CN105987971B - Separation and determination method of dapoxetine hydrochloride intermediate SM1 and related impurities - Google Patents
Separation and determination method of dapoxetine hydrochloride intermediate SM1 and related impurities Download PDFInfo
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Abstract
The invention belongs to the field of analytical chemistry, and particularly relates to a separation and determination method of dapoxetine hydrochloride intermediate SM1 and related impurities, wherein the separation method adopts octadecyl bonded porous silica gel and/or inorganic oxide particles as a stationary phase and acetonitrile aqueous solution as a mobile phase for separation, and the method can realize effective separation of SM1 and related impurities; the determination method comprises the steps of preparing a sample into a sample solution by adopting a high performance liquid chromatography, diluting the sample solution according to a certain multiple to obtain a self-contrast solution, respectively taking the sample solution and the self-contrast solution, carrying out sample injection analysis by adopting the stationary phase and the mobile phase, recording a chromatogram, and calculating the contents of a sample to be determined SM1 and related impurities in the sample according to a main component self-contrast method, so that the effective separation of SM1 and related impurities can be realized, the contents of SM1 and related impurities can be accurately determined, and the method is simple to operate and high in accuracy.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a separation and determination method of a dapoxetine hydrochloride intermediate SM1 and related impurities.
Background
Dapoxetine Hydrochloride (Dapoxetine Hydrochloride), chemically known as S- (+) -N, N-dimethyl-1-phenyl-3- (1-naphthyloxy) propylamine Hydrochloride (S- (+) -N, N-dimethyl-3- (naphthalene-1-yloxy) -1-phenylpropan-1-amine Hydrochloride), is a Hydrochloride salt of Dapoxetine, and is described in its original patent EP 0288188. Dapoxetine hydrochloride is a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), belongs to short-acting SSRI, has the characteristics of quick drug effect, short half-life period, low side effect and the like compared with the traditional long-acting SSRI, and can be used for treating depression and related affective disorders. The dapoxetine hydrochloride can selectively inhibit the reuptake function of presynaptic neurons on serotonin and increase the level of serotonin combined with postsynaptic neuron receptors, thereby achieving the effect of treating premature ejaculation. Dapoxetine hydrochloride is currently used to treat male Premature Ejaculation (PE) patients between 18 and 64 years of age who meet all of the following conditions: (1) the penis is only exposed to minimal sexual stimulation before, during or shortly after insertion into the vagina, and before sexual non-satisfactionContinuous or repeated ejaculation; (2) significant personal distress or impairment of interpersonal communication due to Premature Ejaculation (PE); (3) the control of ejaculation is poor. Prilig as a medicine for treating premature ejaculation in men in 2 months in 2009TM) Approved for marketing in europe, which is the world's first oral therapeutic drug for this indication, is listed by thomson reuters 2009, the major quarterly of progress in global drug development, as one of the five most promising drugs that have been marketed or are being approved.
The preparation method of dapoxetine hydrochloride is disclosed in patents such as WO2008035358, US5292962, CN101012147, CN1821212, CN101875666, US5068432 and US6025517, and the like, and mainly comprises two methods: a method for reducing and forming dapoxetine chiral center with chiral reagent, documents US5068432 and US6025517 both mention that the starting material trichloropropiophenone is firstly subjected to chiral reduction and then undergoes nucleophilic reaction with naphthol, and then amine is formed and salified to obtain the desired product; another is a resolution process to form dapoxetine chiral centers, such as the processes disclosed in patents US5292962 and WO 2008035358.
Chemical name of intermediate SM1 of dapoxetine hydrochloride: 3- (1-naphthoxy) propiophenone, the English name: 3- (naphthalene-1-yloxy) -1-phenylpropan-1-ol, the structural formula of which is shown in formula I:
during the synthesis of intermediate SM1, impurities 3-chloropropiophenone, propiophenone, 1-phenylpropanol, naphthol, impurity SM1a (2-phenyloxetane), impurity SM1b (1-phenyl-2-propenyl-1-one), impurity SM1c (3-phenylpropen-3-ol), impurity SM1d (3- (1-naphthyloxy) propiophenone), impurity SM1e, impurity UI-1 (3-chloropropiophenol) are produced, and the structural formulas of these impurities are as follows:
incomplete removal of the above impurities generated during the synthesis of dapoxetine hydrochloride intermediate SM1 ultimately affects the purity and quality of the drug. Therefore, the realization of the separation and determination of the intermediate SM1 and related impurities has important significance for the production and storage of bulk drugs and preparations. At present, methods for separating SM1 and related impurities and methods for determining SM1 and related impurity contents do not exist.
Disclosure of Invention
In view of the above, an object of the present invention is to provide a method for separating dapoxetine hydrochloride intermediate SM1 and related impurities, which can achieve effective separation of SM1 and related impurities; the second purpose of the invention is to provide a method for separating and determining dapoxetine hydrochloride intermediate SM1 and related impurities by using high performance liquid chromatography, which not only can realize effective separation of SM1 and related impurities, but also can accurately determine the content of SM1 and related impurities.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for separating dapoxetine hydrochloride intermediate SM1 and related impurities is characterized in that octadecyl bonded porous silica gel and/or inorganic oxide particles are used as a stationary phase, and acetonitrile aqueous solution is used as a mobile phase for separation.
The method is suitable for separating the dapoxetine hydrochloride intermediate SM1 and related impurities, can be used for separating a certain substance independently, and can also be used for separating the dapoxetine hydrochloride intermediate SM1 and related impurities simultaneously.
The method for separating the dapoxetine hydrochloride intermediate SM1 and the related impurities is preferably used, wherein the related impurities are one or more of 3-chloropropiophenone, propiophenone, 1-phenylpropanol, naphthol, SM1a, SM1b, SM1c, SM1d, SM1e and UI-1.
A method for separating and measuring dapoxetine hydrochloride intermediate SM1 and related impurities by high performance liquid chromatography comprises the following steps: adding a diluent into a test sample to prepare a test sample solution, then adding the diluent into the test sample solution to dilute the test sample solution and the diluent according to a certain multiple to obtain a self-contrast solution, respectively sampling the test sample solution and the self-contrast solution, carrying out high performance liquid chromatography, recording a chromatogram, and calculating the content of a sample to be detected SM1 and related impurities in the test sample according to a main component self-contrast method; the high performance liquid chromatography adopts a chromatographic column with octadecyl bonded porous silica gel or inorganic oxide particles as a filler, and adopts acetonitrile aqueous solution as a mobile phase for analysis.
The method is suitable for separating and determining dapoxetine hydrochloride intermediate SM1 and related impurities, can be used for independently detecting a certain substance, and can also be used for simultaneously separating and detecting intermediate SM1 and related impurities.
The method for separating and determining dapoxetine hydrochloride intermediate SM1 and related impurities by using the high performance liquid chromatography further comprises the following steps: respectively taking a sample SM1 to be detected and each related impurity reference substance, dissolving the sample SM1 positioning solution and each related impurity positioning solution by using a diluent to prepare a sample SM1 to be detected and each related impurity positioning solution, respectively taking sample injection, carrying out high performance liquid chromatography analysis, and determining the retention time of the sample SM1 to be detected and each related impurity.
Further, in the method for separating and determining the dapoxetine hydrochloride intermediate SM1 and related impurities by high performance liquid chromatography, the diluent is acetonitrile or an acetonitrile aqueous solution.
Further, the method for separating and determining the dapoxetine hydrochloride intermediate SM1 and related impurities by using the high performance liquid chromatography is characterized in that the flow rate of the mobile phase is 0.5-1.5 ml/min.
Further, according to the method for separating and determining the dapoxetine hydrochloride intermediate SM1 and related impurities by using the high performance liquid chromatography, the mobile phase is acetonitrile aqueous solution.
Further, it is preferable that the mobile phase is a 45% acetonitrile aqueous solution.
Furthermore, the acetonitrile water solution is used as a mobile phase for carrying out gradient elution analysis, and the gradient elution conditions are as follows: 0min, 45% acetonitrile in water; 13min, 45% acetonitrile in water; 25min, 70% acetonitrile water solution; 30min, 85% acetonitrile water solution; 38min, 85% acetonitrile water solution; 38.01min, 45% acetonitrile water solution; 45min, 45% acetonitrile in water.
Further, the flow rate of the mobile phase was 1.0 ml/min.
Further, in the method for separating and determining the dapoxetine hydrochloride intermediate SM1 and related impurities by using the high performance liquid chromatography, the detection wavelength of the high performance liquid chromatography is 210 nm.
A method for separating and measuring dapoxetine hydrochloride intermediate SM1 and related impurities by high performance liquid chromatography is disclosed, wherein the related impurities are 3-chloropropiophenone, propiophenone, 1-phenylpropanol, naphthol, SM1a, SM1b, SM1c, SM1d, SM1e and UI-1, and the method specifically comprises the following steps:
(1) respectively taking a sample SM1 to be detected and a reference substance of related impurities, namely 3-chloropropiophenone, propiophenone, 1-phenylpropanol, naphthol, SM1a, SM1b, SM1c, SM1d, SM1e and UI-1, dissolving the reference substance by using a diluent to prepare a sample SM1 positioning solution to be detected and related impurity positioning solutions, respectively taking the sample SM1 positioning solution to be detected and related impurity positioning solutions for sample injection, carrying out high performance liquid chromatography analysis, and determining the retention time of the sample SM1 to be detected and related impurities; the high performance liquid chromatography adopts a chromatographic column with octadecyl bonded porous silica gel or inorganic oxide particles as a filler, and adopts acetonitrile aqueous solution as a mobile phase for analysis; the diluent is acetonitrile solution;
(2) taking a test sample and adding a diluent to prepare a test sample solution, then taking the test sample solution and adding the diluent to dilute according to a certain dilution multiple to obtain a self-contrast solution, respectively taking the test sample solution and the self-contrast solution for sample injection, carrying out high performance liquid chromatography analysis, recording a chromatogram, and calculating the content of a sample SM1 to be detected and related impurities in the test sample according to a main component self-contrast method, wherein the calculation formula is as follows specifically:
total impurity content ∑ single impurity content
In the formula: a. theX-peak area of each impurity in the test sample solution;
Arpeak area of principal component in self control solution.
In one embodiment of the present invention, about 25mg of the sample is dissolved in acetonitrile as a diluent to prepare a 0.5mg/m L sample solution, 0.5ml of the sample solution is precisely transferred and placed in a 100ml measuring flask, the acetonitrile as a diluent is dissolved to prepare a 0.0025mg/m L self-control solution, the dilution multiple is 200 times, 10 μ l of the sample solution and the self-control solution are respectively injected, the chromatogram is recorded, and the sample content is calculated according to the main component self-control method, specifically, the calculation formula is as follows:
total impurity content ∑ single impurity content
In the formula: a. theX-peak area of each impurity in the test sample solution;
Arpeak area of principal component in control solution.
The invention relates to a method for separating and determining dapoxetine hydrochloride intermediate SM1 and related impurities by using a high performance liquid chromatography, wherein the high performance liquid chromatography adopts a chromatographic column using octadecyl bonded porous silica gel or inorganic oxide particles as a filler, the particle size of the octadecyl bonded porous silica gel particles or inorganic oxide particles is 3-5 mu m, preferably 5 mu m, the column length of the chromatographic column is 150-250mm, preferably 250mm, and when the chromatographic column is used for separation, the applicable column temperature range of the chromatographic column is 20-40 ℃, preferably 30 ℃, in a specific embodiment of the invention, the chromatographic column is VP-ODS, and the specification of the chromatographic column is 4.6 × 250mm,5 mu m.
The invention has the beneficial effects that: (1) according to the method for separating the dapoxetine hydrochloride intermediate SM1 and the related impurities, disclosed by the invention, the SM1 and the related impurities can be effectively separated, the impurities can be effectively controlled, the product quality is fundamentally determined, and the method has the advantages of simplicity, convenience, rapidness, high accuracy and the like; (2) the method for separating and determining the dapoxetine hydrochloride intermediate SM1 and related impurities by using the high performance liquid chromatography provided by the invention not only can realize effective separation of SM1 and related impurities, but also can accurately determine the content of SM1 and related impurities, and is simple to operate and high in accuracy by using the high performance liquid chromatography; (3) the method is suitable for separating and/or determining dapoxetine hydrochloride intermediate SM1 and related impurities, can be used for separating and/or determining a certain substance independently, and can also be used for separating and/or determining intermediate SM1 and related impurities simultaneously.
Drawings
FIG. 1 shows a chromatogram peak of 3-chlorophenyl propanone reference HP L C, in which acetonitrile, water and VP-ODS (4.6 × 250mm,5 μm), wavelength: 210nm, flow rate: 1.0ml/min, and injection volume: 10 μ l are used as impurities under chromatographic conditions, the chromatogram peak is the chromatogram peak of 3-chlorophenyl propanone reference, and the retention time is about 16.9 min.
FIG. 2 shows a chromatogram of impurity reference HP L C under the chromatographic conditions of acetonitrile, water, 45:55, chromatographic column VP-ODS (4.6 × 250mm,5 μm), wavelength 210nm, flow rate 1.0ml/min, and sample injection volume 10 μ l, wherein the chromatogram peak is the chromatogram peak of impurity propiophenone, and the retention time is about 13.7 min.
FIG. 3 is a chart of a 1-phenylpropanol reference HP L C as an impurity under chromatographic conditions of acetonitrile, water, 45:55, a chromatographic column VP-ODS (4.6 × 250mm,5 μm), a wavelength of 210nm, a flow rate of 1.0ml/min, and a sample injection volume of 10 μ l, wherein a chromatographic peak in the chart is a chromatographic peak of 1-phenylpropanol, and a retention time of the chromatographic peak is about 8.1 min.
FIG. 4 shows a chromatogram peak of naphthol, in which acetonitrile, water, 45:55, chromatographic column VP-ODS (4.6 × 250mm,5 μm), wavelength 210nm, flow rate 1.0ml/min, sample volume 10 μ l, and reference sample HP L C as an impurity under chromatographic conditions, and the retention time is about 12.4 min.
FIG. 5 shows acetonitrile-water ratio of 45:55, chromatography column VP-ODS (4.6 × 250mm,5 μm), wavelength of 210nm, flow rate of 1.0ml/min, sample volume of 10 μ l impurity SM under chromatography conditions1aReference HP L C with SM as chromatographic peak1aThe retention time of the chromatographic peak of (1) is about 9.2 min.
FIG. 6 shows acetonitrile-water 45:55, column VP-ODS (4.6 × 250mm,5 μm),wavelength: 210nm, flow rate: 1.0ml/min, injection volume: 10 μ l of impurity SM under chromatographic conditions1bReference HP L C with SM as chromatographic peak1bThe retention time of the chromatographic peak of (1) is about 11.4 min.
FIG. 7 shows a chromatogram of impurity SM1C control HP L C under chromatographic conditions of acetonitrile, water, 45:55, chromatographic column VP-ODS (4.6 × 250mm,5 μm), wavelength 210nm, flow rate 1.0ml/min, and injection volume 10 μ l, wherein the chromatogram peak is the chromatogram peak of SM1C, and the retention time is about 7.3 min.
FIG. 8 is a diagram of impurity SM1d control HP L C under chromatographic conditions of acetonitrile, water, 45:55, chromatographic column VP-ODS (4.6 × 250mm,5 μm), wavelength 210nm, flow rate 1.0ml/min, and injection volume 10 μ l, wherein the chromatographic peak in the diagram is the chromatographic peak of impurity SM1d, and the retention time is about 32.1 min.
FIG. 9 shows a chromatogram of impurity SM1e control HP L C under chromatographic conditions of acetonitrile, water, 45:55, chromatographic column VP-ODS (4.6 × 250mm,5 μm), wavelength 210nm, flow rate 1.0ml/min, and injection volume 10 μ l, wherein the chromatogram peak is the chromatogram peak of impurity SM1e, and the retention time is about 28.5 min.
FIG. 10 shows a chromatogram of impurity UI-1 control HP L C under the chromatographic conditions of acetonitrile, water, 45:55, chromatographic column VP-ODS (4.6 × 250mm,5 μm), wavelength 210nm, flow rate 1.0ml/min, and sample injection volume 10 μ l, wherein the chromatogram peak is the chromatogram peak of impurity UI-1, and the retention time is about 10.8 min.
FIG. 11 shows a diagram of SM1 control HP L C under chromatographic conditions of acetonitrile, water, 45:55, chromatography column VP-ODS (4.6 × 250mm,5 μm), wavelength 2106nm, flow rate 1.0ml/min, sample injection volume 10 μ l, where the chromatogram peak is that of SM1, and the retention time is about 29.1 min.
FIG. 12 is a diagram of a mixed HP L C of SM1 and related impurities under chromatographic conditions of acetonitrile: water: 45:55, chromatography column VP-ODS (4.6 × 250mm,5 μm), wavelength: 210nm, flow rate: 1.0ml/min, and injection volume: 10 μ l.
FIG. 13 is a diagram of a control HP L C under chromatographic conditions of acetonitrile/water 45:55, chromatography column VP-ODS (4.6 × 250mm,5 μm), wavelength 210nm, flow rate 1.0ml/min, and sample volume 10 μ l.
FIG. 14 is a diagram of HP L C of a sample solution under chromatographic conditions of acetonitrile, water 45:55, chromatography column VP-ODS (4.6 × 250mm,5 μm), wavelength 210nm, flow rate 1.0ml/min, and injection volume 10 μ l
Detailed Description
The examples are provided for better illustration of the present invention, but the present invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
In the following examples, the apparatus and chromatographic conditions used in the process of the invention were as follows:
high performance liquid chromatograph, SHIMADZU L C-2010 AHT;
column for VP-ODS (4.6 × 250mm,5 μm);
mobile phase: acetonitrile water solution;
wavelength: 210 nm;
column temperature: 30 ℃;
flow rate: 1.0 ml/min;
sample introduction volume: 10 mu l of the mixture;
diluent agent: and (3) acetonitrile.
The samples referred to in the examples, the sources of the controls, are as follows:
SM 1: batch number of Chongqing Huabang pharmaceutical Co., Ltd: dapo-20141003, 96.7%;
3-chlorophenyl propanone: huavereike Limited batch number: b1417043, 99.7%;
propiophenone: batch number of Aladdin reagent Co., Ltd: k1311052, 99.0%;
1-phenylpropanol: batch number of Aladdin reagent Co., Ltd: 21138, 99.7%;
naphthol: shanghaineri Fine Chemicals, Inc.: 20140715, 99.7%;
impurity SM1 a: batch number of Chongqing Huabang pharmaceutical Co., Ltd: Dapo-SM1a-141101, 98.3%;
impurity SM1 b: batch number of Chongqing Huabang pharmaceutical Co., Ltd: Dapo-SM1b-141101, 98.78%;
impurity SM1 c: batch number of Chongqing Huabang pharmaceutical Co., Ltd: Dapo-SM1c-141001-3, 91.7%;
impurity SM1 d: batch number of Chongqing Huabang pharmaceutical Co., Ltd: Dapo-SM1d-141003, 96.7%;
impurity SM1 e: batch number of Chongqing Huabang pharmaceutical Co., Ltd: Dapo-SM1e-141001, 98.9%;
impurity UI-1: batch number of Chongqing Huabang pharmaceutical Co., Ltd: Dapo-UI-1-141002, 95.8%.
Example 1 localization of dapoxetine hydrochloride intermediate SM1 and related impurities 3-chlorophenylacetone, propiophenone, 1-phenylpropanol, naphthol, SM1a, SM1b, SM1c, SM1d, SM1e and UI-1
(1) Preparation of positioning solution of SM1 and impurities of 3-chlorophenylacetone, propiophenone, 1-phenylpropanol, naphthol, SM1a, SM1b, SM1c, SM1d, SM1e and UI-1
Preparing a 3-chloropropiophenone positioning solution: weighing 10.55mg of 3-chloropropiophenone, placing the 3-chloropropiophenone in a 50ml volumetric flask, adding a diluent to dissolve and dilute the 3-chloropropiophenone to a scale, and shaking up to obtain an impurity 3-chloropropiophenone stock solution; precisely transferring 1.0ml of the 3-chloropropiophenone stock solution, placing the 3-chloropropiophenone stock solution in a 100ml volumetric flask, adding a diluent to dilute the solution to a scale, and shaking up to obtain a 3-chloropropiophenone positioning solution with the concentration of 2.11 mu g/ml.
Propiophenone localization solution: weighing 12.40mg of propiophenone, putting the propiophenone into a 25ml volumetric flask, adding a diluent to dissolve and dilute the propiophenone to a scale, and shaking up to obtain an impurity propiophenone stock solution; precisely transferring 1.0ml of the propiophenone stock solution, putting the solution into a 100ml volumetric flask, adding a diluent to dilute the solution to a scale, and shaking the solution uniformly to obtain the propiophenone positioning solution with the concentration of 4.96 mu g/ml.
Phenylpropanol localization solution: weighing 10.30mg of phenylpropanol, placing the phenylpropanol in a 25ml volumetric flask, adding a diluent to dissolve and dilute the phenylpropanol to a scale, and shaking up to be used as impurity phenylpropanol stock solution; precisely transferring 1.0ml of the phenylpropanol stock solution, placing the phenylpropanol stock solution in a 100ml volumetric flask, adding a diluent to dilute the phenylpropanol stock solution to a scale, and shaking up to obtain the phenylpropanol positioning solution with the concentration of 4.12 mu g/ml.
Naphthol positioning solution: weighing 11.50mg of naphthol, putting the naphthol in a 50ml volumetric flask, adding a diluent to dissolve and dilute the naphthol to a scale, and shaking the naphthol evenly to obtain an impurity naphthol stock solution; precisely transferring 1.0ml of the naphthol stock solution, putting the naphthol stock solution into a 100ml volumetric flask, adding a diluent to dilute the solution to a scale, and shaking the solution uniformly to obtain the naphthol positioning solution with the concentration of 2.30 mu g/ml.
SM1aPositioning solution: weighing SM1a16.88mg, put into a 50ml volumetric flask, dissolved and diluted to the scale by adding a diluent, shaken up to be used as an impurity SM1aStoring the liquid; precisely moving the SM1aStoring 1.0ml of stock solution, placing in a 100ml volumetric flask, adding diluent to dilute to scale, shaking up to obtain SM1aThe solution was localized to a concentration of 3.38. mu.g/ml.
SM1bPositioning solution: weighing SM1b50.04mg, placing in a 50ml volumetric flask, adding diluent to dissolve and dilute to the scale, shaking up, as impurity SM1bStoring the liquid; precisely moving the SM1bStoring 1.0ml of stock solution, placing in a 100ml volumetric flask, adding diluent to dilute to scale, shaking up to obtain SM1bThe solution was localized at a concentration of 10.00. mu.g/ml.
SM1cPositioning solution: weighing SM1c10.90mg, placed in a 25ml volumetric flask, dissolved and diluted to the scale by adding a diluent, shaken up as an impurity SM1cStoring the liquid; precisely moving the SM1cStoring 1.0ml of stock solution, placing in a 100ml volumetric flask, adding diluent to dilute to scale, shaking up to obtain SM1cThe solution was localized to a concentration of 4.38. mu.g/ml.
SM1dPositioning solution: weighing SM1d16.88mg, put into a 50ml volumetric flask, dissolved and diluted to the scale by adding a diluent, shaken up to be used as an impurity SM1dStoring the liquid; precisely moving the SM1dStoring 1.0ml of stock solution, placing in a 100ml volumetric flask, adding diluent to dilute to scale, shaking up to obtain SM1dThe solution was localized to a concentration of 3.38. mu.g/ml.
SM1ePositioning solution: weighing SM1e10.21mg, placed in a 50ml volumetric flask, dissolved and diluted to the mark by adding a diluent, shaken up as an impurity SM1eStoring the liquid; precisely moving the SM1eStoring 1.0ml of stock solution, placing in a 100ml volumetric flask, adding diluent to dilute to scale, shaking up to obtain SM1eThe solution was localized to a concentration of 2.04. mu.g/ml.
UI-1 localization solution: weighing UI-110.90mg, placing in a 25ml volumetric flask, adding a diluent to dissolve and dilute to a scale, shaking up to be used as impurity UI-1 stock solution; precisely transferring 1.0ml of the UI-1 stock solution, placing the UI-1 stock solution in a 100ml volumetric flask, adding a diluent to dilute the UI-1 stock solution to a scale, and shaking up to obtain a UI-1 positioning solution with the concentration of 4.36 mu g/ml.
TIC-SM1Control positioning solution: weighing SM125.40mg of the control product is placed in a 50ml volumetric flask, dissolved and diluted to the scale by adding a diluent, and shaken up to be used as TIC-SM1A control stock solution; precisely moving the TIC-SM1Adding 1.5ml of reference stock solution into a 25ml volumetric flask, diluting with diluent to scale, and shaking up to obtain TIC-SM1Control positioning solution with concentration of 30.48. mu.g/ml.
(2) SM1 and the localization of impurities 3-chlorophenyl propanone, propiophenone, 1-phenylpropanol, naphthol, SM1a, SM1b, SM1c, SM1d, SM1e and UI-1
Taking 45% acetonitrile in water (acetonitrile: water: 45:55) as mobile phase, sampling and analyzing the above positioning solutions according to the above chromatographic conditions, as shown in fig. 1-11, the retention time of 3-chloropropiophenone is about 16.9min, the retention time of propiophenone is about 13.7min, the retention time of 1-phenylpropanol is about 8.1min, the retention time of naphthol is about 12.4min, and SM is1aThe retention time of (2) is about 9.2min, SM1bThe retention time of (2) is about 11.4min, the retention time of SM1c is about 7.3min, the retention time of SM1d is about 32.1min, the retention time of SM1e is about 28.5min, the retention time of UI-1 is about 10.8min, and the retention time of SM1 is about 29.1 min.
Example 2 isolation of dapoxetine hydrochloride intermediates SM1, 3-chlorophenylacetone, propiophenone, 1-phenylpropanol, naphthol, SM1a, SM1b, SM1c, SM1d, SM1e and UI-1
(1) Preparation of mixed solution of SM1, 3-chlorophenylacetone, propiophenone, 1-phenylpropanol, naphthol, SM1a, SM1b, SM1c, SM1d, SM1e and UI-1
Precision transfer of SM prepared in example 11a、SM1b、SM1c、SM1d1.0ml of each stock solution, 6.0ml of each stock solution of SM1, 3-chloropropiophenone, propiophenone, 1-phenylpropanol, naphthol, SM1e and UI-1 are put into the same 100ml volumetric flask,diluting with diluent to scale, and shaking to obtain mixed solution.
(2) Taking 45% acetonitrile in water (acetonitrile: water: 45:55) as a mobile phase, sampling and analyzing the prepared mixed solution according to the chromatographic conditions, and recording a chromatogram as shown in figure 12, so that SM1 and related impurities, namely 3-chlorophenyl acetone, propiophenone, 1-phenylpropanol, naphthol, SM1a, SM1b, SM1c, SM1d, SM1e and UI-1 can be effectively separated by adopting the method disclosed by the invention.
Example 3 isolation assay for SM1, 3-Chlorophenone, propiophenone, 1-phenylpropanol, naphthol, SM1a, SM1b, SM1c, SM1d, SM1e and UI-1 in a test sample
(1) Preparing a test solution, namely adding a diluent into about 25mg of a test to be dissolved into the test solution of 0.5mg/m L.
(2) Self-control solution 0.5ml of the test solution prepared in step (1) was precisely transferred and placed in a 100ml volumetric flask, diluted 200 times with a diluent to make 0.0025mg/m L self-control solution.
(3) The mobile phase aqueous acetonitrile solution was subjected to gradient elution under the elution conditions shown in Table 1.
TABLE 1 gradient elution Table (volume ratio of acetonitrile to water)
| Time (min) | Acetonitrile | Water (W) |
| 0 | 45 | 55 |
| 13 | 45 | 55 |
| 25 | 70 | 30 |
| 30 | 85 | 15 |
| 38 | 85 | 15 |
| 38.01 | 45 | 55 |
| 45 | 45 | 55 |
(4) Respectively sampling 10 μ l of test solution and self-control solution, analyzing according to gradient elution conditions and the above chromatographic conditions in Table 1, respectively recording chromatogram, as shown in FIG. 13 and FIG. 14, and calculating sample content according to main component self-control method, wherein the calculation formula is as follows:
total impurity content ∑ single impurity content
In the formula: a. theX-peak area of each impurity in the test sample solution;
Arpeak area of principal component in control solution.
As can be seen from FIGS. 13 and 14, under these conditions, SM1 was completely separated from impurities, the retention time of SM1 was 29.1min, and the SM1 content was 96.89%, the SM1a content was 0.01%, the SM1c content was 0.07%, the 1-phenylpropanol content was 0.15%, the UI-1 content was 0.14%, and other impurities, 3-chlorophenyl propanone, propiophenone, naphthol, SM1b, SM1d, and SM1e were not detected, according to the above formula.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (8)
1. A method for separating dapoxetine hydrochloride intermediate SM1 and related impurities is characterized in that octadecyl bonded porous silica gel and/or inorganic oxide particles are used as a stationary phase, and acetonitrile aqueous solution is used as a mobile phase for separation; the related impurities are one or more of 3-chloropropiophenone, propiophenone, 1-phenylpropanol, naphthol, SM1a, SM1b, SM1c, SM1d, SM1e and UI-1; the gradient elution conditions were: 0min, 45% acetonitrile in water; 13min, 45% acetonitrile in water; 25min, 70% acetonitrile water solution; 30min, 85% acetonitrile water solution; 38min, 85% acetonitrile water solution; 38.01min, 45% acetonitrile water solution; 45min, 45% acetonitrile in water.
2. A method for separating and determining dapoxetine hydrochloride intermediate SM1 and related impurities by using a high performance liquid chromatography is characterized by comprising the following specific steps: adding a diluent into a test sample to prepare a test sample solution, then adding the diluent into the test sample solution to dilute the test sample solution and the diluent according to a certain multiple to obtain a self-contrast solution, respectively sampling the test sample solution and the self-contrast solution, carrying out high performance liquid chromatography, recording a chromatogram, and calculating the content of a sample to be detected SM1 and related impurities in the test sample according to a main component self-contrast method; the high performance liquid chromatography analysis adopts a chromatographic column with octadecyl bonded porous silica gel or inorganic oxide particles as a filler, acetonitrile aqueous solution is used as a mobile phase for analysis, and the related impurities are one or more of 3-chloropropiophenone, propiophenone, 1-phenylpropanol, naphthol, SM1a, SM1b, SM1c, SM1d, SM1e and UI-1; the gradient elution conditions were: 0min, 45% acetonitrile in water; 13min, 45% acetonitrile in water; 25min, 70% acetonitrile water solution; 30min, 85% acetonitrile water solution; 38min, 85% acetonitrile water solution; 38.01min, 45% acetonitrile water solution; 45min, 45% acetonitrile in water.
3. The method for separating and determining dapoxetine hydrochloride intermediate SM1 and related impurities according to claim 2, further comprising the steps of: respectively taking a sample SM1 to be detected and each related impurity reference substance, dissolving the sample SM1 positioning solution and each related impurity positioning solution by using a diluent to prepare a sample SM1 to be detected and each related impurity positioning solution, respectively taking sample injection, carrying out high performance liquid chromatography analysis, and determining the retention time of the sample SM1 to be detected and each related impurity.
4. The method for separating and determining dapoxetine hydrochloride intermediate SM1 and related impurities according to claim 2 or 3, wherein the diluent is acetonitrile or an aqueous acetonitrile solution.
5. The method for separating and determining dapoxetine hydrochloride intermediate SM1 and related impurities by high performance liquid chromatography according to claim 2 or 3, wherein the flow rate of the mobile phase is 0.5-1.5 ml/min.
6. The method for separating and determining dapoxetine hydrochloride intermediate SM1 and related impurities according to claim 2 or 3, wherein the wavelength detected by HPLC is 210 nm.
7. A method for separating and measuring dapoxetine hydrochloride intermediate SM1 and related impurities by high performance liquid chromatography is disclosed, wherein the related impurities are 3-chlorophenylacetone, propiophenone, 1-phenylpropanol, naphthol, SM1a, SM1b, SM1c, SM1d, SM1e and UI-1, and the method is characterized by comprising the following steps:
(1) respectively taking a sample SM1 to be detected and a reference substance of related impurities, namely 3-chloropropiophenone, propiophenone, 1-phenylpropanol, naphthol, SM1a, SM1b, SM1c, SM1d, SM1e and UI-1, dissolving the reference substance by using a diluent to prepare a sample SM1 positioning solution to be detected and related impurity positioning solutions, respectively taking the sample SM1 positioning solution to be detected and related impurity positioning solutions for sample injection, carrying out high performance liquid chromatography analysis, and determining the retention time of the sample SM1 to be detected and related impurities; the high performance liquid chromatography adopts a chromatographic column which adopts octadecyl bonded porous silica gel or inorganic oxide particles as a filler, the particle size of the octadecyl bonded porous silica gel particles or the inorganic oxide particles is 3-5 mu m, the length of the chromatographic column is 150-250mm, the applicable column temperature range of the chromatographic column is 20-40 ℃, the detection wavelength is 210nm, the analysis is carried out by taking acetonitrile aqueous solution as a mobile phase, and the volume ratio of acetonitrile to the aqueous solution is 45: 55; the diluent is acetonitrile solution;
(2) adding a diluent into a test sample to prepare a test sample solution, then adding the diluent into the test sample solution to dilute the test sample solution and the diluent according to a certain multiple to obtain a self-contrast solution, respectively taking the test sample solution and the self-contrast solution for sample injection, carrying out high performance liquid chromatography analysis, recording a chromatogram, and calculating the content of a sample to be detected SM1 and related impurities in the test sample according to a main component self-contrast method.
8. The method for separating and determining dapoxetine hydrochloride intermediate SM1 and related impurities according to claim 7, wherein the size of the chromatographic column is 4.6 × 250mm,5 μm.
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| CN107014914A (en) * | 2017-03-16 | 2017-08-04 | 重庆医药高等专科学校 | A kind of method of formula isomers and nitrobenzoyl phenyl propane compounds while Analyze ＆ separate FCE-20124 is revived |
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| CN109668976A (en) * | 2018-07-09 | 2019-04-23 | 华控创新（北京）药物研究院有限公司 | A method of with the related substance of high effective liquid chromatography for measuring dapoxetine hydrochloride |
| CN109100453B (en) * | 2018-09-27 | 2022-03-01 | 湖北省宏源药业科技股份有限公司 | Method for separating and measuring 1-fluoronaphthalene and related impurities |
| CN114544821B (en) * | 2020-11-24 | 2023-10-24 | 重庆医科大学 | Application of reagent for detecting phosphatidylethanolamine (36:4) in blood plasma in preparation of depression detection kit |
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