CN102746216B - A kind of Benidipine hydrochloride nanoparticle and preparation method thereof - Google Patents
A kind of Benidipine hydrochloride nanoparticle and preparation method thereof Download PDFInfo
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- CN102746216B CN102746216B CN201110096848.5A CN201110096848A CN102746216B CN 102746216 B CN102746216 B CN 102746216B CN 201110096848 A CN201110096848 A CN 201110096848A CN 102746216 B CN102746216 B CN 102746216B
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Abstract
The present invention relates to KW-3049 (±) (R*) Isosorbide-5-Nitrae dihydro 2,6 dimethyl 4 (m-nitro base) 3,5 pyridinecarboxylate [(R*) 1 benzyl 3 piperidines alcohol ester] nanoparticle of hydrochlorate and supersonically preparation method thereof.
Description
Technical field
The present invention relates to pharmaceutical technology field, be a kind of KW-3049 (±)-(R*)-Isosorbide-5-Nitrae-dihydro-2,6-diformazan
Base-4-(m-nitrobenzophenone)-3,5-pyridinecarboxylate [(R*)-1-benzyl-3-piperidines alcohol ester] and hydrochlorate nanoparticle and
Preparation method.
Background technology
Dihydropyridine calcium channel blocker is at present because of its safety and effectiveness, is the most extensively applied.
Especially KW-3049, with the triple channel retardation of its uniqueness, with to the high affinity interaction of cell membrane, cardioselective
Effect and renal protection, be one preferably, safely and effectively resisting hypertension and treatment Renal hypertension, angina pectoris etc.
Disease medicament.
Owing to KW-3049 dissolubility in water is the lowest, in order to make KW-3049 from preparation the most molten
Go out, often medicine must be crushed to nano-particle.CN1794993A provide a kind of KW-3049 is crushed to 1.0～
The method of 50.0 μm.This patent is the method by mechanical lapping, and oarse-grained crystal powder is broken to suitable chi by " from big to little "
Very little crystal.This method not only needs to expend huge energy and time, and crystal footpath is distributed face width.
The present invention unexpectedly obtains, by ultrasonic crystallization technique, the KW-3049 that crystal size size is suitable
Nanoparticle.The present invention is different from CN1794993A, be " from small to large " obtain crystallization, and owing to solvent is the rapidest
Crystallizing evenly, concentration is compared in crystal particle diameter distribution；Required energy consumption is low, time saving and energy saving, it is easy to produce preparation.
Summary of the invention
The present invention provides a kind of method preparing Benidipine hydrochloride nanoparticle by ultrasonic technique.
Regular solution crystallize (crystallization) process reaches typically by reducing the means such as temperature, standing, be one long-time
Process slowly.And at ultrasonic method for crystallising provided by the present invention, be first pass through change temperature, change solvent polarity, add
Enter the methods such as poor solvent, form that KW-3049 is saturated or supersaturated solution, then by ultrasonic acquisition crystal size size
Suitable nanoparticle.The ultrasonic crystallize of solution (crystallization) is to carry out during a rapid equalisation.Owing to crystallize (crystallization) is molten
The difference of agent, the difference of crystallize (crystallization) mode and the difference of rate of crystalline growth, molecule and intermolecular combination must
The most different, the most necessarily cause the difference of molecule crystal formation and crystalline size.
For obtaining the Benidipine hydrochloride nanoparticle described in this patent, can first KW-3049 be dissolved in good solvent,
Then by changing temperature, changing the method such as solvent polarity, addition poor solvent, saturated or supersaturated solution is formed, by ultrasonic
Strengthening, promotes crystallization of solution.Then, by filtering (sucking filtration), washing, the routine operation such as be dried, highly purified salt is directly obtained
Acid benidipine nanoparticle.
Dissolve and/or form the good solvent of Benidipine hydrochloride nanoparticle, poor solvent and be usually lower ketones, lower alcohol, low
Level ether, lower member ester, acetonitrile, dichloromethane, chloroform, acetic anhydride and conventional small molecule solvent, preferably solvent be acetone, ethanol, methanol,
The single common solvent such as N, dinethylformamide (DMF), acetonitrile, ether, dichloromethane, dimethyl sulfoxide (DMSO) and water, or
Two kinds and the combination of two or more solvent, the preferred dehydrated alcohol of single solvent and acetonitrile, co-solvent preferred alcohol-acetone,
DMF-water, acetonitrile-water, acetonitrile-acetone, alcohol-water, the six kinds of solvent combinations of ethanol-acetone-water.Wherein ethanol and the ratio of acetone
Example is 0～100%: 100～0%.DMF is 0～100%: 100～0% with the ratio of water.The ratio of DMF and acetone be 0～
100%: 100～0%.Acetonitrile is 100～0%: 0～100% with the ratio of water.Acetonitrile is 100～0%: 0 with the ratio of acetone
～100%.Ethanol and water ratio are 100～0%: 0～100%.Ethanol, acetone and water ratio be 1～5: 1～5: 0.1～
500。
Ultrasonic crystallization frequency is 20kHz～500kHz, preferably 20kHz～100kHz.Ultrasonic power is 1mW～5000W, excellent
Select 1W～500W.The ultrasonic sound intensity is 0.1mW/cm2～500W/cm2, preferably 0.1W/cm2～50W/cm2；Ultrasonic time is 1min
～24hour, preferably 3min～120min.Ultrasonic crystallization temperature is-78 DEG C～100 DEG C, and preferable temperature is-5 DEG C～30 DEG C.Institute
Obtain Benidipine hydrochloride nanoparticle, its size is 20nm～2000nm, the intermediate value of size be 300nm～
1500nm。
Accompanying drawing illustrates: Fig. 1 is the grain-size graph of crystal formation a size of mean diameter 434.3nm；Fig. 2 is crystal formation a size of average particle
The grain-size graph of footpath 447.2nm；Fig. 3 is the grain-size graph of crystal formation a size of mean diameter 677.8nm；Fig. 4 is that crystal formation is average
Particle diameter is the grain-size graph of 710.8nm；Fig. 5 be crystal formation a size of mean diameter be the grain-size graph of 1159.0nm；Fig. 6 is crystal formation size
It is the grain-size graph of 1220.0nm for mean diameter；Fig. 7 be crystal formation a size of mean diameter be the grain-size graph of 1492.0nm.
Concrete operations are:
Can be appropriate by KW-3049 primary crystallization, add the lower alcohol of 0.1～40 times, be heated to reflux dissolving, reduce
Temperature, ultrasonic wave added crystallize.
Or KW-3049 primary crystallization is appropriate, add the lower alcohol of 0.1～40 times, be heated to reflux dissolving, add
The water of 0.01～100 times amount, reduces temperature, ultrasonic wave added crystallize.
Or KW-3049 primary crystallization is appropriate, add the lower alcohol of 0.1～40 times, be heated to reflux dissolving, add
The water of 1/100 amount, drip ultrasonic limit, limit crystallize.
Or KW-3049 primary crystallization is appropriate, add the lower alcohol of 0.1～40 times, be heated to reflux dissolving, add
The acetone of 0.1～100 times amount, reduces temperature, ultrasonic crystallize.
Or KW-3049 primary crystallization is appropriate, add the lower alcohol of 0.1～40 times, be heated to reflux dissolving, add
The acetone of 1/10 amount, drips acetone and stops to starting crystallize time ultrasonic, stop dropping acetone, continue ultrasonic (less than 60 minutes).
Or KW-3049 primary crystallization is appropriate, add the DMF (DMF) of 0.1～15 times, add
Hot reflux is dissolved, and adds the water of 0.1～100 times amount, reduces temperature, ultrasonic wave added crystallize.
Or KW-3049 primary crystallization is appropriate, add the DMF of 0.1～15 times, be heated to reflux dissolving, add 1/
The water of 100 amounts, drip ultrasonic limit, limit crystallize.
Or KW-3049 primary crystallization is appropriate, add the DMF of 0.1～15 times, be heated to reflux dissolving, add 0.1
～100 acetone of times amount, reduce temperature, ultrasonic crystallize.
Or KW-3049 primary crystallization is appropriate, add the DMSO of 0.1～15 times, be heated to reflux dissolving, add 0.1
～100 water of times amount, reduce temperature, ultrasonic crystallize.
Or KW-3049 primary crystallization is appropriate, add the DMF of 0.1～15 times, be heated to reflux dissolving, add 0.1
～100 acetone of amount, drip acetone time ultrasonic to only starting crystallize, stop dropping acetone, continue ultrasonic (less than 60 minutes).
Or KW-3049 primary crystallization is appropriate, add the acetonitrile of 0.1～40 times, be heated to reflux dissolving, reduce temperature
Degree, ultrasonic wave added crystallize.
Or KW-3049 primary crystallization is appropriate, add the acetonitrile of 0.1～40 times, be heated to reflux dissolving, add
The water of 0.01～100 times amount, reduces temperature, ultrasonic wave added crystallize.
Or KW-3049 primary crystallization is appropriate, add the acetonitrile of 0.1～40 times, be heated to reflux dissolving, add 1/
The water of 100 amounts, drip ultrasonic limit, limit crystallize.
Or KW-3049 primary crystallization is appropriate, add the acetonitrile of 0.1～40 times, be heated to reflux dissolving, add 0.1
～100 acetone of times amount, reduce temperature, ultrasonic crystallize.
Or KW-3049 primary crystallization is appropriate, add the acetonitrile of 0.1～40 times, be heated to reflux dissolving, add 0.1
The acetone of times amount, drips acetone and stops to starting crystallize time ultrasonic, stop dropping acetone, continue ultrasonic (less than 60 minutes).
Or KW-3049 primary crystallization is appropriate, add the alcohol heating reflux dissolving of 0.1～40 times, add 0.1
～100 acetone of times amount, when ultrasonic to a small amount of crystal occurs, be slowly added into the water of 0.1～1000 times amount, continue the most ultrasonic 1～
60min。
Or KW-3049 primary crystallization is appropriate, the acetonitrile adding 0.1～40 times is heated to reflux dissolving, adds 0.1
～100 acetone of times amount, i.e. it is slowly added into the water of 0.1～1000 times amount, ultrasonic 1～60min.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in detail.
Embodiment 1
KW-3049 primary crystallization 10g, adds the dehydrated alcohol of 10mL, is heated to reflux dissolving, and ice bath is lowered the temperature, 150W
Ultrasonic 10min crystallize, sucking filtration, collect to obtain pale yellow crystals, crystal formation size is shown in accompanying drawing 1.
Embodiment 2
KW-3049 primary crystallization 10.1g, adds the methanol of 10mL, is heated to reflux dissolving, and ice bath is lowered the temperature, and 150W surpasses
Sound 10min crystallize, sucking filtration, obtain pale yellow crystals.
Embodiment 3
KW-3049 primary crystallization 10.2g, adds the dehydrated alcohol of 12mL, is heated to reflux dissolving, and add water 12mL, ice
Bath cooling, 150W is ultrasonic, continues ultrasonic 2min after crystallize.
Embodiment 4
KW-3049 primary crystallization 10g, adds the methanol of 10mL, is heated to reflux dissolving, and add water 20mL, and ice bath drops
Temperature, 150W is ultrasonic, continues ultrasonic 7min after crystallize.
Embodiment 5
KW-3049 primary crystallization 10g, adds the dehydrated alcohol of 12mL, is heated to reflux dissolving, and add water 3mL, 150W
Ultrasonic, drip complete to crystallize.
Embodiment 6
KW-3049 primary crystallization 10g, adds the methanol of 10mL, is heated to reflux dissolving, and add water 3mL, and 150W is ultrasonic,
Drip complete to crystallize.
Embodiment 7
KW-3049 primary crystallization 10.3g, adds the dehydrated alcohol of 11mL, is heated to reflux dissolving, adds acetone 11mL,
Ice bath is lowered the temperature, the ultrasonic crystallize of 200W.
Embodiment 8
KW-3049 primary crystallization 10.1g, adds the methanol of 10mL, is heated to reflux dissolving, adds acetone 10mL, ice bath
Cooling, the ultrasonic crystallize of 200W.
Embodiment 9
KW-3049 primary crystallization 10.1g, adds the dehydrated alcohol of 10mL, is heated to reflux dissolving, adds acetone 3mL,
200W is ultrasonic, and dropping acetone, to only starting crystallize, continues the most ultrasonic 3min.
Embodiment 10
KW-3049 primary crystallization 10g, adds the methanol of 10mL, is heated to reflux dissolving, adds acetone 3mL, and 200W surpasses
Sound, dropping acetone, to only starting crystallize, continues the most ultrasonic 3min.
Embodiment 11
KW-3049 primary crystallization 10.1g, adds the DMF of 10mL, is heated to reflux dissolving, and add water 10mL, and 200W surpasses
Sound crystallize.
Embodiment 12
KW-3049 primary crystallization 10g, adds the DMF of 10mL, is heated to reflux dissolving, and add water 5mL, and 150W is ultrasonic,
Drip complete to crystallize.
Embodiment 13
KW-3049 primary crystallization 10g, adds the DMF of 10mL, is heated to reflux dissolving, adds acetone 10mL, and ice bath drops
Temperature, the ultrasonic crystallize of 200W.
Embodiment 14
KW-3049 primary crystallization 10g, adds the DMF of 10mL, is heated to reflux dissolving, adds acetone 3mL, and 200W surpasses
Sound, dropping acetone, to starting crystallize, continues the most ultrasonic 4min.
Embodiment 15
KW-3049 primary crystallization 10g, adds the acetonitrile of 10mL, is heated to reflux dissolving, and ice bath is lowered the temperature, and 150W is ultrasonic
Crystallize.
Embodiment 16
KW-3049 primary crystallization 10.1g, adds the acetonitrile of 10mL, is heated to reflux dissolving, and add water 10mL, and ice bath drops
Temperature, the ultrasonic crystallize of 150W.
Embodiment 17
KW-3049 primary crystallization 10g, adds the acetonitrile of 10mL, is heated to reflux dissolving, and add water 3mL, and 150W is ultrasonic,
Drip complete to crystallize.
Embodiment 18
KW-3049 primary crystallization 10.1g, adds the acetonitrile of 11mL, is heated to reflux dissolving, adds acetone 10mL, ice bath
Cooling, the ultrasonic crystallize of 200W.
Embodiment 19
KW-3049 primary crystallization 10.1g, adds the acetonitrile of 10mL, is heated to reflux dissolving, adds acetone 3mL, 200W
Ultrasonic, dropping acetone, to only starting crystallize, continues the most ultrasonic 3min.
Embodiment 20
KW-3049 primary crystallization 10g, adds 10mL ethanol, is heated to reflux dissolving, adds acetone 20mL, 200W super
Sound, begins with a small amount of crystal when occurring, is slowly added into more than water 20mL, starts a large amount of crystallize, continue the most ultrasonic 3min.
Embodiment 21
KW-3049 primary crystallization 10g, adds the DMSO of 10mL, is heated to reflux dissolving, and add water 30mL, and 200W is ultrasonic
Crystallize.
Claims (13)
1. prepared a preparation method for Benidipine hydrochloride nanoparticle by ultrasonic crystallization technique, described KW-3049 is received
The size of the grain of rice is 20nm～2000nm；Described ultrasonic specifically first passing through changes temperature, change solvent polarity or adds
The method entering poor solvent, forms that KW-3049 is saturated or supersaturated solution, and the most ultrasonic acquisition crystal size size is suitable
Nanoparticle.
Preparation method the most according to claim 1, the intermediate value of the size of described Benidipine hydrochloride nanoparticle is
300nm～1500nm.
Preparation method the most according to claim 1, described ultrasonic temperature is-78 DEG C～100 DEG C.
Preparation method the most according to claim 1, described ultrasonic temperature is-5 DEG C～30 DEG C.
Preparation method the most according to claim 1, described ultrasonic solvent be chloroform, acetic anhydride, acetone, ethanol, methanol, N,
One or more in dinethylformamide, acetonitrile, ether, dichloromethane, dimethyl sulfoxide and water.
Preparation method the most according to claim 1, described ultrasonic frequency is 20kHz～500kHz.
Preparation method the most according to claim 6, described ultrasonic frequency is 20kHz～100kHz.
Preparation method the most according to claim 1, described ultrasonic power is 1mW～5000W.
Preparation method the most according to claim 8, described ultrasonic power is 1W～500W.
Preparation method the most according to claim 1, the described ultrasonic sound intensity is 0.1W/cm2～500W/cm2。
11. preparation methoies according to claim 10, the described ultrasonic sound intensity is 0.1W/cm2～50W/cm2。
12. preparation methoies according to claim 1, the described ultrasonic time is 1min～24hour.
13. preparation methoies according to claim 1, the described ultrasonic time is 3min～160min.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110096848.5A CN102746216B (en) | 2011-04-18 | A kind of Benidipine hydrochloride nanoparticle and preparation method thereof | |
| JP2013510496A JP5590228B2 (en) | 2011-04-18 | 2011-09-28 | Preparation method of nanoparticles of Benidipine hydrochloride |
| PCT/CN2011/080294 WO2012142816A1 (en) | 2011-04-18 | 2011-09-28 | Benidipine hydrochloride nanoparticles and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110096848.5A CN102746216B (en) | 2011-04-18 | A kind of Benidipine hydrochloride nanoparticle and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102746216A CN102746216A (en) | 2012-10-24 |
| CN102746216B true CN102746216B (en) | 2016-12-14 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1794993A (en) * | 2003-06-17 | 2006-06-28 | 协和发酵工业株式会社 | Medicinal composition containing benidipine hydrochloride |
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1794993A (en) * | 2003-06-17 | 2006-06-28 | 协和发酵工业株式会社 | Medicinal composition containing benidipine hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 超声波作用下的溶液结晶过程;王莅等;《化学通报（网络版）》;20011231;第1-5页 * |
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Effective date of registration: 20200930 Address after: Room 312, building 1, Yingfei Optoelectronic Industrial Park, 767 Yulan Avenue, hi tech Zone, Hefei City, Anhui Province Patentee after: HEFEI BEINI MEDICINE TECHNOLOGY Co.,Ltd. Address before: Room 403, family building, South District, China University of science and technology, Hefei, Anhui Province Patentee before: Zhang Zhaoyong |