JP2766073B2 - Single crystal of β-phenylpropiophenone - Google Patents
Single crystal of β-phenylpropiophenoneInfo
- Publication number
- JP2766073B2 JP2766073B2 JP50576190A JP50576190A JP2766073B2 JP 2766073 B2 JP2766073 B2 JP 2766073B2 JP 50576190 A JP50576190 A JP 50576190A JP 50576190 A JP50576190 A JP 50576190A JP 2766073 B2 JP2766073 B2 JP 2766073B2
- Authority
- JP
- Japan
- Prior art keywords
- crystals
- single crystal
- phenylpropiophenone
- range
- propafenone
- 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.)
- Expired - Lifetime
Links
- 239000013078 crystal Substances 0.000 title claims description 24
- QGGZBXOADPVUPN-UHFFFAOYSA-N dihydrochalcone Chemical compound C=1C=CC=CC=1C(=O)CCC1=CC=CC=C1 QGGZBXOADPVUPN-UHFFFAOYSA-N 0.000 title claims description 8
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 229960002443 propafenone hydrochloride Drugs 0.000 description 4
- XWIHRGFIPXWGEF-UHFFFAOYSA-N propafenone hydrochloride Chemical compound Cl.CCCNCC(O)COC1=CC=CC=C1C(=O)CCC1=CC=CC=C1 XWIHRGFIPXWGEF-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- -1 1,1-dimethylpropyl compound Chemical class 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229960000203 propafenone Drugs 0.000 description 2
- JWHAUXFOSRPERK-UHFFFAOYSA-N propafenone Chemical compound CCCNCC(O)COC1=CC=CC=C1C(=O)CCC1=CC=CC=C1 JWHAUXFOSRPERK-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 1
- 229960000564 nitrofurantoin Drugs 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
【発明の詳細な説明】 本発明は、β−フェニルプロピオフェノンの単結晶並
びに貯留形の製造のための単結晶の使用に関する。The present invention relates to single crystals of β-phenylpropiophenone as well as to the use of single crystals for the production of storage forms.
プロパフェノン（I,R＝-CH2-CH2-CH3）は、製薬学的
作用物質であり、これは不整脈に抗して使用されてい
る。この作用物質は、既に久しく使用されているにもか
かわらず、今日までこの作用物質を含有する貯留医薬形
は存在しない。相応する1,1−ジメチルプロピル化合物
のためにすら、今日まで貯留形は存在しない。Propafenone (I, R = -CH 2 -CH 2 -CH 3) is an pharmaceutical agents, which are used against arrhythmias. Although this agent has been used for a long time, there is no stored pharmaceutical form containing this agent to date. No storage form exists to date, even for the corresponding 1,1-dimethylpropyl compound.
Pharmazeutischen-Zeitung No.48、９頁（01.12.88）
の記載から、大結晶体（Makrokrista11）の形成によっ
て、作用物質の緩慢な分解を達成できることは公知であ
る。しかし、ニトロフラントイン（Nitrofurantoin）の
例に示されたように、結晶体の投与によって、濃縮のピ
ークの発生だけが妨げられ得るが、しかし明確な後の最
大の血中濃度を惹起するような貯留形は含有され得な
い。Pharmazeutischen-Zeitung No.48, p.9 (01.12.88)
It is known from the description that slow degradation of the active substance can be achieved by the formation of large crystals (Makrokrista11). However, as shown in the example of Nitrofurantoin, administration of crystals can only prevent the occurrence of a peak of enrichment, but induce a maximal blood concentration after a well-defined Storage forms cannot be contained.
β−フェニルプロピオフェノンの一定の単結晶が、望
ましい血中濃度を有する貯留製剤の製造のために好適で
あることが見い出された。Certain single crystals of β-phenylpropiophenone have been found to be suitable for the production of a depot preparation having the desired blood concentration.
本発明の対象は、式１ ［式中、Ｒは、-CH2-CH2-CH3基または-C(CH3)2-CH2-C
H3基である］のβ−フェニルプロピオフェノンの単結晶
であり、この容量は0.004〜1.2mm3の範囲内である。有
利に単結晶は、0.1〜0.6mm3の容量を有する。The object of the present invention is the formula 1 [Wherein, R represents a —CH 2 —CH 2 —CH 3 group or —C (CH 3 ) 2 —CH 2 —C
H is a 3 group] is in the β- phenylpropyl off E non single crystal, this capacity is in the range of 0.004～1.2Mm 3. Advantageously single crystal has a capacity of 0.1 to 0.6 mm 3.
更に、本発明の対象は、貯留製剤の製造のための前記
単結晶の使用である。Furthermore, the subject of the present invention is the use of said single crystals for the manufacture of a depot preparation.
化合物Ｉの単結晶は、公知方法により製造され得る。
球状の結晶体が有利である、何故なら、かかる結晶体
は、加工して分割された医薬形に変えるために一層好適
だからである。かかる結晶体は、欧州特許出願公開第11
9480号明細書記載の方法により得られる。The single crystal of the compound I can be produced by a known method.
Spherical crystals are advantageous because such crystals are more suitable for processing into converted pharmaceutical forms. Such crystals are described in European Patent Application Publication No. 11
It can be obtained by the method described in JP-A-9480.
投与形の製造のために、単結晶は有利にカプセル中に
充填されている。しかし、単結晶を常法の糖衣錠または
錠剤に加工してもよい。For the production of dosage forms, the single crystals are preferably filled in capsules. However, the single crystals may be processed into conventional sugar-coated tablets or tablets.
単結晶を用いた場合には、物質を１日２回だけ投与す
るとしても、血漿中濃度を長期間に亙って実際に一定に
維持することが可能である。これは殊にプロパフェノン
が該当する。遅延作用は、結局のところ結晶体の時間に
左右される分解の物理的経過に基づいている。When single crystals are used, it is possible to maintain the plasma concentration practically constant over a long period even if the substance is administered only twice a day. This applies in particular to propafenone. The delay effect is based on the physical course of the decomposition, which is ultimately dependent on the time of the crystal.
例１ 傾斜翼型撹拌機、二重壁および電流遮断器を備えた市
販の50l撹拌釜中で、40℃に加熱され、飽和した、メタ
ノール中のプロパフェノン塩酸塩溶液40lを強力に撹拌
した。Example 1 40 l of a saturated, propafenone hydrochloride solution in methanol heated to 40 ° C. were stirred vigorously in a commercial 50 l stirred kettle equipped with a tilting blade stirrer, double wall and current breaker.
100〜200μｍの粒径を有するプロパフェノン塩酸塩種
晶350gの添加後、緩慢に4k/hの冷却率で、ｎ＝100min-1
の回転数で絶えず撹拌しながら、20℃に冷却した。After the addition of 350 g of propafenone hydrochloride seeds having a particle size of 100-200 μm, slowly at a cooling rate of 4 k / h, n = 100 min −1
The solution was cooled to 20 ° C. with constant stirring at a rotational speed of.
発生した結晶体を、僅かに冷たいメタノール中に入
れ、直ちに吸引漏斗に吸引濾過し、僅かに冷たいメタノ
ールで後洗浄し、真空乾燥棚中にて50℃および250〜400
mbarで乾燥させた。The crystals formed are placed in slightly cold methanol, immediately filtered off with suction in a suction funnel, post-washed with slightly cold methanol and placed in a vacuum drying cabinet at 50 ° C. and 250-400.
Dried at mbar.
生成物は、0.4〜1.2mmの粒径範囲を有する無色の球状
結晶体からなり、この場合度数分布の顕著な最大値は、
0.6〜0.8mmの範囲内であり、0.11〜0.27mm3の粒子容積
範囲に相応する。The product consists of colorless spherical crystals with a particle size range of 0.4-1.2 mm, in which case the pronounced maximum of the frequency distribution is:
In the range of 0.6 to 0.8 mm, corresponding to the grain volume range 0.11~0.27mm 3.
例２ 例１による装置中で、飽和メタノール性プロパフェノ
ン塩酸塩溶液を10k/hの冷却率でｎ＝100min-1の回転数
で絶えず撹拌しながら、接種結晶の添加なしに20℃に冷
却した。生成された結晶体を、例１により分離し、乾燥
した。Example 2 In a device according to Example 1, a saturated methanolic propafenone hydrochloride solution was cooled to 20 ° C. without addition of inoculated crystals, with constant stirring at a cooling rate of 10 k / h at a speed of n = 100 min −1 . . The crystals formed were separated according to Example 1 and dried.
生成物は、100〜600μｍの粒径を有する、顕微鏡で確
認可能な球体化された、無色の結晶体であり、この場合
度数分布の最大値は0.2〜0.4mmの範囲内であり、0.004
〜0.034mm3の粒子容積範囲に相応する。The product is microscopically visible, spheroidized, colorless crystals with a particle size of 100-600 μm, where the maximum of the frequency distribution is in the range of 0.2-0.4 mm and 0.004
Corresponds to the grain volume range ~0.034mm 3.
例３ 傾斜翼型撹拌機および二重壁を備えた市販の50l撹拌
釜の中で、40℃に加熱され、飽和した、メタノール中の
プロパフェノン塩酸塩の溶液を強力に撹拌し、20k/hの
冷却率で、ｎ＝60min-1の回転数で撹拌しながら、20℃
に冷却した。生成された結晶体を例１によって分離し、
乾燥した。Example 3 In a commercial 50 l stirrer equipped with a tilting blade stirrer and double walls, a solution of propafenone hydrochloride heated in methanol and saturated at 40 ° C. was vigorously stirred at 20 k / h. At a cooling rate of 20 ° C. while stirring at a rotation speed of n = 60 min −1
And cooled. The crystals formed are separated according to Example 1,
Dried.
生成物は、0.1〜2.0mmの粒径を有し、かつ0.5〜1.2mm
の範囲内の度数分布の幅広の最大を有する無色から白色
に輝く角のある小片からなる。The product has a particle size of 0.1-2.0 mm and 0.5-1.2 mm
From colorless to white glowing horns with a wide maximum of frequency distribution in the range
───────────────────────────────────────────────────── フロントページの続き (72)発明者 ミュラー―ペルツァー，ヘルベルト ドイツ連邦共和国 デー―6900 ハイデ ルベルク ウーファーシュトラーセ 36 (56)参考文献 特開 昭59−182290（ＪＰ，Ａ) 特表 昭58−501324（ＪＰ，Ａ) 英国公開1307455（ＧＢ，Ａ) (58)調査した分野(Int.Cl.6，ＤＢ名) C07C 217/36 A61K 9/16 ＲＥＧＩＳＴＲＹ（ＳＴＮ) ＣＡ（ＳＴＮ) ＣＡＯＬＤ（ＳＴＮ)────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Muller-Pelzer, Herbert Germany 6900 Heidelberg Uferstraße 36 (56) References JP-A-59-182290 (JP, A) Special Table 58-501324 (JP, A) British publication 1307455 (GB, A) (58) Fields investigated (Int. Cl. 6 , DB name) C07C 217/36 A61K 9/16 REGISTRY (STN) CA (STN) CAOLD (STN)
Claims (1)
基である］で示され、かつ容量が0.004〜1.2mm3の範囲
内であるβ−フェニルプロピオフェノンの単結晶。1. Formula I [Wherein, R represents a —CH 2 —CH 2 —CH 3 group or —C (CH 3 ) 2 —CH 2 —CH 3
A single crystal of β-phenylpropiophenone having a capacity in the range of 0.004 to 1.2 mm 3 .
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP1990/000529 WO1990011755A1 (en) | 1989-04-06 | 1990-04-04 | MONOCRYSTALS OF β-PHENYLPROPIOPHENONES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH05505386A JPH05505386A (en) | 1993-08-12 |
| JP2766073B2 true JP2766073B2 (en) | 1998-06-18 |
Family
ID=8165472
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP50576190A Expired - Lifetime JP2766073B2 (en) | 1990-04-04 | 1990-04-04 | Single crystal of β-phenylpropiophenone |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2766073B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101324862B1 (en) * | 2011-07-12 | 2013-11-01 | (주)에이에스텍 | Spherical particle of clopidogrel bisulfate, pharmaceutical composition comprising the same and method of preparation thereof |
-
1990
- 1990-04-04 JP JP50576190A patent/JP2766073B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH05505386A (en) | 1993-08-12 |
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