JPH0631302B2 - Etoposide-2-dimethylamino form hydrochloric acid dihydrate crystal and process for producing the same - Google Patents
Etoposide-2-dimethylamino form hydrochloric acid dihydrate crystal and process for producing the sameInfo
- Publication number
- JPH0631302B2 JPH0631302B2 JP28781288A JP28781288A JPH0631302B2 JP H0631302 B2 JPH0631302 B2 JP H0631302B2 JP 28781288 A JP28781288 A JP 28781288A JP 28781288 A JP28781288 A JP 28781288A JP H0631302 B2 JPH0631302 B2 JP H0631302B2
- Authority
- JP
- Japan
- Prior art keywords
- etoposide
- dimethylamino
- crystal
- hydrochloric acid
- acid dihydrate
- 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
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明の新規結晶は制癌剤として有用なものである。DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The novel crystal of the present invention is useful as a carcinostatic agent.
エトポシド−２−ジメチルアミノ体およびその塩酸塩は
特開昭61−227590に開示されている。The etoposide-2-dimethylamino compound and its hydrochloride salt are disclosed in JP-A-61-227590.
しかしエトポシド−２−ジメチルアミノ体およびその塩
酸塩は吸湿性があり、かつ塩酸塩の場合、塩酸塩を形成
させる際に使用する有機溶媒（アセトン、メタノール
等）が結晶中に残留する（0.3〜５％）欠点がある。However, the etoposide-2-dimethylamino compound and its hydrochloride salt are hygroscopic, and in the case of the hydrochloride salt, the organic solvent (acetone, methanol, etc.) used when forming the hydrochloride salt remains in the crystal (0.3- 5%) There is a drawback.
そこで本発明者らは、有機溶媒が残留せず、かつ吸湿性
もなく製剤化に適するエトポシド−２−ジメチルアミノ
体につき鋭意検討した結果、有機溶媒を含む４′−デメ
チルエピポドフイロトキシン９−（4,6−０−エチリデ
ン−２−ジメチルアミノ−２−デオキシ−β−Ｄ−グル
コピラノシド）塩酸塩（エトポシド−２−ジメチルアミ
ノ体塩酸塩）を、水中で懸濁させ、下記式 で表わされるエトポシド−２−ジメチルアミノ体塩酸二
水和結晶とすることにより、吸湿性がなく、かつ有機溶
媒の残留もほとんどない高純度の結晶が得られることを
見い出し、本発明を完成した。Therefore, as a result of diligent studies on the etoposide-2-dimethylamino compound, which is suitable for formulation without organic solvent remaining and hygroscopicity, the present inventors have found that 4'-demethylepipodophyllotoxin containing an organic solvent. 9- (4,6-0-ethylidene-2-dimethylamino-2-deoxy-β-D-glucopyranoside) hydrochloride (etoposide-2-dimethylamino body hydrochloride) was suspended in water to give the following formula: It was found that a highly pure crystal having no hygroscopicity and almost no residual organic solvent can be obtained by using the etoposide-2-dimethylamino-form hydrochloric acid dihydrate crystal represented by the following, and completed the present invention.
本発明を更に詳しく説明する。エトポシド−２−ジメチ
ルアミノ体塩酸塩は通常フリーのエトポシド−２−ジメ
チルアミノ体をアセトン、メタノール等の有機溶媒に溶
解し、その溶液中に塩化水素ガスを吹き込むことによ
り、結晶として得ることができる。この塩酸塩は乾燥後
においても塩酸塩にする際に用いたアセトン、メタノー
ルなどの有機溶媒を含んでいる。この有機溶媒は通常の
乾燥方法、例えば乾燥温度を上げる、乾燥時間を延長す
る、結晶を粉砕した後再度乾燥する等では除去できず、
かつ、吸湿性があるために正確な含量が求め難く、医薬
品原料として用いるには問題を有していた。本発明にお
いてはアセトン、メタノール等の有機溶媒を含む上記結
晶を約２倍量（Ｖ／Ｗ）以上好ましくは約３〜約３０倍
量（Ｖ／Ｗ）より好ましくは約５〜約１０倍量（Ｖ／
Ｗ）の水に懸濁させて、先ず約０〜約20℃好ましくは約
５〜約10℃で数分以上、好ましくは約0.2〜約１時間よ
り好ましくは約0.3〜約0.6時間懸濁する。The present invention will be described in more detail. Etoposide-2-dimethylamino body hydrochloride can be obtained as crystals by dissolving free etoposide-2-dimethylamino body in an organic solvent such as acetone or methanol and blowing hydrogen chloride gas into the solution. . This hydrochloride contains an organic solvent such as acetone and methanol used for making the hydrochloride even after drying. This organic solvent cannot be removed by a usual drying method, for example, increasing the drying temperature, extending the drying time, crushing the crystals and then drying again,
In addition, since it has hygroscopicity, it is difficult to obtain an accurate content, and there is a problem in using it as a raw material for pharmaceuticals. In the present invention, the above crystal containing an organic solvent such as acetone or methanol is about 2 times or more (V / W), preferably about 3 to about 30 times (V / W), more preferably about 5 to about 10 times. (V /
W) in water and first suspended at about 0 to about 20 ° C, preferably about 5 to about 10 ° C for several minutes or longer, preferably about 0.2 to about 1 hour, more preferably about 0.3 to about 0.6 hours. .
この処理により塩酸二水和結晶（β型結晶）が生成す
る。この結晶は過のしにくい結晶なので、更に次の処
理をすることにより、過のしやすい結晶（γ型結晶）
とすることができる。即ち引き続き、20℃より高い温度
好ましくは約30〜約80℃より好ましくは約40〜約60℃で
約0.5〜約５時間好ましくは約１〜約２時間撹拌を行な
った後再度約５〜約10℃に冷却後結晶を取し、真空乾
燥（25〜30℃、５時間）することにより、過のしやす
いエトポシド−２−ジメチルアミノ体塩酸二水和結晶
（γ型結晶）に変換することができる。By this treatment, hydrochloric acid dihydrate crystals (β type crystals) are produced. Since this crystal is a crystal that does not easily pass, a crystal that easily passes (γ-type crystal) can be obtained by further processing
Can be That is, subsequently, the mixture is stirred at a temperature higher than 20 ° C., preferably about 30 to about 80 ° C., more preferably about 40 to about 60 ° C. for about 0.5 to about 5 hours, preferably about 1 to about 2 hours, and then again about 5 to about 5 hours. Convert to etoposide-2-dimethylamino-form hydrochloric acid dihydrate crystal (γ-type crystal) that is easy to pass by cooling after cooling to 10 ℃ and collecting the crystal and vacuum drying (25-30 ℃, 5 hours). You can
従来の方法では、最終工程で使用した有機溶媒が結晶中
にかなり残留し、乾燥条件を変えても残留有機溶媒を除
去しきれず（表１）、かつ、空気中で吸湿し易い結晶
（表２）であったために製剤化には適さなかったが、本
発明によれば、有機溶媒を含むエトポシド−２−ジメチ
ルアミノ体塩酸塩を水中で懸濁させることにより、容易
に二水和結晶に変換でき、この二水和結晶は吸湿性がな
く、残留溶媒が極めて少ないことから、製剤化に最適な
ものである。According to the conventional method, the organic solvent used in the final step considerably remains in the crystal, the residual organic solvent cannot be completely removed even if the drying conditions are changed (Table 1), and the crystal which easily absorbs moisture in the air (Table 2). However, according to the present invention, the etoposide-2-dimethylamino body hydrochloride containing an organic solvent can be easily converted into a dihydrate crystal by suspending it in water. Since this dihydrate crystal has no hygroscopicity and the residual solvent is extremely small, it is optimal for formulation.
以下実施例により本発明を具体的に説明する。 The present invention will be specifically described below with reference to examples.
実施例 200ml４口フラスコにエトポシド−２−ジメチルアミノ
体塩酸塩結晶＊（アセトン：約5000ppmを含む）20.0g及
び蒸留水100mlを加えた後に内温５℃で１時間撹拌す
る。エトポシド−２−ジメチルアミノ体塩酸二水和結晶
（β型結晶）が生成する。次いで、内温を60℃まで上げ
て１時間撹拌した後、再度10℃まで冷却し、結晶を吸引
過、次いで真空乾燥（30℃／2mmHg/5時間）して、エ
トポシド−２−ジメチルアミノ体塩酸二水和結晶（γ型
結晶）19.7g（収率；93.5%）を得た。得られたβ型結晶
およびγ型結晶をガスクロマトグラフイーにて、分析し
たところ、残留アセトンはそれぞれ27ppmおよび25ppmで
あった。Example 2 To a 200 ml four-necked flask, 20.0 g of etoposide-2-dimethylamino body hydrochloride crystals * (acetone: containing about 5000 ppm) and 100 ml of distilled water were added, and then stirred at an internal temperature of 5 ° C. for 1 hour. Etoposide-2-dimethylamino form hydrochloric acid dihydrate crystal (β type crystal) is formed. Then, the internal temperature was raised to 60 ° C and the mixture was stirred for 1 hour, then cooled again to 10 ° C, and the crystals were suction-dried and then vacuum dried (30 ° C / 2mmHg / 5 hours) to give etoposide-2-dimethylamino compound. 19.7 g (yield: 93.5%) of hydrochloric acid dihydrate crystal (γ type crystal) was obtained. When the obtained β-type crystals and γ-type crystals were analyzed by gas chromatography, residual acetone was 27 ppm and 25 ppm, respectively.
＊フリーのエトポシド−２−ジメチルアミノ体をアセト
ンに溶解し、塩化水素ガスを吹き込み、塩酸塩結晶を析
出させ、乾燥したもの。* Free etoposide-2-dimethylamino compound dissolved in acetone, blown with hydrogen chloride gas to precipitate hydrochloride crystals, and dried.
β型結晶： 融 点；194.0゜（分解） 旋光度；▲〔α〕20 D▼−90.3゜（Ｃ＝0.5、メタノー
ル） ☆脱水物換算値☆ ＩＲ ；3420，3350，3270，3000，2950，2900，1775，
1110（ＣM-1） 水 分；5.70% ＮＭＲ；別途合成品と一致した。β-type crystal: Melting point; 194.0 ° (decomposition) Optical rotation; ▲ [α] 20 D ▼ -90.3 ° (C = 0.5, methanol) ☆ Dehydrated equivalent ☆ IR ； 3420, 3350, 3270, 3000, 2950, 2900, 1775,
1110 (CM -1 ) water content; 5.70% NMR; in agreement with a separately synthesized product.
γ型結晶： 融 点；217〜220℃（分解） 旋光度；▲〔α〕20 D▼−90゜（Ｃ＝0.5、メタノール） ☆脱水物換算値☆ ＩＲ ；3650，3550，3430，3200，1775，1100（Ｃ
M-1） 水 分；5.30% ＮＭＲ；別途合成品と一致したγ-type crystal: Melting point; 217-220 ° C (decomposition) Optical rotation; ▲ [α] 20 D ▼ -90 ° (C = 0.5, methanol) ☆ Dehydrated product conversion value ☆ IR ； 3650, 3550, 3430, 3200, 1775, 1100 (C
M -1 ) water content; 5.30% NMR; separately in agreement with the synthesized product
第１図はエトポシド−２−ジメチルアミノ体塩酸二水和
結晶のγ型結晶のＸ線回折図であり、第２図は同β型結
晶のＸ線回折図であり、第３図は無水のエトポシド−２
−ジメチルアミノ体塩酸塩のＸ線回折図である。FIG. 1 is an X-ray diffraction pattern of a γ-type crystal of an etoposide-2-dimethylamino form hydrochloric acid dihydrate crystal, FIG. 2 is an X-ray diffraction pattern of the same β-type crystal, and FIG. Etoposide-2
-X-ray diffraction pattern of dimethylamino-form hydrochloride.
Claims (2)
−（4,6−０−エチリデン−２−ジメチルアミノ−２−
デオキシ−β−Ｄ−グルコピラノシド）（以下エトポシ
ド−２−ジメチルアミノ体と略す）塩酸二水和結晶。1. A formula 4'-demethylepipodophyllotoxin 9 represented by
-(4,6-0-ethylidene-2-dimethylamino-2-
Deoxy-β-D-glucopyranoside) (hereinafter abbreviated as etoposide-2-dimethylamino compound) hydrochloric acid dihydrate crystal.
を水中に懸濁させることを特徴とするエトポシド−２−
ジメチルアミノ体塩酸二水和結晶の製造法。2. Etoposide-2-dimethylamino derivative hydrochloride is suspended in water.
Method for producing dimethylamino form hydrochloric acid dihydrate crystal.
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28781288A JPH0631302B2 (en) | 1988-11-16 | 1988-11-16 | Etoposide-2-dimethylamino form hydrochloric acid dihydrate crystal and process for producing the same |
| DE89120987T DE68912721T2 (en) | 1988-11-16 | 1989-11-11 | Crystalline hydrochloride of an etoposide-2-dimethylamino compound and process for producing the same. |
| EP89120987A EP0369369B1 (en) | 1988-11-16 | 1989-11-11 | Dihydrate crystals of etoposide-2-dimethylamino compound hydrochloride and a process for production thereof |
| ES89120987T ES2061891T3 (en) | 1988-11-16 | 1989-11-11 | CRYSTALS OF ETHOPOSIDE-2-DIMETHYLAMINE COMPOSITE DIHYDROCHLORIDE DIHYDRATE AND A PROCEDURE FOR ITS PRODUCTION. |
| US07/434,777 US4997923A (en) | 1988-11-16 | 1989-11-13 | Dihydrate crystals of etoposide-2-dimethylamino compound hydrochloride and a process for production thereof |
| AU44672/89A AU613536B2 (en) | 1988-11-16 | 1989-11-15 | Dihydrate crystals of etoposide-2-dimethylamino compound hydrochloride and a process for production thereof |
| CA002003028A CA2003028A1 (en) | 1988-11-16 | 1989-11-15 | Dihydrate crystals of etoposide-2-dimethylamino compound hydrochloride and a process for production thereof |
| CN89108575A CN1023121C (en) | 1988-11-16 | 1989-11-16 | Crystal of hydrochloric salt of etoposide-2-dimethylamino compounds and process for preparing them |
| KR1019890016615A KR900007845A (en) | 1988-11-16 | 1989-11-16 | Dihydrochloride Crystal of Etoposide-2-dimethylamino Compound Hydrochloride and Its Preparation Method |
| CN92112450A CN1025622C (en) | 1988-11-16 | 1992-11-20 | Dihydrate crystals of etoposide-2-dimethylamino compound hydrochloride and process for production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28781288A JPH0631302B2 (en) | 1988-11-16 | 1988-11-16 | Etoposide-2-dimethylamino form hydrochloric acid dihydrate crystal and process for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02134393A JPH02134393A (en) | 1990-05-23 |
| JPH0631302B2 true JPH0631302B2 (en) | 1994-04-27 |
Family
ID=17722077
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28781288A Expired - Lifetime JPH0631302B2 (en) | 1988-11-16 | 1988-11-16 | Etoposide-2-dimethylamino form hydrochloric acid dihydrate crystal and process for producing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0631302B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0714400B1 (en) * | 1993-08-19 | 1999-12-15 | Merck & Co. Inc. | THERMODYNAMICALLY STABLE CRYSTAL FORM OF 4"-DEOXY-4"-(EPI)-METHYLAMINO AVERMECTIN B1a/B1b BENZOIC ACID SALT AND PROCESSES FOR ITS PREPARATION |
| KR100418183B1 (en) * | 2000-01-03 | 2004-02-11 | 한국화학연구원 | 4-o-[2-(n,n-dialkylamino)-2-deoxy-4,6-o,o-(alkenylidene- or alkynylidene)-beta-d-glucosyl]-4'-o-demethyl-epi-podophyllotoxins, preparation thereof and antitumor composition containing same |
-
1988
- 1988-11-16 JP JP28781288A patent/JPH0631302B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02134393A (en) | 1990-05-23 |
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