CN111796031A - High performance liquid analysis method for impurities of lisdexamphetamine dimesylate and intermediate thereof - Google Patents
High performance liquid analysis method for impurities of lisdexamphetamine dimesylate and intermediate thereof Download PDFInfo
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Abstract
The invention discloses a high performance liquid chromatography analysis method for impurities of lisdexamphetamine dimesylate and intermediates thereof. The method can effectively analyze impurities of the lisdexamphetamine dimesylate and the intermediate thereof, and has good separation degree between impurity peaks and between a main peak and adjacent peaks. The method is simple to operate, rapid to analyze, good in stability and specificity, and simple and reliable in analysis method for quality control of the lisdexamphetamine dimesylate.
Description
Technical Field
The invention belongs to the technical field of analysis, and particularly relates to a method for analyzing impurities of lisdexamphetamine dimesylate and intermediates thereof by using high performance liquid chromatography.
Background
Lisdexamphetamine dimesylate, chemical name ((2S) -2, 6-diamino-N- [ (1S) -1-methyl-2-phenylethyl)]Caproamide dimesylate), formula C17H33N3O7S2The chemical structural formula is shown as follows.
Patents WO2015130660a1, WO2015130660a1, WO2015130661a1, US2009234002a1, WO03072046a2, US2007042955a1, US2005054561a1, JP2012006978A and US2012157706a1 disclose the synthesis of lisdexamphetamine dimesylate, the specific synthetic routes being shown below.
During the synthesis of the compound, some important intermediates may be incompletely removed, and process impurities are introduced, thereby affecting the quality of the medicine. There are mainly 3 intermediate impurities to be controlled for lisdexamphetamine dimesylate, namely the "compound of formula 6" ((S) -1-phenylpropan-2-amine), "compound of formula 5" ((((S) -6-oxo-6- (((S) -1-phenylpropan-2-yl) amino) hex-1, 5-diyl) dicarbamic acid di-tert-butyl) and "crude compound" ((S) - (1-phenylpropan-2-yl) diethyl phosphoramidate) in the above synthetic route, designated as impurity 1, impurity 2 and impurity 3, respectively, and having the following structural formula:
at present, no relevant literature report exists on an analysis method for simultaneously detecting the lisdexamphetamine dimesylate and the 3 intermediate impurities.
Disclosure of Invention
The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.
In the quality detection method of the lisdexamphetamine dimesylate reported in patent CN108264537A, the lisdexamphetamine dimesylate and its tetramethylsulfonate impurities can be detected only, wherein the retention time of the lisdexamphetamine dimesylate is about 35-36 min, and the retention time of its tetramethylsulfonate impurities is about 49-50 min, specifically, a Thermo Syncronis-C8(250 × 4.6mM,5 μm) chromatographic column is adopted, the column temperature is 30 ℃, the detection wavelength is 210nm, 20mM potassium dihydrogen phosphate aqueous solution is used as a mobile phase a, acetonitrile is used as a mobile phase B, and the following gradient elution is carried out at 1.5 ml/min:
| time (min) | Mobile phase A (V%) | Mobile phase B (V%) |
| 0 | 95 | 5 |
| 5 | 95 | 5 |
| 10 | 85 | 15 |
| 20 | 80 | 20 |
| 40 | 75 | 25 |
| 50 | 70 | 30 |
| 60 | 20 | 80 |
| 80 | 20 | 80 |
| 81 | 95 | 5 |
| 87 | 95 | 5 |
In the analysis method of the patent, the gradient is complex, the analysis process is long, the retention time of a main peak is long, only impurities of the lisdexamphetamine dimesylate and the tetramethylsulfonate thereof can be detected, and the inventor cannot achieve the effect described in the patent when repeating the analysis method (see example 14 of the application). The present invention solves at least one of the technical problems of the related art to some extent. The invention provides a method for analyzing impurities of the lisdexamphetamine dimesylate and intermediates thereof by using high performance liquid chromatography, the method can realize the simultaneous detection of the impurities of the lisdexamphetamine dimesylate and the intermediates thereof, and the detection result has good stability and durability.
In an embodiment of the present invention, the present invention provides a high performance liquid chromatography analysis method of impurities of lisdexamphetamine dimesylate and intermediates thereof, wherein the conditions of the high performance liquid chromatography comprise: the chromatographic column adopts an octyl silane bonded silica gel column; performing gradient elution by using a buffer solution as a mobile phase A and a polar organic solvent as a mobile phase B; here, the pH of the buffer solution is 6.0 to 8.0, and preferably, the pH is 7.0.
In the embodiment of the invention, the impurities of the intermediate of the lisdexamphetamine dimesylate are impurity 1, impurity 2 and impurity 3, and the structural formulas of the impurities are as follows:
in an embodiment of the invention, the polar organic solvent is acetonitrile or methanol, preferably acetonitrile.
In an embodiment of the invention, the chromatography column may be a Welch Ultimate XB-C8 (150X 4.6mm,5 μm) chromatography column.
In an embodiment of the present invention, the pH of the mobile phase a is optionally adjusted to 6.0 to 8.0, preferably 7.0, using phosphoric acid.
In an embodiment of the invention, the conditions of the high performance liquid chromatography analysis further comprise: using a Diode Array (DAD) detector; optionally, the detection wavelength is 220nm to 240nm, preferably 220 nm.
In an embodiment of the invention, the conditions of the high performance liquid chromatography analysis further comprise: the temperature of the column is from 25 ℃ to 40 ℃, preferably 40 ℃.
In an embodiment of the invention, the conditions of the high performance liquid chromatography analysis further comprise: the flow rate is 1.0ml/min to 2.0ml/min, preferably 1.5 ml/min.
In an embodiment of the invention, the high performance liquid chromatography method further comprises the preparation of a sample: taking a proper amount of each of the lisdexamphetamine dimesylate sample and the intermediate impurity thereof, dissolving the samples by using methanol respectively to prepare a mixed solution containing 0.1-1 mg of the lisdexamphetamine dimesylate and the intermediate impurity thereof in every 1ml, and using the methanol as a blank solvent.
In an embodiment of the present invention, the buffer solution is an aqueous solution of tetrabutylammonium hydrogen sulfate, an aqueous solution of sodium octane sulfonate, or an aqueous solution of sodium dodecylbenzenesulfonate, preferably, an aqueous solution of tetrabutylammonium hydrogen sulfate.
In some embodiments of the invention, the concentration of the aqueous tetrabutylammonium hydrogen sulfate solution is between 0.01M and 0.05M, preferably at a concentration of 0.02M.
In some embodiments of the present invention, the aqueous tetrabutylammonium hydrogen sulfate solution contains triethylamine, wherein the content of triethylamine in the aqueous tetrabutylammonium hydrogen sulfate solution is 0.1 to 0.5 v%, preferably 0.2 v%.
In some embodiments of the invention, an octyl silane bonded silica gel column is used, and gradient elution is performed with aqueous tetrabutylammonium hydrogen sulfate solution containing triethylamine as mobile phase a and a polar organic solvent as mobile phase B.
In some embodiments of the invention, 0.02M aqueous tetrabutylammonium hydrogen sulfate solution containing 0.2 v% triethylamine is used as mobile phase A and acetonitrile as mobile phase B.
In one embodiment of the present invention, the present invention provides a high performance liquid chromatography method for impurities of lisdexamphetamine dimesylate and intermediates thereof, comprising:
(1) chromatographic conditions
Gradient elution was carried out using a Welch Ultimate XB-C8 (150X 4.6mm,5 μ M) column with a 0.02M tetrabutylammonium hydrogen sulfate solution containing 0.2 v% triethylamine as mobile phase A and acetonitrile as mobile phase B, under the gradient elution conditions:
| time (min) | Mobile phase A (V%) | Mobile phase B (V%) |
| 0 | 95 | 5 |
| 20 | 70 | 30 |
| 30 | 15 | 85 |
| 33 | 15 | 85 |
| 34 | 95 | 5 |
| 40 | 95 | 5 |
Wherein the pH value of the mobile phase A is adjusted to 7.0 by phosphoric acid, the column temperature is 40 ℃, the detection wavelength is 220nm, the flow rate is 1.5ml/min, and the sample injection amount is 20 mul; here, the type of the high performance liquid chromatograph is not particularly required, and a chromatograph that can be used is Dionex U3000;
(2) sample preparation
Taking a proper amount of each of the lisdexamphetamine dimesylate sample and the intermediate impurity thereof, dissolving the samples by using methanol respectively to prepare a mixed solution containing 0.1-1 mg of the lisdexamphetamine dimesylate and the intermediate impurity thereof in every 1ml, and using the methanol as a blank solvent.
According to the method for analyzing the impurities of the lisdexamphetamine dimesylate and the intermediate thereof by using the high performance liquid chromatography, all components are completely separated, all response values are in a proper range, and the analysis of the impurities of the lisdexamphetamine dimesylate and the intermediate can be realized simultaneously. Meanwhile, the peak types of the dexamphetamine dimesylate and the impurity 1 can be obviously improved, and the separation degree between the dexamphetamine dimesylate and the impurity 1 is improved; the base line can be effectively improved, the interference of a solvent peak is reduced, and the separation degree between components is increased; and the method has good durability to chromatographic conditions such as different chromatographic columns, mobile phase salt concentration, column temperature and the like.
The method can effectively separate impurities of the lisdexamphetamine dimesylate and the intermediate thereof, simplifies the transformation of a mobile phase during gradient elution, and solves the separation and determination problems of the impurities of the lisdexamphetamine dimesylate and the intermediate thereof.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention will be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.
Drawings
The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the example serve to explain the principles of the invention and not to limit the invention.
FIG. 1 is a space-time white solvent HPLC chart of example 1;
FIG. 2 is an HPLC chart of the impurities of the lisdexamphetamine dimesylate and intermediates thereof in example 1;
FIG. 3 is an HPLC chart of the impurities of lisdexamphetamine dimesylate and intermediates thereof in example 2;
FIG. 4 is an HPLC chart of the impurities of lisdexamphetamine dimesylate and intermediates thereof in example 3;
FIG. 5 is an HPLC chart of the impurities of the lisdexamphetamine dimesylate and intermediates thereof in example 4;
FIG. 6 is an HPLC chart of the impurities of lisdexamphetamine dimesylate and intermediates thereof in example 5;
FIG. 7 is an HPLC plot of the impurities of lisdexamphetamine dimesylate and intermediates thereof for example 6;
FIG. 8 is an HPLC plot of the impurities of lisdexamphetamine dimesylate and intermediates thereof in example 7;
FIG. 9 is an HPLC plot of the impurities of lisdexamphetamine dimesylate and intermediates thereof in example 8;
FIG. 10 is an HPLC plot of the impurities of lisdexamphetamine dimesylate and intermediates thereof in example 9;
FIG. 11 is an HPLC plot of the impurities of lisdexamphetamine mesylate and its intermediates in example 10;
FIG. 12 is an HPLC plot of the impurities of lisdexamphetamine mesylate and its intermediates in example 11;
FIG. 13 is an HPLC plot of the impurities of lisdexamphetamine dimesylate and intermediates thereof for example 12;
FIG. 14 is an HPLC plot of the impurities of lisdexamphetamine dimesylate and intermediates thereof for example 13;
FIG. 15 is an HPLC chart of the impurities of lisdexamphetamine dimesylate and intermediates thereof in example 14.
Detailed Description
Hereinafter, embodiments of the present invention will be described in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.
Example 1:
chromatographic conditions are as follows:
high performance liquid chromatograph: dinoex U3000;
a chromatographic column: welch Ultimate XB-C8 (150X 4.6mm,5 μm);
column temperature: 40 ℃;
detection wavelength: 220 nm;
flow rate: 1.5 ml/min;
sample introduction amount: 20 μ l.
Using a solution containing 0.2 v% of triethylamine and 0.02M tetrabutylammonium hydrogen sulfate as a mobile phase A, adjusting the pH value to 7.0 by phosphoric acid, and using acetonitrile as a mobile phase B, and carrying out gradient elution under the following conditions:
the experimental steps are as follows:
taking a proper amount of the lisdexamphetamine dimesylate and intermediate impurities thereof, dissolving samples by using methanol respectively, preparing a mixed solution containing the lisdexamphetamine dimesylate and about 0.3mg/ml of each intermediate, and taking a proper amount of methanol as a blank solvent. 20. mu.l of the solution was measured and injected into a chromatograph, and a chromatogram was recorded. The results are shown in the attached figures 1-2, and figure 1 is a solvent chromatogram; in fig. 2, the chromatographic peak with retention time of 8.6min is the dexamphetamine dimesylate, and the chromatographic peaks with retention times of 6.7min, 25.1min and 27.6min are impurity 1, impurity 2 and impurity 3 respectively.
Example 2:
high performance liquid chromatograph: dinoex U3000;
a chromatographic column: waters Xbridge-C8 (150X 4.6mm,5 μm);
column temperature: 40 ℃;
detection wavelength: 220 nm;
flow rate: 1.5 ml/min;
sample introduction amount: 20 μ l.
Taking a 0.02M tetrabutylammonium hydrogen sulfate solution containing 0.2 v% of triethylamine as a mobile phase A, adjusting the pH value to 7.0 by phosphoric acid, and taking acetonitrile as a mobile phase B, and carrying out gradient elution under the following conditions:
| time (min) | Mobile phase A (V%) | Mobile phase B (V%) |
| 0 | 95 | 5 |
| 20 | 70 | 30 |
| 30 | 15 | 85 |
| 33 | 15 | 85 |
| 34 | 95 | 5 |
| 40 | 95 | 5 |
The experimental steps are as follows:
taking a proper amount of the lisdexamphetamine dimesylate and the intermediate impurities thereof, dissolving the samples with methanol respectively, preparing a mixed solution containing the lisdexamphetamine dimesylate and about 0.3mg/ml of each intermediate impurity, measuring 20 mu l of the mixed solution, injecting the mixed solution into a chromatograph, and recording a chromatogram. The result is shown in figure 3, wherein the chromatographic peak with retention time of 11.1min is the dexamphetamine dimesylate, and the chromatographic peaks with retention times of 9.7min, 27.5min and 30.2min are respectively impurity 1, impurity 2 and impurity 3.
Example 3:
high performance liquid chromatograph: dinoex U3000;
a chromatographic column: welch Ultimate XB-C8 (150X 4.6mm,5 μm);
column temperature: 40 ℃;
detection wavelength: 220 nm;
flow rate: 1.5 ml/min;
sample introduction amount: 20 μ l.
Taking a solution containing 0.2 v% of triethylamine and 0.01M tetrabutylammonium hydrogen sulfate as a mobile phase A, adjusting the pH value to 7.0 by phosphoric acid, and taking acetonitrile as a mobile phase B, and carrying out gradient elution under the following conditions:
| time (min) | Mobile phase A (V%) | Mobile phase B (V%) |
| 0 | 95 | 5 |
| 20 | 70 | 30 |
| 30 | 15 | 85 |
| 33 | 15 | 85 |
| 34 | 95 | 5 |
| 40 | 95 | 5 |
The experimental steps are as follows:
taking a proper amount of the lisdexamphetamine dimesylate and the intermediate impurities thereof, dissolving the samples with methanol respectively, preparing a mixed solution containing the lisdexamphetamine dimesylate and about 0.3mg/ml of each intermediate impurity, measuring 20 mu l of the mixed solution, injecting the mixed solution into a chromatograph, and recording a chromatogram. The result is shown in figure 4, wherein the chromatographic peak with retention time of 8.7min is the dexamphetamine dimesylate, and the chromatographic peaks with retention times of 6.3min, 27.5min and 30.2min are respectively impurity 1, impurity 2 and impurity 3.
Example 4:
high performance liquid chromatograph: dinoex U3000;
a chromatographic column: welch Ultimate XB-C8 (150X 4.6mm,5 μm);
column temperature: 40 ℃;
detection wavelength: 220 nm;
flow rate: 1.5 ml/min;
sample introduction amount: 20 μ l.
Using 0.05M tetrabutylammonium hydrogen sulfate solution containing 0.2 v% of triethylamine and having pH of 7.0 as a mobile phase A, adjusting pH value to 7.0 with phosphoric acid, and using acetonitrile as a mobile phase B, and performing gradient elution under the following conditions:
| time (min) | Mobile phase A (V%) | Mobile phase B (V%) |
| 0 | 95 | 5 |
| 20 | 70 | 30 |
| 30 | 15 | 85 |
| 33 | 15 | 85 |
| 34 | 95 | 5 |
| 40 | 95 | 5 |
The experimental steps are as follows:
taking a proper amount of the lisdexamphetamine dimesylate and the intermediate impurities thereof, dissolving the samples with methanol respectively, preparing a mixed solution containing the lisdexamphetamine dimesylate and about 0.3mg/ml of each intermediate impurity, measuring 20 mu l of the mixed solution, injecting the mixed solution into a chromatograph, and recording a chromatogram. The result is shown in figure 5, wherein the chromatographic peak with retention time of 8.5min is the dexamphetamine dimesylate, and the chromatographic peaks with retention times of 6.9min, 25.2min and 27.7min are respectively impurity 1, impurity 2 and impurity 3.
Example 5:
high performance liquid chromatograph: dinoex U3000;
a chromatographic column: welch Ultimate XB-C8 (150X 4.6mm,5 μm);
column temperature: 25 ℃;
detection wavelength: 220 nm;
flow rate: 1.5 ml/min;
sample introduction amount: 20 μ l.
Using an aqueous solution containing 0.2 v% of triethylamine and 0.02M of sodium octane sulfonate as a mobile phase A, adjusting the pH value to 7.0 by phosphoric acid, and using acetonitrile as a mobile phase B, and carrying out gradient elution under the following conditions:
| time (min) | Mobile phase A (V%) | Mobile phase B (V%) |
| 0 | 95 | 5 |
| 20 | 70 | 30 |
| 30 | 15 | 85 |
| 33 | 15 | 85 |
| 34 | 95 | 5 |
| 40 | 95 | 5 |
The experimental steps are as follows:
taking a proper amount of the lisdexamphetamine dimesylate and the intermediate impurities thereof, dissolving the samples with methanol respectively, preparing a mixed solution containing the lisdexamphetamine dimesylate and about 0.3mg/ml of each intermediate impurity, measuring 20 mu l of the mixed solution, injecting the mixed solution into a chromatograph, and recording a chromatogram. The result is shown in figure 6, wherein the chromatographic peak with retention time of 8.5min is the dexamphetamine dimesylate, and the chromatographic peaks with retention times of 6.8min, 25.2min and 27.6min are respectively impurity 1, impurity 2 and impurity 3.
Example 6:
high performance liquid chromatograph: dinoex U3000;
a chromatographic column: welch Ultimate XB-C8 (150X 4.6mm,5 μm);
column temperature: 40 ℃;
detection wavelength: 240 nm;
flow rate: 1.5 ml/min;
sample introduction amount: 20 μ l.
Using a solution containing 0.2 v% of triethylamine and 0.02M tetrabutylammonium hydrogen sulfate as a mobile phase A, adjusting the pH value to 7.0 by phosphoric acid, and using acetonitrile as a mobile phase B, and carrying out gradient elution under the following conditions:
| time (min) | Mobile phase A (V%) | Mobile phase B (V%) |
| 0 | 95 | 5 |
| 20 | 70 | 30 |
| 30 | 15 | 85 |
| 33 | 15 | 85 |
| 34 | 95 | 5 |
| 40 | 95 | 5 |
The experimental steps are as follows:
taking a proper amount of the lisdexamphetamine dimesylate and the intermediate impurities thereof, dissolving the samples with methanol respectively, preparing a mixed solution containing the lisdexamphetamine dimesylate and about 0.3mg/ml of each intermediate impurity, measuring 20 mu l of the mixed solution, injecting the mixed solution into a chromatograph, and recording a chromatogram. The result is shown in figure 7, in which the chromatographic peak with retention time of 8.6min is the dexamphetamine dimesylate, and the chromatographic peaks with retention times of 6.7min, 25.1min and 27.6min are impurity 1, impurity 2 and impurity 3 respectively.
Example 7:
high performance liquid chromatograph: dinoex U3000;
a chromatographic column: welch Ultimate XB-C8 (150X 4.6mm,5 μm);
column temperature: 40 ℃;
detection wavelength: 220 nm;
flow rate: 1.0 ml/min;
sample introduction amount: 20 μ l.
Using a solution containing 0.2 v% of triethylamine and 0.02M tetrabutylammonium hydrogen sulfate as a mobile phase A, adjusting the pH value to 7.0 by phosphoric acid, and using acetonitrile as a mobile phase B, and carrying out gradient elution under the following conditions:
the experimental steps are as follows:
taking a proper amount of the lisdexamphetamine dimesylate and the intermediate impurities thereof, dissolving the samples with methanol respectively, preparing a mixed solution containing the lisdexamphetamine dimesylate and about 0.3mg/ml of each intermediate impurity, measuring 20 mu l of the mixed solution, injecting the mixed solution into a chromatograph, and recording a chromatogram. The result is shown in figure 8, wherein the chromatographic peak with retention time of 10.5min is the dexamphetamine dimesylate, and the chromatographic peaks with retention times of 9.0min, 25.5min and 30.5min are respectively impurity 1, impurity 2 and impurity 3.
Example 8:
high performance liquid chromatograph: dinoex U3000;
a chromatographic column: welch Ultimate XB-C8 (150X 4.6mm,5 μm);
column temperature: 40 ℃;
detection wavelength: 220 nm;
flow rate: 1.5 ml/min;
sample introduction amount: 20 μ l.
Using an aqueous solution containing 0.2 v% of triethylamine and 0.02M of sodium dodecyl benzene sulfonate as a mobile phase A, adjusting the pH value to 7.0 by phosphoric acid, and using acetonitrile as a mobile phase B, and carrying out gradient elution under the following conditions:
| time (min) | Mobile phase A (V%) | Mobile phase B (V%) |
| 0 | 95 | 5 |
| 20 | 50 | 50 |
| 25 | 15 | 85 |
| 28 | 15 | 85 |
| 29 | 95 | 5 |
| 35 | 95 | 5 |
The experimental steps are as follows:
taking a proper amount of the lisdexamphetamine dimesylate and the intermediate impurities thereof, dissolving the samples with methanol respectively, preparing a mixed solution containing the lisdexamphetamine dimesylate and about 0.3mg/ml of each intermediate impurity, measuring 20 mu l of the mixed solution, injecting the mixed solution into a chromatograph, and recording a chromatogram. The result is shown in figure 9, in which the chromatographic peak with retention time of 8.3min is the dexamphetamine dimesylate, and the chromatographic peaks with retention times of 6.6min, 24.1min and 25.4min are impurity 1, impurity 2 and impurity 3 respectively.
Example 9:
high performance liquid chromatograph: dinoex U3000;
a chromatographic column: welch Ultimate XB-C8 (150X 4.6mm,5 μm);
column temperature: 40 ℃;
detection wavelength: 220 nm;
flow rate: 2.0 ml/min;
sample introduction amount: 20 μ l.
Using a 0.02M tetrabutylammonium hydrogen sulfate solution containing 0.2 v% of triethylamine as a mobile phase A, adjusting the pH value to 7.0 by using phosphoric acid, and using acetonitrile as a mobile phase B, and performing gradient elution under the following conditions:
| time (min) | Mobile phase A (V%) | Mobile phase B (V%) |
| 0 | 95 | 5 |
| 20 | 50 | 50 |
| 25 | 15 | 85 |
| 28 | 15 | 85 |
| 29 | 95 | 5 |
| 35 | 95 | 5 |
The experimental steps are as follows:
taking a proper amount of the lisdexamphetamine dimesylate and the intermediate impurities thereof, dissolving the samples with methanol respectively, preparing a mixed solution containing the lisdexamphetamine dimesylate and about 0.3mg/ml of each intermediate impurity, measuring 20 mu l of the mixed solution, injecting the mixed solution into a chromatograph, and recording a chromatogram. The result is shown in figure 10, wherein the chromatographic peak with retention time of 7.4min is the dexamphetamine dimesylate, and the chromatographic peaks with retention times of 6.7min, 15.4min and 18.9min are respectively impurity 1, impurity 2 and impurity 3.
Example 10:
high performance liquid chromatograph: dinoex U3000;
a chromatographic column: welch Ultimate XB-C8 (150X 4.6mm,5 μm);
column temperature: 40 ℃;
detection wavelength: 220 nm;
flow rate: 1.5 ml/min;
sample introduction amount: 20 μ l.
Taking 0.02M tetrabutylammonium hydrogen sulfate solution as a mobile phase A, adjusting the pH value to 7.0 by phosphoric acid, and taking acetonitrile as a mobile phase B, and carrying out gradient elution under the conditions that:
| time (min) | Mobile phase A (V%) | Mobile phase B (V%) |
| 0 | 95 | 5 |
| 20 | 50 | 50 |
| 25 | 15 | 85 |
| 28 | 15 | 85 |
| 29 | 95 | 5 |
| 35 | 95 | 5 |
The experimental steps are as follows:
taking a proper amount of the lisdexamphetamine dimesylate and the intermediate impurities thereof, dissolving the samples with methanol respectively, preparing a mixed solution containing the lisdexamphetamine dimesylate and about 0.3mg/ml of each intermediate impurity, measuring 20 mu l of the mixed solution, injecting the mixed solution into a chromatograph, and recording a chromatogram. The result is shown in figure 11, wherein the chromatographic peak with retention time of 8.3min is the dexamphetamine dimesylate, and the chromatographic peaks with retention times of 7.3min, 24.8min and 26.4min are respectively impurity 1, impurity 2 and impurity 3.
Example 11:
high performance liquid chromatograph: dinoex U3000;
a chromatographic column: welch Ultimate XB-C8 (150X 4.6mm,5 μm);
column temperature: 40 ℃;
detection wavelength: 220 nm;
flow rate: 1.5 ml/min;
sample introduction amount: 20 μ l.
Taking a solution containing 0.1 v% of triethylamine and 0.02M tetrabutylammonium hydrogen sulfate as a mobile phase A, adjusting the pH value to 7.0 by phosphoric acid, and taking acetonitrile as a mobile phase B, and carrying out gradient elution under the following conditions:
| time (min) | Mobile phase A (V%) | Mobile phase B (V%) |
| 0 | 95 | 5 |
| 20 | 50 | 50 |
| 25 | 15 | 85 |
| 28 | 15 | 85 |
| 29 | 95 | 5 |
| 35 | 95 | 5 |
The experimental steps are as follows:
taking a proper amount of the lisdexamphetamine dimesylate and the intermediate impurities thereof, dissolving the samples with methanol respectively, preparing a mixed solution containing the lisdexamphetamine dimesylate and about 0.3mg/ml of each intermediate impurity, measuring 20 mu l of the mixed solution, injecting the mixed solution into a chromatograph, and recording a chromatogram. The result is shown in figure 12, wherein the chromatographic peak with retention time of 9.1min is the dexamphetamine dimesylate, and the chromatographic peaks with retention times of 7.9min, 25.1min and 26.4min are impurity 1, impurity 2 and impurity 3 respectively.
Example 12:
high performance liquid chromatograph: dinoex U3000;
a chromatographic column: welch Ultimate XB-C8 (150X 4.6mm,5 μm);
column temperature: 40 ℃;
detection wavelength: 220 nm;
flow rate: 1.5 ml/min;
sample introduction amount: 20 μ l.
Taking a solution containing 0.2 v% of triethylamine and 0.02M tetrabutylammonium hydrogen sulfate as a mobile phase A, adjusting the pH value to be 6.0 by phosphoric acid, and taking acetonitrile as a mobile phase B, and carrying out gradient elution under the following conditions:
| time (min) | Mobile phase A (V%) | Mobile phase B (V%) |
| 0 | 95 | 5 |
| 25 | 15 | 85 |
| 28 | 15 | 85 |
| 29 | 95 | 5 |
| 35 | 95 | 5 |
The experimental steps are as follows:
taking a proper amount of the lisdexamphetamine dimesylate and the intermediate impurities thereof, dissolving the samples with methanol respectively, preparing a mixed solution containing the lisdexamphetamine dimesylate and about 0.3mg/ml of each intermediate impurity, measuring 20 mu l of the mixed solution, injecting the mixed solution into a chromatograph, and recording a chromatogram. The result is shown in figure 13, wherein the chromatographic peak with retention time of 8.9min is the dexamphetamine dimesylate, and the chromatographic peaks with retention times of 8.3min, 17.4min and 20.9min are impurity 1, impurity 2 and impurity 3 respectively.
Example 13:
high performance liquid chromatograph: dinoex U3000;
a chromatographic column: welch Ultimate XB-C8 (150X 4.6mm,5 μm);
column temperature: 40 ℃;
detection wavelength: 210 nm;
flow rate: 1.5 ml/min;
sample introduction amount: 20 μ l.
Using a 0.02M tetrabutylammonium hydrogen sulfate solution containing 0.2 v% of triethylamine as a mobile phase A, adjusting the pH value to 8.0 by using phosphoric acid, and using acetonitrile as a mobile phase B, and performing gradient elution under the following conditions:
the experimental steps are as follows:
taking a proper amount of the lisdexamphetamine dimesylate and the intermediate impurities thereof, dissolving the samples with methanol respectively, preparing a mixed solution containing the lisdexamphetamine dimesylate and about 0.3mg/ml of each intermediate impurity, measuring 20 mu l of the mixed solution, injecting the mixed solution into a chromatograph, and recording a chromatogram. The result is shown in figure 14, wherein the chromatographic peak with retention time of 7.2min is the dexamphetamine dimesylate, and the chromatographic peaks with retention times of 6.8min, 15.6min and 19.1min are respectively impurity 1, impurity 2 and impurity 3.
Example 14:
high performance liquid chromatograph: dinoex U3000;
a chromatographic column: thermo Syncronis-C18 (250X 4.6mm,5 μm);
column temperature: 30 ℃;
detection wavelength: 210 nm;
flow rate: 1.5 ml/min;
sample introduction amount: 20 μ l.
Using 20mM potassium dihydrogen phosphate water solution as a mobile phase A and acetonitrile as a mobile phase B, and carrying out gradient elution as follows:
| time (min) | Mobile phase A (V%) | Mobile phase B (V%) |
| 0 | 95 | 5 |
| 5 | 95 | 5 |
| 10 | 85 | 15 |
| 20 | 80 | 20 |
| 40 | 75 | 25 |
| 50 | 70 | 30 |
| 60 | 20 | 80 |
| 80 | 20 | 80 |
| 81 | 95 | 5 |
| 87 | 95 | 5 |
The experimental steps are as follows:
taking a proper amount of the lisdexamphetamine dimesylate and the intermediate impurities thereof, dissolving the samples with methanol respectively, preparing a mixed solution containing the lisdexamphetamine dimesylate and about 0.3mg/ml of each intermediate impurity, measuring 20 mu l of the mixed solution, injecting the mixed solution into a chromatograph, and recording a chromatogram. The result is shown in figure 15, in which the chromatographic peak with retention time of 11.1min is the dexamphetamine dimesylate, the chromatographic peaks with retention time of 10.5min and 23.9min are impurity 1 and impurity 2 respectively, and impurity 3 is not detected.
Although the embodiments disclosed in the present application are described above, the descriptions are only for the convenience of understanding the present application, and are not intended to limit the present application. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims.
Claims (10)
1. A high performance liquid chromatography analysis method for impurities of lisdexamphetamine dimesylate and intermediates thereof, wherein the conditions of the high performance liquid chromatography comprise the following steps: the chromatographic column adopts an octyl silane bonded silica gel column; performing gradient elution by using a buffer solution as a mobile phase A and a polar organic solvent as a mobile phase B; here, the pH of the buffer solution is 6.0 to 8.0, and preferably, the pH is 7.0.
2. The high performance liquid chromatography method of claim 1, wherein the polar organic phase is acetonitrile or methanol, preferably acetonitrile.
3. The HPLC analysis method according to claim 1, wherein said buffer solution is an aqueous solution of tetrabutylammonium hydrogen sulfate, an aqueous solution of octane sulfonate, or an aqueous solution of sodium dodecylbenzenesulfonate, preferably an aqueous solution of tetrabutylammonium hydrogen sulfate.
4. The high performance liquid chromatography analysis method according to claim 3, wherein the concentration of said aqueous tetrabutylammonium hydrogen sulfate solution is between 0.01M and 0.05M, preferably said concentration is 0.02M.
5. The high performance liquid chromatography analysis method according to claim 4, wherein triethylamine is contained in the aqueous tetrabutylammonium hydrogen sulfate solution, and the content of triethylamine in the aqueous tetrabutylammonium hydrogen sulfate solution is 0.1 to 0.5% by volume, preferably 0.2% by volume.
6. The high performance liquid chromatography analysis method according to any one of claims 1 to 5, wherein the pH of the mobile phase A is adjusted with phosphoric acid.
7. The high performance liquid chromatography analysis method according to any one of claims 1 to 5, wherein a diode array detector is employed;
optionally, the detection wavelength is 220nm to 240nm, preferably 220 nm;
optionally, the temperature of the chromatographic column is from 25 ℃ to 40 ℃, preferably 40 ℃;
alternatively, the flow rate is 1.0ml/min to 2.0ml/min, preferably 1.5 ml/min.
8. The high performance liquid chromatography analysis method according to any one of claims 1 to 5, wherein gradient elution is carried out using 0.02M aqueous tetrabutylammonium hydrogen sulfate solution containing 0.2 v% triethylamine as mobile phase A and acetonitrile as mobile phase B.
9. The high performance liquid chromatography analysis method according to any one of claims 1 to 5, wherein the column is a Welchultimate XB-C8(150 x 4.6mm,5 μm) column.
10. The high performance liquid chromatography method of claim 1, comprising:
(1) chromatographic conditions
Gradient elution was carried out using a Welch Ultimate XB-C8 (150X 4.6mm,5 μ M) column with 0.02M aqueous tetrabutylammonium hydrogen sulfate solution containing 0.2 v% triethylamine as mobile phase A and acetonitrile as mobile phase B, under the gradient elution conditions:
Wherein the pH value of the mobile phase A is adjusted to 7.0 by phosphoric acid, the column temperature is 40 ℃, the detection wavelength is 220nm, the flow rate is 1.5ml/min, and the sample injection amount is 20 mul;
(2) sample preparation
Taking proper amounts of the lisdexamphetamine dimesylate and the intermediate impurities thereof, respectively dissolving samples with methanol to prepare a mixed solution containing 0.1-1 mg of the lisdexamphetamine dimesylate and the intermediate impurities thereof in every 1ml, and taking the methanol as a blank solvent.
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| US20120157706A1 (en) * | 2010-12-20 | 2012-06-21 | Bauer Michael J | Methods and Compositions for Preparing Lisdexamfetamine and Salts Thereof |
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| US20120157706A1 (en) * | 2010-12-20 | 2012-06-21 | Bauer Michael J | Methods and Compositions for Preparing Lisdexamfetamine and Salts Thereof |
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