Detection method of lurasidone hydrochloride hydrolysate

Abstract

The invention discloses a method for detecting a lurasidone hydrochloride hydrolysate. The method is a high performance liquid chromatography, and the chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filler; the mobile phase A is phosphate buffer solution-acetonitrile with the pH value of 6.0 to 8.0; a mobile phase B is acetonitrile water; the flow velocity is 0.5 ml to 1.5 ml per minute; the detection wavelength is 200 to 250 nm; the column temperature is 20-35 DEG C; the temperature of a sample injector is 0-10 DEG C; the sample injection volume is 5-20 microliters. The detection method for the lurasidone hydrochloride hydrolysate is high in specificity, good in separation degree and high in recovery rate.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical quality detection, and in particular relates to a method for detecting a hydrolyzate of lurasidone hydrochloride. Background Art

[0002] Lurasidone hydrochloride tablets are an atypical antipsychotic used to treat schizophrenia. Studies have reported that they can improve cognitive function. The raw material of lurasidone hydrochloride tablets is lurasidone hydrochloride, and its chemical name is (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazine-1-methyl]cyclohexylmethyl}hexahydro-4,7-methylene-2H-isoindole-1,3-dione hydrochloride. Lurasidone hydrochloride can be hydrolyzed to produce impurity 25, whose chemical name is (1S, 2R, 3S, 4R) 3-((((1R, 2R)-2-((4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl)cyclohexyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-carboxylic acid (diastereoisomer mixture), and the generation process is as follows:

[0003]

[0004] This hydrolysis product may be produced during the stability study of lurasidone hydrochloride tablets. This product is unstable and easily hydrolyzed into other impurities. It is a mixture of diastereoisomers and is difficult to separate from other impurities. Summary of the invention

[0005] In order to solve the above problems, the present invention provides a method for detecting lurasidone hydrochloride hydrolysis products.

[0006] The detection method of the hydrolysis product of lurasidone hydrochloride is high performance liquid chromatography, and the chromatographic conditions are: octadecylsilane bonded silica gel as filler; mobile phase A: phosphate buffer-acetonitrile with a pH value of 6.0-8.0; mobile phase B: acetonitrile water; flow rate of 0.5 ml to 1.5 ml per minute; detection wavelength of 200-250 nm; column temperature of 20-35° C.; injector temperature of 0-10° C.; injection volume of 5-20 μl; linear gradient elution according to the following table:

[0007]

[0008]

[0009] The preparation method of phosphate buffer with a pH value of 6.0 to 8.0 is as follows: take 0.002 mol / L to 0.008 mol / L potassium dihydrogen phosphate solution and adjust the pH to 5.0 to 9.0 with 0.002 mol / L to 0.008 mol / L potassium dihydrogen phosphate solution.

[0010] The volume proportion of acetonitrile in mobile phase A is 10% to 30%.

[0011] The volume proportion of acetonitrile in mobile phase B is 70% to 100%.

[0012] The specific steps of the detection method are:

[0013] (1) Preparation of test solution: Grind lurasidone hydrochloride into powder, weigh out the fine powder, equivalent to 160 mg of lurasidone hydrochloride, place in a 250 ml brown volumetric flask, add a mixture of methanol-water-hydrochloric acid in a volume ratio of 20:5:0.1, sonicate to dissolve, dilute to scale, shake well, filter, and take the filtrate;

[0014] (2) Impurity localization solution: Weigh 1.6 mg of the impurity and place it in a 100 ml brown volumetric flask. Dissolve it in a mixture of methanol, water and hydrochloric acid in a volume ratio of 20:5:0.1. Dilute to the mark and shake well.

[0015] (3) Accurately measure the test solution and impurity location solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0016] The detection method of lurasidone hydrochloride hydrolyzate of the present invention has strong specificity, good separation degree and high recovery rate. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 This is the chromatogram of the mixed reference solution in the specificity.

[0018] Figure 2 This is the linear relationship diagram of lurasidone hydrochloride.

[0019] Figure 3 This is the linear relationship diagram of impurity 25. DETAILED DESCRIPTION

[0020] (1) Exclusivity

[0021] Solution preparation:

[0022]

[0023]

[0024] result:

[0025] Exclusive results -1

[0026] Solution name Retention time (min) Test results blank solution none No interference Blank excipient solution none No interference Test solution (main peak) 37.897 /

[0027] Exclusive results -2

[0028]

[0029]

[0030] Conclusion: Blank solution and blank excipient solution have no interference on the detection of lurasidone hydrochloride and impurity 25; other impurities have no interference on the detection of lurasidone hydrochloride and impurity 25; the minimum separation between impurity 25 and its adjacent peaks in the mixed reference solution is 2.99, and the separation between lurasidone hydrochloride and its adjacent peaks is 5.65; the reference solution was measured 6 times continuously, and the RSD of lurasidone peak area was 0.83%, less than 5.0%; the RSD of retention time was 0.018%, less than 2.0%. The method has good specificity.

[0031] (2) Limit of quantification

[0032] Take appropriate amount of impurity 25 reference substance and lurasidone hydrochloride reference substance, and gradually dilute them according to the signal-to-noise ratio of the positioning test until the signal-to-noise ratio (S / N) is about 10 to 30, which corresponds to the quantitative limit. The results are shown in the table below.

[0033] Limit of Quantitation - Impurity 25

[0034]

[0035] Limit of Quantitation-Lurasidone Hydrochloride

[0036]

[0037]

[0038] (3) Detection limit

[0039] According to the signal-to-noise ratio of the quantitative limit test, the sample was diluted step by step until the concentration corresponding to the signal-to-noise ratio (S / N) of about 3 was the detection limit. The results are shown in the table below.

[0040] Detection limit - impurity 25

[0041]

[0042] Detection limit and quantification limit Conclusion: This method has high sensitivity.

[0043] (4) Linear

[0044]

[0045]

[0046] result:

[0047] Impurity 25 linear results

[0048]

[0049] Lurasidone HCl Linearity Results

[0050]

[0051] Conclusion: The peak area and concentration of impurity 25 are linearly related in the range of 0.0421 μg / ml (LOQ) to 2.1045 μg / ml (160%) (y=12.5696x+0.2248, r=0.9999), and the linear correlation coefficient r is greater than 0.990.

[0052] The peak area and concentration of lurasidone hydrochloride are linearly related in the range of 0.1642 μg / ml (LOQ) to 2.6050 μg / ml (200%) μg / ml (y=17.1070x+0.1469, r=1.0000), and the linear correlation coefficient r is greater than 0.990.

[0053] The linear relationship between K25 and lurasidone hydrochloride was good under this method.

[0054] (5) Accuracy

[0055]

[0056]

[0057] result:

[0058]

[0059] Conclusion: The average recovery rate of the quantitative limit concentration accuracy solution (n=3) was 95.6%, and the RSD was 1.85%; the average recovery rate of the 80% accuracy solution and the 130% accuracy solution (n=6) was 98.9%, and the RSD was 1.51%. The recovery rate of K25 was high under this method.

Claims

1. A method for detecting lurasidone hydrochloride hydrolysis products, characterized in that: The method is a high performance liquid chromatography method, and the chromatographic conditions are: octadecylsilane bonded silica gel as a filler; mobile phase A: phosphate buffer-acetonitrile with a pH value of 6.0 to 8.0; mobile phase B: acetonitrile water; flow rate of 0.5 ml to 1.5 ml per minute; detection wavelength of 200 to 250 nm; column temperature of 20 to 35° C.; injector temperature of 0 to 10° C.; injection volume of 5 to 20 μl; linear gradient elution according to the following table: 。 2. The detection method according to claim 1, characterized in that: The preparation method of phosphate buffer with a pH value of 6.0 to 8.0 is as follows: take 0.002 mol / L to 0.008 mol / L potassium dihydrogen phosphate solution and adjust the pH to 5.0 to 9.0 with 0.002 mol / L to 0.008 mol / L potassium dihydrogen phosphate solution.

3. The detection method according to claim 1, characterized in that: The volume proportion of acetonitrile in mobile phase A is 10% to 30%.

4. The detection method according to claim 1, characterized in that: The volume proportion of acetonitrile in mobile phase B is 70% to 100%.

5. The detection method according to claim 1, characterized in that: The specific steps of the detection method are: (1) Preparation of test solution: Grind lurasidone hydrochloride into powder, weigh out the fine powder, equivalent to 160 mg of lurasidone hydrochloride, place in a 250 ml brown volumetric flask, add a mixture of methanol-water-hydrochloric acid in a volume ratio of 20:5:0.1, sonicate to dissolve, dilute to scale, shake well, filter, and take the filtrate; (2) Impurity localization solution: Weigh 1.6 mg of the impurity and place it in a 100 ml brown volumetric flask. Dissolve it in a mixture of methanol, water and hydrochloric acid in a volume ratio of 20:5:0.

1. Dilute to the mark and shake well. Accurately measure the test solution and impurity location solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

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