CN102070537B - Rosuvastatin calcium compound and novel refining method thereof - Google Patents
Rosuvastatin calcium compound and novel refining method thereof Download PDFInfo
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- CN102070537B CN102070537B CN201110032268XA CN201110032268A CN102070537B CN 102070537 B CN102070537 B CN 102070537B CN 201110032268X A CN201110032268X A CN 201110032268XA CN 201110032268 A CN201110032268 A CN 201110032268A CN 102070537 B CN102070537 B CN 102070537B
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- calcium
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- ion exchange
- rosuvastain
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Abstract
The invention provides a rosuvastatin calcium compound and a novel refining method thereof. The method comprises the following steps of: (1) performing absorption and ion exchange on the rosuvastatin calcium by using a highly-acid ion exchange resin; (2) performing elution by using aqueous solution of sodium hydroxide or aqueous solution of calcium bicarbonate; and (3) performing separation and purification by using a chromatographic column to obtain refined rosuvastatin calcium. In the refining method provided by the invention, the high-purity rosuvastatin calcium compound can be obtained; and the method greatly improves the purity of the rosuvastatin calcium, greatly increases rosuvastatin calcium content, improves the product quality of a preparation, reduces toxic or side effect, ensures the safety of clinical medication, low cost and high yield, and is simple and suitable for industrial production.
Description
Technical field
The present invention relates to a kind of Rosuvastatin calcium cpd and new preparation method thereof, belong to medical technical field.
Background technology
Rosuvastain calcium is the Statins blood lipid regulation medicine by the research and development of Japanese Shionogi company; Go on the market in Holland in November, 2002; English by name: Rosuvastatin Calcium, chemical name is: two-(E)-and 7-[4-(the fluorine-based phenyl of 4-)-6-sec.-propyl-2-[methyl (methylsulfonyl) amino]-pyrimidine-5-yl] (3R, 5S)-3; 5-hydroxyl heptan-6-olefin(e) acid] calcium salt (2:1), molecular formula: (C
22H
27FN
3O
6S) 2Ca, molecular weight: 1001.15, structural formula is:
Rosuvastain calcium is white or off-white powder, odorless, and mildly bitter flavor dissolves in the methyl alcohol part omitted, and soluble,very slightly in ethanol is prone to dissolve in water.
Statins is HMG CoA (HMG-CoA) reductase inhibitor, is to use blood lipid regulation medicine the most widely at present clinically.Its main mechanism is to suppress the HMG-CoA reductase enzyme of SUV route of synthesis, can reduce low density lipoprotein cholesterol (LDL-C) level in the blood effectively, and various types of hyperlipidaemias are all had certain curative effect.Therefore rosuvastain calcium is the newcomer of statins family, because of it shows strong effect for reducing fat in many clinical studyes, is paid close attention to by many cardiovascular and mellitus domain experts already.
Rosuvastain calcium is that raw material is synthetic through different route reactions by isobutyryl methyl acetate and p-Fluorobenzenecarboxaldehyde, but the final product yield that obtains is not high, and purity is low, is not suitable for suitability for industrialized production.
The method that obtains high purity, high yield, high-load Singulair sodium compound becomes the focus of current research.
Summary of the invention
In order to overcome the defective of above-mentioned prior art; Particularly overcome the low defective of rosuvastain calcium purity of prior art for preparing, the invention provides a kind of new preparation method of rosuvastain calcium, it is made with extra care through rosuvastain calcium; Obtain the high purity rosuvastain calcium with high yield; Improve the quality product of preparation, reduce toxic side effect, ensure safety of clinical administration.
The rosuvastain calcium that process for purification provided by the invention was directed against is prepared rosuvastain calcium bullion of present known compound method or commercially available Rosuvastatin calcium raw material drug, below is referred to as raw material rosuvastain calcium or rosuvastain calcium bullion that the present invention adopts.
The inventor through comprising the process for purification of following treatment step, can increase substantially the purity of raw material rosuvastain calcium through discovering with keen determination:
(1) with strong-acid ion exchange resin rosuvastain calcium is adsorbed and IX, the form that makes rosuvastain calcium convert Rosuvastatin acid into is adsorbed on the resin;
(2) carry out wash-out with the calcium hydroxide aqueous solution or the Calcium hydrogen carbonate aqueous solution, make Rosuvastatin acid be converted into the form and the dissolving of rosuvastain calcium, collect elutriant, remove by filter insolubles, get the wash-out mother liquor;
(3) the wash-out mother liquor is carried out separation and purification through chromatographic column, collect elutriant, concentrating under reduced pressure, vacuum-drying obtains the purified rosuvastain calcium.
Through aforesaid method, can obtain highly purified rosuvastain calcium with high yield from the rosuvastain calcium bullion.
Embodiment
Describe the present invention below in conjunction with embodiment.Characteristics of the present invention and advantage can become more clear along with these descriptions.
Step (1)
In the step (1) of the process for purification of Rosuvastatin calcium cpd provided by the invention; With strong-acid ion exchange resin rosuvastain calcium is adsorbed and IX, the form that makes rosuvastain calcium convert Rosuvastatin acid into is adsorbed on the resin.
Can use the water dissolution rosuvastain calcium, then gained solution carried out IX and adsorption treatment through strong-acid ion exchange resin, make rosuvastain calcium be converted into the form of Rosuvastatin acid and be adsorbed on the resin.
Generally will on the crosslinking structure macromolecule matrix, have sulfonic ion exchange resin and be called strong-acid ion exchange resin, show acidity through dissociateing hydrogen ion.Its acidity is equivalent to mineral acids such as sulfuric acid, hydrochloric acid, in alkalescence, neutrality even acidic medium, all shows ion exchanging function.Generally commonly used is with the strongly acidic cationic exchange resin that vinylbenzene-divinylbenzene copolymerization spheroid is the basis, is to obtain with the above copolymerization spheroid of sulfonation such as the vitriol oil or oleum, chlorsulfonic acid.
Generally speaking, also contain the solvent of introducing in the preparation process, various raw material and intermediate product in the raw material rosuvastain calcium, owing to drawing the moist moisture of bringing into, bacterial endotoxin, and various inorganics and heavy metal etc.These materials exist with the impurity form, influence the purity of rosuvastain calcium.Highly acidic resin used in the present invention has the general utility functions of ion exchange resin.When contacting with the solution that contains rosuvastain calcium, except playing ion exchange, also have the function of absorption nonelectrolyte class material from solution, therefore can adsorb above-mentioned remaining impurity property material; In addition, itself has decolorization resin, can remove the impurity of colour developing, and its effect is superior to gac.
The present invention can use common strong-acid ion exchange resin, D001 type strongly acidic styrene type cation exchange resin for example, and GB/T 13659-2008001 * 7 strongly acidic styrene type cation exchange resins, or the like.Above-mentioned these strong acidic ion resins all are commercial prods, can certainly use the macroporous type strong-acid ion exchange resin of other trade names.
According to the present invention, the solution that contains rosuvastain calcium can adopt the technology of continous way or discontinuous formula through strong acidic ion resin.Particularly, comprise batch process, fixed-bed process and continuous process.
Batch operation is in retort, to carry out, and will exchange solution from the bottom gets into jar, then feeds gas continuously and makes the resin fluidization or add stirring with speeding-up ion exchange equilibrium process, reach balance after exchange process just stop, emitting solution from the bottom then.
Fixed-bed process is to fill out ion exchange resin to be placed on to form resin bed in the exchange column, feeds solution then and handles.Solution usually is that from the top down concurrent is carried out in the fixed bed operation, also can be opposite with the flow direction of exchange solution, and the counter-current regeneration mode that feeds from bottom to top can also adopt the convection reflux type in addition.
Rosuvastain calcium has carboxyl, itself is again high polar material, and behind strong-acid ion exchange resin, sodium ion is exchanged by hydrogen ion, generates Rosuvastatin acid, and the pH value decreases, and the Rosuvastatin acid of generation is adsorbed on the resin.
Step (2)
In the step (2) of the process for purification of Rosuvastatin calcium cpd provided by the invention; Carry out wash-out with the calcium hydroxide aqueous solution or the Calcium hydrogen carbonate aqueous solution, make Rosuvastatin acid be converted into the form and the dissolving of rosuvastain calcium, collect elutriant; Remove by filter insolubles, get the wash-out mother liquor.
When carrying out wash-out with the calcium hydroxide aqueous solution or the Calcium hydrogen carbonate aqueous solution; Rosuvastatin acid reacts with calcium hydroxide or Calcium hydrogen carbonate, generates rosuvastain calcium and water and carbonic acid gas, and rosuvastain calcium is dissolved in the elutriant; Thereby along with elutriant flows out; Carbonic acid gas is discharged system subsequently, does not introduce impurity, and this possibly be through a high reason of the inventive method products obtained therefrom purity.
As elutriant; Its concentration is not special to be limited; For example can use saturated calcium hydroxide aqueous solution or unsaturation calcium hydroxide aqueous solution or the mass percent concentration calcium hydroxide aqueous solution as 0.1-2.5%, the preferred mass percentage concentration is the calcium hydroxide aqueous solution of 0.5-1.0%.
Because the speed of above-mentioned reaction is comparatively slow; Therefore when wash-out; Need the speed of control wash-out, promptly elutriant flows through the speed of ion exchange resin, makes elutriant flow through resin lentamente; Thereby make conversion that Rosuvastatin acid goes to rosuvastain calcium fully and the dissolving of rosuvastain calcium complete, therefore improve eluted mass.
Preferably, elutriant flows through the speed of ion exchange resin in the 0.5-3.0ml/min scope, in the preferred 1.0-2.0ml/min scope, and 1.5ml/min more preferably from about.Elution speed in this scope helps Rosuvastatin acid to be converted into rosuvastain calcium fully.
After the elutriant of collecting during with wash-out removes by filter insolubles, obtain the wash-out mother liquor.
Behind the wash-out, for ion exchange resin, can use usual manner regeneration.For example, ion exchange resin is used water washing, use immersions such as strong acid such as sulfuric acid then.After the resin regeneration, can reuse in method of the present invention.
In step (2), as replacement, also can carry out through following mode: the sour example hydrochloric acid solution with common carries out wash-out (regeneration of resin); The Rosuvastatin pickling of absorption is taken off; Collect elutriant, concentrating under reduced pressure neutralizes with the calcium hydroxide aqueous solution or the aqueous solution; Regulate the pH value, remove by filter insolubles.
In above-mentioned alternate embodiment, be converted into rosuvastain calcium fully in order to make Rosuvastatin acid, the pH value is adjusted to more than 6.5 in this step, preferred pH value 7.5-9.0.
Though do not receive the constraint of any principle; Step of the present invention (2) is with being with Rosuvastatin acid and then the reason of putting forward rosuvastain calcium purity in the calcium hydroxide aqueous solution or the Calcium hydrogen carbonate aqueous solution: because rosuvastain calcium is soluble in water; So acquisition rosuvastain calcium in the Meng needs accurately control pH value from the aqueous solution, and if not filtering words are also carried insoluble substance unavoidably secretly.In this step, directly form the aqueous solution of rosuvastain calcium, remove by filter insolubles again, improved title product purity.
But, from the angle that operating procedure simplicity and operation are easy to control, the alternate embodiment of above-mentioned steps (2) is more not preferred.In addition, the inventor finds to state in the use under the situation of alternate embodiment of step (2), the somewhat lower purity of products therefrom.
Step (3)
In the step (3) of the process for purification of Rosuvastatin calcium cpd provided by the invention, the wash-out mother liquor is carried out separation and purification through chromatographic column, collect elutriant, concentrating under reduced pressure, vacuum-drying obtains the purified rosuvastain calcium.
As the chromatographic column of using here, stationary phase wherein uses silica gel or aluminum oxide.
As moving phase, methyl alcohol and the volume that preferably uses volume to account for moving phase 15-40% accounts for the mixed solution of 59% the calcium chloride water of moving phase 60-85%.
Preferably, the flow velocity of moving phase is 2.4-5.0ml/min, preferred 4.0ml/min, and the temperature of chromatographic column is 20-30 ℃.
As drying mode, adopt vacuum-drying.
For the rosuvastain calcium that makes through process for purification of the present invention, its purity is very high, and yield is also higher.Detect through HPLC, show that the purity of the rosuvastain calcium that obtains through the inventive method can be up to more than 99.5%.
The heavy metal content of the rosuvastain calcium that makes through process for purification provided by the invention in addition, is extremely low.
The purity of rosuvastain calcium is obvious to the influence of its powder flowbility, intrinsic dissolution rate, Pickering property and the preparation quality prepared; The rosuvastain calcium that purity is improved also correspondingly improves in these areas; Thereby improve the quality product of preparation; Reduce toxic side effect, ensured safety of clinical administration.And present method technology is simple, and cost is low, and yield is high, is suitable for suitability for industrialized production.
In this article; If not explanation especially; Content or consumption are all in weight part; The device that is adopted, instrument, raw material, material, consumption, method, time, appropriateness and other conditions all are well-known in the art, or those skilled in the art combine prior art to obtain according to the description of applying for.
Embodiment
Below further specify the present invention through embodiment, but the present invention is not limited to the preparation method of these embodiment and use.And those skilled in the art can be equal to replacement, combination, improvement or modification to the present invention according to description of the invention, but these all will comprise within the scope of the invention.
The D001 type strongly acidic styrene type cation exchange resin that uses in following examples, GB/T 13659-2008001 * 7 strongly acidic styrene type cation exchange resins are that the resin that extensively adopts is gone up in industry, can be buied by commercially available.
Making with extra care of embodiment 1 rosuvastain calcium
The 100g rosuvastain calcium is dissolved in the 2000ml water, adds and to be filled with in the fixed bed of D001 type strongly acidic styrene type cation exchange resin, continue exchange, for the time 2.5 hours.
The Calcium hydrogen carbonate aqueous solution with 1% carries out wash-out, and elution speed is 1.5ml/min, collects elutriant, and elutriant is filtered, and obtains the wash-out mother liquor.
The wash-out mother liquor is passed through silica gel chromatographic column; Wherein the moving phase used of the chromatographic column methyl alcohol and the volume that account for moving phase 15% as volume accounts for the mixed solution of 59% calcium chloride water of moving phase 85%, and fixed phase stuffing is a silica gel, and flow velocity is 2.4ml/min; Detect wavelength 242nm, column temperature: 30 ℃.Collect filtrating, 50 ℃ of drying under reduced pressure get rosuvastain calcium 87.1g, yield 87.1%, and purity is 99.8%.
Making with extra care of embodiment 2 rosuvastain calciums
The 100g rosuvastain calcium is dissolved in the 2000ml water, adds and to be filled with in the fixed bed of D001 type strongly acidic styrene type cation exchange resin, continue exchange, for the time 2.5 hours.
Carry out wash-out with saturated calcium hydroxide aqueous solution, elution speed is 2.0ml/min, collects elutriant, and elutriant is filtered, and obtains the wash-out mother liquor.
The wash-out mother liquor is passed through silica gel chromatographic column; Wherein the moving phase used of the chromatographic column methyl alcohol and the volume that account for moving phase 40% as volume accounts for the mixed solution of 59% calcium chloride water of moving phase 60%, and fixed phase stuffing is a silica gel, and flow velocity is 5.0ml/min; Detect wavelength 242nm, column temperature: 20 ℃.Collect filtrating, 50 ℃ of drying under reduced pressure get rosuvastain calcium 85.4g, yield 85.4%, and purity is 99.6%.
Making with extra care of embodiment 3 rosuvastain calciums
The 50g rosuvastain calcium is dissolved in the 1000ml water, adds and to be filled with in the fixed bed of D001 type strongly acidic styrene type cation exchange resin, continue exchange, for the time 2.5 hours.
Carry out wash-out with the 0.5% Calcium hydrogen carbonate aqueous solution, elution speed is 1.0ml/min, collects elutriant, and elutriant is filtered, and obtains the wash-out mother liquor.
The wash-out mother liquor is passed through silica gel chromatographic column; Wherein the moving phase used of the chromatographic column methyl alcohol and the volume that account for moving phase 30% as volume accounts for the mixed solution of 59% calcium chloride water of moving phase 70%, and fixed phase stuffing is a silica gel, and flow velocity is 4.0ml/min; Detect wavelength 242nm, column temperature: 20 ℃.Collect filtrating, 50 ℃ of drying under reduced pressure get rosuvastain calcium 43.7g, yield 87.4%, and purity is 99.7%.
Making with extra care of embodiment 4 rosuvastain calciums
The 100g rosuvastain calcium is dissolved in the 2000ml water, adds and to be filled with in the fixed bed of D001 type strongly acidic styrene type cation exchange resin, continue exchange, for the time 2.5 hours.
The Calcium hydrogen carbonate aqueous solution with 0.1% carries out wash-out, and elution speed is 3.0ml/min, collects elutriant, and elutriant is filtered, and obtains the wash-out mother liquor.
The wash-out mother liquor is passed through silica gel chromatographic column; Wherein the moving phase used of the chromatographic column methyl alcohol and the volume that account for moving phase 25% as volume accounts for the mixed solution of 59% calcium chloride water of moving phase 75%, and fixed phase stuffing is a silica gel, and flow velocity is 4.5ml/min; Detect wavelength 242nm, column temperature: 20 ℃.Collect filtrating, 50 ℃ of drying under reduced pressure get rosuvastain calcium 89.9g, yield 89.9%, and purity is 99.8%.
Making with extra care of embodiment 5 rosuvastain calciums
The 50g rosuvastain calcium is dissolved in the 1000ml water, adds and to be filled with in the fixed bed of D001 type strongly acidic styrene type cation exchange resin, continue exchange, for the time 2.5 hours.
The Calcium hydrogen carbonate aqueous solution with 2.5% carries out wash-out, and elution speed is 0.5ml/min, collects elutriant, and elutriant is filtered, and obtains the wash-out mother liquor.
The wash-out mother liquor is passed through silica gel chromatographic column; Wherein the moving phase used of chromatographic column accounts for the mixed solution that methyl alcohol and volume that moving phase accounts for moving phase 25% as volume account for 59% calcium chloride water of moving phase 75% as volume; Fixed phase stuffing is a silica gel; Flow velocity is 5.0ml/min, detects wavelength 242nm, column temperature: 25 ℃.Collect filtrating, 50 ℃ of drying under reduced pressure obtain rosuvastain calcium 42.5.g, yield 83%, and HPLC purity is 99.5%.
Making with extra care of embodiment 6 rosuvastain calciums
To carry out the refining of Menglusitena with embodiment 1 identical mode; Difference only is: the hydrochloric acid soln with 0.5% carries out wash-out, and elution speed is 1.0ml/min, collects elutriant; 60 ℃ of concentrating under reduced pressure; Using 1% calcium hydroxide aqueous solution to regulate the pH value is 7.8, removes by filter insolubles, obtains the wash-out mother liquor.
Get rosuvastain calcium 82.1g, yield 82.1%, purity is 99.5%.
Claims (7)
1. the method for making of the Rosuvastatin calcium cpd of structure shown in the formula (I),
It is characterized in that comprising the steps:
(1) with strong-acid ion exchange resin rosuvastain calcium is adsorbed and IX; The form that makes rosuvastain calcium convert Rosuvastatin acid into is adsorbed on the resin, and said Zeo-karb is D001 type strongly acidic styrene type cation exchange resin or GB/T 13659-2008001 * 7 strongly acidic styrene type cation exchange resins;
(2) carry out wash-out with the calcium hydroxide aqueous solution or the Calcium hydrogen carbonate aqueous solution, make Rosuvastatin acid be converted into the form and the dissolving of rosuvastain calcium, collect elutriant, remove by filter insolubles, get the wash-out mother liquor;
(3) the wash-out mother liquor is carried out separation and purification through chromatographic column, collect elutriant, concentrating under reduced pressure; Vacuum-drying; Obtain the purified rosuvastain calcium, as chromatographic column, stationary phase wherein uses silica gel or aluminum oxide; As moving phase, methyl alcohol and the volume that uses volume to account for moving phase 15-40% accounts for the mixed solution of 59% the calcium chloride water of moving phase 60-85%.
2. method for making according to claim 1 wherein, in step (1), is used the water dissolution rosuvastain calcium, then gained solution is carried out IX and adsorption treatment through strong-acid ion exchange resin.
3. method for making according to claim 1, wherein, in step (2), elutriant flows through the speed of ion exchange resin in the 0.5-3.0ml/min scope.
4. method for making according to claim 1, wherein, in step (2), elutriant flows through the speed of ion exchange resin in the 1.0-2.0ml/min scope.
5. method for making according to claim 1, wherein, in step (2), the speed that elutriant flows through ion exchange resin is 1.5ml/min.
6. method for making according to claim 1, wherein, in step (3), the flow velocity of moving phase is 2.4-5.0ml/min, the temperature of chromatographic column is 20-30 ℃.
7. method for making according to claim 1, wherein, in step (3), the flow velocity of moving phase is 4.0ml/min, the temperature of chromatographic column is 20-30 ℃.
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|---|---|---|---|
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