CN103910722B - A kind of Vinpocetine compound and preparation method thereof - Google Patents
A kind of Vinpocetine compound and preparation method thereof Download PDFInfo
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- CN103910722B CN103910722B CN201310003887.5A CN201310003887A CN103910722B CN 103910722 B CN103910722 B CN 103910722B CN 201310003887 A CN201310003887 A CN 201310003887A CN 103910722 B CN103910722 B CN 103910722B
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- -1 Vinpocetine compound Chemical class 0.000 title claims abstract description 39
- 229960000744 vinpocetine Drugs 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title abstract description 22
- DDNCQMVWWZOMLN-IRLDBZIGSA-N Vinpocetine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OCC)N5C2=C1 DDNCQMVWWZOMLN-IRLDBZIGSA-N 0.000 claims abstract description 42
- 239000013078 crystal Substances 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 239000000843 powder Substances 0.000 claims abstract description 11
- 238000003556 assay Methods 0.000 claims abstract description 4
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 238000002347 injection Methods 0.000 claims description 15
- 239000007924 injection Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 10
- 238000010521 absorption reaction Methods 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 7
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 229960005261 aspartic acid Drugs 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000002329 infrared spectrum Methods 0.000 claims description 5
- 238000001757 thermogravimetry curve Methods 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 239000012467 final product Substances 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 30
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 abstract description 17
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 abstract description 9
- 229960002726 vincamine Drugs 0.000 abstract description 9
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 abstract description 7
- 229940088033 calan Drugs 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000001228 spectrum Methods 0.000 abstract description 5
- 238000013112 stability test Methods 0.000 abstract description 4
- 238000003756 stirring Methods 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000009472 formulation Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000004140 cleaning Methods 0.000 description 4
- 238000005261 decarburization Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 239000012982 microporous membrane Substances 0.000 description 4
- 238000012856 packing Methods 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000003930 cognitive ability Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 230000001777 nootropic effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to medical art, the invention provides a kind of Vinpocetine compound and preparation method thereof.Described formula I Vinpocetine compound
measure by X-ray powder assay method, represent that X-ray powder diffraction pattern demonstrates characteristic diffraction peak at place with 2 θ diffraction angle.The impurity spectrum of this raw materials of compound: impurity Calan does not detect, and impurity dihydro vinpocetin weight percentage is less than 0.1%, and impurity A Piao vincamine does not detect, and impurity methoxyl group vinpocetin weight percentage is less than 0.1%.Stability test shows, crystal type Vinpocetine compound of the present invention, has good stability.
Description
Technical field
The invention belongs to medical art, be specifically related to vinpocetin crystalline compound and preparation method thereof.
Background technology
Vinpocetin (Vinpocetine), has another name called vincamine amino acid ester, and chemical name is: (3 α, 4 α)-eburnamenine-14-carboxylic acid, ethyl ester, molecular formula is C
22h
26n
2o
2, molecular weight 350.64, structural formula is
。
At present the study hotspot of vinpocetin is mainly concentrated in the research of its novel form, new pharmacologically active, novel derivative and mechanism of action.Find that its new pharmacologically active mainly contains anti-oxidant, raising cognitive ability, neuro-protective and nootropic effect.Have many results of study to point out in the recent period, vinpocetin is to the using value as potential in alzheimer's disease and vascular dementia etc. have of some brain neuroblastoma diseases.
Vinpocetin belongs to indoles alkaloid, and it is the vincamine extracted from the periwinkle in South America, is the unit molecule compound of plant origin.Be widely used in the prevention and therapy of ischemic cerebrovascular.The seventies, vinpocetin exploitation was become cerebral circulation metabolism activator by Hungary GedeonRichter company, the formulation of current use is tablet and injection, domestic Clinical practice be injection formulations, in the raw material of injection formulations, how much impurity have vital impact for the security of preparation, therefore, research obtains the less crystal type Vinpocetine compound of impurity, has important scientific meaning.
Summary of the invention
For these reasons, we are through long-term experimental study, obtain a kind of new crystal type Vinpocetine compound, the impurity spectrum of this raw materials of compound: impurity Calan does not detect, impurity dihydro vinpocetin weight percentage is less than 0.1%, impurity A Piao vincamine does not detect, and impurity methoxyl group vinpocetin weight percentage is less than 0.1%.Stability test shows, crystal type Vinpocetine compound of the present invention, has good stability.
The present invention is achieved through the following technical solutions.
A kind of crystallization Vinpocetine compound of formula I, described Vinpocetine compound X-ray powder assay method measures, and represents that X-ray powder diffraction pattern demonstrates characteristic diffraction peak at 11.2 degree, 12.4 degree, 13.9 degree, 14.9 degree, 16.4 degree, 17.6 degree, 18.9 degree, 19.1 degree, 21.8 degree, 22.8 degree, 23.7 degree, 24.7 degree, 26.4 degree, 29.5 degree, 31.0 degree places with 2 θ diffraction angle
formula I.
Compound described above, wherein characteristic diffraction peak intensity 39.2%, 77.6%, 77.5%, 65.4%, 15.6%, 55.9%, 100%, 22.5%, 13.4%, 26.9%, 83.9%, 18.2%, 10.8%, 29.7%, 17.7% successively.
Above-mentioned 2 θ angles, because the reason such as detecting instrument, testing environment, testing staff's operation, allow to have ± the error of 0.5 degree, and in like manner, above-mentioned relative intensity allows to have ± error of 5%.
The d value of above-mentioned diffraction peak is followed successively by: 7.87,7.15,6.35,5.92,5.41,5.03,4.70,4.63,4.08,3.89,3.75,3.60,3.37,3.03,2.88.
Wherein crystallization Vinpocetine compound described above in differential scanning amount method thermogram, peak temperature 158-162 DEG C.Wherein peak value is 160 DEG C.
Wherein crystal KBr compressing tablet-transmission method measures infrared spectra and has following absorption: 2991.1cm
-1, 2929.3cm
-1, 2852.2cm
-1, 1718.3m
-1, 1629.6cm
-1, 1694.5cm
-1, 1454.1cm
-1, 1427.1cm
-1, 1361.5cm
-1, 1284.4m
-1, 1220.7cm
-1, 1205.29cm
-1, 1178.3cm
-1, 1153.2cm
-1, 1116.6cm
-1, 1079.9cm
-1, 1020.2cm
-1, 746.3cm
-1.
Above-mentioned ir data, because the reason such as detecting instrument, testing environment, testing staff's operation, allows to have ± the error of 10.
Its preparation method includes but not limited to following: get vinpocetin crude product, and to add volume be vinpocetin crude product weight 4-6 volume ratio is doubly the methylene dichloride of 6:1: the solution of propyl carbinol, is heated to 40 DEG C-50 DEG C, dissolve completely, place 2-8 DEG C of place and leave standstill 24 hours, leaving standstill 3 constantly little, adding acetic acid, tune solution ph is 4.0-4.5, leave standstill, filter, filtrate is vacuum concentration under 40 DEG C of-50 DEG C of conditions, vacuum-drying under 40 DEG C of-50 DEG C of conditions, to obtain final product.
Wherein compound is prepared into pharmaceutical preparation.
Wherein at least comprise the crystalline compounds of 95% weight.
Wherein at least comprise the crystalline compounds of 99% weight.
Wherein at least comprise the crystalline compounds of 99.5% weight.
Its pharmaceutical formulations comprises:
A the crystal type Vinpocetine compound of () 2 ~ 10mg/ml, by the entire volume of injection;
B () pharmaceutically acceptable acidic substance, the weight ratio of acidic substance and vinpocetin is 0.25:1 ~ 1:0.25, and described acidic substance are selected from: L-Aspartic acid.
(c) pharmaceutically acceptable carrier; With
(d) pharmaceutically acceptable thinner.
The preparation method of preparation is: under the condition of cleaning, 2gL-aspartic acid is dropped in dosing utensil, add stirring and dissolving in 50 DEG C of water for injection 800ml, be cooled to room temperature, add 2g crystal type Vinpocetine compound stir about 30min and make it entirely molten, drop into 40g N.F,USP MANNITOL to dissolve, add 0.3% pin carbon to stir absorption thermal source, filter decarburization, add water to enough, through 0.22 μm of filtering with microporous membrane, obtain 2mg/ml vinpocetin solution.Packing 2.5ml is in ampere bottle, and lyophilize makes aseptic freeze-dried powder injection in 72 hours.Specification 5mg/ bottle.
Described x-ray powder diffraction test condition is (normal condition):
Measuring unit: Jilin University
Test apparatus: UltimaIV type X-ray diffractometer (Rigaku company)
Test parameter: 40KV, 30mACu target wavelength: 1.54 dust Scanrange:5 ~ 95 °
Test method: the powder getting this product, puts into sample cell, compacting, carries out X-ray diffraction analysis.
Described infrared spectrometer operational condition is (normal condition):
Significant parameter:
INSTRUMENT MODEL: FTIR-650 Fourier transform infrared spectrometer
Resolving power: 4cm
-1
Scanning times: 32
Scanning wave-number range: 4000 ~ 400cm
-1
Environment for use:
Voltage of supply: 100V ~ 240V, 47Hz ~ 63Hz, 1.2A
Temperature range: 16 DEG C ~ 25 DEG C
Humidity range: 20% ~ 50%
Accompanying drawing explanation
(1) Fig. 1 is the X-powder diffraction spectrum of the compound crystal that preparation embodiment 1 obtains.
(2) Fig. 2 is the X-powder diffraction spectrum of the compound crystal that preparation embodiment 2 obtains.
(3) Fig. 3 is the X-powder diffraction spectrum of the compound crystal that preparation embodiment 3 obtains.
Embodiment
Embodiment 1
Get vinpocetin crude product, to add volume be the volume ratio of vinpocetin crude product weight 5 times is the methylene dichloride of 6:1: the solution of propyl carbinol, is heated to 45 DEG C, dissolve completely, place 2 DEG C of places and leave standstill 24 hours, leaving standstill 3 constantly little, adding acetic acid, solution ph is adjusted to be 4.2, leave standstill, filter, filtrate is vacuum concentration under 45 DEG C of conditions, vacuum-drying under 45 DEG C of conditions, obtains crystal type Vinpocetine compound.
Wherein crystallization Vinpocetine compound described above in differential scanning amount method thermogram, peak temperature 158-162 DEG C.Wherein peak value is 160 DEG C.
Wherein crystal KBr compressing tablet-transmission method measures infrared spectra and has following absorption: 2991.1cm
-1, 2929.3cm
-1, 2852.2cm
-1, 1718.3m
-1, 1629.6cm
-1, 1694.5cm
-1, 1454.1cm
-1, 1427.1cm
-1, 1361.5cm
-1, 1284.4m
-1, 1220.7cm
-1, 1205.29cm
-1, 1178.3cm
-1, 1153.2cm
-1, 1116.6cm
-1, 1079.9cm
-1, 1020.2cm
-1, 746.3cm
-1.
The preparation method of preparation is: under the condition of cleaning, 2gL-aspartic acid is dropped in dosing utensil, add stirring and dissolving in 50 DEG C of water for injection 800ml, be cooled to room temperature, add 2g crystal type Vinpocetine compound stir about 30min and make it entirely molten, drop into 40g N.F,USP MANNITOL to dissolve, add 0.3% pin carbon to stir absorption thermal source, filter decarburization, add water to enough, through 0.22 μm of filtering with microporous membrane, obtain 2mg/ml vinpocetin solution.Packing 2.5ml is in ampere bottle, and lyophilize makes aseptic freeze-dried powder injection in 72 hours.Specification 5mg/ bottle.
Embodiment 2
Get vinpocetin crude product, to add volume be the volume ratio of vinpocetin crude product weight 6 times is the methylene dichloride of 6:1: the solution of propyl carbinol, is heated to 50 DEG C, dissolve completely, place 8 DEG C of places and leave standstill 24 hours, leaving standstill 3 constantly little, adding acetic acid, solution ph is adjusted to be 4.5, leave standstill, filter, filtrate is vacuum concentration under 50 DEG C of conditions, vacuum-drying under 50 DEG C of conditions, obtains crystal type Vinpocetine compound.
Wherein crystallization Vinpocetine compound described above in differential scanning amount method thermogram, peak temperature 158-162 DEG C.Wherein peak value is 160 DEG C.
Wherein crystal KBr compressing tablet-transmission method measures infrared spectra and has following absorption: 2991.1cm
-1, 2929.3cm
-1, 2852.2cm
-1, 1718.3m
-1, 1629.6cm
-1, 1694.5cm
-1, 1454.1cm
-1, 1427.1cm
-1, 1361.5cm
-1, 1284.4m
-1, 1220.7cm
-1, 1205.29cm
-1, 1178.3cm
-1, 1153.2cm
-1, 1116.6cm
-1, 1079.9cm
-1, 1020.2cm
-1, 746.3cm
-1.
The preparation method of preparation is: under the condition of cleaning, 2gL-aspartic acid is dropped in dosing utensil, add stirring and dissolving in 50 DEG C of water for injection 800ml, be cooled to room temperature, add 2g crystal type Vinpocetine compound stir about 30min and make it entirely molten, drop into 40g N.F,USP MANNITOL to dissolve, add 0.3% pin carbon to stir absorption thermal source, filter decarburization, add water to enough, through 0.22 μm of filtering with microporous membrane, obtain 2mg/ml vinpocetin solution.Packing 2.5ml is in ampere bottle, and lyophilize makes aseptic freeze-dried powder injection in 72 hours.Specification 5mg/ bottle.
Embodiment 3
Get vinpocetin crude product, to add volume be the volume ratio of vinpocetin crude product weight 4 times is the methylene dichloride of 6:1: the solution of propyl carbinol, is heated to 40 DEG C, dissolve completely, place 2 DEG C of places and leave standstill 24 hours, leaving standstill 3 constantly little, adding acetic acid, solution ph is adjusted to be 4.0, leave standstill, filter, filtrate is vacuum concentration under 40 DEG C of conditions, vacuum-drying under 40 DEG C of conditions, obtains crystal type Vinpocetine compound.
Wherein crystallization Vinpocetine compound described above in differential scanning amount method thermogram, peak temperature 158-162 DEG C.Wherein peak value is 160 DEG C.
Wherein crystal KBr compressing tablet-transmission method measures infrared spectra and has following absorption: 2991.1cm
-1, 2929.3cm
-1, 2852.2cm
-1, 1718.3m
-1, 1629.6cm
-1, 1694.5cm
-1, 1454.1cm
-1, 1427.1cm
-1, 1361.5cm
-1, 1284.4m
-1, 1220.7cm
-1, 1205.29cm
-1, 1178.3cm
-1, 1153.2cm
-1, 1116.6cm
-1, 1079.9cm
-1, 1020.2cm
-1, 746.3cm
-1.
The preparation method of preparation is: under the condition of cleaning, 2gL-aspartic acid is dropped in dosing utensil, add stirring and dissolving in 50 DEG C of water for injection 800ml, be cooled to room temperature, add 2g crystal type Vinpocetine compound stir about 30min and make it entirely molten, drop into 40g N.F,USP MANNITOL to dissolve, add 0.3% pin carbon to stir absorption thermal source, filter decarburization, add water to enough, through 0.22 μm of filtering with microporous membrane, obtain 2mg/ml vinpocetin solution.Packing 2.5ml is in ampere bottle, and lyophilize makes aseptic freeze-dried powder injection in 72 hours.Specification 5mg/ bottle.
One, determination method
(1) defects inspecting analytical procedure
1, chromatographic condition:
Be weighting agent with octadecylsilane chemically bonded silica, with 0.2mol/L Spirit of Mindererus-acetonitrile (40: 60) for moving phase, determined wavelength is 280nm, take Calan, A Piao vincamine and vinpocetin reference substance respectively appropriate, put in same measuring bottle, add moving phase dissolve and dilute the solution made all containing 0.02mg in every 1ml, as system suitability solution, get 10 μ l injection liquid chromatographies, record color atlas, impurity Calan, resolution between impurity A Piao vincamine and vinpocetin all should meet the requirements.Theoretical plate number calculates by vinpocetin peak and is not less than 3000.
2, detection method: measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).
Get this product appropriate (being about equivalent to vinpocetine raw material 50mg), put in 50ml measuring bottle, be diluted to scale by moving phase, shake up, as need testing solution; Precision measures in right amount, quantitatively dilutes the solution made containing 5 μ g in every 1ml, solution in contrast by moving phase.Precision measures contrast solution and each 10 μ l of need testing solution, respectively injection liquid chromatography, record color atlas.As aobvious impurity peaks in the color atlas of need testing solution, impurity Calan is 0.40 to the relative retention time of vinpocetin, impurity dihydro vinpocetin is 0.66 to the relative retention time of vinpocetin, impurity A Piao vincamine is 0.78 to the relative retention time of vinpocetin, and impurity methoxyl group vinpocetin is 0.87 to the relative retention time of vinpocetin.The content of each impurity is calculated according to area normalization method.
(2) content detection analytical procedure
1, chromatographic condition: be weighting agent with octadecylsilane chemically bonded silica, with 0.2mol/L Spirit of Mindererus-acetonitrile (40: 60) for moving phase, determined wavelength is 280nm, take Calan, A Piao vincamine and vinpocetin reference substance respectively appropriate, put in same measuring bottle, add moving phase dissolve and dilute the solution made all containing 0.02mg in every 1ml, as system suitability solution, get 10 μ l injection liquid chromatographies, record color atlas, impurity Calan, resolution between impurity A Piao vincamine and vinpocetin all should meet the requirements.Theoretical plate number calculates by vinpocetin peak and is not less than 3000.
2, detection method: measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).
Assay method: get this product, precision measures or takes and (is about equivalent to vinpocetin 10mg) in right amount, put in 50ml measuring bottle, with methanol dilution to scale, shake up, precision measures 5ml, put in 50ml measuring bottle, be diluted to scale by moving phase, shake up, precision measures 10 μ l injection liquid chromatographies, record color atlas; Separately get vinpocetin reference substance, be measured in the same method, by external standard method with calculated by peak area, to obtain final product.
Reference substance described above is all purchased from National Institute for Food and Drugs Control.
Detected result: in table 1.
The different embodiment of table 1 is mixed mass spectrometric detection and content detection
Two, raw material stability test
The crystal type Vinpocetine compound of Example 1, embodiment 2, embodiment 3, deposits under temperature (40 ± 2) DEG C, relative humidity 75% ± 5% condition, respectively at 1,2,3 sampling at the end of month, measures the content of drug content and different impurities.
Test-results is in Table 2-table 4:
Content and the impurity of a table 21 month different embodiment compare
Content and the impurity of a table 32 month different embodiment compare
Content and the impurity of a table 43 month different embodiment compare
Conclusion (of pressure testing): aforementioned stable experiment shows, crystal type Vinpocetine compound of the present invention has good stability.
Four, preparation stability test
By the raw material of embodiment 1, embodiment 2, embodiment 3, vinpocetin injection formulations is obtained according to formulation preparation method, deposit under temperature (40 ± 2) DEG C, relative humidity 75% ± 5% condition, respectively at 1,2,3 sampling at the end of month, measure the content of different impurities.
Test-results is in Table 5-table 7:
A table 51 month different embodiment preparation impurity compares
A table 62 month different embodiment preparation impurity compares
A table 73 month different embodiment preparation impurity compares
Conclusion (of pressure testing): aforementioned stable experiment shows, the injection formulations that crystal type Vinpocetine compound of the present invention is prepared into has good stability.
Claims (7)
1. the crystallization Vinpocetine compound of a formula I, it is characterized in that: described Vinpocetine compound X-ray powder assay method measures, and represents that X-ray powder diffraction pattern demonstrates characteristic diffraction peak at 11.2 degree, 12.4 degree, 13.9 degree, 14.9 degree, 16.4 degree, 17.6 degree, 18.9 degree, 19.1 degree, 21.8 degree, 22.8 degree, 23.7 degree, 24.7 degree, 26.4 degree, 29.5 degree, 31.0 degree places with 2 θ diffraction angle
Wherein characteristic diffraction peak intensity 39.2%, 77.6%, 77.5%, 65.4%, 15.6%, 55.9%, 100%, 22.5%, 13.4%, 26.9%, 83.9%, 18.2%, 10.8%, 29.7%, 17.7% successively;
Wherein crystallization Vinpocetine compound in differential scanning amount method thermogram, peak temperature 158-162 DEG C; Wherein crystal KBr compressing tablet-transmission method measures infrared spectra and has following absorption: 2991.1cm
-1, 2929.3cm
-1, 2852.2cm
-1, 1718.3m
-1, 1629.6cm
-1, 1694.5cm
-1, 1454.1cm
-1, 1427.1cm
-1, 1361.5cm
-1, 1284.4m
-1, 1220.7cm
-1, 1205.29cm
-1, 1178.3cm
-1, 1153.2cm
-1, 1116.6cm
-1, 1079.9cm
-1, 1020.2cm
-1, 746.3cm
-1.
2. prepare the method for the crystallization Vinpocetine compound of formula I according to claim 1 for one kind, its concrete steps are: get vinpocetin crude product, to add volume be vinpocetin crude product weight 4-6 volume ratio is doubly the methylene dichloride of 6:1: the solution of propyl carbinol, be heated to 40 DEG C-50 DEG C, dissolve completely, place 2-8 DEG C of place and leave standstill 24 hours, leave standstill 3 constantly little, add acetic acid, tune solution ph is 4.0-4.5, leaves standstill, filter, filtrate is vacuum concentration under 40 DEG C of-50 DEG C of conditions, and vacuum-drying under 40 DEG C of-50 DEG C of conditions, to obtain final product.
3. a pharmaceutical preparation, it comprises the crystallization Vinpocetine compound of formula I according to claim 1.
4. the crystallization Vinpocetine compound of a kind of formula I according to claim 1, wherein at least comprises the crystalline compounds of 95% weight.
5. the crystallization Vinpocetine compound of a kind of formula I according to claim 1, wherein at least comprises the crystalline compounds of 99% weight.
6. the crystallization Vinpocetine compound of a kind of formula I according to claim 1, wherein at least comprises the crystalline compounds of 99.5% weight.
7. pharmaceutical preparation according to claim 3, it comprises:
A the crystal type Vinpocetine compound of () 2 ~ 10mg/ml, by the entire volume of injection;
(b) pharmaceutically acceptable acidic substance, the weight ratio of acidic substance and crystal type Vinpocetine compound is 0.25:1 ~ 1:0.25, and described acidic substance are L-Aspartic acid;
(c) pharmaceutically acceptable carrier; With
(d) pharmaceutically acceptable thinner.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1058966A (en) * | 1991-08-30 | 1992-02-26 | 东北制药总厂 | The novel method of vincamine amino acid ester preparation |
| CN102311432A (en) * | 2011-08-26 | 2012-01-11 | 贺金凤 | Stable vinpocetine compound and pharmaceutical composition thereof |
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2013
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1058966A (en) * | 1991-08-30 | 1992-02-26 | 东北制药总厂 | The novel method of vincamine amino acid ester preparation |
| CN102311432A (en) * | 2011-08-26 | 2012-01-11 | 贺金凤 | Stable vinpocetine compound and pharmaceutical composition thereof |
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Denomination of invention: A Changchun Sitin Compound and Its Preparation Method Effective date of registration: 20231226 Granted publication date: 20151223 Pledgee: China Construction Bank Co.,Ltd. Changchun Science and Technology Sub branch Pledgor: CHANGCHUN HAIYUE PHARMACEUTICAL Co.,Ltd. Registration number: Y2023220000146 |