CN109851562A - A kind of Telmisartan crystal and preparation method thereof - Google Patents
A kind of Telmisartan crystal and preparation method thereof Download PDFInfo
- Publication number
- CN109851562A CN109851562A CN201910091311.6A CN201910091311A CN109851562A CN 109851562 A CN109851562 A CN 109851562A CN 201910091311 A CN201910091311 A CN 201910091311A CN 109851562 A CN109851562 A CN 109851562A
- Authority
- CN
- China
- Prior art keywords
- telmisartan
- crystal
- telmisartan crystal
- preparation
- 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Battery Electrode And Active Subsutance (AREA)
Abstract
The invention discloses a kind of Telmisartan crystal and preparation method thereof, the X-ray powder diffraction collection of the Telmisartan crystal is 5.0 ± 0.2,6.1 ± 0.2,7.3 ± 0.2,9.2 ± 0.2,11.3 ± 0.2,12.3 ± 0.2,11.9 ± 0.2,13.4 ± 0.2,14.8 ± 0.2,15.8 ± 0.2,16.8 ± 0.2,17.6 ± 0.2,18.5 ± 0.2,19.1 ± 0.2,20.0 ± 0.2,20.5 ± 0.2,21.3 ± 0.2,21.9 ± 0.2,22.8 ± 0.2,23.5 ± 0.2,24.2 ± 0.2,24.8 ± 0.2,25.7 ± 0.2,25.9 ± 0 in 2 θ of the angle of diffraction .2, 27.1 ± 0.2, 27.8 ± 0.2, 28.8 ± 0.2, 29.4 ± 0.2, 30.1 ± 0.2, 30.6 ± 0.2, 31.0 ± 0.2, 32.0 ± 0.2, 32.7 ± 0.2, 33.4 ± 0.2, 34.2 ± 0.2, 350 ± 0.2, 35.7 ± 0.2, 36.4 ± 0.2, 37.1 ± 0.2, 38.7 ± 0.2, 39.5 ± 0.2, 40.8 ± 0.2, 41.5 ± 0.2, 42.2 ± 0.2, 42.6 ± 0.2, 43.4 ± 0.2, 46.0 ± 0.2, 46.9 ± 0.2, 49.8 ± 0.2, 50.5 ± 0.2, 52.6 ± 0.2, have at 54.6 ± 0.2 and spreads out Penetrate peak.Telmisartan crystal of the present invention has the advantages that purity is high and preferably stability, solubility and crystallinity, and preparation method is realized by anti-solvent method, 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 Telmisartan 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.
Telmisartan, chemical name 4 '-[(Isosorbide-5-Nitrae '-dimethyl -2 '-propyl [2,6 '-two -1H- benzimidazole] -1 ' -
Base) methyl]-[1,1 '-dibiphenylyl] -2- carboxylic acid is a kind of non-peptides angiotensin-ii receptor retarding agent, the property of can choose
, irreversible inhibition angiotensin-ii receptor, for treating hypertension, structural formula are as follows:
Telmisartan crystal disclosed in existing commercially available and patent (such as US2006/0276525), in stability, dissolution
There is also certain defects in the performance indicators such as degree, crystallinity and production technology.Therefore, it is badly in need of searching out a kind of with better
The performance indicators such as stability, solubility, crystallinity, the Telmisartan crystal being convenient for industrialized production, to improve Telmisartan
Drug quality and clinical efficacy.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the technological deficiency of background technique, a kind of Telmisartan crystal is provided
And preparation method thereof.Telmisartan crystal of the present invention has the advantages that purity is high and preferably stability, solubility and crystallinity,
Preparation method is realized by anti-solvent method, and this method is simple, is suitable for industrialized production.
It is as follows that the present invention solves technical solution used by above-mentioned technical problem:
A kind of Telmisartan crystal, the X-ray powder diffraction collection of the Telmisartan crystal are 5.0 in 2 θ of the angle of diffraction
±0.2、6.1±0.2、7.3±0.2、9.2±0.2、11.3±0.2、12.3±0.2、11.9±0.2、13.4±0.2、14.8
±0.2、15.8±0.2、16.8±0.2、17.6±0.2、18.5±0.2、19.1±0.2、20.0±0.2、20.5±0.2、
21.3±0.2、21.9±0.2、22.8±0.2、23.5±0.2、24.2±0.2、24.8±0.2、25.7±0.2、25.9±
0.2、27.1±0.2、27.8±0.2、28.8±0.2、29.4±0.2、30.1±0.2、30.6±0.2、31.0±0.2、
32.0±0.2、32.7±0.2、33.4±0.2、34.2±0.2、350±0.2、35.7±0.2、36.4±0.2、37.1±
0.2、38.7±0.2、39.5±0.2、40.8±0.2、41.5±0.2、42.2±0.2、42.6±0.2、43.4±0.2、
There is diffraction maximum at 46.0 ± 0.2,46.9 ± 0.2,49.8 ± 0.2,50.5 ± 0.2,52.6 ± 0.2,54.6 ± 0.2.
Preferably, the Telmisartan crystal has following X-ray powder diffraction collection:
It is highly preferred that the Telmisartan crystal has X-ray powder diffraction collection substantially as shown in.
Preferably, the infrared spectroscopy of the Telmisartan crystal is in 3215 ± 2cm-1、3052±2cm-1、2968±2cm-1、
2934±2cm-1、2874±2cm-1、2742±2cm-1、2451±2cm-1、1954±2cm-1、1700±2cm-1、1614±
2cm-1、1595±2cm-1、1536±2cm-1、1508±2cm-1、1479±2cm-1、1458±2cm-1、1444±2cm-1、1414
±2cm-1、1394±2cm-1、1338±2cm-1、1322±2cm-1、1307±2cm-1、1286±2cm-1、1260±2cm-1、
1237±2cm-1、1128±2cm-1、1093±2cm-1、1045±2cm-1、1005±2cm-1、926±2cm-1、878±2cm-1、
867±2cm-1、850±2cm-1、824±2cm-1、795±2cm-1、766±2cm-1、748±2cm-1、738±2cm-1、706±
2cm-1、662±2cm-1、649±2cm-1、630±2cm-1、598±2cm-1、575±2cm-1、541±2cm-1There is absorption peak at place.
Preferably, the Raman spectrum of the Telmisartan crystal is in 1609 ± 2cm-1、1521±2cm-1、1444±2cm-1、
1271±2cm-1、1111±2cm-1There is absorption peak at place.
A kind of preparation method of Telmisartan crystal includes the following steps: that it is 25 that Telmisartan crude product is dissolved in volume ratio
~50: 50: 50 formic acid-water-isopropanol in the mixed solvent;It is heated to reflux;Water-first that volume ratio is 100: 1~10 is added dropwise
The anti-solvent of alcohol;Stand crystallization;Recycle Telmisartan crystal.
Compared with prior art, the beneficial effects of the present invention are:
Telmisartan crystal of the present invention has the advantages that purity is high and preferably stability, solubility and crystallinity, system
Preparation Method is realized by anti-solvent method, 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 Telmisartan crystal made from the embodiment of the present invention 1;
Fig. 2 is the high-efficient liquid phase chromatogram of Telmisartan crystal made from the embodiment of the present invention 1;
Fig. 3 is the infrared spectrogram of Telmisartan crystal made from the embodiment of the present invention 1;
Fig. 4 is the Raman spectrogram of Telmisartan 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.
Telmisartan crude product described in Examples 1 to 5 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 US2006/0276525.
Embodiment 1
Take 5.0g Telmisartan crude product set in a round bottom flask, be added about 130ml formic acid-water-isopropanol (50: 50:
50) mixed solvent is heated to reflux to whole dissolutions, continues the 2h that flows back, and cooling room temperature is added dropwise about 50ml water-methanol (100: 1)
Anti-solvent, stand, filter, obtained solid drying at room temperature, weighing, obtain 2.4g.
Embodiment 2
Take 5.0g Telmisartan crude product set in a round bottom flask, be added about 130ml formic acid-water-isopropanol (50: 50:
50) mixed solvent is heated to reflux to whole dissolutions, continues the 2h that flows back, and cooling room temperature is added dropwise about 50ml water-methanol (100: 5)
Anti-solvent, stand, filter, obtained solid drying at room temperature, weighing, obtain 2.1g.
Embodiment 3
Take 5.0g Telmisartan crude product set in a round bottom flask, be added about 130ml formic acid-water-isopropanol (50: 50:
50) mixed solvent is heated to reflux to whole dissolutions, continues the 2h that flows back, cooling room temperature, be added dropwise about 50ml water-methanol (100:
10) anti-solvent is stood, and is filtered, obtained solid drying at room temperature, and weighing obtains 2.2g.
Embodiment 4
Take 5.0g Telmisartan crude product set in a round bottom flask, be added about 130ml formic acid-water-isopropanol (35: 50:
50) mixed solvent is heated to reflux to whole dissolutions, continues the 2h that flows back, and cooling room temperature is added dropwise about 50ml water-methanol (100: 5)
Anti-solvent, stand, filter, obtained solid drying at room temperature, weighing, obtain 3.1g.
Embodiment 5
Take 5.0g Telmisartan crude product set in a round bottom flask, be added about 130ml formic acid-water-isopropanol (25: 50:
50) mixed solvent is heated to reflux to whole dissolutions, continues the 2h that flows back, and cooling room temperature is added dropwise about 50ml water-methanol (100: 5)
Anti-solvent, stand, filter, obtained solid drying at room temperature, weighing, obtain 2.9g.
As a result:
1 crystal form is investigated
Telmisartan crystal prototype, is measured using Powder X-ray Diffractometer made from Example 1, diffraction data
It is 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 °
Telmisartan crystal X-ray powder diffraction data made from 1 embodiment 1 of table
As seen from Figure 1, find that the X-ray powder diffraction figure of Telmisartan crystal prototype made from embodiment 1 is aobvious after measured
It is shown with 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
Telmisartan crystal prototype made from Example 1, is measured using HPLC method, chromatographic condition and preparation method
As follows, map is shown in Fig. 2.
Instrument: Agilent1260 high performance liquid chromatograph
Chromatographic condition:
Mobile phase: (25:75 contains 0.2% triethylamine, extremely with phosphorus acid for adjusting pH to 0.1% potassium dihydrogen phosphate-methanol
5.0)
Wavelength: 230nm
Chromatographic column: Venusil MP C18(5 μm, 4.6 × 250mm)
Test sample is prepared: being weighed Telmisartan crystal prototype 10mg made from embodiment 1, is placed in 20ml volumetric flask, uses
Methanol dissolves and is diluted to scale, and precision measures 2ml, sets in 20ml volumetric flask, with methanol dilution to scale to get.
It uses area normalization method to measure Telmisartan crystal prototype purity made from embodiment 1 as 98.7%, shows this
Product purity is good.
3 solubility tests
Telmisartan crystal prototype made from Example 1 is appropriate, finely ground, is placed in the n-octyl alcohol of 25 DEG C of certain volumes,
Every strength shaking in 5 minutes 30 seconds, continue 30 minutes, supersaturated solution is made, centrifugation measures its concentration using HPLC, i.e.,
?.The solubility test of different Telmisartan crystal the results are shown in Table 2.
The solubility test result of the different Telmisartan crystal 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
Telmisartan crystal prototype 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 3215 ± 2cm-1、3052±2cm-1、2968±2cm-1、2934±
2cm-1、2874±2cm-1、2742±2cm-1、2451±2cm-1、1954±2cm-1、1700±2cm-1、1614±2cm-1、1595
±2cm-1、1536±2cm-1、1508±2cm-1、1479±2cm-1、1458±2cm-1、1444±2cm-1、1414±2cm-1、
1394±2cm-1、1338±2cm-1、1322±2cm-1、1307±2cm-1、1286±2cm-1、1260±2cm-1、1237±
2cm-1、1128±2cm-1、1093±2cm-1、1045±2cm-1、1005±2cm-1、926±2cm-1、878±2cm-1、867±
2cm-1、850±2cm-1、824±2cm-1、795±2cm-1、766±2cm-1、748±2cm-1、738±2cm-1、706±2cm-1、662±2cm-1、649±2cm-1、630±2cm-1、598±2cm-1、575±2cm-1、541±2cm-1There is absorption peak at place.
4.2 Raman spectroscopy
Instrument: Invia Rama laser co-focusing micro-Raman spectroscopy
Telmisartan crystal prototype made from Example 1 is measured Raman map using 532nm laser light source, figure
Spectrum is shown in Fig. 4.
Raman spectroscopy the results show that this product in 1609 ± 2cm-1、1521±2cm-1、1444±2cm-1、1271±
2cm-1、1111±2cm-1There is absorption peak at place.
5 stability of crystal form are investigated
Telmisartan crystal prototype made from the embodiment 1 for being placed at room temperature for 3 months is taken, according to the method for " investigation of 1 crystal form "
It is measured, the powder x-ray diffraction map and powder X-ray when rigid preparation for placing 3 months samples as the result is shown spread out
The diffraction maximum position consistency in map is penetrated, shows that the crystal form of this product does not change, 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 Telmisartan crystal, which is characterized in that the X-ray powder diffraction collection of the Telmisartan crystal is in diffraction
2 θ of angle is 5.0 ± 0.2,6.1 ± 0.2,7.3 ± 0.2,9.2 ± 0.2,11.3 ± 0.2,12.3 ± 0.2,11.9 ± 0.2,13.4
±0.2、14.8±0.2、15.8±0.2、16.8±0.2、17.6±0.2、18.5±0.2、19.1±0.2、20.0±0.2、
20.5±0.2、21.3±0.2、21.9±0.2、22.8±0.2、23.5±0.2、24.2±0.2、24.8±0.2、25.7±
0.2、25.9±0.2、27.1±0.2、27.8±0.2、28.8±0.2、29.4±0.2、30.1±0.2、30.6±0.2、
31.0±0.2、32.0±0.2、32.7±0.2、33.4±0.2、34.2±0.2、350±0.2、35.7±0.2、36.4±
0.2、37.1±0.2、38.7±0.2、39.5±0.2、40.8±0.2、41.5±0.2、42.2±0.2、42.6±0.2、
There is diffraction at 43.4 ± 0.2,46.0 ± 0.2,46.9 ± 0.2,49.8 ± 0.2,50.5 ± 0.2,52.6 ± 0.2,54.6 ± 0.2
Peak.
2. a kind of Telmisartan crystal as described in claim 1, which is characterized in that the Telmisartan crystal has following
X-ray powder diffraction collection:
3. a kind of Telmisartan crystal as claimed in claim 2, which is characterized in that the Telmisartan crystal has substantially
X-ray powder diffraction collection as shown in Figure 1.
4. a kind of Telmisartan crystal as described in claim 1, which is characterized in that the infrared spectroscopy of the Telmisartan crystal
In 3215 ± 2cm-1、3052±2cm-1、2968±2cm-1、2934±2cm-1、2874±2cm-1、2742±2cm-1、2451±
2cm-1、1954±2cm-1、1700±2cm-1、1614±2cm-1、1595±2cm-1、1536±2cm-1、1508±2cm-1、1479
±2cm-1、1458±2cm-1、1444±2cm-1、1414±2cm-1、1394±2cm-1、1338±2cm-1、1322±2cm-1、
1307±2cm-1、1286±2cm-1、1260±2cm-1、1237±2cm-1、1128±2cm-1、1093±2cm-1、1045±
2cm-1、1005±2cm-1、926±2cm-1、878±2cm-1、867±2cm-1、850±2cm-1、824±2cm-1、795±2cm-1、766±2cm-1、748±2cm-1、738±2cm-1、706±2cm-1、662±2cm-1、649±2cm-1、630±2cm-1、
598±2cm-1、575±2cm-1、541±2cm-1There is absorption peak at place.
5. a kind of Telmisartan crystal as described in claim 1, which is characterized in that the Raman spectrum of the Telmisartan crystal
In 1609 ± 2cm-1、1521±2cm-1、1444±2cm-1、1271±2cm-1、1111±2cm-1There is absorption peak at place.
6. the preparation method of Telmisartan crystal as claimed in any one of claims 1 to 5, wherein, which is characterized in that including as follows
Step: Telmisartan crude product is dissolved in formic acid-water-isopropanol in the mixed solvent that volume ratio is 25~50: 50: 50;Heating
Reflux;The anti-solvent for the water-methanol that volume ratio is 100: 1~10 is added dropwise;Stand crystallization;Recycle Telmisartan crystal.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910091311.6A CN109851562A (en) | 2019-01-30 | 2019-01-30 | A kind of Telmisartan crystal and preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910091311.6A CN109851562A (en) | 2019-01-30 | 2019-01-30 | A kind of Telmisartan crystal and preparation method thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN109851562A true CN109851562A (en) | 2019-06-07 |
Family
ID=66896894
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910091311.6A Pending CN109851562A (en) | 2019-01-30 | 2019-01-30 | A kind of Telmisartan crystal and preparation method thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109851562A (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1336920A (en) * | 1999-01-19 | 2002-02-20 | 贝林格尔英格海姆法玛公司 | Telmisartan polymorphs, methods for producing same and their use in prepn. of a medicament |
US20060276525A1 (en) * | 2005-05-18 | 2006-12-07 | Itai Adin | Processes of preparing highly pure telmisartan form A, suitable for pharmaceutical compositions |
-
2019
- 2019-01-30 CN CN201910091311.6A patent/CN109851562A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1336920A (en) * | 1999-01-19 | 2002-02-20 | 贝林格尔英格海姆法玛公司 | Telmisartan polymorphs, methods for producing same and their use in prepn. of a medicament |
US20060276525A1 (en) * | 2005-05-18 | 2006-12-07 | Itai Adin | Processes of preparing highly pure telmisartan form A, suitable for pharmaceutical compositions |
Non-Patent Citations (2)
Title |
---|
ROBERT E. DINNEBIER等: "Structural Characterization of Three Crystalline Modifications of Telmisartan by Single Crystal and High-Resolution X-ray Powder Diffraction", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
陈佳星: "《河南工业大学专业硕士学位论文》", 1 May 2015 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105223223A (en) | The raw quantitative detecting method for effective constituent in Buddhist nun's bulk drug of two p-toluenesulfonic acid edge | |
BRPI0608671B1 (en) | PROCESSES FOR PRODUCING A FORM A CRYSTAL OF 17-CYCLOPROPYLMETHYL-3,14 B-DIHYDROXY-4,5A-EPOXY-6B-[N-METHYL-TRANS-3-(3-FURYL)-ACRYL AMIDO]-MORPHINAN HYDROCHLORIDE | |
CN106132408A (en) | A kind of preparation method of bicycloplatin | |
WO2024037138A1 (en) | Phloretin-isoniazid cocrystal and preparation method therefor | |
Sopyan et al. | Co-crystallization: a tool to enhance solubility and dissolution rate of simvastatin | |
CN107664630B (en) | Dopamine detection method based on metal organic framework material | |
CN111217799A (en) | Indole salt-coumarin derivative and synthesis method and application thereof | |
CN111217798A (en) | Coumarin-quinoline derivative and synthesis method and application thereof | |
CN109851562A (en) | A kind of Telmisartan crystal and preparation method thereof | |
Katrincic et al. | Characterization, selection, and development of an orally dosed drug polymorph from an enantiotropically related system | |
CN105732647B (en) | A kind of chlorin e6Metal salt compound and its preparation method and application | |
JP2022525125A (en) | E crystal form of braiaconitine A and its manufacturing method and application | |
CN109503550B (en) | 2-azaaryl-6-substituted amino quinazolinone compound and preparation method and application thereof | |
CN109776503A (en) | A kind of candesartan cilexetil crystal and preparation method thereof | |
CN109734704A (en) | A kind of candesartan cilexetil crystal and preparation method thereof | |
CN109627234A (en) | A kind of candesartan cilexetil crystal and preparation method thereof | |
CN109851612A (en) | A kind of candesartan cilexetil crystal and preparation method thereof | |
CN110057943A (en) | A kind of efficient liquid phase chromatographic analysis detection method of Amlodipine Besylate Tablet intermediate | |
CN109761966A (en) | A kind of Olmesartan medoxomil crystal and preparation method thereof | |
CN106661040B (en) | A kind of crystallization and preparation method thereof of 6- arylamino pyridine ketone benzamide compound | |
CN114075145A (en) | Favipiravir salt, crystal form and preparation method thereof | |
CN104072491A (en) | Azilsartan derivative compound and preparation method and application thereof | |
CN108794383A (en) | The eutectic of nifedipine and Pyrazinamide | |
CN114594168A (en) | Method for detecting indobufen impurity | |
CN113063889A (en) | Method for detecting content of folic acid enantiomer |
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 | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190607 |