A suspending agent compound of sodium carboxymethyl cellulose and its preparation method

Abstract

The application discloses a suspension aid compound of sodium carboxymethyl cellulose, relates to the field of medicine and chemical industry, and is composed of sodium carboxymethyl cellulose and sodium alginate with a weight ratio of 10:1-2. The two components are prepared through acidification co-precipitation, resuspension and redispersion, and spray drying. The compound solves the problems of difficult resuspension and easy agglomeration of sodium carboxymethyl cellulose, and has excellent viscosity recovery after high shear in application.

Description

Technical Field

[0001] This invention relates to suspending agent complexes of carboxymethyl cellulose derivatives, particularly a method for preparing a complex of sodium carboxymethyl cellulose and sodium alginate, and its application in industrial fields or in food and pharmaceutical excipients. Background Technology

[0002] Sodium carboxymethyl cellulose (CMC-Na, listed in the Chinese Pharmacopoeia as "sodium carboxymethyl cellulose") is a water-soluble anionic cellulose ether, prepared from natural cellulose through alkalization and etherification reactions. Sodium carboxymethyl cellulose possesses excellent water solubility, biocompatibility, and a controllable molecular structure, and is widely used in the food, pharmaceutical, daily chemical, and petroleum industries.

[0003] In the food and pharmaceutical industries, CMC-Na is widely used in various dosage forms such as health foods, dairy products, oral suspensions, and dry syrups due to its thickening, suspending, binding, and emulsifying functions. It is generally considered a non-toxic and non-irritating pharmaceutical excipient. When used as a suspending agent, the molecular chains of CMC-Na form an entangled and cross-linked structure in solution. It has high viscosity when standing, effectively inhibiting particle sedimentation. When subjected to shear force, the viscosity decreases, facilitating processing and transportation. After shearing stops, the viscosity rebounds. This characteristic of being stable when standing and flowing easily under shear effectively solves the contradiction between storage stability and flowability during use.

[0004] In industrial applications such as oil drilling, CMC-Na is an important component of drilling fluids, primarily acting as a viscosity improver, filtration reducer, and rheology modifier. Drilling fluids are subjected to intense shearing at high speeds at the drill bit. CMC-Na, through its viscosity-enhancing effect, carries drill cuttings and forms a filter cake on the wellbore to reduce fluid loss, while simultaneously regulating rheology to adapt to different downhole conditions.

[0005] Although sodium carboxymethyl cellulose is an important industrial material and excipient in the food and pharmaceutical industries, some of its inherent characteristics limit its application scenarios or increase its application costs.

[0006] For example, sodium carboxymethyl cellulose (CMC) dissolves in water and forms "encapsulated clumps." Its molecular chains are rich in hydrophilic groups such as carboxyl groups, which easily aggregate due to intermolecular hydrogen bonding. Furthermore, its high viscosity causes the surface to dissolve first, forming a viscous film that hinders further water penetration. In industrial applications, special handling procedures must be followed to prevent clumping from affecting efficacy or subsequent production operations. In the production of solid pharmaceutical dosage forms, CMC is typically dissolved and added in liquid form. The preparation of the CMC solution requires even sprinkling into purified water with continuous stirring, followed by sufficient dissolution time. This not only increases costs due to operational simplicity and production cycle time but also poses a risk of increased microbial load on the product due to prolonged dissolution time. Sodium carboxymethyl cellulose produced by existing technology has poor powder properties and a large angle of repose in its flowability. If it is directly added to the formulation production by mixing with dry powder, it is easy to produce uneven mixing, which affects the batch quality uniformity of the formulation. When used as the main suspending agent in drug suspensions, it is often prone to clumping and agglomeration during the reconstitution operation before patient administration, which may hinder its clinical application. Or, when using hot water or high-speed shaking, the solution viscosity drops rapidly, which often fails to provide the ideal suspending effect. Therefore, in the production of pharmaceutical formulations, it is often made into a suspension solution rather than a dry suspension (i.e., the powdered drug formulation is packaged into an oral solution bottle, and the patient adds warm water and shakes to dissolve it into a suspension solution before use).

[0007] Sodium carboxymethyl cellulose is a typical pseudoplastic fluid; as the shear rate increases, the solution viscosity decreases rapidly, the molecular chains stretch and align themselves along the shear direction, the network structure is disrupted, and the flow resistance decreases. Although its thixotropic recovery behavior is a reversible process in which viscosity gradually recovers after the shear force is removed, an excessively long recovery time often affects its effectiveness in process applications or inevitably increases the concentration used.

[0008] The existing technology published by Li Zhongbao et al. in Liaoning Journal of Pharmaceuticals and Clinical Medicine, titled "Improvement of the Preparation Process of Sodium Carboxymethyl Cellulose Gel", suggests that dissolving sodium carboxymethyl cellulose in glycerol first to prepare a gel can facilitate subsequent solutions. However, this introduces glycerol, which is not conducive to the food and pharmaceutical industries, which have strict control over ingredients.

[0009] Patent CN121495003A discloses a preparation method: cellulose, solid alkali, and solid etherifying agent are directly mixed in a dry process, then a flowable wet powder is formed using a humidifying medium, followed by mechanical activation and heat treatment to finally obtain the product. However, this preparation method is cumbersome, and the resulting product is mainly used as a key binder in dust suppressants. It cannot solve the problems of slow dissolution and uneven dispersion that occur when sodium carboxymethyl cellulose is used directly as a powder product.

[0010] Patent CN121895640A discloses a method for preparing CMC by spraying a special porous nanomaterial (a gradient mesoporous silica core-shell heterostructure with a ZnO template) onto the surface of CMC particles, followed by drying to obtain fast-dissolving CMC. While this strategy of externally introducing nanomaterials with specific physical structures to regulate the dissolution interface process of polymer materials can solve the dissolution problem, the process is complex and its compliance is questionable. This technology only focuses on the dissolution rate itself, neglecting the dispersibility and non-caking properties of the powder in dry powder mixing scenarios, as well as the important property of maintaining viscosity after high shear.

[0011] In the field of suspending agents, sodium alginate can reduce the sedimentation rate of particles by increasing the viscosity of the dispersion medium. Simultaneously, due to its unique molecular chain entanglement ability, it can form a gel network structure under static conditions, providing physical barrier and spatial stability. However, it suffers from defects similar to sodium carboxymethyl cellulose (CMC). Because of the differences in the molecular chain groups of the two materials, there are some literature reports exploring whether they can exert a synergistic effect. For example, Zhu Ping et al. from the Key Laboratory of Green Processing and Functionalization of Novel Textile Materials of the Ministry of Education and Wuhan University of Science and Technology published "Compatibility Study of Carboxymethyl Cellulose and Sodium Alginate." This study investigated the compatibility of different ratios of sodium carboxymethyl cellulose and sodium alginate from a compatibility perspective. It involved the physical mixing of sodium carboxymethyl cellulose and sodium alginate, and the results showed a narrow compatibility range.

[0012] Given the technical biases in the research of compound formulations of sodium carboxymethyl cellulose and sodium CMC-alginate, there is an urgent need to provide an improved suspending agent that is safe, simple to process, and can also ensure powder dispersibility and rapid resolution. Summary of the Invention

[0013] In collecting questions from customers using sodium carboxymethyl cellulose, the inventors, through continuous improvement of product quality, invented a compound by preparing sodium carboxymethyl cellulose and sodium alginate, which can effectively solve the above problems.

[0014] Sodium carboxymethyl cellulose (CMC-Na) and sodium alginate are both naturally derived anionic polysaccharide polymers. The former is a semi-synthetic cellulose derivative, while the latter is a natural polymer extracted from brown algae. Both exhibit good biocompatibility, biodegradability, and thickening and suspending properties. Both components are clearly listed in the Chinese Pharmacopoeia and can be safely used in pharmaceuticals. They are rich in hydroxyl and carboxyl groups, respectively, which can form intermolecular hydrogen bonds. The two substances combine to enhance the system's stability and improve viscosity. Furthermore, under appropriate ratios, after the acidification, precipitation, resolution, redispersing, and spray drying processes of this invention, they help improve the surface agglomeration problem of single-component powders, reducing the tendency for powder clumping caused by strong hydrogen bond aggregation. This improves the powder's flowability and dispersibility, making the composite powder highly operable in dry powder mixing processes.

[0015] This invention is achieved through the following means:

[0016] In a first aspect, the present invention provides a method for preparing a suspending agent compound of sodium carboxymethyl cellulose, comprising the following steps:

[0017] S1, Acidification Co-precipitation:

[0018] Add sodium carboxymethyl cellulose and sodium alginate to purified water and stir until dissolved. Add 1M hydrochloric acid solution dropwise to adjust the pH to 2.5-3.5. After the pH reaches the required value, continue stirring at 10-25 rpm for 30-90 minutes until flocculent matter or precipitate is produced. Centrifuge to collect the precipitate.

[0019] S2, Redissolution and redispersion:

[0020] Dissolve the precipitate in purified water, add citrate-sodium citrate buffer to redissolve, adjust the pH to 6.5-7.5, and continue stirring the reaction for 60-120 minutes after the pH is reached.

[0021] S3, Spray drying

[0022] The obtained liquid material is spray-dried with a nozzle diameter of 0.5-2.0 mm, an inlet air temperature of 140-170℃, an outlet air temperature of 75-95℃, and a feed rate of 30-60 mL / min. The dried powder is then collected to obtain the compound.

[0023] Furthermore, the pH adjustment of the hydrochloric acid solution is carried out in two stages;

[0024] The first stage involves stirring at 150-300 rpm and adding 1M hydrochloric acid solution at a rate of 1-5 ml / min. When the pH of the solution drops to 3.5-4.0, the second stage of acid adjustment is initiated.

[0025] The stirring speed in the second stage is 10-25 rpm, and the dropping speed of 1M hydrochloric acid solution is 0.2-0.8 ml / min.

[0026] Furthermore, the pH value of the citrate-sodium citrate buffer solution is 5-6.

[0027] Furthermore, after the stirring reaction in step S2 is completed, activated carbon is added to the complex solution for stirring and adsorption. The solution is then filtered through a microporous membrane and passed through an ion exchange resin column to remove metal ions. Using this preparation process, sodium carboxymethyl cellulose-sodium alginate complex can be decolorized, impurities and metal ions removed, and the resulting product can meet the needs of food and general pharmaceutical excipients.

[0028] Furthermore, the amounts of sodium carboxymethyl cellulose and sodium alginate used are in a mass ratio of sodium carboxymethyl cellulose: sodium alginate = 10:1-2.

[0029] Furthermore, the sodium carboxymethyl cellulose, on a dry basis, should have a degree of substitution of 0.7–1.0; the sodium alginate has a molecular weight of 30,000–100,000. Different ratios of rigid and flexible chains yield compounds with suitable apparent viscosity and optimal rheological stability. Selecting sodium carboxymethyl cellulose with a suitable degree of substitution, combined with sodium alginate with a molecular weight of 30,000–100,000, ensures rapid hydration while avoiding excessive hydrophilicity that could lead to film formation.

[0030] Secondly, the present invention also provides the application of the compound in the production processes of oil drilling, building cement materials, building gypsum materials, coatings, inks, pesticide suspensions, daily creams and chemicals, and daily chemical emulsions, where the viscosity recovers quickly after high-speed shearing and the viscosity value does not decrease.

[0031] Furthermore, after the compound of the present invention undergoes decolorization with activated carbon, removal of impurities, and removal of metal ions with an ion exchange resin column, the present invention also provides the application of the compound in food.

[0032] Thirdly, the present invention provides a method for preparing a sodium carboxymethyl cellulose compound of pharmaceutical excipient grade for injection. The preparation method involves replacing the purified water in the preparation method of food-grade compound with water for injection, and then passing the feed solution through an ion exchange resin column and then through a 1.0 μm pre-filter and a 0.22 μm sterilization filter for two-stage filtration to obtain the sodium carboxymethyl cellulose compound of pharmaceutical excipient grade for injection.

[0033] Fourthly, this invention provides the application of sodium carboxymethyl cellulose compound of injection grade pharmaceutical excipient in human pharmaceutical injections and veterinary drug injections.

[0034] The beneficial effects of this invention are as follows:

[0035] 1. The sodium carboxymethyl cellulose compound provided by the present invention improves the agglomeration tendency of the single component, giving the compound good flowability and dispersibility. It can be directly used in dry powder mixing process without pre-dissolving, simplifying the process flow, reducing energy consumption, and also reducing the risk of microbial load in drug production.

[0036] 2. The main component of the sodium carboxymethyl cellulose compound provided by this invention is sodium carboxymethyl cellulose, which is used as a major suspending agent in drug suspensions. Because it is prone to clumping and agglomeration during dissolution, it is often supplied in the form of a suspension solution in clinical practice. The compound of this invention solves this problem, making the drug suspension easier to dissolve, disperse and resuspend. It also makes it easier to make the suspension solution into a dry suspension (the suspension powder is transferred into the oral liquid bottle, and the patient adds warm water to prepare an oral suspension solution before taking it), which enriches the dosage form of drug preparations and reduces a series of problems such as transportation and drug stability.

[0037] 3. Sodium carboxymethyl cellulose is a typical pseudoplastic fluid, exhibiting a slightly longer thixotropic recovery time and a significant decrease in viscosity after high shear. This invention unexpectedly discovered that when sodium carboxymethyl cellulose and sodium alginate are compounded in a specific ratio and with specific mass parameters, the system exhibits rapid viscosity recovery without a significant decrease under high-speed shearing conditions (such as sand milling, homogenization, pumping, and spraying). This ensures excellent suspending properties in fields subjected to high shear operations, such as oil extraction, pesticide suspensions, and water-based coatings. Attached Figure Description

[0038] Figure 1 Sample 1 of group 3 in test example

[0039] Figure 2 The sample after reconstitution in group 2 of test example 3.

[0040] Figure 3 The sample after reconstitution in group 3 of test example 3.

[0041] Figure 4 The sample after reconstitution in group 4 of test example 3.

[0042] Figure 5 The graph shows the trend of viscosity recovery rate of each group of samples in Experiment Example 4. Detailed Implementation

[0043] The following description illustrates exemplary embodiments of the present invention, including various details to aid understanding, and should be considered merely exemplary. Therefore, those skilled in the art will recognize that various changes and modifications can be made to the embodiments described herein without departing from the scope and spirit of the invention. Similarly, for clarity and brevity, descriptions of well-known functions, operations, and structures are omitted in the following description.

[0044] Unless otherwise defined, the technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. While similar or identical methods and materials may be applied in experimental or practical applications, the present invention describes materials and methods hereinafter. In case of conflict, the definitions included herein shall prevail.

[0045] Unless otherwise specified, all experiments in the following experiments were conducted under standard conditions or conditions recommended by the manufacturer. The active pharmaceutical ingredients (APIs) or excipients, as well as the reagents or instruments used, unless otherwise specified, are all commercially available products. Unless otherwise stated, all percentages, ratios, proportions, or quantities are by weight. Unless otherwise specified, all materials in this invention are commercially available pharmaceutical-grade excipients, provided they do not significantly affect the overall efficacy of the formulation.

[0046] Example 1: Preparation of a suspending compound of sodium carboxymethyl cellulose

[0047] formula

[0048] Preparation process:

[0049] S1, Acidification Co-precipitation:

[0050] Sodium carboxymethyl cellulose and sodium alginate were added to 5 times their weight of purified water (i.e., 28.75 kg) and stirred until dissolved at 250 rpm. 1M hydrochloric acid solution was added dropwise at a rate of 3 ml / min to adjust the pH. When the pH reached 3.8, the stirring speed was reduced to 20 rpm, and the 1M hydrochloric acid solution was added at a rate of 0.5 ml / min. When the pH reached 2.8, the addition was stopped, and stirring was continued at 20 rpm for 60 minutes until flocculent matter or precipitate formed. The precipitate was collected by centrifugation.

[0051] S2, Redissolution and redispersion:

[0052] Dissolve the precipitate in 5 times the mass of the original dry material in purified water (i.e., 28.75 kg), add citrate-sodium citrate buffer solution with pH 5.5 to redissolve, adjust the pH value to 7.2, and continue stirring the reaction for 90 min after the pH value reaches the requirement.

[0053] Preparation method of citrate-sodium citrate buffer solution with pH 5.5:

[0054] To prepare a 0.1 mol / L citric acid solution: Weigh 21.01 g of citric acid (C6H8O7·H2O, molecular weight 210.14), dissolve it in distilled water and bring the volume to 1000 ml, then shake well.

[0055] To prepare a 0.1 mol / L sodium citrate solution: Weigh 29.41 g of sodium citrate (C6H5Na3O7·2H2O, molecular weight 294.12), dissolve it in distilled water and bring the volume to 1000 ml, then shake well.

[0056] Take approximately 5.95 ml of the above 0.1 mol / L citric acid solution and approximately 14.05 ml of the 0.1 mol / L sodium citrate solution, measure the pH using a precision pH meter, and add a small amount of 0.1 mol / L citric acid solution or 0.1 mol / L sodium citrate solution to adjust the pH to 5.5, thus obtaining the 0.1 mol / L citric acid-sodium citrate buffer solution (pH 5.5).

[0057] S3, Spray drying

[0058] The obtained liquid was spray-dried with a nozzle diameter of 1.0 mm, an inlet air temperature of 150°C, an outlet air temperature of 85°C, and a feed rate of 45 mL / min. The dried powder was then collected to obtain the compound.

[0059] Example 2 Preparation of a suspending compound of sodium carboxymethyl cellulose

[0060] formula

[0061] Same as in Example 1.

[0062] Preparation process:

[0063] S1, Acidification Co-precipitation:

[0064] Sodium carboxymethyl cellulose and sodium alginate were added to 8 times their weight of purified water and stirred until dissolved at 300 rpm. 1M hydrochloric acid solution was added dropwise at a rate of 5 ml / min to adjust the pH. When the pH reached 4.0, the stirring speed was reduced to 25 rpm, and the 1M hydrochloric acid solution was added at a rate of 0.8 ml / min. When the pH reached 2.6, the addition was stopped, and stirring was continued at 25 rpm for 90 minutes until flocculent material or precipitate formed. The precipitate was collected by centrifugation.

[0065] S2, Redissolution and redispersion:

[0066] Dissolve the precipitate in purified water at 8 times the mass of the original dry material, add citrate-sodium citrate buffer solution at pH 5.3 to redissolve, adjust the pH to 7.0, and continue stirring the reaction for 120 min after the pH reaches the required value.

[0067] S3, Spray drying

[0068] The obtained liquid was spray-dried with a nozzle diameter of 0.5 mm, an inlet air temperature of 160℃, an outlet air temperature of 90℃, and a feed rate of 60 mL / min. The dried powder was then collected to obtain the compound.

[0069] Example 3 Preparation of a suspending compound of sodium carboxymethyl cellulose

[0070] formula

[0071] Same as in Example 1.

[0072] Preparation process:

[0073] S1, Acidification Co-precipitation:

[0074] Add sodium carboxymethyl cellulose and sodium alginate to 4 times their weight of purified water and stir until dissolved. Stir at 160 rpm and add 1M hydrochloric acid solution dropwise to adjust the pH at a rate of 2 ml / min. When the pH of the solution reaches 3.6, reduce the stirring speed to 10 rpm and add the 1M hydrochloric acid solution at a rate of 0.2 ml / min. When the pH reaches 3.0, stop adding the solution and continue stirring at 10 rpm for 45 min until flocculent matter or precipitate is formed. Centrifuge to collect the precipitate.

[0075] S2, Redissolution and redispersion:

[0076] Dissolve the precipitate in purified water at 4 times the mass of the original dry material, add citrate-sodium citrate buffer solution at pH 5.6 to redissolve, adjust the pH to 7.3, and continue stirring the reaction for 60 minutes after the pH reaches the required value.

[0077] S3, Spray drying

[0078] The obtained liquid was spray-dried with a nozzle diameter of 2.0 mm, an inlet air temperature of 170℃, an outlet air temperature of 95℃, and a feed rate of 40 mL / min. The dried powder was then collected to obtain the compound.

[0079] Examples 4-6 Preparation of sodium carboxymethyl cellulose suspending agent complexes with different degrees of substitution

[0080] formula

[0081] Preparation process:

[0082] Same as Example 1.

[0083] Examples 7-10: Preparation of sodium carboxymethyl cellulose suspending agent complexes with different dosage ratios

[0084] formula

[0085] Except for the dosage, the source and type of materials are the same as in Example 1. The specific dosages for each example are as follows:

[0086] Preparation process:

[0087] Same as Example 1.

[0088] Example 11 Preparation of a suspending compound of sodium carboxymethyl cellulose (a pharmaceutical excipient grade) for injection

[0089] formula

[0090] Same as in Example 1.

[0091] Preparation process:

[0092] S1, Acidification Co-precipitation:

[0093] Except for replacing purified water with water for injection, it is the same as S1 in Example 1.

[0094] S2, Redissolution and redispersion:

[0095] Except for replacing purified water with water for injection and adding the subsequent step of "continuing to stir the reaction for 90 minutes after the pH value reaches the required level", it is the same as S2 in Example 1.

[0096] The added process is as follows:

[0097] Activated carbon (0.1% by weight / volume, g / L) was added to the solution after stirring and adsorption for 20 min. After filtration through a microporous membrane, metal ions were removed by passing through an ion exchange resin column, and then the solution was subjected to two-stage filtration through a 1.0 μm pre-filter and a 0.22 μm sterilization filter.

[0098] S3, Spray drying

[0099] Same as in Example 1.

[0100] Comparative Example 1: Preparation of Sodium Carboxymethyl Cellulose Suspension Compound by Physical Mixing

[0101] formula

[0102] Preparation process:

[0103] S1. Pass both materials through a 60-mesh sieve, weigh them, and set aside.

[0104] S2. Weigh the materials using the equal-volume incremental method and place them in a three-dimensional motion mixer, mixing for 15 minutes each time.

[0105] (The equal-volume incremental addition method involves weighing 0.75 kg of sodium alginate and 0.75 kg of sodium carboxymethyl cellulose, mixing for 15 minutes, then adding 1.5 kg of sodium carboxymethyl cellulose and mixing for another 15 minutes, and so on, until the last remaining amount of sodium carboxymethyl cellulose is added. This ensures that the sample is mixed evenly.)

[0106] Comparative Example 2: Preparation of Sodium Carboxymethyl Cellulose Suspension Compound by Spray Drying

[0107] formula

[0108] Preparation process:

[0109] S1, Dissolve

[0110] Sodium carboxymethyl cellulose and sodium alginate were added to 5 times their weight of purified water (i.e., 28.75 kg), stirred until dissolved, and stirred for another 60 minutes to allow the reaction to proceed.

[0111] S2, Spray drying

[0112] The obtained liquid was spray-dried with a nozzle diameter of 1.0 mm, an inlet air temperature of 150°C, an outlet air temperature of 85°C, and a feed rate of 45 mL / min. The dried powder was then collected to obtain the compound.

[0113] Comparative Example 3: Preparation of Ibuprofen Suspension

[0114] Suspension formulation

[0115] Suspension preparation process:

[0116] 1. Take 80% purified water, add sodium carboxymethyl cellulose, stir, and let stand until it is completely dissolved;

[0117] 2. Add ibuprofen, sucrose powder, sucralose, and fruit flavoring in sequence and stir until dissolved;

[0118] 3. Pour the sample into an oral solution bottle at 100ml / bottle to obtain ibuprofen suspension solution.

[0119] Dry suspension formulation

[0120] The suspending agents in the formulations are compound preparations prepared in Example 1, Comparative Example 1, and Comparative Example 2, respectively.

[0121] Dry suspension preparation process:

[0122] 1. Mix all the above materials thoroughly.

[0123] 2. Dispense the sample as ibuprofen (2g / bottle) in dry powder form into oral solution bottles (reconstitute before use) to obtain ibuprofen dry suspension.

[0124] Experimental Example 1: Powder Geometric Determination of Samples

[0125] Sodium carboxymethyl cellulose and sodium alginate are both common suspending agents used in food and pharmaceuticals. However, due to the inherent characteristics of these materials, such as their fibrous form and abundant hydrophilic groups in their molecular structure, they have poor flowability and are prone to clumping. This poses a challenge when used in the dry mixing process of powders in food and pharmaceutical production, often affecting the uniformity of mixing and consequently the quality of the finished product.

[0126] To demonstrate the significant improvement in the powder properties of the compound of the present invention, the bulk density, tap density, Karl index, and angle of repose were systematically measured with reference to the relevant standards and guidelines of the Chinese Pharmacopoeia.

[0127] Bulk density: The density of excipient powder in a loose state. Loose state refers to the state formed when a powder sample is poured into a container without compressive force.

[0128] The bulk density was determined using the first method of the calibrated barrel recording method according to the Chinese Pharmacopoeia 2025 edition 0993.

[0129] Tapped density: refers to the packing density of powder in a tapped state. The tapped state is the state of the powder column when the powder sample in the container is tapped downwards at a specific frequency until the volume no longer changes.

[0130] The tap density was determined using the first method according to Chinese Pharmacopoeia 2025 edition 0993.

[0131] Powder compressibility: The interaction between powder particles affects not only the packing properties of the powder but also its flowability. Therefore, comparing the difference between bulk density and tapped density can effectively assess the relative importance of the interaction between powder particles. The parameter differences between loose and tapped states of powder are also commonly used, with the Karl Fischer index serving as an evaluation index for powder flowability.

[0132] Carr index = (tap density - loose density) ÷ tap density × 100%

[0133] Angle of repose: The angle of repose has been widely used in many disciplines to characterize the flow properties of solids. It is a characteristic parameter related to interparticle friction or relative motion resistance between particles.

[0134] The test was conducted according to the recommended test method in the "Draft Standard for Guiding Principles of Powder Flowability Determination" issued by the Pharmacopoeia Commission.

[0135] Measurement results:

[0136] Experimental conclusion:

[0137] The compound of CMC-Na and sodium alginate prepared by the present invention through a three-step process of acidification co-precipitation, resolution and redispersion, and spray drying has significantly improved powder properties compared with pure raw materials and physical mixtures, and simple dissolution and spray drying mixtures.

[0138] The angles of repose of Examples 1, 3, and 11 were 30°, 29°, and 31°, respectively, and the Karl Fischer indexes were 14%, 13%, and 15%, respectively. All of them reached the "good" to "excellent" flowability level, which was significantly better than the raw materials and the two comparative examples.

[0139] Examples 2, 5, 6, 8, and 9 have an angle of repose between 32 and 35°, a Karl Fischer index between 15 and 18%, and good flowability, meeting the requirements for solid dosage form production.

[0140] The angle of repose and Karl quotient of Example 4 (sodium carboxymethyl cellulose degree of substitution 0.6) and Example 10 (sodium alginate dosage 2.0 kg) are relatively high, indicating that the performance decreases when the formulation deviates from the preferred range.

[0141] Experimental Example 2: Determination of Reconstitution Effect of Representative Batch Samples

[0142] To demonstrate that the reconstitution effect of the compound provided by the present invention has been greatly improved, the principle of shaking dissolution in the "Equilibrium Solubility Determination Method" under the Solubility Measurement Guidelines of the 2025 edition of the Chinese Pharmacopoeia was referenced, and the water bath constant temperature shaker method was established for evaluation in combination with the actual application scenario of the present invention.

[0143] Instrument manufacturer: Tianjin Caiboteri Instrument Equipment Co., Ltd., Instrument model: SYWF-50

[0144] Vibration frequency: 100 Hz, measurement temperature: 40℃, measurement concentration: 1% (i.e., 10 g / L)

[0145] The time it takes for the powder to be completely dispersed and dissolved by visual inspection, with no visible particles, no clumping, and the solution in a homogeneous colloidal state, is defined as the complete dissolution time (unit: seconds). When the time exceeds 600 seconds, the measurement is stopped.

[0146] Measurement results:

[0147] Experimental conclusion:

[0148] The above experimental results show that the preparation method of the present invention has a significant improvement on the resolubility of the compound. Among them, the process of restoring the ionization of carboxyl groups during acid precipitation and resolubilization is the key step in changing the hydrophilicity of the particles and making them less prone to agglomeration.

[0149] Under the optimized formulation (degree of substitution 0.86–1.0, sodium alginate molecular weight 60–100 kD, dosage 0.5–1.0 kg) and process parameters, the resulting compound can be completely dispersed in water within 200 seconds, with excellent resolubility.

[0150] Even if the formulation deviates from the preferred range (such as in Examples 4 and 10), the reconstitution time of the compound is still controlled within 250 seconds, which is significantly better than all comparative examples and the two simple components.

[0151] In summary, the sodium carboxymethyl cellulose-sodium alginate compound prepared by this invention can be rapidly and uniformly dispersed in water. When used as a suspending agent, it has convenient operation and stable suspension effect, and has significant practical value.

[0152] Experimental Example 3: Performance Testing of Suspension Complexes for Dry Suspension of Drugs

[0153] To demonstrate that the suspending agent compound prepared in this invention can be directly used in the production of dry suspensions, thereby promoting the transformation of existing clinical suspensions into dry suspensions to reduce costs and improve quality, samples were prepared according to Comparative Example 3, and the difficulty of reconstitution and the effect after reconstitution of each simulated group of samples were investigated.

[0154] Reconstitution: Add cooled boiled water, simulate clinical use, and shake vigorously for 3 minutes. Sedimentation volume ratio is tested according to the requirements of the Chinese Pharmacopoeia.

[0155] Test Results

[0156]

[0157] Images of the samples after reconstitution are attached. Figure 1 Appendix Figure 2 Appendix Figure 3 Appendix Figure 4 .

[0158] Experimental Conclusion: The experimental results show that the suspending agent compound prepared in this invention exhibits excellent resolvability in dry suspensions, forming a uniform and stable suspension system. However, in Comparative Examples 1 and 2, because the suspending agent formulations did not follow the preparation method provided by this invention, lumps appeared after resolvability, making it difficult to reconstitute a uniformly dispersed suspension. In summary, the suspending agent compound of this invention performs excellently in reconstituted suspensions and can be directly used in the production of dry suspensions, possessing significant application value.

[0159] Example 4: Determination of high-shear viscosity of representative batches of samples

[0160] To demonstrate the viscosity recovery over time of the suspending agent compound prepared in this invention after its viscosity is disrupted during application (such as high-intensity rotation of oil well heads, homogenization, and high-shear processes in food and pharmaceutical production), this experiment was conducted.

[0161] Tests were conducted using the viscosity test under the "Sodium Carboxymethyl Cellulose" section of the 2025 edition of the Chinese Pharmacopoeia. The sodium carboxymethyl cellulose concentration was 2%, and the test temperature was 25°C.

[0162] The sodium carboxymethyl cellulose used in Example 1 and the test samples prepared in the corresponding examples and comparative examples were prepared to a concentration of 2% (i.e., 20 g / L). The initial viscosity value was measured, and then the samples were placed in a water bath at 50°C and sheared at high shear at 15,000 rpm for 30 minutes. After that, they were placed in a cold water bath to cool to room temperature. The viscosity of each sample was measured precisely at 30 min and 60 min after the shearing was completed.

[0163] Test results:

[0164]

[0165] The trend graphs of each group of samples are attached. Figure 5 .

[0166] Experimental Conclusion: This experiment shows that under high-intensity shearing, such as the sodium carboxymethyl cellulose group tested, its viscosity decreases due to the untangling of molecular chains under sustained high-intensity shearing. However, after the shearing stops, its physical entanglement structure can reform, but the degree of recovery is limited. Compared with the recovery rate of approximately 67% for sodium carboxymethyl cellulose alone and the recovery rate of the two comparative groups (77%), the sample of Example 1 of this invention, prepared by the process of this invention, exhibits a synergistic effect, significantly improving the reconstruction ability of the molecular network, achieving rapid viscosity recovery and a high recovery rate, fully demonstrating the beneficial effects of this invention.

[0167] It should be emphasized that the foregoing embodiments are merely illustrative of preferred implementations of the present invention and are not intended to limit the scope of protection of the present invention. This application also provides a computer-readable storage medium having computer program instructions stored thereon.

Claims

1. A method for preparing a suspending agent compound of sodium carboxymethyl cellulose, characterized in that, Includes the following steps: S1, Acidification Co-precipitation: Add sodium carboxymethyl cellulose and sodium alginate to purified water and stir until dissolved. Add 1M hydrochloric acid solution dropwise to adjust the pH to 2.5-3.

5. After the pH reaches the required value, continue stirring at 10-25 rpm for 30-90 minutes until flocculent matter or precipitate is produced. Centrifuge to collect the precipitate. S2, Redissolution and redispersion: Dissolve the precipitate in purified water, add citrate-sodium citrate buffer to redissolve, adjust the pH to 6.5-7.5, and continue stirring the reaction for 60-120 minutes after the pH is reached. S3, Spray drying The obtained liquid material is spray-dried with a nozzle diameter of 0.5-2.0 mm, an inlet air temperature of 140-170℃, an outlet air temperature of 75-95℃, and a feed rate of 30-60 mL / min. The dried powder is then collected to obtain the compound.

2. The method for preparing the sodium carboxymethyl cellulose suspending agent compound according to claim 1, characterized in that, The pH adjustment of the hydrochloric acid solution is carried out in two stages; The first stage involves stirring at 150-300 rpm and adding 1M hydrochloric acid solution at a rate of 1-5 ml / min. When the pH of the solution drops to 3.5-4.0, the second stage of acid adjustment is initiated. The stirring speed in the second stage is 10-25 rpm, and the dropping speed of 1M hydrochloric acid solution is 0.2-0.8 ml / min.

3. The method for preparing the sodium carboxymethyl cellulose suspending agent compound according to claim 1, characterized in that, The pH value of the citrate-sodium citrate buffer solution is 5-6.

4. The method for preparing the sodium carboxymethyl cellulose suspending agent compound according to claim 1, characterized in that, After the stirring reaction in step S2 is completed, activated carbon is added to the complex solution for stirring and adsorption. After filtration through a microporous membrane, the metal ions are removed by passing the solution through an ion exchange resin column.

5. The method for preparing the sodium carboxymethyl cellulose suspending agent compound according to claim 1, characterized in that, The amounts of sodium carboxymethyl cellulose and sodium alginate used are in a mass ratio of sodium carboxymethyl cellulose: sodium alginate = 10:1-2.

6. The method for preparing the sodium carboxymethyl cellulose suspending agent compound according to claim 1, characterized in that, The sodium carboxymethyl cellulose, on a dry basis, should have a degree of substitution of 0.7-1.0; the sodium alginate has a molecular weight of 30,000-100,000.

7. A sodium carboxymethyl cellulose compound prepared by the method described in claim 1, characterized in that, This compound is used in high-shear processes in oil drilling, building cement materials, building gypsum materials, coatings, inks, pesticide suspensions, daily creams and chemicals, and daily chemical emulsion production.

8. A sodium carboxymethyl cellulose compound prepared by the method described in claim 4, characterized in that, Application of this compound in food.

9. The method for preparing the sodium carboxymethyl cellulose suspending agent compound according to claim 4, characterized in that, The purified water is replaced with water for injection. The feed solution is filtered through an ion exchange resin column and then through a 1.0 μm pre-filter and a 0.22 μm sterile filter for two-stage filtration. After a subsequent spray drying process, sodium carboxymethyl cellulose compound for injection pharmaceutical excipients is obtained.

10. A sodium carboxymethyl cellulose compound prepared by the method of the sodium carboxymethyl cellulose suspending agent compound as described in claim 9, characterized in that, Application of this compound in human and veterinary injectable drugs.

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