CN103012369B - Lansoprazole N crystal form and preparation method and application thereof - Google Patents
Lansoprazole N crystal form and preparation method and application thereof Download PDFInfo
- Publication number
- CN103012369B CN103012369B CN201210405800.2A CN201210405800A CN103012369B CN 103012369 B CN103012369 B CN 103012369B CN 201210405800 A CN201210405800 A CN 201210405800A CN 103012369 B CN103012369 B CN 103012369B
- Authority
- CN
- China
- Prior art keywords
- lansoprazole
- crystal form
- preparation
- crystal formation
- crystal
- 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.)
- Expired - Fee Related
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a lansoprazole N crystal form and a preparation method and application thereof. The X-ray powder diffraction of the lansoprazole N crystal form has characteristic peaks when the diffraction angle 2(theta) is 5.438, 7.062, 8.230, 9.216, 11.022, 11.789, 12.610, 13.541, 20.603, 21.862 and 26.242. The preparation method comprises the following steps of: dissolving lansoprazole in ethyl acetate or a mixed solvent of n-butyl alcohol and water; cooling to separate out crystals; and filtering and drying to obtain the lansoprazole N crystal form. The new lansoprazole crystal form disclosed by the invention is easy to prepare; the preparation method requires little solvent and is simple to operate, and the production cost is low; the reaction conditions are mild, and the control is easy; and the reproducibility is good, and a target product crystal form can be stably obtained. Through the method disclosed by the invention, the prepared lansoprazole crystal form has high purity and low impurity content, maintains all pharmacologic characteristics of lansoprazole, and can be used for treating gastric ulcer, duodenal ulcer and reflux esophagitis and eradicating helicobacter pylori.
Description
Technical field
The present invention relates to lansoprazole new crystal and preparation method thereof.
Background technology
Lansoprazole (Lansoprazole) chemistry is by name: (R)-2-[[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridyl] methyl] sulfinyl]-1H-benzoglyoxaline, its chemical structural formula is:
Lansoprazole is the benzimidazoles derivative with antiacid effect by the exploitation of Japanese Wu Tian company in December, 1991, and it acts on the H of parietal cell
+-K
+-ATP enzyme, makes the H of parietal cell
+can not be transported in stomach and go, so that in gastric juice, hydrochloric acid in gastric juice amount greatly reduces, be used for the treatment of stomach ulcer, duodenal ulcer and reflux esophagitis, and be used for eliminating pylorus.
Lansoprazole is novel proton pump inhibitor, it is the upgraded product of omeprazole, lansoprazole is because importing fluorine and have trifluoro ethoxy substituting group at 4 side chains of pyridine ring, its bioavailability is improved more than 30% compared with omeprazole, lipotropy is also better than omeprazole, therefore this product can be promptly under acidic conditions sees through parietal cell film and change sulfenic acid and time sulfonyl derivative into and bring into play drug effect, the bacteriostatic activity of HP is risen to four times of omeprazole.
The crystal formation of existing lansoprazole is a lot, but owing to there being the solvate of organic solvent in existing crystal formation, therefore as medicinal lansoprazole crystal formation, only has I type, II type, A type and Type B.
The preparation method of anhydrous crystal forms (I type) and 1.5 crystal types (II type) has been described in CN1355798A.Anhydrous crystal forms (I type) preparation method that this patent is described comprises recrystallization process four times: first amorphous lansoprazole (9.17g) is dissolved in acetone (20mL), under thermal condition, add water (15mL), at room temperature hold over night, add again water (20mL), after supersound process, solid collected by filtration, completes recrystallization for the first time; Then gained solid is dissolved in after acetone (30mL) filters and adds diisopropyl ether (50mL), add crystal seed, mixture is hold over night at room temperature, and filtration drying completes recrystallization for the second time; Gained solid is dissolved in acetone, aqueous precipitation, standing 1h collects solid, and drying under reduced pressure, obtains white solid, completes recrystallization for the third time; Finally gained lansoprazole solid (3.88g) is dissolved in to acetone (4mL), add Di Iso Propyl Ether (14mL), at room temperature standing this solution 30 minutes, filter, the crystallization that collecting precipitation goes out, by Di Iso Propyl Ether (6mL) washed twice, obtain anhydrous crystal forms (I) lansoprazole solid, fusing point: 147.0-148.0 ℃.In this patent, the preparation method of 1.5 crystal types (II type) is: unformed lansoprazole (100mg) is dissolved in ethanol (0.15mL), add water (0.15mL), add after crystal seed, under room temperature standing one hour, collect gained solid, wash twice with water, drying under reduced pressure, obtain 1.5 crystal types (II type) lansoprazole, fusing point: 76.0-80.0 ℃.
The preparation method of lansoprazole A crystal formation has been described in US 2009/0018339A1: lansoprazole (100g) is dissolved in acetone (1500mL), slow cooling to 0 ℃, cooling 3h, filters, and at 50 ℃, dry 2h, obtains lansoprazole A crystal formation.Lansoprazole (35g) is dissolved in ethanol (300mL) under 55 ℃ of conditions, solution is cooled to 0 ℃, by 50mL washing with alcohol precipitation, the dry B crystal formation that obtains.
Lansoprazole anhydrous crystal forms (I type) preparation method who describes in CN1355798A, successively through four recrystallizations, preparation process complexity, consuming time; The lansoprazole B crystal formation of describing in US 2009/0018339A1 is metastable-state crystal, can experience solid-to-solid transition under certain condition, forms A crystal formation.
Especially; the existing crystal formation preparation method of lansoprazole is all in patent protection period; therefore; exploitation has the lansoprazole new crystal of independent intellectual property right can break the patent monoply that external pharmacy corporation is produced for lansoprazole, produces lansoprazole technical support and assurance are provided for Chinese pharmaceutical enterprises.
Summary of the invention
The object of the present invention is to provide a kind of novel, stable lansoprazole new crystal and preparation method thereof.
Another object of the present invention is to provide this novel rope to draw the application in azoles crystal formation preparation treatment stomach ulcer, duodenal ulcer and reflux esophagitis and eliminating pylorus medicine.
Lansoprazole N crystal formation, its X-ray powder diffraction is in angle of diffraction 2
θfor: 5.438, there is characteristic peak at 7.062,8.230,9.216,11.022,11.789,12.610,13.541,20.603,21.862,26.242 o'clock; Its
1h-NMR (CDCl
3) data are: 8.34 (d, 1H), 7.65 (br., 2H), 7.30 (d, 1H), 6.67 (d, 1H), 4.74 (q, 2H), 4.40 (d, 1H), 4.32 (d, 1H), 2.21 (s, 3H); Its IR (KBr, cm
-1) data are: 3628,3382,3133,3071,2974,2896,2818,1645,1582,1475,1441,1315,1265,1198,1168,1111,1036,972,916,857,744,661.
The preparation method of lansoprazole N crystal formation, comprises the following steps:
1) lansoprazole is dissolved in ethyl acetate, or in propyl carbinol and the water volume ratio mixed solvent that is 10:1;
2) above-mentioned solution is cooled to-20～-10 ℃, crystallize out;
3) crystal is filtered, dry, obtain lansoprazole N crystal formation.
Lansoprazole new crystal of the present invention, is easy to preparation.
Ultimate analysis and nuclear magnetic resonance hydrogen spectruming determining result show that lansoprazole crystal formation purity prepared by the present invention is high, and foreign matter content is low.
The required quantity of solvent of preparation method the present invention relates to is few, low production cost.
The preparation method who the present invention relates to is simple to operate, and reaction conditions gentleness is easily controlled.
The preparation method's favorable reproducibility the present invention relates to, acquisition target product crystal formation that can be stable.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of lansoprazole N crystal formation.
Fig. 2 is the differential scanning calorimeter figure (DSC figure) of lansoprazole N crystal formation.
Fig. 3 is infrared spectra (IR) figure of lansoprazole N crystal formation.
Fig. 4 is scanning electron microscope (SEM) figure of lansoprazole N crystal formation.
Embodiment
Lansoprazole N crystal formation, its X-ray powder diffraction is in angle of diffraction 2
θfor: 5.438, there is characteristic peak at 7.062,8.230,9.216,11.022,11.789,12.610,13.541,20.603,21.862,26.242 o'clock; Its
1h-NMR (CDCl
3) data are: 8.34 (d, 1H), 7.65 (br., 2H), 7.30 (d, 1H), 6.67 (d, 1H), 4.74 (q, 2H), 4.40 (d, 1H), 4.32 (d, 1H), 2.21 (s, 3H); Its IR (KBr, cm
-1) data are: 3628,3382,3133,3071,2974,2896,2818,1645,1582,1475,1441,1315,1265,1198,1168,1111,1036,972,916,857,744,661.
The preparation method of lansoprazole N crystal formation, comprises the following steps:
1) lansoprazole is dissolved in ethyl acetate, or in propyl carbinol and the water volume ratio mixed solvent that is 10:1;
2) above-mentioned solution is cooled to-20～-10 ℃, crystallize out;
3) crystal is filtered, dry, obtain lansoprazole N crystal formation.
Below in conjunction with embodiment, further illustrate the present invention.
lansoprazole N crystal formation preparation method
Embodiment 1
1) 50mg lansoprazole is dissolved in 0.1mL ethyl acetate, filters;
2) settled solution is cooled to-10 ℃, its sufficient crystallising is separated out, filter, dry.
Obtain off-white color crystalline powder 42.7mg, productive rate 85.4%.
Embodiment 2
1) 100mg lansoprazole is dissolved in 0.5mL ethyl acetate, filters;
2) settled solution is cooled to-10 ℃, its sufficient crystallising is separated out, filter, dry.
Obtain off-white color crystalline powder 79.6mg, productive rate 79.6%.
Embodiment 3
1) 100mg lansoprazole is dissolved in 0.5mL ethyl acetate, filters;
2) settled solution is cooled to-15 ℃, its sufficient crystallising is separated out, filter, dry.
Obtain off-white color crystalline powder 82.9mg, productive rate 82.9%.
Embodiment 4
1) 1g lansoprazole is dissolved in 1mL ethyl acetate, filters;
2) settled solution is cooled to-20 ℃, its sufficient crystallising is separated out, filter, dry.
Obtain off-white color crystalline powder 0.853g, productive rate 85.3%.
Embodiment 5
1) 1g lansoprazole is dissolved in 1mL ethyl acetate, filters;
2) settled solution is cooled to-20 ℃, its sufficient crystallising is separated out, filter, dry.
Obtain off-white color crystalline powder 0.838g, productive rate 83.8%.
Embodiment 6
1) 100mg lansoprazole is dissolved in to 0.1mL propyl carbinol: water=10:1(volume ratio) mixed solvent in, filter;
2) settled solution is cooled to-10 ℃, its sufficient crystallising is separated out, filter, dry.
Obtain off-white color crystal type powder 87.5mg, productive rate 87.5%.
Get embodiment 4 and obtain off-white color crystalline powder and carry out structural analysis, its result is as follows:
The angle of diffraction 2 of X-ray powder diffraction
θfor: 5.438,7.062,8.230,9.216,11.022,11.789,12.610,13.541,20.603,21.862,26.242, its X-ray powder diffraction figure is as shown in Figure 1;
Results of elemental analyses is: C(%): 48.43, N(%): 10.47, H(%): 4.50;
1h-NMR (CDCl
3) data are: 8.34 (d, 1H), 7.65 (br., 2H), 7.30 (d, 1H), 6.67 (d, 1H), 4.74 (q, 2H), 4.40 (d, 1H), 4.32 (d, 1H), 2.21 (s, 3H);
Its differential scanning calorimeter figure (DSC figure) as shown in Figure 2;
IR (KBr, cm
-1) data are: 3628,3382,3133,3071,2974,2896,2818,1645,1582,1475,1441,1315,1265,1198,1168,1111,1036,972,916,857,744,661, its infrared spectra (IR) is schemed as shown in Figure 3;
Its scanning electron microscope (SEM) is schemed as shown in Figure 4.
The results of structural analysis of embodiment 1～3,5,6 and the results of structural analysis no significant difference of embodiment 4.
Lansoprazole new crystal of the present invention, has retained all pharmacological properties of lansoprazole, has in vivo the effect identical with existing crystal formation, can be used for treating in stomach ulcer, duodenal ulcer and reflux esophagitis and eliminating pylorus.
Claims (5)
1. lansoprazole N crystal formation, its X-ray powder diffraction is in angle of diffraction 2
θfor: 5.438, have characteristic peak at 7.062,8.230,9.216,11.022,11.789,12.610,13.541,20.603,21.862,26.242 o'clock, X-ray powder diffraction figure is substantially as shown in Figure 1.
2. lansoprazole N crystal formation according to claim 1, its
1h-NMR (CDCl
3) data are: 8.34 (d, 1H), 7.65 (br., 2H), 7.30 (d, 1H), 6.67 (d, 1H), 4.74 (q, 2H), 4.40 (d, 1H), 4.32 (d, 1H), 2.21 (s, 3H).
3. lansoprazole N crystal formation according to claim 1, its IR (KBr, cm
-1) data are: 3628,3382,3133,3071,2974,2896,2818,1645,1582,1475,1441,1315,1265,1198,1168,1111,1036,972,916,857,744,661.
4. the preparation method of lansoprazole N crystal formation claimed in claim 1, comprises the following steps:
1) lansoprazole is dissolved in ethyl acetate, or in propyl carbinol and the water volume ratio mixed solvent that is 10:1;
2) above-mentioned solution is cooled to-20～-10 ℃, crystallize out;
3) crystal is filtered, dry, obtain lansoprazole N crystal formation.
5. the application of lansoprazole N crystal formation claimed in claim 1 in preparation treatment stomach ulcer, duodenal ulcer and reflux esophagitis and eliminating pylorus medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210405800.2A CN103012369B (en) | 2011-05-23 | 2011-05-23 | Lansoprazole N crystal form and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210405800.2A CN103012369B (en) | 2011-05-23 | 2011-05-23 | Lansoprazole N crystal form and preparation method and application thereof |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110069233 Division CN102180866B (en) | 2011-05-23 | 2011-05-23 | New crystal form of lansoprazole and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103012369A CN103012369A (en) | 2013-04-03 |
| CN103012369B true CN103012369B (en) | 2014-04-23 |
Family
ID=47961526
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210405800.2A Expired - Fee Related CN103012369B (en) | 2011-05-23 | 2011-05-23 | Lansoprazole N crystal form and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103012369B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103254174B (en) * | 2013-06-05 | 2014-06-11 | 湖北济生医药有限公司 | Lansoprazole compound and pharmaceutical composition thereof |
| CN104997738A (en) * | 2015-08-10 | 2015-10-28 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicine lansoprazole compound dry suspension treating gastropathy |
| CN107011328B (en) * | 2017-05-05 | 2019-10-15 | 广州大光制药有限公司 | A kind of crystal form and its crystallization preparation method of compound of Lansoprazole |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1237167A (en) * | 1996-11-14 | 1999-12-01 | 武田药品工业株式会社 | Crystal of benzimidazole derivatives and their production |
| CN1267295A (en) * | 1997-07-11 | 2000-09-20 | 卫材株式会社 | Processes for preparation of pyridine derivs. |
| US6423846B1 (en) * | 2001-09-28 | 2002-07-23 | Hanmi Pharm. Co., Ltd. | High-yield method for preparing lansoprazole |
| CN101475562A (en) * | 2009-01-21 | 2009-07-08 | 海南美大制药有限公司 | Method for synthesizing lansoprazole and salt thereof |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100430575B1 (en) * | 2001-02-21 | 2004-05-10 | 주식회사 씨트리 | Method of Preparing Lansoprazole and Its Intermediate |
| JP4115751B2 (en) * | 2002-05-31 | 2008-07-09 | 株式会社パーマケム・アジア | Production method of fine water benzimidazole compounds |
| PT1501824E (en) * | 2002-08-21 | 2007-11-28 | Teva Pharma | A method for the purification of lansoprazole |
| WO2004072061A1 (en) * | 2003-02-05 | 2004-08-26 | Teva Pharmaceutical Industries Ltd. | Method of stabilizing lansoprazole |
| WO2007017244A2 (en) * | 2005-08-10 | 2007-02-15 | Sandoz Ag | A PROCESS FOR THE PURIFICATION OF SUBSTITUTED 2-(2-PYRIDYLMETHYL)SULFINYL-lH-BENZIMIDAZOLE COMPOUNDS BY PRECIPITATION IN THE PRESENCE OF A QUATERNARY AMMONIUM SALT |
| KR100758600B1 (en) * | 2006-01-05 | 2007-09-13 | 주식회사 대웅제약 | Process for preparing Crystalline Form A of Lansoprazole |
| US8129536B2 (en) * | 2006-09-22 | 2012-03-06 | Orchid Chemicals & Pharmaceuticals Limited | Method for the purification of lansoprazole |
| EP2030973A1 (en) * | 2007-08-31 | 2009-03-04 | KRKA, tovarna zdravil, d.d., Novo mesto | Process for preparing 2-sulfinyl-1H-benzimidazoles |
-
2011
- 2011-05-23 CN CN201210405800.2A patent/CN103012369B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1237167A (en) * | 1996-11-14 | 1999-12-01 | 武田药品工业株式会社 | Crystal of benzimidazole derivatives and their production |
| CN1267295A (en) * | 1997-07-11 | 2000-09-20 | 卫材株式会社 | Processes for preparation of pyridine derivs. |
| US6423846B1 (en) * | 2001-09-28 | 2002-07-23 | Hanmi Pharm. Co., Ltd. | High-yield method for preparing lansoprazole |
| CN101475562A (en) * | 2009-01-21 | 2009-07-08 | 海南美大制药有限公司 | Method for synthesizing lansoprazole and salt thereof |
Non-Patent Citations (5)
| Title |
|---|
| JP特开2004-2230A 2004.01.08 |
| 兰索拉哇的合成;段凤辉 等;《黑龙江医药》;20001231;第13卷(第5期);第273-274页 * |
| 兰索拉唑的合成工艺改进;王庆河 等;《中国药物化学杂志》;20090228;第19卷(第1期);第42-44页 * |
| 段凤辉 等.兰索拉哇的合成.《黑龙江医药》.2000,第13卷(第5期),第273-274页. |
| 王庆河 等.兰索拉唑的合成工艺改进.《中国药物化学杂志》.2009,第19卷(第1期),第42-44页. |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103012369A (en) | 2013-04-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102180866B (en) | New crystal form of lansoprazole and preparation method and application thereof | |
| CN103012369B (en) | Lansoprazole N crystal form and preparation method and application thereof | |
| CN103087048B (en) | Method for purifying esomeprazole sodium | |
| CN105622535A (en) | Preparation method for LCZ696 and prepared high-purity LCZ696 | |
| CN103467451A (en) | Preparation method for S-pantoprazole sodium | |
| CN103709139A (en) | Preparation method of anhydrous dexilant | |
| CN102267957A (en) | Method for preparing Febuxostat crystal A | |
| CN105017218A (en) | R-lansoprazole crystal form and preparation method therefor | |
| CN107739396A (en) | It is a kind of to improve heap density, mobility and prepare the method for crystallising for not coalescing azithromycin | |
| CN103420979A (en) | Esomeprazole sodium refining method | |
| CN105055342A (en) | Sodium ilaprazole medicine composition freeze-dried powder injection for treating peptic ulcer | |
| CN104370886B (en) | Iprazole crystal formation and its preparation method and application | |
| CN104530006A (en) | Lansoprazole preparation method | |
| CN102603621B (en) | Novel chiral sulfoxide compound and method for preparing esomeprazole by using novel chiral sulfoxide compound | |
| CN106632246A (en) | Crystalline form of pyrrole-type gastric acid secretion inhibitor compound salt and preparation thereof | |
| CN104447459A (en) | Novel crystal form of isotretinoin as well as preparation method and application thereof | |
| CN104327048A (en) | Lansoprazole thioether crystal form, and preparation method and application thereof | |
| CN106432326A (en) | Purification method of L-alpha-glycerophosphoryl choline | |
| US8071781B2 (en) | Process for preparing rabeprazole sodium | |
| CN103242294A (en) | (S)-pantoprazole sodium dihydrate and preparation method thereof | |
| JP2017031126A (en) | Method for producing pyrrolo-quinoline quinone crystal | |
| CN104784146A (en) | Pharmaceutical Ilaprazole sodium composition for treating peptic ulcer | |
| CN104557866A (en) | Method for preparing esomeprazole sodium salt from esomeprazole solution | |
| WO2015149638A1 (en) | Dabigatran etexilate mesylate crystalline form, preparation method and pharmaceutical composition thereof | |
| CN102108076A (en) | Method for preparing amorphous dexlansoprazole |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140423 Termination date: 20200523 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |