CN105891392A - Method for separating and measuring lurasidone hydrochloride intermediate related substances through liquid chromatography - Google Patents
Method for separating and measuring lurasidone hydrochloride intermediate related substances through liquid chromatography Download PDFInfo
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- CN105891392A CN105891392A CN201610187445.4A CN201610187445A CN105891392A CN 105891392 A CN105891392 A CN 105891392A CN 201610187445 A CN201610187445 A CN 201610187445A CN 105891392 A CN105891392 A CN 105891392A
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- mobile phase
- separating
- lurasidone
- related substance
- lurasidone hcl
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/60—Construction of the column
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
Abstract
The invention belongs to the field of analytical chemistry and discloses a method for separating and detecting lurasidone hydrochloride intermediate 3-(1-piperazinyl)-1,2-benzisothiazole and related substances through liquid chromatography. According to the method, octyl silane bonded silica gel serves as a chromatographic column of filler, ion-pairing reagent-buffer salt solution-organic phase in a certain proportion serves as a mobile phase, and the content of the lurasidone hydrochloride intermediate and the related substances of the intermediate can be measured, so that purity of reactants in the production process of lurasidone hydrochloride is effectively controlled, side reactions and impurities are reduced, the yield of the product is increased, and the quality of the product is improved. The method is high in specificity, high in accuracy and easy and convenient to operate.
Description
Technical field
The invention belongs to analytical chemistry field, be specifically related to the method for liquid chromatography for separating and determining Lurasidone HCl intermediate and related substance thereof.
Background technology
Lurasidone HCl is a kind of atypical antipsychotic, clinically for schizoid treatment, cognitive function can be improved. Lurasidone HCl chemistry (3aR, 4S, 7R by name, 7aS)-2-(1R, 2R)-2-4-(1,2-benzisothiazole-3-yl) and piperazine-1-methylene ］ cyclohexyl methyl } hexahydro-4,7-endo-methylene group-2H-iso-indoles-1,3-dione hydrochloride, molecular formula is C28H36N4O2SHCl. Lurasidone HCl intermediated chemistry is called 3-(1-piperazinyl)-1,2-benzisothiazole, and molecular formula is C11H13N3S, structural formula is:
In the process of synthetic hydrochloric acid Lurasidone, the purity of some important intermediate need to be controlled, to reduce the generation of side reaction and the generation of impurity, thus improve product yield and purity. For Lurasidone HCl intermediate 3-(1-piperazinyl)-1,2-benzisothiazole, need the related substance controlling to have 2, namely 1,2-benzisothiazole-3-ketone (related substance 1), structural formula is:
The chloro-1H-iso-indoles of 3-(related substance 2), structural formula is:
Impurity removal in Lurasidone HCl intermediate is incomplete, the generation of side reaction and the generation of impurity will be caused, thus affect pharmaceutical purity and quality. Therefore, realize separation determination Lurasidone HCl intermediate and related substance thereof, the purity of in synthetic hydrochloric acid Lurasidone process reactant can be ensured, improve product yield and quality, have important practical significance at production and the quality control aspect thereof of Lurasidone HCl.
Summary of the invention
The object of the present invention is to provide a kind of Lurasidone HCl intermediate 3-(1-piperazinyl)-1 that analyzes, the chemical purity of 2-benzisothiazole and the method for separated its related substance, thus realize the separated island form of Lurasidone HCl intermediate and its related substance, to ensure the purity of Lurasidone HCl intermediate, reduce the generation of side reaction, thus effectively control the quality of Lurasidone HCl finished product.
Of the present invention a kind of measure Lurasidone HCl intermediate and related substance thereof method, be to adopt the chromatographic column that octyl silane group silica gel is filler, taking a certain proportion of ion-pairing agent-buffer salt solution-organic phase as mobile phase;
Above-mentioned said chromatographic column, taking octyl silane group silica gel as filler, is selected from the chromatographic column of the brands such as Phenomenex, Kromasil and Apollo.
Above-mentioned said organic phase is selected from one or more in methyl alcohol, acetonitrile, isopropyl alcohol or oxolane.
Above-mentioned said buffer salt can be phosphate, formates, acetate, perchlorate, preferably phosphate.
Above-mentioned said ion-pairing agent can be sodium heptanesulfonate, perfluorooctane sulfonate, lauryl sodium sulfate, dodecyl sodium sulfonate etc., preferably sodium heptanesulfonate.
Method of separating and assaying of the present invention, can realize in accordance with the following methods:
1) get Lurasidone HCl intermediate and related substance sample thereof appropriate, by methyl alcohol or mobile phase sample dissolution, be mixed with the sample solution of the hydrochloric Lurasidone of every 1 mL and related substance 0.1 ~ 1.5 mg thereof respectively;
2) it is 0.5 ~ 1.5 mL/min that flow rate of mobile phase is set, determined wavelength 205 ~ 280 nm;
3) mobile phase A is 5 ~ 25 mmol/L potassium dihydrogen phosphate and heptane sulfonic acid sodium salt, and pH is 4.0 ~ 7.0; Mobile phase B is acetonitrile.
4) get 1) sample solution 10 ~ 50 μ L injection liquid chromatography, complete the separation determination of Lurasidone HCl intermediate and related substance thereof. Wherein:
The model of high performance liquid chromatograph, has no special requirements, and the chromatograph that the present invention adopts is Shimadzu high performance liquid chromatograph:
LC-20AT，CBM-20A，SIL-20AC，SPD-M20A，CTO-10ASvp
Chromatographic column: C8(Phenomenex, 250 × 4.6 mm, 5 μm)
Mobile phase: A:20 mmol/L potassium dihydrogen phosphate and 10 mmol/L heptane sulfonic acid sodium salt (pH 6.0)
B: acetonitrile
Flow velocity: 1.0 mL/min
Determined wavelength: 230 nm
Sampling volume: 10 μ L
Gradient:
| Time (min) | Mobile phase A | Mobile phase B |
| 0 | 70 | 30 |
| 12 | 70 | 30 |
| 17 | 58 | 42 |
| 27 | 40 | 60 |
| 32 | 70 | 30 |
| 50 | 70 | 30 |
The present invention adopts C8(Phenomenex, 250 × 4.6 mm, 5 μm) chromatographic column, effectively separation determination Lurasidone HCl intermediate and related substance thereof. The invention solves the separation determination problem of Lurasidone HCl intermediate and related substance thereof, ensure that the purity of intermediate in Lurasidone HCl production process, decrease the generation of side reaction, achieve the quality controllable of Lurasidone HCl.
Accompanying drawing explanation
The liquid chromatogram of blank solvent when Fig. 1 is embodiment 1;
Lurasidone HCl intermediate and related substance liquid chromatogram thereof when Fig. 2 is embodiment 1;
Lurasidone HCl intermediate liquid chromatogram when Fig. 3 is embodiment 1;
Lurasidone HCl intermediate and related substance liquid chromatogram thereof when Fig. 4 is embodiment 2. .
Detailed description of the invention:
Following examples for understanding the present invention further, but are not limited to the scope of this enforcement. Below by way of example forms, the Lurasidone HCl intermediate the present invention relates to and related substance detection method thereof are described in further detail, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following instance, all technology realizing based on content of the present invention all belong to scope of the present invention.
Embodiment
1
Instrument and condition
High performance liquid chromatograph: Shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp
Chromatographic column: C8(Phenomenex, 250 × 4.6 mm, 5 μm)
Mobile phase: A:20 mmol/L potassium dihydrogen phosphate and 10 mmol/L heptane sulfonic acid sodium salt (pH 6.0)
B: acetonitrile
Flow velocity: 1.0 mL/min
Determined wavelength: 230 nm
Sampling volume: 10 μ L
Gradient:
| Time (min) | Mobile phase A | Mobile phase B |
| 0 | 70 | 30 |
| 12 | 70 | 30 |
| 17 | 58 | 42 |
| 27 | 40 | 60 |
| 32 | 70 | 30 |
| 50 | 70 | 30 |
Experimental procedure
Get Lurasidone HCl intermediate and related substance thereof appropriate, dissolve with methyl alcohol, be mixed with the solution of the hydrochloric Lurasidone intermediate of every 1 mL and each 0.5 mg of related substance thereof. Get above-mentioned Lurasidone HCl intermediate and related substance solution thereof appropriate, be mixed with system suitability solution; Separately get methyl alcohol as blank solution. Record chromatogram is analyzed by above-mentioned chromatographic condition. The results are shown in accompanying drawing 1 ~ 3, Fig. 1 is blank solvent chromatogram; In Fig. 2, the chromatographic peak of retention time 11.767 min is Lurasidone HCl intermediate, and all the other chromatographic peaks are the related substance of Lurasidone HCl intermediate. In Fig. 3, the chromatographic peak of retention time 11.750 min is Lurasidone HCl intermediate. Fig. 1 ~ Fig. 3 shows: method of the present invention can be effectively separated with its related substance by Lurasidone HCl intermediate, and can accurately quantitatively detect, to calculate the purity of Lurasidone HCl intermediate.
Embodiment
2
Instrument and condition
High performance liquid chromatograph: Shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp
Chromatographic column: C8(Phenomenex, 250 × 4.6 mm, 5 μm)
Mobile phase: A:20 mmol/L potassium dihydrogen phosphate and 10 mmol/L heptane sulfonic acid sodium salt (pH 6.0)
B: acetonitrile
Flow velocity: 1.0 mL/min
Determined wavelength: 230 nm
Sampling volume: 10 μ L
Gradient:
| Time (min) | Mobile phase A | Mobile phase B |
| 0 | 70 | 30 |
| 12 | 70 | 30 |
| 17 | 58 | 42 |
| 30 | 45 | 55 |
| 40 | 70 | 30 |
| 50 | 70 | 30 |
Experimental procedure
Get Lurasidone HCl intermediate and related substance thereof appropriate, dissolve with methyl alcohol, be mixed with the solution of the hydrochloric Lurasidone intermediate of every 1 mL and each 0.5 mg of related substance thereof. Get above-mentioned Lurasidone HCl intermediate and related substance solution thereof appropriate, be mixed with system suitability solution; Record chromatogram is analyzed by above-mentioned chromatographic condition. The results are shown in accompanying drawing 4, in Fig. 4, the chromatographic peak of retention time 11.764 min is Lurasidone HCl intermediate, and all the other chromatographic peaks are the related substance of Lurasidone HCl intermediate.
The present invention verifies the following items of described Lurasidone HCl intermediate and Related substance method thereof:
System suitability experiment
Get Lurasidone HCl intermediate and related substance thereof appropriate, dissolve with methyl alcohol respectively, be mixed with the test liquid of hydrochloric Lurasidone intermediate and related substance thereof. Liquid-phase chromatographic analysis is carried out, record chromatogram by the chromatographic condition of embodiment 1. As seen from Figure 2, between related substance and main peak, separating degree meets the requirements with this understanding;
Sample introduction replica test
By Lurasidone HCl intermediate test liquid, by the chromatographic condition of embodiment 1, repeat sample introduction 6 times, the repeatability of investigation method. Can be added by result, the method sample introduction repeatability is good;
Stability of solution
Get the test liquid of Lurasidone HCl intermediate and related substance thereof, press the chromatographic condition of embodiment 1, respectively at sample introduction after 0,2,4,6,8,12,16,20,24 hour, stability of solution when investigating this product quantitative assay, from result, this sample solution is stable in 24 hours.
| Time (h) | Lurasidone HCl intermediate peak (A) |
| 0 | 22729162 |
| 2 | 22755680 |
| 4 | 22823405 |
| 6 | 22833111 |
| 8 | 22847659 |
| 12 | 22871632 |
| 16 | 22911547 |
| 20 | 23001278 |
| 24 | 23052867 |
| Mean value | 22869593 |
| RSD% | 0.46 |
Durability
For the stability of further verification method, chromatographic column brand, flow velocity, column temperature, these conditions of pH value of buffer solution are finely tuned by accordingly, to investigate the durability of chromatographic condition;
Result shows, this method chromatographic column brand good tolerance, and change in flow is within the scope of ± 0.1ml/min, and chromatogram peak-to-peak type does not change, only retention time have corresponding reach and after move. Column temperature changes ± 5 DEG C, pH of buffer variation ± 0.2 scope is interior also changes without obvious appearance time. Above-mentioned investigation shows this method good tolerance.
Claims (10)
1. a liquid chromatography separated detect Lurasidone HCl intermediate and related substance thereof method, it is characterized in that: adopt reversed-phased high performace liquid chromatographic, taking octyl silane group silica gel as the chromatographic column of filler, taking certain proportion ion-pairing agent-buffer salt solution-organic phase as mobile phase.
2. method of separating and assaying according to claim 1, chromatographic column is selected from the brands such as Phenomenex, Kromasil and Apollo.
3. method of separating and assaying according to claim 1, said organic phase is selected from one or more in methyl alcohol, acetonitrile, isopropyl alcohol and oxolane.
4. method of separating and assaying according to claim 1, said buffer salt can be phosphate, formates, acetate, perchlorate.
5. method of separating and assaying according to claim 1, said ion-pairing agent can be sodium heptanesulfonate, perfluorooctane sulfonate, lauryl sodium sulfate, dodecyl sodium sulfate.
6. method of separating and assaying according to claim 1, said ion-pairing agent-buffer salt solution pH is 4.0 ~ 7.0.
7. method of separating and assaying according to claim 4, said buffer salt preferably phosphate.
8. method of separating and assaying according to claim 1, is characterized in that:
1) get Lurasidone HCl intermediate and related substance sample thereof appropriate, by methyl alcohol or mobile phase sample dissolution, be mixed with the sample solution of the hydrochloric Lurasidone of every 1 mL and related substance 0.1 ~ 1.5 mg thereof respectively;
2) it is 0.5 ~ 1.5 mL/min that flow rate of mobile phase is set, determined wavelength 205 ~ 280 nm;
3) mobile phase A is 5 ~ 25 mmol/L potassium dihydrogen phosphate and heptane sulfonic acid sodium salt, and pH is 4.0 ~ 7.0; Mobile phase B is acetonitrile; The gradient of mobile phase arranges as follows:
4) get 1) sample solution 10 ~ 50 μ L injection liquid chromatography, complete the separation determination of Lurasidone HCl intermediate and related substance thereof.
9. the method for mensuration Lurasidone HCl intermediated chemistry purity according to claim 8, is characterized in that: mobile phase A is 20 mmol/L potassium dihydrogen phosphates and 10 mmol/L heptane sulfonic acid sodium salt, with pH be 6.0; Mobile phase B is acetonitrile.
10. the new method of mensuration Lurasidone HCl intermediated chemistry purity according to claim 8, is characterized in that: chromatographic column is C8,5 μm, 250 × 4.6 mm(I.D.), flow velocity is 1.0 mL/min, and determined wavelength is 230 nm, under room temperature condition, can detect.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610187445.4A CN105891392A (en) | 2016-03-29 | 2016-03-29 | Method for separating and measuring lurasidone hydrochloride intermediate related substances through liquid chromatography |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610187445.4A CN105891392A (en) | 2016-03-29 | 2016-03-29 | Method for separating and measuring lurasidone hydrochloride intermediate related substances through liquid chromatography |
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| CN105891392A true CN105891392A (en) | 2016-08-24 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106525996A (en) * | 2016-09-21 | 2017-03-22 | 北京万全德众医药生物技术有限公司 | Method for separating and measuring relevant substance of lurasidone hydrochloride intermediate by using gas chromatographic technique |
| CN107064323A (en) * | 2016-12-05 | 2017-08-18 | 北京万全德众医药生物技术有限公司 | A kind of use liquid chromatography for separating and determining Lurasidone HCl and its method about material |
| CN112305096A (en) * | 2020-09-30 | 2021-02-02 | 辰欣药业股份有限公司 | Detection method of related substances of lurasidone hydrochloride tablets |
| CN113009042A (en) * | 2021-03-16 | 2021-06-22 | 海南鑫开源医药科技有限公司 | Analysis and detection method of 3- (1-piperazinyl) -1, 2-benzisothiazole hydrochloride and related substances thereof |
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| CN1201457A (en) * | 1995-11-07 | 1998-12-09 | 辉瑞大药厂 | Process and intermediates for preparing 30(1-piperazinyl)-1,2-benzisothiazole |
| CN103207246A (en) * | 2012-12-21 | 2013-07-17 | 北京万全德众医药生物技术有限公司 | Method of separating and determining lurasidone and optical isomers thereof by using liquid chromatography |
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| CN1201457A (en) * | 1995-11-07 | 1998-12-09 | 辉瑞大药厂 | Process and intermediates for preparing 30(1-piperazinyl)-1,2-benzisothiazole |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106525996A (en) * | 2016-09-21 | 2017-03-22 | 北京万全德众医药生物技术有限公司 | Method for separating and measuring relevant substance of lurasidone hydrochloride intermediate by using gas chromatographic technique |
| CN107064323A (en) * | 2016-12-05 | 2017-08-18 | 北京万全德众医药生物技术有限公司 | A kind of use liquid chromatography for separating and determining Lurasidone HCl and its method about material |
| CN112305096A (en) * | 2020-09-30 | 2021-02-02 | 辰欣药业股份有限公司 | Detection method of related substances of lurasidone hydrochloride tablets |
| CN113009042A (en) * | 2021-03-16 | 2021-06-22 | 海南鑫开源医药科技有限公司 | Analysis and detection method of 3- (1-piperazinyl) -1, 2-benzisothiazole hydrochloride and related substances thereof |
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