WO2012142816A1 - Benidipine hydrochloride nanoparticles and preparation method thereof - Google Patents
Benidipine hydrochloride nanoparticles and preparation method thereof Download PDFInfo
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- WO2012142816A1 WO2012142816A1 PCT/CN2011/080294 CN2011080294W WO2012142816A1 WO 2012142816 A1 WO2012142816 A1 WO 2012142816A1 CN 2011080294 W CN2011080294 W CN 2011080294W WO 2012142816 A1 WO2012142816 A1 WO 2012142816A1
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- C—CHEMISTRY; METALLURGY
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- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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Abstract
A method to prepare nanoparticles of benidipine hydrochloride and the preparation method thereof via ultrasonic techniques are disclosed.
Description
Benidipine hydrochloride nanoparticles and preparation method thereof
Field of the invention
The present invention relates to the field of medicine, more specifically to nanoparticles of benidipine hydrochloride ((±)-(R*)-l,4-dihydro- 2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate [(R*)-l- benzyl-3-piperidine alcohol ester]) and the preparation method thereof.
Background of the invention
Dihydropyridine calcium channel blockers are safe and effective, which have nowadays been clinically used widely. Inter alia, benidipine hydrochloride has unique inhibitory effect on three channels and high affinity to cell membrane, vascular selectivity and has a renal protection effect. Therefore, it is an ideal, safe and effective drug useful for treatment of hypertension, renal parenchymal hypertension, angina and the like.
Because benidipine hydrochloride has a very low solubility, for dissolving in a solvent quickly, benidipine hydrochloride is often grounded into nanoparticles. CN 1794993 A provided a method to grind benidipine hydrochloride into particles of 1.0^50.0 μπι. The mechanical grinding method is performed by grinding larger particles of crystals into desired smaller size of crystals. This method consumes large amount of energy and time, and results in a widely distribution of the crystal particle size.
The present inventor surprisingly found the desired sizes of benidipine hydrochloride nanoparticles could be obtained by ultrasonic crystallization technology. Unlike the method of CN 1794993 A, the method according to the present invention obtains crystals from smaller to larger sizes. The distribution of particle sizes in the method of the present invention is relatively narrower since the solvent crystalizes rapidly and steadily in the solution. Overall, the present invention can save time and energy, and is readily for preparation.
Summary of the invention
This present invention provides a method for preparing nanoparticles of benidipine hydrochloride by ultrasonic technology.
Conventional crystallization of solution is typically achieved by decreasing temperature and allowing standing, which is a slow and long-time procedure. However, the ultrasonic crystallization method in the present invention comprises first forming a saturated or oversaturated solution of benidipine hydrochloride, by changing temperature, solvent polarity or by adding inferior solvent and the like, and then obtaining nanoparticles of appropriate size by ultrasound application. Ultrasonic crystallization of the solution is carried out quickly and in an equilibrated fashion. The differences of crystallization solution, crystallization style, crystal growth rate, and mode of bonding between molecules inevitably lead to different molecular crystal forms and sizes.
Preparing of benidipine hydrochloride nanoparticles in the present invention, benidipine hydrochloride may be dissolved in a good solvent, then a saturated or oversaturated solution could be formed by changing temperature, solvent polarity or adding inferior solvent, and then ultrasound is applied to promote crystallization of solution. Then, highly purified benidipine hydrochloride nanoparticles can be obtained by conventional operations, such as filtering (filtering in a vacuum), washing or drying.
The superior or inferior solvents used to dissolve and/or to form benidipine hydrochloride nanoparticles are typically lower-carbon-number ketones, lower-carbon-number alcohols, lower-carbon-number ethers, lower-carbon-number esters, acetonitrile, dichloromethane, chloroform, acetic anhydride and other commonly used small molecule solvents. Preferred solvents are acetone, ethanol, methanol, Ν,Ν-dimethylformamide, acetonitrile, diethyl ether, dichloromethane, dimethyl sulfoxide (DMSO) and water alone, or the combination of two or more above-mentioned solvents. Ethanol and acetonitrile are preferred single solvents, while ethanol-acetone, DMF-water, acetonitrile-water, acetonitrile-acetone, ethanol-water, ethanol-acetone-water are preferred combined solvents. Among them, the
ratio of ethanol and acetone is 0—100% : 100—0%. The ratio of DMF and water is 0—100% : 100—0%. The ratio of DMF and acetone is 0— 100% : 100—0%. The ratio of acetonitrile and water is 100—0% : 0— 100%. The ratio of acetonitrile and acetone is 100—0% : 0—100%. The ratio of ethanol and water is 100—0% : 0—100%. The ratio of ethanol, acetone and water is 1—5 : 1—5 : 0.1—500.
The frequency of ultrasonic crystallization is 20 kHz— 500 kHz, preferably 20kHz to 100kHz. The power for ultrasonic is in the range of 1 mW— 5000 W, preferably 1 W— 500 W. The intensity is 0.1 mW/cm2—
500 W/cm 2 , preferably 0.1 W/cm 2—50 W/cm 2 ; the ultrasonic time is 1 min— 24 hours, preferably 3 mins— 120 mins. The ultrasonic crystallization temperature is -78 °C~100°C , and preferably -5 °C ~30°C . The size of benidipine hydrochloride nanoparticles is between 20 nm ~2000 nm, and the median thereof is 300 nm~1500 nm.
Brief description of the drawings
Fig. 1 shows crystal nanoparticles with an average particle size of 434.3 nm;
Fig. 2 shows crystal nanoparticles with an average particle size of 447.2 nm;
Fig. 3 shows crystal nanoparticles with an average particle size of 677.8 nm;
Fig. 4 shows crystal nanoparticles with an average particle size of 710.8 nm;
Fig. 5 shows crystal nanoparticles with an average particle size of 1159.0 nm;
Fig. 6 shows crystal nanoparticles with an average particle size of 1220.0 nm; and
Fig. 7 shows crystal nanoparticles with an average particle size of 1492.0 nm.
The specific operations are as follows:
Add 0.1-40 times of lower-carbon-number alcohol to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then decrease the temperature and sonicate to assist crystallization.
Alternatively, add 0.1-40 times of lower-carbon-number alcohol into an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then add 0.01-100 times of water, decrease the temperature and sonicating to assist crystallization.
Alternatively, add 0.1-40 times of lower-carbon-number alcohol to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then add 1/100 times of water, and sonicate while dripping water for crystallization.
Alternatively, to add 0.1-40 times of lower-carbon-number alcohol to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then add 0.01-100 times of acetone, decrease the temperature and sonicating to assist crystallization.
Alternatively, add 0.1-40 times of lower-carbon-number alcohol to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then add 1/10 times of acetone while sonicate, when crystals begins to precipitate stop addition of acetone, then perform further sonication (not more than 60 minutes).
Alternatively, add 0.1-15 times of Ν,Ν-dimethylformamide (DMF) to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then add 0.1-100 times of water, decrease the temperature and sonicating to assist crystallization.
Alternatively, add 0.1-15 times of DMF to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then adding 1/100 times of water, and sonicate while drip water for crystallization.
Alternatively, add 0.1-15 times of DMF to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then adding 0.1-100 times of acetone, decrease the temperature and sonicating to assist crystallization.
Alternatively, add 0.1-15 times of DMSO to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then add 0.1-100 times of water, decreasing the temperature and sonicate to assist crystallization.
Alternatively, add 0.1-15 times of DMF to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then add 0.1-100 times of acetone while sonicating, when crystals begins to precipitate stop addition of acetone, then perform further sonication (not more than 60 minutes).
Alternatively, add 0.1-40 times of acetonitrile to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, decrease the temperature and sonicate to assist crystallization.
Alternatively, add 0.1-40 times of acetonitrile to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then add 0.1-100 times of water, decrease the temperature and sonicate to assist crystallization.
Alternatively, add 0.1-40 times of acetonitrile to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then add 1/100 times of water, and sonicate while drip water for crystallization.
Alternatively, add 0.1-40 times of acetonitrile to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then add 0.1-100 times of acetone, decrease the temperature and sonicate to assist crystallization.
Alternatively, add 0.1-40 times of acetonitrile to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then add 0.1 times of acetone while sonicate, when crystals begins to precipitate stop addition of acetone, then perform further sonication (not more than 60 minutes).
Alternatively, add 0.1-40 times of ethanol to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then add 0.1-100 times of acetone, sonicate,
when crystals begins to appear add 0.1-1000 times of water, then perform further sonication for 1-60 minutes.
Alternatively, add 0.1-40 times of acetonitrile to an appropriate amount of benidipine hydrochloride primary crystal as raw material, heat under refluxing for dissolution, then add 0.1-100 times of acetone, add slowly 0.1-1000 times of water, then sonicatr for 1-60 minutes.
Detailed description of the invention
The invention will be described in detail in combination with the following examples.
Example 1
10 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of absolute ethanol. The reaction mixture was heated under refluxing for dissolving , cooled by ice-bath, and sonicated at 150 W for 10 min to assist crystallization, then was filtered in vacuum to obtain a product as light yellow crystal. The size of the crystal form is shown in Figure 1.
Example 2
10.1 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of methanol. The reaction mixture was heated under refluxing for dissolution, cooled by ice-bath, and sonicated at 150 W for 10 min to assist crystallization, then was filtered in vacuum to obtain a product as light yellow crystal.
Example 3
10.2 g of benidipine hydrochloride primary crystal as raw material was added into 12 mL of absolute ethanol. The reaction mixture was heated under refluxing for dissolution, to which 12 ml water was added. The reaction mixture was cooled by ice-bath, and sonicated at 150 W, when crystal appears, performing further sonication for 2 minutes.
Example 4
10 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of methanol. The reaction mixture was heated under
refluxing for dissolving, and then 20 ml of water was added. The reaction mixture was cooled by ice-bath, and sonicated at 150 W, when crystal appears, continuously sonication for 70 minutes.
Example 5
10 g of benidipine hydrochloride primary crystal as raw material was added into 12 mL of absolute ethanol. The reaction mixture was heated under refluxing for dissolution, to which 3 ml water was added. The reaction mixture was sonicated at 150 W, and water was added dropwise until the crystallization was complete.
Example 6
10 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of methanol. The reaction mixture was heated under refluxing for dissolution, to which 3 ml water was added. The reaction mixture was sonicated at 150 W, to which water was added dropwise until the crystallization was complete.
Example 7
10.3 g of benidipine hydrochloride primary crystal as raw material was added into 11 mL of absolute ethanol. The reaction mixture was heated under refluxing for dissolution, to which 11 ml acetone was added. The reaction mixture was cooled by ice-bath, and sonicated at 200 W to assist crystallization.
Example 8
10.1 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of methanol. The reaction mixture was heated under refluxing for dissolution, to which 10 ml acetone was added. The reaction mixture was cooled by ice-bath, and sonicated at 200 W to assist crystallization.
Example 9
10.1 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of absolute ethanol. The reaction mixture was heated under refluxing for dissolution, to which 3 ml acetone was added. The reaction mixture was sonicated at 200 W, to which acetone was added
dropwise until crystal began to appear, then further sonication was performed for 3 minutes.
Example 10
10 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of methanol. The reaction mixture was heated under refluxing for dissolution, to which 3 ml acetone was added. The reaction mixture was sonicated at 200 W, to which acetone was added dropwise until crystal began to appear, then further sonication was performed for 3 minutes.
Example 11
10.1 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of DMF. The reaction mixture was heated under refluxing for dissolution, to which 10 ml water was added. The reaction mixture was sonicated at 200 W to assist crystallization.
Example 12
10 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of DMF. The reaction mixture was heated under refluxing for dissolution, to which 5 ml water was added. The reaction mixture was sonicated at 150 W, to which water was added dropwise until the crystallization was complete.
Example 13
10 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of DMF. The reaction mixture was heated under refluxing for dissolution, to which 10 ml acetone was added. The reaction mixture was cooled by ice-bath, and sonicated at 200 W to assist crystallization.
Example 14
10 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of DMF. The reaction mixture was heated under refluxing for dissolution, to which 3 ml acetone was added. The reaction mixture was sonicated at 200 W, to which acetone was added dropwise until crystal began to appear, then further sonication was performed for 4
minutes.
Example 15
10 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of acetonitrile. The reaction mixture was heated under refluxing for dissolution and cooled by ice-bath, and sonicated at 150 W to assist crystallization.
Example 16
10.1 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of acetonitrile. The reaction mixture was heated under refluxing for dissolution, to which 10 ml water was added. The reaction mixture was cooled by ice-bath, and sonicated at 150 W to assist crystallization.
Example 17
10 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of acetonitrile. The reaction mixture was heated under refluxing for dissolution, to which 3 ml water was added. The reaction mixture was sonicated at 150 W, to which water was added dropwise until the crystallization was complete.
Example 18
10.1 g of benidipine hydrochloride primary crystal as raw material was added into 11 mL of acetonitrile. The reaction mixture was heated under refluxing for dissolution, to which 10 ml acetone was added. The reaction mixture was cooled by ice-bath, and sonicated at 200 W to assist crystallization.
Example 19
10.1 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of acetonitrile. The reaction mixture was heated under refluxing for dissolution, to which 3 ml acetone was added. The reaction mixture was sonicated at 200 W, to which acetone was added dropwise until crystal began to appear, then further sonication was performed for 3 minutes.
Example 20
10 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of ethanol. The reaction mixture was heated under refluxing for dissolution, to which 20 ml acetone was added. The reaction mixture was sonicated at 200 W, when small amount of crystal began to appear more than 20 ml water was added and a large amount of crystal began to appear, then further sonication was performed for 3 minutes.
Example 21
10 g of benidipine hydrochloride primary crystal as raw material was added into 10 mL of DMSO. The reaction mixture was heated under refluxing for dissolution, to which 30 ml water was added. The reaction mixture was sonicated at 200 W to assist crystallization.
Claims
1. A method for preparing benidipine hydrochloride by ultrasonic crystallization techniques.
2. The method according to claim 1, which is performed by first forming a saturated or oversaturated solution of benidipine hydrochloride by changing temperature, solvent polarity or adding inferior solvents, then obtaining nanoparticles with suitable size by sonication.
3. The method according to Claim 1 or Claim 2, wherein the temperature for preparing benidipine hydrochloride by sonication is -78 °C ~ 100 °C , preferably -5 °C -30 °C .
4. The method according to Claim 1 or Claim 2, wherein the solvent for preparing benidipine hydrochloride nanoparticles by sonication is lower-carbon-number ketone, lower-carbon-number alcohol, lower-carbon-number ether, lower-carbon-number acid, lower-carbon-number ester, dichloromethane, chloroform, acetic anhydride or commonly used small molecule solvents, prefereably acetone, ethanol, methanol, N,N-dimethylformamide(DMF), acetonitrile, dimethyl ether, dichloromethane, dimethyl sulfoxide (DMSO) or water alone, or a combination of two or more above-mentioned solvents.
5. The method according to Claim 1 or Claim 2, wherein the ultrasonic frequency is 20kHz - 500kHz, preferably 20kHz^ l00kHz.
6. The method according to Claim 1 or Claim 2, wherein the ultrasonic power is lmW^5000W, preferably 1W^3000W.
7. The method according to Claim 1 or Claim 2, wherein the ultrasonic intensity is O. lmW/cm 2 ^500W/cm 2 , preferably O. lW/cm 2 - 50W/cm2.
8. The method according to Claim 1 or Claim 2, wherein the ultrasonic duration is 1 minute ~ 24 hour, preferably 3 minutes ~160 minutes.
9. Benidipine hydrochloride prepared by the method according to any one of Claims 3-9.
10. The benidipine hydrochloride according to claim 9, which is in the form of nanoparticle.
11. The benidipine hydrochloride according to claim 10, wherein the particle size of the nanoparticle ranges from 20nm to 2000nm and the median size is between 300nm to 1500nm.
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| Application Number | Priority Date | Filing Date | Title |
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| JP2013510496A JP5590228B2 (en) | 2011-04-18 | 2011-09-28 | Preparation method of nanoparticles of Benidipine hydrochloride |
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| CN201110096848.5A CN102746216B (en) | 2011-04-18 | A kind of Benidipine hydrochloride nanoparticle and preparation method thereof | |
| CN201110096848.5 | 2011-04-18 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2700632A1 (en) * | 2011-04-18 | 2014-02-26 | Hefei Beini Medical Technology Company, Ltd | Method for purification of calcium channel blockers of dihydropyridine type and preparation of nanoparticles thereof |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746215A (en) * | 2011-04-18 | 2012-10-24 | 张兆勇 | Method for preparing high-purity benidipine hydrochloride |
| JP5786576B2 (en) * | 2011-09-14 | 2015-09-30 | コニカミノルタ株式会社 | Method for producing water vapor barrier film |
| JP5825016B2 (en) * | 2011-09-29 | 2015-12-02 | コニカミノルタ株式会社 | Barrier film manufacturing method |
| WO2014201236A1 (en) * | 2013-06-12 | 2014-12-18 | Surmodics, Inc. | Solvent methods for preparing crystalline macrolide particulates, compositions, and articles containing particulates |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4501748A (en) * | 1983-06-03 | 1985-02-26 | Kyowa Hakko Kogyo Co., Ltd. | 1,4-Dihydropyridine derivatives |
| CN1794993A (en) * | 2003-06-17 | 2006-06-28 | 协和发酵工业株式会社 | Medicinal composition containing benidipine hydrochloride |
| JP2007008819A (en) * | 2005-06-28 | 2007-01-18 | Daito Kk | Industrial method for producing high-purity benidipine hydrochloride |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59137461A (en) * | 1983-01-27 | 1984-08-07 | Kyowa Hakko Kogyo Co Ltd | 1,4-dihydropyridine derivative |
| JPS5970667A (en) * | 1982-10-15 | 1984-04-21 | Kyowa Hakko Kogyo Co Ltd | 1,4-dihydropyridine derivative |
| JP4606258B2 (en) * | 2003-06-17 | 2011-01-05 | 協和発酵キリン株式会社 | Pharmaceutical composition containing benidipine hydrochloride |
| US20070042049A1 (en) * | 2005-06-03 | 2007-02-22 | Elan Pharma International, Limited | Nanoparticulate benidipine compositions |
| TWI437007B (en) * | 2008-07-24 | 2014-05-11 | Food Industry Res & Dev Inst | Process for preparing nanoparticles of chitosan in water phase |
| JP2010082776A (en) * | 2008-10-01 | 2010-04-15 | Tohoku Univ | Nano-particle synthetic method by organic solvent sono-chemistry |
| JP5554413B2 (en) * | 2009-08-21 | 2014-07-23 | ルブリゾル アドバンスド マテリアルズ， インコーポレイテッド | Hydrolysis-stable polyurethane nanocomposites |
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- 2011-09-28 JP JP2013510496A patent/JP5590228B2/en not_active Expired - Fee Related
- 2011-09-28 WO PCT/CN2011/080294 patent/WO2012142816A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4501748A (en) * | 1983-06-03 | 1985-02-26 | Kyowa Hakko Kogyo Co., Ltd. | 1,4-Dihydropyridine derivatives |
| CN1794993A (en) * | 2003-06-17 | 2006-06-28 | 协和发酵工业株式会社 | Medicinal composition containing benidipine hydrochloride |
| JP2007008819A (en) * | 2005-06-28 | 2007-01-18 | Daito Kk | Industrial method for producing high-purity benidipine hydrochloride |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2700632A1 (en) * | 2011-04-18 | 2014-02-26 | Hefei Beini Medical Technology Company, Ltd | Method for purification of calcium channel blockers of dihydropyridine type and preparation of nanoparticles thereof |
| EP2700632A4 (en) * | 2011-04-18 | 2014-09-03 | Hefei Beini Medical Technology Company Ltd | Method for purification of calcium channel blockers of dihydropyridine type and preparation of nanoparticles thereof |
Also Published As
| Publication number | Publication date |
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| CN102746216A (en) | 2012-10-24 |
| JP5590228B2 (en) | 2014-09-17 |
| JP2013520520A (en) | 2013-06-06 |
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