A method for determining the content of cetirizine hydrochloride and various preservatives in cetirizine hydrochloride oral solution.

Abstract

The present application relates to the field of pharmaceutical analysis, and particularly relates to a method for determining the content of cetirizine hydrochloride and preservatives in cetirizine hydrochloride oral solution. The method provided by the present application uses octadecyl bonded silica as the filler of the chromatographic column, uses a mixed solution with specific composition and proportion as the mobile phase, adopts isocratic elution, uses a content volumetric pipette to prepare the test sample solution, injects the test sample solution and the mixed control solution into the liquid chromatograph respectively to perform liquid chromatography, thereby obtaining the chromatogram of the test sample solution and the chromatogram of the mixed control solution respectively; and then according to the external standard method, the content of cetirizine hydrochloride, the content of the hydroxy methylbenzoate preservative and the content of the hydroxy propylbenzoate preservative in the cetirizine hydrochloride oral solution are calculated by the peak area. The method has strong specificity, high accuracy, good precision, linear relationship and stability, and is conducive to the evaluation of sample quality.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical analysis, and in particular to a method for determining the content of cetirizine hydrochloride and various preservatives in cetirizine hydrochloride oral solution. Background Technology

[0002] Cetirizine hydrochloride oral solution is an antihistamine, mainly used to relieve seasonal rhinitis, perennial allergic rhinitis, allergic conjunctivitis, and itching and urticaria caused by allergies.

[0003] In the production process of cetirizine hydrochloride oral solution, in addition to the active ingredient, various excipients are added, including glycerin, propylene glycol, non-crystalline sorbitol solution, sodium saccharin, flavoring, glacial acetic acid, sodium acetate, and preservatives methylparaben and propylparaben. To ensure the quality of the oral solution, it is necessary to eliminate the interference of various excipients and to accurately and effectively separate the two preservatives and the active ingredient cetirizine hydrochloride. Furthermore, the antibacterial effect of the preservatives in long-term stability makes it crucial to effectively monitor the content of the preservatives. Therefore, the accurate quantitative determination of cetirizine hydrochloride and the two preservatives in cetirizine hydrochloride oral solution is particularly important for production and quality control. Summary of the Invention

[0004] In view of this, the present invention provides a method for determining the content of cetirizine hydrochloride and various preservatives in cetirizine hydrochloride oral solution. The test method provided by the present invention can effectively determine the content of the active ingredient cetirizine hydrochloride and the two preservatives (methylparaben and propylparaben) in cetirizine hydrochloride oral solution, which is beneficial to the quality control in the production of cetirizine hydrochloride oral solution.

[0005] This invention provides a method for determining the content of cetirizine hydrochloride and various preservatives in cetirizine hydrochloride oral solution, comprising the following steps:

[0006] A) Preparation of the test solution:

[0007] Accurately measure 5 mL of this product using a pipette and place it in a 100 mL volumetric flask. Dilute to the mark with the mobile phase, shake well, and obtain the test solution.

[0008] B) Preparation of a mixed solution of reference standards:

[0009] Preparation of cetirizine hydrochloride reference standard stock solution: Weigh 20 mg of cetirizine hydrochloride reference standard accurately, place it in a 20 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well, and the solution is ready;

[0010] Preparation of methylparaben reference standard stock solution: Accurately weigh 27 mg of methylparaben reference standard, place it in a 20 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well, and the solution is ready;

[0011] Preparation of propylparaben reference standard stock solution: Accurately weigh 30 mg of propylparaben reference standard, place it in a 20 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well to obtain the initial solution; then accurately measure 2 mL of the initial solution, place it in a 20 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well to obtain the final solution;

[0012] Accurately measure 5 mL each of the cetirizine hydrochloride reference stock solution, methylparaben reference stock solution, and propylparaben reference stock solution, place them in a 100 mL volumetric flask, dilute to the mark with mobile phase, and shake well to obtain a mixed reference solution.

[0013] C) Liquid chromatography test:

[0014] Accurately measure the test solution and the mixed solution of the reference standard, and inject them into a liquid chromatograph for liquid chromatography testing to obtain chromatograms of the test solution and the mixed solution of the reference standard, respectively; then, according to the external standard method, obtain the contents of cetirizine hydrochloride, methylparaben preservative and propylparaben preservative in the cetirizine hydrochloride oral solution, respectively.

[0015] The conditions for the liquid chromatography test are as follows:

[0016] Column: Octadecylsilane-bonded silica gel packing material;

[0017] Mobile phase: Adjust the pH of a 0.1 mol / L potassium dihydrogen phosphate solution to 3.7 with phosphoric acid, and then mix it with acetonitrile at a volume ratio of 65:35 to obtain the mobile phase;

[0018] Mobile phase flow rate: 0.8–1.2 mL / min;

[0019] Column temperature: 25–35℃;

[0020] Detection wavelength: 232nm;

[0021] Injection volume: 20 μL;

[0022] Elution method: isocratic elution;

[0023] There is no order restriction between steps A) and B).

[0024] Preferably, in step A), the concentration of the test solution is: 50 μg of cetirizine hydrochloride per 1 mL of test solution.

[0025] Preferably, in step B), the concentration of the reference solution mixture is: 50 μg of cetirizine hydrochloride, 67.5 μg of methylparaben, and 7.5 μg of propylparaben per 1 mL of the reference solution mixture.

[0026] Preferably, in step C), the external standard method is calculated using the following formulas (1) to (2):

[0027]

[0028] In formula (1):

[0029] F: Correction factor;

[0030] m s The sample weight (mg) of each reference standard of cetirizine hydrochloride, methylparaben, or propylparaben;

[0031] p: Purity of each reference standard of cetirizine hydrochloride, methylparaben, or propylparaben;

[0032] V s : The dilution volume of each reference standard to the reference standard mixture, in mL;

[0033] A s Peak areas of cetirizine hydrochloride, methylparaben, or propylparaben in the reference standard mixture;

[0034]

[0035] In formula (2):

[0036] W: Content of cetirizine hydrochloride, methylparaben, or propylparaben in cetirizine hydrochloride oral solution, %;

[0037] F: The correction factor calculated by formula (1);

[0038] A R Peak areas of cetirizine hydrochloride, methylparaben, or propylparaben in the test solution;

[0039] V R : The volume of the test solution diluted, in mL;

[0040] V: The volume of cetirizine hydrochloride oral solution measured in the test solution, in mL;

[0041] C: Cetirizine Hydrochloride Oral Solution. The labeled amount of cetirizine hydrochloride, methylparaben, or propylparaben in this product is mg / mL.

[0042] Preferably, in formula (2), the parameter C is as follows:

[0043] The oral solution of cetirizine hydrochloride contains 1 mg / mL of cetirizine hydrochloride, 1.35 mg / mL of methylparaben, and 0.15 mg / mL of propylparaben.

[0044] Preferably, the chromatographic column is one of Agilent SB / XDB / EXTEND C18, Welch Xtimate, or MORHCHEMCaprisil C18-P.

[0045] Preferably, the chromatographic column has the following specifications: 250 mm in length, 4.6 mm in inner diameter, and 5 μm particle size of packing material.

[0046] Preferably, the flow rate of the mobile phase is 1.0 mL / min.

[0047] Preferably, the temperature of the chromatographic column is 30°C.

[0048] Preferably, in step C), the liquid chromatography test is a high-performance liquid chromatography test.

[0049] The detection method provided by this invention uses an octadecyl-bonded silica gel column as the packing material, a mixture of specific composition and proportions as the mobile phase, and isocratic elution. A test solution is prepared using a volumetric pipette. The test solution and the reference solution are injected separately into a liquid chromatograph for liquid chromatography testing, thereby obtaining chromatograms of the test solution and the reference solution, respectively. The content of cetirizine hydrochloride, methylparaben preservative, and propylparaben preservative in the cetirizine hydrochloride oral solution is then calculated based on peak area using the external standard method. This method can quantitatively determine the content of cetirizine hydrochloride and various preservatives in cetirizine hydrochloride oral solution, thereby ensuring the quality control of the cetirizine hydrochloride oral solution. The method of this invention is highly specific and accurate, with good precision, linearity, and stability. It can accurately detect the content of cetirizine hydrochloride and two preservatives in cetirizine hydrochloride oral solution, which is beneficial for evaluating sample quality. In addition, the method of this invention is simple to operate and easy to implement. Attached Figure Description

[0050] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0051] Figure 1 The chromatogram of the blank solvent used in the specificity verification of Example 1 is shown below.

[0052] Figure 2 The chromatogram of blank excipient solution 1 (without cetirizine hydrochloride) in the specificity verification of Example 1;

[0053] Figure 3The chromatogram of blank excipient solution 2 (without the preservatives methylparaben and propylparaben) in the specificity verification of Example 1 is shown.

[0054] Figure 4 This is the chromatogram of the reference solution used in the specificity verification of Example 1;

[0055] Figure 5 This is the chromatogram of the test solution used in the specificity verification of Example 1;

[0056] Figure 6 Linear graph of cetirizine hydrochloride;

[0057] Figure 7 Linear graph of methylparaben;

[0058] Figure 8 Linear graph of propylparaben;

[0059] Figure 9 The chromatogram is shown on a MORHCHEM Caprisil column with a mobile phase ratio of 60:40.

[0060] Figure 10 The chromatogram is shown on a MORHCHEM Caprisil column with a mobile phase ratio of 65:35.

[0061] Figure 11 The chromatogram is for an Agilent column, SB / XDB / EXTEND, with a mobile phase ratio of 60:40.

[0062] Figure 12 The chromatogram is for an Agilent column, SB / XDB / EXTEND, with a mobile phase ratio of 65:35.

[0063] Figure 13 The chromatogram is shown for a Welch Xtimate column with a mobile phase ratio of 60:40.

[0064] Figure 14 This is a chromatogram of a Welch column with a mobile phase ratio of 65:35 in the Xtimate configuration. Detailed Implementation

[0065] Unless otherwise defined, 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 application belongs. The terminology used herein in the specification of this application is for the purpose of describing particular embodiments only and is not intended to be limiting of this application.

[0066] In this article, the technical features described in an open-ended manner include both closed technical solutions composed of the listed features and open technical solutions that include the listed features.

[0067] The term “and / or” as used herein includes any and all combinations of one or more of the related listed items.

[0068] In this document, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when a range refers to an integer, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0069] In this article, when referring to units for data ranges, if the unit is only followed by the right endpoint, it indicates that the units for the left and right endpoints are the same. For example, 0.8–1.2 mL / min means that the units for the left endpoint “0.8” and the right endpoint “1.2” are both mL / min.

[0070] This invention provides a method for determining the content of cetirizine hydrochloride and various preservatives in cetirizine hydrochloride oral solution, comprising the following steps:

[0071] A) Preparation of the test solution:

[0072] Accurately measure 5 mL of this product using a pipette and place it in a 100 mL volumetric flask. Dilute to the mark with the mobile phase, shake well, and obtain the test solution.

[0073] B) Preparation of a mixed solution of reference standards:

[0074] Preparation of cetirizine hydrochloride reference standard stock solution: Weigh 20 mg of cetirizine hydrochloride reference standard accurately, place it in a 20 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well, and the solution is ready;

[0075] Preparation of methylparaben reference standard stock solution: Accurately weigh 27 mg of methylparaben reference standard, place it in a 20 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well, and the solution is ready;

[0076] Preparation of propylparaben reference standard stock solution: Accurately weigh 30 mg of propylparaben reference standard, place it in a 20 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well to obtain the initial solution; then accurately measure 2 mL of the initial solution, place it in a 20 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well to obtain the final solution;

[0077] Accurately measure 5 mL each of the cetirizine hydrochloride reference stock solution, methylparaben reference stock solution, and propylparaben reference stock solution, place them in a 100 mL volumetric flask, dilute to the mark with mobile phase, and shake well to obtain a mixed reference solution.

[0078] C) Liquid chromatography test:

[0079] Accurately measure the test solution and the mixed solution of the reference standard, and inject them into a liquid chromatograph for liquid chromatography testing to obtain chromatograms of the test solution and the mixed solution of the reference standard, respectively; then, according to the external standard method, obtain the contents of cetirizine hydrochloride, methylparaben preservative and propylparaben preservative in the cetirizine hydrochloride oral solution, respectively.

[0080] The conditions for the liquid chromatography test are as follows:

[0081] Column: Octadecylsilane-bonded silica gel packing material;

[0082] Mobile phase: Adjust the pH of a 0.1 mol / L potassium dihydrogen phosphate solution to 3.7 with phosphoric acid, and then mix it with acetonitrile at a volume ratio of 65:35 to obtain the mobile phase;

[0083] Mobile phase flow rate: 0.8–1.2 mL / min;

[0084] Column temperature: 25–35℃;

[0085] Detection wavelength: 232nm;

[0086] Injection volume: 20 μL;

[0087] Elution method: isocratic elution;

[0088] There is no order restriction between steps A) and B).

[0089] [Regarding step A]:

[0090] A) Preparation of test solution: Accurately measure 5 mL of this product using a volumetric pipette, place it in a 100 mL volumetric flask, dilute to the mark with the mobile phase, and shake well to obtain the test solution.

[0091] In this invention, the product referred to is cetirizine hydrochloride oral solution. Cetirizine hydrochloride oral solution has a certain viscosity; when using ordinary pipettes to transfer the test sample, the prepared test solution easily adheres to the inner wall of the pipette, causing some error. This invention uses a volumetric pipette to prepare the test solution, which can reduce errors in the preparation of the test solution.

[0092] In this invention, the mobile phase is the same as the mobile phase used in subsequent liquid chromatography tests. The mobile phase is prepared by the following method: adjusting the pH of a 0.1 mol / L potassium dihydrogen phosphate solution to 3.7 with phosphoric acid, and then mixing it with acetonitrile at a volume ratio of 65:35 to obtain the mobile phase. The potassium dihydrogen phosphate solution is an aqueous solution of potassium dihydrogen phosphate. Adjusting the pH of the potassium dihydrogen phosphate solution to 3.7 with phosphoric acid, and then mixing it with acetonitrile at a volume ratio of 65:35, yields the mobile phase.

[0093] In this invention, the cetirizine hydrochloride oral solution is diluted with a mobile phase to obtain the test solution. Specifically, 5 mL of the product is accurately measured using a volumetric pipette and placed in a 100 mL volumetric flask. The solution is then diluted to the mark with the mobile phase and shaken well to obtain the test solution.

[0094] In this invention, preferably, the concentration of the test solution is: 50 μg of cetirizine hydrochloride per 1 mL of test solution. That is, the product is accurately measured using a volumetric pipette and diluted with the mobile phase to prepare a solution containing 50 μg of cetirizine hydrochloride per 1 mL, thus obtaining the test solution.

[0095] [Regarding step B]:

[0096] B) Preparation of a mixed solution of reference standards:

[0097] Preparation of cetirizine hydrochloride reference standard stock solution: Weigh 20 mg of cetirizine hydrochloride reference standard accurately, place it in a 20 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well, and the solution is ready;

[0098] Preparation of methylparaben reference standard stock solution: Accurately weigh 27 mg of methylparaben reference standard, place it in a 20 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well, and the solution is ready;

[0099] Preparation of propylparaben reference standard stock solution: Accurately weigh 30 mg of propylparaben reference standard, place it in a 20 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well to obtain the initial solution; then accurately measure 2 mL of the initial solution, place it in a 20 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well to obtain the final solution;

[0100] Accurately measure 5 mL each of the cetirizine hydrochloride reference stock solution, methylparaben reference stock solution, and propylparaben reference stock solution, place them in a 100 mL volumetric flask, dilute to the mark with mobile phase, and shake well to obtain a mixed reference solution.

[0101] This invention uses cetirizine hydrochloride, methylparaben, and propylparaben as reference standards. There are no special restrictions on the source of the above reference standards; they can be commercially available products.

[0102] There are no special restrictions on the order in which the above-mentioned cetirizine hydrochloride reference stock solution, methylparaben reference stock solution, and propylparaben reference stock solution are prepared.

[0103] In this invention, the mobile phase is the same as the mobile phase used in subsequent liquid chromatography tests. The mobile phase is prepared by the following method: adjusting the pH of a 0.1 mol / L potassium dihydrogen phosphate solution to 3.7 with phosphoric acid, and then mixing it with acetonitrile at a volume ratio of 65:35 to obtain the mobile phase. The potassium dihydrogen phosphate solution is an aqueous solution of potassium dihydrogen phosphate. Adjusting the pH of the potassium dihydrogen phosphate solution to 3.7 with phosphoric acid, and then mixing it with acetonitrile at a volume ratio of 65:35, yields the mobile phase.

[0104] In this invention, cetirizine hydrochloride reference standard, methylparaben reference standard, and propylparaben reference standard are accurately weighed, dissolved in the mobile phase, and diluted with the mobile phase to prepare stock solutions of each reference standard. Then, a certain volume (5 mL) of each stock solution is measured and placed in a 100 mL volumetric flask, diluted with the mobile phase to the mark, and shaken well to obtain a mixed solution of reference standards.

[0105] In this invention, the concentration of the reference standard mixed solution is: each 1 mL of the reference standard mixed solution contains 50 μg of cetirizine hydrochloride, 67.5 μg of methylparaben, and 7.5 μg of propylparaben.

[0106] This invention does not impose any order restrictions on steps A) and B).

[0107] [Regarding step C]:

[0108] C) Liquid Chromatography Test: Accurately measure the test solution and the mixed solution of the reference standard, and inject them into the liquid chromatograph for liquid chromatography test to obtain the chromatograms of the test solution and the mixed solution of the reference standard, respectively; then, according to the external standard method, obtain the contents of cetirizine hydrochloride, methylparaben preservative and propylparaben preservative in the cetirizine hydrochloride oral solution, respectively.

[0109] In this invention, the liquid chromatography test is preferably a high-performance liquid chromatography test, i.e., HPLC test.

[0110] In this invention, the conditions for the liquid chromatography test are as follows:

[0111] Column: Octadecylsilane-bonded silica gel packing material;

[0112] Mobile phase: Adjust the pH of a 0.1 mol / L potassium dihydrogen phosphate solution to 3.7 with phosphoric acid, and then mix it with acetonitrile at a volume ratio of 65:35 to obtain the mobile phase;

[0113] Mobile phase flow rate: 0.8–1.2 mL / min;

[0114] Column temperature: 25–35℃;

[0115] Detection wavelength: 232nm;

[0116] Injection volume: 20 μL;

[0117] Elution method: isocratic elution.

[0118] in:

[0119] The chromatographic column is preferably one of Agilent SB / XDB / EXTEND C18, Welch Xtimate, or MORHCHEMCaprisil C18-P. The preferred specifications of the column are: 250 mm in length, 4.6 mm in inner diameter, and 5 μm particle size of the packing material.

[0120] The mobile phase is prepared by adjusting the pH of a 0.1 mol / L potassium dihydrogen phosphate solution to 3.7 with phosphoric acid, and then mixing it with acetonitrile at a volume ratio of 65:35. Liquid chromatography achieves separation by the exchange of sample components between the column packing and the mobile phase; therefore, the mobile phase must have a certain solubility for the sample, not react chemically with the sample, and be compatible with the detector. The specific mobile phase used in this invention achieves better detection results than other mobile phases. The specific flow rate of the mobile phase can be 0.8 mL / min, 0.9 mL / min, 1.0 mL / min, 1.1 mL / min, or 1.2 mL / min, more preferably 1.0 mL / min.

[0121] The specific temperature of the chromatographic column can be 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, or 35℃, and more preferably 30℃.

[0122] The test solution and the mixed solution of the reference standard were injected into a liquid chromatograph for liquid chromatography to obtain chromatograms of the test solution and the mixed solution of the reference standard, respectively. Then, the contents of cetirizine hydrochloride, methylparaben preservative and propylparaben preservative in the cetirizine hydrochloride oral solution were calculated by peak area according to the external standard method.

[0123] In this invention, the external standard method is calculated using the following formulas (1) to (2):

[0124]

[0125] In formula (1):

[0126] F: Correction factor;

[0127] m s The sample weight (mg) of each reference standard of cetirizine hydrochloride, methylparaben, or propylparaben;

[0128] p: Purity of each reference standard of cetirizine hydrochloride, methylparaben, or propylparaben;

[0129] V s : The dilution volume of each reference standard to the reference standard mixture, in mL;

[0130] A s Peak areas of cetirizine hydrochloride, methylparaben, or propylparaben in the reference standard mixture;

[0131]

[0132] In formula (2):

[0133] W: Content of cetirizine hydrochloride, methylparaben, or propylparaben in cetirizine hydrochloride oral solution, %;

[0134] F: The correction factor calculated by formula (1);

[0135] A R Peak areas of cetirizine hydrochloride, methylparaben, or propylparaben in the test solution;

[0136] V R : The volume of the test solution diluted, in mL;

[0137] V: The volume of cetirizine hydrochloride oral solution measured in the test solution, in mL;

[0138] C: Cetirizine Hydrochloride Oral Solution. The labeled amount of cetirizine hydrochloride, methylparaben, or propylparaben in this product is mg / mL.

[0139] In the above formula (1), the dilution volume V of each reference standard to the reference standard mixture solution is... s V refers to the dilution volume (or dilution factor) when preparing a mixed solution of reference standard from the stock solution. The dilution volume of methylparaben is 20 × 100 / 5 = 400, the dilution volume of propylparaben is 20 × 20 × 100 / 2 / 5 = 4000, and the dilution volume of cetirizine hydrochloride is 20 × 100 / 5 = 400. In formula (2), the dilution volume V of the test solution is... R / V refers to the dilution volume (or dilution factor) when preparing the test solution from cetirizine hydrochloride oral solution, specifically 100 / 5 = 20.

[0140] High-performance liquid chromatography (HPLC) is a known method for the quantitative detection of substances. However, existing technologies do not report how to use HPLC to quantitatively detect the active ingredient of cetirizine hydrochloride and two preservatives (methylparaben and propylparaben) in cetirizine hydrochloride oral solution. Furthermore, to use HPLC to detect a new substance, it is necessary to design appropriate experimental procedures and process conditions to ensure that the method meets requirements in terms of accuracy, specificity, system suitability, linearity, precision, and robustness.

[0141] The detection method provided by this invention uses an octadecyl-bonded silica gel column as the packing material, a mixture of specific composition and proportions as the mobile phase, and isocratic elution. A test solution is prepared using a volumetric pipette. The test solution and the reference solution are injected separately into a liquid chromatograph for liquid chromatography testing, thereby obtaining chromatograms of the test solution and the reference solution, respectively. The content of cetirizine hydrochloride, methylparaben preservative, and propylparaben preservative in the cetirizine hydrochloride oral solution is then calculated based on peak area using the external standard method. This method can quantitatively determine the content of cetirizine hydrochloride and various preservatives in cetirizine hydrochloride oral solution, thereby ensuring the quality control of the cetirizine hydrochloride oral solution. The method of this invention is highly specific and accurate, with good precision, linearity, and stability. It can accurately detect the content of cetirizine hydrochloride and two preservatives in cetirizine hydrochloride oral solution, which is beneficial for evaluating sample quality. In addition, the method of this invention is simple to operate and easy to implement.

[0142] To further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims of the present invention.

[0143] In this invention, all medicines, reagents and instruments used can be purchased from the market.

[0144] instrument:

[0145] The instrument used for liquid chromatography detection was an Agilent 1260 Infinity II with a UV detector.

[0146] The pH meter used is a Mettler FE28.

[0147] The weighing instrument used was a Mettler XSR 105 electronic analytical balance.

[0148] Drug trials:

[0149] The reference standard, methylparaben (batch number: 100278-201906, purity 99.9%), was purchased from the National Institutes for Food and Drug Control.

[0150] The reference standard, propylparaben (batch number: 100444-202005, purity 99.9%), was purchased from the National Institutes for Food and Drug Control.

[0151] The reference standard, cetirizine hydrochloride (batch number: 100660-201803, purity 99.6%), was purchased from the National Institutes for Food and Drug Control.

[0152] Potassium dihydrogen phosphate (analytical grade, Chengdu Kelong Chemical Co., Ltd.);

[0153] Phosphoric acid (analytical grade, Chengdu Kelong Chemical Co., Ltd.);

[0154] Acetonitrile (chromatographic grade, MORELLK), water is ultrapure water;

[0155] Cetirizine Hydrochloride Oral Solution: Produced by Sichuan Jianneng Pharmaceutical Co., Ltd.

[0156] Example 1: Specificity of the Method of the Invention

[0157] 1. Solution preparation:

[0158] Blank solvent: mobile phase.

[0159] Blank excipient solution 1: Accurately measure 5 mL of blank excipient (excluding cetirizine hydrochloride, i.e., a solution composed of all components except cetirizine hydrochloride prepared according to the process formulation order), place it in a 100 mL volumetric flask, add mobile phase to dilute to the mark, and shake well to obtain the solution.

[0160] Blank excipient solution 2: Accurately measure 5 mL of blank excipient (excluding the preservatives methylparaben and propylparaben, i.e., prepare a solution of all components except methylparaben and propylparaben according to the process formula), place it in a 100 mL volumetric flask, add mobile phase to dilute to the mark, and shake well to obtain the solution.

[0161] Stock solution of methylparaben reference standard: Weigh 27 mg of methylparaben reference standard accurately, place it in a 20 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well, and the solution is ready.

[0162] Cetirizine hydrochloride reference standard stock solution: Weigh 20 mg of cetirizine hydrochloride reference standard accurately, place it in a 20 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well, and the solution is ready.

[0163] Propylparaben reference standard stock solution: Accurately weigh 30 mg of propylparaben reference standard, place it in a 20 mL volumetric flask, dissolve and dilute to the mark with mobile phase, and shake well. Then accurately measure 2 mL, place it in a 20 mL volumetric flask, dissolve and dilute to the mark with mobile phase, and shake well to obtain the solution.

[0164] Methylparaben positioning solution: Accurately measure 1 mL of methylparaben stock solution, place it in a 20 mL volumetric flask, dilute to the mark with mobile phase, and shake well to obtain the solution (each 1 mL contains 67.5 μg of methylparaben).

[0165] Propylparaben positioning solution: Accurately measure 1 mL of propylparaben stock solution, place it in a 20 mL volumetric flask, dilute to the mark with mobile phase, and shake well to obtain the solution (each 1 mL contains 7.5 μg of propylparaben).

[0166] Cetirizine hydrochloride positioning solution: Accurately measure 1 mL of cetirizine hydrochloride reference stock solution, place it in a 20 mL volumetric flask, dilute to the mark with mobile phase, and shake well to obtain the solution (each 1 mL contains 50 μg of cetirizine hydrochloride).

[0167] Reference solutions: Accurately measure 5 mL each of methylparaben reference stock solution, propylparaben reference stock solution, and cetirizine hydrochloride reference stock solution, place them in a 100 mL volumetric flask, dilute to the mark with mobile phase, and shake well to obtain the solution (each 1 mL contains 50 μg of cetirizine hydrochloride, 67.5 μg of methylparaben, and 7.5 μg of propylparaben).

[0168] Test solution: Accurately measure 5 mL of this product using a volumetric pipette, place it in a 100 mL volumetric flask, dilute to the mark with the mobile phase, and shake well to obtain the test solution.

[0169] 2. Test Results

[0170] Blank solvent, blank excipient solution 1, blank excipient solution 2, test solution, reference solution, and each positioning solution were respectively sent to liquid chromatography for detection to examine the retention time of each component.

[0171] Testing conditions:

[0172] Column: Welch Xtimate C18, 250mm × 4.6mm, 5μm;

[0173] Mobile phase: Adjust the pH of a 0.1 mol / L potassium dihydrogen phosphate solution to 3.7 with phosphoric acid, and then mix it with acetonitrile at a volume ratio of 65:35 to obtain the mobile phase;

[0174] Mobile phase flow rate: 1.0 mL / min;

[0175] Column temperature: 30℃;

[0176] Detection wavelength: 232nm;

[0177] Injection volume: 20 μL;

[0178] Elution method: isocratic elution.

[0179] The chromatograms of the blank solvent, blank excipient solution 1, blank excipient solution 2, reference solution, and test solution are shown below. Figure 1-5 As shown.

[0180] The test results are shown in Table 1:

[0181] Table 1: Results of Specificity Test

[0182]

[0183] The results showed that the blank solvent, blank excipient solution 1, and blank excipient solution 2 did not interfere with the determination, and the resolution of methylparaben, propylparaben, and cetirizine hydrochloride was greater than 1.5, indicating that the invention has good specificity.

[0184] Example 2: Limit of Quantification and Precision of Limit of Quantification

[0185] 1. Solution preparation:

[0186] Methylparaben reference standard stock solution: Same as in Example 1.

[0187] Propylparaben reference standard stock solution: Same as in Example 1.

[0188] Diluent: Accurately measure appropriate amounts of methylparaben reference stock solution and propylparaben reference stock solution, and gradually dilute with mobile phase to a solution with a signal-to-noise ratio ≥10, which is used as the limit of quantitation solution.

[0189] Take a sample of the limit of quantitation solution (6 parallel injections) and send it into a liquid chromatograph for detection (detection conditions are the same as in Example 1).

[0190] 2. Test Results:

[0191] The test results are shown in Table 2-3:

[0192] Table 2: Results of Limit of Quantitation Test

[0193]

[0194] Table 3: Results of Precision Test at Limit of Quantitation

[0195]

[0196] The results showed that the limit of quantification for methylparaben was 0.033 μg / mL, and the limit of quantification for propylparaben was 0.154 μg / mL.

[0197] Example 3: Linearity and Range of the Method of the Invention

[0198] 1. Solution preparation:

[0199] Reference stock solution (1): Weigh 30 mg of propylparaben reference standard accurately, place it in a 20 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well, and the solution is ready.

[0200] Reference stock solution (2): Weigh 67.5 mg of methylparaben reference standard accurately, place it in a 100 mL volumetric flask, add 5 mL of reference stock solution (1) accurately, dissolve and dilute to the mark with mobile phase, shake well, and the solution is ready.

[0201] Reference stock solution (3): Weigh 25 mg of cetirizine hydrochloride reference standard accurately, place it in a 50 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well, and the solution is ready.

[0202] For each linear solution: accurately measure 2.5 mL, 4.0 mL, 5.0 mL, 6.0 mL, and 7.5 mL of the control stock solution (2) and place them in five 50 mL volumetric flasks respectively. Then accurately measure 2.5 mL, 4.0 mL, 5.0 mL, 6.0 mL, and 7.5 mL of the control stock solution (3) and place them in the five 50 mL volumetric flasks mentioned above. Dilute to the mark with the mobile phase and mix well to obtain the solution.

[0203] 2. Test Results

[0204] The above linear solutions were analyzed by liquid chromatography (detection conditions were the same as in Example 1), and the results are shown in Tables 4-6 and 6-6. Figure 6-8 .

[0205] Table 4: Linearity test results of cetirizine hydrochloride

[0206]

[0207] Table 5: Linearity test results of methylparaben

[0208]

[0209] Table 6: Linearity test results of propylparaben

[0210]

[0211] The results showed that methylparaben, propylparaben, and cetirizine hydrochloride exhibited good linearity within the concentration limit range of 50% to 150%.

[0212] Example 4: Precision of the method of the present invention

[0213] 1. Solution preparation:

[0214] Reference solution: Prepare two portions using the same method as in Example 1.

[0215] Test solution: Prepare 6 portions in the same manner as in Example 1.

[0216] 2. Test Results

[0217] Two reference solutions were injected in parallel with five injections in one sample and two injections in the other. The test solution was injected once in each sample. The samples were then sent to a liquid chromatograph for detection (the detection conditions were the same as in Example 1). The results are shown in Tables 7-8.

[0218] Table 7: Precision Test Results of Cetirizine Hydrochloride

[0219]

[0220] Table 8: Precision Test Results of Methylparaben and Propylparaben

[0221]

[0222] The results showed that the average content of cetirizine hydrochloride in the test solution was 97.7%, with a relative standard deviation (RSD) of 0.89%; the average content of methylparaben was 98.7%, with a RSD of 0.45%; and the average content of propylparaben was 96.3%, with a RSD of 0.66%, confirming that the method of the present invention has good precision.

[0223] Example 5: Accuracy of the Method of the Invention

[0224] 1. Solution preparation:

[0225] Cetirizine hydrochloride reference standard stock solution: Weigh 100 mg of cetirizine hydrochloride reference standard accurately, place it in a 100 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well, and the solution is ready.

[0226] Stock solution of methylparaben reference standard: Weigh 135 mg of methylparaben reference standard accurately, place it in a 100 mL volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well, and the solution is ready.

[0227] Propylparaben reference standard stock solution: Accurately weigh 30 mg of propylparaben reference standard, place it in a 20 mL volumetric flask, dissolve and dilute to the mark with mobile phase. Then accurately measure 10 mL, place it in a 100 mL volumetric flask, dilute to the mark with mobile phase, and shake well to obtain the solution.

[0228] Reference solutions: Accurately measure 5 mL each of cetirizine hydrochloride reference stock solution, methylparaben reference stock solution, and propylparaben reference stock solution, place them in a 100 mL volumetric flask, dilute to the mark with mobile phase, and shake well to obtain the solution. Prepare two aliquots using the same method.

[0229] 50% Cetirizine Hydrochloride Accuracy Solution: Accurately measure 5 mL of blank excipient solution 1 and place it in a 100 mL volumetric flask. Then accurately measure 2.5 mL of cetirizine hydrochloride reference stock solution and dilute to the mark with the mobile phase. Prepare 3 portions in the same manner.

[0230] 100% Cetirizine Hydrochloride Accuracy Solution: Accurately measure 5 mL of blank excipient solution 1 and place it in a 100 mL volumetric flask. Then, accurately measure 5 mL of cetirizine hydrochloride reference stock solution and dilute to the mark with the mobile phase. Prepare 3 aliquots in the same manner.

[0231] 150% Cetirizine Hydrochloride Accuracy Solution: Accurately measure 5 mL of blank excipient solution 1 and place it in a 100 mL volumetric flask. Then, accurately measure 7.5 mL of cetirizine hydrochloride reference stock solution and dilute to the mark with the mobile phase. Prepare 3 aliquots in the same manner.

[0232] 50% methylparaben and propylparaben accuracy solutions: Accurately measure 5 mL of blank excipient solution 2 and place it in a 100 mL volumetric flask. Then accurately measure 2.5 mL each of methylparaben reference stock solution and propylparaben reference stock solution, add mobile phase to dilute to the mark, and prepare 3 aliquots in the same way.

[0233] 100% methylparaben and propylparaben accuracy solutions: Accurately measure 5 mL of blank excipient solution 2 and place it in a 100 mL volumetric flask. Then, accurately measure 5 mL each of methylparaben reference stock solution and propylparaben reference stock solution, and dilute to the mark with mobile phase. Prepare 3 aliquots in the same manner.

[0234] 150% methylparaben and propylparaben accuracy solutions: Accurately measure 5 mL of blank excipient solution 2 and place it in a 100 mL volumetric flask. Then accurately measure 7.5 mL each of methylparaben reference stock solution and propylparaben reference stock solution, add mobile phase to dilute to the mark, and prepare 3 aliquots in the same way.

[0235] 2. Test Results:

[0236] Two reference solutions were injected into a liquid chromatograph for detection, one with 5 parallel injections and the other with 2 parallel injections, and each accuracy solution was injected with one injection (the detection conditions were the same as in Example 1). The results are shown in Tables 9-11.

[0237] Table 9: Accuracy Test Results of Methylparaben

[0238]

[0239] Table 10: Accuracy Test Results of Propylparaben

[0240]

[0241] Table 11: Accuracy Test Results of Cetirizine Hydrochloride

[0242]

[0243] The results showed that the recovery rates of cetirizine hydrochloride were 98.10%–98.71%; the recovery rates of methylparaben were 98.08%–100.59%; and the recovery rates of propylparaben were 99.07%–100.87%, indicating that the method has high accuracy.

[0244] Example 6: Solution Stability

[0245] 1. Solution preparation:

[0246] Reference solution: Same as in Example 1.

[0247] Test solution: Same as in Example 1.

[0248] 2. Test Results:

[0249] The reference solution and the test solution were stored at room temperature for 0h, 4h, 8h, 12h, 24h, 48h and 72h respectively, and then sent to a liquid chromatograph for detection (the detection conditions are the same as in Example 1). The results are shown in Table 12.

[0250] Table 12: Results of Solution Stability Test

[0251]

[0252] The results showed that both the reference solution and the test solution were stable within 72 hours, indicating that the method of the present invention has good robustness.

[0253] Example 7:

[0254] 1. Solution preparation:

[0255] Reference solution: Same as in Example 1.

[0256] 2. Test Results:

[0257] The reference solution was analyzed using a liquid chromatograph, and the results were examined under different chromatographic conditions. The chromatograms are shown below. Figure 9-14 As shown (the detection conditions are the same as in Example 1, except for the flow ratio).

[0258] Table 13: Results of Chromatographic Condition Tests

[0259]

[0260] The results showed that when the reference solution was used with a mobile phase ratio of 65:35, the chromatographic peaks of most components were baseline separated, indicating better resolution. However, with a mobile phase ratio of 60:40, baseline separation was not achieved. This demonstrates that the mobile phase ratio described above is beneficial for detection results in this invention. Furthermore, a mobile phase ratio of 65:35 is more suitable for most chromatographic columns, and the method of this invention exhibits good robustness.

[0261] Example 8

[0262] Three batches of cetirizine hydrochloride oral solution were tested according to the test method of this invention, and the results are shown in the table below.

[0263] Table 14: Test results of three batches of cetirizine hydrochloride oral solution

[0264]

[0265] The cetirizine hydrochloride, methylparaben, and propylparaben mentioned in this article are three different substances in the formulation of this preparation, and their dosages in the process differ. Specifically, the theoretical concentration (labeled amount) of cetirizine hydrochloride is 1 mg / mL, the theoretical concentration (labeled amount) of methylparaben is 1.35 mg / mL, and the theoretical concentration (labeled amount) of propylparaben is 0.15 mg / mL. According to the formula: content (%) = F × A R ×V R / (V×C)×100%, taking batch 20230401 in Table 14 as an example: where the measured amount (mg / mL) = F×A R ×V R For example, if the measured concentrations of cetirizine hydrochloride are 0.992 mg / mL, methylparaben 1.35 mg / mL, and propylparaben 0.1466 mg / mL, then the corresponding content of cetirizine hydrochloride (%) is 0.992 / 1 × 100% = 99.2%, the content of methylparaben (%) is 1.35 / 1.35 × 100% = 100.0%, and the content of propylparaben (%) is 0.1466 / 0.15 × 100% = 97.7%. Furthermore, the content determination limits in the Chinese Pharmacopoeia are generally specified as "this product should contain ××% to ××% of the labeled amount," for example, "this product should contain 95% to 105% of the labeled amount of cetirizine hydrochloride, and 90% to 110% of the labeled amount of methylparaben and propylparaben."

[0266] Table 14 shows that this method can accurately determine methylparaben, propylparaben, and cetirizine hydrochloride in cetirizine hydrochloride oral solution, and blank excipients do not interfere with the detection.

[0267] Specific examples are used to illustrate the principles and implementation methods of this invention. The descriptions of the embodiments above are only for the purpose of helping to understand the method and core ideas of this invention, including the best mode, and also to enable any person skilled in the art to practice this invention, including manufacturing and using any device or system, and implementing any combined method. It should be noted that for those skilled in the art, several improvements and modifications can be made to this invention without departing from the principles of this invention, and these improvements and modifications also fall within the protection scope of the claims of this invention. The scope of protection of this patent is defined by the claims and may include other embodiments that can be conceived by those skilled in the art. If these other embodiments have structural elements similar to the wording of the claims, or if they include equivalent structural elements that are not substantially different from the wording of the claims, then these other embodiments should also be included within the scope of the claims.

Claims

1. A method for determining the content of cetirizine hydrochloride and each preservative in cetirizine hydrochloride oral solution, characterized by, It comprises the following steps: A) Preparation of test sample solution: Take 5 mL of the product with a content volumetric pipette, and place it in a 100 mL volumetric flask. Dilute to the mark with the mobile phase, shake well, and obtain the test sample solution; B) Preparation of control sample mixture solution: Prepare the cetirizine hydrochloride control sample stock solution: take 20 mg of cetirizine hydrochloride control sample, accurately weigh, place in a 20 mL volumetric flask, dissolve and dilute to the mark with the mobile phase, shake well, and obtain; Prepare the hydroxybenzoic acid methyl ester control sample stock solution: take 27 mg of hydroxybenzoic acid methyl ester control sample, accurately weigh, place in a 20 mL volumetric flask, dissolve and dilute to the mark with the mobile phase, shake well, and obtain; Prepare the hydroxybenzoic acid propyl ester control sample stock solution: take 30 mg of hydroxybenzoic acid propyl ester control sample, accurately weigh, place in a 20 mL volumetric flask, dissolve and dilute to the mark with the mobile phase, shake well, and obtain the initial solution; then accurately take 2 mL of the initial solution, place it in a 20 mL volumetric flask, dissolve and dilute to the mark with the mobile phase, shake well, and obtain; Accurately take 5 mL of each of the cetirizine hydrochloride control sample stock solution, hydroxybenzoic acid methyl ester control sample stock solution, and hydroxybenzoic acid propyl ester control sample stock solution, and place them in a 100 mL volumetric flask. Dilute to the mark with the mobile phase, shake well, and obtain the control sample mixture solution; The concentration of the control sample mixture solution is: 50 μg of cetirizine hydrochloride, 67.5 μg of hydroxybenzoic acid methyl ester, and 7.5 μg of hydroxybenzoic acid propyl ester per 1 mL of control sample mixture solution; C) Liquid chromatography test: Accurately take the test sample solution and the control sample mixture solution, and inject them into the liquid chromatograph for liquid chromatography test, respectively, to obtain the chromatogram of the test sample solution and the chromatogram of the control sample mixture solution, respectively; then according to the external standard method, the content of cetirizine hydrochloride, the content of hydroxybenzoic acid methyl ester preservative, and the content of hydroxybenzoic acid propyl ester preservative in the cetirizine hydrochloride oral solution are obtained, respectively; The conditions of the liquid chromatography test are as follows: Chromatographic column: octadecylsilane bonded silica gel filler; Mobile phase: 0.1 mol / L potassium dihydrogen phosphate solution with pH adjusted to 3.7 with phosphoric acid, mixed with acetonitrile at a volume ratio of 65:35 to obtain the mobile phase; Flow rate of mobile phase: 0.8~1.2 mL / min; Chromatographic column temperature: 25~35℃; Detection wavelength: 232 nm; Injection volume: 20 μL; Elution mode: isocratic elution; The external standard method is calculated by the following formulas (1)~(2): correction factor: formula (1); In formula (1): F: correction factor; m s : Cetirizine hydrochloride, each of the reference samples of methyl or propyl paraben, mg; p: purity of each control sample of cetirizine hydrochloride, hydroxybenzoic acid methyl ester, or hydroxybenzoic acid propyl ester; V s : Dilution volume of each control to control mixture solution, mL; A s : peak area of cetirizine hydrochloride, methylparaben or propylparaben in the control mixture solution; Ingredient Content: W Formula (2); In formula (2): W: content of cetirizine hydrochloride, hydroxybenzoic acid methyl ester, or hydroxybenzoic acid propyl ester in the cetirizine hydrochloride oral solution, %; F: correction factor calculated by formula (1); A R : peak area of cetirizine hydrochloride, methylparaben or propylparaben in the test solution; V R : volume of dilution of the test solution, mL; V: volume of the cetirizine hydrochloride oral solution product taken in the test sample solution, mL; C: labeled amount of cetirizine hydrochloride, hydroxybenzoic acid methyl ester, or hydroxybenzoic acid propyl ester in the cetirizine hydrochloride oral solution product, mg / mL; In formula (2), the parameter C is as follows: The cetirizine hydrochloride oral solution has a cetirizine hydrochloride marked amount of 1 mg / mL, a hydroxybenzyl methyl ester marked amount of 1.35 mg / mL, and a hydroxybenzyl propyl ester marked amount of 0.15 mg / mL. Wherein, steps A) and B) are not limited in sequence.

2. The method of claim 1, wherein, In step A), the concentration of the test solution is: 50 μg of cetirizine hydrochloride per 1 mL of test solution.

3. The method of claim 1, wherein, The chromatographic column is one of Agilent SB / XDB / EXTEND C18, Welch Xtimate, and MORHCHEM Caprisil C18-P.

4. The method of claim 1, wherein, The specification of the chromatographic column is: length 250 mm, inner diameter 4.6 mm, and packing particle size 5 μm.

5. The method of claim 1, wherein, The flow rate of the mobile phase is 1.0 mL / min.

6. The method of claim 1, wherein, The temperature of the chromatographic column is 30℃.

7. The method of claim 1, wherein, In step C), the liquid chromatography test is high performance liquid chromatography test.

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