CN111289653B - Method for detecting 5-hydroxymethylfurfural impurity and impurity I in nicardipine hydrochloride glucose injection - Google Patents
Method for detecting 5-hydroxymethylfurfural impurity and impurity I in nicardipine hydrochloride glucose injection Download PDFInfo
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Abstract
The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for detecting 5-hydroxymethylfurfural impurities and impurities I in nicardipine hydrochloride glucose injection. The detection method adopts ion pair dual-wavelength high performance liquid chromatography for determination. The method is simple and convenient to operate, and can accurately determine related substances such as 5-hydroxymethylfurfural, impurity I and the like in the nicardipine hydrochloride glucose injection.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for detecting 5-hydroxymethylfurfural impurities and impurities I in nicardipine hydrochloride glucose injection.
Background
The nicardipine hydrochloride mainly inhibits the calcium ion inflow of the crotch membrane of cardiac muscle and vascular smooth muscle, but does not change the blood calcium concentration, the glucose injection is clinically suitable for emergency treatment of abnormal angina pectoris and hypertension in operation, and the product can obviously improve the heart and kidney functions of patients while reducing blood pressure and does not influence the heart rate.
The nicardipine hydrochloride injection is easy to decompose by visible light to generate nicardipine degradation impurities I without pharmacological activity; in addition, the glucose injection is easy to introduce toxic impurity 5-hydroxymethyl furfural from glucose raw materials. It is easily produced by dehydrating hexose (glucose, fructose, etc.) and amino acid under high temperature and acidic condition or under the action of microorganism, and can cause damage to striated muscle and viscera of human body.
Nicardipine hydrochloride glucose injection is a variety accepted by pharmacopoeia, the current national drug standard-the pharmacopoeia of the people's republic of China (hereinafter referred to as the Chinese pharmacopoeia) 2015 edition two, the research guidance principles of raw material drugs and preparation impurities (ICH Q3A, ICH Q3B) respectively formulated by the international harmonization conference (ICH) for related substance items and the technical requirement of human drug registration have larger difference, except that degradation impurity I and toxic impurity 5-methylfurfural are not controlled, the standard single impurity (degradation impurity and byproduct impurity) and the total impurity limit are respectively 2.0% and 4.0%, which are too loose for the safety of drug injection and generate larger safety risk for the drug administration of patients.
Disclosure of Invention
In order to solve the practical problem that related substances such as 5-hydroxymethylfurfural and impurity I are lack of control and detection in the existing national standard analysis method, the invention provides a method for detecting the toxic impurities related to nicardipine hydrochloride glucose injection.
The invention provides a method for detecting 5-hydroxymethyl furfural impurities, impurities I and other related substances in nicardipine hydrochloride glucose injection, which adopts ion pair dual-wavelength high performance liquid chromatography to measure, wherein the chromatographic conditions are as follows:
a chromatographic column: c18 silane bond and silica gel are used as stationary phase;
mobile phase: ion pair 3.4 g.L-1Tetrabutylammonium hydrogen sulfate solution-methanol-acetonitrile (60:30: 10); wherein tetrabutylammonium hydrogen sulfate is the ion pairing agent.
Detection wavelength: 284nm of 5-hydroxymethylfurfural, 236nm of impurity I and other related substances;
temperature of the column oven: 35 ℃;
flow rate: 1.0 mL/min-1；
Sample introduction amount: 20 μ L.
Preferably, the chromatographic column is: kromasil100-5C18 (250 mm. times.4.6 mm).
Preferably, the detection limit of the 5-hydroxymethylfurfural in the detection method is 0.002 mu g/mL-1(ii) a The detection limit of the nicardipine hydrochloride impurity I is 0.05 mu g/mL-1(ii) a The detection limit of the nicardipine hydrochloride is 0.03 mu g/mL-1。
Preferably, the limit of quantitation of 5-hydroxymethylfurfural by the detection method is 0.007. mu.g.mL-1(ii) a The limit of the quantification of the nicardipine hydrochloride impurity I is 0.15 mu g.mL-1(ii) a The limit of quantification of nicardipine hydrochloride is 0.10 mug.mL-1。
Preferably, nicardipine hydrochloride glucose injection is taken out in dark operation.
Preferably, the detection method comprises the following steps:
(1) sample preparation
Accurately weighing appropriate amounts of 5-hydroxymethylfurfural, nicardipine hydrochloride impurity I and nicardipine hydrochloride respectively into measuring bottles, and diluting to scales by using a mobile phase; precisely measuring a proper amount of the solution into a volumetric flask, and diluting the solution into a mixed reference substance stock solution by using a mobile phase;
accurately measuring appropriate amount of the mixed reference stock solution respectively, diluting to scale with mobile phase, and making into reference solutions with different mass concentrations;
carrying out operation in a dark place, and taking nicardipine hydrochloride glucose injection as a test solution;
(2) drawing of standard curve
Injecting the reference solution into a high performance liquid chromatograph, measuring corresponding peak areas, drawing a standard curve by taking the mass concentration of the reference solution as a horizontal coordinate and taking the peak areas as a vertical coordinate, and listing a mathematical equation and a linear range of the standard curve;
(3) detection of
Precisely injecting a sample solution into a high performance liquid chromatograph to obtain the chromatographic peak area of the sample;
(4) computing
Substituting the chromatographic peak area of the test sample into the standard curve to calculate the content.
The related substances of the impurity I and the like comprise degradation impurities and by-product impurities.
Compared with the prior art, the invention has the following beneficial effects:
the existing standard is too loose for the safety of the medicine injection, and generates larger safety risk for the patient to take medicine. The quality control method for simultaneously measuring the degraded impurity I and the specific impurity 5-hydroxymethylfurfural by dual wavelengths is established by an HPLC ion pair chromatography, and is simple and convenient to operate, accurate in result and capable of obtaining satisfactory results by combining impurity reference substance comparison and self control.
The method adopts the ion pair dual-wavelength high performance liquid chromatography, can simultaneously determine the impurities of related substances such as 5-hydroxymethylfurfural, nicardipine hydrochloride impurity I and the like at one time, realizes the simultaneous determination of different types of impurities, and has the advantage of simplicity and convenience.
Ion pair tetrabutylammonium hydrogen sulfate 3.4 g.L-1The tetrabutylammonium hydrogen sulfate solution-methanol-acetonitrile (60:30:10) (volume ratio) mobile phase well solves the problem that the number of theoretical pedals of the chromatography cannot be well realized under the condition of low pH value of the mobile phase in the inhibition chromatography of the hydrochloride medicaments, and greatly improves the column efficiency and the loading capacity of a sample injection column.
The invention adopts an ion pair chromatography, and the tetrabutylammonium sulfate solution-methanol-acetonitrile (60:30:10) mobile phase overcomes the harsh condition that the inhibition chromatography needs lower pH value for hydrochloride drugs, and simultaneously, the tetrabutylammonium sulfate is different from the general ion pair of sodium heptanesulfonate, is convenient to clean, can be well mixed with polar or organic solvents such as water, methanol, acetonitrile and the like, and greatly prolongs the service life of a chromatographic column.
The invention can correct the shortage of national standard, and can play the roles of improving the standard and promoting the national standard to be improved.
The invention relates to fund items, which are as follows: the social scientific development fund funding project in Shaanxi province (number: 2018 SF-100).
Drawings
FIG. 1 is a high performance liquid chromatography analysis profile of a control solution at 236 nm.
FIG. 2 is a high performance liquid chromatography chromatogram of a control solution at 284 nm.
FIG. 3 is a high performance liquid chromatography analysis profile of a blank solution at 236 nm.
FIG. 4 is a high performance liquid chromatography chromatogram of a blank solution at 284 nm.
FIG. 5 is a high performance liquid chromatography chromatogram of the test solution at 236 nm.
FIG. 6 is a high performance liquid chromatography chromatogram of the test solution at 284 nm.
FIG. 7 is a high performance liquid chromatography analysis chart of a test solution measured according to the method of pharmacopoeia of the 2015 edition.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the embodiments of the present invention are not limited thereto. The examples of the present invention are given for illustrative purposes only and are not intended to limit the present invention.
The detection method is a standard curve method specified by pharmacopoeia, and the following experimental processes and experimental methods are not described in detail and all adopt standard operation procedures, such as operation methods of solution preparation and systematic adaptability test.
The instrument comprises the following steps:
high performance liquid chromatograph: agilent 1260 high performance liquid chromatograph; a DAD diode array detector; mettler AE240 electronic analytical balance (mettler-toledo instruments ltd, switzerland).
Reagent testing:
nicardipine hydrochloride glucose injection (A pharmaceutical company, Inc. A121, A131 and A141), nicardipine hydrochloride (00586-; methanol (chromatographically pure TEDIA); the water is high-purity water; tetrabutylammonium hydrogen sulfate (chromatographically pure); the tested injection is provided by each manufacturer.
The chromatographic conditions (using ion pair dual wavelength high performance liquid chromatography) were as follows:
a chromatographic column: kromasil100-5C18 (250 mm. times.4.6 mm);
mobile phase: 0.34% tetrabutylammonium hydrogen sulfate solution-methanol-acetonitrile (60:30:10) (volume ratio);
detection wavelength: 284nm of 5-hydroxymethylfurfural, 236nm of impurity I and other related substances;
temperature of the column oven: 35 ℃;
flow rate: 1.0 mL/min-1。
Sample introduction amount: 20 μ L
Example 1:
(1) sample preparation
Precisely weighing about 20mg of 5-hydroxymethylfurfural, nicardipine hydrochloride impurity I and nicardipine hydrochloride respectively to 100mL measuring bottles, and diluting to scales by using a mobile phase; precisely measuring into 5-20 mL volumetric flasks, and diluting with mobile phase to obtain stock solutions (each having a mass concentration of about 50 μ g/mL)-1)；
Accurately weighing appropriate amount of the above stock solution, diluting with mobile phase to scale to obtain solutions with mass concentrations of 0.1, 0.5, 1.0, 5.0, 10 and 20 μ g/mL-1As a control solution;
carrying out operation in a dark place, and taking nicardipine hydrochloride glucose injection as a test solution;
(2) drawing of standard curve
Injecting the reference solution into a high performance liquid chromatograph, measuring corresponding peak areas, drawing a standard curve by taking the concentration of the reference solution as a horizontal coordinate and the peak area as a vertical coordinate, and listing a mathematical equation and a linear range of the standard curve;
(3) detection of
Precisely injecting 20 μ l of sample, and injecting into high performance liquid chromatograph to obtain chromatographic peak area of the sample;
(4) computing
Substituting the chromatographic peak area of the test sample into the standard curve to calculate the content.
The chromatograms obtained are shown in FIGS. 1-7. FIG. 1 is a high performance liquid chromatography analysis profile of a control solution at 236 nm. FIG. 2 is a high performance liquid chromatography chromatogram of a control solution at 284 nm. FIG. 3 is a high performance liquid chromatography analysis profile of a blank solution at 236 nm. FIG. 4 is a high performance liquid chromatography chromatogram of a blank solution at 284 nm. FIG. 5 is a high performance liquid chromatography chromatogram of the test solution at 236 nm. FIG. 6 is a high performance liquid chromatography chromatogram of the test solution at 284 nm. FIG. 7 is a high performance liquid chromatography analysis chart of a test solution measured according to the method of pharmacopoeia of the 2015 edition.
By comparing chromatograms, impurities were determined: according to the detection maps of related substances such as the nicardipine hydrochloride glucose injection 5-hydroxymethyl furfural, the nicardipine hydrochloride impurity I and the like, the reference peak impurities are respectively 5-hydroxymethyl furfural and the nicardipine hydrochloride impurity I.
The results of the content measurement are shown in Table 1.
TABLE 1 measurement results Table
As can be seen from Table 1, in the detection system, two toxic impurities can be effectively detected, and the detection sensitivity of 5-hydroxymethylfurfural can reach 0.002 mu g/mL-1And the nicardipine hydrochloride impurity I can reach 0.05 mu g/mL-1。
Example 2 methodological examination
The detection method of 5-methylfurfural and nicardipine hydrochloride impurity I in the nicardipine hydrochloride glucose injection is examined by methodologies such as specificity, linearity, precision, repeatability, accuracy, stability, detection limit and quantitative limit. The specific investigation method comprises the following steps:
(1) investigation of linear relationships
Accurately weighing about 20mg of 5-hydroxymethylfurfural, nicardipine hydrochloride impurity I and nicardipine hydrochloride respectively into 100mL measuring bottles, and diluting to the scale by using a mobile phase. Precisely measuring into 5-20 mL volumetric flasks, and diluting with mobile phase to obtain stock solutions (each having a mass concentration of about 50 μ g/mL)-1)。
Accurately weighing appropriate amount of the above stock solution, diluting with mobile phase to scale to obtain solutions with mass concentrations of 0.1, 0.5, 1.0, 5.0, 10 and 20 μ g/mL-1As a control linear solution.
The measurement was carried out under the chromatographic conditions as in example 1, and a linear regression was carried out with the mass concentration as abscissa (X) and the peak area as ordinate (Y). The results of the linear investigation of 5-hydroxymethylfurfural, nicardipine hydrochloride impurity i and nicardipine hydrochloride are shown in table 2:
TABLE 2 Linear survey table
As can be seen from table 2: the linear ranges are: 0.1 to 20. mu.g/mL-1. 5-hydroxymethylfurfural, nicardipine hydrochloride impurity I and nicardipine hydrochloride are in good linear relation in a linear range.
(2) Detection limit and quantification limit
Taking a reference substance solution, diluting the reference substance solution to an appropriate mass concentration by using a mobile phase, wherein the sampling amount at the signal-to-noise ratio of 10:1 is taken as a quantification limit, and the sampling amount at the signal-to-noise ratio of 3:1 is taken as a detection limit.
As a result: under the chromatographic conditions, when the sample injection volume is 20 mu L, the detection limit of the 5-hydroxymethylfurfural is 0.002 mu g/mL-1The limit of quantitation is 0.007. mu.g/mL-1(ii) a The detection limit of the nicardipine hydrochloride impurity I is 0.05 mu g/mL-1The limit of quantitation is 0.15. mu.g/mL-1(ii) a The limit of detection of the nicardipine hydrochloride is 0.03 mu g/mL-1The limit of quantitation is 0.10. mu.g/mL-1。
(3) Precision degree
Taking the mass concentrations of 0.5, 1.0 and 5.0 mu g/mL under linear experimental items-1The sample was injected 3 times under the above chromatographic conditions, and the RSD value was calculated by recording the peak area, with the sample amount being 20. mu.L.
As a result: RSD values of 5-hydroxymethylfurfural, nicardipine hydrochloride impurity i and nicardipine hydrochloride were 0.19%, 0.73% and 0.26%, respectively (n ═ 6). Indicating that the precision of the instrument is good.
(4) Repeatability of
Taking the mass concentration of 1.0 mu g/mL under a linear experimental item-1The sample injection is repeated for 6 times in the dark.
As a result: RSD values of 5-hydroxymethylfurfural, nicardipine hydrochloride impurity i and nicardipine hydrochloride were 0.24%, 0.56% and 0.72%, respectively (n ═ 6).
(5) Stability of
Taking the mass concentration of 1.0 mu g/mL under a linear experimental item-1The control solution is injected and measured under the chromatographic conditions for 0, 2, 6, 8, 12 and 24 hours in a dark place.
As a result: RSD values of 5-hydroxymethylfurfural, nicardipine hydrochloride impurity i and nicardipine hydrochloride were 0.16%, 0.88% and 0.52%, respectively (n ═ 9). Shows that the 5-hydroxymethylfurfural, the impurities I of the nicardipine hydrochloride and the nicardipine hydrochloride are stable within 24 hours under the condition of keeping out of the sun.
(6) Sample addition recovery experiment
Taking 9 parts of a 10% glucose solution sample (batch A145) with known 5-hydroxyfurfural content, adding 5-hydroxyfurfural, nicardipine hydrochloride impurity I and nicardipine hydrochloride into 3 parts of the sample at a concentration level to make the concentrations of the sample about 1.0, 5.0 and 10 mu g/mL-1The recovery was calculated as determined by the method described above for the chromatographic conditions, and the results are shown in Table 3.
TABLE 3 sample addition recovery test results table
(7) Specificity experiments
The control solutions were taken in linear relationship and measured under the chromatographic conditions described above. The result shows that the impurity I of the nicardipine hydrochloride and the nicardipine hydrochloride can be effectively separated (the separation degree is 4.0); the peak separation degree of the 5-hydroxymethylfurfural and the blank solvent meets the requirement. The chromatograms are shown in FIGS. 1-6.
ICH guide principle the impurity control guide principle (Q3A) and the impurity research guide principle of the appendix of the 'Chinese pharmacopoeia' 2015 edition both require that the drug should carry out limited control on degraded impurities and special toxic impurities (0.1%). China is officially brought into member countries by the international harmonization Institute (ICH) required by the registration technology of human drugs in 2017 in 6 months, and needs to be improved in drug research and development, quality standard improvement and drug safety guarantee so as to meet the requirement of international competition as soon as possible. The problems of the standard and degradation impurities of the nicardipine hydrochloride glucose injection in the second part of the 'traditional Chinese pharmacopoeia' 2015 edition, the control loss of the pentamethyl furfural, the over-high total amount of the impurities and the like are also highly regarded, and the actual content of the impurities I is nearly doubled by measuring the impurities I according to the original impurity measurement method, so that the inventor researches and prepares a nicardipine hydrochloride impurity I reference substance in the earlier stage and revises the impurity limit of the national standard raw material medicine, so that the national standard principle of the nicardipine hydrochloride glucose injection is timely revised, the medicine safety of patients is ensured, and the product quality of enterprises is improved.
Inhibition chromatography (pH value is not specified) in the second part of the 'Chinese pharmacopoeia' 2015 edition which adopts phosphate buffer as a mobile phase is not suitable for nicardipine hydrochloride (strong acid and weak alkaline drugs), on one hand, low pH value greatly contributes to the column efficiency of inhibition chromatography, but also can greatly influence the retention behavior of chromatography and the service life of a chromatographic column, and meanwhile, the changed pH can cause the change of the peak appearance sequence of an impurity chromatographic peak and a main component peak. The dual-wavelength method of tetrabutylammonium hydrogen sulfate ion pair can simply and simultaneously measure related substances such as 5-hydroxyfurfural, degraded impurities I and the like, greatly improve the column efficiency of the chromatographic column, increase the separation degree of the degraded impurities I and the main component peak, and greatly improve the applicability of the system; meanwhile, the ion pair reagent can be mixed with a high-proportion organic phase for gradient elution, the phenomenon of blockage which damages the service life of a chromatographic column can not occur, and the ion pair reagent has unique advantages compared with a phosphate buffer solution system.
Dihydropyridine drugs are easy to generate degradation impurities when exposed to light, the injection needs to pay more attention to the problem, the nicardipine hydrochloride glucose injection sold on the market adopts transparent packaging materials, the degradation impurities are difficult to avoid in the processes of production, transportation, storage and use, and meanwhile, the method for determining the related substances of the variety in the 'Chinese pharmacopoeia' 2015 edition two parts adopts a main component self-contrast method[20]For the impurity I of nicardipine hydrochloride, the actual result is about twice as low, so the variety detection method in Chinese pharmacopoeia should be revised as soon as possible.
The invention can correct the shortage of national standard, and can play the roles of improving the standard and promoting the national standard to be improved.
Based on the above description of the summary of the invention, a person skilled in the art can apply the invention in its entirety, and all changes that are the same principle or similar are to be considered as included in the scope of the invention.
Claims (7)
1. A detection method of 5-hydroxymethyl furfural impurities and impurities I in nicardipine hydrochloride glucose injection is characterized in that ion pair dual-wavelength high performance liquid chromatography is adopted for determination, and the chromatographic conditions are as follows:
a chromatographic column: c18 silane bonded silica gel is used as a stationary phase;
mobile phase: ion pair 3.4 g.L-1Tetrabutylammonium hydrogen sulfate solution-methanol-acetonitrile with the volume ratio of 60:30: 10;
detection wavelength: 284nm and 236 nm;
temperature of the column oven: 35 ℃;
flow rate: 1.0 mL/min-1；
Sample introduction amount: 20 μ L.
2. The detection method according to claim 1, wherein the chromatographic column is: kromasil100-5C18, specification 250mm x 4.6 mm.
3. The detection method of claim 1The method is characterized in that the detection limit of the 5-hydroxymethylfurfural in the detection method is 0.002 mu g/mL-1(ii) a The detection limit of the nicardipine hydrochloride impurity I is 0.05 mu g/mL-1(ii) a The detection limit of the nicardipine hydrochloride is 0.03 mu g/mL-1。
4. The detection method according to claim 1, wherein the limit of quantitation of 5-hydroxymethylfurfural in the detection method is 0.007 μ g-mL-1(ii) a The limit of the quantification of the nicardipine hydrochloride impurity I is 0.15 mu g.mL-1(ii) a The limit of quantification of nicardipine hydrochloride is 0.10 mug.mL-1。
5. The detection method according to claim 1, wherein the nicardipine hydrochloride glucose injection is collected by being protected from light.
6. The detection method according to claim 1, characterized by comprising the steps of:
(1) sample preparation
Accurately weighing appropriate amounts of 5-hydroxymethylfurfural, nicardipine hydrochloride impurity I and nicardipine hydrochloride respectively into measuring bottles, and diluting to scales by using a mobile phase; precisely measuring a proper amount of the solution into a volumetric flask, and diluting the solution into a mixed reference substance stock solution by using a mobile phase;
accurately measuring appropriate amount of the mixed reference stock solution respectively, diluting to scale with mobile phase, and making into reference solutions with different mass concentrations;
carrying out operation in a dark place, and taking nicardipine hydrochloride glucose injection as a test solution;
(2) drawing of standard curve
Injecting the reference solution into a high performance liquid chromatograph, measuring corresponding peak areas, drawing a standard curve by taking the mass concentration of the reference solution as a horizontal coordinate and taking the peak areas as a vertical coordinate, and listing a mathematical equation and a linear range of the standard curve;
(3) detection of
Precisely injecting a sample solution into a high performance liquid chromatograph to obtain the chromatographic peak area of the sample;
(4) computing
Substituting the chromatographic peak area of the test sample into the standard curve to calculate the content.
7. The detection method according to claim 1, wherein the measurement wavelength of 5-hydroxymethylfurfural is 284 nm; the measurement wavelength of the impurity I is 236 nm.
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| CN102397245A (en) * | 2011-11-05 | 2012-04-04 | 辽宁海神联盛制药有限公司 | Nicardipine hydrochloride glucose injection |
| CN104280473A (en) * | 2014-10-23 | 2015-01-14 | 江苏正大丰海制药有限公司 | Analysis method of 5-hydroxymethylfurfural in linezolid injection |
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