CN109627234A - A kind of candesartan cilexetil crystal and preparation method thereof - Google Patents
A kind of candesartan cilexetil crystal and preparation method thereof Download PDFInfo
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- CN109627234A CN109627234A CN201910091330.9A CN201910091330A CN109627234A CN 109627234 A CN109627234 A CN 109627234A CN 201910091330 A CN201910091330 A CN 201910091330A CN 109627234 A CN109627234 A CN 109627234A
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- Prior art keywords
- candesartan cilexetil
- crystal
- cilexetil crystal
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- candesartan
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- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 229960004349 candesartan cilexetil Drugs 0.000 title claims abstract description 55
- 239000013078 crystal Substances 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 11
- 239000012046 mixed solvent Substances 0.000 claims abstract description 5
- 238000010521 absorption reaction Methods 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 238000001069 Raman spectroscopy Methods 0.000 claims description 5
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000002329 infrared spectrum Methods 0.000 claims description 3
- 238000001228 spectrum Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000000047 product Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000006837 decompression Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 238000001530 Raman microscopy Methods 0.000 description 1
- 238000001237 Raman spectrum Methods 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000012362 drug development process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of candesartan cilexetil crystal and preparation method thereof, the X-ray powder diffraction collection of the candesartan cilexetil crystal is 6.0 ± 0.2,7.1 ± 0.2,8.5 ± 0.2,9.8 ± 0.2,11.6 ± 0.2,11.9 ± 0.2,13.6 ± 0.2,14.2 ± 0.2,15.2 ± 0.2,16.3 ± 0.2,16.8 ± 0.2,18.0 ± 0.2,19.0 ± 0.2,19.6 ± 0.2,19.7 ± 0.2,21.2 ± 0.2,22.1 ± 0.2,23.3 ± 0.2,24.0 ± 0.2,24.4 ± 0.2,25.4 ± 0.2,25.9 ± 0.2,26.6 ± 0.2,27.1 in 2 θ of the angle of diffraction There is diffraction maximum at ± 0.2,29.4 ± 0.2,30.0 ± 0.2,30.7 ± 0.2,31.4 ± 0.2,32.8 ± 0.2,34.2 ± 0.2,34.5 ± 0.2,35.9 ± 0.2,36.5 ± 0.2,38.0 ± 0.2,41.3 ± 0.2,43.5 ± 0.2,44.4 ± 0.2,46.3 ± 0.2,48.2 ± 0.2.Candesartan cilexetil crystal of the present invention has the advantages that purity is high and preferably stability, solubility and crystallinity, and preparation method is realized by recrystallizing in the mixed solvent, and this method is simple, is suitable for industrialized production.
Description
Technical field
The present invention relates to drug crystallization technical fields, and in particular to a kind of candesartan cilexetil crystal and preparation method thereof.
Background technique
Since in physicochemical property, (such as solubility, stability, mobility, resists dissolution rate between same drug different crystal forms
Compressibility etc.) on have differences, and the physicochemical property of crystal form drug is related to the bioavilability of drug and clinical efficacy, therefore
The polymorphic of research solid drugs just becomes one of important research content very important in drug development process.
Candesartan Cilexetil, chemical name are (±) -1- [(cyclohexyloxy) carbonyl oxygroup] ethyl -2- ethyoxyl -1- [[2 ' -
(1H- tetrazole base -5- base) biphenyl -4- base] methyl] -1H- benzimidazole-7-carboxylate is a kind of highly selective vasotonia
Plain II receptor antagonist class antihypertensive, structural formula are as follows:
Candesartan cilexetil crystal disclosed in existing commercially available and patent (such as WO2004085426, CN100400536),
There is also certain defects in the performance indicators such as stability, solubility, crystallinity and production technology.Therefore, it is badly in need of searching out one
Kind is with performance indicators such as better stability, solubility, crystallinity, the candesartan cilexetil crystal being convenient for industrialized production, from
And improve the drug quality and clinical efficacy of candesartan Cilexetil.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the technological deficiency of background technique, it is brilliant to provide a kind of candesartan Cilexetil
Body and preparation method thereof.Candesartan cilexetil crystal of the present invention has purity is high and preferably stability, solubility and crystallinity etc.
Advantage, preparation method are realized by recrystallizing in the mixed solvent, and this method is simple, are suitable for industrialized production.
It is as follows that the present invention solves technical solution used by above-mentioned technical problem:
The X-ray powder diffraction collection of a kind of candesartan cilexetil crystal, the candesartan cilexetil crystal is in 2 θ of the angle of diffraction
6.0±0.2、7.1±0.2、8.5±0.2、9.8±0.2、11.6±0.2、11.9±0.2、13.6±0.2、14.2±0.2、
15.2±0.2、16.3±0.2、16.8±0.2、18.0±0.2、19.0±0.2、19.6±0.2、19.7±0.2、21.2±
0.2、22.1±0.2、23.3±0.2、24.0±0.2、24.4±0.2、25.4±0.2、25.9±0.2、26.6±0.2、
27.1±0.2、29.4±0.2、30.0±0.2、30.7±0.2、31.4±0.2、32.8±0.2、34.2±0.2、34.5±
0.2、35.9±O.2、36.5±0.2、38.0±0.2、41.3±0.2、43.5±0.2、44.4±0.2、46.3±0.2、
There is diffraction maximum at 48.2 ± 0.2.
Preferably, the candesartan cilexetil crystal has following X-ray powder diffraction collection:
。
It is highly preferred that the candesartan cilexetil crystal has X-ray powder diffraction collection substantially as shown in.
Preferably, the infrared spectroscopy of the candesartan cilexetil crystal is in 2992 ± 2cm-1、2938±2cm-1、2860±2cm-1、1756±2cm-1、1725±2cm-1、1616±2cm-1、1573±2cm-1、1551±2cm-1、1477±2cm-1、1465±
2cm-1、1437±2cm-1、1415±2cm-1、1387±2cm-1、1349±2cm-1、1312±2cm-1、1280±2cm-1、1241
±2cm-1、1214±2cm-1、1158±2cm-1、1111±2cm-1、1073±2cm-1、1032±2cm-1、1001±2cm-1、
987±2cm-1、938±2cm-1、911±2cm-1、889±2cm-1、873±2cm-1、763±2cm-1、751±2cm-1、693±
2cm-1There is absorption peak at place.
Preferably, the Raman spectrum of the candesartan cilexetil crystal is in 1710 ± 2cm-1、1598±2cm-1、1283±2cm-1There is absorption peak at place.
A kind of preparation method of candesartan cilexetil crystal includes the following steps: candesartan Cilexetil crude product being dissolved in volume ratio
For the in the mixed solvent of 10: 7~15 first benzol-cyclohexane;It is heated to reflux;It is placed at room temperature for crystallization;Recycle candesartan cilexetil crystal.
Compared with prior art, the beneficial effects of the present invention are:
Candesartan cilexetil crystal of the present invention has the advantages that purity is high and preferably stability, solubility and crystallinity,
Preparation method is realized by recrystallizing in the mixed solvent, and this method is simple, is suitable for industrialized production.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction figure of candesartan cilexetil crystal made from the embodiment of the present invention 1;
Fig. 2 is the high-efficient liquid phase chromatogram of candesartan cilexetil crystal made from the embodiment of the present invention 1;
Fig. 3 is the infrared spectrogram of candesartan cilexetil crystal made from the embodiment of the present invention 1;
Fig. 4 is the Raman spectrogram of candesartan cilexetil crystal made from the embodiment of the present invention 1.
Specific embodiment
In order to better understand the content of the present invention, it is described further combined with specific embodiments below with attached drawing.Ying Li
Solution, these embodiments are only used for that the present invention is further described, rather than limit the scope of the invention.In addition, it should also be understood that,
After having read content of the present invention, person skilled in art makes some nonessential changes or adjustment to the present invention,
Still fall within protection scope of the present invention.
Candesartan Cilexetil crude product described in Examples 1 to 3 can be amorphous substance or known any crystal form, such as commercial product
Or it is made using the preparation method as described in patent WO2004085426, CN100400536.
Embodiment 1
It weighs 1.0g candesartan Cilexetil crude product to set in a round bottom flask, the mixed of about 30ml first benzol-cyclohexane (10: 7) is added
Bonding solvent is heated to reflux to whole dissolutions, continues the 2h that flows back, left at room temperature over night crystallization, and decompression filters, and obtained solid room temperature is dry
Dry, weighing obtains 0.82g.
Embodiment 2
It weighs 1.0g candesartan Cilexetil crude product to set in a round bottom flask, the mixed of about 30ml first benzol-cyclohexane (10: 9) is added
Bonding solvent is heated to reflux to whole dissolutions, continues the 2h that flows back, left at room temperature over night crystallization, and decompression filters, and obtained solid room temperature is dry
Dry, weighing obtains 0.84g.
Embodiment 3
It weighs 1.0g candesartan Cilexetil crude product to set in a round bottom flask, the mixed of about 30ml first benzol-cyclohexane (10: 15) is added
Bonding solvent is heated to reflux to whole dissolutions, continues the 2h that flows back, left at room temperature over night crystallization, and decompression filters, and obtained solid room temperature is dry
Dry, weighing obtains 0.75g.
As a result:
1 crystal form is investigated
Candesartan cilexetil crystal sample, is measured using Powder X-ray Diffractometer made from Example 1, diffraction number
According to being shown in Table 1, map is shown in Fig. 1.
Instrument: D8-advance Powder X-ray Diffractometer
X-ray target: Cu
Power supply: 40kv/40mA
The angle of diffraction (2 θ) scanning range: 3 ° -80 °
Step-length: 0.02 °
Candesartan cilexetil crystal X-ray powder diffraction data made from 1 embodiment 1 of table
As seen from Figure 1, the X-ray powder diffraction figure of candesartan cilexetil crystal sample made from embodiment 1 is found after measured
It shows and is different from having diffraction maximum reported in the literature, show that this product is new crystal.
Meanwhile the peak type of this product diffraction maximum is sharp, shows that crystallinity is good.
2 purity detectings
Candesartan cilexetil crystal sample made from Example 1, is measured, chromatographic condition and preparation side using HPLC method
Method is as follows, and map is shown in Fig. 2.
Instrument: Agilent1260 high performance liquid chromatograph
Chromatographic condition:
Mobile phase: acetonitrile-glacial acetic acid-water (65: 1: 34)
Wavelength: 254nm
Chromatographic column: Venusil MP C18(5 μm, 4.6 × 250mm)
Test sample is prepared: candesartan cilexetil crystal sample 10mg made from embodiment 1 weighed, is placed in 50ml volumetric flask,
Scale is dissolved and is diluted to acetonitrile-water (3: 2), and precision measures 2ml, sets in 10ml volumetric flask, be diluted to quarter with above-mentioned solvent
Degree to get.
It uses area normalization method to measure candesartan cilexetil crystal sample purity made from embodiment 1 as 100%, shows this
Product purity is good.
3 solubility tests
Candesartan cilexetil crystal sample made from Example 1 is appropriate, finely ground, is placed in the 0.1mol/L of 25 DEG C of certain volumes
In hydrochloric acid solution, every strength shaking in 5 minutes 30 seconds, continues 30 minutes, supersaturated solution is made, centrifugation is surveyed using HPLC
Its fixed concentration to get.The solubility test of different candesartan cilexetil crystals the results are shown in Table 2.
The solubility test result of the different candesartan cilexetil crystals of table 2
The results show that this product solubility is more preferable, higher than the product of commercialized product and existing patent report.
4 other characteristic spectrums
4.1 infrared spectrum measurement
Candesartan cilexetil crystal sample made from Example 1, is measured, map is shown in Fig. 3 using KBr tabletting.
Instrument: 6700Thermo Fisher Nicole infrared spectrophotometer
Infrared spectrum measurement the results show that this product in 2992 ± 2cm-1、2938±2cm-1、2860±2cm-1、1756±
2cm-1、1725±2cm-1、1616±2cm-1、1573±2cm-1、1551±2cm-1、1477±2cm-1、1465±2cm-1、1437
±2cm-1、1415±2cm-1、1387±2cm-1、1349±2cm-1、1312±2cm-1、1280±2cm-1、1241±2cm-1、
1214±2cm-1、1158±2cm-1、1111±2cm-1、1073±2cm-1、1032±2cm-1、1001±2cm-1、987±2cm-1、938±2cm-1、911±2cm-1、889±2cm-1、873±2cm-1、763±2cm-1、751±2cm-1、693±2cm-1Place
There is absorption peak.
4.2 Raman spectroscopy
Instrument: Invia Rama laser co-focusing micro-Raman spectroscopy
Candesartan cilexetil crystal sample made from Example 1 is measured Raman map using 532nm laser light source,
Map is shown in Fig. 4.
Raman spectroscopy the results show that this product in 1710 ± 2cm-1、1598±2cm-1、1283±2cm-1There is absorption at place
Peak.
5 stability of crystal form are investigated
Candesartan cilexetil crystal sample made from the embodiment 1 for being placed at room temperature for 3 months is taken, according to the side of " investigation of 1 crystal form "
Method is measured, powder X-ray when placing the powder x-ray diffraction map of 3 months samples as the result is shown and just preparing
Diffraction maximum position consistency in diffracting spectrum shows that the crystal form of this product does not change, and this product stability of crystal form is good.
Above description is not limitation of the present invention, and the present invention is also not limited to the example above.The art it is common
Within the essential scope of the present invention, the variations, modifications, additions or substitutions made also should belong to protection of the invention to technical staff
Range.
Claims (6)
1. a kind of candesartan cilexetil crystal, which is characterized in that the X-ray powder diffraction collection of the candesartan cilexetil crystal exists
2 θ of the angle of diffraction be 6.0 ± 0.2,7.1 ± 0.2,8.5 ± 0.2,9.8 ± 0.2,11.6 ± 0.2,11.9 ± 0.2,13.6 ± 0.2,
14.2±0.2、15.2±0.2、16.3±0.2、16.8±0.2、18.0±0.2、19.0±0.2、19.6±0.2、19.7±
0.2、21.2±0.2、22.1±0.2、23.3±0.2、24.0±0.2、24.4±0.2、25.4±0.2、25.9±0.2、
26.6±0.2、27.1±0.2、29.4±0.2、30.0±0.2、30.7±0.2、31.4±0.2、32.8±0.2、34.2±
0.2、34.5±0.2、35.9±0.2、36.5±0.2、38.0±0.2、41.3±0.2、43.5±0.2、44.4±0.2、
There is diffraction maximum at 46.3 ± 0.2,48.2 ± 0.2.
2. a kind of candesartan cilexetil crystal as described in claim 1, which is characterized in that the candesartan cilexetil crystal has such as
Under X-ray powder diffraction collection:
3. a kind of candesartan cilexetil crystal as claimed in claim 2, which is characterized in that the candesartan cilexetil crystal has base
X-ray powder diffraction collection as shown in Figure 1 in sheet.
4. a kind of candesartan cilexetil crystal as described in claim 1, which is characterized in that the candesartan cilexetil crystal it is infrared
Spectrum is in 2992 ± 2cm-1、2938±2cm-1、2860±2cm-1、1756±2cm-1、1725±2cm-1、1616±2cm-1、
1573±2cm-1、1551±2cm-1、1477±2cm-1、1465±2cm-1、1437±2cm-1、1415±2cm-1、1387±
2cm-1、1349±2cm-1、1312±2cm-1、1280±2cm-1、1241±2cm-1、1214±2cm-1、1158±2cm-1、1111
±2cm-1、1073±2cm-1、1032±2cm-1、1001±2cm-1、987±2cm-1、938±2cm-1、911±2cm-1、889±
2cm-1、873±2cm-1、763±2cm-1、751±2cm-1、693±2cm-1There is absorption peak at place.
5. a kind of candesartan cilexetil crystal as described in claim 1, which is characterized in that the Raman of the candesartan cilexetil crystal
Spectrum is in 1710 ± 2cm-1、1598±2cm-1、1283±2cm-1There is absorption peak at place.
6. the preparation method of candesartan cilexetil crystal as claimed in any one of claims 1 to 5, wherein, which is characterized in that including such as
Lower step: candesartan Cilexetil crude product is dissolved in the in the mixed solvent for the first benzol-cyclohexane that volume ratio is 10: 7~15;It heats back
Stream;It is placed at room temperature for crystallization;Recycle candesartan cilexetil crystal.
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5578733A (en) * | 1994-01-28 | 1996-11-26 | Takeda Chemical Industries, Ltd. | Process for the production of tetrazolyl compounds |
WO2004085426A1 (en) * | 2003-03-27 | 2004-10-07 | Hetero Drugs Limited | Novel crystalline forms of candesartan cilexetil |
WO2005077941A2 (en) * | 2004-02-11 | 2005-08-25 | Teva Pharmaceutical Industries Ltd. | Candesartan cilexetil polymorphs |
EP1655298A1 (en) * | 2004-11-03 | 2006-05-10 | LEK Pharmaceuticals d.d. | Novel polymorph forms of candesartan cilexetil |
WO2008035360A2 (en) * | 2006-06-13 | 2008-03-27 | Alembic Limited | Novel crystalline forms of candesartan cilexetil, candesartan, tritylated candesartan and tritylated candesartan cilexetil |
CN100400536C (en) * | 2005-04-30 | 2008-07-09 | 重庆圣华曦药业有限公司 | Process for preparing candesartan cilexetil C-form crystal |
-
2019
- 2019-01-30 CN CN201910091330.9A patent/CN109627234A/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5578733A (en) * | 1994-01-28 | 1996-11-26 | Takeda Chemical Industries, Ltd. | Process for the production of tetrazolyl compounds |
WO2004085426A1 (en) * | 2003-03-27 | 2004-10-07 | Hetero Drugs Limited | Novel crystalline forms of candesartan cilexetil |
WO2005077941A2 (en) * | 2004-02-11 | 2005-08-25 | Teva Pharmaceutical Industries Ltd. | Candesartan cilexetil polymorphs |
EP1655298A1 (en) * | 2004-11-03 | 2006-05-10 | LEK Pharmaceuticals d.d. | Novel polymorph forms of candesartan cilexetil |
CN100400536C (en) * | 2005-04-30 | 2008-07-09 | 重庆圣华曦药业有限公司 | Process for preparing candesartan cilexetil C-form crystal |
WO2008035360A2 (en) * | 2006-06-13 | 2008-03-27 | Alembic Limited | Novel crystalline forms of candesartan cilexetil, candesartan, tritylated candesartan and tritylated candesartan cilexetil |
Non-Patent Citations (2)
Title |
---|
欧阳卉 等: "《药物分析 第3版》", 31 January 2017, 中国医药科技出版社 * |
翁玲玲 主编: "《临床药物化学》", 31 August 2007, 人民卫生出版社 * |
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