CN102636600A - Method for determination of optical isomers in palonosetron hydrochloride composition - Google Patents

Abstract

The invention provides a method for detecting palonosetron hydrochloride isomers in a palonosetron hydrochloride composition. The method adopts a chiral chromatographic column with amylose tris(3,5-dimethylphenylcarbamate) as filler; n-hexane/absolute ethyl alcohol /diethylamine as a mobile phase; and a detection wavelength of 240nm. The method comprises the following steps of preparing 0.5mug/ml of a solution containing palonosetron hydrochloride isomers with the mobile phase as a reference solution, performing determination and recording the spectra. The method provided by the invention can effectively separate three optical isomers of palonosetron hydrochloride under the same chromatographic conditions, and the separation degree between palonosetron hydrochloride and each of the isomers of palonosetron hydrochloride can be up to 1.5 to 2.0, which is in line with the requirements of Chinese Pharmacopoeia. The method provided by the invention can also be used for quantitative determination of palonosetron hydrochloride isomers.

Description

A method for measuring optical isomers in palonosetron hydrochloride composition

technical field

The invention belongs to the field of medicine, and more specifically relates to a method for detecting isomers of palonosetron hydrochloride in a palonosetron hydrochloride composition.

Background technique

Palonosetron hydrochloride (Palonosetron Hydrochloride) chemical structural formula is:

The chemical name is: 2-[1-azabicyclo(2.2.2)oct-3S-yl]-2,3,3aS,4,5,6-hexahydro-1H-benzo[de]isoquinoline- 1-Keto hydrochloride.

Palonosetron hydrochloride is a 5-hydroxytryptamine receptor antagonist developed by Helsinn Healthine Company in Switzerland. It is a white or off-white powder. This product is very soluble in 0.1mol/L hydrochloric acid solution and water, dissolved in methanol, Very slightly soluble in ethanol, almost insoluble in 0.1mol/L sodium hydroxide solution. Its injection was launched in the U.S. in September 2003 under the trade name Aloxi ^® ; it is mainly used clinically to treat vomiting reactions during cancer chemotherapy and radiotherapy; the main drug has little toxic and side effects and has a long biological life in the body (about 40h ), has obvious inhibitory effect on delayed vomiting, and is a safe, effective and long-lasting antiemetic.

There are two chiral centers in the structural formula of palonosetron hydrochloride, and there are three optical isomers, which are R, R isomers, S, R isomers, and R, S isomers. The detection method in the prior art, the chromatographic conditions in the Chinese patent ZL200710074410.0 (notification number CN101303331B) can only control the enantiomer, but cannot detect the other two diastereoisomers at the same time, need to use Two different chromatographic conditions were determined separately. When one of the diastereomers is determined, the other diastereomer will overlap with the main peak, which will affect the accurate determination of the impurity content. In order to strictly control the product quality, through research, a chromatogram capable of simultaneously detecting palonosetron hydrochloride and its RR isomers, RS isomers, and SR isomers in the palonosetron hydrochloride composition was established. condition.

Contents of the invention

Aiming at the deficiencies of the prior art, the present invention provides a method for simultaneously detecting one enantiomer and two diastereomers of palonosetron hydrochloride in a palonosetron hydrochloride composition under the same chromatographic condition isomer approach.

The object of the present invention is to provide R, R isomers, S, R isomers, R, S forms of palonosetron hydrochloride in palonosetron hydrochloride compositions detected by high performance liquid chromatography. The isomer content ensures the product quality of the palonosetron hydrochloride composition produced.

The method for detecting the optical isomers of palonosetron hydrochloride in the composition of palonosetron hydrochloride described in the present invention is based on three (3,5-dimethylphenylcarbamate) amylose A chiral chromatographic column with filler, the mobile phase is n-hexane-absolute ethanol-diethylamine for detection, the detection wavelength is 240nm, and the column temperature is 20°C.

Wherein the volume ratio of the mobile phase n-hexane, absolute ethanol and diethylamine is 90-95:5-10:0.1-0.5; preferably 93:7:0.2. Wherein the flow rate is 0.5~0.8ml/min, preferably 0.6ml/min.

The preparation of sample solution among the present invention is as follows:

(1) Test solution: Take 10 sticks of palonosetron hydrochloride composition, put it in an evaporating dish, concentrate it in a water bath to about 5ml, let it cool, add 40ml of ethanol, mix well to make the precipitation complete, filter, Get the filtrate and evaporate to dryness, transfer the residue to a 25ml measuring bottle after dissolving with an appropriate amount of ethanol, dilute to the mark with mobile phase, shake well, and use it as the test solution;

(2) Reference substance solution: Accurately weigh appropriate amounts of R, R-type palonosetron reference substance, S, R-type palonosetron reference substance and R, S-type palonosetron reference substance, and add The mobile phase was quantitatively diluted to make a mixed solution containing about 0.5 μg in each 1 ml, as a reference solution.

Determination: Accurately measure 100 μl each of the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. If there is a chromatographic peak corresponding to the retention time of the isomer in the control solution, , according to the external standard method to calculate the content of isomers.

This chromatographic condition can be used to simultaneously determine the content of three optical isomers in the palonosetron hydrochloride composition under one chromatographic condition, and the separation degree of palonosetron hydrochloride and each isomer is 1.5 ~ 2.0, which meets Chinese Pharmacopoeia requirements. At the same time, this chromatographic condition can be used for the quantification of palonosetron hydrochloride isomers. Compared with the method in the prior art that needs to be measured separately under different chromatographic conditions, the measurement result has high accuracy, is simpler, and is more suitable for application in the pharmaceutical production process.

Description of drawings

Figure 1 Separation diagram of palonosetron hydrochloride and its isomers (peak A: R, R type palonosetron; B peak: R, S type palonosetron; C peak: S, S type Palonosetron lonosetron; D: Palonosetron S, R).

Fig. 2 isomer detection results of Palonosetron Hydrochloride Composition (100501) in Example 3 (Peak A: Palonosetron S, S-type).

Detailed ways

Example 1

Instrument: Shimadzu LC-10AT high performance liquid chromatography system, including LC-10AT pump, SPD-10A ultraviolet detector and HW chromatography workstation.

Chromatographic column: chiral chromatographic column Chiralpak ADH column (250mm×4.6mm, 5μm).

Mobile phase: n-hexane-absolute ethanol-diethylamine (93:7:0.2)

Detection wavelength: 240nm

Flow rate: 0.6ml/min

Column temperature: 20°C

Reference substance solution: Accurately weigh an appropriate amount of R, R-type palonosetron reference substance, S, R-type palonosetron reference substance and R, S-type palonosetron reference substance, add mobile phase to quantitatively dilute Prepare a mixed solution containing about 0.5 μg in each 1 ml as a reference solution.

Need testing solution: take 10 palonosetron hydrochloride compositions, put them in an evaporating dish, concentrate in a water bath to about 5ml, let it cool, add 40ml of ethanol, mix well to make the precipitation complete, filter, and evaporate the filtrate to dryness , the residue was dissolved with an appropriate amount of ethanol and transferred to a 25ml volumetric bottle, diluted to the mark with mobile phase, shaken up, and used as the test solution.

Determination: Precisely measure 100 μl each of the test solution and the reference solution, inject them into the liquid chromatograph, and record the chromatograms. If there is a chromatographic peak with the corresponding retention time of the isomer in the contrast solution in the chromatogram of the test solution, calculate the content of the isomer by the external standard method.

Example 2 Determination of Palonosetron Hydrochloride Composition Preparation Method

prescription:

Palonosetron Hydrochloride 0.28g

Mannitol 207.5g

Sodium edetate 0.5g

citric acid 25g

Water for Injection 5000ml

production 1000 pieces

Weigh the prescribed amount of mannitol, edetate sodium and citric acid, add to 96% water for injection, stir to dissolve, add 0.1mol/L sodium hydroxide solution, adjust the pH value to about 5.0 (4.5-5.5), Add 0.1% activated carbon for needles, stir at 80°C for 30 minutes, decarbonize with a titanium alloy rod while it is hot, then add the prescribed amount of palonosetron hydrochloride, stir to dissolve, make up to the full amount with water for injection, and then inject 0.22μm Filter through a microporous membrane until clear, measure the intermediate content and pH value, and fill it in ampoules with 5ml per bottle, seal it, sterilize it at 121°C for 15 minutes, perform quality inspection, and pack it.

Example 3

According to Example 2, three batches of palonosetron hydrochloride composition samples were prepared and the content of palonosetron hydrochloride isomers in each batch of compositions was detected. The specific results are shown in Table 1.

Table 1 Inspection results of palonosetron hydrochloride isomers in the palonosetron hydrochloride composition

batch Number RR isomer RS type isomer SR isomer 100501 not detected not detected not detected 100502 not detected not detected not detected 100503 not detected not detected not detected

Claims (5)

1. method that detects the palonosetron hydrochloride optical isomer in the palonosetron Hcl composition; Be with three (3; 5-3,5-dimethylphenyl carbamate) amylose is the chiral chromatographic column of filling agent; Moving phase is that normal hexane-absolute ethyl alcohol-diethylamine detects, and it is characterized in that detecting wavelength is 240nm, and column temperature is 20 ℃.

2. method according to claim 1, the volume ratio that it is characterized in that normal hexane, absolute ethyl alcohol and diethylamine is 90 ~ 95:5 ~ 10:0.1 ~ 0.5.

3. method according to claim 2, the volume ratio that it is characterized in that normal hexane, absolute ethyl alcohol and diethylamine is 93:7:0.2.

4. method according to claim 1 is characterized in that flow velocity is 0.6ml/min.

5. according to the described method of one of claim 1 ~ 4, it is characterized in that the palonosetron Hcl composition is concentrated into 5ml earlier, add ethanol; After will precipitating filtering; The evaporate to dryness of will filtrating is transferred to the 25ml measuring bottle with ethanol after with the residue dissolving again, is diluted to scale with moving phase; Hydrochloric palonosetron 0.1mg/ml is as need testing solution.

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