JPH09257781A - Analysis of impurities of platinum compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To separate and determine impurities in platinum by a high- performance liquid chromatography(HPLC) method by specifying a specific substance represented by a formula as impurities. SOLUTION: In formula, steric configration of 1,2-cyclohexanediamine is cis, trans-d or trans-1 and R1 and R2 become cyclic along with Pt(II) and Pt(IV). In an HPLC method, the length of an CDS column is set to 20-50cm. As a setting condition, it is efficient to use water as a moving phase.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a cis-platinum (II) complex of a 1,2-cyclohexanediamine isomer, which is a drug substance for a drug (anticancer drug), and particularly cis-oxalate (trans-(-)-1,2. -Cyclohexanediamine) platinum
The present invention relates to a method for analyzing impurities in (II), a cis-platinum (IV) trans-dihydroxo complex of 1,2-cyclohexanediamine isomer (hereinafter referred to as a dihydroxo body).

[0002]

2. Description of the Related Art It is necessary to identify all impurities contained in a drug substance of a drug, and it is particularly important to detect and quantify impurities having toxicity and anticancer activity. As one of the conventional methods for analyzing contained components, there was a high performance liquid chromatography (HPLC) method using an ODS column. However, it was found that each method has its own characteristics by setting various conditions, and based on this finding, it has been possible to separate and detect conventional methods. The present invention has been made paying attention to the identification of impurities that were not present.

[0003]

The present invention is directed to cis-platinum (II) complexes of 1,2-cyclohexanediamine isomers, especially cis-oxalate (trans-(-)-1,2-cyclohexanediamine) platinum (II). It is intended to provide a method for separating and quantifying impurities in).

[0004]

According to the present invention, the dihydroxo form is specified as an impurity in the separation and quantification of the cis-platinum (II) complex of the 1,2-cyclohexanediamine isomer represented by the chemical formulas 1 to 7. , High-performance liquid chromatography (HPLC) method for separation and quantification, and particularly cis-oxalate (trans-(-)-
1,2-cyclohexanediamine) platinum (II) (l-OH
It is remarkable in P).

Further, according to the present invention, in the above high performance liquid chromatography (HPLC) method, an ODS column having a length of 20 is used.
The length is less than 20 cm, the separation of the dihydroxo body is insufficient, and the separation effect does not change much even if the length exceeds 50 cm, and the workability and efficiency are improved. The above range was defined from the point.

[0006] Further, as a set condition, the mobile phase is water, acetonitrile, or a mixed solution of any one or two kinds of buffer solutions, and it is particularly efficient to use water.

Further, the flow rate of the eluent is 0.1-5 ml / m
In is preferable, and 1 ml / min is more preferable.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the separation of the ODS column differs depending on the compound having an octadecyl group and the like, and therefore, the ODS column cannot be separated by setting an appropriate ODS column or setting an appropriate eluent and conditions. It is now possible to separate the body of Hijidroxo.

[0009]

EXAMPLES Examples and conventional examples will be described below. In Chemical Formula 1 according to the present invention, separation and quantification of impurities in 1-OHP of Chemical formula 2 were performed. Perform according to the absolute calibration method, introduce stepwise a known amount of the standard of the component considered as an impurity, measure the peak area of the chromatograph, plot the component amount on the horizontal axis, and plot the peak area on the vertical axis for calibration. Created a line.

Next, l-OHP was measured by HPLC,
The amount of the test component was determined from the peak area by a calibration curve, and the content rate in the sample was calculated. Table 1 shows the results.

[0011]

[Table 1]

At that time, the operating conditions of the chromatograph were as follows. As an example, a column: a stainless tube having an inner diameter of about 4.6 mm and a length of 25 cm packed with octadecylsilylated silica gel (Hypersil: trade name of GL Sciences Inc.) Column temperature: room temperature Mobile phase: water flow rate: 1 ml / min Detector: uv-210 nm (ultraviolet absorptiometer) Injection amount: 20 μl Sample: l-OHP standard solution was 40 mg / 100 ml, and dihydroxo was 1 mg / 100 ml (sample amount: 20 mg / 100 ml).

On the other hand, as a conventional example, a column: a stainless tube having an inner diameter of about 4.6 mm and a length of 15 cm filled with octadecylsilylated shikagel (Cosmosil: trade name of Nacalai Tesque, Inc.) Column temperature 40 ° C. Mobile phase: methanol and water The solvent was used in the same mixing ratio (6: 4), the flow rate was 0.7 ml / min, and the detector was uv-220 nm (ultraviolet absorptiometer).

As is clear from the above results, the content of dihydroxo form which could not be separated and quantified in the conventional example was "0.12%" in the example and could be quantified.

[0015]

As described above, according to the method for analyzing impurities of the platinum compound of the present invention, the cis-platinum (II) complex of 1,2-cyclohexanediamine isomer, especially cis-oxalate (trans-(-)-1) is used. , 2-Cyclohexanediamine) platinum (II) can be separated and quantified, which contributes to the proper evaluation, management, and operation of the drug substance of a drug (anticancer drug).

Claims (5)

[Claims] [Claim 1] (Wherein the steric configuration of 1,2-cyclohexanediamine is cis, trans-d or trans-1 isomer;
₁ , R ₂ becomes a ring with Pt (II) to form 2, 3, and 4,
Chemical formula 5, Chemical formula 6 or Chemical formula 7) Embedded image Embedded image Embedded image [Chemical 6] Embedded image In the separation and quantification of cis-platinum (II) complex of 1,2-cyclohexanediamine isomer represented by (Wherein the steric configuration of 1,2-cyclohexanediamine is cis, trans-d or trans-1 isomer;
₁ , R ₂ becomes a ring with Pt (IV) to form
Chemical formula 5, chemical formula 6 or chemical formula 7), a cis-platinum (IV) trans-form of the 1,2-cyclohexanediamine isomer
A method for analyzing impurities in a platinum compound, which comprises separating and quantifying a dihydroxo complex (hereinafter referred to as a dihydroxo form) as an impurity by a high performance liquid chromatography (HPLC) method. 2. A cis-platinum (II) complex of a 1,2-cyclohexanediamine isomer is cis-oxalate (trans-(-)-1,2-cyclohexanediamine) platinum (II) (1-OHP). The method for analyzing impurities of a platinum compound according to claim 1. 3. High performance liquid chromatography (HPLC)
The method for analyzing impurities of a platinum compound according to claim 1 or 2, wherein the ODS column in the method has a length of 20 cm to 50 cm. 4. High performance liquid chromatography (HPLC)
In the method, the mobile phase is water, acetonitrile, or a mixed solution of any one or two kinds of buffer solutions.
And a method for analyzing impurities in a platinum compound according to claim 3. 5. The method for analyzing impurities of platinum compounds according to claim 1, claim 2, claim 3 or claim 4, wherein the flow rate of the eluent is 0.1 to 5 ml / min in the high performance chromatography (HPLC) method.