CN107056853A - A kind of Gastrodin compound and preparation method thereof, preparation and application - Google Patents
A kind of Gastrodin compound and preparation method thereof, preparation and application Download PDFInfo
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- CN107056853A CN107056853A CN201710282994.4A CN201710282994A CN107056853A CN 107056853 A CN107056853 A CN 107056853A CN 201710282994 A CN201710282994 A CN 201710282994A CN 107056853 A CN107056853 A CN 107056853A
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- gastrodin
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/02—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of urea, its salts, complexes or addition compounds
- C07C273/14—Separation; Purification; Stabilisation; Use of additives
- C07C273/16—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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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- 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 Gastrodin compound and preparation method thereof, preparation and application.Described Gastrodin compound is a kind of formula（Ⅰ）The eutectic of compound and urea, formula（Ⅰ）Structural formula of compound is as follows：Preparation method is to react Gastrodin and urea in organic solvent system to prepare, and described organic solvent is the one or more in alcohols, ketone, alkyl nitrile and cyclic ethers class.Preparation prepares powder, granule, tablet, capsule and pill to add pharmaceutically acceptable auxiliary material in described Gastrodin compound.Using the application for described Gastrodin compound in preventing/treating cardiovascular and cerebrovascular diseases medicament is prepared.The Gastrodin and the eutectic solubility of urea that the present invention is provided are high, are conducive to improving drug absorption efficiency, improve the bioavilability of medicine, the raising for curative effect of medication and security is significant.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of Gastrodin compound and preparation method thereof, preparation are with answering
With.
Background technology
Gastrodin：English name is Gastrodin, CAS：62499-27-8, molecular formula：C13H18O7, molecular weight：
286.28, English language Chemical title：4- (hydroxymethyl) phenyl- β-D-Glucopyranoside, Chinese chemical name
Claim：4- hydroxymethyl phenyl-β-D- glucopyanosides.
Gastrodin extracts for the dry root block of orchid rhizoma Gastrodiae, and the places of origin of raw materials is Yunnan.Gastrodin has preferable town
Neurasthenia, insomnia, headache syndromes are had mitigation by quiet and soporific function.Gastrodia elata can treat dizziness of having a headache, limbs fiber crops
Wood, tic of fainting from fear.Clinical practice：Treat vertebral-basilar artery insufficiency；Treat vestibular neuronitis；Treat vertigo.
Clinically had using the common formulations of Gastrodin：Parenteral solution, powder pin, tablet, capsule etc., because Gastrodin is steady
Qualitative poor, to solve this problem, prior art typically uses a large amount of auxiliary materials, such as：Stabilizer, complexing agent, buffer salt, greatly
The addition of amount auxiliary material adds the security risk that Gastrodin is used, the prior art also having, such as：Chinese patent application
CN102964403A discloses a kind of Gastrodin compound, and the Gastrodin compound is crystal, and the Gastrodin compound is used
The X- ray powder diffractions that Cu-K alpha ray measurements are obtained 2 θ be 9.4 °, 9.9 °, 15.1 °, 15.6 °, 18.4 °,
Characteristic peak is shown at 22.5 °, 25.6 °, 27.9 °, 28.6 °, 29.1 °, 30.5 °, 30.9 °, 31.5 °, 32.6 °, 32.7 °.Should
Gastrodin compound has higher lattice energy, and stability is good, substantially increases drug safety.In addition, present invention also offers
The preparation method of the Gastrodin compound, and the pharmaceutical composition containing the rhizoma Gastrodiae cellulose crystal.Gastrodin in this application
Preparation needs microwave and magnetic field to control, and technique is extremely complex, and we are in experiments it is found that Gastrodin prepared by this application
Compound pH values are unstable, and relevant material is also unstable, and increase is very fast, adds the use security risk of Gastrodin.Thus may be used
To find out, prior art is not all fully solved the problem of Gastrodin is stabilized, and limits the Clinical practice of Gastrodin.Cause
This, develops a kind of product that can solve above-mentioned technical problem and is very important.
The content of the invention
The first object of the present invention is to provide a kind of Gastrodin compound；Second purpose is the Gastrodin described in offer
The preparation method of compound；3rd purpose is the preparation of the Gastrodin compound described in offer；4th purpose is to provide institute
The application for the Gastrodin compound stated.
The first object of the present invention is achieved in that described Gastrodin compound is a kind of formula（Ⅰ）Compound and urine
The eutectic of element, formula（Ⅰ）Structural formula of compound is as follows：
The second object of the present invention is achieved in that to react Gastrodin and urea in organic solvent system and is prepared into
Arrive, described organic solvent is the one or more in alcohols, ketone, alkyl nitrile and cyclic ethers class.
The third object of the present invention be achieved in that in described Gastrodin compound add it is pharmaceutically acceptable auxiliary
Material prepares powder, granule, tablet, capsule and pill.
The fourth object of the present invention is achieved in that described Gastrodin compound is preparing preventing/treating heart and brain blood
Application in pipe disease medicament.
The present inventor have developed a kind of eutectic of Gastrodin, solve existing stability of crystal form difference and dissolving
Property difference problem.Eutectic is the crystal containing two kinds of molecules in same crystal structure.Acting as between two kinds of molecules is non-covalent
Key (such as hydrogen bond, π-pi-conjugated, halogen key etc.).The formation of pharmaceutical co-crystals will not destroy the covalent bond of active constituents of medicine, and organic
The crystal property and physico-chemical property of medicine in itself can be improved, such as bioavilability, stability and technique exploitability etc. turn into
The new selection of one of pharmaceutical solid preparation.
The eutectic stability that the present invention is provided is good, low in hygroscopicity, compared with prior art in crystal formation, solubility improve, have
Beneficial to the bioavilability for improving medicine, the raising for curative effect of medication and security is significant.
The Gastrodin and the eutectic stability of urea that the present invention is provided are good, and with preferable dissolubility, in preparation process
In without special drying condition, simplify preparation and the aftertreatment technology of medicine, it is easy to industrialized production.And in DIFFERENT WET
Moisture is held essentially constant under the conditions of degree, is easy to the long-term storage of medicine, with very strong economic value.
The Gastrodin and the eutectic solubility of urea that the present invention is provided are high, are conducive to improving drug absorption efficiency, improve medicine
The bioavilability of thing, the raising for curative effect of medication and security is significant.
Brief description of the drawings
Fig. 1 is the XRPD schematic diagrames of Gastrodin compound of the present invention；
Fig. 2 is DSC the and TGA schematic diagrames of Gastrodin compound of the present invention；
Fig. 3 is Gastrodin compound of the present invention1H NMR schematic diagrames；
Fig. 4 is crystal formation change schematic diagram of the Gastrodin compound of the present invention in humidity 25 ~ 60%；
Fig. 5 is crystal formation change schematic diagram of the Gastrodin compound of the present invention in humidity 40 ~ 75%.
Embodiment
With reference to embodiment and accompanying drawing, the present invention is further illustrated, but the present invention is not subject in any way
Limitation, based on present invention teach that any conversion or replacement made, belong to protection scope of the present invention.
Gastrodin compound of the present invention is a kind of formula（Ⅰ）The eutectic of compound and urea, formula（Ⅰ）Compound structure
Formula is as follows：
The structural formula of described Gastrodin compound is as follows：
The X-ray powder diffraction figure of described Gastrodin compound is the o of 8.7o ± 0.2, the o of 22.3 o ± 0.2,24.3 in 2 θ values
There is characteristic peak at the o of o ± 0.2.
The X-ray powder diffraction figure of described Gastrodin compound is the o of 13.1 o ± 0.2,17.5 o ± 0.2 in 2 θ values
O, the o of 22.2 o ± 0.2, there is characteristic peak at the o of 16.4 o ± 0.2.
The X-ray powder diffraction figure of described Gastrodin compound is the o of 8.4 o ± 0.2,18.8 o ± 0.2 in 2 θ values
O, the o of 22.0 o ± 0.2, there is characteristic peak at the o of 27.1 o ± 0.2.
Described Gastrodin compound is heated to 80 DEG C and nearby starts endothermic peak occur.
When described Gastrodin compound is heated to 110 DEG C, with about 1.36% weight loss gradient.
The preparation method of Gastrodin compound of the present invention, be by Gastrodin and urea in organic solvent system it is anti-
It should prepare, described organic solvent is the one or more in alcohols, ketone, alkyl nitrile and cyclic ethers class.
The quality proportioning of Gastrodin and urea is 4 ~ 5:1.
Described alcohols is ethanol；Described ketone is acetone.
The preparation of Gastrodin compound of the present invention is pharmaceutically acceptable to be added in described Gastrodin compound
Auxiliary material prepare powder, granule, tablet, capsule and pill.
The application of Gastrodin compound of the present invention is that described Gastrodin compound is preparing preventing/treating heart and brain
Application in vascular diseases medicine.
So that case is embodied, the invention will be further described below：
In following embodiments, the condition that described test method is generally advised according to normal condition or manufacturer is implemented；
Used abbreviation is explained as follows in the present invention：
XRPD：X-ray powder diffraction
DSC：Differential scanning calorimetric analysis
TGA：Thermogravimetric analysis
1H NMR ：Liquid nucleus magnetic hydrogen spectrum
X-ray powder diffraction figure of the present invention is gathered on Panalytical Empyrean x-ray powder diffraction instruments.
The method parameter of X-ray powder diffraction of the present invention is as follows：
X ray reflection parameter：Cu,Kα
Kα2：1.540598； Kα1：1.544426
The intensities of K α 2/K α 1：0.50
Voltage：45 KVs (kV)
Electric current：40 milliamperes (mA)
Scanning range：From 3.0 to 40.0 degree
Differential scanning calorimetric analysis (DSC) figure of the present invention gathers differential scanning amounts of the present invention on TA Q200
The method parameter of heat analysis (DSC) is as follows：
Sweep speed：10℃/min；
Protective gas：Nitrogen.
Thermogravimetric analysis (TGA) figure of the present invention is gathered on TA Q5000.Thermogravimetric analysis (TGA) of the present invention
Method parameter it is as follows：
Sweep speed：10℃/min；
Protective gas：Nitrogen.
Embodiment 1
The preparation of Gastrodin and urea cocrystalization compound：
2.86g Gastrodins are dissolved in 20mL ethanol, 0.6g urea is added, is heated to after 60 DEG C, 60min is stirred at 60 DEG C,
Then 5 DEG C, after reaction terminates are cooled to, filtering, the solid of gained is washed with ethanol, dried, collect solid.After testing, this reality
It is Gastrodin and urea cocrystalization compound to apply the solid that example obtains, its XRPD figures such as Fig. 1, its DSC figures such as Fig. 2, and its TGA figures are as schemed
2, its 1H NMR figure such as Fig. 3.
Embodiment 2
The preparation of Gastrodin and urea cocrystalization compound：
2.86g Gastrodin is dissolved in 20mL ethanol, is added 0.6g urea, is heated to after 60 DEG C, is stirred at 60 DEG C
60min, is then cooled to 5 DEG C, reaction terminates the rear alcohol solvent that volatilizees naturally, the solid of gained is washed with ethanol, dried.Through inspection
Survey, it is consistent with the gained crystal formation of embodiment 1 that the present embodiment obtains solid.
Embodiment 3
The preparation of Gastrodin and urea cocrystalization compound：
2.86g Gastrodins are dissolved in 20mL acetone, 0.6g urea is added, is heated to after 60 DEG C, 60min is stirred at 60 DEG C,
Then 5 DEG C, after reaction terminates are cooled to, filtering, the solids washed with acetone of gained is dried, and collects solid.After testing, this reality
Applying example, to obtain solid consistent with the gained crystal formation of embodiment 1.
Embodiment 4
The Gastrodin prepared with the embodiment of the present invention 1 and crystal formation in urea cocrystalization compound and patent CN102964403A are molten
Solution degree comparative study：
The Gastrodin that the embodiment of the present invention 1 is prepared and crystalline substance in urea cocrystalization compound crystal formation and patent CN102964403A
Type uses pH1.8 SGF (simulation simulated gastric fluid), pH6.5 FaSSIF (simulated intestinal fluid under fasted conditions) to be configured to saturation respectively
Solution, determines the content of sample in saturated solution after 1 hour and 4 hours by high performance liquid chromatography (HPLC) method.It is real
Test result as shown in the table.
It can be seen that and placed in SGF after 1 hour by above-mentioned comparing result, the embodiment of the present invention 1 after 4 hours
The Gastrodin prepared is with urea cocrystalization compound crystal formation compared with patent CN102964403A crystal formations, and solubility is higher；
The Gastrodin and urea cocrystalization compound crystal formation solubility that the embodiment of the present invention 1 is prepared after being placed 4 hours in FaSSIF are more
It is high.
Embodiment 5
It is that the Gastrodin that embodiment 2 and embodiment 3 are prepared is tested with urea cocrystalization compound respectively, method is while reality
Example 4 is applied, as a result shows that Gastrodin of the present invention is high with urea cocrystalization compound solubility.
Embodiment 6
The stability study of Gastrodin and urea cocrystalization compound：
Gastrodin made from the embodiment of the present invention 1 is taken to be positioned over 25 DEG C/60%RH with two parts of sample openings of urea cocrystalization compound
Under the conditions of (relative humidity), 40 DEG C/75%RH, XRPD is surveyed in sampling after 30 days.The experimental results are shown inthe following table.
As a result show, Gastrodin of the invention and urea cocrystalization compound are in 25 DEG C/60%RH, two kinds of 40 DEG C/75%RH
Under the conditions of place 30 days, crystal formation does not change.
The explanation of above example is only intended to the method and its core concept for helping to understand the present invention.It should be pointed out that pair
, under the premise without departing from the principles of the invention, can also be to present invention progress for those skilled in the art
Some improvement and modification, these are improved and modification is also fallen into the protection domain of the claims in the present invention.
Claims (10)
1. a kind of Gastrodin compound, it is characterised in that described Gastrodin compound is a kind of formula（Ⅰ）Compound and urea
Eutectic, formula（Ⅰ）Structural formula of compound is as follows：
。
2. Gastrodin compound according to claim 1, it is characterised in that the structural formula of described Gastrodin compound is such as
Shown in lower：
。
3. Gastrodin compound according to claim 1 or 2, it is characterised in that the X-ray of described Gastrodin compound
Powder diagram is the o of 8.7o ± 0.2, the o of 22.3 o ± 0.2, the o of 24.3 o ± 0.2 places with characteristic peak in 2 θ values.
4. Gastrodin compound according to claim 3, it is characterised in that the x-ray powder of described Gastrodin compound
It is special that diffraction pattern is that the o of 13.1 o ± 0.2, the o of 17.5 o ± 0.2, the o of 22.2 o ± 0.2, the o of 16.4 o ± 0.2 places have in 2 θ values
Levy peak.
5. Gastrodin compound according to claim 3, it is characterised in that the x-ray powder of described Gastrodin compound
It is special that diffraction pattern is that the o of 8.4 o ± 0.2, the o of 18.8 o ± 0.2, the o of 22.0 o ± 0.2, the o of 27.1 o ± 0.2 places have in 2 θ values
Levy peak.
6. a kind of preparation method of any described Gastrodin compound of claim 1 ~ 5, it is characterised in that be by Gastrodin and
Urea reacts in organic solvent system to be prepared, and described organic solvent is in alcohols, ketone, alkyl nitrile and cyclic ethers class
It is one or more.
7. the preparation method of Gastrodin compound according to claim 6, it is characterised in that the quality of Gastrodin and urea
Match as 4 ~ 5:1.
8. the preparation method of Gastrodin compound according to claim 6, it is characterised in that described alcohols is ethanol；Institute
The ketone stated is acetone.
9. a kind of preparation of any described Gastrodin compound of claim 1 ~ 5, it is characterised in that described Gastrodin chemical combination
Pharmaceutically acceptable auxiliary material is added in thing and prepares powder, granule, tablet, capsule and pill.
10. a kind of application of any described Gastrodin compound of claim 1 ~ 5, it is characterised in that described Gastrodin chemical combination
Application of the thing in preventing/treating cardiovascular and cerebrovascular diseases medicament is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710282994.4A CN107056853B (en) | 2017-04-26 | 2017-04-26 | Gastrodin compound and preparation method, preparation and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710282994.4A CN107056853B (en) | 2017-04-26 | 2017-04-26 | Gastrodin compound and preparation method, preparation and application thereof |
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| CN107056853A true CN107056853A (en) | 2017-08-18 |
| CN107056853B CN107056853B (en) | 2020-04-10 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964403A (en) * | 2012-12-03 | 2013-03-13 | 罗军 | Gastrodin compound and medicine composition thereof |
| CN103788148A (en) * | 2014-02-13 | 2014-05-14 | 悦康药业集团有限公司 | Gastrodin compound and preparation thereof |
| CN104447904A (en) * | 2014-08-04 | 2015-03-25 | 昆明制药集团股份有限公司 | Stable gastrodin crystal with high bioavailability for oral administration as well as preparation method, preparation and application thereof |
| CN104744530A (en) * | 2015-01-19 | 2015-07-01 | 昆明制药集团股份有限公司 | Gastrodia elata derivative crystal form as well as preparation method, preparation and application thereof |
| CN105524127A (en) * | 2015-12-18 | 2016-04-27 | 昆药集团股份有限公司 | Gastrodin compound and preparation thereof |
-
2017
- 2017-04-26 CN CN201710282994.4A patent/CN107056853B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964403A (en) * | 2012-12-03 | 2013-03-13 | 罗军 | Gastrodin compound and medicine composition thereof |
| CN103788148A (en) * | 2014-02-13 | 2014-05-14 | 悦康药业集团有限公司 | Gastrodin compound and preparation thereof |
| CN104447904A (en) * | 2014-08-04 | 2015-03-25 | 昆明制药集团股份有限公司 | Stable gastrodin crystal with high bioavailability for oral administration as well as preparation method, preparation and application thereof |
| CN104744530A (en) * | 2015-01-19 | 2015-07-01 | 昆明制药集团股份有限公司 | Gastrodia elata derivative crystal form as well as preparation method, preparation and application thereof |
| CN105524127A (en) * | 2015-12-18 | 2016-04-27 | 昆药集团股份有限公司 | Gastrodin compound and preparation thereof |
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| CN107056853B (en) | 2020-04-10 |
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Effective date of registration: 20210804 Address after: No. 166, Keyi Road, national high tech Development Zone, Wuhua District, Kunming, Yunnan 650106 Patentee after: Kunming Pharmaceutical Corp. Patentee after: Shanghai kunheng Medical Technology Co.,Ltd. Address before: 650106 No. 166, medical Road, hi tech Industrial Development Zone, Yunnan, Kunming Patentee before: Kunming Pharmaceutical Corp. |
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