JP3118184B2 - Platinum compound impurity analysis method - Google Patents
Platinum compound impurity analysis methodInfo
- Publication number
- JP3118184B2 JP3118184B2 JP08067558A JP6755896A JP3118184B2 JP 3118184 B2 JP3118184 B2 JP 3118184B2 JP 08067558 A JP08067558 A JP 08067558A JP 6755896 A JP6755896 A JP 6755896A JP 3118184 B2 JP3118184 B2 JP 3118184B2
- Authority
- JP
- Japan
- Prior art keywords
- platinum
- cis
- cyclohexanediamine
- trans
- isomer
- 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 - Fee Related
Links
Landscapes
- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、医薬品（制ガン
剤）の原薬となる１、２−シクロヘキサンジアミン異性
体のシス白金(II)錯体、特にシス−オキザラート（トラ
ンス−（−）−１、２−シクロヘキサンジアミン）白金
(II)中の不純物、１、２−シクロヘキサンジアミン異性
体のシス白金(IV)トランス−ジヒドロキソ錯体（以下ジ
ヒドロキソ体という）の分析方法に関する。The present invention relates to a cis-platinum (II) complex of 1,2-cyclohexanediamine isomer, particularly cis-oxalate (trans-(-)-1,2) -Cyclohexanediamine) platinum
The present invention relates to a method for analyzing a cis-platinum (IV) trans-dihydroxo complex (hereinafter referred to as a dihydroxo form) of an impurity in (II) and an isomer of 1,2-cyclohexanediamine.
【０００２】[0002]
【従来の技術】医薬品の原薬としては、含有するすべて
の不純物を特定する必要があり、特に毒性や制ガン活性
を持つ不純物は検出定量が重要となる。従来の含有成分
分析方法の１つとしてＯＤＳカラムを用いた高速液体ク
ロマトグラフィ（ＨＰＬＣ）法があったが、種々の条件
設定により各々特徴を有することを見いだし、その知見
に基づいて従来特に分離検出できなかった不純物を特定
することに着目し、本発明に至った。2. Description of the Related Art It is necessary to specify all impurities contained in a drug substance, and it is particularly important to detect and quantify impurities having toxicity and anticancer activity. High-performance liquid chromatography (HPLC) using an ODS column has been known as one of the conventional methods for analyzing the contained components. The present invention has been made by paying attention to the identification of the impurities that did not exist.
【０００３】[0003]
【発明が解決しようとする課題】本発明は、１、２−シ
クロヘキサンジアミン異性体のシス白金(II)錯体、特に
シス−オキザラート（トランス−（−）−１、２−シク
ロヘキサンジアミン）白金(II)中の不純物の分離定量す
る方法を提供することを目的とする。The present invention relates to cis-platinum (II) complexes of 1,2-cyclohexanediamine isomers, especially cis-oxalate (trans-(-)-1,2-cyclohexanediamine) platinum (II). It is an object of the present invention to provide a method for separating and quantifying impurities in ().
【０００４】[0004]
【課題を解決するための手段】本発明は、前記化１〜化
７で示される１、２−シクロヘキサンジアミン異性体の
シス白金(II)錯体の分離定量において、前記ジヒドロキ
ソ体を不純物として特定し、高速液体クロマトグラフィ
（ＨＰＬＣ）法にて分離定量することを特徴とするもの
で、特に、シス−オキザラート（トランス−（−）−
１、２−シクロヘキサンジアミン）白金(II)（ｌ−ＯＨ
Ｐ）において顕著である。According to the present invention, in the separation and quantification of the cis-platinum (II) complex of the 1,2-cyclohexanediamine isomer represented by the above formulas (1) to (7), the dihydroxo isomer is specified as an impurity. And quantification by high-performance liquid chromatography (HPLC). In particular, cis-oxalate (trans-(-)-
1,2-cyclohexanediamine) platinum (II) (1-OH
P) is remarkable.
【０００５】また、本発明は、上記高速液体クロマトグ
ラフィ（ＨＰＬＣ）法において、ＯＤＳカラムを長さ20
cm〜50cmとすることを特徴とするもので、長さ20cm未満
では、ジヒドロキソ体の分離に不十分で、長さ50cmを超
えても分離効果にあまり変わりはみられず、作業性、効
率の点から前記範囲とした。[0005] The present invention also relates to the above-mentioned high performance liquid chromatography (HPLC) method, wherein the ODS column has a length of 20 μm.
If the length is less than 20 cm, it is insufficient for separation of the dihydroxo compound, and even if the length exceeds 50 cm, the separation effect does not change much. From the point, the above range was set.
【０００６】また、設定条件として移動相を水、アセト
ニトリル又は緩衝液のいずれか１種又は２種の混液とす
るもので、特に水を用いることが効率的である。[0006] Further, as a set condition, the mobile phase is a mixture of one or two of water, acetonitrile and a buffer, and it is particularly efficient to use water.
【０００７】さらに溶離液の流量としては 0.1〜５ml/m
inが好ましく、１ml/minがより好ましい。Further, the flow rate of the eluent is 0.1 to 5 ml / m
in is preferred, and 1 ml / min is more preferred.
【０００８】[0008]
【発明の実施の形態】本発明においては、ＯＤＳカラム
は担持されるオクタデシル基をもつ化合物他によって分
離が異なり、その為、適切なＯＤＳカラムの設定や適切
な溶離液や条件の設定によって、初めてヒジドロキソ体
の分離が可能となったものである。DESCRIPTION OF THE PREFERRED EMBODIMENTS In the present invention, the separation of an ODS column differs depending on the compound having a supported octadecyl group and the like. Therefore, the ODS column must be set by setting an appropriate ODS column and setting an appropriate eluent and conditions. It is possible to separate the hydridoxo form.
【０００９】[0009]
【実施例】以下に実施例と従来例について述べる。本発
明に係わる化１のなかで化２のｌ−ＯＨＰにおける不純
物の分離定量を行った。絶対検量法に従って行い、不純
物として考えられる成分のスタンダードの既知量を段階
的に導入し、そのクロマトグラフのピーク面積を測定
し、成分量を横軸に、ピーク面積を縦軸にプロットして
検量線を作成した。DESCRIPTION OF THE PREFERRED EMBODIMENTS An embodiment and a conventional example will be described below. The separation and quantification of impurities in 1-OHP of Chemical Formula 2 in Chemical Formula 1 according to the present invention was performed. Perform the calibration according to the absolute calibration method, gradually introduce the known amount of the standard of the component considered as an impurity, measure the peak area of the chromatogram, plot the component amount on the horizontal axis, and plot the peak area on the vertical axis. Created a line.
【００１０】次に、ｌ−ＯＨＰをＨＰＬＣにて測定し、
ピーク面積から検量線にて披検成分の量を求め、試料中
の含有率を算出した。その結果を表１に示す。Next, 1-OHP was measured by HPLC,
The amount of the test component was determined from the peak area by a calibration curve, and the content in the sample was calculated. Table 1 shows the results.
【００１１】[0011]
【表１】 [Table 1]
【００１２】その際、クロマトグラフの操作条件として
以下のように行った。実施例として、 カラム：内径約 4.6mm、長さ25cmのステンレス管にオク
タデシルシリル化シリカゲルを充填したもの（ハイパー
シル：ジーエルサイエンス社製商品名） カラム温度：室温 移動相：水 流 量：１ml/min 検出器：uv− 210nm（紫外線吸光光度計） 注入量：20μｌ 試料：ｌ−ＯＨＰ標準液を40mg／ 100ml、ジヒドロキソ
体を１mg／ 100ml（サンプル量：20mg／ 100ml） の条件にて行った。At that time, the following conditions were used as operating conditions of the chromatograph. As an example, a column: a stainless steel tube having an inner diameter of about 4.6 mm and a length of 25 cm filled with octadecylsilylated silica gel (Hypersil: a product name of GL Sciences Inc.) Column temperature: room temperature Mobile phase: water flow: 1 ml / min Detector: uv-210 nm (ultraviolet absorption spectrophotometer) Injection amount: 20 μl Sample: 1-OHP standard solution was 40 mg / 100 ml, and dihydroxo compound was 1 mg / 100 ml (sample amount: 20 mg / 100 ml).
【００１３】一方、従来例として カラム：内径約 4.6mm、長さ15cmのステンレス管にオク
タデシルシリル化シカゲルを充填したもの（コスモシ
ル：ナカライテスク社製商品名） カラム温度40℃ 移動相：メタノールと水の混合比（６：４）の溶媒、 流 量： 0.7ml/min 検出器：uv− 220nm（紫外線吸光光度計） とした他は実施例と同じにした。On the other hand, as a conventional example, a column: a stainless steel tube having an inner diameter of about 4.6 mm and a length of 15 cm filled with octadecylsilylated silica gel (Cosmosil: trade name of Nacalai Tesque, Inc.) Column temperature 40 ° C. Mobile phase: methanol and water Solvent having a mixing ratio of (6: 4), flow rate: 0.7 ml / min, detector: uv-220 nm (ultraviolet absorption spectrophotometer), except that it was the same as the example.
【００１４】上記の結果から明らかなように、従来例に
おいては分離定量できなかったジヒドロキソ体含量が実
施例においては「0.12％」と分離定量できた。As is clear from the above results, the dihydroxo compound content, which could not be separated and quantified in the conventional example, was separated and quantified as "0.12%" in the examples.
【００１５】[0015]
【発明の効果】以上説明したように、本発明の白金化合
物の不純物分析方法により、１、２−シクロヘキサンジ
アミン異性体のシス白金(II)錯体、特にシス−オキザラ
ート（トランス−（−）−１、２−シクロヘキサンジア
ミン）白金(II)中の不純物の分離定量が可能となり、医
薬品（制ガン剤）の原薬の適正な評価、管理、運用に寄
与するところ大である。As described above, according to the method for analyzing impurities of platinum compounds of the present invention, a cis-platinum (II) complex of 1,2-cyclohexanediamine isomer, particularly cis-oxalate (trans-(-)-1) is obtained. , 2-cyclohexanediamine) platinum (II) can be separated and quantified, which greatly contributes to the appropriate evaluation, management and operation of the drug substance (cancer drug).
Claims (5)
は、シス、トランス−ｄ又はトランス−ｌ体であり、Ｒ
1 、Ｒ2 はＰｔ(II)と環状となって化２、化３、化４、
化５、化６又は化７となるもの） 【化２】 【化３】 【化４】 【化５】 【化６】 【化７】 で示される１、２−シクロヘキサンジアミン異性体のシ
ス白金(II)錯体の分離定量において、 【化８】 （式中、１、２−シクロヘキサンジアミンの立体配位
は、シス、トランス−ｄ又はトランス−ｌ体であり、Ｒ
1 、Ｒ2 はＰｔ(IV)と環状になって化２、化３、化４、
化５、化６又は化７となるもの）で示される１、２−シ
クロヘキサンジアミン異性体のシス白金(IV)トランス−
ジヒドロキソ錯体（以下ジヒドロキソ体）を不純物とし
て高速液体クロマトグラフィ（ＨＰＬＣ）法にて分離定
量することを特徴とする白金化合物の不純物分析方法。[Claim 1] (Wherein the steric configuration of 1,2-cyclohexanediamine is cis, trans-d or trans-1 isomer;
1 , R 2 is cyclic with Pt (II),
(Chemical Formula 5, Chemical Formula 6 or Chemical Formula 7) Embedded image Embedded image Embedded image Embedded image Embedded image In the separation and quantification of the cis-platinum (II) complex of the 1,2-cyclohexanediamine isomer represented by the following formula: (Wherein the steric configuration of 1,2-cyclohexanediamine is cis, trans-d or trans-1 isomer;
1 and R 2 become cyclic with Pt (IV),
1,2-cyclohexanediamine isomer cis-platinum (IV) trans-
A method for analyzing impurities of a platinum compound, comprising separating and quantifying a dihydroxo complex (hereinafter referred to as a dihydroxo compound) as an impurity by high performance liquid chromatography (HPLC).
のシス白金(II)錯体において、シス−オキザラート（ト
ランス−（−）−１、２−シクロヘキサンジアミン）白
金(II)（ｌ−ＯＨＰ）とする請求項１記載の白金化合物
の不純物分析方法。2. In a cis-platinum (II) complex of 1,2-cyclohexanediamine isomer, cis-oxalate (trans-(−)-1,2-cyclohexanediamine) platinum (II) (1-OHP) is used. The method for analyzing impurities of a platinum compound according to claim 1.
法におけるＯＤＳカラムを長さ20cm〜50cmとする請求項
１及び請求項２記載の白金化合物の不純物分析方法。3. High performance liquid chromatography (HPLC)
3. The method for analyzing impurities of a platinum compound according to claim 1, wherein the ODS column in the method has a length of 20 cm to 50 cm.
法において、移動相を水、アセトニトリル又は緩衝液の
いずれか１種又は２種の混液とする請求項１、請求項２
及び請求項３記載の白金化合物の不純物分析方法。4. High performance liquid chromatography (HPLC)
3. The method according to claim 1, wherein the mobile phase is water, acetonitrile, or a mixture of one or two of a buffer.
And the method for analyzing impurities of a platinum compound according to claim 3.
おいて、溶離液の流量を 0.1〜５ml/minとする請求項
１、請求項２、請求項３及び請求項４記載の白金化合物
の不純物分析方法。5. The method for analyzing impurities of a platinum compound according to claim 1, wherein the flow rate of the eluent is 0.1 to 5 ml / min in high performance chromatography (HPLC).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP08067558A JP3118184B2 (en) | 1996-03-25 | 1996-03-25 | Platinum compound impurity analysis method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP08067558A JP3118184B2 (en) | 1996-03-25 | 1996-03-25 | Platinum compound impurity analysis method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH09257781A JPH09257781A (en) | 1997-10-03 |
| JP3118184B2 true JP3118184B2 (en) | 2000-12-18 |
Family
ID=13348423
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP08067558A Expired - Fee Related JP3118184B2 (en) | 1996-03-25 | 1996-03-25 | Platinum compound impurity analysis method |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3118184B2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111175423B (en) * | 2016-12-23 | 2022-07-12 | 江苏奥赛康药业有限公司 | Method for analyzing nedaplatin |
| CN110596282B (en) * | 2018-06-13 | 2021-08-13 | 上海医药工业研究院 | Nedaplatin compound, separation method and application |
| CN109580822B (en) * | 2018-12-21 | 2021-03-19 | 山东铂源药业有限公司 | Method for detecting cis-1, 2-cyclohexanediamine impurity in levo-trans-1, 2-cyclohexanediamine |
-
1996
- 1996-03-25 JP JP08067558A patent/JP3118184B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH09257781A (en) | 1997-10-03 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |