes up,
Produce.
The preparation of need testing solution takes this product 10mg, accurately weighed, puts in 100ml measuring bottles, plus methanol 70ml, ultrasonically treated
(power 300W, frequency 50kHz) 45 minutes, takes out, and places room temperature, plus methanol dilution is to scale, shakes up, and filtration takes subsequent filtrate,
Produce.
Determination method is accurate respectively to draw reference substance solution and each 5 μ l of need testing solution, injects liquid chromatograph, determines, i.e.,
.
Impurity determination：Take this product appropriate (equivalent to scutellarin 20mg), put in 50ml measuring bottles, plus appropriate methanol, ultrasound
Handle (power 300W, frequency 50kHz) 45 minutes, put to room temperature, plus methanol dilution is to scale, shakes up, and is used as need testing solution.
Precision measures need testing solution 1ml, puts in 100ml measuring bottles, plus methanol dilution is to scale, shakes up, and is used as reference substance solution.According to
Chromatographic condition under [assay] item, takes the μ l of contrast solution 5, injects liquid chromatograph, adjusts detection sensitivity, makes principal component
The peak height of chromatographic peak is the 10% of full scale, then precision measures need testing solution and each 5 μ l of contrast solution, is injected separately into liquid phase color
Spectrometer, 2.5 times of record chromatogram to principal component peak retention time.In need testing solution chromatogram, the sum of other compositions peak area
It cannot be greater than 2 times of contrast solution main peak peak area.
Claims (10)
1. a kind of lamp-dish flower acetic crystal formation, it is characterised in that be named as lamp-dish flower acetic crystal formation III, is radiated using Cu-K α, and λ=
1.5405A, it is as follows with the X-ray powder diffraction spectral signature that 2 θ angles are represented：
2. lamp-dish flower acetic crystal formation as claimed in claim 1, it is characterised in that X-ray powder diffraction 2 is spread out at θ positions 16.18
It is 100% to penetrate peak intensity.
3. lamp-dish flower acetic crystal formation as claimed in claim 1, it is characterised in that its dsc analysis endothermic transition temperature is 107-
137℃。
4. lamp-dish flower acetic crystal formation as claimed in claim 1, it is characterised in that its fusion and decomposition temperature is 195-201 DEG C.
5. lamp-dish flower acetic crystal formation as claimed in claim 1, it is characterised in that be a kind of crystal formation of lamp-dish flower acetic micronizing,
Its particle diameter is below 50 microns.
6. lamp-dish flower acetic crystal formation as claimed in claim 5, it is characterised in that described particle diameter is 1-10 microns.
7. the preparation method of lamp-dish flower acetic crystal formation as claimed in claim 1, it is characterised in that comprise the following steps：
First, lamp-dish flower acetic is added in organic solvent, the addition of organic solvent is to make under room temperature to solvent reflux temperature
Lamp-dish flower acetic is completely dissolved, then the solution of dissolving is slowly added in the aqueous solvent of 5-12 times of liquor capacity, and is stirred
Mix, lamp-dish flower acetic is separated out and is dispersed in aqueous solvent immediately；
2nd, filter, isolate solid, be dried under reduced pressure, produce the lamp-dish flower acetic crystal formation III of micronizing.
8. the preparation method of lamp-dish flower acetic crystal formation as claimed in claim 7, it is characterised in that described mixing speed is
500-1500r/min。
9. the preparation method of lamp-dish flower acetic crystal formation as claimed in claim 7, it is characterised in that described organic solvent is first
One or more in alcohol, ethanol, isopropanol, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide.
10. the preparation method of lamp-dish flower acetic crystal formation as claimed in claim 7, it is characterised in that described aqueous solvent is water
With the mixed solvent of above-mentioned organic solvent, described aqueous solvent reclaimed water and the consumption volume ratio of organic solvent are 100：0~40.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101993462A (en) * | 2009-08-11 | 2011-03-30 | 昆明制药集团股份有限公司 | Scutellarin crystal I and preparation method thereof |
| CN103102337A (en) * | 2013-01-24 | 2013-05-15 | 昆明理工大学 | Preparation method of wild baicalein |
| CN105273018A (en) * | 2014-06-17 | 2016-01-27 | 昆明制药集团股份有限公司 | Scutellarin dihydrate crystal II and preparation method thereof |
-
2017
- 2017-05-24 CN CN201710372392.8A patent/CN106967139B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101993462A (en) * | 2009-08-11 | 2011-03-30 | 昆明制药集团股份有限公司 | Scutellarin crystal I and preparation method thereof |
| CN103102337A (en) * | 2013-01-24 | 2013-05-15 | 昆明理工大学 | Preparation method of wild baicalein |
| CN105273018A (en) * | 2014-06-17 | 2016-01-27 | 昆明制药集团股份有限公司 | Scutellarin dihydrate crystal II and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 冯博闻: "高纯度灯盏乙素的多晶型制备及改善其溶解性的初步研究", 《中国优秀硕士学位论文全文数据库-医药卫生科技辑》 * |
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