Novel carboxymethylcellulose and method for preparing the same

Abstract

This invention relates to a novel preparation process for carboxymethyl (CMC), a novel type of carboxymethylcellulose, a method for preparing the same, and its uses.

Description

[Technical Field]

[0001] This invention relates to a novel preparation process for carboxymethylcellulose (CMC), a novel type of carboxymethylcellulose (CMC), a method for preparing the same, and its use. [Background technology]

[0002] CMC is used in a wide variety of technological fields. Areas that benefit from the thickening and gel-forming properties of CMC include, for example, the petroleum industry (e.g., drilling fluids), the food industry, the pharmaceutical industry, the paper industry, the electrical and electronics industry, the textile industry, and the construction industry.

[0003] Enteric coatings typically contain carboxyl functional groups that dissolve polymers at high pH and insoluble at low pH. CMC has carboxyl carboxymethyl groups, which should make CMC insoluble at low pH; however, due to its high pKa value, CMC is not completely insoluble even at low pH. Therefore, the use of CMC as an enteric coating in prescription drugs (Rx) and dietary supplement formulations has been restricted. A coating for tablets containing CMC as an ingredient is described in U.S. Patent No. 4,547,571A.

[0004] Carbohydrate-containing polymers (CMCs) with low desequence (DS) are attracting attention due to their potential biodegradability, enteric coating, cohesive thickening properties, and thixotropy. According to the literature (James N. BeMiller, in Carbohydrate Chemistry for Food Scientists (Third Edition), 2019, 223-240), CMCs with a DS of less than 0.4 are known to be insoluble in water. The preparation of CMCs with low desequence (DS) by alkalization with sodium hydroxide (NaOH) or potassium hydroxide (KOH) and subsequent carboxymethylation with monochloroacetic acid is described in numerous publications, such as the international publication No. 2011 / 120533. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] However, there is still a need to prepare CMCs with low substitution (DS) and high solution quality, such as low turbidity.

[0006] To overcome the current challenge of providing CMC with a low degree of substitution (DS) and high solution quality, such as low turbidity, the inventors have shown that CMC with low DS and high solution quality can be obtained by using more than 2.5 moles of alkalizing agent in a method for preparing carboxymethylcellulose.

[0007] The inventors have further discovered that the CMC of the present invention, having a low or very low DS, can be used as an enteric coating agent. This is surprising because those skilled in the art would have expected that the more carboxymethyl groups in the CMC (higher DS), the better the enteric properties the CMC would exhibit, and the opposite is true. Low DS CMCs meet the requirements of the United States Pharmacopeial Convention (USP) for delayed drug release dependent on coating thickness. They also meet the requirements for dietary supplement formulations (the film is stable in HCl for at least one hour).

[0008] Therefore, an object of the present invention is to provide a novel method for preparing a type of CMC having a low degree of substitution (DS) and high solution quality, and the use thereof. Furthermore, an object of the present invention is to provide a novel CMC. Furthermore, an object of the present invention is to provide the use of the CMC of the present invention as a controlled release coating. [Means for solving the problem]

[0009] This task involves the following steps: a) A step of suspending non-regenerated cellulose powder in a solvent / water mixture containing water and isopropyl alcohol, adding an alkalizing agent in solid or aqueous form, and reacting the non-regenerated cellulose with the alkalizing agent in the presence of isopropyl alcohol and water; b) A step in which monohaloacetic acid or a salt thereof is added to the alkalized cellulose of step a), and the alkalized cellulose of step a) is reacted with monohaloacetic acid or a salt thereof. The problem is solved by a method for preparing carboxymethylcellulose (CMC), which includes the following, where, based on 1 mole of anhydrous glucose units of cellulose, more than 2.5 moles of alkalizing agent are used in step a), and 0.2 to 2 moles of monohaloacetic acid or a salt thereof are used in step b).

[0010] The present invention also relates to novel CMCs obtained and obtainable by this method.

[0011] The present invention further relates to a CMC having a substitution degree of 0.25 or less, preferably 0.2 or less, more preferably 0.19 or less, and a turbidity of 1500 NTU or less, preferably 1200 NTU or less, more preferably 700 NTU or less, and most preferably 500 NTU or less, as measured as a 2 wt% aqueous solution.

[0012] Another aspect of the present invention is the use of CMC according to the present invention as a controlled-release coating agent.

[0013] A further aspect of the present invention is the use of CMC according to the present invention in various fields in which it can act as a thickener and / or gelling agent, binder, stabilizer, emulsifier, film-forming agent, suspension agent, protective colloid, crystallization inhibitor, or enteric coating. [Brief explanation of the drawing]

[0014] [Figure 1] This graph shows the diffusion of APAP (N-acetyl-para-aminophenol or paracetamol) through a 1 cm² CMC membrane in simulated gastric juice (0.1NHCl) at 37°C. The APAP concentration is 2 mg / ml, and the maximum drug diffusion amount of 0.2 mg / ml after 2 hours indicates compliance with the USP test for sustained release. Although the drug release amount exceeded 0.2 mg / ml, the membrane did not break, demonstrating suitability for nutraceuticals. [Figure 2] APAP penetration resulted in a drug release exceeding 0.2 mg / ml, but the membrane did not break, demonstrating its suitability for nutraceuticals. Due to the thicker film thickness, the drug release rate was slower than shown in Figure 1. [Figure 3] APAP's penetration rate did not exceed 0.2 mg / ml, demonstrating its suitability as a pharmaceutical product. [Modes for carrying out the invention]

[0015] Detailed aspects of the present invention are described below. Some of the detailed aspects are discussed in separate sections. This is for ease of reference and is not limiting. Unless otherwise indicated in the context, all embodiments described below apply equally to all aspects of the present invention.

[0016] As used herein, the terms "CMC" or "carboxymethylcellulose" refer to the formula -CH2CO2A (wherein A is hydrogen or K). + monovalent cations such as, or preferably Na + It includes cellulose substituted with the group (which is).

[0017] The method for preparing carboxymethylcellulose according to the present invention includes a step of reacting non-regenerated cellulose with an alkalizing agent and monohaloacetic acid or a salt thereof (preferably a sodium salt).

[0018] In this specification, the term "regenerated cellulose" refers to cellulose prepared by regeneration (i.e., returning to a solid form) from a solution containing dissolved cellulose fibers. The term "unregenerated cellulose" refers to cellulose, typically cellulose fibers, that have not undergone a process of dissolving in a solvent and then regeneration (i.e., recovery of cellulose in a solid form) from that solution. In particular, "unregenerated cellulose" refers to cellulose that has not been recovered from a cellulose xanthogenet solution, or a cellulose / cupramonium solution, or a cellulose solution in N-methylmorpholine-N-oxide.

[0019] The alkalizing agent is preferably NaOH, KOH, or a mixture thereof. In one embodiment of the present invention, NaOH is used as the alkalizing agent. In other embodiments, KOH is used as the alkalizing agent. In the latter case, the residual K + ions are preferably exchanged with Na + ions in a subsequent step.

[0020] The monohaloacetic acid can be used as the free acid or in the form of its salt. Preferably, monochloroacetic acid or its salt is used in the process of the present invention including all the preferred embodiments described below.

[0021] According to the present invention, it is important to observe the molar ratios of the above components during the preparation of CMC.

[0022] The alkalizing agent containing the above-described preferred alkalizing agent is used in an amount of 2.5 to 10 moles, preferably 3.1 to 10 moles, more preferably 3.5 to 8 moles, and most preferably 4 to 7 moles, based on 1 mole of the anhydroglucose unit of cellulose.

[0023] The monohaloacetic acid, preferably monochloroacetic acid, is used in an amount of 0.2 to 2 moles, preferably 0.3 to 1.5 moles, more preferably 0.4 to 1 mole, and more preferably 0.5 to 0.8 moles of the monohaloacetic acid or its salt, respectively, based on 1 mole of the anhydroglucose unit of cellulose. These preferred amounts of monohaloacetic acid are preferably used in combination with the preferred amounts of the alkalizing agent shown above.

[0024] The ratio of the alkalizing agent / monohaloacetic acid is preferably 2.4 to 20, more preferably 2.6 to 20, and most preferably 2.8 to 20. The ratio of the alkalizing agent / monohaloacetic acid is further preferably 3.0 to 15, more preferably 3.5 to 14, and most preferably 4.0 to 13.

[0025] In alkalization step (a), water is used in an amount of preferably less than 15 moles based on 1 mole of anhydrous glucose units of cellulose. In another embodiment, in alkalization step (a), water is used in an amount of preferably 15 moles or more based on 1 mole of anhydrous glucose units of cellulose. In another embodiment, in alkalization step (a), water is used in an amount of preferably 10 to 14.95 moles, more preferably 12 to 14.92 moles, and most preferably 14 to 14.9 moles, based on 1 mole of anhydrous glucose units of cellulose. In another embodiment, in alkalization step (a), water is used in an amount of preferably 15 to 45 moles, more preferably 15.5 to 45 moles, more preferably 20 to 45 moles, and most preferably 30 to 45 moles, based on 1 mole of anhydrous glucose units of cellulose.

[0026] These preferred amounts of water are preferably used in combination with the preferred amounts of alkalizing agent and monohaloacetic acid shown above. Isopropyl alcohol is generally used in alkalizing step (a) in amounts of 100 to 10 moles, preferably 80 to 20 moles, more preferably 60 to 30 moles, and most preferably 55 to 32 moles, based on 1 mole of anhydrous glucose units of cellulose. These preferred amounts of isopropyl alcohol are preferably used in combination with the preferred amounts of alkalizing agent, monohaloacetic acid, and water shown above.

[0027] In a preferred embodiment of the present invention, unregenerated cellulose is reacted with an alkalizing agent in the presence of water, isopropyl alcohol, and an additional amount of methanol. Methanol, if present, is preferably used in alkalizing step (a) in an amount of 10 to 1 mole, more preferably 9 to 2 moles, even more preferably 8 to 3 moles, and most preferably 7 to 4 moles, based on 1 mole of anhydrous glucose units of cellulose. These preferred amounts of methanol are preferably used in combination with the preferred amounts of alkalizing agent, monohaloacetic acid, water, and isopropyl alcohol shown above.

[0028] The solvents introduced in alkalization step (a) (i.e., water, isopropyl alcohol, and optionally methanol) are typically not intentionally removed before or during the reaction between alkalized cellulose and monohaloacetic acid, and it is understood that these solvents also constitute the reaction medium in step (b). However, the amounts of water, isopropyl alcohol, and optionally methanol specified above refer only to the amounts present during the alkalization step of step (b) and do not include any additional amounts of the aforementioned solvents that may be optionally added in later stages of the process, for example, during the reaction with monohaloacetic acid in step (b).

[0029] In some embodiments, including embodiments using preferred amounts of the components shown above, the alkalizing agent and monohaloacetic acid are used in a molar ratio of 20 to 2.5, more preferably 15 to 2.8, even more preferably 12 to 3, and most preferably about 11 to 4.

[0030] The method of preparing CMC as described above generates a novel type of CMC.

[0031] Typically, the novel CMC according to the present invention has a degree of substitution of 0.25 or less, preferably 0.2 or less, more preferably 0.19 or less, and a turbidity of 1500 NTU or less, preferably 1200 NTU or less, for example, 1000 NTU or less, more preferably 700 NTU or less, and most preferably 500 NTU or less, as measured as a 2 wt% aqueous solution.

[0032] The degree of substitution is the average number of OH groups substituted on a single anhydrous glucose unit. This is determined according to ASTM D 1439-03, "Standard Test Methods for Sodium Carboxymethylcellulose; Degree of Etherification, Test Method B: Nonaqueous Titration." When a solid sample of CMC is treated with glacial acetic acid at its boiling point, an amount of acetate ions corresponding to sodium carboxymethyl groups is released. These acetate ions can be titrated as a strong base in acetic anhydride using a perchloric acid standard solution. The titration endpoint is determined by potentiometric measurement. Other alkali salts of carboxylic acids (e.g., sodium glycolate and disodium diglycolate) behave similarly and can be co-titrated.

[0033] It is quite remarkable that the novel types of CMC according to the present invention form high-viscosity solutions or gels in aqueous media despite low to moderate levels of substitution.

[0034] In one embodiment of the present invention, the novel CMC having the above-described preferred degree of substitution typically has a viscosity of at least 100 mPa·s, preferably at least 440 mPa·s, more preferably at least 600 mPa·s, and most preferably at least 800 mPa·s, when measured as a 2% by weight aqueous solution as described below. The viscosity is generally up to 30,000 mPa·s, preferably up to 25,000 mPa·s, and more preferably up to 20,000 mPa·s, when measured as a 1% by weight aqueous solution as described below.

[0035] To determine the viscosity, a 2% solution was prepared as follows (total solution volume 300g). 294g of deionized water (minus the water in the CMC) was placed in a 500ml screw-cap bottle kept at a constant temperature of 25°C. Next, 6g (dry weight) of CMC was uniformly stirred at a rotation speed of approximately 1300 rpm to prepare the solution. The solution was then stirred at a constant rotation speed (approximately 1000-1500 rpm) and a temperature of 25°C for 1 hour and 30 minutes. After that, stirring was stopped, and the solution was held at 25°C for 30 minutes without stirring before determining the viscosity. The viscosity of the solution was measured using a Brookfield LVT viscometer at 30 rpm and 25°C, using spindle 3 for Example A; spindle 2 for Example B; spindle 3 for Examples C, D, and E; and spindle 1 for Examples F, G, and H.

[0036] The aqueous solution of CMC of the present invention not only has high viscosity, but even more surprisingly, the transparency of the aqueous solution of CMC is good, that is, much better than expected based on a relatively low degree of substitution.

[0037] In another aspect of the present invention, in a novel CMC comprising the above preferred CMC, the carboxymethylcellulose has a degree of substitution of 0.25 or less, preferably 0.2 or less, more preferably 0.19 or less, and a turbidity of 1500 NTU or less, preferably 1200 NTU or less, for example, 1000 NTU or less, more preferably 700 NTU or less, and most preferably 500 NTU or less, as measured as a 2 wt% aqueous solution.

[0038] Preferably, a 2 wt% aqueous solution of the CMC according to the present invention, which contains the CMC described as preferred above, has a transmittance of 100-5%, more preferably 100-5%, and even more preferably 100-8%, when measured by the method shown below.

[0039] A 2 wt% aqueous solution of CMC is prepared in the same manner as described above for viscosity analysis and further rolled on a roller device for 24 hours. Transmittance and turbidity are analyzed using a Turbidimeter 2100AN (Hach Company, Loveland, Colorado, USA) with tungsten filament lamp emission having wavelengths of 300–1000 nm. Transmittance is an optical analysis of light passing through the sample cell (diameter: 24 mm) at a specified wavelength (610 nm in this case). It is expressed as the percentage of transmitted light. This system is calibrated against water (100% transmittance). The results are the average of 8 measurements. Turbidity is an analysis of scattered light passing through the sample cell (diameter: 24 mm) and is expressed in NTU (nephelometric turbidity units) according to USEPA Method 180.1. The analysis is performed against a formazin standard (StablCal®, catalog number 2659505) in the range of less than 0.1 NTU to 7500 NTU. A USEPA Method 180.1 filter module (catalog number 3031200, 400-600 nm) was used. The results are the average of 10 measurements.

[0040] In the context of this application, the terms "high viscosity CMC" or "CMC having high or low viscosity" or similar expressions refer to the viscosity of an aqueous solution of CMC.

[0041] The type of non-regenerated cellulose used to prepare the CMC is not essential to the present invention and is governed by the intended end use of the CMC. Conventional non-regenerated starting materials include natural cellulose, e.g., cotton linter, and wood pulp, e.g., hardwood or softwood pulp. Typically, cotton linter or wood pulp is used depending on the desired use of the CMC. The pulp according to the present invention has a limiting viscosity number measured according to ISO 5351:2010 of 50-300 mL / g, preferably 1000-3000 mL / g, more preferably 300-1000 mL / g.

[0042] This invention makes it possible to prepare food-grade CMC derived from wood pulp, which, due to its excellent viscosity and gel-forming properties, can be used as a powerful thickener in the food industry. For economic reasons, wood pulp is the preferred raw material in this process, but if for any reason an extremely high viscosity CMC is required, cotton linters can also be used.

[0043] The essential steps of the method for preparing carboxymethylcellulose are alkalizing cellulose by reaction with an alkalizing agent (alkalization step (a)) and adding monohaloacetic acid to induce etherification of the alkalized cellulose (carboxymethylation step (b)).

[0044] Cellulose is first alkalized in an alkalization step (a) in the presence of water and isopropyl alcohol, and optionally methanol, and then monohaloacetic acid is added in a carboxymethylation step. In the alkalization step, the individual components (e.g., cellulose, water, isopropyl alcohol, alkalizing agent, and optionally methanol) can be added in any order. However, it is preferable to mix the cellulose with water, isopropyl alcohol, and optionally methanol in the first step, and then add the alkalizing agent in a subsequent step. When methanol is used, it can be added to the reaction mixture before, simultaneously with, or immediately after the addition of monohaloacetic acid, but it is preferably added simultaneously with water and / or isopropyl alcohol, separately, or as a mixture with water and / or isopropyl alcohol.

[0045] There are various options for the method of contacting cellulose with an alkalizing agent. Preferably, cellulose powder is used as the starting material. Typically, the cellulose powder is suspended (slurried) in a solvent / water mixture containing water, isopropyl alcohol, and optionally methanol before the alkalizing agent is added as a solid or aqueous solution. However, the total amount of water used in the alkalizing step should be less than 15 moles of water based on 1 mole of anhydrous glucose units of cellulose. In another embodiment, the amount of water is 15 moles or more based on 1 mole of anhydrous glucose units of cellulose. In another embodiment, the amount of water is 10 to 14.95 moles, more preferably 12 to 14.92 moles, and most preferably 14 to 14.9 moles, based on 1 mole of anhydrous glucose units of cellulose. In another embodiment, the amount of water is 15 to 45 moles, more preferably 15.5 to 45 moles, more preferably 20 to 45 moles, and most preferably 30 to 45 moles, based on 1 mole of anhydrous glucose units of cellulose. The amount of cellulose in the initial slurry of cellulose in the solvent / water mixture is preferably in the range of 1 to 14% by weight, more preferably 3 to 12% by weight, and most preferably 4 to 10% by weight, based on the total weight of cellulose and the solvent / water mixture, respectively.

[0046] According to the preferred slurry method, the alkalization step (a) is typically carried out at a temperature in the range of 10 to 40°C, preferably 15 to 40°C, more preferably 15 to 30°C, even more preferably 18 to 25°C, and most preferably about 20°C. The typical reaction time for the alkalization step is in the range of 15 to 120 minutes, preferably 40 to 100 minutes, and more preferably 50 to 80 minutes, depending on the reaction temperature. In one embodiment, the alkalization step is carried out at about 20°C for 50 to 70 minutes, preferably 60 minutes.

[0047] In the carboxymethylation step (b), monohaloacetic acid or a salt thereof, preferably a sodium salt, can be added undiluted, or as a solution, preferably as an aqueous solution, or as a solution in water and isopropyl alcohol and optionally methanol. The carboxymethylation step is typically carried out at a temperature in the range of 40 to 100°C, preferably 50 to 90°C, more preferably 60 to 80°C, and most preferably about 70°C. In preferred embodiments, the monohaloacetic acid is already added to the reaction mixture before the carboxymethylation temperature is reached; more preferably, the monohaloacetic acid is added before the heating step begins or within the first few minutes of the heating step, generally at the temperatures described above for the alkalizing step, for example, 15 to 40°C. Early addition of monohaloacetic acid at lower temperatures can avoid undesirable decomposition of cellulose (resulting in a decrease in viscosity) that may occur at higher temperatures in the absence of monohaloacetic acid. After the desired temperature (carboxymethylation temperature) of the carboxymethylation step described above is reached, the carboxymethylation temperature is typically maintained for a period of 0 to 180 minutes, preferably 20 to 140 minutes.

[0048] The product obtained from the carboxymethylation step, i.e., etherification, is a sodium or potassium salt of carboxymethylcellulose, depending on the alkalizing agent used. According to a preferred embodiment, the CMC salt is neutralized by adding an acid, preferably an organic acid such as acetic acid or formic acid, more preferably acetic acid. Here, "neutralization" means adjusting the pH value to 6-9, preferably 7-8. The CMC is then separated from the reaction mixture and, if necessary, purified and dried according to the intended end use. Purification is carried out according to standard methods well known to those skilled in the art. For example, the CMC can be washed with organic solvents including methanol, acetone, methanol / water mixtures, acetone / methanol mixtures, methanol / isopropyl alcohol / water mixtures, and solvent(mixture) / water mixtures.

[0049] The excellent properties of CMC according to the present invention are its ability to form highly viscous aqueous solutions or gels with low turbidity in combination with a low to medium degree of substitution of cellulose. Further, CMC according to the present invention having a DS of less than 0.5, for example, a DS of 0.4 - 0.5, is biodegradable, in contrast to currently commercially available CMC.

[0050] In this method, it has been found that when KOH is used as the alkalizing agent, CMC having even more excellent gel-forming properties (viscosity and transparency) can be obtained compared to the case where NaOH is used. The improved gel-forming properties of CMC are due to the K + ions remaining even after the K + ions are exchanged with Na + ions in a subsequent step. After separating the CMC from the reaction mixture, the K + ions in the produced CMC can be exchanged with Na + ions, for example, by thoroughly washing with methanol containing about 20% by weight of a saturated aqueous sodium chloride solution. After exchanging the K + ions with Na

[0051] The CMCs of the present invention are promising candidates for many different applications. For example, they can be used as thickeners and / or gelling agents, binders, stabilizers, emulsifiers, film-forming agents, suspending agents, protective colloids, or crystallization inhibitors. Due to their beneficial properties, the CMCs of the present invention are useful in a wide range of technical fields, including drilling fluids, e.g., petroleum drilling fluids; pharmaceutical dosage forms, e.g., capsules, tablets, solutions, suspensions, emulsions, creams and lotions; food products, e.g., structured, extruded or coated food products such as processed meat products, dairy products, bakery products, meat substitutes, dressings, sauces, marinades, soups and spreads; cosmetic applications, e.g., hair styling products, toothpaste, emulsions, creams and lotions; detergents; paper coatings or paper binding; welding electrodes; textile applications, e.g., textile printing and dyeing; ceramic applications, e.g., clay body and tile manufacturing; adhesives; paints; and construction applications, e.g., their use in gypsum or cement-based dry mortar applications.

[0052] While some dosage forms are effective even when released immediately into the bloodstream, it may be advantageous to release the active ingredient in a sustained manner or to target its release to a specific site in the body. The CMC according to the present invention is a promising candidate for use as a controlled-release coating for solid dosage forms. Controlled release may be either delayed release or sustained release.

[0053] The following embodiments are provided for illustrative purposes only and are not intended to limit the scope of the following claims. Unless otherwise specified, all parts and percentages are by weight. [Examples]

[0054] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the following claims. Unless otherwise specified, all parts and percentages are by weight.

[0055] Cellulose starting material Examples A, B, and C used ground cellulose wood pulp (Biofloc 96 from Tartas) with an intrinsic viscosity of 660 ml / g. Examples D and E used cotton pulp (PCS 2400 from Gaomi) with an intrinsic viscosity of 1740 ml / g. Examples F, G, and H used wood pulp (Cellunier F from Rayonier) with an intrinsic viscosity of 410 ml / g.

[0056] In all examples, 129.7 g of dry cellulose (equivalent to 0.8 moles of anhydrous glucose units (AGU)) was used with various amounts of isopropyl alcohol (IPA), methanol (MeOH), water, NaOH or KOH, and monochloroacetic acid (MCA), as shown in the table. MCA was added as an 80% solution in water.

[0057] First, under a nitrogen atmosphere, cellulose powder was introduced into a dry 3-liter experimental reactor, and then a solvent mixture of isopropyl alcohol, methanol, and water was added. NaOH (granular) or KOH (granular) was added at 20°C with stirring, and stirring continued for 15 minutes, after which hydrogen peroxide was added at a concentration of 3% in water (Examples D-H); stirring continued at 20°C for a total of 60 minutes. The reaction mixture was then heated to 70°C within 40 minutes, and monochloroacetic acid was added as an 80% by weight aqueous solution during the first few minutes of the heating stage. The temperature was maintained at 70°C for 120 minutes during the carboxymethylation step, and then the reaction mixture was cooled to 20°C within approximately 60 minutes. The pH of the cooled reaction mixture was adjusted to 7.5 with acetic acid, and then the solution was filtered. The filtered residue was then washed at least five times with 2 L of isopropanol / methanol / water mixture (isopropanol / methanol / water weight ratio 5:3:2) until no chloride ions were detected in the filtrate. Next, a final washing step was performed using pure methanol. The washed sample was dried overnight in a drying cabinet at 55°C, and then ground using a laboratory mill.

[0058] The degree of substitution of the obtained CMC was determined as described in the summary section of the specification. A 2 wt% CMC sample solution was also prepared, and its viscosity, turbidity, and transmittance were determined as described in the summary section of the specification. The results are shown in the table below.

[0059] [Table 1]

[0060] The two CMC synthesis methods described above, Samples D and E, were carried out with water concentrations below 15 mol / mol AGU and high sodium hydroxide concentrations above 4 mol / mol AGU, yielding CMCs with a DS of less than 0.5. Solutions obtained from these CMCs exhibited very low turbidity and high transmittance. The synthesis was carried out according to the method described on page 11 of International Publication No. 2011 / 120533, except that the amounts of reactants and solvents shown in the table above were used. Sample D had a DS of 0.4 and a turbidity of 3.1 NTU, which is lower turbidity than the CMC of Example 5 in International Publication No. 2011 / 120533, which had a DS of 0.4 and a turbidity of 14 NTU. Sample E had a DS of 0.34 and a turbidity of 3 NTU, which is lower turbidity than the CMC of Example 18 in International Publication No. 2011 / 120533, which had a DS of 0.36 and a turbidity of 10 NTU.

[0061] The turbidity of the sample in International Publication No. 2011 / 120533 was measured at a lower concentration (1%) than the turbidity of sample D / E, which was measured at 2%. Turbidity of a solution increases with increasing concentration. Nevertheless, even at a 2% concentration, sample D / E shows lower turbidity than the prior art.

[0062] CMC synthesis of samples A, B, and C yielded CMCs with DS values ​​of 0.19, 0.16, and 0.22, respectively. All solutions were turbid or viscous. Films were cast multiple times from the 2% solution onto a glass plate and dried at room temperature. The films cast from the solution were uniform, rigid, and elastic, indicating that the CMC was functional. The films contained many fibers, but these did not hinder film formation or adversely affect the film's properties. The films were uniform and not nonwoven. A piece of film from sample A (123 μm) was placed in a Franz diffusion cell, and the diffusion of paracetamol (APAP) was measured over 2 hours in HCl at 37°C. The film was stable in gastric juice and capable of sustained drug release over time.

[0063] Sample H is a CMC with a DS of 0.6, synthesized using a high concentration of alkali but with a water concentration of less than 15 mol / mol AGU.

[0064] The film (165 μm thick) from sample H decomposed within 15 minutes in a Franz cell in HCl.

[0065] Sample F is a CMC with a DS of 0.33, synthesized using a high concentration of alkali but with a water concentration higher than 15 mol / mol AGU. A film (155 μm thick) cast from Sample F in a 4% solution maintains its perfect state within Franz cells. Acid resistance does not meet USP requirements, but it does meet the requirements for dietary supplements. See Figure 2. As shown for Sample G (see top of the table for Sample G), a slight increase in film thickness should be sufficient to meet USP requirements.

[0066] Sample G has a DS of 0.33, synthesized using a high concentration of alkali but with a water concentration higher than 15 mol / mol AGU. Multiple films were cast from a 7.5% solution onto a glass plate and dried at room temperature. A piece of the film (1 cm × 1 cm, 189 μm thick) remained intact within the Franz cell. The drug release after 2 hours was APAP 0.2 mg, which is the limit of the USP. This film passed the USP test. See Figure 3.

[0067] All publications referenced in the above specification are incorporated herein by reference. Various improvements and modifications of the methods and systems of the present invention described will be apparent to those skilled in the art without departing from the scope and spirit of the invention. While the invention is described in relation to specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various improvements of the described embodiments for carrying out the invention, which will be obvious to those skilled in the art of biochemistry and biotechnology or related fields, are intended to fall within the scope of the following claims.

Claims

1. a) A step of suspending non-regenerated cellulose powder in a solvent / water mixture containing water and isopropyl alcohol, adding an alkalizing agent in solid or aqueous form, and reacting the non-regenerated cellulose with the alkalizing agent in the presence of isopropyl alcohol and water; b) A step of adding monohaloacetic acid or a salt thereof to the alkalized cellulose of step a), and reacting the alkalized cellulose of step a) with the monohaloacetic acid or a salt thereof. A method for preparing carboxymethylcellulose, comprising: In each case, based on 1 mole of anhydrous glucose units of the cellulose, a method is used in which more than 2.5 moles of alkalizing agent is used in step a), and 0.2 to 2 moles of monohaloacetic acid or a salt thereof is used in step b).

2. The method according to claim 1, wherein the alkalizing agent / monohaloacetic acid ratio is 2.4 to 20, preferably 2.6 to 20, and more preferably 2.8 to 20.

3. The method according to claim 2, wherein the alkalizing agent / monohaloacetic acid ratio is 3.0 to 15, more preferably 3.5 to 14, and most preferably 4.0 to 13.

4. The method according to any one of claims 1 to 3, wherein step a) is carried out in the presence of water, isopropyl alcohol, and methanol.

5. The method according to any one of claims 1 to 4, wherein in step a), 100 to 10 moles of isopropyl alcohol are used based on 1 mole of anhydrous glucose units of the cellulose.

6. The method according to any one of claims 1 to 5, which is carried out in the presence of less than 15 moles of water, based on 1 mole of anhydrous glucose units of the cellulose.

7. The method according to any one of claims 1 to 6, which is carried out in the presence of 15 moles or more of water based on 1 mole of anhydrous glucose units of the cellulose.

8. The method according to any one of claims 1 to 6, each carried out in the presence of 10 to 14.95 moles, more preferably 12 to 14.92 moles, and most preferably 14 to 14.9 moles of water, based on 1 mole of anhydrous glucose units of the cellulose.

9. The method according to any one of claims 1 to 5 or 7, each carried out in the presence of 15 to 45 moles, more preferably 15.5 to 45 moles, most preferably 20 to 45 moles, and most preferably 30 to 45 moles of water, based on 1 mole of anhydrous glucose units of the cellulose.

10. The method according to any one of claims 1 to 9, wherein the alkalizing agent is used in an amount of 2.5 to 10 moles, preferably 3.1 to 10 moles, more preferably 3.5 to 8 moles, and most preferably 4 to 7 moles, based on 1 mole of anhydrous glucose units of the cellulose.

11. The method according to any one of claims 1 to 10, wherein the alkalizing agent is sodium hydroxide (NaOH), potassium hydroxide (KOH), or a mixture thereof, preferably sodium hydroxide.

12. When KOH is used as the alkalizing agent, K in the subsequent step ＋ Ions are Na ＋ The method according to claim 11, wherein ions are exchanged.

13. The method according to any one of claims 1 to 12, wherein the monohaloacetic acid or a salt thereof is used in an amount of 0.3 to 1.5 moles, preferably 0.4 to 1 mole, more preferably 0.5 to 0.8 moles, based on 1 mole of anhydrous glucose units of the cellulose.

14. The method according to any one of claims 1 to 13, wherein the monohaloacetic acid or salt thereof is monochloroacetic acid or a salt thereof.

15. The method according to any one of claims 1 to 14, wherein the alkalizing agent is added as a solid.

16. The method according to any one of claims 1 to 15, wherein the product obtained after alkalization and reaction with monohaloacetic acid or a salt thereof is neutralized by adding an acid, preferably acetic acid.

17. Carboxymethylcellulose obtained or obtainable by the method described in any one of claims 1 to 16.

18. Carboxymethylcellulose having a degree of substitution of 0.25 or less, preferably 0.2 or less, more preferably 0.19 or less, and a turbidity of 1500 NTU or less, preferably 1200 NTU or less, more preferably 700 NTU or less, and most preferably 500 NTU or less, as measured as a 2% by weight aqueous solution.

19. Use of carboxymethylcellulose as a controlled release coating according to claim 17 or 18.

20. The use according to claim 19, wherein the regulated release is a delayed release.

21. The use according to claim 19, wherein the regulated release is a sustained release.

22. Use of carboxymethylcellulose as a thickener and / or gelling agent, binder, stabilizer, emulsifier, film-forming agent, suspending agent, protective colloid, crystallization inhibitor, or enteric coating according to claim 17 or 18.

23. Use of carboxymethylcellulose according to claim 17 or 18 in drilling fluids, e.g., petroleum drilling fluids; pharmaceutical dosage forms, e.g., capsules, tablets, solutions, suspensions, emulsions, creams and lotions; food products, e.g., structured, extruded or coated food products such as processed meat products, dairy products, bakery products, meat substitutes, dressings, sauces, marinades, soups and spreads; cosmetic applications, e.g., hair styling products, toothpaste, emulsions, creams and lotions; detergents; paper coatings or paper binding; welding electrodes; textile applications, e.g., textile printing and dyeing; household care applications such as laundry and dishwashing; ceramic applications, e.g., clay bodies and tile manufacturing; adhesives; paints; and construction applications, e.g., gypsum or cement-based dry mortar applications.

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