CN115980210A - Method for determining sodium stearyl fumarate in oseltamivir phosphate pharmaceutical composition - Google Patents
Method for determining sodium stearyl fumarate in oseltamivir phosphate pharmaceutical composition Download PDFInfo
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Abstract
The invention discloses a method for determining sodium stearyl fumarate in an oseltamivir phosphate pharmaceutical composition, which comprises the following steps: adding methanol into a test sample to prepare a test sample solution, and injecting the test sample solution into a high performance liquid chromatograph for detection to obtain a chromatogram; the chromatographic conditions of the detection comprise that a mobile phase A and a mobile phase B are used for preparing the mobile phase, wherein the mobile phase A is selected from an aqueous solution containing a modifying agent, and the mobile phase B is an acetonitrile solution. The invention belongs to the technical field of pharmaceutical analysis, and provides a method for determining sodium stearyl fumarate in an oseltamivir phosphate pharmaceutical composition with strong specificity, which can accurately determine the content of the sodium stearyl fumarate in the oseltamivir phosphate pharmaceutical composition.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for determining sodium stearyl fumarate in an oseltamivir phosphate pharmaceutical composition.
Background
Sodium stearyl fumarate (Sodium stearyl fumarate) is an agglomerate of flattened spherical particles obtained by reacting stearyl alcohol with maleic anhydride, isomerizing the reaction product and then forming the salt, again the Sodium salt of stearyl (E) to butenedioate, as a white or off-white powder. Sodium stearyl fumarate is a hydrophilic lubricant, is used as a lubricant in pharmaceutical adjuvants, and can overcome many problems related to magnesium stearate, such as influence and excessive lubrication of main drug. Sodium stearyl fumarate can form protective film in effervescent tablet, and has effects of improving disintegration, promoting dissolution, and increasing bioavailability.
According to the regulations in the four pharmaceutical excipients of the Chinese pharmacopoeia, the content determination method of sodium stearyl fumarate is a potentiometric titration method, but the potentiometric titration method has high requirements on the precision of instruments, the equipment investment cost is higher, and the accuracy of titration results is influenced by whether the concentration of a standard titration solution is accurate or not. Patent CN113267584A discloses an HPLC-related substance analysis method for pharmaceutical substances, raw materials for preparing the pharmaceutical substances include active substances with pyridine substituent and sodium stearyl fumarate, and the technical scheme of the patent has obvious disadvantages, and is poor in specificity for determining the content of sodium stearyl fumarate in pharmaceutical compositions.
The oseltamivir phosphate pharmaceutical composition comprises oseltamivir phosphate and sodium stearyl fumarate, is a solid preparation, and is disintegrated and released after oral administration. The addition of sodium stearyl fumarate ensures better flowability of the formulation intermediate powder during processing, but affects the release of the drug. In the development process, the most appropriate addition amount of the sodium stearyl fumarate can be obtained by accurately measuring the content of the sodium stearyl fumarate in a product and the dissolution and release of a medicament. Therefore, it is necessary to establish a method for determining sodium stearyl fumarate in an oseltamivir phosphate pharmaceutical composition with strong specificity, and provide a basis for determining the optimal addition amount of sodium stearyl fumarate in the pharmaceutical composition, so as to ensure that the pharmaceutical composition has the optimal physicochemical properties and the optimal bioavailability and clinical efficacy.
Disclosure of Invention
Therefore, the invention aims to solve the problem of poor specificity of a method for determining the content of sodium stearyl fumarate in an oseltamivir phosphate pharmaceutical composition in the prior art, provides a method for determining sodium stearyl fumarate in an oseltamivir phosphate pharmaceutical composition with strong specificity, and can accurately determine the sodium stearyl fumarate in the oseltamivir phosphate pharmaceutical composition.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a method for determining sodium stearyl fumarate in an oseltamivir phosphate pharmaceutical composition is characterized by comprising the steps of adding methanol into a sample to prepare a sample solution, and injecting the sample solution into a high performance liquid chromatograph for detection to obtain a chromatogram.
Preferably, the preparation of the test solution comprises adding methanol to the test and sonicating to prepare the test solution.
Further preferably, the test solution is prepared by: precisely weighing a proper amount of contents (about 5mg equivalent to sodium stearyl fumarate), putting the contents into a 100mL measuring flask, adding 80mL of methanol, carrying out ultrasonic treatment for 20-30 minutes, taking out the contents, cooling the contents, adding methanol to dilute the contents to a scale, shaking the contents uniformly, filtering the mixture, and taking out a subsequent filtrate.
Most preferably, the preparation of the test article solution: precisely weighing a proper amount of contents (about 5mg equivalent to sodium stearyl fumarate), putting the contents into a 100mL measuring flask, adding 80mL of methanol, carrying out ultrasonic treatment for 20 minutes, taking out the contents, cooling the contents, adding methanol to dilute the contents to a scale, shaking the contents uniformly, filtering the mixture, and taking out a subsequent filtrate.
Preferably, the chromatographic conditions detected by the high performance liquid chromatograph comprise that a mobile phase is prepared from a mobile phase A and a mobile phase B, wherein the mobile phase A is selected from an aqueous solution containing a modifying agent, and the mobile phase B is an acetonitrile solution.
Preferably, the modifier is selected from at least one or more of phosphoric acid, phosphate, and perfluoro-substituted linear organic acid.
Preferably, the modifier is selected from phosphoric acid, trifluoroacetic acid.
More preferably, the mobile phase a is a 0.1% phosphoric acid solution.
Preferably, the chromatographic conditions detected by the high performance liquid chromatograph include elution with the mobile phase in an isocratic elution manner.
Preferably, the ratio of isocratic elution of mobile phase a to mobile phase B is 10: 90-14: 86.
preferably, the ratio of isocratic elution of mobile phase a to mobile phase B is 12:88.
preferably, the determination method further comprises the steps of preparing a reference substance solution by using sodium stearyl fumarate and injecting the reference substance solution into a high performance liquid chromatograph for detection to obtain a reference substance map.
Further preferably, the control solution is prepared by weighing an appropriate amount of sodium stearyl fumarate, dissolving in methanol, and diluting to give a solution containing about 50 μ g of sodium stearyl fumarate per 1 mL.
Preferably, the chromatographic conditions further comprise the adoption of an octadecylsilane chemically bonded silica chromatographic column, wherein the column temperature is 28-32 ℃, the flow rate is 0.8-1.2 mL/min, and the wavelength is 210nm.
More preferably, the chromatographic conditions are: octadecylsilane chemically bonded silica was used as a filler (XBridge C1850 × 4.6mm,3.5 μm or equivalent performance column), column temperature: 30 ℃, detection wavelength: 210nm, flow rate 1.0mL/min, mobile phase: 0.1% phosphoric acid solution to acetonitrile solution (12: 5 μ L.
Preferably, the determination method detects that sodium stearyl fumarate has a good linear relation in the concentration range of 23.77 mu g/mL-72.32 mu g/mL.
The method for determining the sodium stearyl fumarate in the oseltamivir phosphate pharmaceutical composition provided by the invention effectively avoids the influence of water-soluble auxiliary materials on the detection of the sodium stearyl fumarate, has strong specificity, accurate detection and good durability, adopts methanol to prepare a test solution, completely extracts the sodium stearyl fumarate, has relatively high content of detected components, relatively good separation effect of each characteristic peak, good peak shape, stable baseline and less extracted impurities. Meanwhile, through ultrasonic extraction, the ultrasonic time of the test sample is 20-30 min, preferably 20min, the operation is simple and convenient, and the time is saved.
The method for determining sodium stearyl fumarate in the oseltamivir phosphate pharmaceutical composition further optimizes chromatographic conditions, including optimization of a mobile phase and optimization of the pH of the mobile phase, preferably uses a 0.1% phosphoric acid solution, more preferably uses a 0.1% phosphoric acid solution: acetonitrile solution 12:88, the elution has better peak shape when the elution is carried out at equal ratio, and can be analyzed and quantified; other peaks are well separated from the main peak; buffer salt is not used, so that the influence on an experimental result caused by the separation of the buffer salt during mixing can be avoided; the sodium stearyl fumarate can be comprehensively, clearly and effectively measured.
The method for determining the sodium stearyl fumarate in the oseltamivir phosphate pharmaceutical composition provided by the invention can effectively improve the peak shape and improve the chromatographic peak separation degree, has good linearity, good repeatability, high accuracy, high analysis rate and strong specificity in the range, and can accurately determine the content of the sodium stearyl fumarate in the oseltamivir phosphate pharmaceutical composition.
Drawings
FIG. 1 is a HPLC detection profile of example 1;
FIG. 2 is a HPLC detection profile of method 1 of example 2;
FIG. 3 is a HPLC detection profile of method 2 of example 2;
FIG. 4 is a HPLC detection profile of method 3 of example 2;
FIG. 5 is an HPLC detection profile of chromatographic condition 1 of example 3;
FIG. 6 is an HPLC detection profile of chromatographic condition 2 of example 3;
FIG. 7 is an HPLC detection profile of chromatographic condition 3 of example 3;
FIG. 8 is an HPLC detection profile of chromatographic condition 4 of example 3;
FIG. 9 is an HPLC detection profile of chromatographic condition 5 of example 3;
FIG. 10 is a linear HPLC detection profile of example 4.5.
Detailed Description
To make the objects, technical solutions and advantages of the present disclosure more apparent, the present disclosure is further described in detail below with reference to specific embodiments. Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or instruments used are conventional reagent products which are commercially available, and manufacturers are not indicated.
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EXAMPLE 1 determination of sodium stearyl fumarate in pharmaceutical composition
Preparation of a test solution: precisely weighing 20 oseltamivir phosphate capsules of 211101 batches, pouring out the contents, wiping the capsule shells with a small brush or other suitable tools, precisely weighing the capsule shells respectively, calculating the average filling amount, uniformly mixing, precisely weighing an appropriate amount of the contents (about 5mg of sodium stearyl fumarate), putting the contents into a 100mL measuring flask, adding 80mL of methanol, performing ultrasonic treatment for 20 minutes, taking out the contents, cooling the mixture, adding the methanol to dilute the mixture to a scale, shaking the mixture uniformly, filtering the mixture, and taking the subsequent filtrate.
Preparation of control solutions: precisely weighing a proper amount of sodium stearyl fumarate, adding methanol for dissolving, and quantitatively diluting to obtain a solution containing about 50 μ g of sodium stearyl fumarate per 1 mL.
Chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica was used as a filler (XBridge C1850 × 4.6mm,3.5 μm or equivalent performance column), column temperature: 30 ℃, detection wavelength: 210nm, flow rate 1.0mL/min, mobile phase: 0.1% phosphoric acid solution to acetonitrile solution (12: 5 μ L.
The determination method comprises the following steps: the results of high performance liquid chromatography analysis under the above-mentioned chromatographic conditions are shown in FIG. 1 and Table 1.
TABLE 1
The retention time of the main peak is 7min, the other peaks are well separated from the main peak, the separation degree of sodium stearyl fumarate and other impurities is 25.9, and the number of theoretical plates is 7016 calculated according to the sodium stearyl fumarate peak;
example 2
Preparation of a test solution:
the method comprises the following steps: 211101 batches of oseltamivir phosphate capsules are taken, the weight is precisely weighed, the contents are poured out, the capsule shells are wiped clean by a small brush or other suitable tools, the weight of the capsule shells is precisely weighed respectively, the average filling amount is calculated, the mixture is uniformly mixed, a proper amount of the contents (about 5mg of sodium stearyl fumarate) is precisely weighed, the mixture is placed into a 100mL measuring flask, 80mL of methanol is added, ultrasonic treatment is carried out for 20 minutes, the mixture is taken out and cooled, methanol is added to be diluted to a scale, the mixture is shaken uniformly and filtered, and the subsequent filtrate is taken.
The method 2 comprises the following steps: weighing 20 oseltamivir phosphate capsules of 200901 batches, precisely weighing, pouring out contents, wiping the capsule shells with a small brush or other suitable tools, precisely weighing the capsule shells respectively, calculating the average loading, uniformly mixing, precisely weighing a proper amount of the contents (about 5mg of sodium stearyl fumarate), putting the contents into a 100mL measuring flask, adding 80mL of 50% methanol aqueous solution, carrying out ultrasonic treatment for 20 minutes, taking out, cooling, adding 50% methanol aqueous solution for diluting to a scale, shaking uniformly, filtering, and taking a subsequent filtrate.
The method 3 comprises the following steps: taking 20 oseltamivir phosphate capsules of 200901 batches, precisely weighing, pouring out contents, wiping the capsule shells with a small brush or other suitable tools, precisely weighing the capsule shells respectively, calculating the average loading amount, uniformly mixing, precisely weighing a proper amount of the contents (about 5mg of sodium stearyl fumarate), putting the contents into a 100mL measuring flask, adding 80mL of acetonitrile, performing ultrasonic treatment for 20 minutes, taking out, cooling, adding the acetonitrile to dilute to a scale, shaking uniformly, filtering, and taking a subsequent filtrate.
Chromatographic conditions and system applicability test: the chromatographic parameters include octadecylsilane chemically bonded silica as a filler (XBridge C1850 × 4.6mm,3.5 μm or equivalent performance column), column temperature: 30 ℃, detection wavelength: 210nm, flow rate 1.0mL/min, mobile phase: 0.1% phosphoric acid solution to acetonitrile solution (12: 5 μ L.
The determination method comprises the following steps: and (3) carrying out high performance liquid chromatography analysis on the test solution prepared by the three methods according to the chromatographic conditions. The results of the detection are shown in FIGS. 2 to 4 and Table 2.
TABLE 2
And (3) displaying a detection result: the retention time of the main peak in method 1 was 6.851min, the other peaks were well separated from the main peak, the degree of separation of sodium stearyl fumarate from other impurities was 25.9, and the number of theoretical plates was 6906 in terms of the sodium stearyl fumarate peak. In the method 2, the retention time of the main peak is 4.034min, other peaks are well separated from the main peak, the separation degree of sodium stearyl fumarate from other impurities is 17.0, the theoretical plate number is 5598 in terms of the sodium stearyl fumarate peak, but the sodium stearyl fumarate can obviously not be completely extracted. In method 3, the retention time of the main peak is 4.001min, other peaks are well separated from the main peak, the separation degree of sodium stearyl fumarate from other impurities is 23.9, the theoretical plate number is 5665 in terms of the sodium stearyl fumarate peak, but the baseline fluctuation is large.
Example 3
Preparation of a test solution: taking 200901 batches of oseltamivir phosphate capsules, precisely weighing the capsules, pouring out contents, wiping the capsule shells clean by a small brush or other suitable tools, precisely weighing the capsule shells respectively, calculating the average filling amount, uniformly mixing, precisely weighing a proper amount of the contents (about 5mg of sodium stearyl fumarate), putting the contents into a 100mL measuring flask, adding 80mL of methanol, performing ultrasonic treatment for 20 minutes, taking out the contents, cooling the contents, adding the methanol to dilute the contents to a scale, shaking the mixture uniformly, filtering the mixture, and taking a subsequent filtrate.
Chromatographic conditions and system applicability test:
chromatographic conditions 1: the chromatographic parameters include octadecylsilane chemically bonded silica as a filler (XBridge C1850 × 4.6mm,3.5 μm or equivalent performance column), column temperature: 30 ℃, detection wavelength: 210nm, flow rate 1.0mL/min, mobile phase: 0.1% phosphoric acid solution to acetonitrile solution (12: 5 μ L.
Chromatographic conditions 2: the chromatographic parameters include octadecylsilane chemically bonded silica as a filler (XBridge C1850 × 4.6mm,3.5 μm or equivalent performance column), column temperature: 30 ℃, detection wavelength: 210nm, flow rate 1.0mL/min, mobile phase: 0.1% trifluoroacetic acid solution to acetonitrile solution (12: 5 μ L.
Chromatographic conditions 3: chromatographic parameters include octadecylsilane bonded silica gel as a filler (XBridge C1850 × 4.6mm,3.5 μm or equivalent performance column), column temperature: 30 ℃, detection wavelength: 210nm, flow rate 1.0mL/min, mobile phase: 10mmol potassium dihydrogen phosphate (pH = 2.0) solution — acetonitrile solution (12: 5 μ L.
Chromatographic conditions 4: the chromatographic parameters include octadecylsilane chemically bonded silica as a filler (XBridge C1850 × 4.6mm,3.5 μm or equivalent performance column), column temperature: 30 ℃, detection wavelength: 210nm, flow rate 1.0mL/min, mobile phase: 5mmol potassium dihydrogen phosphate (pH = 4.5) solution — acetonitrile solution (12: 5 μ L.
Chromatographic conditions 5: the chromatographic parameters include octadecylsilane chemically bonded silica as a filler (XBridge C1850 × 4.6mm,3.5 μm or equivalent performance column), column temperature: 30 ℃, detection wavelength: 210nm, flow rate 1.0mL/min, mobile phase: 5mmol potassium dihydrogen phosphate (pH = 7.5) solution — acetonitrile solution (12: 5 μ L.
The determination method comprises the following steps: the prepared test solution is subjected to high performance liquid chromatography analysis according to the 5 chromatographic conditions. The detection results are shown in fig. 5 to 9 and table 3.
TABLE 3
And (3) displaying a detection result:
in chromatographic condition 1, the retention time of the main peak is 6.851min, other peaks are well separated from the main peak, the separation degree of sodium stearyl fumarate from other impurities is 25.9, and the number of theoretical plates is 6906 in terms of the sodium stearyl fumarate peak.
Chromatographic conditions 2: performing high performance liquid chromatography analysis according to the above chromatographic conditions, wherein the retention time of the main peak is 4.051min, other peaks are well separated from the main peak, the separation degree of sodium stearyl fumarate and other impurities is 8.7, and the number of theoretical plates is 5389 according to the peak of sodium stearyl fumarate.
Chromatographic conditions 3: high performance liquid chromatography analysis was performed according to the above chromatographic conditions, and as a result, the retention time of the main peak was 3.945min, the other peaks were well separated from the main peak, the degree of separation of sodium stearyl fumarate from other impurities was 16.7, and the number of theoretical plates was 5111 in terms of the sodium stearyl fumarate peak.
Chromatographic conditions 4: when the high performance liquid chromatography analysis is carried out according to the chromatographic conditions, the main peak of the sodium stearyl fumarate is split into 2 peaks, and the quantitative analysis cannot be carried out.
Chromatographic conditions 5: when the high performance liquid chromatography analysis is carried out according to the chromatographic conditions, the main peak of the sodium stearyl fumarate is basically not reserved and is coincided with the solvent peak, and the quantitative determination cannot be carried out.
Example 4 methodology
4.1 System applicability
Preparation of control solutions: taking about 5mg of sodium stearyl fumarate, precisely weighing, placing in a 100mL measuring flask, dissolving with methanol, diluting to scale, and shaking.
The determination method comprises the following steps: the control solution was measured 6 times in succession under the chromatographic conditions of example 1, and the results are shown in Table 4.
TABLE 4 System suitability test results
And (4) conclusion: the retention time RSD of the sodium stearyl fumarate peak in the chromatogram obtained by continuously taking 6 needles of the reference solution should not exceed 1.0 percent, the RSD of the peak area should not exceed 2.0 percent, and the theoretical plate number calculated according to the sodium stearyl fumarate peak should not be lower than 3000, which indicates that the system for detecting the content of the sodium stearyl fumarate in the oseltamivir phosphate capsule by the method has good applicability.
4.2 precision (repeatability)
Preparing a repetitive test solution: taking 211101 batches of oseltamivir phosphate capsules of 20 granules, pouring out the contents, mixing uniformly, precisely weighing an appropriate amount of the contents (about 5mg equivalent to sodium stearyl fumarate), putting the contents into a 100mL measuring flask, adding 80mL of methanol, carrying out ultrasonic treatment for 20 minutes, taking out, cooling, adding the methanol to dilute to a scale, shaking uniformly, filtering, and taking a subsequent filtrate. 6 parts are prepared in parallel.
The determination method comprises the following steps: the chromatographic conditions of example 1 were followed to measure 6 times of repeated test solutions, and the results are shown in Table 5.
TABLE 5 results of repeated measurements
And (4) conclusion: the content RSD of the sodium stearyl fumarate in the 6 repeated test samples is 1.0 percent and is not more than 2.0 percent, which shows that the repeatability of the analysis method for detecting the content of the sodium stearyl fumarate in the oseltamivir phosphate capsule is good.
4.3 specificity test:
blank solution: methanol.
Preparation of control solutions: taking about 5mg of sodium stearyl fumarate, precisely weighing, placing in a 100mL measuring flask, dissolving with methanol, diluting to scale, and shaking.
Preparing a test solution: precisely weighing 20 oseltamivir phosphate capsules of 211101 batches, pouring out the contents, wiping the capsule shells with a small brush or other suitable tools, precisely weighing the capsule shells respectively, calculating the average loading, uniformly mixing, precisely weighing an appropriate amount of fine powder (about 5mg of sodium stearyl fumarate), placing the fine powder into a 100mL measuring flask, adding 80mL of methanol, performing ultrasonic treatment for 20 minutes, taking out the mixture, cooling the mixture, adding the methanol to dilute the mixture to a scale, shaking the mixture uniformly, filtering the mixture, and taking the subsequent filtrate.
Preparation of a blank raw material and auxiliary material solution without sodium stearyl fumarate: taking about 485mg of blank raw and auxiliary materials without sodium stearyl fumarate, putting the blank raw and auxiliary materials into a 100mL measuring flask, adding 80mL of methanol, carrying out ultrasonic treatment for 20 minutes, taking out the mixture, cooling the mixture, adding methanol to dilute the mixture to a scale, shaking up, filtering, and taking out a subsequent filtrate.
The determination method comprises the following steps: the results of the chromatographic conditions of example 1 are shown in Table 6.
TABLE 6 results of specificity test
And (4) conclusion: the blank solution and the blank raw and auxiliary material solution without the sodium stearyl fumarate are not interfered, the retention time of the sodium stearyl fumarate in the test solution is consistent with that of the sodium stearyl fumarate in the reference solution, the separation degree between a sodium stearyl fumarate peak and an adjacent impurity peak in the test solution is 25.9 and is more than 1.5, and the method is proved to have good specificity in detecting the content of the sodium stearyl fumarate in the oseltamivir phosphate capsule.
4.4 accuracy test
Blank solution: methanol
Preparation of a blank raw material and auxiliary material solution without sodium stearyl fumarate: taking about 485mg of blank raw and auxiliary materials without sodium stearyl fumarate, putting the blank raw and auxiliary materials into a 100mL measuring flask, adding 80mL of methanol, carrying out ultrasonic treatment for 20 minutes, taking out the mixture, cooling the mixture, adding the methanol to dilute the mixture to a scale, shaking up the mixture, filtering the mixture, and taking a subsequent filtrate.
Preparation of control solution 1: taking about 5mg of sodium stearyl fumarate, precisely weighing, placing in a 100mL measuring flask, dissolving with methanol, diluting to scale, and shaking up to obtain the final product.
Preparation of control solution 2: taking about 5mg of sodium stearyl fumarate, precisely weighing, placing in a 100mL measuring flask, dissolving with methanol, diluting to scale, and shaking up to obtain the final product.
Preparation of 60% recovery solution: precisely weighing about 3mg of sodium stearyl fumarate, precisely weighing about 485mg of blank raw and auxiliary materials without sodium stearyl fumarate, putting the raw and auxiliary materials into a same 100mL measuring flask, adding 80mL of methanol, carrying out ultrasonic treatment for 20 minutes, taking out, cooling, adding methanol to dilute to a scale, shaking up, filtering, and taking out a subsequent filtrate. 3 parts are prepared in parallel.
Preparation of 100% recovery solution: precisely weighing about 5mg of sodium stearyl fumarate, precisely weighing about 485mg of blank raw and auxiliary materials without sodium stearyl fumarate, placing into the same 100mL measuring flask, adding 80mL of methanol, performing ultrasonic treatment for 20min, taking out, cooling, diluting with methanol to scale, shaking, filtering, and collecting the filtrate. 3 parts are prepared in parallel.
Preparation of 120% recovery solution: precisely weighing about 6mg of sodium stearyl fumarate, precisely weighing about 485mg of blank raw and auxiliary materials without sodium stearyl fumarate, placing into the same 10mL measuring flask, adding 80mL of methanol, performing ultrasonic treatment for 20min, taking out, cooling, diluting with methanol to scale, shaking, filtering, and collecting the filtrate. 3 parts are prepared in parallel.
The determination method comprises the following steps: the results of the measurement under the chromatographic conditions of example 1 are shown in Table 7.
TABLE 7 accuracy test results
And (4) conclusion: adding sodium stearyl fumarate with concentration range of 60-120% corresponding to that of the reference solution into blank adjuvant without sodium stearyl fumarate, wherein the recovery rate of each recovery rate solution is 98.45-100.51%, and is 92-105% of standard specification; the average recovery rate is 99.7%, and the RSD of the recovery rate is 0.8% and less than 2.0%, which indicates that the analysis method has good detection accuracy.
4.5 Linearity and Range
Blank solution: methanol
Preparation of a linear solution 1 (corresponding to a test solution concentration of 50%): precisely weighing about 2.5mg of sodium stearyl fumarate, placing in a 100mL measuring flask, diluting with methanol to scale, and shaking.
Preparation of linear solution 2 (corresponding to a test solution concentration of 60%): accurately weighing about 3.0mg of sodium stearyl fumarate, placing in a 100mL measuring flask, diluting with methanol to scale, and shaking.
Preparation of a linear solution 3 (corresponding to a test solution concentration of 80%): accurately weighing about 4.0mg of sodium stearyl fumarate, placing in a 100mL measuring flask, diluting with methanol to scale, and shaking.
Preparation of a linear solution 4 (corresponding to a test solution concentration of 100%): accurately weighing about 5.0mg of sodium stearyl fumarate, placing in a 100mL measuring flask, diluting with methanol to scale, and shaking.
Preparation of a linear solution 5 (corresponding to a test solution concentration of 120%): precisely weighing about 6.0mg of sodium stearyl fumarate, placing in a 100mL measuring flask, diluting with methanol to scale, and shaking.
Preparation of a linear solution 6 (corresponding to a test solution concentration of 150%): accurately weighing about 7.5mg of sodium stearyl fumarate, placing in a 100mL measuring flask, diluting with methanol to scale, and shaking.
The determination method comprises the following steps: the results of the measurement under the chromatographic conditions of example 1 are shown in FIG. 10 and Table 8.
TABLE 8 Linear and Range measurements
And (4) conclusion: the sodium stearyl fumarate is in the concentration range of 23.77 mu g/mL-72.32 mu g/mL, the concentration is used as a horizontal coordinate, the peak area is used as a vertical coordinate to be used as a standard curve, the obtained linear equation is y =12560 x-7414.6, the correlation coefficient is 1.000 and is more than 0.998; RSD of the response factor is 0.7%, less than 2.0%; the Y-axis intercept accounts for 1.2% and less than 2.0% of the 100% response. The good linear relation of the sodium stearyl fumarate detected by the analysis method in the concentration range of 23.77 mu g/mL-72.32 mu g/mL is shown.
4.6 durability
Blank solution: methanol
Preparation of control solution 1: taking about 5mg of sodium stearyl fumarate, precisely weighing, placing in a 100mL measuring flask, dissolving with methanol, diluting to scale, and shaking.
Preparation of control solution 2: taking about 5mg of sodium stearyl fumarate, precisely weighing, placing in a 100mL measuring flask, dissolving with methanol, diluting to scale, and shaking.
Durability test article solution: precisely weighing 20 oseltamivir phosphate capsules of 211101 batches, pouring out the contents, wiping the capsule shells with a small brush or other suitable tools, precisely weighing the capsule shells respectively, calculating the average filling amount, uniformly mixing, precisely weighing an appropriate amount of the contents (about 5mg of sodium stearyl fumarate), putting the contents into a 100mL measuring flask, adding 80mL of methanol, performing ultrasonic treatment for 20 minutes, taking out the contents, cooling the mixture, adding the methanol to dilute the mixture to a scale, shaking the mixture uniformly, filtering the mixture, and taking the subsequent filtrate. 2 parts are prepared in parallel.
The determination method comprises the following steps: the results of measurement under the chromatographic conditions shown in Table 9 are shown in Table 10.
TABLE 9 chromatographic Condition Change for durability test
TABLE 10 durability test results
And (4) conclusion: changing the column temperature to be 28-32 ℃, the flow rate to be 0.8-1.2 mL/min, the proportion of acetonitrile-0.1% phosphoric acid solution to be 86:14 to 90: under the condition of 10, the theoretical plate numbers of the reference substances under the same chromatographic parameter and different conditions are more than 3000 according to the calculation of a sodium stearyl fumarate peak, and the RSD of the sodium stearyl fumarate content in the test sample is less than 2.0%, which shows that the durability of the method for detecting the sodium stearyl fumarate content in the oseltamivir phosphate capsule is good.
The method takes 0.1% phosphoric acid solution and acetonitrile as flowing phase to detect sodium stearyl fumarate, analyzes the stability of the sodium stearyl fumarate by using a high performance liquid chromatography, can be used for content determination of the sodium stearyl fumarate, has the advantages of simple operation, strong specificity, high accuracy and good linearity, and has stronger practicability in the aspects of production and quality control of sodium stearyl fumarate.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered as the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (10)
1. A method for determining sodium stearyl fumarate in an oseltamivir phosphate pharmaceutical composition is characterized by comprising the following steps: the determination method comprises the steps of adding methanol into a sample to prepare a sample solution, and injecting the sample solution into a high performance liquid chromatograph for detection to obtain a chromatogram.
2. The method for determining sodium stearyl fumarate in oseltamivir phosphate pharmaceutical composition according to claim 1, which is characterized in that: the chromatographic conditions detected by the high performance liquid chromatograph comprise that a mobile phase A and a mobile phase B are used for preparing the mobile phase, wherein the mobile phase A is selected from an aqueous solution containing a modifier, and the mobile phase B is an acetonitrile solution.
3. The method for determining sodium stearyl fumarate in oseltamivir phosphate pharmaceutical composition according to claim 2, which is characterized in that: the modifier is selected from phosphoric acid and trifluoroacetic acid.
4. The method for determining sodium stearyl fumarate in oseltamivir phosphate pharmaceutical composition according to claim 3, wherein the method comprises the following steps: the mobile phase A is 0.1% phosphoric acid solution.
5. The method for determining sodium stearyl fumarate in oseltamivir phosphate pharmaceutical composition according to claim 2, which is characterized in that: the chromatographic conditions detected by the high performance liquid chromatograph comprise elution with the mobile phase in an isocratic elution mode.
6. The method for determining sodium stearyl fumarate in oseltamivir phosphate pharmaceutical composition according to claim 5, wherein the method comprises the following steps: the ratio of isocratic elution of the mobile phase A and the mobile phase B is 10: 90-14: 86.
7. the method for determining sodium stearyl fumarate in oseltamivir phosphate pharmaceutical composition according to claim 6, wherein the method comprises the following steps: the ratio of isocratic elution of the mobile phase A and the mobile phase B is 12:88.
8. the method for determining sodium stearyl fumarate in oseltamivir phosphate pharmaceutical composition according to claim 1, which is characterized in that: the determination method also comprises the step of preparing a reference substance solution by adopting sodium stearyl fumarate and the step of injecting the reference substance solution into a high performance liquid chromatograph for detection to obtain a reference substance map.
9. The method for determining sodium stearyl fumarate in oseltamivir phosphate pharmaceutical composition according to claim 2, which is characterized in that: the chromatographic conditions also comprise that an octadecylsilane chemically bonded silica chromatographic column is adopted, the column temperature is 28-32 ℃, the flow rate is 0.8-1.2 mL/min, and the wavelength is 210nm.
10. The method for determining sodium stearyl fumarate in the oseltamivir phosphate pharmaceutical composition according to any one of claims 2 to 7, which is characterized in that: the sodium stearyl fumarate detected by the determination method has good linear relation in the concentration range of 23.77 mu g/mL-72.32 mu g/mL.
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| CN117214369B (en) * | 2023-11-09 | 2024-02-02 | 山东百诺医药股份有限公司 | Liquid chromatography method for detecting related substances of oseltamium phosphate Wei Ganhun suspension |
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