CN114487134A - Method for detecting hydroxylamine hydrochloride in itopride hydrochloride - Google Patents
Method for detecting hydroxylamine hydrochloride in itopride hydrochloride Download PDFInfo
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- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 title claims abstract description 190
- QQQIECGTIMUVDS-UHFFFAOYSA-N N-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4-dimethoxybenzamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NCC1=CC=C(OCCN(C)C)C=C1 QQQIECGTIMUVDS-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 229960005302 itopride Drugs 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000001514 detection method Methods 0.000 claims abstract description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 69
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- -1 polysiloxane Polymers 0.000 claims description 3
- 229920001296 polysiloxane Polymers 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims 1
- 235000019796 monopotassium phosphate Nutrition 0.000 claims 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 abstract description 16
- 238000012360 testing method Methods 0.000 abstract description 10
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 abstract description 8
- 239000000463 material Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 4
- 238000006146 oximation reaction Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 76
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 32
- 239000011550 stock solution Substances 0.000 description 28
- 239000012085 test solution Substances 0.000 description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 18
- 239000012490 blank solution Substances 0.000 description 18
- 239000003085 diluting agent Substances 0.000 description 18
- 239000000523 sample Substances 0.000 description 18
- 230000035945 sensitivity Effects 0.000 description 15
- 238000003260 vortexing Methods 0.000 description 14
- 238000005303 weighing Methods 0.000 description 12
- 239000012088 reference solution Substances 0.000 description 11
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- 235000017550 sodium carbonate Nutrition 0.000 description 8
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000011084 recovery Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000012488 sample solution Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000012795 verification Methods 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 230000005176 gastrointestinal motility Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000011003 system suitability test Methods 0.000 description 1
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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
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Abstract
The invention provides a method for testing hydroxylamine hydrochloride in itopride hydrochloride, wherein the hydroxylamine hydrochloride is a key material used in a synthesis process of 4- [ (2-dimethylamino) ethoxy ] benzylamine, and is caused to remain in the 4- [ (2-dimethylamino) ethoxy ] benzylamine when an oximation reaction is not completely carried out, and the 4- [ (2-dimethylamino) ethoxy ] benzylamine is a key material for synthesizing the itopride hydrochloride, so that the hydroxylamine hydrochloride in the 4- [ (2-dimethylamino) ethoxy ] benzylamine is possibly introduced into an itopride hydrochloride finished product. In order to detect the content of hydroxylamine hydrochloride in itopride hydrochloride, the invention provides the detection method of hydroxylamine hydrochloride in itopride hydrochloride, which has the characteristics of high accuracy, high precision, good reproducibility, good stability, strong specificity and the like, and has the advantages of short time consumption, simple operation, low cost and the like.
Description
Technical Field
The invention relates to the field of medical analysis, in particular to a method for detecting hydroxylamine hydrochloride in itopride hydrochloride.
Background
Itopride hydrochloride (Itopride hydrochloride) was developed by pharmaceutical development in north japan and was first marketed in japan in 1989. China is successfully developed at the beginning of this century and is approved as a second class of new drugs by CFDA. Itopride hydrochloride is a new generation benzamide gastrointestinal motility promoting drug, and is a novel drug with the action mechanism which is not completely the same as that of the existing gastrointestinal motility promoting drug.
Hydroxylamine hydrochloride is a key material used in the synthesis process of 4- [ (2-dimethylamino) ethoxy ] benzylamine, and remains in 4- [ (2-dimethylamino) ethoxy ] benzylamine if the reaction is incomplete during the oximation reaction, and 4- [ (2-dimethylamino) ethoxy ] benzylamine is a key material for synthesizing itopride hydrochloride, so that hydroxylamine hydrochloride in 4- [ (2-dimethylamino) ethoxy ] benzylamine is likely to be introduced into an itopride hydrochloride finished product, the detection of hydroxylamine hydrochloride in itopride is realized according to a gas chromatography method independently developed by developers, and the effectiveness and feasibility of the method are verified, refer to ICH Q2 and the guidance of the four parts 9101 of the chinese pharmacopoeia.
As a pharmaceutical industry, strict control of the content of impurities in a product is very necessary, and the method is helpful for optimizing the synthesis process and controlling the quality of a medicament, researches on a detection method of hydroxylamine hydrochloride in itopride hydrochloride, provides a better reference for evaluating the quality of itopride hydrochloride and a synthesis intermediate thereof, provides a technical basis for optimizing the synthesis process of itopride hydrochloride, and has great significance for determining adverse reactions caused by hydroxylamine hydrochloride in itopride hydrochloride. The invention provides a simple, convenient, efficient and accurate detection method for solving the problem of detection of hydroxylamine hydrochloride in itopride hydrochloride.
Disclosure of Invention
The invention aims to provide a method for detecting hydroxylamine hydrochloride in itopride hydrochloride, which is simple, convenient, efficient and accurate, completely accords with the guiding principles of method verification in ICH Q2 and Chinese pharmacopoeia' four part 9101 guiding principles in aspects of system applicability, specificity, precision, quantitative limit, detection limit, linearity and range, accuracy, durability and the like, and can be used for quality control of itopride hydrochloride bulk drugs.
In order to achieve the purpose, the invention provides the following technical scheme:
a detection method of hydroxylamine hydrochloride in itopride hydrochloride comprises the following steps: (1) preparing solutions, namely respectively preparing a blank solution, a hydroxylamine hydrochloride stock solution I, a hydroxylamine hydrochloride stock solution II, a sensitivity solution, a reference solution and a test solution; the blank solution comprises a sodium carbonate solution, cyclohexanone and a dichloromethane solution; the hydroxylamine hydrochloride stock solution (I) comprises a hydroxylamine hydrochloride solution and purified water; the hydroxylamine hydrochloride stock solution comprises hydroxylamine hydrochloride and a sodium carbonate solution; the sensitivity solution comprises hydroxylamine hydrochloride, a sodium carbonate solution, a cyclohexanone solution and a dichloromethane solution; the reference solution comprises hydroxylamine hydrochloride, a sodium carbonate solution, a cyclohexanone solution and a dichloromethane solution; the test solution comprises itopride hydrochloride, a sodium carbonate solution, a cyclohexanone solution and a dichloromethane solution;
(2) the determination method comprises the following steps: respectively injecting the blank solution, the sensitivity solution, the reference solution and the test solution into a gas chromatograph, and recording a chromatogram, wherein the chromatogram conditions are as follows: a chromatographic column: (5% phenyl) methyl polysiloxane; column temperature: keeping the temperature at 40 ℃ for 2min, heating to 120 ℃ at 10 ℃/min, and heating to 200 ℃ at 30 ℃/min for 2 min; sample inlet temperature: 220 ℃; detector temperature: 250 ℃; sample introduction amount: 2 mu l of the solution; the split ratio is as follows: 3: 1; line rate: 30 cm/sec; needle washing liquid: dichloromethane.
The invention provides a method for detecting hydroxylamine hydrochloride in itopride hydrochloride, and further comprises the following steps of: taking Na2CO3Placing the solution in a centrifuge tube, adding cyclohexanone for vortex, adding dichloromethane for vortex, standing for layering, and taking the lower organic phase to obtain a blank solution;
the preparation method of the hydroxylamine hydrochloride stock solution comprises the following steps: weighing hydroxylamine hydrochloride, precisely weighing, placing in a volumetric flask, adding a diluent I to dissolve and dilute to a scale, and shaking uniformly to obtain a hydroxylamine hydrochloride stock solution I;
the preparation method of the hydroxylamine hydrochloride stock solution II comprises the following steps: precisely measuring hydroxylamine hydrochloride stock solution I, placing the hydroxylamine hydrochloride stock solution I in a volumetric flask, adding diluent II to dissolve and dilute the hydroxylamine hydrochloride stock solution to a scale, and shaking up to obtain hydroxylamine hydrochloride stock solution II;
the preparation steps of the sensitivity solution are as follows: measuring diluent II and hydroxylamine hydrochloride stock solution II, placing the diluent II and hydroxylamine hydrochloride stock solution II in a centrifugal tube, adding cyclohexanone for vortex, adding dichloromethane for vortex, standing for layering, and taking a lower-layer organic phase to obtain a sensitivity solution;
the preparation steps of the reference substance solution are as follows: measuring diluent II and hydroxylamine hydrochloride stock solution II, placing the diluent II and hydroxylamine hydrochloride stock solution II in a centrifugal tube, adding cyclohexanone for vortex, adding dichloromethane for vortex, standing for layering, and taking the lower layer to obtain a reference solution;
the preparation steps of the test solution are as follows: weighing an itopride hydrochloride test sample, precisely weighing, placing the test sample in a centrifuge tube, adding diluent II, performing vortex, adding dichloromethane vortex for dissolution, standing for layering, taking an upper layer aqueous solution, placing the upper layer aqueous solution in the centrifuge tube, adding cyclohexanone vortex, adding dichloromethane vortex, standing for layering, and taking a lower layer organic phase to obtain a test sample solution;
the diluent (I) is purified water, and the diluent (II) is 100mg/ml Na2CO3The solution comprises sodium carbonate, cyclohexanone and dichloromethane which are AR and above, and ultrapure water which is HPLC; the hydroxylamine hydrochloride is purchased or manufactured by self;
the column may be an HP-530 m x 0.32mm, 0.25 μm, or equivalent performance column.
Hydroxylamine hydrochloride (ppm) = (Ru/Rs) × (Cs/Cu); wherein: ru: peak area of hydroxylamine hydrochloride in the test solution atlas; rs: average peak area of hydroxylamine hydrochloride in 6-pin control solutions; cs: concentration of hydroxylamine hydrochloride in the control solution (μ g/ml); cu: concentration of test solution (g/ml).
The method for measuring the content of the hydroxylamine hydrochloride further comprises method verification before detection, wherein the method verification is that according to the chromatographic conditions of formal detection, the measurement result is as follows:
advantageous effects
According to the technical scheme, the detection method disclosed by the invention has high chromatographic peak separation degree on hydroxylamine hydrochloride in itopride hydrochloride, has high system applicability, and meets the standards in specificity, precision, quantification limit, detection limit, accuracy, linearity, range and durability. In order to confirm the residual quantity of hydroxylamine hydrochloride in itopride hydrochloride, the method is verified by using a convenient and rapid high-efficiency gas chromatography to prove the effectiveness and feasibility of the method. The detection of the hydroxylamine hydrochloride in the itopride hydrochloride can be used for monitoring the quality of the itopride hydrochloride raw material medicine and the preparation. The method for detecting hydroxylamine hydrochloride in itopride hydrochloride provided by the invention has the characteristics of high accuracy, high precision, good reproducibility, good stability, strong specificity and the like, and has the advantages of short time consumption, simple operation, low cost and the like.
Drawings
FIG. 1 is a gas chromatogram of a blank solution for detecting hydroxylamine hydrochloride in itopride hydrochloride;
FIG. 2 is a gas chromatogram of a detection-sensitive solution of hydroxylamine hydrochloride in itopride hydrochloride;
FIG. 3 is a gas chromatogram of a hydroxylamine hydrochloride detection control solution in itopride hydrochloride;
FIG. 4 is a gas chromatogram of a test solution for detecting hydroxylamine hydrochloride in itopride hydrochloride;
FIG. 5 is a gas chromatogram of a selective solution for detecting hydroxylamine hydrochloride in itopride hydrochloride;
FIG. 6 is a gas chromatogram of a test sample (labeled) solution for detecting hydroxylamine hydrochloride in itopride hydrochloride;
FIG. 7 is a gas chromatogram of a LOQ solution for detecting hydroxylamine hydrochloride in itopride hydrochloride;
FIG. 8 is a gas chromatogram of an LOD solution for detecting hydroxylamine hydrochloride in itopride hydrochloride;
FIG. 9 is a line graph of hydroxylamine hydrochloride in itopride hydrochloride.
Detailed Description
Example 1
(1) Experimental materials and instrumentation conditions
Experimental materials: sodium carbonate, manufacturer: guangdong Guanghua science and technology, Inc.; dichloromethane, manufacturer: tianjin Damao chemical reagent plant; cyclohexanone, manufacturer: tianjin Damao chemical reagent plant; hydroxylamine hydrochloride, manufacturer: a Mecang; itopride hydrochloride, manufacturer: zhuhairun pharmaceutical products, Inc.; ultrapure water, manufacturer: zhuhairun all pharmaceutical Co.
The instrument comprises the following steps: gas chromatograph: 7890B; electronic analytical balance XSE205DU, GR-200; a chromatographic column: HP-530 m.times.0.32 mm, 0.25 μm.
Respectively injecting the blank solution, the sensitivity solution, the reference solution and the test solution into a gas chromatograph, and recording a chromatogram, wherein the chromatogram conditions are as follows: a chromatographic column: (5% phenyl) methyl polysiloxane; column temperature: keeping the temperature at 40 ℃ for 2min, heating to 120 ℃ at 10 ℃/min, and heating to 200 ℃ at 30 ℃/min for 2 min; sample inlet temperature: 220 ℃; detector temperature: 250 ℃; sample introduction amount: 2 mul; the split ratio is as follows: 3: 1; line rate: 30 cm/sec; needle washing liquid: dichloromethane.
(2) Experimental procedure
Preparation of blank solution: taking 1.0ml of 100mg/ml Na2CO3 solution, placing the solution in a 10ml centrifuge tube, adding 30 mu l of cyclohexanone, vortexing for 5min, adding 2.0ml of dichloromethane, vortexing for 5min, standing for layering, and taking the lower organic phase for direct injection.
② hydroxylamine hydrochloride stock solution (I): weighing 45mg of hydroxylamine hydrochloride, precisely weighing, placing in a 100ml measuring flask, adding a diluent I to dissolve and dilute to a scale, and shaking uniformly to obtain a hydroxylamine hydrochloride stock solution I. (concentration: 0.45 mg/ml)
③ hydroxylamine hydrochloride stock solution: precisely measuring 1.0ml of hydroxylamine hydrochloride stock solution, placing the hydroxylamine hydrochloride stock solution into a 10ml measuring flask, adding diluent (namely, diluting to a scale), and shaking uniformly to obtain the hydroxylamine hydrochloride stock solution (namely, the hydroxylamine hydrochloride stock solution). (concentration: 45. mu.g/ml)
Preparing a sensitivity solution: measuring 1.0ml of diluent and 50 mul of hydroxylamine hydrochloride stock solution, putting the diluent and the hydroxylamine hydrochloride stock solution into a 10ml centrifuge tube together, adding 30 mul of cyclohexanone, whirling for 5min, adding 2.0ml of dichloromethane, whirling for 5min, standing for layering, and taking the lower organic phase for direct sample injection. (concentration: 1.125. mu.g/ml)
Preparing a reference substance solution: measuring 1.0ml of diluent and 100 mul of hydroxylamine hydrochloride stock solution, putting the diluent and the hydroxylamine hydrochloride stock solution into a 10ml centrifuge tube, adding 30 mul of cyclohexanone, whirling for 5min, adding 2.0ml of dichloromethane, whirling for 5min, standing for layering, and taking the lower organic phase for direct sample injection. (concentration: 2.25. mu.g/ml)
Preparing a test solution: weighing about 0.45g of itopride hydrochloride sample, precisely weighing, placing in a 10ml centrifuge tube, adding 1.0ml of diluent, vortexing for 2min, adding 1.0ml of dichloromethane, vortexing to dissolve, standing for layering, taking 1.0ml of upper-layer aqueous solution, placing in a 10ml centrifuge tube, adding 30 mu l of cyclohexanone, vortexing for 5min, adding 2.0ml of dichloromethane, vortexing for 5min, standing for layering, and taking a lower-layer organic phase for direct sample injection. (concentration: 0.225 g/ml)
Preparing selective solution: weighing about 0.45g of itopride hydrochloride sample, precisely weighing, placing in a 10ml centrifuge tube, adding 1.0ml of diluent (II) and 100 mul of hydroxylamine hydrochloride stock solution (II), vortexing for 2min, adding 1.0ml of dichloromethane, vortexing for dissolving, standing for layering, taking 1.0ml of upper layer aqueous solution, placing in a 10ml centrifuge tube, adding 30 mul of cyclohexanone, vortexing for 5min, adding 2.0ml of dichloromethane, vortexing for 5min, standing for layering, and taking a lower layer organic phase for direct sample injection. (concentration: itopride hydrochloride 0.225g/ml, hydroxylamine hydrochloride 2.25. mu.g/ml)
Preparing a test article solution (adding a label): weighing about 0.45g of itopride hydrochloride sample, precisely weighing, placing in a 10ml centrifuge tube, adding 1.0ml of diluent (II) and 100 mul of hydroxylamine hydrochloride stock solution (II), vortexing for 2min, adding 1.0ml of dichloromethane, vortexing for dissolving, standing for layering, taking 1.0ml of upper layer aqueous solution, placing in a 10ml centrifuge tube, adding 30 mul of cyclohexanone, vortexing for 5min, adding 2.0ml of dichloromethane, vortexing for 5min, standing for layering, and taking a lower layer organic phase for direct sample injection. (concentration: itopride hydrochloride 0.225g/ml, hydroxylamine hydrochloride 2.25. mu.g/ml)
Ninthly, preparing LOQ solution: according to the S/N value of hydroxylamine hydrochloride obtained from the sensitivity solution, the dilution ratio is regulated until the S/N value of hydroxylamine hydrochloride is not less than 10, and 6 parts of the solution is prepared by the same method after shaking up.
Preparation of LOD solution in R: and (3) according to the S/N value of the hydroxylamine hydrochloride obtained from the LOQ solution, adjusting the dilution ratio until the S/N value of the hydroxylamine hydrochloride is not less than 3, and shaking up to obtain the LOD solution.
After the system is stabilized, 1 needle of blank solution, 1 needle of sensitivity solution, 6 needles of contrast solution and 1 needle of test solution are added, and chromatogram is recorded. Hydroxylamine hydrochloride (ppm) = (Ru/Rs) × (Cs/Cu); wherein: ru: peak area of hydroxylamine hydrochloride in the test solution atlas; rs: average peak area of hydroxylamine hydrochloride in 6-pin control solutions; cs: concentration of hydroxylamine hydrochloride in the control solution (μ g/ml); cu: concentration of test solution (g/ml).
Example 2 detection method of the invention System suitability test
System applicability was achieved by determining the S/N value of hydroxylamine hydrochloride in the sensitivity solution and the RSD of the hydroxylamine hydrochloride peak area in the 6-pin control solution. The S/N value of hydroxylamine hydrochloride in the sensitivity solution is required to be more than or equal to 10; the RSD of the peak area of hydroxylamine hydrochloride in the 6-pin control solution should be not more than 10.0%.
Preparing blank solution, sensitivity solution and reference solution as described in example 1, and performing chromatogram by using blank solution 1 needle, sensitivity solution 1 needle and reference solution 6 needle under the chromatographic conditions described in example 1, wherein the chromatogram is shown in FIG. 1, FIG. 2 and FIG. 3, and the conversion results according to the formula are shown in the following table:
example 3 specificity test of the detection method of the invention
The specificity of the method is that the detection is not interfered by measuring a blank solution; the separation degree between the hydroxylamine hydrochloride and the adjacent peak in the selective solution and the recovery rate of the hydroxylamine hydrochloride before and after sample loading. Blank solution is required to be free from interference to detection; the separation between hydroxylamine hydrochloride and the adjacent peaks in the selective solution should be not less than 1.2; the recovery rate of the hydroxylamine hydrochloride before and after sample loading is between 80.0% and 120.0%.
Preparing blank solution, reference solution, test solution and selective solution as described in example 1, after the system is balanced, feeding blank solution 1 needle, reference solution 3 needle, test solution 1 needle and selective solution 3 needle, recording chromatogram, and obtaining specificity detection results as follows according to fig. 1, fig. 3, fig. 4 and fig. 5:
example 4 precision test of the detection method of the invention
Precision is achieved by testing 6 test solutions (spiked) for RSD. It is required that the RSD measured in 6 test sample solutions (spiked) should not be greater than 10.0%.
Blank solutions, control solutions, test solutions and test solutions (spiked) were prepared as described in example 1. After the system is balanced, 1 needle of blank solution, 1 needle of reference solution (reference solution under the condition of system applicability can be quoted), 1 needle of test solution (test solution under the condition of specificity can be quoted), and 1 needle of each of 6 parts of test solution (labeled) are entered, chromatogram is recorded, as shown in fig. 1, fig. 3, fig. 4 and fig. 6, the result obtained by conversion according to the formula is shown in the following table:
example 5 quantitation and detection limits of the detection methods of the invention
The quantitative limit and the detection limit are realized by detecting the ratio of response signals to noise, and the signal-to-noise ratio of the quantitative limit is not less than 10: 1, the signal-to-noise ratio of the detection limit is not less than 3: 1; at the quantitative limit concentration level, 6 minimal quantitative limit solutions were repeatedly examined. Request LOQHydroxylamine hydrochlorideShould be not more than 10ppm, S/N is not less than 10; RSD of the peak area of hydroxylamine hydrochloride in 6 parts of LOQ solution is not more than 10.0 percent, and LOD<LOQ，S/N≥3。
Blank solution, sensitivity solution, 6 parts LOQ solution and LOD solution were prepared as described in example 1. After the system was equilibrated, 1 pin of blank solution, 1 pin of sensitivity solution, 1 pin of 6 parts of LOQ solution, and 1 pin of LOD solution were introduced, and chromatograms were recorded as shown in fig. 1, fig. 2, fig. 7, and fig. 8. The results obtained are shown in the following table:
example 6 accuracy of the detection method of the invention
Accuracy was achieved by the recovery between the measured and theoretical concentrations of each component measured and the RSD (n = 9) for the recovery of each component. The recovery rate of hydroxylamine hydrochloride in the solution with the accuracy of each concentration point is required to be between 80.0% and 120.0%, and the RSD (n = 9) is required to be not more than 10.0%.
Example 7 solution stability of the assay method of the invention
Inspecting the rule of the sample injection after the control solution, the sample solution and the selective solution are placed at room temperature for 0hr, 6hr, 12hr and 24hr, and providing basis for the placing time of the control solution and the sample solution during detection. Comparing with 0hr, and keeping the recovery rate of hydroxylamine hydrochloride at 90.0% -110.0% within 24hr at room temperature to obtain stable solution; comparing with 0hr, and standing the sample solution at room temperature for 24hr to determine that the variation value of the measurement result is within 20% of the limit, so that the solution is stable; the recovery rate of hydroxylamine hydrochloride should be between 80.0% and 120.0% within 24hr of the selective solution at room temperature, and the solution is stable.
Claims (2)
1. A method for detecting hydroxylamine hydrochloride in itopride hydrochloride is characterized in that a gas chromatograph is adopted for detection, and the chromatographic conditions are as follows: and (3) chromatographic column: (5% phenyl) methyl polysiloxane; column temperature: keeping the temperature at 40 ℃ for 2min, heating to 120 ℃ at 10 ℃/min, and heating to 200 ℃ at 30 ℃/min for 2 min; sample inlet temperature: 220 ℃; detector temperature: 250 ℃; sample introduction amount: 2 mu l of the solution; the split ratio is as follows: 3: 1; line rate: 30 cm/sec; needle washing liquid: dichloromethane; the mobile phase is a mobile phase A-mobile phase B system, wherein the mobile phase A is 0.01mol/L potassium dihydrogen phosphate solution, and the mobile phase B is acetonitrile.
2. The method according to claim 1, wherein the chromatographic column is HP-530 m x 0.32mm, 0.25 μm or a chromatographic column with equivalent performance.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090177008A1 (en) * | 2005-12-28 | 2009-07-09 | Cadila Pharmaceuticals Ltd. | Novel process for synthesis of itopride and its novel intermediate n-(4-hydroxybenzyl)- 3,4-dimethoxybenzamide |
| CN103913537A (en) * | 2014-04-11 | 2014-07-09 | 南京工业大学 | Method for rapidly determining content of hydroxylamine hydrochloride based on gas-phase derivative chromatography |
| CN111812249A (en) * | 2020-07-24 | 2020-10-23 | 济南同路医药科技发展有限公司 | Detection method of trace hydroxylamine hydrochloride |
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2020
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| US20090177008A1 (en) * | 2005-12-28 | 2009-07-09 | Cadila Pharmaceuticals Ltd. | Novel process for synthesis of itopride and its novel intermediate n-(4-hydroxybenzyl)- 3,4-dimethoxybenzamide |
| CN103913537A (en) * | 2014-04-11 | 2014-07-09 | 南京工业大学 | Method for rapidly determining content of hydroxylamine hydrochloride based on gas-phase derivative chromatography |
| CN111812249A (en) * | 2020-07-24 | 2020-10-23 | 济南同路医药科技发展有限公司 | Detection method of trace hydroxylamine hydrochloride |
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