A method for determining the sodium carboxymethylcellulose content of a gel

Abstract

This invention discloses a method for determining the sodium carboxymethyl cellulose content in a gel, comprising the following steps: (1) accurately weighing a drug gel containing sodium carboxymethyl cellulose and placing it in an Erlenmeyer flask; (2) adding ethanol and shaking thoroughly, followed by ultrasonic treatment; (3) placing it under refrigeration or room temperature conditions and then filtering it through a G4 sintered funnel at 105°C to constant weight; (4) returning the ethanol to the Erlenmeyer flask, washing the liquid through the same G4 sintered funnel, and rinsing the filter residue; (5) drying the G4 sintered funnel at 105°C to constant weight, recording the difference between the two constant weights of the G4 sintered funnels as the weight of sodium carboxymethyl cellulose, and calculating its content. The determination method of this invention is simple and convenient to operate, with relatively low requirements for experimental equipment and the technical level of the test personnel, and does not require the use of reference standards or standard products, thus having low cost.

Description

Technical Field

[0001] This invention relates to a method for determining the sodium carboxymethyl cellulose content in a gel, belonging to the field of pharmaceutical analysis technology. Background Technology

[0002] Sodium carboxymethyl cellulose, with the following structure: Carboxymethyl cellulose sodium salt is a class of sodium salts produced by the reaction of cellulose with sodium monochloroacetate under alkaline conditions. Due to its wide availability and unique physical properties, it has prominent applications in food, pharmaceuticals, polymer materials and other fields.

[0003] Sodium carboxymethyl cellulose is a common pharmaceutical excipient, often used as a coating material, disintegrant, thickener, and binder for drugs. In the research and development of generic drugs, it is necessary to reverse engineer the formulation of a reference drug to determine the types and amounts of pharmaceutical excipients in its prescription, in order to produce a generic drug that is as consistent as possible with the reference drug in terms of various indicators.

[0004] Sodium carboxymethyl cellulose is a common matrix component of gel drugs. The amount used can affect the viscosity, rheological properties, and other characteristics of gel drugs, and further affect the release of active ingredients and irritation to the body. Therefore, there is an urgent need for a method that can reverse analyze the sodium carboxymethyl cellulose content in gel drugs.

[0005] Currently, the methods for detecting sodium carboxymethyl cellulose content are mostly gel chromatography, iodometric titration, and colorimetry. However, these methods are cumbersome to operate and have high requirements for equipment and reference standards, making it impossible to determine the sodium carboxymethyl cellulose content in gel drugs simply, conveniently, and at low cost. Summary of the Invention

[0006] At least to address one of the problems existing in the prior art, the present invention provides a method for determining the sodium carboxymethyl cellulose content in gels. The method uses gravimetric analysis and relies on the different solubility properties of raw materials and excipients in the gel drug to separate and determine the sodium carboxymethyl cellulose content. The determination method of the present invention is simple and convenient to operate, with relatively low requirements for experimental equipment and the technical level of experimental personnel, and does not require the use of control standards or reference standards, thus reducing costs.

[0007] To achieve the above objectives, the present invention adopts the following technical solution: a method for determining the sodium carboxymethyl cellulose content in a gel, comprising the following steps:

[0008] (1) Accurately weigh 0.5~2.0g of the drug gel containing sodium carboxymethyl cellulose, and record it as W. 供 Placed in an Erlenmeyer flask;

[0009] (2) Add 30-70 ml of ethanol to the drug gel from step (1), shake thoroughly, and then sonicate.

[0010] (3) Dry the clean G4 sintered funnel at 105°C to constant weight and set aside. The G4 sintered funnel with constant weight at this time is recorded as W1. Place the ethanol solution of the drug gel in step (2) under refrigeration or room temperature conditions and let it stand for 0.5~2h. Then transfer all the substances in the conical flask to the prepared G4 sintered funnel for filtration.

[0011] (4) Rinse the conical flask in step (3) three times with 50ml of ethanol. Combine the washings into the same G4 sintered funnel for filtration. Finally, rinse the filter residue with 20~100ml of ethanol.

[0012] (5) Dry the G4 sintered funnel containing the filter residue at 105°C to constant weight. The G4 sintered funnel at constant weight is denoted as W2. The weight difference between W2 and W1 is the weight of sodium carboxymethyl cellulose. According to the calculation formula: (W2-W1) / W 供 The content of sodium carboxymethyl cellulose in the gel drug was obtained by multiplying by 100%.

[0013] Preferably, in step (1), the drug gel is lidocaine hydrochloride gel.

[0014] Preferably, in step (1), the sodium carboxymethyl cellulose content in the drug gel is 1.0~10.0%.

[0015] Preferably, in step (1), the sodium carboxymethyl cellulose content in the drug gel is 3.5%.

[0016] Preferably, in step (1), the amount of the drug gel used for testing is 1g.

[0017] Preferably, in step (2), the amount of ethanol used is 50 ml.

[0018] Preferably, in step (2), the ultrasound time is 5~15 min.

[0019] Preferably, in step (2), the ultrasound time is 10 min.

[0020] Preferably, in step (3), the refrigeration conditions are 2~8℃.

[0021] Preferably, in step (3), the room temperature is 20~25℃.

[0022] Preferably, in step (3), the mixture is left to stand for 1 hour.

[0023] Preferably, in step (4), the amount of ethanol used for rinsing the filter residue is 50 ml.

[0024] Compared with existing technologies, the beneficial effects of this invention are as follows: The method for determining the sodium carboxymethyl cellulose content in gels, using gravimetric analysis, relies on the different solubility properties of raw materials and excipients in the gel to separate and determine the sodium carboxymethyl cellulose content; the method uses only ethanol as a reagent and only an oven and an electronic balance, resulting in low detection costs; the method involves three steps: precipitation, filtration, and drying, making it simple and time-saving; and the method for determining the sodium carboxymethyl cellulose content in gels has relatively low requirements for experimental equipment and the technical level of the test personnel. Detailed Implementation

[0025] The following is a clear and complete description of the technical solutions in the implementation of this invention. The described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents, instruments, or components used that do not specify the manufacturer are all conventional products that can be purchased commercially.

[0026] Example 1

[0027] A method for determining the sodium carboxymethyl cellulose content in a gel, the specific determination steps are as follows:

[0028] (1) Accurately weigh 1g of lidocaine hydrochloride gel with a sodium carboxymethyl cellulose content of 3.5%, and record it as W. 供 Placed in an Erlenmeyer flask;

[0029] (2) Add 50 ml of ethanol to the lidocaine hydrochloride gel in step (1), shake thoroughly, and then sonicate. The sonication power is 500 W and the sonication time is 10 min.

[0030] (3) Dry the clean G4 sintered funnel at 105°C to constant weight and set aside. The G4 sintered funnel with constant weight at this time is recorded as W1. Place the ethanol solution of lidocaine hydrochloride gel in step (2) at room temperature of 20~25°C and let it stand for 1 hour. Then transfer all the substances in the conical flask to the prepared G4 sintered funnel for filtration.

[0031] (4) Rinse the conical flask in step (3) three times with 50ml of ethanol. Combine the washings into the same G4 sintered funnel for filtration. Finally, rinse the filter residue with 50ml of ethanol.

[0032] (5) Dry the G4 sintered funnel containing the filter residue at 105°C to constant weight. The G4 sintered funnel at constant weight is denoted as W2. The weight difference between W2 and W1 is the weight of sodium carboxymethyl cellulose. According to the calculation formula: (W2-W1) / W 供 The content of sodium carboxymethyl cellulose in the gel drug was obtained by multiplying by 100%.

[0033] In this embodiment, lidocaine hydrochloride gel was used as the drug gelling agent. The source was Sandofa Co., Ltd. (Sandoxa Pharmaceutical Co., Ltd.), with a specification of 2% (30ml: 0.6g) and batch number 42620.

[0034] This embodiment is one of the most representative implementations of the method of the present invention. Therefore, based on Example 1, and referring to the 2020 edition of the Chinese Pharmacopoeia 9101 Analytical Method Validation Guidelines, methodological validation was performed on it. The validation content is as follows:

[0035] Example 2 Specificity Test

[0036] Weigh approximately 1.0 g each of water, lidocaine hydrochloride, methylparaben, propylparaben, and sodium carboxymethyl cellulose. The weights are measured precisely and the results are determined according to the method described in Example 1. The data are shown in Table 1.

[0037] The water used was purified water prepared in the pure water room of Yaoda Pharmaceutical Co., Ltd.; the lidocaine hydrochloride used was from Shandong Chenghui Shuangda Pharmaceutical Co., Ltd., batch number 018210501; the methylparaben used was from Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd., pharmaceutical excipient grade, batch number 20220801; the propylparaben used was from Shanghai Aladdin Biochemical Technology Co., Ltd., chemically pure, batch number I2111243; and the sodium carboxymethyl cellulose used was from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., pharmaceutical excipient grade, model SH-SJJ-4000, batch number 211221.

[0038] In subsequent verifications in Examples 3-6, unless otherwise specified, the information on the reagents used is the same as that in Example 2.

[0039] Table 1 Specificity Tests

[0040]

[0041] The results showed that the weight of the filter residue in the G4 sintered funnels corresponding to water, lidocaine hydrochloride, methylparaben, and propylparaben was almost zero (within ±0.0003 g); while in the G4 sintered funnel corresponding to sodium carboxymethyl cellulose, the weight of the filter residue was basically consistent with the sample weight, indicating that the method has good specificity.

[0042] Example 3 Repeatability Test

[0043] Accurately weigh 1.0 g of lidocaine hydrochloride gel with a sodium carboxymethyl cellulose content of approximately 3.5%, and weigh out 6 portions. Perform parallel determinations according to the method in Example 1. The data are shown in Table 2.

[0044] The lidocaine hydrochloride gel used was sourced from Sandofa Co., Ltd. (Sandofa Pharmaceutical Co., Ltd.), with a specification of 2% (30ml: 0.6g) and batch number 42620.

[0045] Table 2 Repeatability Tests

[0046]

[0047] The results showed that the average content of sodium carboxymethyl cellulose was 3.55% and the RSD was 0.4% in six parallel determinations of lidocaine hydrochloride gels, with good repeatability and meeting the validation requirements.

[0048] Example 4 Intermediate Precision Test

[0049] Six identical batches of lidocaine hydrochloride gel were measured in parallel by different personnel at different times, referring to the repeatability test in Example 6. The results are shown in Table 3.

[0050] The lidocaine hydrochloride gel used was sourced from Sandofa Co., Ltd. (Sandofa Pharmaceutical Co., Ltd.), with a specification of 2% (30ml: 0.6g) and batch number 42620.

[0051] Table 3 Intermediate Precision Test

[0052]

[0053] The results showed that in two repeatability tests, the average content of sodium carboxymethyl cellulose was 3.55% and 3.53% in six lidocaine hydrochloride gels, respectively, with RSDs of 0.4% and 0.3%. The relative deviation of the average content of sodium carboxymethyl cellulose in the six lidocaine hydrochloride gels measured in the two repeatability tests was 0.2%.

[0054] In this intermediate precision test, 12 lidocaine hydrochloride gels were measured in parallel by different personnel at different times. The average content of sodium carboxymethyl cellulose was found to be 3.54%, with an RSD of 0.4%, indicating good intermediate precision and meeting the validation requirements.

[0055] Example 5 Accuracy Test

[0056] Lidocaine hydrochloride gels with sodium carboxymethyl cellulose contents of approximately 1.0%, 3.5%, and 10.0% were prepared respectively, and were measured in parallel three times according to the method in Example 1. The results are shown in Table 4.

[0057] The lidocaine hydrochloride gel containing approximately 1.0% sodium carboxymethyl cellulose is composed of: 50.0015g water, 1.0168g lidocaine hydrochloride, 0.0306g methylparaben, 0.0159g propylparaben, and 0.5428g sodium carboxymethyl cellulose.

[0058] The composition of lidocaine hydrochloride gel with a sodium carboxymethyl cellulose content of approximately 3.5% is as follows: 50.0446g water, 1.0091g ​​lidocaine hydrochloride, 0.0301g methylparaben, 0.0151g propylparaben, and 1.8805g sodium carboxymethyl cellulose.

[0059] The composition of lidocaine hydrochloride gel containing approximately 10% sodium carboxymethyl cellulose is as follows: 50.0202g water, 1.0243g lidocaine hydrochloride, 0.0299g methylparaben, 0.0155g propylparaben, and 5.8857g sodium carboxymethyl cellulose.

[0060] Table 4 Accuracy Test

[0061]

[0062] The results showed that the recovery rate of sodium carboxymethyl cellulose in lidocaine hydrochloride gels with sodium carboxymethyl cellulose contents of approximately 1.0%, 3.5%, and 10.0% was in the range of 98.1% to 101.1%, with an RSD of 1.1%, which was highly accurate and met the validation requirements.

[0063] Example 6 Durability Test

[0064] I. Based on the method provided in Example 1, control is performed separately for each of the following:

[0065] A. Control the amount of lidocaine hydrochloride gel: In step (1), the sample weight of lidocaine hydrochloride gel is 0.5g and 2.0g;

[0066] B. Control the amount of ethanol used: In step (2), the amount of ethanol used is 30ml and 70ml;

[0067] C. Control the ultrasound time: In step (2), the ultrasound time is 5 min and 15 min;

[0068] E. Controlling ultrasonic power: In step (2), the ultrasonic power is 400W and 600W;

[0069] F. Control the static environment: In step (3), the static environment is refrigerated (2~8℃).

[0070] In addition, the other determination conditions and operations were not changed. The content of sodium carboxymethyl cellulose in the same batch of lidocaine hydrochloride gel was determined and compared with the detection amount of the determination method provided in Example 1. The results are shown in Table 5.

[0071] The lidocaine hydrochloride gel used was sourced from Sandofa Co., Ltd. (Sando Pharmaceutical Co., Ltd.), with a specification of 2% (30ml: 0.6g) and batch number 42620.

[0072] II. Lidocaine hydrochloride gels were prepared using three different types of sodium carboxymethyl cellulose (a, b, and c). The gels were measured in parallel three times according to the method in Example 1. The results are shown in Table 6.

[0073] The sodium carboxymethyl cellulose used was sourced from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., and was classified as pharmaceutical excipient grade. The grades were: a) SH-SJJ-4000, batch number 211221; b) SH-SJJ-1000, batch number 220812; and c) SH-SJJ-8000, batch number 220501.

[0074] The composition of lidocaine hydrochloride gel prepared using sodium carboxymethyl cellulose of types a, b, and c is as follows:

[0075] Type A lidocaine hydrochloride gel: 50.0446g water, 1.0091g ​​lidocaine hydrochloride, 0.0301g methylparaben, 0.0151g propylparaben, 1.8805g sodium carboxymethyl cellulose;

[0076] Type B lidocaine hydrochloride gel: 50.0164g water, 1.0004g lidocaine hydrochloride, 0.0302g methylparaben, 0.0156g propylparaben, 1.8692g sodium carboxymethyl cellulose;

[0077] Type A lidocaine hydrochloride gel: 50.0441g water, 1.0033g lidocaine hydrochloride, 0.0298g methylparaben, 0.0153g propylparaben, 1.9145g sodium carboxymethyl cellulose.

[0078] Table 5. Durability test (lidocaine hydrochloride gel of the same batch under different conditions)

[0079]

[0080] Table 6 Durability Tests (Different Types of Lidocaine Hydrochloride Gel under the Same Conditions)

[0081]

[0082] Validation results: Under various durability conditions, the content of sodium carboxymethyl cellulose in the same batch of lidocaine hydrochloride gel ranged from 3.50% to 3.58%, and the ratio of the amount measured under standard conditions ranged from 0.99 to 1.01. In lidocaine hydrochloride gel prepared with the same type of sodium carboxymethyl cellulose, the recovery rate of sodium carboxymethyl cellulose ranged from 98.6% to 101.4%, and the RSD was less than 5.0%, indicating good durability and meeting the validation requirements.

[0083] Through the above embodiments, the method for determining the sodium carboxymethyl cellulose content in gels provided by the present invention has undergone complete methodological validation. The validation results show that the method has high specificity, good repeatability, good intermediate precision, high accuracy, and good robustness. It can be used as a routine determination method for quality control of the sodium carboxymethyl cellulose content in lidocaine hydrochloride gel.

[0084] Comparative Example 1

[0085] A method for determining the sodium carboxymethyl cellulose content in a gel, the specific determination steps of which differ from those in Example 1 are: the amount of ethanol used in step (2) is 10 ml;

[0086] Everything else is exactly the same as in Example 1.

[0087] Comparative Example 2

[0088] A method for determining the sodium carboxymethyl cellulose content in a gel, which differs from Example 1 in that: ultrasonic treatment is not performed in step (2);

[0089] Everything else is exactly the same as in Example 1.

[0090] Comparative Example 3

[0091] A method for determining the sodium carboxymethyl cellulose content in a gel, which differs from Example 1 in that: in steps (3) and (4), the G4 sintered funnel is kept at constant weight at 80°C;

[0092] Everything else is exactly the same as in Example 1.

[0093] Comparative Example 4

[0094] A method for determining the sodium carboxymethyl cellulose content in a gel differs from Example 1 in that: in step (3), the ashless filter paper weighing at 105°C is filtered in a glass funnel, and in step (4), the ashless filter paper containing filter residue is weighed at 105°C in a glass funnel.

[0095] Everything else is exactly the same as in Example 1.

[0096] The lidocaine hydrochloride gels used in determining the sodium carboxymethyl cellulose content in Examples 1 and Comparative Examples 1 to 4 were from the same batch, and the results are summarized in Table 7 in terms of recovery rate.

[0097] Table 7 Recovery rates of Example 1 and Comparative Examples 1 to 4

[0098]

[0099] From Tables 1 to 6, it can be seen that the embodiments of the present invention are the most representative implementation methods. The measurement method of the present invention has passed complete methodological verification, so the measurement accuracy is high and the reproducibility is good.

[0100] As shown in Table 7, in Comparative Example 1, due to the low amount of ethanol used for precipitating sodium carboxymethyl cellulose, some sodium carboxymethyl cellulose failed to precipitate, resulting in a reduced amount of filter residue in the funnel and a lower final content result. Since the amount of sodium carboxymethyl cellulose precipitated is correlated with the amount of ethanol used within a certain range, the RSD is still within an acceptable range. In Comparative Example 2, because the precipitation step did not involve ultrasound, the precipitated sodium carboxymethyl cellulose easily agglomerated and adsorbed onto the bottle wall, failing to transfer to the funnel, resulting in a lower final content result. Furthermore, due to the varying adsorption conditions of different samples, the final content result was lower. The RSD is too high. In Comparative Example 3, the temperature at which the final constant weight was reached was too low, which was insufficient to completely evaporate the residual moisture or ethanol in the filter residue, resulting in a higher measured content. Since all three samples were constant-weighted at 80℃, the residual moisture or ethanol levels should be similar, so the RSD is still within an acceptable range. In Comparative Example 4, the use of ashless filter paper resulted in trace amounts of components that could be washed away by the solvent, leading to a decrease in the total weight of the filter paper and filter residue after constant weight. This resulted in a lower measured content, and it was also impossible to ensure that the washing degree of each filter paper was consistent, hence the RSD is too high.

[0101] In summary, the method provided by this invention is a gravimetric analysis method that relies on the different solubility properties of raw materials and excipients in gel-like drugs to separate and determine the content of sodium carboxymethyl cellulose. The method involves three steps: precipitation, filtration, and drying. It is simple to operate, requiring only an oven and an electronic balance, and has relatively low requirements for experimental equipment and the technical level of the experimental personnel. Furthermore, it avoids the use of commercially available reference standards or standards of varying quality, thus reducing costs and significantly improving the parallelism and reproducibility of the detection. This method can meet the detection requirements for sodium carboxymethyl cellulose content in drug gels.

[0102] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit and essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

[0103] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for determining the sodium carboxymethyl cellulose content in a gel, characterized in that, Includes the following steps: (1) Accurately weigh 0.5–2.0 g of the drug gel containing sodium carboxymethyl cellulose, denoted as W. 供 Placed in an Erlenmeyer flask; (2) Add 30-70 ml of ethanol to the drug gel in step (1), shake thoroughly, and then sonicate. (3) Dry the clean G4 sintered funnel at 105°C to constant weight and set aside. The G4 sintered funnel with constant weight at this time is recorded as W1. Place the ethanol solution of the drug gel in step (2) under refrigeration or room temperature conditions and let it stand for 0.5 to 2 hours. Then transfer all the substances in the conical flask to the prepared G4 sintered funnel for filtration. (4) Rinse the conical flask in step (3) three times with 50ml of ethanol. Combine the washings into the same G4 sintered funnel for filtration. Finally, rinse the filter residue with 20-100ml of ethanol. (5) Dry the G4 sintered metal funnel containing the filter residue at 105℃ to constant weight. The G4 sintered metal funnel at this constant weight is denoted as W2. The weight difference between W2 and W1 is the weight of sodium carboxymethyl cellulose. The formula is: (W2 - W1) / W 供 ×100% yields the sodium carboxymethyl cellulose content in the gel drug; The drug gel is lidocaine hydrochloride gel.

2. The method for determining the sodium carboxymethyl cellulose content in a gel according to claim 1, characterized in that, In step (1), the sodium carboxymethyl cellulose content in the drug gel is 1.0-10.0%.

3. The method for determining the sodium carboxymethyl cellulose content in a gel according to claim 2, characterized in that, In step (1), the sodium carboxymethyl cellulose content in the drug gel is 3.5%.

4. The method for determining the sodium carboxymethyl cellulose content in a gel according to claim 1, characterized in that, In step (1), the amount of the drug gel used for testing is 1g.

5. The method for determining the sodium carboxymethyl cellulose content in a gel according to claim 1, characterized in that, In step (2), the amount of ethanol used is 50 ml.

6. The method for determining the sodium carboxymethyl cellulose content in a gel according to claim 1, characterized in that, In step (2), the ultrasound time is 5 to 15 minutes.

7. A method for determining the sodium carboxymethyl cellulose content in a gelling agent according to claim 1 or 6, characterized in that, In step (2), the ultrasound time is 10 minutes.

8. The method for determining the sodium carboxymethyl cellulose content in a gelling agent according to claim 1, characterized in that, In step (3), let it stand for 1 hour.

9. The method for determining the sodium carboxymethyl cellulose content in a gel according to claim 1, characterized in that, In step (3), the refrigeration conditions are 2 to 8°C; the room temperature conditions are 20 to 25°C.

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