CN104744530A - Gastrodia elata derivative crystal form as well as preparation method, preparation and application thereof - Google Patents
Gastrodia elata derivative crystal form as well as preparation method, preparation and application thereof Download PDFInfo
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- CN104744530A CN104744530A CN201510025239.9A CN201510025239A CN104744530A CN 104744530 A CN104744530 A CN 104744530A CN 201510025239 A CN201510025239 A CN 201510025239A CN 104744530 A CN104744530 A CN 104744530A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The invention discloses a gastrodia elata derivative crystal form as well as a preparation method, a preparation and an application thereof. In a powder X-ray diffraction pattern, the gastrodia elata derivative crystal form shows characteristic diffraction peaks at reflection angles 2thea+/-0.2 degrees, namely 4.7+/-0.2, 8.1+/-0.2, 9.9+/-0.2, 17.8+/-0.2, 19.6+/-0.2, 22.6+/-0.2 and 23.4+/-0.2 degrees. The preparation method of the gastrodia elata derivative crystal form comprises the following steps: adding an inorganic solvent with mass-to-volume ratio in g/ml of 1:(10-200) into a gastrodia elata derivative crude product, refluxing for 0.5-3 hours at the temperature of 60-90 DEG C, cooling to 0-30 DEG C, standing for 1-5 hours, carrying out crystallization, carrying out suction filtration, washing a filter cake, and carrying out reduced pressure drying at the temperature of 40-80 DEG C, so that the gastrodia elata derivative crystal form target product is obtained. The preparation can be tablets, capsules, granules, freeze-dried powder injection and injection prepared by adding pharmaceutically acceptable carriers and auxiliary materials into the gastrodia elata derivative crystal form. The application is namely application of the gastrodia elata derivative crystal form in preparation of a medicine used for treating central nervous system diseases. The gastrodia elata derivative crystal form has extremely high quality stability, the preparation method of the gastrodia elata derivative crystal form is easy to operate, production cost is low, industrial production can be easily realized, and product purity is high and can reach up to more than 99%.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to a kind of rhizoma Gastrodiae derivative crystal formation and preparation method thereof, preparation and application.
Background technology
Gastrodin derivative is known compound, chemistry 4-(3,4,5-trihydroxy--6-methylol by name)-tetrahydrochysene-2H-pyrans-2-base oxygen benzaldehyde, structural formula is as follows:
4-(3,4,5-trihydroxy--6-methylol)-tetrahydrochysene-2H-pyrans-2-base oxygen benzaldehyde is the peculiar impurity of synthetic gastrodin raw material, and Gastrodine is central nervous system medication, is mainly used in calmness, sleeping, analgesia.Decline for god, god declines syndrome and vascular headache, brain traumatic syndrome; Migraine, trigeminal neuralgia, neuralgia of greater occipital nerve, dizzy, sudden deafness, vestibular neuronitis, vertebro-basilar artery insufficiency, can also be used for the diseases such as assisting therapy epilepsy.Gastrodine is more and more paid close attention to by scientist as medicine.Thus the derivative relevant to Gastrodine is carried out great for the evaluative meaning of Gastrodine drug effect, quality.
Summary of the invention
The first object of the present invention is to provide a kind of gastrodin derivative crystal formation; Second object is to provide the preparation method of described gastrodin derivative crystal formation; 3rd object is to provide the preparation of described gastrodin derivative crystal formation; 4th object is to provide the application of described gastrodin derivative crystal formation.
The first object of the present invention is achieved in that the powder x-ray diffraction collection of illustrative plates of described gastrodin derivative crystal formation is 4.7 ± 0.2,8.1 ± 0.2,9.9 ± 0.2,17.8 ± 0.2,19.6 ± 0.2,2 θ ± 0.2 DEG C reflection angle place indicating characteristic the diffraction peak of 22.6 ± 0.2,23.4 ± 0.2.
The second object of the present invention realizes like this, will add mass volume ratio in gastrodin derivative crude product and to count with g/ml the organic solvent of 1:10 ~ 200, in 60 ~ 90 DEG C of backflow 0.5 ~ 3h, be cooled to 0 ~ 30 DEG C and leave standstill 1 ~ 5h crystallization, suction filtration, washing leaching cake, 40 ~ 80 DEG C of drying under reduced pressure obtain target compound.
The third object of the present invention is achieved in that in described gastrodin derivative crystal formation and adds pharmaceutically acceptable carrier and auxiliary material is prepared into tablet, capsule, granule, lyophilized injectable powder and injection liquid.
The fourth object of the present invention is achieved in that the application of described gastrodin derivative crystal formation in preparation treatment central nervous system disease medicine.
Gastrodin derivative crystal formation of the present invention, i.e. 4-(3,4,5-trihydroxy--6-methylol) crystal formation of-tetrahydrochysene-2H-pyrans-2-base oxygen benzaldehyde has high quality stability, its preparation method is simple to operate, production cost is low, easy suitability for industrialized production and product purity is high, reaches more than 99%.
Accompanying drawing explanation
Fig. 1 is the HPLC figure of gastrodin derivative crystallization;
Fig. 2 is the HPLC figure of gastrodin derivative crystallization;
Fig. 3 is the HPLC figure of gastrodin derivative crystallization;
Fig. 4 is the HPLC figure of gastrodin derivative crystallization;
Fig. 5 is the HPLC figure of gastrodin derivative crystallization;
Fig. 6 is the HPLC figure of gastrodin derivative crystallization;
Fig. 7 is the X-ray powder diffraction pattern of gastrodin derivative crystallization;
Fig. 8 is the DSC figure of gastrodin derivative crystallization;
Fig. 9 is the TG-DTA figure of gastrodin derivative crystallization.
Embodiment
Below in conjunction with embodiment and accompanying drawing, the present invention is further illustrated, but limited the present invention never in any form, and any conversion done based on training centre of the present invention or replacement, all belong to protection scope of the present invention.
The powder x-ray diffraction collection of illustrative plates of gastrodin derivative crystal formation of the present invention 4.7 ± 0.2, the 2 θ ± 0.2 DEG C reflection angle place indicating characteristic diffraction peak of 8.1 ± 0.2,9.9 ± 0.2,17.8 ± 0.2,19.6 ± 0.2,22.6 ± 0.2,23.4 ± 0.2.
Gastrodin derivative crystal formation of the present invention is at use Cu-K α
1radiation, the x-ray Powder Diffraction pattern feature represented with 2 θ ± 0.2 DEG C angle is specific as follows:
| 2θ | d-spacing | I/I0% |
| 4.7341 | 18.66618 | 100.00 |
| 8.1296 | 10.87598 | 17.61 |
| 9.8692 | 8.96241 | 20.78 |
| 14.8711 | 5.95729 | 10.45 |
| 17.8254 | 4.97605 | 54.01 |
| 19.6469 | 4.51864 | 82.06 |
| 22.5739 | 3.93893 | 61.72 |
| 23.4154 | 3.79610 | 32.45 |
| 24.4372 | 3.63963 | 18.21 |
| 27.7034 | 3.22016 | 11.23 |
The powder x-ray diffraction 2 θ position 4.7341 place diffraction peak intensity of described gastrodin derivative crystal formation is 100%.
The dsc analysis endothermic transition temperature of described gastrodin derivative crystal formation is 143 ~ 156 DEG C.
The fusion and decomposition temperature of described gastrodin derivative crystal formation is 350 ~ 352 DEG C.
With the mass attenuation of 59 ~ 62% when the TGA of described gastrodin derivative crystal formation analyzes fusion and decomposition.
The preparation method of gastrodin derivative crystal formation of the present invention, will add mass volume ratio in gastrodin derivative crude product and to count with g/ml the organic solvent of 1:10 ~ 200, in 60 ~ 90 DEG C of backflow 0.5 ~ 3h, be cooled to 0 ~ 30 DEG C and leave standstill 1 ~ 5h crystallization, suction filtration, washing leaching cake, 40 ~ 80 DEG C of drying under reduced pressure obtain target compound.
Described organic solvent is one or more in methyl alcohol, ethanol, Virahol or methylene dichloride.
Described organic solvent is the ethanol of volumetric concentration 50 ~ 100% and/or the methyl alcohol of volumetric concentration 50 ~ 100%.
Described washing leaching cake adopts solid-liquid volume ratio 1:10 ~ 1:15 anhydrous methanol, dehydrated alcohol, 95% ethanol, 80% methyl alcohol or mixed methanol-ethanol solvent doubly to wash.
Preparation of the present invention is add pharmaceutically acceptable carrier in described gastrodin derivative crystal formation and auxiliary material is prepared into tablet, capsule, granule, lyophilized injectable powder and injection liquid.
Of the present inventionly be applied as the application of described gastrodin derivative crystal formation in preparation treatment central nervous system disease medicine.
Embodiment 1
Get gastrodin derivative and treat highly finished product 100g, add 95% ethanol of 1L, at 70 DEG C of oil bath reflux 2h.Naturally cool to room temperature, leave standstill at 2 DEG C of ice-water baths and within 2 hours, make abundant crystallization, suction filtration, washing leaching cake, 60 DEG C of drying under reduced pressure, obtain the gastrodin derivative crystal 80g process for refining rate of recovery 80%, purity 99.21%.
Embodiment 2
Get gastrodin derivative and treat highly finished product 70g, add the ethanol solution of 1.5L, at 80 DEG C of oil bath reflux 1.5h.Naturally cool to room temperature, leave standstill and within 5 hours, make abundant crystallization, suction filtration, washing leaching cake, 60 DEG C of drying under reduced pressure, obtain the gastrodin derivative crystal 63g process for refining rate of recovery 90%, purity 99.25%.
Embodiment 3
Get gastrodin derivative and treat highly finished product 150g, add the absolute methanol solution of 2L, at 90 DEG C of oil bath reflux 1.5h.Naturally cool to room temperature, rest in 2 DEG C of frozen water and cool 2h crystallization, suction filtration, washing leaching cake, 60 DEG C of drying under reduced pressure, obtain the gastrodin derivative crystal 125g process for refining rate of recovery 83%, purity 99.06%.
Embodiment 4
Get gastrodin derivative and treat highly finished product 100g, add the aqueous ethanolic solution of 80% of 1.5L, at 60 DEG C of oil bath reflux 3h.Naturally cool to room temperature, leave standstill at 5 DEG C of ice-water baths and within 2 hours, make abundant crystallization, suction filtration, washing leaching cake, 50 DEG C of drying under reduced pressure, obtain the gastrodin derivative crystal 76g process for refining rate of recovery 76%, purity 99.68%.
Embodiment 5
Get gastrodin derivative and treat highly finished product 100g, add the mixing solutions of 1L EtOH-MeOH (volume ratio 6:4), at 60 DEG C of oil bath reflux 3h.Naturally cool to room temperature, leave standstill at 2 DEG C of ice-water baths and within 2 hours, make abundant crystallization, suction filtration, washing leaching cake, 60 DEG C of drying under reduced pressure, obtain gastrodin derivative crystal 84g.The process for refining rate of recovery 84%, purity 99.25%.
Embodiment 6
Get gastrodin derivative and treat highly finished product 100g, add the methanol aqueous solution of 80% of 1.5L, at 85 DEG C of oil bath reflux 1h.Naturally cool to room temperature, leave standstill at 1 DEG C of ice-water bath and within 1 hour, make abundant crystallization, suction filtration, washing leaching cake, 60 DEG C of drying under reduced pressure, collecting by filtration crystal, dry, obtain the gastrodin derivative crystal 74g process for refining rate of recovery 74%, purity 99.26%.
Embodiment 7
Add pharmaceutically acceptable auxiliary material in gastrodin derivative crystal prepared by Example 1 and make tablet.
Embodiment 8
Add pharmaceutically acceptable auxiliary material in gastrodin derivative crystal prepared by Example 3 and make capsule.
Embodiment 9
Add pharmaceutically acceptable auxiliary material in gastrodin derivative crystal prepared by Example 4 and make granule.
Embodiment 10
Add pharmaceutically acceptable auxiliary material in gastrodin derivative crystal prepared by Example 5 and make lyophilized injectable powder.
Embodiment 11
Add pharmaceutically acceptable auxiliary material in gastrodin derivative crystal prepared by Example 6 and make injection.
Embodiment 12
The method for detecting purity of the gastrodin derivative in gastrodin derivative crystallization of the present invention:
Use instrument is Waters e2695 high performance liquid chromatograph (chromatographic column is LunaC18 250 × 4.6mm for 2489 UV-detector, Empower3 chem workstation).
Be weighting agent with 18 silane group silica gel, take acetonitrile as mobile phase A, 0.1% phosphoric acid water mixing solutions is Mobile phase B, gradient elution, and determined wavelength is 220nm, and number of theoretical plate is calculated as 5000 by Gastrodine derivative peak.
Embodiment 1,2,3,4,5,6 sample getting gastrodin derivative product adds water dissolution respectively and dilution obtains concentration is that the solution of 0.5mg/ml is as need testing solution, measure described need testing solution 10 μ l injection liquid chromatography, record color atlas, as shown in figs. 1 to 6, stratographic analysis result is as following table:
The stratographic analysis result of gastrodin derivative test soln
| Peak is numbered | Retention time (min) | Area | Area percentage (%) | Peak heights |
| 1 | 9.429 | 24280363 | 99.68 | 3135257 |
Usable floor area normalization method, namely obtains the purity of described trial-product by the ratio calculating the main peak peak area in described test trial-product.The result of test sample is embodiment 1 by dry product calculating gastrodin derivative purity is 99.21%, and embodiment 2 is 99.25, and embodiment 3 is 99.06, and embodiment 4 is 99.68, and embodiment 5 is 99.25, and embodiment 6 is 99.26.
Embodiment 13
The X-ray diffraction check analysis method of gastrodin derivative crystallization of the present invention:
Detecting instrument: sharp shadow (Empyrean) X-ray diffractometer.
Testing conditions: Cu target Ka
1ray, voltage 40kV, electric current, 40mA, divergent slit 1/32 °, antiscatter slits 1/16 °, antiscatter slits 7.5mm, 2 θ scopes 3 °-50 °, step-length 0.02 °, often walks residence time 40s.
Detect foundation: turn target multiple crystal X-ray diffraction method general rule JY/T009-1996.
The crystallization of gastrodin derivative described in the present invention uses Cu-K α 1 radiation, and as shown in Figure 1, its spectral signature is as follows for the x-ray powder diffraction represented with 2 θ angles:
| 2θ | d-spacing | I/I0% |
| 4.7341 | 18.66618 | 100.00 |
| 8.1296 | 10.87598 | 17.61 |
| 9.8692 | 8.96241 | 20.78 |
| 14.8711 | 5.95729 | 10.45 |
| 17.8254 | 4.97605 | 54.01 |
| 19.6469 | 4.51864 | 82.06 |
| 22.5739 | 3.93893 | 61.72 |
| 23.4154 | 3.79610 | 32.45 |
| 24.4372 | 3.63963 | 18.21 |
| 27.7034 | 3.22016 | 11.23 |
Embodiment 14
Means of differential scanning calorimetry (DSC) analytical procedure of gastrodin derivative crystallization of the present invention:
Detecting instrument: German NETZSCH company DSC204F1 differential scanning calorimeter.
Testing conditions: atmosphere: nitrogen (purity: >=99.99%), 20mL/min; Scanning sequence: be warming up to 200 DEG C with 10 DEG C/min from room temperature, record heating curve.
Detect foundation: heat analysis method general rule JY/T014-1996.
The DSC endothermic transition temperature of gastrodin derivative crystallization of the present invention is 143-156 DEG C, fusion and decomposition temperature 350-352 DEG C.
Embodiment 15
Gastrodin derivative crystallization weight-differential thermal (TGA) analytical procedure of the present invention:
Detecting instrument: German NETZSCH company's T G209F1 thermogravimetric analyzer.
Testing conditions: atmosphere: air, 20mL/min;
Scanning sequence: room temperature ~ 350 DEG C, temperature rise rate: 5 DEG C/min.
Detect foundation: heat analysis method general rule JY/T014-1996.
Result shows that gastrodin derivative crystalline fusion decomposition temperature of the present invention is at 350-352 DEG C, and with the mass attenuation of 59%-62%.
Claims (10)
1. a gastrodin derivative crystal formation, is characterized in that the powder x-ray diffraction collection of illustrative plates of described gastrodin derivative crystal formation is 4.7 ± 0.2,8.1 ± 0.2,9.9 ± 0.2,17.8 ± 0.2,19.6 ± 0.2,2 θ ± 0.2 DEG C reflection angle place indicating characteristic the diffraction peak of 22.6 ± 0.2,23.4 ± 0.2.
2. gastrodin derivative crystal formation according to claim 1, is characterized in that the powder x-ray diffraction 2 θ position 4.7341 place diffraction peak intensity of described gastrodin derivative crystal formation is 100%.
3. gastrodin derivative crystal formation according to claim 1, is characterized in that the dsc analysis endothermic transition temperature of described gastrodin derivative crystal formation is 143 ~ 156 DEG C.
4. gastrodin derivative crystal formation according to claim 1, is characterized in that the fusion and decomposition temperature of described gastrodin derivative crystal formation is 350 ~ 352 DEG C.
5. gastrodin derivative crystal formation according to claim 1, it is characterized in that described gastrodin derivative crystal formation TGA analyze fusion and decomposition time with 59 ~ 62% mass attenuation.
6. the preparation method of the arbitrary described gastrodin derivative crystal formation of claim 1 ~ 5, it is characterized in that to add mass volume ratio in gastrodin derivative crude product and to count with g/ml the organic solvent of 1:10 ~ 200, in 60 ~ 90 DEG C of backflow 0.5 ~ 3h, be cooled to 0 ~ 30 DEG C and leave standstill 1 ~ 5h crystallization, suction filtration, washing leaching cake, 40 ~ 80 DEG C of drying under reduced pressure obtain target compound.
7. preparation method according to claim 6, is characterized in that described organic solvent is one or more in methyl alcohol, ethanol, Virahol or methylene dichloride.
8. the preparation method according to claim 6 or 7, is characterized in that described organic solvent is the ethanol of volumetric concentration 50 ~ 100% and/or the methyl alcohol of volumetric concentration 50 ~ 100%.
9. a preparation for the arbitrary described gastrodin derivative crystal formation of claim 1 ~ 5, is characterized in that adding pharmaceutically acceptable carrier in described gastrodin derivative crystal formation and auxiliary material is prepared into tablet, capsule, granule, lyophilized injectable powder and injection liquid.
10. an application for the arbitrary described gastrodin derivative crystal formation of claim 1 ~ 5, is characterized in that the application of described gastrodin derivative crystal formation in preparation treatment central nervous system disease medicine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056853A (en) * | 2017-04-26 | 2017-08-18 | 昆药集团股份有限公司 | A kind of Gastrodin compound and preparation method thereof, preparation and application |
| CN107383124A (en) * | 2017-08-15 | 2017-11-24 | 昆药集团股份有限公司 | A kind of gastrodin derivative and preparation method thereof, preparation and application |
| CN114573649A (en) * | 2020-11-30 | 2022-06-03 | 昆药集团股份有限公司 | High-purity gastrodin crystal and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006176420A (en) * | 2004-12-21 | 2006-07-06 | Univ Of Tokushima | Tyrosinase activity inhibitor, method for producing the same and use |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006176420A (en) * | 2004-12-21 | 2006-07-06 | Univ Of Tokushima | Tyrosinase activity inhibitor, method for producing the same and use |
Non-Patent Citations (1)
| Title |
|---|
| 王亚男等: "天麻水提取物的化学成分研究", 《中国中药杂志》, vol. 37, no. 12, 30 June 2012 (2012-06-30), pages 1775 - 1781 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056853A (en) * | 2017-04-26 | 2017-08-18 | 昆药集团股份有限公司 | A kind of Gastrodin compound and preparation method thereof, preparation and application |
| CN107056853B (en) * | 2017-04-26 | 2020-04-10 | 昆药集团股份有限公司 | Gastrodin compound and preparation method, preparation and application thereof |
| CN107383124A (en) * | 2017-08-15 | 2017-11-24 | 昆药集团股份有限公司 | A kind of gastrodin derivative and preparation method thereof, preparation and application |
| CN114573649A (en) * | 2020-11-30 | 2022-06-03 | 昆药集团股份有限公司 | High-purity gastrodin crystal and preparation method and application thereof |
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Address after: 650106 Kunming science and Technology Industrial Development Zone, Yunnan Province Road No. 166 Applicant after: Kun Yao Group Plc Address before: 650106 Kunming science and Technology Industrial Development Zone, Yunnan Province Road No. 166 Applicant before: Kunming Pharmaceutical Industry Group Corp., Ltd. |
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Free format text: CORRECT: APPLICANT; FROM: KUNMING PHARMACEUTICAL INDUSTRY GROUP CORP., LTD. TO: KPC CO., LTD. |
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