JP3763538B1 - Industrial production method of high-purity benidipine hydrochloride - Google Patents
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Abstract
【課題】 従来の再結晶の繰り返し、その再結晶による化合物のロス等を回避し、簡単な操作で、収率よく、かつ高純度で塩酸ベニジピンを得る工業的製造方法を提供すること。
【解決手段】 塩酸ベニジピンの粗結晶を、水単独あるいは水と混合する有機溶媒との混合溶液に加熱溶解した後、冷却することにより塩酸ベニジピンの一水和物の結晶を得、次いで得られた塩酸ベニジピンの一水和物の結晶をケトン系溶媒単独、あるいはこれとアルコール系溶媒との混合溶媒に加熱処理し、次いで冷却することを特徴とする高純度の塩酸ベニジピンの工業的製造方法である。
【選択図】 なし
PROBLEM TO BE SOLVED: To provide an industrial production method for obtaining benidipine hydrochloride with high yield and high purity by a simple operation while avoiding repeated recrystallization and compound loss due to the recrystallization.
SOLUTION: A crude crystal of benidipine hydrochloride was dissolved in water alone or in a mixed solution of an organic solvent mixed with water, and then cooled to obtain a monohydrate crystal of benidipine hydrochloride, which was then obtained. This is an industrial process for producing high-purity benidipine hydrochloride, characterized in that the crystal of benidipine hydrochloride monohydrate is heat-treated with a ketone solvent alone or a mixed solvent of this with an alcohol solvent and then cooled. .
[Selection figure] None
Description
本発明は、高純度塩酸ベニジピンの工業的な製造方法に関する。 The present invention relates to an industrial process for producing high-purity benidipine hydrochloride.
塩酸ベニジピン（一般名）は、化学名が（±）−（Ｒ＊）−３−［（Ｒ＊）−１−ベンジル−３−ピペリジル］メチル １，４−ジヒドロ−２，６−ジメチル−４−（ｍ−ニトロフェニル）−３，５−ピリジンジカルボン酸の塩酸塩であり、血圧降下剤、血管拡張剤等の循環器用薬として、高血圧症、狭心症の治療薬として臨床的に使用されている有用な化合物である。 Benidipine hydrochloride (generic name) has the chemical name (±)-(R * )-3-[(R * )-1-benzyl-3-piperidyl] methyl 1,4-dihydro-2,6-dimethyl-4 -(M-Nitrophenyl) -3,5-pyridinedicarboxylic acid hydrochloride, clinically used as a cardiovascular drug such as antihypertensive agent, vasodilator, etc., as a therapeutic agent for hypertension and angina. Useful compounds.
この塩酸ベニジピンには、融点の相違により、低融点の化合物Ａと高融点の化合物Ｂの両者が存在することが知られており（特許文献１）、臨床的に使用されている塩酸ベニジピンは高融点の化合物Ｂである。
この化合物Ｂの製造法は、例えば、ｍ−ニトロベンズアルデヒドとβ−アミノクロトン酸メチル及びアセト酢酸−Ｎ−ベンジル−３−ピペリジルエステルとの反応による方法（特許文献２）、２，６−ジメチル４−（３−ニトロフェニル）−１，４−ジヒドロピリジン−３，５−ジカルボン酸モノメチルエステルと１−ベンジル−３−ヒドロキシピペリジンとの反応による方法（特許文献３）、３−ニトロベンジリデンアセト酢酸メチルと３−アミノクロトン酸−１−ベンジル−３−ピペリジルエステルとの反応による方法（特許文献４）等が知られている。
This benidipine hydrochloride is known to contain both a low melting point compound A and a high melting point compound B due to the difference in melting point (Patent Document 1), and clinically used benidipine hydrochloride has a high melting point. Compound B having a melting point.
The compound B can be produced by, for example, a method of reacting m-nitrobenzaldehyde with methyl β-aminocrotonate and acetoacetic acid-N-benzyl-3-piperidyl ester (Patent Document 2), 2,6-dimethyl 4 -(3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester and 1-benzyl-3-hydroxypiperidine reaction (Patent Document 3), 3-nitrobenzylidene acetoacetate methyl and A method of reacting with 3-aminocrotonic acid-1-benzyl-3-piperidyl ester (Patent Document 4) is known.
従来の方法にあっては、高純度の化合物Ｂを得るには、繰り返し再結晶操作を行わなければならず、再結晶操作を繰り返す煩雑さ、再結晶による化合物のロス等があり、工業的製造方法としては好ましいものではなく、簡単に収率よく高純度で化合物Ｂを得る工業的製造方法の開発が望まれていた。
したがって本発明は、従来行われていた再結晶の繰り返し、その再結晶による化合物のロス等を回避し、簡単な操作で、収率よく、かつ高純度で塩酸ベニジピン（いわゆる化合物Ｂ）を得る工業的製造方法を提供することを課題とする。 Therefore, the present invention avoids the repetition of recrystallization that has been conventionally performed, the loss of the compound due to the recrystallization, and the like to obtain benidipine hydrochloride (so-called compound B) with high yield and high purity by a simple operation. It is an object to provide a manufacturing method.
かかる課題を解決するべく、本発明者等は鋭意検討した結果、従来の製造方法に従って製造された塩酸ベニジピンの粗結晶を、塩酸ベニジピンの一水和物の結晶へ誘導した後、この塩酸ベニジピンの一水和物の結晶をケトン系溶媒単独あるいはこれとアルコール系溶媒との混合溶媒で処理することにより、高収率で純度よく塩酸ベニジピンを製造しうることを新規に見出し、本発明を完成させるに至った。 In order to solve this problem, the present inventors have intensively studied. As a result, after the benidipine hydrochloride crude crystals produced according to the conventional production method were induced into the monohydrate crystals of benidipine hydrochloride, It was newly found that benidipine hydrochloride can be produced with high yield and high purity by treating monohydrate crystals with a ketone solvent alone or a mixed solvent of an alcohol solvent and the ketone solvent, thereby completing the present invention. It came to.
したがって、基本的な態様としての請求項１に記載の発明は、塩酸ベニジピンの粗結晶を、水単独あるいは水と混合する有機溶媒との混合溶液に加熱溶解した後、冷却することにより塩酸ベニジピンの一水和物の結晶を得、次いで得られた塩酸ベニジピンの一水和物の結晶をケトン系溶媒単独、あるいはこれとアルコール系溶媒との混合溶媒に加熱処理し、次いで冷却することを特徴とする高純度塩酸ベニジピンの工業的製造方法である。 Therefore, the invention according to claim 1 as a basic aspect is that the crude crystals of benidipine hydrochloride are dissolved in water alone or in a mixed solution of an organic solvent mixed with water and then cooled to cool the benidipine hydrochloride. A monohydrate crystal is obtained, and then the obtained monohydrate crystal of benidipine hydrochloride is heat-treated with a ketone solvent alone or a mixed solvent thereof with an alcohol solvent, and then cooled. This is an industrial process for producing high-purity benidipine hydrochloride.
さらに本発明は、別の態様として、請求項２に記載の発明は、塩酸ベニジピンの一水和物の結晶をケトン系溶媒単独、あるいはこれとアルコール系溶媒との混合溶媒に加熱処理し、次いで冷却することを特徴とする高純度塩酸ベニジピンの工業的製造方法である。 Furthermore, the present invention provides, as another aspect, the invention according to claim 2, wherein the crystal of benidipine hydrochloride monohydrate is heat-treated with a ketone solvent alone or a mixed solvent of this with an alcohol solvent, It is an industrial manufacturing method of high-purity benidipine hydrochloride characterized by cooling.
より具体的な請求項３に記載の本発明は、水と混合する有機溶媒が、炭素原子数１〜４のアルコール系溶媒；ケトン系溶媒；アセトニトリル；酢酸エチルまたはジオキサンである上記の工業的製造方法である。 More specifically, the present invention according to claim 3 is the industrial production described above, wherein the organic solvent mixed with water is an alcohol solvent having 1 to 4 carbon atoms; a ketone solvent; acetonitrile; ethyl acetate or dioxane. Is the method.
本発明は、基本的には、通常の工業的な製造方法により得られた塩酸ベニジピンの粗結晶を、塩酸ベニジピンの一水和物の結晶へ誘導した後、かかる結晶をケトン系溶媒単独、あるいはこれとアルコール系溶媒との混合溶媒で処理することにより、高収率で純度よく塩酸ベニジピンを得る方法であって、従来法に比較して繰り返し再結晶を行う操作の煩雑さを回避しうるものである。
また得られた塩酸ベニジピンはその純度がよく、したがって、本発明方法により、そのまま医薬品として使用しうる高純度を保持した塩酸ベニジピンが提供される利点を有している。
さらに、再結晶操作の繰り返しが無いため、目的とする塩酸ベニジピンのロスが少なく、高収率で製造しうることから、その経済的利点は多大なものである。
In the present invention, basically, after the benidipine hydrochloride crude crystals obtained by the usual industrial production method are induced to benidipine hydrochloride monohydrate crystals, such crystals are converted into ketone solvents alone, or A method of obtaining benidipine hydrochloride with high yield and high purity by treating with a mixed solvent of this and an alcohol solvent, which can avoid the trouble of repeated recrystallization as compared with the conventional method It is.
Further, the obtained benidipine hydrochloride has a good purity. Therefore, the method of the present invention has an advantage that benidipine hydrochloride having a high purity that can be used as a pharmaceutical as it is is provided.
Furthermore, since the recrystallization operation is not repeated, the loss of the target benidipine hydrochloride is small and it can be produced in a high yield, so that its economic advantage is great.
本発明は、上記したように、通常の工業的な製造方法により得られた塩酸ベニジピンの粗結晶を、塩酸ベニジピンの一水和物の結晶へ誘導した後、かかる結晶をケトン系溶媒単独、あるいはこれとアルコール系溶媒との混合溶媒で処理することによる、高収率で純度よく塩酸ベニジピンを得る方法である。
なお、本発明で目的とする高純度の塩酸ベニジピンは、特許文献１に記載される高融点の塩酸ベニジピンである「化合物Ｂ」である。
In the present invention, as described above, after the benidipine hydrochloride crude crystals obtained by the usual industrial production method are induced to benidipine hydrochloride monohydrate crystals, such crystals are converted to ketone solvents alone, or This is a method of obtaining benidipine hydrochloride with high yield and high purity by treating with a mixed solvent of this and an alcohol solvent.
The high-purity benidipine hydrochloride targeted in the present invention is “Compound B” which is a high-melting point benidipine hydrochloride described in Patent Document 1.
この塩酸ベニジピンの一水和物については、既にその存在が知られていたものであるが（非特許文献１）、この一水和物の結晶を用いてケトン系溶媒単独、あるいはこれとアルコール系溶媒との混合溶媒と処理することにより純度よく塩酸ベニジピンが製造できることは、一切知られていなかった。その点で本発明は極めて特異的なものである。 The benidipine hydrochloride monohydrate has already been known to exist (Non-patent Document 1). The monohydrate crystal is used alone, or the alcohol solvent and the ketone solvent are used. It has never been known that benidipine hydrochloride can be produced with high purity by treatment with a mixed solvent with a solvent. In that respect, the present invention is very specific.
塩酸ベニジピンの一水和物の結晶を得るには、具体的には、塩酸ベニジピンの粗結晶を、水単独あるいは水と混合する有機溶媒との混合溶液に加熱溶解した後、冷却することにより塩酸ベニジピンの一水和物の結晶を得ることができる。 In order to obtain the monohydrate crystals of benidipine hydrochloride, specifically, the crude crystals of benidipine hydrochloride were dissolved in water alone or in a mixed solution with an organic solvent mixed with water, and then cooled to give hydrochloric acid. Benidipine monohydrate crystals can be obtained.
本明細書において有機溶媒とは、水と混合する有機溶媒を意味し、アルコール系溶媒；ケトン系溶媒；アセトニトリル；酢酸エチルまたはジオキサンをいう。アルコール系溶媒とは、炭素原子数１〜４のアルコール溶媒をいい、具体的には、メタノール、エタノール、プロパノール、ブタノール等をいう。さらにケトン系溶媒とはアセトンまたはメチルエチルケトンから選択されるケトン系溶媒をいう。In this specification, an organic solvent means an organic solvent mixed with water, and refers to an alcohol solvent; a ketone solvent; acetonitrile; ethyl acetate or dioxane. The alcohol solvent refers to an alcohol solvent having 1 to 4 carbon atoms, and specifically refers to methanol, ethanol, propanol, butanol and the like. Further, the ketone solvent refers to a ketone solvent selected from acetone or methyl ethyl ketone.
具体的には、これら溶媒と水との混合溶媒、なかでもエタノール−水あるいはアセトニトリル−水との混合溶媒、あるいは水単独溶媒中に塩酸ベニジピンの粗結晶を加熱溶解した後、その加熱状態を維持し、その後冷却することにより、目的とする塩酸ベニジピンの一水和物の結晶を得ることができる。 Specifically, after heating and dissolving the crude crystals of benidipine hydrochloride in a mixed solvent of these solvents and water, especially a mixed solvent of ethanol-water or acetonitrile-water, or a single solvent of water, the heating state is maintained. Then, by cooling, the target benidipine hydrochloride monohydrate crystal can be obtained.
水と有機溶媒の混合溶媒を使用する場合の有機溶媒と水との混合比は一概に限定できないが、有機溶媒：水として４０〜８０：６０〜２０程度の比率が好ましく使用される。塩酸ベニジピンの粗結晶を上記の溶媒中に加熱溶解するが、加熱温度としては用いる溶媒の還流温度までが好ましい。また、塩酸ベニジピンの一水和物の結晶を析出させるために冷却するが、冷却温度としては０℃〜室温程度までが好ましく、冷却時間は１〜４８時間、好ましくは５〜３０時間程度がよい。 When the mixed solvent of water and organic solvent is used, the mixing ratio of the organic solvent and water cannot be generally limited, but a ratio of about 40 to 80:60 to 20 is preferably used as the organic solvent: water. The crude crystals of benidipine hydrochloride are dissolved by heating in the above solvent, and the heating temperature is preferably up to the reflux temperature of the solvent used. Moreover, although cooling is performed in order to precipitate a monohydrate crystal of benidipine hydrochloride, the cooling temperature is preferably from 0 ° C. to room temperature, and the cooling time is 1 to 48 hours, preferably about 5 to 30 hours. .
加熱後、冷却することにより目的とする塩酸ベニジピンの一水和物は溶液中に結晶として析出してくるので、これを濾取して風乾することにより塩酸ベニジピンの一水和物の結晶を得ることができる。
なおこの水和物の確認は、カールフィッシャー法による水分の測定、融点（１７８℃）の測定、赤外線吸収スペクトル（ＩＲ）、示差熱走査曲線（ＤＳＣ）、粉末Ｘ−線回折等の測定により行うことができる。
After heating and cooling, the target benidipine hydrochloride monohydrate precipitates in the solution as crystals, and this is filtered and air-dried to obtain the crystals of benidipine hydrochloride monohydrate. be able to.
This hydrate is confirmed by measuring moisture by Karl Fischer method, measurement of melting point (178 ° C.), infrared absorption spectrum (IR), differential thermal scanning curve (DSC), powder X-ray diffraction, and the like. be able to.
次いで、かくして得られた塩酸ベニジピンの一水和物をケトン系溶媒単独、あるいはこれとアルコール系溶媒との混合溶媒に穏やかに加熱処理し、その後冷却することにより、高純度の塩酸ベニジピンが製造される。用いるケトン系溶媒としてはアセトン、メチルエチルケトン等が挙げられ、なかでもアセトンが好ましく使用される。また、アルコール系溶媒としては、メタノール、エタノール、プロパノール、ブタノール等の炭素原子数１〜４のアルコール系溶媒があげられ、好ましくはエタノールを用いるのがよい。 Next, the monohydrate of benidipine hydrochloride thus obtained is gently heated to a ketone solvent alone or a mixed solvent of this with an alcohol solvent, and then cooled to produce high-purity benidipine hydrochloride. The Examples of the ketone solvent to be used include acetone and methyl ethyl ketone. Among these, acetone is preferably used. Examples of the alcohol solvent include alcohol solvents having 1 to 4 carbon atoms such as methanol, ethanol, propanol, and butanol. Preferably, ethanol is used.
ケトン系溶媒に対するアルコール系溶媒の比率は一概に限定できないが、容量比で、ケトン系溶媒１に対してアルコール系溶媒を０．１〜１程度使用するのがよい。 Although the ratio of the alcohol solvent to the ketone solvent cannot be generally limited, it is preferable to use about 0.1 to 1 alcohol solvent with respect to the ketone solvent 1 in terms of volume ratio.
加熱後、冷却することにより目的とする塩酸ベニジピンが結晶として析出してくるので、これを濾取して風乾することにより塩酸ベニジピン結晶を得ることができ、得られた結晶は、そのまま医薬品原料として使用し得る高純度のものであった。
なおこの塩酸ベニジピンの確認は、融点（２０４℃）の測定、赤外線吸収スペクトル（ＩＲ）、示差熱走査曲線（ＤＳＣ）、粉末Ｘ−線回折等の測定により行うことができる。
Since the target benidipine hydrochloride precipitates as crystals by cooling after heating, the benidipine hydrochloride crystals can be obtained by filtration and air drying, and the obtained crystals are used as raw materials for pharmaceuticals as they are. It was of high purity that could be used.
The confirmation of this benidipine hydrochloride can be carried out by measuring the melting point (204 ° C.), infrared absorption spectrum (IR), differential thermal scanning curve (DSC), powder X-ray diffraction and the like.
以下に本発明を、参考例、実施例により説明するが、本発明はこれらの実施例に限定されるものではない。
なお、下記の実施例においては機器データの測定は、以下の分析機器を使用した。
ＤＳＣ：Rigaku DSC8230
ＩＲ：日本分光 FT/IR-430
粉末Ｘ線回折：Rigaku RAD-1C
The present invention will be described below with reference examples and examples, but the present invention is not limited to these examples.
In the following examples, the following analytical instruments were used for measuring instrument data.
DSC: Rigaku DSC8230
IR: JASCO FT / IR-430
X-ray powder diffraction: Rigaku RAD-1C
参考例：塩酸ベニジピンの粗結晶の製造
ｍ−ニトロベンズアルデヒドとβ−アミノクロトン酸メチル及びアセト酢酸−Ｎ−ベンジル−３−ピペリジルエステルを用いて、特開昭５７−１７１９６８（特許文献２）に記載されている製造方法により、塩酸ベニジピンの粗結晶を得た。この物のＨＰＬＣによる相対純度は９６．８％であった。
Reference Example: Preparation of crude crystals of benidipine hydrochloride described in JP-A-57-171968 (patent document 2) using m-nitrobenzaldehyde, methyl β-aminocrotonate and acetoacetic acid-N-benzyl-3-piperidyl ester By the production method described above, crude crystals of benidipine hydrochloride were obtained. The relative purity of this product by HPLC was 96.8%.
実施例１：塩酸ベニジピンの一水和物の結晶の製造
上記の参考例により得た塩酸ベニジピンの粗結晶２０．０ｇにエタノール８０ｍＬを加えて、加熱還流下溶解した後、この溶液に水２０ｍＬを加えた。冷却下攪拌した後に析出した結晶を濾過し、乾燥することにより塩酸ベニジピンの一水和物結晶１７．６ｇ（収率８５％）を得た。
Example 1 Production of Benidipine Hydrochloride Monohydrate Crystals 80 mL of ethanol was added to 20.0 g of the crude crystals of benidipine hydrochloride obtained in the above Reference Example and dissolved under heating to reflux, and then 20 mL of water was added to this solution. added. The crystals precipitated after stirring under cooling were filtered and dried to obtain 17.6 g (yield 85%) of monohydrate crystals of benidipine hydrochloride.
この結晶のＨＰＬＣによる相対純度は９９．６％であり、機器分析の結果は次の通りであった。
水分：３．３％（カールフィッシャー法）
融点：１７８℃
ＩＲ（ＫＣｌ、ｃｍ−１）：1674，1484，1281，1210
粉末Ｘ線回折（２θ）：7.2，10.3，13.7，20.4，22.1
The relative purity by HPLC of this crystal was 99.6%, and the results of instrumental analysis were as follows.
Moisture: 3.3% (Karl Fischer method)
Melting point: 178 ° C
IR (KCl, cm −1 ): 1674, 1484, 1281, 1210
Powder X-ray diffraction (2θ): 7.2, 10.3, 13.7, 20.4, 22.1
実施例２：塩酸ベニジピンの一水和物の結晶の製造
参考例で得た塩酸ベニジピンの粗結晶２０．０ｇにアセトニトリル４８ｍＬ及び水１２ｍＬを加えて、加熱還流下に溶解した。冷却下攪拌した後に析出した結晶を濾過し、乾燥を行い、塩酸ベニジピンの一水和物結晶１６．６ｇ（収率８０％）を得た。この結晶のＨＰＬＣによる相対純度は９９．５％であり、機器分析の結果は実施例１で得られた結晶と同様であった。
Example 2 Production of Benidipine Hydrochloride Monohydrate Crystals 48 mL of acetonitrile and 12 mL of water were added to 20.0 g of the crude crystals of benidipine hydrochloride obtained in the Reference Example, and dissolved under heating and reflux. The crystals precipitated after stirring under cooling were filtered and dried to obtain 16.6 g (yield 80%) of monohydrate crystals of benidipine hydrochloride. The relative purity of this crystal by HPLC was 99.5%, and the result of instrumental analysis was the same as that of the crystal obtained in Example 1.
実施例３：塩酸ベニジピンの結晶の製造
実施例１で得た塩酸ベニジピンの一水和物結晶１５．０ｇにエタノール４５ｍＬを加えて、加熱還流下溶解した後、この溶液にアセトン９０ｍＬを加えた。冷却下攪拌した後に析出した結晶を濾過し、乾燥を行い塩酸ベニジピンの結晶１３．１ｇ（収率９０％）を得た。この結晶の機器分析結果は次の通りであった。
融点：２０４℃
ＩＲ（ＫＣｌ、ｃｍ−１）：1666，1492，1300，1219
粉末Ｘ線回折（２θ）：8.1，10.4，12.7，19.5，24.1
Example 3 Preparation of Benidipine Hydrochloride Crystals 45 mL of ethanol was added to 15.0 g of monohydrate crystals of benidipine hydrochloride obtained in Example 1 and dissolved under heating to reflux, and then 90 mL of acetone was added to this solution. After stirring under cooling, the precipitated crystals were filtered and dried to obtain 13.1 g (yield 90%) of benidipine hydrochloride crystals. The instrumental analysis results of this crystal were as follows.
Melting point: 204 ° C
IR (KCl, cm −1 ): 1666, 1492, 1300, 1219
Powder X-ray diffraction (2θ): 8.1, 10.4, 12.7, 19.5, 24.1
以上記載のように、本発明方法により塩酸ベニジピンを、そのまま医薬品として使用しうる高純度を保持した塩酸ベニジピンが製造できる工業的方法が提供される。
本発明方法は、従来法に比較して繰り返し再結晶を行う操作の煩雑さを回避しうるものであり、再結晶操作の繰り返しが無いため、目的とする塩酸ベニジピンのロスが少なく、高収率で製造しうることから、その経済的利点は多大なものである。
As described above, the method of the present invention provides an industrial method capable of producing benidipine hydrochloride having high purity that can be used as it is as a pharmaceutical product.
The method of the present invention is capable of avoiding the complexity of the operation of repeated recrystallization as compared with the conventional method, and since there is no repetition of the recrystallization operation, the loss of the target benidipine hydrochloride is small and the yield is high. Its economic advantages are enormous.
Claims (4)
The method for industrial production of high-purity benidipine hydrochloride according to claim 1 or 2, wherein the ketone solvent is acetone.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102351784A (en) * | 2011-10-20 | 2012-02-15 | 华夏药业集团有限公司 | Benidipine hydrochloride crystal form and application thereof |
| EP3185050A1 (en) | 2015-12-23 | 2017-06-28 | Essilor International (Compagnie Générale D'Optique) | Optical article comprising a multilayered interferential coating obtained from an organic precursor or a mixture of organic precursors |
| WO2019053491A1 (en) | 2017-09-15 | 2019-03-21 | Deva Holding Anonim Sirketi | Crystalline solid forms of benidipine hcl and methods of preparing same |
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| WO2012142816A1 (en) * | 2011-04-18 | 2012-10-26 | Hefei Beini Medical Technology Company, Ltd | Benidipine hydrochloride nanoparticles and preparation method thereof |
| CN102746215A (en) * | 2011-04-18 | 2012-10-24 | 张兆勇 | Method for preparing high-purity benidipine hydrochloride |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102351784A (en) * | 2011-10-20 | 2012-02-15 | 华夏药业集团有限公司 | Benidipine hydrochloride crystal form and application thereof |
| EP3185050A1 (en) | 2015-12-23 | 2017-06-28 | Essilor International (Compagnie Générale D'Optique) | Optical article comprising a multilayered interferential coating obtained from an organic precursor or a mixture of organic precursors |
| WO2019053491A1 (en) | 2017-09-15 | 2019-03-21 | Deva Holding Anonim Sirketi | Crystalline solid forms of benidipine hcl and methods of preparing same |
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