CN110988169B - High performance liquid chromatography analysis and detection method for formaldehyde content in ranitidine hydrochloride - Google Patents
High performance liquid chromatography analysis and detection method for formaldehyde content in ranitidine hydrochloride Download PDFInfo
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Abstract
The invention discloses a high performance liquid chromatography analysis and detection method for formaldehyde content in ranitidine hydrochloride, which takes an organic solvent and water as mobile phases and adopts gradient elution to determine the formaldehyde content; during measurement, a derivatization reagent is adopted to derivatize formaldehyde, then a test sample is prepared into a test sample derivatization solution by using a diluent, a formaldehyde solution is prepared into a formaldehyde derivatization reference solution by using a diluent, the test sample derivatization solution and the formaldehyde derivatization reference solution are directly sampled respectively, and a chromatogram is collected; calculating the formaldehyde content in ranitidine hydrochloride according to an external standard method; the method has the characteristics of simple operation, high sensitivity, quantitative determination, high accuracy and good reproducibility, and meets the process production requirements.
Description
Technical Field
The invention relates to the technical field of pharmaceutical analysis, in particular to a high performance liquid chromatography analysis and detection method for formaldehyde content in ranitidine hydrochloride.
Background
Ranitidine hydrochloride N- [2- [ [5- [ (dimethylamino) methyl ] furfuryl ] thio ] ethyl ] -N' -methyl-2-nitrovinylidenediamine monohydrochloride; ranitidinehydr ochloride; ranitidine hcl; (E) -N- {2- [ ({ 5- [ (dimethylamino) methyl ] furan-2-yl } methyl) sulfonyl ] ethyl } -N' -methyl-2-nitroethane-1, 1-diamine hyd ochloride; (E) -N- [2- ({ [5- (dimethylamino) furan-2-yl ] methyl } sulfonyl) et yl ] -N' -methyl-2-nitroethane-1, 1-diamine hydrochloride (1) is a histamine H2 receptor blocker with CAS number: 71130-06-8, molecular formula is C13H22N4O3S & HCl, molecular weight is: 350.86, the chemical structure is:
ranitidine hydrochloride is used for treating gastric ulcer, reflux esophagitis, zollinger-Ellison syndrome, chinese pharmacopoeia, united states pharmacopoeia and European pharmacopoeia.
The existing dosage forms of ranitidine hydrochloride are tablets, capsules and injections. During the production of ranitidine hydrochloride, formaldehyde solvent is used, and formaldehyde has mutagenicity to a certain extent, can induce increase of micronucleus rate, increase of apoptosis rate, change of cell cycle and cross-linking of DNA, and is harmful to body health, so that WHO has already determined that the ranitidine hydrochloride is a malformation-causing and carcinogenic substance. Therefore, the residual amount of formaldehyde in the raw material medicines needs to be strictly controlled.
At present, a plurality of related technical reports are available on the synthesis process of ranitidine hydrochloride and the preparation process thereof, related researches are also available on possible impurities, and the existing methods for measuring the content of formaldehyde also include a colorimetric method, an electrochemical method, a sensor method, a chromatography method and a fluorescence method, but no formaldehyde content detection method is available on the quality control of ranitidine hydrochloride.
Disclosure of Invention
The invention aims to: the invention aims to provide a high performance liquid chromatography analysis and detection method for the formaldehyde content in ranitidine hydrochloride, which solves the problem that the formaldehyde content of ranitidine hydrochloride cannot be detected in the prior art.
The technical scheme is as follows: the invention relates to a high performance liquid chromatography analysis and detection method for formaldehyde content in ranitidine hydrochloride, which comprises the following steps:
(1) The chromatographic conditions are as follows:
and (3) chromatographic column: a reversed phase chromatographic column using octaalkylsilane bonded silica gel or octadecylsilane bonded silica gel as a filler;
mobile phase: a: an aqueous solution; b: an organic solvent; gradient elution is adopted, and the elution conditions are as follows:
| elution time (minutes) | Aqueous solution | |
| 0 | 0～50 | 100～50 |
| A | 0～50 | 100～50 |
Wherein A is more than 10 and less than or equal to 60 minutes;
(2) Test sample derivative solution: accurately weighing 100mg of derivatization reagent into a 10ml measuring flask, adding acetonitrile to dilute to 10ml scale, and taking the diluted solution as a derivatization reagent mother solution; precisely measuring 1ml of derivatization reagent mother liquor and 100mg of a test sample, adding a diluent into a 10ml measuring flask to be diluted to 10ml scale to be used as a test sample derivatization solution;
(3) Formaldehyde derivative control solution: accurately weighing 10mg of formaldehyde into a 10ml measuring flask, adding water to dilute to 10ml scale, accurately weighing 1ml of the solution into the 10ml measuring flask, and adding water to dilute to 10ml scale to obtain formaldehyde mother liquor; precisely measuring a derivatization reagent mother solution and a formaldehyde mother solution in measuring bottles of 1ml to 10ml respectively, adding a diluent to dilute to 10ml scales, and using the diluted solution as a formaldehyde derivatization control solution;
(4) The determination method comprises the following steps: precisely measuring 10 mul of each of the sample derivative solution and the formaldehyde derivative reference solution, injecting into a liquid chromatograph, recording the chromatogram, and calculating the formaldehyde content in the ranitidine hydrochloride according to an external standard method.
Furthermore, the filler particle diameter of the chromatographic column is 3.0-5.0 μm, the chromatographic column length is 150-250 mm, and the chromatographic column diameter is 2.0-4.6 nm.
Furthermore, the chromatographic column takes octadecylsilane chemically bonded silica as a filler, the particle size is 5 mu m, the length of the chromatographic column is 250mm, and the diameter of the chromatographic column is 4.6nm.
Further, the aqueous solution and the organic solvent are eluted in a gradient manner according to the following ratio:
| elution time (minutes) | Aqueous solution | |
| 0 | 30～50 | 70～50 |
| A | 30～50 | 70～50 |
Wherein A is more than 10 and less than or equal to 60 minutes.
Further, the organic solvent is one or more of methanol, ethanol, acetonitrile, isopropanol and tetrahydrofuran.
Further, the organic solvent is acetonitrile.
Further, the ratio of acetonitrile in the diluent is: water: the volume ratio of the hydrochloric acid is 60:40:0.5 to 2.0. The selection of the diluents was as follows:
further, the ratio of acetonitrile in the diluent: water: the volume ratio of the hydrochloric acid is 60:40:1.5. the solution stability of the diluent is good at this time.
Further, the derivatization reagent is 2, 4-dinitrophenylhydrazine.
The invention also comprises a high performance liquid chromatography analysis and detection method for the formaldehyde content in ranitidine hydrochloride, which comprises the following steps:
(1) The chromatographic conditions are as follows:
a chromatograph: a reversed-phase high performance liquid chromatograph;
a detector: a DAD detector;
detection wavelength: 365nm;
and (3) chromatographic column: octadecylsilane chemically bonded silica is used as filler, the particle size is 5 μm, the length of a chromatographic column is 250mm, and the diameter of the chromatographic column is 4.6nm;
column temperature: 25 ℃;
flow rate: 1.0ml/min;
mobile phase: the mobile phase A is aqueous solution; the mobile phase B is acetonitrile; isocratic elution is adopted for 30min, and the conditions are as follows:
| elution time (minutes) | Aqueous solution | |
| 0 | 0～50 | 100～50 |
| A | 0～50 | 100～50 |
(2) Test sample derivative solution: accurately weighing 100mg of 2, 4-dinitrophenylhydrazine to a 10ml measuring flask, adding acetonitrile to dilute to 10ml of scales to be used as a 2, 4-dinitrophenylhydrazine mother solution; precisely measuring 1ml of 2, 4-dinitrophenylhydrazine mother liquor and 100mg of a test sample, adding a diluent into a 10ml measuring flask to be diluted to 10ml scales to be used as a test sample derivative solution;
(3) Formaldehyde derivatization control solution: accurately weighing 10mg of formaldehyde into a 10ml measuring flask, adding water to dilute to 10ml scale, accurately weighing 1ml of the solution into the 10ml measuring flask, and adding water to dilute to 10ml scale to obtain formaldehyde mother liquor; precisely measuring 2, 4-dinitrophenylhydrazine mother liquor and formaldehyde mother liquor in measuring bottles of 1ml to 10ml respectively, and adding a diluent to dilute to 10ml scales to serve as formaldehyde derivative reference solution;
(4) The determination method comprises the following steps: precisely measuring 10 mul of each of the sample derivative solution and the formaldehyde derivative reference solution, injecting into a liquid chromatograph, recording the chromatogram, and calculating the formaldehyde content in the ranitidine hydrochloride according to an external standard method.
The invention has the following beneficial effects:
the invention makes up the shortage of research on the aspect of measuring the content of formaldehyde in ranitidine hydrochloride by reasonable method design; the high performance liquid chromatography is used as a measuring method, the mobile phase is acetonitrile and water, the method is convenient and easy to obtain, the preparation is simple, the formaldehyde is subjected to derivatization treatment by using a derivatization reagent in advance, and gradient elution is adopted, so that the ranitidine hydrochloride and the formaldehyde can be well separated, and the tests of specificity, linearity, range, precision, durability and the like of the formaldehyde are good; a reliable and effective detection standard is established.
Drawings
FIG. 1 is a line graph of a formaldehyde derivative in example 1;
FIG. 2 is a solvent HPLC profile;
FIG. 3 is an HPLC chromatogram of a 2, 4-dinitrophenylhydrazine solution;
FIG. 4 is a formaldehyde derivative control solution HPLC profile;
FIG. 5 is an HPLC chromatogram of a sample-derived solution.
Detailed Description
The invention is further described below with reference to examples:
example 1
The method comprises the following establishing processes:
1. instruments and reagents
The instrument comprises: high performance liquid chromatograph (Shimadzu 20A), DAD detector, water chromatographic workstation
Reagent: acetonitrile, beijing lark technologies ltd, HPLC grade;
2, 4-dinitrophenylhydrazine: kreister, su;
formaldehyde: the national medicine group reagent company, analytically pure;
2. establishment of method for measuring formaldehyde content in ranitidine hydrochloride
(1) Determination of detection wavelength: according to the physicochemical properties and chemical structures of ranitidine hydrochloride and formaldehyde, 365nm is selected as an absorption wavelength under the condition of a DAD detector.
(2) Linearity and range
Formaldehyde derivatization control solution: accurately weighing 10mg of formaldehyde into a 10ml measuring flask, adding water to dilute to 10ml scale, accurately weighing 1ml of the solution into the 10ml measuring flask, and adding water to dilute to 10ml scale to obtain formaldehyde mother liquor; precisely measuring 2, 4-dinitrophenylhydrazine mother liquor and formaldehyde mother liquor in measuring bottles of 1ml to 10ml respectively, adding a diluent to dilute to 10ml scales to serve as formaldehyde derivative reference solution, then diluting the solution or directly taking 0.00005ug/ml, 0.00010ug/ml, 0.00015ug/ml, 0.00020ug/ml, 0.0198ug/ml and 14.8808ug/ml as linear measuring solutions, measuring according to a method, recording chromatograms, and indicating that when the concentration of the formaldehyde solution is in the range of 0.0198ug/ml to 14.8808ug/ml, the concentration and the peak area form a remarkable linear relation, namely a linear equation: y =3.8872x +0.0135, correlation coefficient R 2 =0.9999, the results are shown in fig. 1.
(3) Precision of sample introduction
Taking a test sample of 0.020ug/ml (which is equal to 0.0002% of the concentration of the test sample), continuously injecting a sample for 6 needles, recording a chromatogram, and recording the average value of signal-to-noise ratio (SNR) of 11.7; RSD of retention time is less than 1%, and RSD of peak area is less than 10%. The results are shown below:
the result shows that the injection precision RSD of ranitidine hydrochloride is 0.08 percent, which meets the requirement, so the injection precision is good under the chromatographic condition.
(4) Repeatability of
Taking each solution in the determination of ranitidine hydrochloride, precisely absorbing 10uL of sample injection, changing the chromatographic condition within a certain range, wherein the measured quantity RSD of a test sample is less than 78 percent, the measured quantity RSD of the sample injection test sample is less than 2 percent, and under each durability condition, the method does not influence the detection of formaldehyde and has good durability. The statistical results are as follows:
example 2
High performance liquid chromatograph: daian U3000-DAD detector
Mobile phase: phase A: water (I)
Phase B: acetonitrile
Mobile phase A: the mobile phase B is 40:60 isocratic for 30min, as follows:
| elution time (minutes) | Aqueous solution | Acetonitrile (ACN) |
| 0 | 40 | 60 |
| A | 40 | 60 |
A chromatographic column: YMC-Pack ODS-A (4.6 × 250mm, 5um)
Detection wavelength: 365nm
Flow rate: 1.0ml/min
Column temperature: 25 deg.C
Sample introduction amount: 10ul of
Solution preparation: accurately weighing 100mg of 2, 4-dinitrophenylhydrazine to a 10ml measuring flask, adding acetonitrile to dilute to 10ml of scales to be used as a 2, 4-dinitrophenylhydrazine mother solution; precisely weighing about 10mg of formaldehyde into a 10ml measuring flask, adding water to dilute to 10ml scale, precisely weighing 1ml into the 10ml measuring flask, adding water to dilute to 10ml scale, and taking the obtained product as formaldehyde mother liquor; precisely measuring 1ml of 2, 4-dinitrophenylhydrazine mother liquor and 1ml of formaldehyde mother liquor into a 10ml measuring flask, diluting a diluent to 10ml scales as a formaldehyde derivative control solution, wherein the diluent is prepared from acetonitrile: water: the volume ratio of the hydrochloric acid is 60:40:0.5, and preparing the mixed solution. Precisely measuring 1ml of 2, 4-dinitrophenylhydrazine mother liquor and 100mg of a test sample, adding a diluent into a 10ml measuring flask to dilute to 10ml of scales to be used as a test sample derivative solution, wherein the diluent is a derivative solution according to the weight ratio of acetonitrile: water: the volume ratio of the hydrochloric acid is 60:40:0.5, and preparing the mixed solution. Precisely measuring 10ul of each of the reference solution and the sample derived solution, injecting the reference solution and the sample derived solution into a liquid chromatograph, recording a chromatogram, calculating the formaldehyde content according to an external standard method, and referring to the detection results in the attached figures 2, 3, 4 and 5, wherein the attached figure 2 is a solvent HPLC (high performance liquid chromatography) spectrum, the attached figure 3 is a 2, 4-dinitrophenylhydrazine solution HPLC spectrum, the attached figure 4 is a formaldehyde derived reference solution HPLC spectrum, and the attached figure 5 is a sample derived solution HPLC spectrum, which shows that the ranitidine hydrochloride and formaldehyde impurity peak are well separated and meet the requirements. The following table shows the calculation results:
example 3
A high performance liquid chromatograph: daian U3000-DAD detector
Mobile phase: phase A: water (I)
Phase B: ethanol and isopropanol, wherein the volume ratio of ethanol to isopropanol is 1; the aqueous solution and the organic solvent are subjected to gradient elution for 60 minutes according to the following proportion:
| elution time (minutes) | Aqueous solution | Ethanol and |
| 0 | 50 | 50 |
| 60min | 30 | 70 |
And (3) chromatographic column: YMC-Pack ODS-A (2.0 x 150mm,3 um);
detection wavelength: 365nm;
flow rate: 1.0ml/min;
column temperature: 25 ℃;
sample injection amount: 10ul;
solution preparation: accurately weighing 100mg of 2, 4-dinitrophenylhydrazine to a 10ml measuring flask, adding acetonitrile to dilute to 10ml of scales to be used as a 2, 4-dinitrophenylhydrazine mother solution; precisely weighing about 10mg of formaldehyde into a 10ml measuring flask, adding water to dilute to 10ml scale, precisely weighing 1ml into the 10ml measuring flask, adding water to dilute to 10ml scale, and taking the obtained product as formaldehyde mother liquor; precisely measuring 1ml of 2, 4-dinitrophenylhydrazine mother liquor and 1ml of formaldehyde mother liquor, diluting to 10ml scales by using a diluent as a formaldehyde derivative reference solution in a 10ml measuring flask, wherein the diluent is prepared from acetonitrile: water: the volume ratio of the hydrochloric acid is 60:40:2.0 to obtain a mixed solution. Precisely measuring 1ml of 2, 4-dinitrophenylhydrazine mother liquor and 100mg of a test sample, adding a diluent into a 10ml measuring flask to be diluted to 10ml scales to serve as a test sample derivative solution, wherein the diluent is a solution prepared from acetonitrile: water: the volume ratio of the hydrochloric acid is 60:40:0.5 to prepare a mixed solution. Precisely measuring 10ul of each of the reference solution and the sample derivative solution, injecting into a liquid chromatograph, recording the chromatogram, and calculating the formaldehyde content according to an external standard method.
Example 4
A high performance liquid chromatograph: daian U3000-DAD detector
Mobile phase: phase A: water (I)
Phase B: tetrahydrofuran and methanol, wherein the tetrahydrofuran and the methanol are prepared according to a volume ratio of 1; the aqueous solution, tetrahydrofuran and methanol solution are eluted for 60 minutes according to the following proportion gradient:
| elution time (minutes) | Aqueous solution | Tetrahydrofuran and |
| 0 | 30 | 70 |
| 60min | 50 | 50 |
A chromatographic column: YMC-Pack ODS-A (4.6X 250mm,5 um);
detection wavelength: 365nm;
flow rate: 1.0ml/min;
column temperature: 25 ℃;
sample introduction amount: 10ul;
solution preparation: accurately weighing 100mg of 2, 4-dinitrophenylhydrazine to a 10ml measuring flask, adding acetonitrile to dilute to scale, and taking the solution as a mother solution of the 2, 4-dinitrophenylhydrazine; precisely weighing about 10mg of formaldehyde, diluting the formaldehyde to 10ml of scale in a 10ml measuring flask, precisely weighing 1ml of formaldehyde to 10ml of scale in a 10ml measuring flask, and diluting the formaldehyde to 10ml of scale as formaldehyde mother liquor; precisely measuring 1ml of 2, 4-dinitrophenylhydrazine mother liquor and 1ml of formaldehyde mother liquor, diluting to 10ml scales by using a diluent as a formaldehyde derivative reference solution in a 10ml measuring flask, wherein the diluent is prepared from acetonitrile: water: the volume ratio of the hydrochloric acid is 60:40:2.0 to obtain a mixed solution. Precisely measuring 1ml of 2, 4-dinitrophenylhydrazine mother liquor and 100mg of a test sample, adding a diluent into a 10ml measuring flask to dilute to 10ml of scales to be used as a test sample derivative solution, wherein the diluent is a derivative solution according to the weight ratio of acetonitrile: water: the volume ratio of the hydrochloric acid is 60:40:2.0 to obtain a mixed solution. Precisely measuring 10ul of each of the reference solution and the sample derivative solution, injecting into a liquid chromatograph, recording the chromatogram, and calculating the formaldehyde content according to an external standard method.
Example 5
A high performance liquid chromatography analysis detection method for formaldehyde content in ranitidine hydrochloride comprises the following steps:
(1) The chromatographic conditions are as follows:
chromatograph: a reversed-phase high performance liquid chromatograph;
a detector: a DAD detector with a detection wavelength of 365nm;
detection wavelength: 365nm;
a chromatographic column: octadecylsilane chemically bonded silica is used as filler, the particle size is 5 μm, the length of a chromatographic column is 250mm, and the diameter of the chromatographic column is 4.6nm;
column temperature: 25 ℃;
flow rate: 1.0ml/min;
mobile phase: mobile phase A: an aqueous solution; mobile phase B: acetonitrile; isocratic elution was used for 30min, with the isocratic gradient as follows:
| elution time (minutes) | | Acetonitrile | |
| 0 | 50 | 50 | |
| 10 | 0 | 100 | |
| 60 | 50 | 50 |
(2) Preparing solution
Test sample derivative solution: accurately weighing 100mg of 2, 4-dinitrophenylhydrazine to a 10ml measuring flask, and adding acetonitrile to dilute to 10ml of scales to obtain 2, 4-dinitrophenylhydrazine mother liquor; precisely measuring 1ml of 2, 4-dinitrophenylhydrazine mother liquor and 100mg of a test sample, adding a diluent into a 10ml measuring flask to dilute to 10ml of scales to be used as a test sample derivative solution, wherein the diluent is acetonitrile: water: the hydrochloric acid is mixed according to the volume ratio of 60:40:1.5 is prepared;
formaldehyde derivative control solution: accurately weighing 10mg of formaldehyde, diluting the formaldehyde to 10ml of scale mark in a 10ml measuring flask, accurately weighing 1ml of the solution to 10ml of scale mark, and diluting the solution to 10ml of scale mark as formaldehyde mother liquor; precisely measuring 2, 4-dinitrophenylhydrazine mother liquor and formaldehyde mother liquor in measuring bottles of 1ml to 10ml respectively, adding a diluent to be diluted to 10ml scales as formaldehyde derivative reference solution, wherein the diluent is acetonitrile: water: the volume ratio of the hydrochloric acid is 60:40:1.5 is prepared;
(3) The determination method comprises the following steps: precisely measuring 10 mu l of sample derivative solution and formaldehyde derivative reference solution, injecting into a liquid chromatograph, recording chromatogram, and calculating the formaldehyde content in ranitidine hydrochloride according to an external standard method.
The foregoing shows and describes the general principles of the present invention, its general features, and advantages. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the invention as defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (3)
1. A high performance liquid chromatography analysis and detection method for the formaldehyde content in ranitidine hydrochloride is characterized by comprising the following steps:
(1) The chromatographic conditions are as follows:
and (3) chromatographic column: the reverse phase chromatographic column takes octadecylsilane chemically bonded silica as a filler, the particle size of the filler of the chromatographic column is 3.0-5.0 mu m, the length of the chromatographic column is 150-250 mm, and the diameter of the chromatographic column is 2.0-4.6 mm;
the mobile phase is phase A: water; phase B: ethanol and isopropanol, wherein the volume ratio of ethanol to isopropanol is 1; the water and organic solvent are eluted for 60 minutes in a gradient manner according to the following proportion:
Or the mobile phase is phase A: water; phase B: tetrahydrofuran and methanol, wherein the tetrahydrofuran and the methanol are prepared according to a volume ratio of 1; the water, tetrahydrofuran and methanol solution are eluted for 60 minutes according to the following proportion gradient:
；
(2) Test sample derivative solution: accurately weighing 100mg of derivatization reagent into a 10ml measuring flask, adding acetonitrile to dilute to 10ml scale, and taking the diluted solution as a derivatization reagent mother solution; precisely measuring 1ml of derivatization reagent mother liquor and 100mg of a test sample, adding a diluent to dilute to 10ml of scales in a 10ml measuring flask to serve as a test sample derivatization solution, wherein the derivatization reagent is 2, 4-dinitrophenylhydrazine;
(3) Formaldehyde derivative control solution: accurately weighing 10mg of formaldehyde into a 10ml measuring flask, adding water to dilute to 10ml scale, accurately weighing 1ml of the solution into the 10ml measuring flask, and adding water to dilute to 10ml scale to obtain formaldehyde mother liquor; precisely measuring a derivatization reagent mother solution and a formaldehyde mother solution in measuring bottles of 1ml to 10ml respectively, adding a diluent to dilute to 10ml scales, and taking the diluted solution as a formaldehyde derivatization control solution;
(4) The determination method comprises the following steps: precisely measuring 10 mul of each of the sample derivative solution and the formaldehyde derivative reference solution, injecting into a liquid chromatograph, recording a chromatogram, and calculating the formaldehyde content in the ranitidine hydrochloride according to an external standard method;
acetonitrile in the diluent: water: the volume ratio of the hydrochloric acid is 60:40:0.5 to 2.0.
2. The high performance liquid chromatography analysis and detection method for the formaldehyde content in ranitidine hydrochloride according to claim 1, characterized in that: the chromatographic column takes octadecylsilane chemically bonded silica as a filler, the particle size is 5 mu m, the length of the chromatographic column is 250mm, and the diameter of the chromatographic column is 4.6nm.
3. The high performance liquid chromatography analysis and detection method for the formaldehyde content in ranitidine hydrochloride according to claim 1, characterized in that: acetonitrile in the diluent: water: the volume ratio of the hydrochloric acid is 60:40:1.5.
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