JP5590228B2 - Preparation method of nanoparticles of Benidipine hydrochloride - Google Patents
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Description
本発明は、医薬の分野、特に、ベニジピン塩酸塩((±)−(Ｒ＊)−１，４−ジヒドロ−２，６−ジメチル−４−(３−ニトロフェニル)−３，５−ピリジンジカルボン酸塩[(Ｒ＊)−１−ベンジル−３−ピペリジンアルコールエステル])のナノ粒子の調製方法に関する。 The present invention relates to the field of medicine, in particular to benidipine hydrochloride ((±)-(R *)-1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid). salt [(R *) - 1- benzyl-3-piperidine alcohol ester]) relates to the preparation how nanoparticles.
ジヒドロピリジンカルシウムチャンネル遮断薬は、安全で効果的であって、今日、臨床的に広く使用されている。とりわけ、ベニジピン塩酸塩は三つのチャンネルに対するユニークな抑制作用と、細胞膜に対する高い親和性、血管選択性を有し、腎臓保護作用を有する。従って、それは高血圧、腎実質性高血圧、アンギーナ等の治療に有用な、理想的で安全かつ効果的な薬剤である。 Dihydropyridine calcium channel blockers are safe and effective and are widely used clinically today. In particular, benidipine hydrochloride has a unique inhibitory action on three channels, a high affinity for cell membranes, blood vessel selectivity, and a renal protective action. Therefore, it is an ideal safe and effective drug useful for the treatment of hypertension, renal parenchymal hypertension, angina and the like.
ベニジピン塩酸塩は非常に溶解性が低いので、溶媒中において迅速に溶解するには、ベニジピン塩酸塩はしばしばナノ粒子に粉砕される。特許文献１は、ベニジピン塩酸塩を１．０〜５０．０μｍの粒子へ砕く方法を提供した。この物理的粉砕方法は、大きな粒子の結晶を所望の小さな結晶へと粉砕することによって行われる。この方法は多量のエネルギーと時間を消費し、結晶粒子サイズのばらつきが大きくなる。 Because benidipine hydrochloride is very poorly soluble, benidipine hydrochloride is often ground into nanoparticles for rapid dissolution in a solvent. Patent Document 1 provided a method for crushing benidipine hydrochloride into particles of 1.0 to 50.0 μm. This physical comminution method is performed by comminuting large particle crystals into the desired small crystals. This method consumes a large amount of energy and time, and the variation in crystal grain size increases.
本発明者は、超音波結晶技術によって所望サイズのベニジピン塩酸塩ナノ粒子を得ることができるという驚くべき発見をした。特許文献１の方法と異なり、本発明による方法では、小サイズから大サイズの結晶が得られる。溶媒が溶液中において急速かつ確実に結晶化することから、本発明の方法における粒子サイズの分布範囲は比較的狭い。全体として、本発明は、時間とエネルギーの節約を可能にし、調製が容易である。 The inventor has made the surprising discovery that the desired size of benidipine hydrochloride nanoparticles can be obtained by ultrasonic crystal technology. Unlike the method of Patent Document 1, with the method according to the present invention, crystals of a small size to a large size can be obtained. Since the solvent crystallizes rapidly and reliably in solution, the particle size distribution range in the method of the present invention is relatively narrow. Overall, the present invention allows for time and energy savings and is easy to prepare.
本発明は、超音波技術によってベニジピン塩酸塩のナノ粒子を調製する方法を提供する。 The present invention provides a method of preparing nanoparticles of benidipine hydrochloride by ultrasonic techniques.
従来式の溶液の結晶化は、通常、温度を下げ静置することによって行われるが、これはゆっくりとした長時間かかる手続きである。しかしながら、本発明の超音波法は、まず、温度、溶媒極性を変化させることによって、又は、低溶解度溶媒（ｉｎｆｅｒｉｏｒ ｓｏｌｖｅｎｔ）等を添加することによって、ベニジピン塩酸塩の飽和又は過飽和溶液を形成し、次に、超音波を適用することによって適当なサイズのナノ粒子を得るものである。溶液の超音波結晶化は迅速に、かつ、平衡状態で行われる。結晶化溶液、結晶化態様、結晶成長速度、分子間の結合態様、の違いによって必然的に、分子結晶形状とサイズが異なるものとなる。 Conventional solution crystallization is usually carried out by lowering the temperature and allowing it to stand, which is a slow and time-consuming procedure. However, the ultrasonic method of the present invention first forms a saturated or supersaturated solution of benidipine hydrochloride by changing the temperature, solvent polarity, or by adding a low solubility solvent or the like, Next, nanoparticles of an appropriate size are obtained by applying ultrasonic waves. Ultrasonic crystallization of the solution takes place rapidly and in equilibrium. Depending on the difference in the crystallization solution, the crystallization mode, the crystal growth rate, and the bonding mode between molecules, the molecular crystal shape and size are inevitably different.
本発明においてベニジピン塩酸塩ナノ粒子を調製する場合、ベニジピン塩酸塩を良好な（ｇｏｏｄ）溶媒中で溶解させ、その後、温度、溶媒極性を変化させることによって、又は、低溶解度溶媒（ｉｎｆｅｒｉｏｒ ｓｏｌｖｅｎｔ）等を添加することによって、ベニジピン塩酸塩の飽和又は過飽和溶液を形成し、その後に、超音波を当てて溶液の結晶化を促進する。その後に、フィルタリング（真空でのフィルタリング）、洗浄、又は乾燥などの従来の作業によって高度に精製されたベニジピン塩酸塩ナノ粒子を得ることができる。 When preparing benidipine hydrochloride nanoparticles in the present invention, benidipine hydrochloride is dissolved in a good solvent, and then the temperature, the solvent polarity is changed, or the low solubility solvent is used. Is added to form a saturated or supersaturated solution of benidipine hydrochloride, followed by sonication to promote crystallization of the solution. Thereafter, highly purified benidipine hydrochloride nanoparticles can be obtained by conventional operations such as filtering (filtering in vacuum), washing, or drying.
ベニジピン塩酸塩ナノ粒子の溶解および／又は形成に使用される高溶解度又は低溶解度溶媒としては、典型的には、低炭素数ケトン、低炭素数アルコール、低炭素数エーテル、低炭素数エステル、アセトニトリル、ジクロロメタン、クロロホルム、無水酢酸、その他の一般的に使用される小分子溶媒がある。好適な溶媒は、アセトン、エタノール、メタノール、Ｎ，Ｎ−ジメチルホルムアミド、アセトニトリル、ジエチルエーテル、ジクロロメタン、ジメチル・スルホキシド（ＤＭＳＯ）、水、の単体、又は、上述の溶媒の二種類以上の混合物、である。エタノールとアセトニトリルとが好適な単体溶媒であり、エタノール−アセトン、ＤＭＦ−水、アセトニトリル−水、アセトニトリル−アセトン、エタノール−水、エタノール−アセトン−水が好適な混合溶媒である。それらの中で、エタノールとアセトンとの比率は０〜１００％：１００〜０％である。ＤＭＦと水との比率は、０〜１００％：１００〜０％である。ＤＭＦとアセトンとの比率は、０〜１００％：１００〜０％である。アセトニトリルと水との比率は１００〜０％：０〜１００％である。アセトニトリルとアセトンとの比率は１００〜０％：０〜１００％である。エタノールと水との比率は１００〜０％：０〜１００％である。エタノールとアセトンと水との比率は１〜５：１〜５：０．１〜５００である。 High or low solubility solvents used to dissolve and / or form benidipine hydrochloride nanoparticles typically include low carbon ketones, low carbon alcohols, low carbon ethers, low carbon esters, acetonitrile , Dichloromethane, chloroform, acetic anhydride, and other commonly used small molecule solvents. Suitable solvents are acetone, ethanol, methanol, N, N-dimethylformamide, acetonitrile, diethyl ether, dichloromethane, dimethyl sulfoxide (DMSO), water alone, or a mixture of two or more of the above solvents. is there. Ethanol and acetonitrile are suitable simple solvents, and ethanol-acetone, DMF-water, acetonitrile-water, acetonitrile-acetone, ethanol-water, and ethanol-acetone-water are suitable mixed solvents. Among them, the ratio of ethanol to acetone is 0 to 100%: 100 to 0%. The ratio of DMF to water is 0 to 100%: 100 to 0%. The ratio of DMF to acetone is 0 to 100%: 100 to 0%. The ratio of acetonitrile to water is 100-0%: 0-100%. The ratio of acetonitrile to acetone is 100-0%: 0-100%. The ratio of ethanol to water is 100-0%: 0-100%. The ratio of ethanol, acetone and water is 1-5: 1 to 5: 0.1-500.
超音波結晶化の周波数は、２０ｋＨｚ〜５００ｋＨｚ、好ましくは、２０ｋＨｚ〜１００ｋＨｚである。超音波の出力は、１ｍＷ〜５０００Ｗ、好ましくは、１Ｗ〜５００Ｗである。強度は０．１ｍＷ／ｃｍ２〜５００Ｗ／ｃｍ２、好ましくは、０．１Ｗ／ｃｍ２〜５０Ｗ／ｃｍ２であり、超音波時間は１分間〜２４時間、好ましくは、３分間〜１２０分間である。超音波結晶化温度は、−７８℃〜１００℃、好ましくは、−５℃〜３０℃である。ベニジピン塩酸塩ナノ粒子の大きさは、２０ｎｍ〜２０００ｎｍ、であり、その中央値は３００ｎｍ〜１５００ｎｍである。 The frequency of ultrasonic crystallization is 20 kHz to 500 kHz, preferably 20 kHz to 100 kHz. The output of ultrasonic waves is 1 mW to 5000 W, preferably 1 W to 500 W. The intensity is 0.1 mW / cm 2 to 500 W / cm 2 , preferably 0.1 W / cm 2 to 50 W / cm 2 , and the ultrasonic time is 1 minute to 24 hours, preferably 3 minutes to 120 minutes. is there. The ultrasonic crystallization temperature is −78 ° C. to 100 ° C., preferably −5 ° C. to 30 ° C. The size of the benidipine hydrochloride nanoparticles is 20 nm to 2000 nm, and the median value is 300 nm to 1500 nm.
具体的な作業は以下の通りである。 The specific work is as follows.
原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜４０倍の低炭素数アルコールを添加し、溶解のために還流させながら加熱し、その後、結晶化を補助するために温度を下げて超音波処理を行う。 To add 0.1 to 40 times the low carbon number alcohol to the appropriate amount of benidipine hydrochloride primary crystal as a raw material, heat while refluxing for dissolution, and then assist crystallization The temperature is lowered to sonication.
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜４０倍の低炭素数アルコールを添加し、溶解のために還流させながら加熱し、その後、０．０１〜１００倍の水を加え、結晶化を補助するために温度を下げて超音波処理を行う。 Alternatively, 0.1 to 40 times lower carbon number alcohol is added to the primary crystal of an appropriate amount of benidipine hydrochloride as a raw material, heated while refluxing for dissolution, and then 0.01 to Add 100 times water and sonicate at lower temperature to aid crystallization.
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜４０倍の低炭素数アルコールを添加し、溶解のために還流させながら加熱し、その後、１／１００倍の水を加え、結晶化のため水を滴下しながら超音波処理を行う。 Alternatively, 0.1 to 40 times the low carbon number alcohol is added to the primary crystal of a suitable amount of benidipine hydrochloride as a raw material, heated while refluxing for dissolution, and then 1/100 times Then, ultrasonic treatment is performed while dropping water for crystallization.
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜４０倍の低炭素数アルコールを添加し、溶解のために還流させながら加熱し、その後、０．０１〜１００倍のアセトンを加え、結晶化を補助するために温度を下げて超音波処理を行う。 Alternatively, 0.1 to 40 times lower carbon number alcohol is added to the primary crystal of an appropriate amount of benidipine hydrochloride as a raw material, heated while refluxing for dissolution, and then 0.01 to Add 100 times acetone and sonicate at lower temperature to aid crystallization.
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜４０倍の低炭素数アルコールを添加し、溶解のために還流させながら加熱し、その後、超音波処理行いながら１／１０倍のアセトンを加え、結晶の析出が始まった時に、アセトンの添加を停止し、その後、更なる超音波処理を行う（６０分間未満）。 Alternatively, 0.1 to 40 times lower carbon number alcohol is added to the appropriate amount of benidipine hydrochloride primary crystal as a raw material, heated while refluxing for dissolution, and then sonicated. While adding 1/10 times the acetone, and when the precipitation of crystals begins, the addition of acetone is stopped and then further sonication is performed (less than 60 minutes).
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜１５倍のＮ，Ｎ−ジメチルホルムアミド（ＤＭＦ）を添加し、溶解のために還流させながら加熱し、その後、０．１〜１００倍の水を加え、結晶化を補助するために温度を下げて超音波処理を行う。 Alternatively, 0.1 to 15 times as much N, N-dimethylformamide (DMF) is added to the primary crystal of an appropriate amount of benidipine hydrochloride as a raw material, and heated while refluxing for dissolution, and then Then, 0.1 to 100 times as much water is added and sonication is performed at a reduced temperature to assist crystallization.
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜１５倍のＤＭＦを添加し、溶解のために還流させながら加熱し、その後、１／１００倍の水を加え、結晶化のために水を滴下しながら超音波処理を行う。 Alternatively, 0.1 to 15 times as much DMF is added to the primary crystal of a suitable amount of benidipine hydrochloride as a raw material, heated while refluxing for dissolution, and then 1/100 times as much water is added. In addition, ultrasonic treatment is performed while dropping water for crystallization.
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜１５倍のＤＭＦを添加し、溶解のために還流させながら加熱し、その後、０．１〜１００倍のアセトンを加え、結晶化を補助するために温度を下げて超音波処理を行う。 Alternatively, 0.1 to 15 times of DMF is added to the primary crystal of a suitable amount of benidipine hydrochloride as a raw material, and heated while refluxing for dissolution, and then 0.1 to 100 times. Acetone is added and sonicated at a lower temperature to aid crystallization.
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜１５倍のＤＭＳＯを添加し、溶解のために還流させながら加熱し、その後、０．１〜１００倍の水を加え、結晶化を補助するために温度を下げて超音波処理を行う。 Alternatively, 0.1 to 15 times DMSO is added to the appropriate amount of the primary crystal of benidipine hydrochloride as a raw material, heated while refluxing for dissolution, and then 0.1 to 100 times Add water and sonicate at lower temperature to aid crystallization.
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜１５倍のＤＭＦを添加し、溶解のために還流させながら加熱し、その後、超音波処理行いながら０．１〜１００倍のアセトンを加え、結晶の析出が開始した時に、アセトンの添加を停止し、その後、更なる超音波処理を行う（６０分間未満）。 Alternatively, 0.1 to 15 times as much DMF is added to the primary crystal of an appropriate amount of benidipine hydrochloride as a raw material, heated while refluxing for dissolution, and then subjected to ultrasonic treatment while performing sonication. Add 1 to 100 times more acetone, stop the addition of acetone when crystal precipitation begins, then perform further sonication (less than 60 minutes).
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜４０倍のアセトニトリルを添加し、溶解のために還流させながら加熱し、結晶化を補助するために温度を下げて超音波処理を行う。 Alternatively, 0.1 to 40 times acetonitrile is added to the appropriate amount of benidipine hydrochloride primary crystal as a raw material, heated while refluxing for dissolution, and the temperature is adjusted to assist crystallization. Lower and perform sonication.
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜４０倍のアセトニトリルを添加し、溶解のために還流させながら加熱し、その後、０．１〜１００倍の水を加え、結晶化のために水を滴下しながら超音波処理を行う。 Alternatively, 0.1 to 40 times acetonitrile is added to the appropriate amount of benidipine hydrochloride primary crystal as a raw material, heated while refluxing for dissolution, and then 0.1 to 100 times Add water and sonicate while dropping water for crystallization.
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜４０倍のアセトニトリルを添加し、溶解のために還流させながら加熱し、その後、１／１００倍の水を加え、結晶化のために水を滴下しながら超音波処理を行う。 Alternatively, 0.1 to 40 times as much acetonitrile is added to the primary crystal of an appropriate amount of benidipine hydrochloride as a raw material, heated while refluxing for dissolution, and then 1/100 times as much water is added. In addition, ultrasonic treatment is performed while dropping water for crystallization.
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜４０倍のアセトニトリルを添加し、溶解のために還流させながら加熱し、その後、０．１〜１００倍のアセトンを加え、結晶化を補助するために温度を下げて超音波処理を行う。 Alternatively, 0.1 to 40 times acetonitrile is added to the appropriate amount of benidipine hydrochloride primary crystal as a raw material, heated while refluxing for dissolution, and then 0.1 to 100 times Acetone is added and sonicated at a lower temperature to aid crystallization.
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜４０倍のアセトニトリルを添加し、溶解のために還流させながら加熱し、その後、超音波処理を行いながら０．１倍のアセトンを添加し、結晶の析出が開始した時に、アセトンの添加を停止し、その後、更なる超音波処理を行う（６０分間未満）。 Alternatively, 0.1 to 40 times as much acetonitrile is added to the primary crystal of an appropriate amount of benidipine hydrochloride as a raw material, heated while refluxing for dissolution, and then subjected to sonication and 0 Add 1x acetone and stop adding acetone when crystal precipitation begins, then perform further sonication (less than 60 minutes).
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜４０倍のエタノールを添加し、溶解のために還流させながら加熱し、その後、０．１〜１００倍のアセトンを添加し、超音波処理し、結晶が出現し始めた時に、０．１〜１０００倍の水を添加し、その後、１〜６０分間、更なる超音波処理を行う。 Alternatively, 0.1 to 40 times ethanol is added to the appropriate amount of benidipine hydrochloride primary crystal as a raw material, heated while refluxing for dissolution, and then 0.1 to 100 times Acetone is added and sonicated, and when crystals begin to appear, 0.1 to 1000 times the water is added, followed by further sonication for 1 to 60 minutes.
或いは、原料としての適当な量のベニジピン塩酸塩の初晶に対して、０．１〜４０倍のアセトニトリルを添加し、溶解のために還流させながら加熱し、その後、０．１〜１００倍のアセトンを添加し、ゆっくりと０．１〜１０００倍の水を添加し、その後、１〜６０分間超音波処理を行う。 Alternatively, 0.1 to 40 times acetonitrile is added to the appropriate amount of benidipine hydrochloride primary crystal as a raw material, heated while refluxing for dissolution, and then 0.1 to 100 times Add acetone, slowly add 0.1 to 1000 times the water, and then sonicate for 1 to 60 minutes.
以下、本発明について下記の実験例とともにより詳細に記載する。 Hereinafter, the present invention will be described in more detail together with the following experimental examples.
〔例１〕
原料としての１０ｇのベニジピン塩酸塩の初晶を１０ｍＬの無水エタノールに添加した。この反応混合物を溶解のために還流しながら加熱し、その後、氷浴によって冷却し、結晶化を補助するために１５０Ｗで１０分間の超音波処理を行い、その後、真空中でフィルタリングすることによって淡黄色の結晶としての生成物を得た。この結晶体のサイズを図１に示す。
[Example 1]
The primary crystal of 10 g of benidipine hydrochloride as a raw material was added to 10 mL of absolute ethanol. The reaction mixture is heated at reflux for dissolution, then cooled by an ice bath, sonicated at 150 W for 10 minutes to aid crystallization, and then lightly filtered by vacuum. The product was obtained as yellow crystals. The size of this crystal is shown in FIG.
〔例２〕
原料としての１０．１ｇのベニジピン塩酸塩の初晶を１０ｍＬのメタノールに添加した。この反応混合物を溶解のために還流しながら加熱し、その後、氷浴によって冷却し、結晶化を補助するために１５０Ｗで１０分間の超音波処理を行い、その後、真空中でフィルタリングすることによって淡黄色の結晶としての生成物を得た。
[Example 2]
The primary crystal of 10.1 g of benidipine hydrochloride as a raw material was added to 10 mL of methanol. The reaction mixture is heated at reflux for dissolution, then cooled by an ice bath, sonicated at 150 W for 10 minutes to aid crystallization, and then lightly filtered by vacuum. The product was obtained as yellow crystals.
〔例３〕
原料としての１０．２ｇのベニジピン塩酸塩の初晶を１２ｍＬの無水エタノールに添加した。この反応混合物を溶解のために還流しながら加熱し、これに１２ｍｌの水を添加した。その反応混合物を氷浴によって冷却し１５０Ｗで超音波処理し、結晶が出現した時に、２分間更に超音波処理を行った。
[Example 3]
The primary crystal of 10.2 g of benidipine hydrochloride as a raw material was added to 12 mL of absolute ethanol. The reaction mixture was heated at reflux for dissolution, to which 12 ml of water was added. The reaction mixture was cooled in an ice bath and sonicated at 150 W and further sonicated for 2 minutes when crystals appeared.
〔例４〕
原料としての１０ｇのベニジピン塩酸塩の初晶を１０ｍＬのメタノールに添加した。この反応混合物を溶解のために還流しながら加熱し、その後、２０ｍｌの水を添加した。その反応混合物を氷浴によって冷却し１５０Ｗで超音波処理し、結晶が出現した時に、７０分間連続で超音波処理を行った。
[Example 4]
The primary crystal of 10 g of benidipine hydrochloride as a raw material was added to 10 mL of methanol. The reaction mixture was heated at reflux for dissolution, after which 20 ml of water was added. The reaction mixture was cooled in an ice bath and sonicated at 150 W and sonicated continuously for 70 minutes when crystals appeared.
〔例５〕
原料としての１０ｇのベニジピン塩酸塩の初晶を１２ｍＬの無水エタノールに添加した。この反応混合物を溶解のために還流しながら加熱し、これに３ｍｌの水を添加した。その反応混合物を１５０Ｗで超音波処理し、これに、結晶化が完了するまで水を滴下によって添加した。
[Example 5]
The primary crystal of 10 g of benidipine hydrochloride as a raw material was added to 12 mL of absolute ethanol. The reaction mixture was heated at reflux for dissolution, to which 3 ml of water was added. The reaction mixture was sonicated at 150 W and water was added dropwise thereto until crystallization was complete.
〔例６〕
原料としての１０ｇのベニジピン塩酸塩の初晶を１０ｍＬのメタノールに添加した。この反応混合物を溶解のために還流しながら加熱し、これに３ｍｌの水を添加した。その反応混合物を１５０Ｗで超音波処理し、これに、結晶化が完了するまで水を滴下によって添加した。
[Example 6]
The primary crystal of 10 g of benidipine hydrochloride as a raw material was added to 10 mL of methanol. The reaction mixture was heated at reflux for dissolution, to which 3 ml of water was added. The reaction mixture was sonicated at 150 W and water was added dropwise thereto until crystallization was complete.
〔例７〕
原料としての１０．３ｇのベニジピン塩酸塩の初晶を１１ｍＬの無水エタノールに添加した。この反応混合物を溶解のために還流しながら加熱し、これに１１ｍｌのアセトンを添加した。その反応混合物を氷浴によって冷却し、結晶化を補助するために２００Ｗで超音波処理した。
[Example 7]
The primary crystal of 10.3 g of benidipine hydrochloride as a raw material was added to 11 mL of absolute ethanol. The reaction mixture was heated at reflux for dissolution, to which 11 ml of acetone was added. The reaction mixture was cooled with an ice bath and sonicated at 200 W to aid crystallization.
〔例８〕
原料としての１０．１ｇのベニジピン塩酸塩の初晶を１０ｍＬのメタノールに添加した。この反応混合物を溶解のために還流しながら加熱し、これに１０ｍｌのアセトンを添加した。その反応混合物を氷浴によって冷却し、結晶化を補助するために２００Ｗで超音波処理した。
[Example 8]
The primary crystal of 10.1 g of benidipine hydrochloride as a raw material was added to 10 mL of methanol. The reaction mixture was heated at reflux for dissolution, to which 10 ml of acetone was added. The reaction mixture was cooled with an ice bath and sonicated at 200 W to aid crystallization.
〔例９〕
原料としての１０．１ｇのベニジピン塩酸塩の初晶を１０ｍＬの無水エタノールに添加した。この反応混合物を溶解のために還流しながら加熱し、これに３ｍｌのアセトンを添加した。その反応混合物を２００Ｗで超音波処理し、これに、結晶が出現し始めるまでアセトンを滴下によって添加し、更に、３分間、超音波処理を行った。
[Example 9]
The primary crystal of 10.1 g of benidipine hydrochloride as a raw material was added to 10 mL of absolute ethanol. The reaction mixture was heated at reflux for dissolution, to which 3 ml of acetone was added. The reaction mixture was sonicated at 200 W, acetone was added dropwise thereto until crystals began to appear, and sonicated for an additional 3 minutes.
〔例１０〕
原料としての１０ｇのベニジピン塩酸塩の初晶を１０ｍＬのメタノールに添加した。この反応混合物を溶解のために還流しながら加熱し、これに３ｍｌのアセトンを添加した。その反応混合物を２００Ｗで超音波処理し、これに、結晶が出現し始めるまでアセトンを滴下によって添加し、更に、３分間、超音波処理を行った。
[Example 10]
The primary crystal of 10 g of benidipine hydrochloride as a raw material was added to 10 mL of methanol. The reaction mixture was heated at reflux for dissolution, to which 3 ml of acetone was added. The reaction mixture was sonicated at 200 W, acetone was added dropwise thereto until crystals began to appear, and sonicated for an additional 3 minutes.
〔例１１〕
原料としての１０．１ｇのベニジピン塩酸塩の初晶を１０ｍＬのＤＭＦに添加した。この反応混合物を溶解のために還流しながら加熱し、これに１０ｍｌの水を添加した。その反応混合物を、結晶化を補助するために２００Ｗで超音波処理した。
[Example 11]
The primary crystal of 10.1 g of benidipine hydrochloride as a raw material was added to 10 mL of DMF. The reaction mixture was heated at reflux for dissolution, to which 10 ml of water was added. The reaction mixture was sonicated at 200 W to aid crystallization.
〔例１２〕
原料としての１０ｇのベニジピン塩酸塩の初晶を１０ｍＬのＤＭＦに添加した。この反応混合物を溶解のために還流しながら加熱し、これに５ｍｌの水を添加した。その反応混合物を１５０Ｗで超音波処理し、これに、結晶化が完了するまで水を滴下によって添加した。
[Example 12]
10 g of benidipine hydrochloride primary crystal as raw material was added to 10 mL of DMF. The reaction mixture was heated at reflux for dissolution, to which 5 ml of water was added. The reaction mixture was sonicated at 150 W and water was added dropwise thereto until crystallization was complete.
〔例１３〕
原料としての１０ｇのベニジピン塩酸塩の初晶を１０ｍＬのＤＭＦに添加した。この反応混合物を溶解のために還流しながら加熱し、これに１０ｍｌのアセトンを添加した。その反応混合物を氷浴によって冷却し、結晶化を補助するために２００Ｗで超音波処理した。
[Example 13]
10 g of benidipine hydrochloride primary crystal as raw material was added to 10 mL of DMF. The reaction mixture was heated at reflux for dissolution, to which 10 ml of acetone was added. The reaction mixture was cooled with an ice bath and sonicated at 200 W to aid crystallization.
〔例１４〕
原料としての１０ｇのベニジピン塩酸塩の初晶を１０ｍＬのＤＭＦに添加した。この反応混合物を溶解のために還流しながら加熱し、これに３ｍｌのアセトンを添加した。その反応混合物を２００Ｗで超音波処理し、これに、結晶が出現し始めるまでアセトンを滴下によって添加し、更に、４分間、超音波処理を行った。
[Example 14]
10 g of benidipine hydrochloride primary crystal as raw material was added to 10 mL of DMF. The reaction mixture was heated at reflux for dissolution, to which 3 ml of acetone was added. The reaction mixture was sonicated at 200 W, to which acetone was added dropwise until crystals began to appear, and further sonicated for 4 minutes.
〔例１５〕
原料としての１０ｇのベニジピン塩酸塩の初晶を１０ｍＬのアセトニトリルに添加した。この反応混合物を溶解のために還流しながら加熱し、氷浴によって冷却し、結晶化を補助するために１５０Ｗで超音波処理した。
[Example 15]
The primary crystal of 10 g of benidipine hydrochloride as a raw material was added to 10 mL of acetonitrile. The reaction mixture was heated at reflux for dissolution, cooled by an ice bath and sonicated at 150 W to aid crystallization.
〔例１６〕
原料としての１０．１ｇのベニジピン塩酸塩の初晶を１０ｍＬのアセトニトリルに添加した。この反応混合物を溶解のために還流しながら加熱し、これに１０ｍｌの水を添加した。その反応混合を氷浴によって冷却し、結晶化を補助するために１５０Ｗで超音波処理した。
[Example 16]
The primary crystal of 10.1 g of benidipine hydrochloride as a raw material was added to 10 mL of acetonitrile. The reaction mixture was heated at reflux for dissolution, to which 10 ml of water was added. The reaction mixture was cooled with an ice bath and sonicated at 150 W to aid crystallization.
〔例１７〕
原料としての１０ｇのベニジピン塩酸塩の初晶を１０ｍＬのアセトニトリルに添加した。この反応混合物を溶解のために還流しながら加熱し、これに３ｍｌの水を添加した。その反応混合を１５０Ｗで超音波処理し、これに、結晶化が完了するまで水を滴下によって添加した。
[Example 17]
The primary crystal of 10 g of benidipine hydrochloride as a raw material was added to 10 mL of acetonitrile. The reaction mixture was heated at reflux for dissolution, to which 3 ml of water was added. The reaction mixture was sonicated at 150 W and water was added dropwise thereto until crystallization was complete.
〔例１８〕
原料としての１０．１ｇのベニジピン塩酸塩の初晶を１１ｍＬのアセトニトリルに添加した。この反応混合物を溶解のために還流しながら加熱し、これに１０ｍｌのアセトンを添加した。その反応混合を氷浴によって冷却し、結晶化を補助するために２００Ｗで超音波処理した。
[Example 18]
The primary crystal of 10.1 g of benidipine hydrochloride as a raw material was added to 11 mL of acetonitrile. The reaction mixture was heated at reflux for dissolution, to which 10 ml of acetone was added. The reaction mixture was cooled with an ice bath and sonicated at 200 W to aid crystallization.
〔例１９〕
原料としての１０．１ｇのベニジピン塩酸塩の初晶を１０ｍＬのアセトニトリルに添加した。この反応混合物を溶解のために還流しながら加熱し、これに３ｍｌのアセトンを添加した。その反応混合物を２００Ｗで超音波処理し、これに、結晶が出現し始めるまでアセトンを滴下によって添加し、更に、３分間、超音波処理を行った。
Example 19
The primary crystal of 10.1 g of benidipine hydrochloride as a raw material was added to 10 mL of acetonitrile. The reaction mixture was heated at reflux for dissolution, to which 3 ml of acetone was added. The reaction mixture was sonicated at 200 W, acetone was added dropwise thereto until crystals began to appear, and sonicated for an additional 3 minutes.
〔例２０〕
原料としての１０ｇのベニジピン塩酸塩の初晶を１０ｍＬのエタノールに添加した。この反応混合物を溶解のために還流しながら加熱し、これに２０ｍｌのアセトンを添加した。その反応混合物を２００Ｗで超音波処理し、少量の結晶が出現し始めた時に、２０ｍｌ以上の水を添加し、大量の結晶が出現し始め、その後、更に、３分間、超音波処理を行った。
[Example 20]
The primary crystal of 10 g of benidipine hydrochloride as a raw material was added to 10 mL of ethanol. The reaction mixture was heated at reflux for dissolution, to which 20 ml of acetone was added. The reaction mixture was sonicated at 200 W and when a small amount of crystals began to appear, 20 ml or more of water was added and a large amount of crystals began to appear, followed by sonication for an additional 3 minutes. .
〔例２１〕
原料としての１０ｇのベニジピン塩酸塩の初晶を１０ｍＬのＤＭＳＯに添加した。この反応混合物を溶解のために還流しながら加熱し、これに３０ｍｌの水を添加した。この反応混合物を、結晶化を補助するために２００Ｗで超音波処理した。
[Example 21]
10 g of benidipine hydrochloride primary crystal as raw material was added to 10 mL of DMSO. The reaction mixture was heated at reflux for dissolution, to which 30 ml of water was added. The reaction mixture was sonicated at 200 W to aid crystallization.
Claims (7)
まず、温度、溶媒極性を変化させることによって、又は、低溶解度溶媒（ｉｎｆｅｒｉｏｒｓｏｌｖｅｎｔ）を添加することによって、ベニジピン塩酸塩の飽和又は過飽和溶液を形成し、次に、超音波処理によって適当なサイズのナノ粒子を得る、ベニジピン塩酸塩のナノ粒子の調製方法。 A method of preparing benidipine hydrochloride nanoparticles by ultrasonic technology , comprising:
First, a saturated or supersaturated solution of benidipine hydrochloride is formed by changing the temperature, solvent polarity, or by adding a low solubility solvent, and then sonicated to the appropriate size of the nano-sized solution. A method for preparing nanoparticles of benidipine hydrochloride to obtain particles .
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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 | ||
| PCT/CN2011/080294 WO2012142816A1 (en) | 2011-04-18 | 2011-09-28 | Benidipine hydrochloride nanoparticles and preparation method thereof |
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| JP2014511867A (en) * | 2011-04-18 | 2014-05-19 | 合肥貝霓医薬科技有限公司 | Purification of dihydropyridine calcium channel blocker and method for preparing nanoparticles thereof |
| JP2014511881A (en) * | 2011-04-18 | 2014-05-19 | ヘフェイ ベイニ メディカル テクノロジー カンパニー リミテッド | Method for preparing high-purity benidipine hydrochloride |
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| 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 |
| JP6416242B2 (en) * | 2013-06-12 | 2018-10-31 | サーモディクス，インコーポレイティド | Solvent method for preparing crystalline macrolide microparticles, composition, and article comprising microparticles |
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| JPS59225162A (en) * | 1983-06-03 | 1984-12-18 | Kyowa Hakko Kogyo Co Ltd | 1,4-dihydropyridine derivative |
| 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 |
| WO2004110448A1 (en) * | 2003-06-17 | 2004-12-23 | Kyowa Hakko Kogyo Co., Ltd. | Medicinal composition containing benidipine hydrochloride |
| JP4606258B2 (en) * | 2003-06-17 | 2011-01-05 | 協和発酵キリン株式会社 | Pharmaceutical composition containing benidipine hydrochloride |
| WO2006133045A1 (en) * | 2005-06-03 | 2006-12-14 | Elan Pharma International, Limited | Nanoparticulate benidipine compositions |
| JP3763538B1 (en) * | 2005-06-28 | 2006-04-05 | ダイト株式会社 | Industrial production method of high-purity benidipine hydrochloride |
| 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 |
| BR112012003817A2 (en) * | 2009-08-21 | 2016-03-22 | Lubrizol Advanced Mat Inc | hydrolytically stable polyester-polyurethane nanocomposite, aqueous dispersion thereof, and process for preparing aqueous dispersion |
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| JP2014511867A (en) * | 2011-04-18 | 2014-05-19 | 合肥貝霓医薬科技有限公司 | Purification of dihydropyridine calcium channel blocker and method for preparing nanoparticles thereof |
| JP2014511881A (en) * | 2011-04-18 | 2014-05-19 | ヘフェイ ベイニ メディカル テクノロジー カンパニー リミテッド | Method for preparing high-purity benidipine hydrochloride |
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| CN102746216A (en) | 2012-10-24 |
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