CN100429202C - Preparation method of amorphous fluvastatin sodium - Google Patents
Preparation method of amorphous fluvastatin sodium Download PDFInfo
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- CN100429202C CN100429202C CNB2006100522204A CN200610052220A CN100429202C CN 100429202 C CN100429202 C CN 100429202C CN B2006100522204 A CNB2006100522204 A CN B2006100522204A CN 200610052220 A CN200610052220 A CN 200610052220A CN 100429202 C CN100429202 C CN 100429202C
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- fluvastatin sodium
- alkane
- methyl alcohol
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Abstract
The present invention relates to a method for preparing amorphous fluvastatin sodium. Various defects exist in the prior art. The present invention comprises: firstly, the dissolution liquid of a saturated paraffin hydrocarbon methanol phase is prepared; crystal-type fluvastatin sodium is dissolved in the dissolution liquid; the distilled dissolution liquid of a saturated paraffin hydrocarbon methanol phase is circularly used as solvent used for dissolution when amorphous fluvastatin sodium is prepared, and the solvent can be directly and indiscriminately used without separation. Compared with the prior art, the present invention has the advantages of simple technology and high yield of amorphous fluvastatin sodium.
Description
Technical field
The invention belongs to pharmacy field, particularly relate to a kind of preparation method of amorphous fluvastatin sodium.
Background technology:
Fluvastatin sodium is a kind of blood lipid-lowering medicine, and its structural formula is as follows:
Fluvastatin sodium can exist by multiple crystal formation, and different crystal formations has different rerum naturas and bioavailability, it is generally acknowledged that amorphous fluvastatin sodium has better solubleness in vivo, thereby has better medicament activity and bioavailability.
About the existing two pieces of patent documentations report of the preparation method of amorphous fluvastatin sodium.
The WO2006038219 reported method is that fluvastatin sodium is dissolved in the methyl alcohol, vacuum concentration, the filtration crystallization of separating out, and drying obtains amorphous fluvastatin sodium.
The USP2005209259 reported method is that fluvastatin sodium is dissolved in the non-hydroxyl solvent (as THF), add non-polar solvent (as normal hexane, hexanaphthene, heptane) then to obtain the precipitation of product, the crystallization that filtration is separated out, dry amorphous fluvastatin sodium.
More than two kinds of methods when preparing amorphous fluvastatin sodium because fluvastatin sodium has big solubleness in methyl alcohol, THF, thereby yield is not high, and has the separation problem that can produce the azeotropic mixed solvent in second kind of preparation method.
Summary of the invention
Purpose of the present invention is exactly at the deficiencies in the prior art, proposes a kind of technical scheme of amorphous preparation method of fluvastatin sodium.
The present invention adopts following method to prepare amorphous fluvastatin sodium:
(1) at normal temperatures, alkane is constantly added in the methyl alcohol, stirring and dissolving reaches capacity, and makes the saturated methyl alcohol phased soln liquid of alkane, the solvent of dissolving usefulness when preparing as amorphous fluvastatin sodium.
(2) crystal type fluvastatin sodium input is had in the still kettle of whipping appts and distillation tower, add methyl alcohol phased soln liquid, be warming up to boiling, the crystal type fluvastatin sodium is dissolved fully.
(3) whipped state constantly drips alkane down, constantly steam the azeotrope of alkane and methyl alcohol simultaneously by distillation tower, with azeotrope layering in quantizer, lower floor is the saturated methyl alcohol phased soln liquid of alkane, the solvent of dissolving usefulness when collection prepares as the amorphous fluvastatin sodium of next batch separately, the upper strata is back to the top of distillation tower.
(4) when temperature reaches boiling point of alkanes in the distillation tower, stop distillation and drip alkane.Under the whipped state material in the distillation tower is cooled to 15～35 ℃, filters, filter cake vacuum-drying to residual solvent obtains amorphous fluvastatin sodium after reaching requirement, and filtrate drips the alkane of usefulness as next batch.
In the present invention, above-mentioned alkane is meant a kind of in normal hexane, hexanaphthene, the normal heptane.
The present invention is by preparing the saturated methyl alcohol phased soln liquid of alkane earlier, with the dissolving of crystal type fluvastatin sodium wherein, the solvent of dissolving usefulness used when the methyl alcohol phased soln liquid circulation that the alkane that distills out is saturated prepared as amorphous fluvastatin sodium, and solvent for use need not to separate again and can directly apply mechanically.The present invention is with respect to prior art, and technology is simple, the yield height of amorphous fluvastatin sodium.
Description of drawings
Fig. 1 is one embodiment of the invention process flow diagram;
Fig. 2 is the x-ray diffraction pattern of one embodiment of the invention;
Fig. 3 is the x-ray diffraction pattern of another embodiment of the present invention;
Fig. 4 is the x-ray diffraction pattern of further embodiment of this invention.
Embodiment
Below in conjunction with embodiment the present invention is described in detail.
Fig. 1 is one embodiment of the invention process flow diagram, wherein 1. still kettles, 2. alkane header tank, 3. distillation tower, 4. condenser, 5. quantizer, 6. methyl alcohol phase storage tank, 7. strainer, 8. filtrate tank, 9. vacuum drier.
20.0Kg crystal type fluvastatin sodium is dropped into the 500L band to be stirred and distillation tower 3 (diameter of phi 300,4 meters BX wire packings are housed) stainless steel still kettle 1 in, add the methyl alcohol 300L that uses the saturated mistake of normal hexane in advance, stir and be warming up to boiling, the fluvastatin sodium crystallization is dissolved fully.Open alkane header tank 2 valves, drip normal hexane, rate of addition is controlled at about 100L/hr.The alkane that the distillation cat head steams and azeotrope condensation in condenser 4 of methyl alcohol, regulate heating, the amount that makes methyl alcohol phase in the phlegma is about 100L/hr, layering in quantizer 5, constantly tell methyl alcohol and place methyl alcohol phase storage tank 6 mutually, the upper strata normal hexane all is back to the distillation tower top mutually.Behind about 3hr, when temperature in the kettle rises to normal hexane boiling point (68～69 ℃), stop to drip alkane, stop heating.Stir down material in the still kettle 1 is cooled to 35 ℃, use N
2Material in the still kettle is depressed in the strainer 7, press dry the back and take out filter cake, put to vacuum drier 9, be dried to and get amorphous fluvastatin sodium 19.7Kg after dissolvent residual reaches requirement, filtrate collection is applied mechanically when the amorphous fluvastatin sodium of next batch prepares in filtrate tank 8.
The x-ray diffraction pattern of pressing the prepared amorphous fluvastatin sodium of present embodiment as shown in Figure 2, fluvastatin sodium has reached amorphous as can be seen.
In the device identical, drop into 20.0Kg crystal type fluvastatin sodium with embodiment 1, the methyl alcohol of telling when batch distilling addings the in 300L that makes an appointment, stirring is warming up to boiling, and the fluvastatin sodium crystallization is dissolved fully.Open and drip valve, the mixed solution that the 50L normal hexane that drips the about 250L of filtrate among the embodiment 1 and add is formed, rate of addition is controlled at about 100L/hr, equally carries out component distillation, cooling, filtration, drying operation with embodiment 1, obtains amorphous fluvastatin sodium 20.0Kg.
In the device identical, drop into 20.0Kg crystal type fluvastatin sodium with embodiment 1, add the methyl alcohol 300L that uses the saturated mistake of hexanaphthene in advance, control distillation temperature in the kettle stops heating when reaching 80 ℃ of left and right sides and drips, stir down material is cooled to 15 ℃, other operation obtains amorphous fluvastatin sodium 19.8Kg at last with embodiment 1.
The x-ray diffraction pattern of pressing the prepared amorphous fluvastatin sodium of present embodiment as shown in Figure 3, fluvastatin sodium has reached amorphous as can be seen.
Embodiment 4
In the device identical, drop into 20.0Kg crystal type fluvastatin sodium with embodiment 1, add the methyl alcohol 300L that uses the saturated mistake of normal heptane in advance, control distillation temperature in the kettle stops heating when reaching 98 ℃ of left and right sides and drips, stir down material is cooled to 25 ℃, other operation finally obtains fluvastatin sodium 19.9Kg with embodiment 1.
The x-ray diffraction pattern of pressing the prepared amorphous fluvastatin sodium of present embodiment as shown in Figure 4, fluvastatin sodium has reached amorphous as can be seen.
Claims (2)
1, a kind of preparation method of amorphous fluvastatin sodium is characterized in that this method may further comprise the steps:
(1) at normal temperatures, alkane is constantly added in the methyl alcohol, stirring and dissolving reaches capacity, and makes the saturated methyl alcohol phased soln liquid of alkane, the solvent of dissolving usefulness when preparing as amorphous fluvastatin sodium;
(2) crystal type fluvastatin sodium input is had in the still kettle of whipping appts and distillation tower, add methyl alcohol phased soln liquid, be warming up to boiling, the crystal type fluvastatin sodium is dissolved fully;
(3) whipped state constantly drips alkane down, constantly steam the azeotrope of alkane and methyl alcohol simultaneously by distillation tower, with azeotrope layering in quantizer, lower floor is the saturated methyl alcohol phased soln liquid of alkane, the solvent of dissolving usefulness when collection prepares as the amorphous fluvastatin sodium of next batch separately, the upper strata is back to the top of distillation tower;
(4) when temperature reaches boiling point of alkanes in the distillation tower, stop distillation and drip alkane; Under the whipped state material in the distillation tower is cooled to 15～35 ℃, filters, filter cake vacuum-drying to residual solvent obtains amorphous fluvastatin sodium after reaching requirement, and filtrate drips the alkane of usefulness as next batch.
2, the preparation method of a kind of amorphous fluvastatin sodium as claimed in claim 1 is characterized in that described alkane is a kind of in normal hexane, hexanaphthene, the normal heptane.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100522204A CN100429202C (en) | 2006-06-30 | 2006-06-30 | Preparation method of amorphous fluvastatin sodium |
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| CNB2006100522204A CN100429202C (en) | 2006-06-30 | 2006-06-30 | Preparation method of amorphous fluvastatin sodium |
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| CN1876630A CN1876630A (en) | 2006-12-13 |
| CN100429202C true CN100429202C (en) | 2008-10-29 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001042209A1 (en) * | 1999-12-10 | 2001-06-14 | Lek Pharmaceutical And Chemical Company D.D. | Process for the preparation of amorphous atorvastatin |
| US20050209259A1 (en) * | 2004-03-17 | 2005-09-22 | Le Huang | Novel anhydrous amorphous forms of rosuvastatin calcium, pitavastatin calcium and fluvastatin sodium |
| WO2006030304A2 (en) * | 2004-09-17 | 2006-03-23 | Ranbaxy Laboratories Limited | Novel forms of fluvastatin sodium, processes for preparation and pharmaceutical compositions thereof |
| WO2006038219A1 (en) * | 2004-10-05 | 2006-04-13 | Biocon Limited | Process for the preparation of amorphous fluvastatin sodium |
| WO2006048893A2 (en) * | 2004-11-05 | 2006-05-11 | Morepen Laboratories Limited | A process for synthesis of large particle size statin compounds |
-
2006
- 2006-06-30 CN CNB2006100522204A patent/CN100429202C/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001042209A1 (en) * | 1999-12-10 | 2001-06-14 | Lek Pharmaceutical And Chemical Company D.D. | Process for the preparation of amorphous atorvastatin |
| US20050209259A1 (en) * | 2004-03-17 | 2005-09-22 | Le Huang | Novel anhydrous amorphous forms of rosuvastatin calcium, pitavastatin calcium and fluvastatin sodium |
| WO2006030304A2 (en) * | 2004-09-17 | 2006-03-23 | Ranbaxy Laboratories Limited | Novel forms of fluvastatin sodium, processes for preparation and pharmaceutical compositions thereof |
| WO2006038219A1 (en) * | 2004-10-05 | 2006-04-13 | Biocon Limited | Process for the preparation of amorphous fluvastatin sodium |
| WO2006048893A2 (en) * | 2004-11-05 | 2006-05-11 | Morepen Laboratories Limited | A process for synthesis of large particle size statin compounds |
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| CN1876630A (en) | 2006-12-13 |
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Address after: 318000 Jiefang Road, Jiaojiang District, Taizhou, Zhejiang Province, No. 83 Co-patentee after: Zhejiang University Patentee after: Zhejiang Le Pu pharmaceutical Limited by Share Ltd Address before: 318000 Jiefang Road, Jiaojiang District, Taizhou, Zhejiang Province, No. 83 Co-patentee before: Zhejiang University Patentee before: Xindonggang Pharmaceutical Co., Ltd., Zhejiang |
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