CN107778187A - A kind of dezocine crystal formation A and preparation method thereof - Google Patents
A kind of dezocine crystal formation A and preparation method thereof Download PDFInfo
- Publication number
- CN107778187A CN107778187A CN201610749837.5A CN201610749837A CN107778187A CN 107778187 A CN107778187 A CN 107778187A CN 201610749837 A CN201610749837 A CN 201610749837A CN 107778187 A CN107778187 A CN 107778187A
- Authority
- CN
- China
- Prior art keywords
- dezocine
- crystal formation
- ethyl alcohol
- absolute ethyl
- ray powder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
- C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of dezocine (Dezocine) crystal formation A, it is characterised in that is about in the θ of angle of reflection 2 by the generation of X ray powder diffractions:6.478 ± 0.2,9.110 ± 0.2,10.254 ± 0.2,12.063 ± 0.2,13.147 ± 0.2,13.986 ± 0.2,14.664 ± 0.2,16.765 ± 0.2,19.026 ± 0.2,21.817 ± 0.2,23.017 ± 0.2.
Description
Technical field：
The present invention relates to medicinal chemistry arts, and in particular to a kind of dezocine crystal formation A and preparation method thereof.
Background technology：
Its chemical name of dezocine is:(-)-[5R- (5 α, 11 α, 13S*)] -13- amino -5,6,7,8,9,10,11,12-
Octahydro -5- methyl -5,11- methylene benzo cyclodecene -3- phenol.CAS：53648-55-8.
Structural formula is as follows：
Dezocine belongs to a kind of typical opium alkaloids bases antalgesic, is developed by Astra companies of Sweden.Such medicine leads to
Cross exciting opiate receptor and play a role.Dezocine analgesic activity is better than pentazocine, is kappa receptor activator, and μ acceptors resist
Tie agent.Dezocine is additive small, and side effect is slight, better tolerance.Suitable for Post operation it is medium to severe pain, internal organ angina and
The pain of patient with advanced cancer.At present, the injection of dezocine lists at home.
A kind of preparation method of dezocine is described in Chinese patent CN 102503840B, wherein refined dezocine be
Mixed solution (the absolute ethyl alcohol of alcohol-water：Water=1:1, V:V, 25K/L) it is recrystallized to give.Obtained crystal formation is named as " brilliant
Type I ", as shown in Figure 1.
The content of the invention：
The present invention provides a kind of dezocine crystal formation A and preparation method thereof.
On the one hand, the present invention provides a kind of dezocine crystal formation A, the X-ray powder diffraction represented with the 2 θ ± 0.2 ° angles of diffraction
Spectrogram 6.478,9.110,10.254,12.063,13.147,13.986,14.664,16.765,19.026,21.817,
23.017 place shows characteristic peak.Further, the X-ray powder diffraction spectrogram that the dezocine crystal formation A 2 θ ± 0.2 ° angles of diffraction represent
Also 17.493,8.395,19.553,22.407,23.483,24.245,25.687,27.132,30.244,31.404,
Characteristic peak is shown at 33.727,35.860,37.599,38.827,39.870,46.149.Further, it is provided by the invention
Dezocine crystal formation A has X-ray powder diffraction figure substantially as shown in Figure 2.Wherein " ± 0.2 " measurement error to allow
Scope
Further, dezocine crystal formation A provided by the invention, its differential scanning calorimetery (DSC) is near 109.8 DEG C
Occur one and turn brilliant exothermic peak, 169.6 DEG C an endothermic peak occur in peak temperature, as shown in Figure 3.
Further, dezocine crystal formation A provided by the invention, its thermogravimetric analysis (TG), as shown in Figure 4.
Further, dezocine crystal formation A provided by the invention, its Raman spectrum (RM) analysis of spectra 3315.18,
2928.27,2849.76,2663.66,2528.81,2437.18,1628.54,1533.12,1452.40,1261.95,
955.31,783.95,576.43 ± 2cm-1There is characteristic absorption peak at place.Wherein " ± 2 " be the measurement error model allowed as shown in Figure 5
Enclose
On the other hand, dezocine crystal formation A provided by the invention preparation method, it is characterised in that method therefor is dissolving
The precipitation method, comprise the following steps：
1) dezocine sample is dissolved in absolute ethyl alcohol and is prepared into dezocine ethanol solution；The wherein dosage of absolute ethyl alcohol
20-30 times (ml/g) of dezocine is should be, more preferably should be 20-25 times (ml/g).
2) above-mentioned dezocine ethanol solution is poured into rapidly in a large amount of pure water, separate out a large amount of off-white colors precipitate to be formed it is outstanding
Turbid；The dosage of wherein described pure water should be more than 10 times (v/v) of absolute ethyl alcohol dosage.
3) above-mentioned suspension is stood, is filtered under diminished pressure, filter cake petroleum ether 2 times, recovery filter cake obtains in 60 DEG C of dryings
Crystal formation A target products.
The present invention relates to a kind of new crystal formation A of dezocine, the stability and dissolubility having had.The invention further relates to this
The preparation method of crystal formation：Dissolving precipitated method；Preparation method is simple, high income, and energy consumption is small.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction spectrogram of dezocine crystal formation I
Fig. 2 is dezocine crystal formation A of the present invention X-ray powder diffraction spectrogram
Fig. 3 is dezocine crystal formation A of the present invention differential scanning calorimetery (DSC) analysis chart
Fig. 4 is dezocine crystal formation A of the present invention thermogravimetric (TG) analysis chart
Fig. 5 is dezocine crystal formation A of the present invention Raman spectrum (RM) spectrogram
Fig. 6 is the X-ray powder diffraction spectrogram that dezocine crystal formation A of the present invention accelerates June
Embodiment：
The present invention, but the protection domain being not intended to limit the invention will be expanded on further by specific embodiment below.
Those skilled in the art can make improvement to preparation method and using instrument within the scope of the claims, and these improvement also should be regarded as
Protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
In following embodiments, unless otherwise indicated, described experimental method is generally built according to normal condition or manufacturer
The condition of view is implemented；Shown raw material, reagent can be obtained by way of commercially available purchase.
X-ray powder diffraction figure of the present invention gathers on Bruker D8Focus X-ray powder diffraction instrument.
The method parameter of X-ray powder diffraction of the present invention is as follows：
X-ray parameter：Cu/Kα
Voltage：40 KVs (kV)
Electric current：40 milliamperes (mA)
Scanning range：From 3.0 to 60 degree
Sampling step length：0.02 degree
Sample leg speed：0.5 second/step
Means of differential scanning calorimetry (DSC) analysis chart of the present invention is by the resistance to DSC 200F3 detections of speeding of Germany, temperature range
35~180 DEG C, heating rate 10K/min；Hole is pricked in aluminium crucible, sealing, and purge gass are nitrogen (60ml/min), and protection gas is nitrogen
(40ml/min)。
Thermogravimetric analysis (TG) of the present invention is by the resistance to TG 209F3 detections of speeding of Germany, and balance, temperature are kept at 25 DEG C
40~250 DEG C, heating rate 10K/min of scope, be open aluminium crucible, and purge gass are nitrogen (40ml/min), and protection gas is nitrogen
(20ml/min)。
Fourier's Raman spectrum (FT-RM) of the present invention is by Thermo SCIENTIFIC DXR SmartRaman light
Spectrometer detects.Sample is placed on quartz slide, Raman spectroscopy is gathered through quartz slide.
HPLC content measurings in the present invention：
Instrument：The liquid chromatographs of Agilent 1200
Foundation：Chinese Pharmacopoeia the 4th high performance liquid chromatography of general rule 0512 of version in 2015
Test condition：
Chromatographic column：Agilent XDB C18 posts (150*4.6mm, 5 μm)
Mobile phase A：0.025M potassium dihydrogen phosphates (containing 0.2% triethylamine)-acetonitrile (80:20)
Mobile phase B：Acetonitrile-water (80:20)
Diluent：Acetonitrile-water (80:20)
Detection wavelength：281nm
Column temperature：40℃
Flow velocity：1.2ml/min
Gradient condition：
Comparative example 1
The crystal formation I that " dezocine " prepares dezocine is refined according to Chinese patent CN 102503840B embodiments 1.Production
Thing proves the crystal formation I of dezocine through X-ray powder diffraction.As shown in Figure 1.
Embodiment 1
Dezocine sample 1.01g additions absolute ethyl alcohol 20ml is allowed to be completely dissolved；Above-mentioned solution is poured into rapidly 200ml
In pure water solution, a large amount of white solids separate out to form suspension；Suspension is stood, decompression filters, petroleum ether 2*50ml.Filter
Cake is in 60 DEG C of drying.Obtain product 0.98g, purity 99.75%.The product proves dezocine through X-ray powder diffraction
Crystal formation A.As shown in Figure 2.
Embodiment 2
Dezocine sample 1.01g additions absolute ethyl alcohol 25ml is allowed to be completely dissolved；Above-mentioned solution is poured into rapidly 300ml
In pure water solution, a large amount of white solids separate out to form suspension；Suspension is stood, decompression filters, petroleum ether 2*50ml.Filter
Cake is in 80 DEG C of drying.Obtain product 0.99g, purity 99.7%.The product proves dezocine through X-ray powder diffraction
Crystal formation A.
Embodiment 3
Dezocine sample 1.01g additions absolute ethyl alcohol 30ml is allowed to be completely dissolved；Above-mentioned solution is poured into rapidly 250ml
In pure water solution, a large amount of white solids separate out to form suspension；Suspension is stood, decompression filters, petroleum ether 2*50ml.Filter
Cake is in 70 DEG C of drying.Obtain product 0.985g, purity 99.8%.The product proves dezocine through X-ray powder diffraction
Crystal formation A.
Test example 1
The crystal formation I for the dezocine that comparative example 1 and embodiment 1 obtain, crystal formation A stability are investigated.
Carry out high humidity (RH 92%), high temperature (60 DEG C), illumination (4500 ± 500lx) respectively to dezocine crystal formation I, crystal formation A
Under the conditions of factors affecting stability experiment.PXRD detections are carried out respectively at 5 days, sampling in 10 days, and are carried out pair with the result of 0 day
According to, and HPLC assays are carried out, it the results are shown in Table 1.PXRD detections are carried out after accelerated test terminates within 6 months.
Two kinds of the dezocine crystal formation I of table 1., crystal formation A stability of crystal form influence factor experiments
Learnt from the data of table 1, crystal formation I, two kinds of crystal formations of crystal formation A crystal formation under high temperature, high humidity and illumination condition can
Keep stable well, and chemical property is stable, and content can reach more than 99.70.Other 6 months Acceleration studies, ground
It is consistent with primary data (see accompanying drawing 6) to help the x-ray diffraction pattern of pungent A crystal formations, also without crystal phenomenon occurs, shows the present invention
The crystal stability of offer is good, beneficial to the storage of preparation.
Embodiment 10:The dissolubility of A types crystal of the present invention and I type crystal contrasts
Take test sample appropriate, grind into powder, add pure water 100ml, it is strong every 5min under the conditions of 25 DEG C ± 2 DEG C
Shaking 30 seconds, observe the dissolving situation in 30min.The dissolubility pair of A types crystal of the present invention and I type crystal (prepared by comparative example 1)
Than the results are shown in Table 2.
The hydrochloric acid dezocine dissolubility test of table 2
The above results show that crystal formation A of the invention is similar to crystal formation I solubility, can meet pharmaceutical formulations demand.
Claims (8)
1. a kind of dezocine crystal formation A, it is characterised in that the X- that described dezocine crystal formation A is represented with the 2 θ ± 0.2 ° angles of diffraction is penetrated
Line powder diffractogram 6.478,9.110,10.254,12.063,13.147,13.986,14.664,16.765,19.026,
Characteristic peak is shown at 21.817,23.017.
2. dezocine crystal formation A according to claim 1, it is characterised in that described dezocine crystal formation A is spread out with 2 θ ± 0.2 °
The X-ray powder diffraction spectrogram that firing angle represents also 17.493,8.395,19.553,22.407,23.483,24.245,
Spy is shown at 25.687,27.132,30.244,31.404,33.727,35.860,37.599,38.827,39.870,46.149
Levy peak.
3. dezocine crystal formation A according to claim 1, it is characterised in that described crystal formation A X-ray powder diffraction spectrum
In figure as shown in Figure 2.
4. according to any described dezocine crystal formation A of claim 1-3, it is characterised in that described dezocine crystal formation A Raman
Displacement 3371.22,3046.35,2921.06,1626.07,1440.44,1295.65,1202.14,965.47,776.49,
663.82 541.67 ± 2cm-1Place shows characteristic peak.
5. according to any described dezocine crystal formation A of claim 1-4, it is characterised in that described crystal formation A Raman spectrum is such as
Shown in Fig. 5.
6. it can be prepared according to any described dezocine crystal formation A of claim 1-5 by dissolving precipitated method.
7. dissolving precipitated method according to claim 6, it is characterised in that comprise the following steps：
1) dezocine is dissolved in absolute ethyl alcohol and is prepared into dezocine ethanol solution；Wherein the dosage of absolute ethyl alcohol is dezocine
20-30 times (ml/g).
2) above-mentioned dezocine ethanol solution is poured into rapidly in pure water, separates out off-white color and precipitate to form suspension；
3) above-mentioned suspension is stood, is filtered under diminished pressure, petroleum ether, 60~80 DEG C of dryings of filter cake, obtains crystal formation A.
8. according to the method for claim 7, it is characterised in that the dosage of described absolute ethyl alcohol is preferably dezocine
20-25 times (ml/g).
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110719489.8A CN113429306A (en) | 2016-08-26 | 2016-08-26 | Dezocine crystal form A and preparation method thereof |
| CN201610749837.5A CN107778187A (en) | 2016-08-26 | 2016-08-26 | A kind of dezocine crystal formation A and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610749837.5A CN107778187A (en) | 2016-08-26 | 2016-08-26 | A kind of dezocine crystal formation A and preparation method thereof |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110719489.8A Division CN113429306A (en) | 2016-08-26 | 2016-08-26 | Dezocine crystal form A and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107778187A true CN107778187A (en) | 2018-03-09 |
Family
ID=61441695
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610749837.5A Pending CN107778187A (en) | 2016-08-26 | 2016-08-26 | A kind of dezocine crystal formation A and preparation method thereof |
| CN202110719489.8A Pending CN113429306A (en) | 2016-08-26 | 2016-08-26 | Dezocine crystal form A and preparation method thereof |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110719489.8A Pending CN113429306A (en) | 2016-08-26 | 2016-08-26 | Dezocine crystal form A and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN107778187A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107337609A (en) * | 2017-05-22 | 2017-11-10 | 扬子江药业集团有限公司 | A kind of dezocine crystal formation and preparation method thereof |
| CN113979875A (en) * | 2020-07-27 | 2022-01-28 | 扬子江药业集团有限公司 | Dezocine derivative crystal form A and preparation method and application thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3836670A (en) * | 1971-11-19 | 1974-09-17 | American Home Prod | Benzobicycloalkane amines for inducing analgesia |
| CN1514729A (en) * | 2001-06-05 | 2004-07-21 | ���ܿ���ϵͳ����˾ | Sustained-release analgesic compounds |
| CN101671269A (en) * | 2009-10-26 | 2010-03-17 | 扬子江药业集团有限公司 | Preparation method of substituted methylene benzocyclodecene ketoxime |
| CN102503840A (en) * | 2011-12-15 | 2012-06-20 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of dezocine |
| CN102573845A (en) * | 2009-04-02 | 2012-07-11 | 夏尔有限责任公司 | Novel dicarboxylic acid linked amino acid and peptide prodrugs of opioids and uses thereof |
| WO2014190271A2 (en) * | 2013-05-24 | 2014-11-27 | Alkermes Pharma Ireland Limted | Methods for treating depressive symptoms |
-
2016
- 2016-08-26 CN CN201610749837.5A patent/CN107778187A/en active Pending
- 2016-08-26 CN CN202110719489.8A patent/CN113429306A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3836670A (en) * | 1971-11-19 | 1974-09-17 | American Home Prod | Benzobicycloalkane amines for inducing analgesia |
| CN1514729A (en) * | 2001-06-05 | 2004-07-21 | ���ܿ���ϵͳ����˾ | Sustained-release analgesic compounds |
| CN102573845A (en) * | 2009-04-02 | 2012-07-11 | 夏尔有限责任公司 | Novel dicarboxylic acid linked amino acid and peptide prodrugs of opioids and uses thereof |
| CN101671269A (en) * | 2009-10-26 | 2010-03-17 | 扬子江药业集团有限公司 | Preparation method of substituted methylene benzocyclodecene ketoxime |
| CN102503840A (en) * | 2011-12-15 | 2012-06-20 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of dezocine |
| WO2014190271A2 (en) * | 2013-05-24 | 2014-11-27 | Alkermes Pharma Ireland Limted | Methods for treating depressive symptoms |
Non-Patent Citations (1)
| Title |
|---|
| 谢宗波，乐长高主编: "《有机化学实验操作与设计》", 30 November 2014 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107337609A (en) * | 2017-05-22 | 2017-11-10 | 扬子江药业集团有限公司 | A kind of dezocine crystal formation and preparation method thereof |
| WO2018214877A1 (en) * | 2017-05-22 | 2018-11-29 | 扬子江药业集团有限公司 | Crystal form of dezocine and preparation method therefor |
| CN111606816A (en) * | 2017-05-22 | 2020-09-01 | 扬子江药业集团有限公司 | Dezocine crystal form and preparation method thereof |
| US10947185B2 (en) | 2017-05-22 | 2021-03-16 | Yangtze River Pharmaceutical Group Co., Ltd. | Crystal form of dezocine and preparation method therefor |
| CN113979875A (en) * | 2020-07-27 | 2022-01-28 | 扬子江药业集团有限公司 | Dezocine derivative crystal form A and preparation method and application thereof |
| CN113979875B (en) * | 2020-07-27 | 2022-11-08 | 扬子江药业集团有限公司 | Dezocine derivative crystal form A and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113429306A (en) | 2021-09-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Cen et al. | Development of tacrine-bifendate conjugates with improved cholinesterase inhibitory and pro-cognitive efficacy and reduced hepatotoxicity | |
| Deng et al. | Preparation, crystal structures, and oral bioavailability of two cocrystals of emodin with berberine chloride | |
| CN107827724B (en) | Curcumin-2, 5-dihydroxybenzoic acid eutectic crystal and preparation method thereof | |
| Zhou et al. | Structure determination and in vitro/vivo study on carbamazepine-naringenin (1: 1) cocrystal | |
| CN107778187A (en) | A kind of dezocine crystal formation A and preparation method thereof | |
| Gong et al. | Structure, characterization, solubility and stability of podophyllotoxin polymorphs | |
| Liu et al. | Bergenin-isonicotinamide (1: 1) cocrystal with enhanced solubility and investigation of its solubility behavior | |
| Bothiraja et al. | Improved pharmaceutical properties of surface modified bioactive plumbagin crystals | |
| CN109400598B (en) | Eutectic crystal of berberine hydrochloride and lactic acid, preparation method and application thereof | |
| CN103044364B (en) | Amorphous crystalline substance of a kind of Cabazitaxel and preparation method thereof | |
| CN106317033B (en) | Silybin 23-substituted derivative and preparation method and application of injection thereof | |
| Zhang et al. | Insights into the properties of amygdalin solvatomorphs: X-ray structures, intermolecular interactions, and transformations | |
| CN109010348B (en) | Lacidipine-spironolactone co-amorphous solid dispersion and preparation thereof | |
| CN109675050A (en) | Using camptothecine as the conjugate and its preparation and application of the analog of parent nucleus and nonsteroidal anti-inflammatory drug | |
| CN106543105B (en) | A kind of cariprazine hydrochloride crystal form IV and preparation method thereof | |
| CN108863748B (en) | Curcumin eutectic crystal and preparation method thereof | |
| CN107935958B (en) | Valsartan puerarin sodium salt compound and preparation method thereof | |
| CN108794383B (en) | Eutectic of nifedipine and isonicotinamide | |
| CN109111419A (en) | 7,8- coumarin derivatives containing substituent group and its preparation method and application | |
| CN115124531A (en) | 4-azatryptanthrin aromatic thioether derivatives, and preparation method and application thereof | |
| CA2931291C (en) | Taxanes compounds, preparation method therefor, and uses thereof | |
| CN107235914A (en) | A kind of drug hydrate for the treatment of cancer and preparation method thereof | |
| CN108840794B (en) | Novel curcumin drug cocrystal and preparation method thereof | |
| CN114174264A (en) | Crystal form XI of varlitinib mesylate and preparation method thereof | |
| CN106957312B (en) | Raltitrexed hydrate crystal forms and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180309 |
|
| RJ01 | Rejection of invention patent application after publication |