CN109836413A - A kind of Dexlansoprazole sodium crystal and its preparation method and application - Google Patents
A kind of Dexlansoprazole sodium crystal and its preparation method and application Download PDFInfo
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- CN109836413A CN109836413A CN201711205960.1A CN201711205960A CN109836413A CN 109836413 A CN109836413 A CN 109836413A CN 201711205960 A CN201711205960 A CN 201711205960A CN 109836413 A CN109836413 A CN 109836413A
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- Prior art keywords
- dexlansoprazole
- preparation
- dexlansoprazole sodium
- sodium
- acetone
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- MJIHNNLFOKEZEW-RUZDIDTESA-N dexlansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1C[S@@](=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-RUZDIDTESA-N 0.000 title claims abstract description 48
- 229960003568 dexlansoprazole Drugs 0.000 title claims abstract description 48
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 44
- 239000011734 sodium Substances 0.000 title claims abstract description 44
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title claims abstract description 43
- 239000013078 crystal Substances 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000003851 azoles Chemical class 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000003610 charcoal Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 5
- 230000006837 decompression Effects 0.000 description 4
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 4
- 229960003174 lansoprazole Drugs 0.000 description 4
- 239000000126 substance Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 201000006549 dyspepsia Diseases 0.000 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 208000024798 heartburn Diseases 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- 206010063655 Erosive oesophagitis Diseases 0.000 description 1
- PKCZFBCOFIKEFK-UHFFFAOYSA-N O.OC.OP(O)(O)=O.CCN(CC)CC Chemical compound O.OC.OP(O)(O)=O.CCN(CC)CC PKCZFBCOFIKEFK-UHFFFAOYSA-N 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides Dexlansoprazole sodium, the 2 θ angles of diffraction are corresponding with characteristic diffraction peak in 11.480 ± 0.2,11.900 ± 0.2,14.260 ± 0.2,16.540 ± 0.2,17.460 ± 0.2,20.759 ± 0.2,21.819 ± 0.2,22.540 ± 0.2,22.939 ± 0.2,23.860 ± 0.2,24.560 ± 0.2,25.801 ± 0.2,26.080 ± 0.2,26.601 ± 0.2,32.519 ± 0.2,49.260 ± 0.2 position in the X-ray powder diffraction figure of the crystal form；Invention additionally provides the preparation method of crystal form.In addition, the preparation method of Dexlansoprazole sodium crystal provided by the invention is easy, stability is preferable, is easy to industrial application.
Description
Technical field
The invention belongs to chemicals crystallization technique field, in particular to a kind of Dexlansoprazole sodium and its preparation side
Method.
Background technique
Dexlansoprazole sodium, Chinese chemical name are S-(+) -2- [[3- methyl -4- (2,2,2- trifluoro ethoxy) pyrrole
Pyridine -2- base] methylsulfinyl] -1H- benzimidazole sodium, molecular formula C16H13F3N3O2SNa, molecular weight are about 391.35, right
It is as follows to revolve Lansoprazole sodium structural formula:
The esophagitis that U.S. FDA ratifies Japanese Takeda Pharmaceutical Company Limited's research and development on January 30th, 2009 treats new drug R-lansoprazole
(general entitled Dexlansoprazole) listing.The medicine is the enantiomer of proton pump inhibitor Lansoprazole, and be otherwise known as dextrorotation
Lansoprazole, for treating and the sick relevant heartburn of Non-erosive gastroesophageal reflux and different degrees of erosive esophagitis.
This time listing dosage form is spansule, built-in two layers of enteric coating unit, can make drug 1 ~ 2 hour and 4 ~ 5 small upon administration
When after occur two peak plasma concentrations respectively, action time is more than Lansoprazole, and the administration time of Kapidex is not eaten
The influence of object and meal time.Third stage test display, the medicine can in the daytime or night with heartburn symptom stomach oesophagus
Reflux patient provides Acidinhibitor and lasting remission effect up to 24 hours.
Currently, existing patent discloses Dexlansoprazole crystal form, such as Chinese patent CN106866631A,
CN106749182A, CN104844576A, CN106279107A,.For drug, we are to it at the crystal form prepared after salt
There may be different physicochemical properties, such as solubility, fusing point, stability, these properties directly will affect the steady of pharmaceutical preparation
Qualitative, dissolubility, or even influence most heavy clinical efficacy.
It therefore, is significantly to the preparation and research of the crystal form of Dexlansoprazole sodium.
Summary of the invention
The purpose of the present invention is to provide a kind of Dexlansoprazole sodium and preparation method thereof.
The present invention provides Dexlansoprazole sodium crystal, in the X-ray powder diffraction figure of the crystal form, 2 θ diffracted rays
Angle 11.480 ± 0.2,11.900 ± 0.2,14.260 ± 0.2,16.540 ± 0.2,17.460 ± 0.2,20.759 ± 0.2,
21.819±0.2、22.540±0.2、22.939±0.2、23.860±0.2、24.560±0.2、25.801±0.2、
26.080 ± 0.2,26.601 ± 0.2,32.519 ± 0.2,49.260 ± 0.2 position is corresponding with characteristic diffraction peak.
In organic compound field of crystals, XRPD atlas analysis is the common method that qualitative analysis is carried out to crystal, however
What is provided in XRPD map contains much information, and may will also include the interference informations such as impurity peaks.Therefore, in order to accurately identify crystal,
The present invention has chosen several representative peaks as characteristic peak to characterize crystal structure of the invention in XRPD map.
It is complete etc. multi-party that the present invention has comprehensively considered d value, low angle, intensity, characteristic curve and peak shape when selecting characteristic peak
Face factor.The most preferred characteristic peak of the present invention does not only belong in map that (2 θ are less than 36 ° and cover big portion with respect to the peak of low angle
Divide characteristic peak), meanwhile, the absorption peak that the present invention selects has complete and apparent peak shape, intensity relatively high, is highly susceptible to making
Peak is characterized to be distinguished, identify.And other peaks in X-ray powder diffraction figure, peak shape are bad, peak intensity is extremely low, wherein may
It will include impurity peaks interference information, therefore the characteristic peak proper name in the present invention not as this crystal form is listed.
X-ray powder diffraction of the present invention uses Cu K α radiation source.
The X-ray powder diffraction of crystal form of the present invention is as shown in Figure 1.
The present invention also provides the preparation methods of above-mentioned Dexlansoprazole sodium, it includes following preparation method:
Preparation method: taking Dexlansoprazole sodium, is added acetone/water system, after heating for dissolving, adds active carbon decoloring, mistake
Filter, filtrate stirring or standing cooled to room temperature, stir or are stood under the conditions of -5 ± 5 DEG C, and filtering is dried under reduced pressure, obtains
Dexlansoprazole.
Wherein in preparation method, ratio shared by acetone is 10%~80% in the acetone/water system；Acetone/water body
The volume that series solvent uses is that Dexlansoprazole mass ratio is 2~60 times of amounts；Dissolving by heating temperature is 30 DEG C~80 DEG C.
Wherein in preparation method, the temperature that is dried under reduced pressure is 25 DEG C~80 DEG C.
Room temperature of the present invention refers to 25 ± 2 DEG C.
The preparation method of Dexlansoprazole sodium provided by the invention is easy, is easy to industrial application, and it is blue to be used in dextrorotation
The method that rope draws strict control crystal form in azoles sodium raw materials medicine preparation process.
The Dexlansoprazole sodium that the present invention obtains, purity is high, stable crystal form and favorable reproducibility, stability are high.
Detailed description of the invention
Attached drawing 1 is the X-ray powder diffraction pattern of Dexlansoprazole sodium of the present invention.
Specific embodiment
Below with reference to embodiment, invention is further described in detail, it should be understood that the scope of the present invention is non-to be only limitted to this
The range of a little embodiments.
Embodiment 1: the preparation of Dexlansoprazole sodium
Dexlansoprazole sodium 10g is taken, 25% acetone water 100ml is added, 50 DEG C of heating stirrings add 0.2g activity to dissolving
Charcoal is stirred 5 minutes and is filtered, and filtrate stands crystallization 10 hours, is then placed 0 DEG C again and is stood 5 hours, and filtering, 40 DEG C are dried under reduced pressure,
Up to 7.4g Dexlansoprazole sodium crystal, yield 74%.
The X-ray powder diffraction data of 1 Dexlansoprazole sodium crystal of table
Embodiment 2: the preparation of Dexlansoprazole sodium crystal
Dexlansoprazole sodium 10g is taken, 50% acetone water 40ml is added, 60 DEG C of heating stirrings add 0.1g activity to dissolving
Charcoal is stirred 5 minutes and is filtered, and filtrate stands crystallization 10 hours, is then placed -5 DEG C again and is stood 10 hours, filtering, and 40 DEG C of decompressions are dry
It is dry to get 8.3g Dexlansoprazole sodium crystal, yield 83%.
Embodiment 3: the preparation of Dexlansoprazole sodium crystal
Dexlansoprazole sodium 10g is taken, 40% acetone water 200ml is added, 40 DEG C of heating stirrings add 0.5g activity to dissolving
Charcoal is stirred 10 minutes and is filtered, and filtrate stands crystallization 3 hours, is then placed 0 DEG C again and is stood 12 hours, filtering, and 30 DEG C of decompressions are dry
It is dry to get 7.1g Dexlansoprazole sodium crystal, yield 71%.
Embodiment 4: the preparation of Dexlansoprazole sodium crystal
Dexlansoprazole sodium 200g is taken, 25% acetone water 3000ml is added, 50 DEG C of heating stirrings add 10g activity to dissolving
Charcoal is stirred 15 minutes and is filtered, and filtrate stands crystallization 3 hours, is then placed -5 DEG C again and is stood 15 hours, filtering, and 60 DEG C of decompressions are dry
It is dry to get 174.9g Dexlansoprazole sodium crystal, yield 87%.
Embodiment 5: the preparation of Dexlansoprazole sodium crystal
Dexlansoprazole sodium 50g is taken, 20% acetone water 750ml is added, 50 DEG C of heating stirrings add 10g activity to dissolving
Charcoal is stirred 15 minutes and is filtered, and filtrate stands crystallization 10 hours, is then placed 0 DEG C again and is stood 8 hours, filtering, and 50 DEG C of decompressions are dry
It is dry to get 42.5g Dexlansoprazole sodium crystal, yield 85.0%.
Embodiment 6: the purity of Dexlansoprazole sodium crystal
Dexlansoprazole sodium crystal prepared in the above embodiments measures purity result by following chromatographic condition:
Chromatographic column: C18 column (5 μm of 250mm × 4.6mm)
Mobile phase: with methanol-water-triethylamine-phosphoric acid (600:400:5:1.5) [adjusting pH value to 7.3 with phosphoric acid solution]
Column temperature: 25 DEG C of flow velocitys: 1.0ml/min Detection wavelength: 284nm
| Sample ID | Crystal form |
| Content | 99.97% |
| Related substance | Single miscellaneous 0.01% total miscellaneous 0.02% |
Embodiment 7: the stability result of Dexlansoprazole sodium crystal and Dexlansoprazole crystal form (CN104844576A)
Stability of crystal form of the invention is substantially better than Dexlansoprazole crystal form.
Claims (5)
1. Dexlansoprazole sodium, it is characterised in that: in the X-ray powder diffraction figure of the crystal form, the 2 θ angles of diffraction are 11.480
±0.2、11.900±0.2、14.260±0.2、16.540±0.2、17.460±0.2、20.759±0.2、21.819±
0.2、22.540±0.2、22.939±0.2、23.860±0.2、24.560±0.2、25.801±0.2、26.080±0.2、
26.601 ± 0.2,32.519 ± 0.2,49.260 ± 0.2 position is corresponding with characteristic diffraction peak.
2. Dexlansoprazole sodium crystal according to claim 1, it is characterised in that: the x-ray powder of the crystal form spreads out
It penetrates as shown in Figure 1.
3. the preparation method of Dexlansoprazole sodium crystal according to claim 1, it is characterised in that: preparation process is such as
Under:
It takes Dexlansoprazole sodium, is added acetone/water system, after heating for dissolving, add active carbon decoloring, filter, filtrate is stirred
Cooled to room temperature is mixed or stood, stirs or stands under the conditions of -5 ± 5 DEG C, filtering is dried under reduced pressure, obtains dextrorotation Lan Suola
Azoles sodium crystal.
4. the preparation method of Dexlansoprazole sodium crystal according to claim 3, it is characterised in that: the acetone/
Ratio shared by acetone is 10%~80% in aqueous systems；The volume that acetone/water system solvent uses is Dexlansoprazole sodium matter
Amount for 2~60 times than measuring；Dissolving by heating temperature is 30 DEG C~80 DEG C.
5. the preparation method of Dexlansoprazole sodium crystal according to claim 3, it is characterised in that: the room temperature is put
Setting the time is 1~12 hour；Standing time 1~12 hour under the conditions of -5 ± 5 DEG C, preferably 3~8 hours.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711205960.1A CN109836413A (en) | 2017-11-27 | 2017-11-27 | A kind of Dexlansoprazole sodium crystal and its preparation method and application |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711205960.1A CN109836413A (en) | 2017-11-27 | 2017-11-27 | A kind of Dexlansoprazole sodium crystal and its preparation method and application |
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| Publication Number | Publication Date |
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| CN109836413A true CN109836413A (en) | 2019-06-04 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1810245A (en) * | 2006-02-27 | 2006-08-02 | 锦州九泰药业有限责任公司 | Prepn process of Lansoprazole sodium for treating peptic ulcer |
| CN101250182A (en) * | 2008-03-26 | 2008-08-27 | 江苏奥赛康药业有限公司 | Lansoprazole sodium |
| WO2012095859A1 (en) * | 2011-01-12 | 2012-07-19 | Hetero Research Foundation | Polymorphs of dexlansoprazole salts |
| CN103788068A (en) * | 2014-02-26 | 2014-05-14 | 南京海融医药科技有限公司 | High-melting point chiral benzimidazole compound sodium salt as well as preparation method and application thereof |
-
2017
- 2017-11-27 CN CN201711205960.1A patent/CN109836413A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1810245A (en) * | 2006-02-27 | 2006-08-02 | 锦州九泰药业有限责任公司 | Prepn process of Lansoprazole sodium for treating peptic ulcer |
| CN101250182A (en) * | 2008-03-26 | 2008-08-27 | 江苏奥赛康药业有限公司 | Lansoprazole sodium |
| WO2012095859A1 (en) * | 2011-01-12 | 2012-07-19 | Hetero Research Foundation | Polymorphs of dexlansoprazole salts |
| CN103788068A (en) * | 2014-02-26 | 2014-05-14 | 南京海融医药科技有限公司 | High-melting point chiral benzimidazole compound sodium salt as well as preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 杜冠华等: "化学药物晶型关键技术体系的建立与应用", 《药学进展》 * |
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