CN111423412A - Crystalline form of d-rabeprazole sodium anhydride - Google Patents
Crystalline form of d-rabeprazole sodium anhydride Download PDFInfo
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- CN111423412A CN111423412A CN202010278229.7A CN202010278229A CN111423412A CN 111423412 A CN111423412 A CN 111423412A CN 202010278229 A CN202010278229 A CN 202010278229A CN 111423412 A CN111423412 A CN 111423412A
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- rabeprazole sodium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- C07B2200/07—Optical isomers
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- 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
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Abstract
The invention relates to the field of preparation of crystal forms of polymorphic medicaments, and discloses characteristics of a crystal form II of a medicinal compound dextro-rabeprazole sodium anhydrate and a preparation method thereof. The XRPD spectrum 2 theta angle of the crystal form has main characteristic diffraction peaks at 4.3,4.9,6.1,9.2,9.6,10.4,11.0,11.6,13.6,17.7,18.3,19.2,20.0,20.9,22.4 and 23.6. The invention has the advantages that the effective dose of the dextro-rabeprazole sodium monohydrate is smaller than that of a racemate, the metabolic half-life period is long, the curative effect can be obviously improved, and the occurrence of toxic and side effects can be obviously reduced. The product has definite curative effect and good safety, thus having development value. The crystal form of the dextro-rabeprazole sodium monohydrate provided by the invention has the advantages of good stability, solubility, dissolution rate, low hygroscopicity, simple preparation method, easiness in operation, high yield and wide industrial application prospect.
Description
Technical Field
The invention relates to the characteristics of a crystal form of a dextro-rabeprazole sodium anhydrate of a pharmaceutical compound and a preparation method thereof.
Background
The dextro-rabeprazole sodium is dextro-isomer of rabeprazole sodium. Rabeprazole sodium is developed and marketed by the pharmaceutical industry of Japanese medical supplies, and dextro-rabeprazole sodium is developed and marketed by reading Chiral Emcure. The D-rabeprazole sodium is used for treating digestive system diseases such as hyperacidity, gastroesophageal reflux, duodenal ulcer and the like.
The main marketed dosage form of the dextro-rabeprazole sodium is a tablet, and the common crystal form is amorphous. The dextro-rabeprazole sodium has poor stability and is easy to degrade. The amorphous stability is inferior to the crystalline form, which is not favorable for the long-term storage of the preparation product. The dextro-rabeprazole sodium is a high-dissolution medicament, and the dissolution speed of the medicament is improved without using an amorphous solid form.
Patent CN104725358 discloses a crystalline form Z of d-rabeprazole sodium monohydrate, which has good stability and is suitable for preparation production.
To date, no patent has disclosed the anhydrate form of d-rabeprazole sodium. The anhydrous crystalline form is more advantageous in long-term stability studies.
Disclosure of Invention
The invention provides a novel crystal form of dextro-rabeprazole sodium anhydride.
The technical scheme of the invention is that the crystal form of the dextro-rabeprazole sodium anhydride has main characteristic diffraction peaks at the XRPD (X-ray diffraction pattern) angles 2 theta of 4.3,4.9,6.1,9.2,9.6,10.4,11.0,11.6,13.6,17.7,18.3,19.2,20.0,20.9,22.4 and 23.6.
Furthermore, the provided D-rabeprazole sodium crystal form II does not contain crystal water.
A method for preparing crystal form of dextro-rabeprazole sodium anhydride comprises the following steps: dissolving amorphous dextral rabeprazole sodium in ethyl acetate with the volume of 10 times, stirring and dissolving at 30-40 ℃, filtering by using a microporous filter membrane, standing for crystallization, filtering, and drying. The water content of the ethyl acetate used is less than 0.05%.
A method for preparing crystal form of dextro-rabeprazole sodium anhydride comprises the following steps: dissolving amorphous dextral rabeprazole sodium in ethyl acetate with the volume of 5-20 times, stirring and dissolving at 20-50 ℃, filtering by using a microporous filter membrane, standing for crystallization, filtering and drying. The water content of the ethyl acetate used is less than 0.05%.
The dextro-rabeprazole sodium monohydrate has the advantages of smaller effective dose than a racemate, long metabolic half life, obviously improved curative effect and reduced toxic and side effects. The product has definite curative effect and good safety, thus having development value. The crystal form of the dextro-rabeprazole sodium monohydrate provided by the invention has the advantages of good stability, solubility, dissolution rate, low hygroscopicity, simple preparation method, easiness in operation, high yield and wide industrial application prospect.
Drawings
FIG. 1 is an XRPD spectrum of D-rabeprazole sodium anhydrate crystal form II;
FIG. 2 is a TGA spectrum of right-handed rabeprazole sodium anhydrate crystal form II;
FIG. 3 is an amorphous XRPD spectrum of dextro-rabeprazole sodium;
FIG. 4 is a Z-type XRPD spectrum of crystalline form of dextro-rabeprazole sodium monohydrate.
Detailed Description
The invention is described in detail with reference to the accompanying drawings, and as shown in fig. 1, the crystal form of the D-rabeprazole sodium anhydride is (R) -2- [ [ [4- (3-methoxypropoxy) -3-methylpyridin-2-yl ] methyl ] sulfinyl ] -1H-benzimidazole sodium which is a proton pump inhibitor and has the following structural formula.
The XRPD spectrum 2 theta angle of the crystal form has main characteristic diffraction peaks at 4.3,4.9,6.1,9.2,9.6,10.4,11.0,11.6,13.6,17.7,18.3,19.2,20.0,20.9,22.4 and 23.6.
The provided D-rabeprazole sodium crystal form II does not contain crystal water.
A method for preparing crystal form of dextro-rabeprazole sodium anhydride comprises the following steps: dissolving amorphous dextral rabeprazole sodium in ethyl acetate with the volume of 10 times, stirring and dissolving at 30-40 ℃, filtering by using a microporous filter membrane, standing for crystallization, filtering, and drying. The water content of the ethyl acetate used is less than 0.05%.
A method for preparing crystal form of dextro-rabeprazole sodium anhydride comprises the following steps: dissolving amorphous dextral rabeprazole sodium in ethyl acetate with the volume of 5-20 times, stirring and dissolving at 20-50 ℃, filtering by using a microporous filter membrane, standing for crystallization, filtering and drying. The water content of the ethyl acetate used is less than 0.05%.
The following examples are intended to further illustrate the invention and should not be construed as limiting the invention.
EXAMPLE 1 amorphous preparation of D-rabeprazole sodium
15.0g of dextro-rabeprazole sodium is dissolved in 80ml of anhydrous dichloromethane, 20g of anhydrous magnesium sulfate is added, and stirring, drying and dehydration are carried out. Anhydrous magnesium sulfate is filtered out, the filtrate is distilled under reduced pressure to be dry, and then is dried under reduced pressure under high vacuum (< -0.099MPa) to be constant in weight, so that the dextro-rabeprazole sodium amorphous state is obtained.
Example 2 preparation of crystalline form II seeds of d-rabeprazole sodium
Dissolving 1.0g of dextro-rabeprazole sodium in 10ml of anhydrous ethyl acetate, stirring and dissolving the solution to be clear, and filtering the solution by a microporous filter membrane with the diameter of 0.4 mu m. The resulting solution was added to a petri dish with the liquid film thickness controlled below 1 mm. And (3) placing the watch glass into a closed container, and after ethyl acetate naturally diffuses, the crystallization process is approximately two-dimensional. And taking out after 24 hours to obtain the dextro-rabeprazole sodium crystal form II.
Example 3 preparation of crystalline form II of d-rabeprazole sodium
Under the protection of nitrogen, 5.0g of dextro-rabeprazole sodium amorphous is dissolved in 50ml of anhydrous ethyl acetate, stirred and dissolved to be clear, and filtered by a 0.4 mu m microporous filter membrane. Adding 100mg of seed crystal into the filtrate, and stirring at 20-25 ℃ for crystallization. Filtering and drying to obtain the dextro-rabeprazole sodium crystal form II.
Example 4 preparation of crystalline form II of dexrabeprazole sodium
Under the protection of nitrogen, 45g of amorphous dextral rabeprazole sodium is dissolved in 1550ml of anhydrous ethyl acetate, the temperature is raised to 35-40 ℃, the solution is stirred and dissolved clearly, and the solution is filtered by a 0.4-micron microporous membrane. Cooling the filtrate to 20-25 ℃, stirring and crystallizing, and protecting with nitrogen. Filtering and drying to obtain the dextro-rabeprazole sodium crystal form II.
EXAMPLE 5 preparation of crystalline form Z of D-rabeprazole sodium
2.0g of D-rabeprazole sodium crystal form II is added with 25ml of methyl isobutyl ketone and 0.5ml of purified water. Stirring for 24 hours at 15-25 ℃. Filtering and drying to obtain the D-rabeprazole sodium crystal form Z.
XRPD detection conditions
The instrument model is as follows: rigaku D/max 2550VB/PC diffractometer in Japan.
The measurement conditions were as follows: 40kv 100mA, Range:3-50 DEG, scan Rate: 6 °/min, step: 0.02 degree.
TGA detection conditions
The instrument model is as follows: TGA Q500 thermogravimetric analyzer.
The measurement conditions were as follows: mg of sample; the heating rate is 10 ℃/min.
The technical solutions described above only represent the preferred technical solutions of the present invention, and some possible modifications to some parts of the technical solutions by those skilled in the art all represent the principles of the present invention, and fall within the protection scope of the present invention.
Claims (4)
1. The crystal form of the dextro-rabeprazole sodium anhydrate is characterized in that the XRPD pattern 2 theta angle of the crystal form has main characteristic diffraction peaks at 4.3,4.9,6.1,9.2,9.6,10.4,11.0,11.6,13.6,17.7,18.3,19.2,20.0,20.9,22.4 and 23.6.
2. The crystalline form of rabeprazole sodium anhydrate of claim 1 which provides form I I of rabeprazole sodium crystalline form free of water of crystallization.
3. A method for preparing crystal form of dextro-rabeprazole sodium anhydride comprises the following steps: the method is characterized by dissolving amorphous dextro-rabeprazole sodium in ethyl acetate with the volume of 10 times, stirring and dissolving at 30-40 ℃, filtering by using a microporous filter membrane, standing for crystallization, filtering and drying. The water content of the ethyl acetate used is less than 0.05%.
4. A method for preparing crystal form of dextro-rabeprazole sodium anhydride comprises the following steps: the method is characterized by dissolving amorphous dextro-rabeprazole sodium in ethyl acetate with the volume of 5-20 times, stirring and dissolving at 20-50 ℃, filtering by using a microporous filter membrane, standing for crystallization, filtering and drying. The water content of the ethyl acetate used is less than 0.05%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113336741A (en) * | 2021-05-07 | 2021-09-03 | 湖南德虹制药有限公司 | Rabeprazole sodium anhydrate crystal form and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101343266A (en) * | 2008-06-23 | 2009-01-14 | 陕西新安医药科技有限公司 | Preparation method for optical pure rebeprazole |
| CN104311540A (en) * | 2014-10-22 | 2015-01-28 | 湖南明瑞制药有限公司 | Method for synthesizing rabeprazole sodium |
| CN104418841A (en) * | 2013-09-09 | 2015-03-18 | 江苏神龙药业有限公司 | Preparation methods of optically pure rabeprazole and sodium salt thereof |
| CN104910135A (en) * | 2014-03-11 | 2015-09-16 | 南京柯菲平盛辉制药有限公司 | Preparation method of new crystal form of dexrabeprazole sodium |
| CN109111428A (en) * | 2017-06-23 | 2019-01-01 | 南京海润医药有限公司 | A kind of dextral-rabeprazole sodium compound and its pharmaceutical composition |
| CN109111429A (en) * | 2017-06-23 | 2019-01-01 | 南京海润医药有限公司 | Dextral-rabeprazole sodium compound and its pharmaceutical composition |
-
2020
- 2020-04-10 CN CN202010278229.7A patent/CN111423412A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101343266A (en) * | 2008-06-23 | 2009-01-14 | 陕西新安医药科技有限公司 | Preparation method for optical pure rebeprazole |
| CN104418841A (en) * | 2013-09-09 | 2015-03-18 | 江苏神龙药业有限公司 | Preparation methods of optically pure rabeprazole and sodium salt thereof |
| CN104910135A (en) * | 2014-03-11 | 2015-09-16 | 南京柯菲平盛辉制药有限公司 | Preparation method of new crystal form of dexrabeprazole sodium |
| CN104311540A (en) * | 2014-10-22 | 2015-01-28 | 湖南明瑞制药有限公司 | Method for synthesizing rabeprazole sodium |
| CN109111428A (en) * | 2017-06-23 | 2019-01-01 | 南京海润医药有限公司 | A kind of dextral-rabeprazole sodium compound and its pharmaceutical composition |
| CN109111429A (en) * | 2017-06-23 | 2019-01-01 | 南京海润医药有限公司 | Dextral-rabeprazole sodium compound and its pharmaceutical composition |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113336741A (en) * | 2021-05-07 | 2021-09-03 | 湖南德虹制药有限公司 | Rabeprazole sodium anhydrate crystal form and preparation method thereof |
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