JPH0477422A - Spherical granule of chlorprenaline-hydrochloric acid and its production - Google Patents
Spherical granule of chlorprenaline-hydrochloric acid and its productionInfo
- Publication number
- JPH0477422A JPH0477422A JP18805290A JP18805290A JPH0477422A JP H0477422 A JPH0477422 A JP H0477422A JP 18805290 A JP18805290 A JP 18805290A JP 18805290 A JP18805290 A JP 18805290A JP H0477422 A JPH0477422 A JP H0477422A
- Authority
- JP
- Japan
- Prior art keywords
- chlorprenaline
- solvent
- chlorprenaline hydrochloride
- hydrochloride
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 239000008187 granular material Substances 0.000 title claims abstract description 38
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 239000002904 solvent Substances 0.000 claims abstract description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- -1 dichloromathane Chemical compound 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 18
- 229940011051 isopropyl acetate Drugs 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 15
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 14
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- 239000004809 Teflon Substances 0.000 claims description 7
- 229920006362 Teflon® Polymers 0.000 claims description 7
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002270 dispersing agent Substances 0.000 claims description 6
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 claims description 6
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 5
- 229930195729 fatty acid Natural products 0.000 claims description 5
- 239000000194 fatty acid Substances 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 229940093499 ethyl acetate Drugs 0.000 claims description 3
- 229940117955 isoamyl acetate Drugs 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract description 4
- 239000006185 dispersion Substances 0.000 abstract description 3
- 230000015271 coagulation Effects 0.000 abstract 1
- 238000005345 coagulation Methods 0.000 abstract 1
- 238000002425 crystallisation Methods 0.000 description 17
- 230000008025 crystallization Effects 0.000 description 17
- 239000011521 glass Substances 0.000 description 11
- 239000002245 particle Substances 0.000 description 8
- 239000013078 crystal Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000007906 compression Methods 0.000 description 4
- 230000006835 compression Effects 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- NPHULPIAPWNOOH-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-(2,3-dihydroindol-1-ylmethyl)pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)CN1CCC2=CC=CC=C12 NPHULPIAPWNOOH-UHFFFAOYSA-N 0.000 description 1
- DFGKGUXTPFWHIX-UHFFFAOYSA-N 6-[2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]acetyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)C1=CC2=C(NC(O2)=O)C=C1 DFGKGUXTPFWHIX-UHFFFAOYSA-N 0.000 description 1
- GWESVXSMPKAFAS-UHFFFAOYSA-N Isopropylcyclohexane Natural products CC(C)C1CCCCC1 GWESVXSMPKAFAS-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- BTLNWAFOJAREMJ-UHFFFAOYSA-N cyclohexane;ethanol;hydrate Chemical compound O.CCO.C1CCCCC1 BTLNWAFOJAREMJ-UHFFFAOYSA-N 0.000 description 1
- LRZCOABZEULHCP-UHFFFAOYSA-N cyclohexane;methanol Chemical compound OC.C1CCCCC1 LRZCOABZEULHCP-UHFFFAOYSA-N 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000004154 testing of material Methods 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は塩酸クロルプレナリンの球形晶析造粒物および
その製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to spherical crystallized granules of chlorprenaline hydrochloride and a method for producing the same.
［従来の技術及び発明が解決しようとするｍＨＥ液体と
固体の分散系に分散媒と混和せずかつ分散した粒子と親
和性を有する少量の溶媒を加えると分散していた粒子が
凝集する現象が知られている（Ｄ、１．５ｔｏｃｋ、
Ｎａｔｕｒｅ、 Ｎｏ４３２３．４２３（１９５２）。[The conventional technology and the invention aim to solve the phenomenon that when a small amount of solvent that is immiscible with the dispersion medium and has an affinity for the dispersed particles is added to the dispersion system of mHE liquid and solid, the dispersed particles aggregate. known (D, 1.5tock,
Nature, No. 4323.423 (1952).
本発明者の一人はこの現象を利用して新しい晶析球形造
粒法を開発した（Ｐｈａｒｍ Ｔｅｃｈ Ｊａｐａｎ）
。One of the inventors of the present invention utilized this phenomenon to develop a new crystallization spherical granulation method (Pharm Tech Japan)
.
この方法は晶析操作によりできるだけ微細な結晶を生成
させその結晶を系内で直接造粒物にする方法である。This method is a method in which crystallization operations are performed to generate as fine crystals as possible, and the crystals are directly made into granules within the system.
一方、塩酸クロルプレナリンは、微細な板状結晶を有し
、付着凝集性が強いという欠点を有する。On the other hand, chlorprenaline hydrochloride has the disadvantage of having fine plate-like crystals and strong adhesion and cohesion.
本発明者は、塩酸クロルプレナリンの有する上記の欠点
を克服するため、晶析球形造粒法についで鋭意研究を行
なった結果、下記に示す方法を採用することにより問題
を解決することができることを見い出し、本発明を完成
した。In order to overcome the above-mentioned drawbacks of chlorprenaline hydrochloride, the present inventor conducted intensive research on the crystallization spherical granulation method, and found that the problem can be solved by adopting the method shown below. They discovered this and completed the present invention.
［課題を解決するための手段］
すなわち、本発明は、塩酸クロルプレナリンを良溶媒に
溶解し、それを非溶媒中に撹拌しながら滴下後、溶媒を
乾燥させて得られる晶析球形造粒物に関するものである
。更に本発明は、塩酸クロルプレナリンを良溶媒に溶解
し、それを非溶媒中に撹拌しながら滴下後、溶媒を乾燥
させる晶析球形造粒物の製造方法に関するものである。[Means for Solving the Problems] That is, the present invention provides crystallized spherical granules obtained by dissolving chlorprenaline hydrochloride in a good solvent, dropping it into a non-solvent while stirring, and then drying the solvent. It is about things. Furthermore, the present invention relates to a method for producing crystallized spherical granules, which comprises dissolving chlorprenaline hydrochloride in a good solvent, dropping it into a non-solvent while stirring, and then drying the solvent.
本発明により、付着凝集性の強い塩酸クロルプレナリン
の微細な板状結晶を付着凝集性の弱い直接打錠可能な球
形造粒物とすることができる。According to the present invention, fine plate-like crystals of chlorprenaline hydrochloride, which has a strong adhesive and cohesive property, can be made into spherical granules that have a weak adhesive and cohesive property and can be directly compressed into tablets.
したがって、本発明の目的は塩酸クロルプレナリンの付
着凝集性を改善し、取り扱いやすく、さらに直接打錠可
能とした球形晶析造粒物を提供することにあり、更に球
形晶析造粒物の製造方法を提供することである。Therefore, an object of the present invention is to provide a spherical crystallized granule that improves the adhesion and aggregation properties of chlorprenaline hydrochloride, is easy to handle, and can be directly compressed into tablets. An object of the present invention is to provide a manufacturing method.
本発明における良溶媒とは塩酸クロルプレナリンの溶解
度が約２０■／ｄ以上である溶媒を意味し、具体的には
、水、メタノール、ジメチルスルホキシド、Ｎ、Ｎ−ジ
メチルホルムアミド、エタノール、イソプロパノールか
ら選ばれた一種あるいは二種以上の溶媒が好ましく、さ
らに好ましくは水またはエタノールまたは水とエタノー
ルの混合溶媒である。In the present invention, a good solvent means a solvent in which the solubility of chlorprenaline hydrochloride is about 20 μ/d or more, and specifically, it includes water, methanol, dimethyl sulfoxide, N,N-dimethylformamide, ethanol, and isopropanol. One or more selected solvents are preferred, and water, ethanol, or a mixed solvent of water and ethanol are more preferred.
また、本発明における非溶媒とは塩酸クロルプレナリン
の溶解度が６．７■／ｄ以下である溶媒を意味し、具体
的にはクロロホルム、ジクロロメタン、アセトン、アセ
トフェノン、テトラヒドロフラン、クロロベンゼン、エ
ーテル、ヘキサン、酢酸エチル、酢酸イソプロピル、酢
酸イソアミル、シクロヘキサンから選ばれた一種あるい
は二種以上の溶媒が好ましく、さらに好ましくは酢酸イ
ソプロピル、シクロヘキサンを挙げることができる。In addition, the non-solvent in the present invention means a solvent in which the solubility of chlorprenaline hydrochloride is 6.7 μ/d or less, and specifically, chloroform, dichloromethane, acetone, acetophenone, tetrahydrofuran, chlorobenzene, ether, hexane, One or more solvents selected from ethyl acetate, isopropyl acetate, isoamyl acetate, and cyclohexane are preferred, and isopropyl acetate and cyclohexane are more preferred.
本発明における塩酸クロルプレナリンの晶析造粒法を例
を挙げてさらに詳しく説明すると次の如くである。The crystallization and granulation method of chlorprenaline hydrochloride according to the present invention will be explained in more detail using an example as follows.
まず、塩酸クロルプレナリンを良溶媒である水またはエ
タノールに溶解する。この際、塩酸クロルプレナリンの
溶解度を高めるために加温してもよい。良溶媒中の塩酸
クロルプレナリン濃度は、良溶媒の種類と温度に依存す
るため、−概に決められないが、室温の水の場合には３
ｄ／ｇ、８０℃の水の場合には１ｄ／Ｈの濃度にするこ
とができる。First, chlorprenaline hydrochloride is dissolved in water or ethanol, which is a good solvent. At this time, heating may be performed to increase the solubility of chlorprenaline hydrochloride. The concentration of chlorprenaline hydrochloride in a good solvent depends on the type of good solvent and the temperature.
d/g, and in the case of water at 80° C., the concentration can be 1 d/H.
次に上記の塩酸クロルプレナリン溶解液を非溶媒である
酢酸イソプロピル中に添加し、系を撹拌すると白色の球
形造粒物が沈澱する。この沈澱物を通常用いられる方法
で分取し、溶媒を乾燥させ、塩酸クロルプレナリンの球
形造粒物を得ることができる。Next, the above chlorprenaline hydrochloride solution is added to isopropyl acetate, which is a non-solvent, and when the system is stirred, white spherical granules are precipitated. This precipitate is separated by a commonly used method and the solvent is dried to obtain spherical granules of chlorprenaline hydrochloride.
従来の晶析造粒は非溶媒と良溶媒が互いに混合しない非
混和系で行なわれていた。本発明の顕著な特徴の一つは
非溶媒と良溶媒が互いに混和する系でも塩酸クロルプレ
ナリンの球形造粒物が得られることにある。例えば、本
発明において、水−シクロヘキサン、メタノール−シク
ロヘキサンの場合は溶媒非混和系であり、エタノール土
水−シクロヘキサン、水−酢酸イソプロピルの場合は混
和系と非混和系の両方の場合がある。水−酢酸イソプロ
ビル系の場合、水の量が酢酸イソプロピル２００ｍに対
して２．７ ｄ以上では溶媒混和系、２．７ ｄ以上で
は溶媒非混和系である。Conventional crystallization granulation has been carried out in an immiscible system in which the non-solvent and the good solvent do not mix with each other. One of the remarkable features of the present invention is that spherical granules of chlorprenaline hydrochloride can be obtained even in a system where a non-solvent and a good solvent are mixed with each other. For example, in the present invention, water-cyclohexane and methanol-cyclohexane are solvent-immiscible systems, and ethanol-water-cyclohexane and water-isopropyl acetate systems can be both miscible and immiscible systems. In the case of a water-isopropyl acetate system, if the amount of water is 2.7 d or more per 200 m of isopropyl acetate, it is a solvent-miscible system, and if it is 2.7 d or more, it is a solvent-immiscible system.
上記操作は通常用いられる装置即ちガラス製あるいは金
属製の装置を用いることができる。しかし良溶媒として
水またはエタノールまたは水とエタノールの混合溶媒を
用い、非溶媒としてシクロヘキサンを用いる場合は、晶
析する結晶がガラス表面に付着して回収率が低下するこ
とがある。上記現象を回避するためにはテフロン容器あ
るいはテフロンコーティングした容器を用いればよい。The above operations can be carried out using commonly used equipment, ie, equipment made of glass or metal. However, when water, ethanol, or a mixed solvent of water and ethanol is used as a good solvent and cyclohexane is used as a non-solvent, the crystals to be crystallized may adhere to the glass surface and the recovery rate may decrease. In order to avoid the above phenomenon, a Teflon container or a Teflon-coated container may be used.
さらに良溶媒として水を用い、非溶媒としてシクロヘキ
サンを用いる場合は、晶析造粒物の粒子径が大きくなる
ことがある。粒子径を小さくするにはシクロヘキサン中
に分散剤を添加すればよい。Furthermore, when water is used as a good solvent and cyclohexane is used as a non-solvent, the particle size of the crystallized granules may become large. To reduce the particle size, a dispersant may be added to cyclohexane.
この場合の分散剤の種類および量は特に限定されないが
好ましくはショ糖脂肪酸エステル、ポリオキシエチレン
ポリオキシブロビレングリコール、ポリオキシエチレン
硬化ヒマシ油から選ばれる一種または二種以上の分散剤
でシクロヘキサン２０〇−中に０．４〜１，２ｇ添加す
ることが好ましい。In this case, the type and amount of the dispersant are not particularly limited, but preferably one or more dispersants selected from sucrose fatty acid ester, polyoxyethylene polyoxybrobylene glycol, and polyoxyethylene hydrogenated castor oil are used in cyclohexane. It is preferable to add 0.4 to 1.2 g in 〇-.
以下に本発明の具体的な実施例を示し、本発明を更に詳
細に説明するが、本発明がこれらのみに限定されること
がないことはいうまでもない。The present invention will be described in more detail by showing specific examples below, but it goes without saying that the present invention is not limited to these.
［実施例］
実施例１
塩酸クロルプレナリン３ｇを９０℃の水Ｉｙｄに溶解し
、２０℃の酢酸イソプロピル２００ｄ中に滴下し、６０
０ ｒｐｍで１０分間撹拌した。得られた沈澱物を分取
し、溶媒をデシケータ中で一日乾燥させ、塩酸クロルプ
レナリンの球形造粒物を得た。晶析にはガラス製セパラ
ブルフラスコを使用した。[Example] Example 1 3 g of chlorprenaline hydrochloride was dissolved in 90°C water Iyd, and added dropwise to 200d of isopropyl acetate at 20°C.
Stirred for 10 minutes at 0 rpm. The obtained precipitate was separated and the solvent was dried in a desiccator for one day to obtain spherical granules of chlorprenaline hydrochloride. A separable glass flask was used for crystallization.
実施例２
塩酸クロルプレナリン２４ｇを９０°Ｃの水８ｄに溶解
し、２０℃の酢酸イソプロピル２０Ｏｄ中に滴下し、６
００ｒｐ−で１０分間撹拌した。以下実施例１と同様に
操作し、塩酸クロルプレナリンの球形造粒物を得た。晶
析にはガラス製セパラブルフラスコを使用した。Example 2 24 g of chlorprenaline hydrochloride was dissolved in 8 d of water at 90°C, and added dropwise to 20 Od of isopropyl acetate at 20°C.
Stirred at 00 rpm for 10 minutes. Thereafter, the same procedure as in Example 1 was carried out to obtain spherical granules of chlorprenaline hydrochloride. A separable glass flask was used for crystallization.
実施例３
塩酸クロルプレナリン４８ｇを９０℃の水１６ｄに溶解
し、２０℃の酢酸イソプロピル２００Ｉｄｌ中に滴下し
、６００ｒｐｍで１０分間撹拌した。以下実施例１と同
様に操作し、塩酸クロルプレナリンの球形造粒物を得た
。晶析にはガラス製セパラブルフラスコを使用した。Example 3 48 g of chlorprenaline hydrochloride was dissolved in 16 d of water at 90°C, added dropwise to 200 Idl of isopropyl acetate at 20°C, and stirred at 600 rpm for 10 minutes. Thereafter, the same procedure as in Example 1 was carried out to obtain spherical granules of chlorprenaline hydrochloride. A separable glass flask was used for crystallization.
実施例４
塩酸クロルプレナリン６ｇを９０°Ｃの水２．ｄに溶解
し、６０℃の酢酸イソプロピル２００ｄ中に滴下し、６
００ｒｐｍで１０分間撹拌した。得られた沈澱を分取し
、９０℃の棚で１時間乾燥させ塩酸クロルプレナリンの
球形造粒物を得た。晶析にはガラス製セパラブルフラス
コを使用した。Example 4 6 g of chlorprenaline hydrochloride was added to 90°C water 2. d and added dropwise to 200 d of isopropyl acetate at 60°C.
Stirred at 00 rpm for 10 minutes. The obtained precipitate was collected and dried on a shelf at 90° C. for 1 hour to obtain spherical granules of chlorprenaline hydrochloride. A separable glass flask was used for crystallization.
実施例５
塩酸クロルプレナリン３ｇを９０℃の水１ｄに溶解し、
２０℃のシクロヘキサン２００ｄ中に滴下し、６００ｒ
ｐｍで５分間撹拌した。以下実施例１と同様に操作し、
塩酸クロルプレナリンの球形造粒物を得た。晶析にはテ
フロン製容器を使用した。Example 5 3 g of chlorprenaline hydrochloride was dissolved in 1 d of water at 90°C,
Dropped into 200d of cyclohexane at 20°C, heated at 600r
Stir for 5 minutes at pm. The following operations were carried out in the same manner as in Example 1,
Spherical granules of chlorprenaline hydrochloride were obtained. A Teflon container was used for crystallization.
実施例６
塩酸クロルプレナリン３ｇを９０℃の水ｌＮｌ１に溶解
し、２０℃のシクロヘキサン２０Ｏａｄ中に滴下し、１
１０００ｒｐで１０分間撹拌した。以下実施例１と同様
に操作し、塩酸クロルプレナリンの球形造粒物を得た。Example 6 3 g of chlorprenaline hydrochloride was dissolved in 1N1 of water at 90°C, and added dropwise to 20Oad of cyclohexane at 20°C.
Stirred at 1000 rpm for 10 minutes. Thereafter, the same procedure as in Example 1 was carried out to obtain spherical granules of chlorprenaline hydrochloride.
晶析にはガラス製セパラブルフラスコを使用した。A separable glass flask was used for crystallization.
実施例７
塩酸クロルプレナリン３ｇを９０℃の水ＩＭ１に溶解し
、シヨ糖脂肪酸エステル０．４ｇを溶解させた２０℃の
シクロヘキサン２００ｊｄ中に滴下し、１０００ｒｐ−
で１０分間撹拌した。以下実施例１と同様に操作し、塩
酸クロルプレナリンの球形造粒物を得た。晶析にはガラ
ス製セパラブルフラスコを使用した。Example 7 3 g of chlorprenaline hydrochloride was dissolved in water IM1 at 90°C, added dropwise to 200jd of cyclohexane at 20°C in which 0.4 g of sucrose fatty acid ester was dissolved, and heated at 1000 rpm.
The mixture was stirred for 10 minutes. Thereafter, the same procedure as in Example 1 was carried out to obtain spherical granules of chlorprenaline hydrochloride. A separable glass flask was used for crystallization.
実施例８
塩酸クロルプレナリン３ｇを９０℃の水１１Ｉｉに溶解
し、シヨ糖脂肪酸エステル１．２ｇを溶解した２０℃の
シクロヘキサン２０Ｏｄ中に滴下し、１１０００ｒｐで
１０分間撹拌した。以下実施例１と同様に操作し、塩酸
クロルプレナリンの球形造粒物を得た。晶析にはガラス
製セパラブルフラスコを使用した。Example 8 3 g of chlorprenaline hydrochloride was dissolved in 11Ii of water at 90° C., and added dropwise into 20 Od of cyclohexane at 20° C. in which 1.2 g of sucrose fatty acid ester was dissolved, and stirred at 11,000 rpm for 10 minutes. Thereafter, the same procedure as in Example 1 was carried out to obtain spherical granules of chlorprenaline hydrochloride. A separable glass flask was used for crystallization.
実施例９
塩酸クロルプレナリン５ｇを７０℃のエタノール１０ｄ
に溶解し、２０℃のシクロヘキサン２００ｉ中に滴下し
、６００ｒｐ＋ｉで５分間撹拌した。以下実施例１と同
様に操作し、塩酸クロルプレナリンの球形造粒物を得た
。晶析にはテフロン製容器を使用した。Example 9 5 g of chlorprenaline hydrochloride was added to 10 d of ethanol at 70°C.
The solution was added dropwise to 200 i of cyclohexane at 20° C., and stirred at 600 rp+i for 5 minutes. Thereafter, the same procedure as in Example 1 was carried out to obtain spherical granules of chlorprenaline hydrochloride. A Teflon container was used for crystallization.
実施例１Ｏ
塩酸クロルプレナリン３ｇを９０℃の水１ｄに溶解する
。別に塩酸クロルプレナリン５ｇを７０℃のエタノール
１０ｄに溶解し、先に調整した水溶液と混合し、２０℃
のシクロヘキサン２０Ｏｄ中に滴下して６００ｒｐ■で
５分間撹拌した。以下実施例１と同様に操作し、塩酸ク
ロルプレナリンの球形造粒物を得た。晶析にはテフロン
製容器を使用した。Example 1O 3 g of chlorprenaline hydrochloride is dissolved in 1 d of water at 90°C. Separately, 5 g of chlorprenaline hydrochloride was dissolved in 10 d of ethanol at 70°C, mixed with the aqueous solution prepared earlier, and heated to 20°C.
The mixture was added dropwise to 20 Od of cyclohexane and stirred at 600 rpm for 5 minutes. Thereafter, the same procedure as in Example 1 was carried out to obtain spherical granules of chlorprenaline hydrochloride. A Teflon container was used for crystallization.
実施例１１
塩酸クロルプレナリン１４ｇを９０℃の水７ｄに溶解し
、２０℃の酢酸イソプロピル２０Ｏｄ中に滴下し、６０
０ｒｐｍで５分間撹拌した。得られた沈澱物を分取し、
溶媒をデシケータ中で１日乾燥させ、塩酸クロルプレナ
リンの球形造粒物を得た。晶析にはガラス製セパラブル
フラスコを使用した。Example 11 14 g of chlorprenaline hydrochloride was dissolved in 7 d of water at 90°C and added dropwise to 20 Od of isopropyl acetate at 20°C.
Stirred at 0 rpm for 5 minutes. Separate the obtained precipitate,
The solvent was dried in a desiccator for one day to obtain spherical granules of chlorprenaline hydrochloride. A separable glass flask was used for crystallization.
実施例１２
塩酸クロルプレナリン４ｇを９０℃の水２ｄに溶解し、
２０℃の酢酸イソプロピル２０ＯＪｄ中に滴下し、６０
０ ｒｐｍで５分間撹拌した。得られた沈澱物を分取し
、溶媒をデシケータ中で１日乾燥させ、塩酸クロルプレ
ナリンの球形造粒物を得た。Example 12 4 g of chlorprenaline hydrochloride was dissolved in 2 d of water at 90°C,
Add dropwise to 200Jd of isopropyl acetate at 20°C,
Stirred for 5 minutes at 0 rpm. The obtained precipitate was separated and the solvent was dried in a desiccator for one day to obtain spherical granules of chlorprenaline hydrochloride.
晶析にはガラス製セパラブルフラスコを使用した。A separable glass flask was used for crystallization.
［発明の効果］
実施例１，２，４，９．１０で得られた塩酸クロルプレ
ナリンの平均粒子径を表１に示した。[Effects of the Invention] Table 1 shows the average particle diameters of chlorprenaline hydrochloride obtained in Examples 1, 2, 4, 9.10.
表１
各実施例とも３４０〜８７０μｍの平均粒子径をもつ球
形造粒物となっていることがわかる。Table 1 It can be seen that in each example, the spherical granules had an average particle diameter of 340 to 870 μm.
また、実施例５．６で得られた塩酸クロルプレナリンの
回収率を表２に示した。Table 2 also shows the recovery rate of chlorprenaline hydrochloride obtained in Example 5.6.
表２
テフロン容器を用いた場合、回収率が増大することがわ
かる。Table 2 It can be seen that the recovery rate increases when a Teflon container is used.
さらに実施例６〜８で得られた塩酸クロルプレナリンの
平均粒子系を表３に示した。Furthermore, Table 3 shows the average particle system of chlorprenaline hydrochloride obtained in Examples 6 to 8.
表３ 横軸は圧縮圧、 縦軸は破壊強度を示す。Table 3 The horizontal axis is compression pressure, The vertical axis shows the breaking strength.
シａ’ｌｌｌ脂肪酸エステルを添加することにより平均
粒子径が小さくなることがわかる。It can be seen that the average particle diameter becomes smaller by adding the sia'llll fatty acid ester.
実施例１１．１２及び塩酸クロルプレナリン原末を用い
、島津材料試験機（ＡＧ−５０００Ａ）により打錠した
錠剤の圧縮圧と破壊強度の関係を図１に示した。FIG. 1 shows the relationship between compression pressure and breaking strength of tablets compressed using a Shimadzu material testing machine (AG-5000A) using Example 11.12 and chlorprenaline hydrochloride bulk powder.
図１より、本発明による塩酸クロルプレナリン造粒物の
圧縮成型性（図１中、実施例１１を−へ−及び実施例１
２を一口−で示す）が原末（図１中−〇−で示す）より
顕著に改善されていることが明らかである。From FIG. 1, the compression moldability of the chlorprenaline hydrochloride granules according to the present invention (in FIG. 1, Example 11 to - and Example 1
It is clear that the bulk powder (indicated by - in Fig. 1) is significantly improved over the bulk powder (indicated by - in Figure 1).
図１は圧縮圧と破壊強度の関係を示す。 Figure 1 shows the relationship between compression pressure and fracture strength.
Claims (11)
媒中に添加して分散後、両溶媒を乾燥して得られる塩酸
クロルプレナリンの球形造粒物。(1) Spherical granules of chlorprenaline hydrochloride obtained by dissolving chlorprenaline hydrochloride in a good solvent, adding it to a non-solvent, dispersing it, and then drying both solvents.
ド、Ｎ，Ｎ−ジメチルホルムアミド、エタノール、イソ
プロピルアルコールから選ばれた一種または二種以上の
良溶媒である請求項１記載の塩酸クロルプレナリンの球
形造粒物。(2) Spherical shape of chlorprenaline hydrochloride according to claim 1, wherein the good solvent is one or more good solvents selected from water, methanol, dimethyl sulfoxide, N,N-dimethylformamide, ethanol, and isopropyl alcohol. Granules.
ロフラン、クロロベンゼン、ヘキサン、シクロヘキサン
、酢酸エチル、酢酸イソプロピル、酢酸イソアミル、エ
ーテルから選ばれる一種または二種以上の非溶媒である
請求項１記載の塩酸クロルプレナリンの球形造粒物。(3) Chlorprenaline hydrochloride according to claim 1, wherein the nonsolvent is one or more nonsolvents selected from acetone, acetophenone, tetrahydrofuran, chlorobenzene, hexane, cyclohexane, ethyl acetate, isopropyl acetate, isoamyl acetate, and ether. spherical granules.
溶媒に塩酸クロルプレナリンを溶解後、酢酸イソプロピ
ル、シクロヘキサン、ヘキサン、エーテル、酢酸エチル
から選ばれる少なくとも一種の溶媒中に分散させ、両溶
媒を乾燥して得られる塩酸クロルプレナリンの球形造粒
物。(4) After dissolving chlorprenaline hydrochloride in water, ethanol, or a mixed solvent of water and ethanol, it is dispersed in at least one solvent selected from isopropyl acetate, cyclohexane, hexane, ether, and ethyl acetate, and both solvents are dried. Spherical granules of chlorprenaline hydrochloride obtained by
加したシクロヘキサン中に加えて撹拌し、溶媒を乾燥し
て得られる塩酸クロルプレナリンの球形造粒物。(5) Spherical granules of chlorprenaline hydrochloride obtained by dissolving chlorprenaline hydrochloride in water, adding it to cyclohexane containing a dispersant, stirring, and drying the solvent.
レンポリオキシプロピレングリコール、ポリオキシエチ
レン硬化ヒマシ油から選ばれた一種または二種以上の分
散剤である請求項９記載の塩酸クロルプレナリンの球形
造粒物。(6) Spherical shape of chlorprenaline hydrochloride according to claim 9, wherein the dispersant is one or more dispersants selected from sucrose fatty acid ester, polyoxyethylene polyoxypropylene glycol, and polyoxyethylene hydrogenated castor oil. Granules.
媒中に添加して分散後、両溶媒を乾燥して得られる塩酸
クロルプレナリン球形造粒物の製造方法。(7) A method for producing chlorprenaline hydrochloride spherical granules obtained by dissolving chlorprenaline hydrochloride in a good solvent, adding it to a non-solvent, dispersing it, and then drying both solvents.
、Ｎ，Ｎ−ジメチルホルムアミド、エタノール、イソプ
ロパノールから選ばれた一種または二種以上の良溶媒で
ある請求項１記載の塩酸クロルプレナリン球形造粒物の
製造方法。(8) The chlorprenaline hydrochloride spherical granules according to claim 1, wherein the good solvent is one or more good solvents selected from water, methanol, dimethyl sulfoxide, N,N-dimethylformamide, ethanol, and isopropanol. manufacturing method.
ロフラン、クロロベンゼン、ヘキサン、シクロヘキサン
、酢酸エチル、酢酸イソプロピル、酢酸イソアミル、エ
ーテルから選ばれた一種または二種以上の非溶媒である
請求項１記載の塩酸クロルプレナリン球形造粒物の製造
方法。(9) Chlorprena hydrochloride according to claim 1, wherein the nonsolvent is one or more nonsolvents selected from acetone, acetophenone, tetrahydrofuran, chlorobenzene, hexane, cyclohexane, ethyl acetate, isopropyl acetate, isoamyl acetate, and ether. Method for producing phosphorus spherical granules.
合溶媒に塩酸クロルプレナリンを溶解後、酢酸イソプロ
ピル、シクロヘキサン、ヘキサン、エーテル、酢酸エチ
ルから選ばれる少なくとも一種の溶媒中で分散させ、両
溶媒を乾燥して得られる塩酸クロルプレナリン球形造粒
物の製造方法。(10) After dissolving chlorprenaline hydrochloride in water, ethanol, or a mixed solvent of water and ethanol, it is dispersed in at least one solvent selected from isopropyl acetate, cyclohexane, hexane, ether, and ethyl acetate, and both solvents are dried. A method for producing chlorprenaline hydrochloride spherical granules obtained by
合溶媒に塩酸クロルプレナリンを溶解後シクロヘキサン
に添加して分散後溶媒を乾燥して得られる塩酸クロルプ
レナリン球形造粒物の製造方法において、テフロン製容
器あるいはテフロンコーティングした容器を用いること
を特徴とする塩酸クロルプレナリン球形造粒物の製造方
法。(11) A method for producing chlorprenaline hydrochloride spherical granules obtained by dissolving chlorprenaline hydrochloride in water, ethanol, or a mixed solvent of water and ethanol, adding it to cyclohexane, dispersing it, and then drying the solvent. 1. A method for producing spherical chlorprenaline hydrochloride granules, the method comprising using a container or a Teflon-coated container.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18805290A JPH0477422A (en) | 1990-07-18 | 1990-07-18 | Spherical granule of chlorprenaline-hydrochloric acid and its production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18805290A JPH0477422A (en) | 1990-07-18 | 1990-07-18 | Spherical granule of chlorprenaline-hydrochloric acid and its production |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0477422A true JPH0477422A (en) | 1992-03-11 |
Family
ID=16216848
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP18805290A Pending JPH0477422A (en) | 1990-07-18 | 1990-07-18 | Spherical granule of chlorprenaline-hydrochloric acid and its production |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0477422A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000076504A1 (en) * | 1999-06-10 | 2000-12-21 | Astrazeneca Ab | Production of agglomerates of inogatran and the compound inogatran anhydrate |
-
1990
- 1990-07-18 JP JP18805290A patent/JPH0477422A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000076504A1 (en) * | 1999-06-10 | 2000-12-21 | Astrazeneca Ab | Production of agglomerates of inogatran and the compound inogatran anhydrate |
| US6531490B1 (en) | 1999-06-10 | 2003-03-11 | Astrazeneca Ab | Production of agglomerates of inogatran and the compound inogatran anhydrate |
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