Novel carboxymethyl cellulose and preparation method

Abstract

The present invention relates to a novel process for the preparation of carboxymethyl groups (CMC), to novel carboxymethyl celluloses, to a process for the preparation thereof and to the use thereof.

Description

Technical Field

[0001] The present invention relates to a novel method for preparing carboxymethyl cellulose (CMC), novel carboxymethyl cellulose (CMC), and a preparation method and application thereof. Background Art

[0002] CMC is used in a wide variety of technical fields. Areas that benefit from the thickening and gel-forming properties of CMC are, for example, the oil industry (for example in 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 coating agents typically have carboxylic acid functional groups that render the polymer soluble at high pH and insoluble at low pH. CMC has carboxylic acid methyl groups that should also render CMC insoluble at low pH, but due to its high pKa value, CMC is not completely insoluble at low pH. Therefore, the use of CMC as an enteric coating agent in prescription drugs (Rx) and nutraceutical formulations is limited. Tablet coatings containing CMC as an ingredient have been described in US Pat. No. 5,475,711.

[0004] CMC with a low degree of substitution (DS) has attracted attention due to its potential biodegradability, enteric solubility, associative thickening, and thixotropic properties. According to the literature (James N. BeMiller, in Carbohydrate Chemistry for Food Scientists (3rd ed.), 2019, 223-240), CMC with a DS below 0.4 is known to be insoluble in water. The preparation of CMC with a low degree of substitution (DS) by alkalization with sodium hydroxide (NaOH) or potassium hydroxide (KOH) and subsequent carboxymethylation with monochloroacetic acid is described in many documents (e.g., WO 2011 / 120533).

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

[0006] Purpose of the Invention

[0007] To overcome the current challenge of providing CMC with high solution quality (e.g., low turbidity) with a low degree of substitution (DS), the inventors have shown that using greater than 2.5 mol of an alkalizing agent in a process for preparing carboxymethyl cellulose provides CMC with low DS and high solution quality.

[0008] The inventors have also discovered that CMC of the present invention with low or very low DS can be used as an enteric coating agent. This is surprising because one skilled in the art would expect that the more carboxymethyl groups (high DS) present in CMC, the better enteric properties the CMC would exhibit, rather than the opposite. Low DS CMC meets the United States Pharmacopoeia (USP) requirements for delayed drug release depending on coating thickness. In addition, it meets the requirements for nutraceutical formulations (films are stable in HCl for 1 hour).

[0009] Therefore, the object of the present invention is to provide a novel process for preparing a CMC type with a low degree of substitution (DS) having high solution quality and the use thereof. Another object of the present invention is to provide a novel CMC. Another object of the present invention is to provide the use of the CMC of the present invention as a modified release coating. Summary of the Invention

[0010] This problem is solved by a method for preparing carboxymethyl cellulose (CMC), which comprises the following steps:

[0011] a) suspending non-regenerated cellulose powder in a solvent / water mixture comprising water and isopropanol, adding an alkalizing agent in the form of a solid or aqueous solution, and reacting the non-regenerated cellulose with the alkalizing agent in the presence of isopropanol and water; and

[0012] b) then adding a haloacetic acid or a salt thereof to the alkalized cellulose of step a), and reacting the alkalized cellulose of step a) with the haloacetic acid or a salt thereof,

[0013] wherein more than 2.5 mol of an alkalizing agent is used in step a), and wherein 0.2 to 2 mol of a monohaloacetic acid or a salt thereof is used in step b), each based on 1 mol of anhydroglucose units of the cellulose.

[0014] The invention also relates to novel CMC obtained and obtainable by this process.

[0015] The present invention further relates to CMC having a degree of substitution equal to or lower than 0.25, preferably equal to or lower than 0.2, more preferably equal to or lower than 0.19 and a turbidity equal to or lower than 1500 NTU, preferably equal to or lower than 1200 NTU, more preferably equal to or lower than 700 NTU, most preferably equal to or lower than 500 NTU, measured as a 2 wt% aqueous solution.

[0016] Another aspect of the invention is the use of the CMC according to the invention as a modified release coating.

[0017] Another aspect of the invention is the use of the CMC according to the invention in various technical fields, where they can act as thickeners and / or gelling agents, binders, stabilizers, emulsifiers, film formers, suspending agents, protective colloids, crystallization inhibitors, or as enteric coatings. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 : This figure shows the APAP (N-acetyl-p-aminophenol or acetaminophen) at 37 ° C through a 1 cm 2 Diffusion through the CMC membrane. APAP concentration was 2 mg / ml and maximum drug diffusion after 2 hours at 0.2 mg / ml indicated that the USP test for delayed release passed. Drug release was above 0.2 mg / ml, but the membrane remained intact, indicating suitability for neutraceuticals.

[0019] Figure 2 : The permeation of APAP showed drug release higher than 0.2 mg / ml, but the membrane remained intact, which indicates that it is suitable for nutrients. Due to the high membrane thickness, the drug release ratio Figure 1 slow.

[0020] Figure 3 : The permeation of APAP showed that the drug release was not higher than 0.2 mg / ml, which indicated suitability for the drug. DETAILED DESCRIPTION

[0021] The following describes detailed aspects of the present invention. Some detailed aspects are discussed in separate sections. This is for ease of reference and is not intended to be limiting. All embodiments described below are equally applicable to all aspects of the present invention, unless the context otherwise specifically provides otherwise.

[0022] As used herein, the term "CMC" or "carboxymethyl cellulose" encompasses cellulose substituted with groups having the formula -CH2CO2A, where A is hydrogen or a monovalent cation such as K + or preferably Na + .

[0023] The method for preparing carboxymethyl cellulose according to the present invention comprises reacting non-regenerated cellulose with an alkalizing agent and a monohaloacetic acid or a salt thereof, preferably a sodium salt.

[0024] As used herein, the term "regenerated cellulose" refers to cellulose prepared by regeneration (i.e., returning to solid form) from a solution containing dissolved cellulose fibers. The term "non-regenerated cellulose" refers to cellulose that has not undergone a process in which the cellulose (typically cellulose fibers) is dissolved in a solvent and then regenerated from the solution (i.e., recovering the cellulose in solid form). In particular, "non-regenerated cellulose" refers to cellulose that has not been recovered from a cellulose xanthate solution or a cellulose / copperammonium solution or a solution of cellulose in N-methylmorpholine-N-oxide.

[0025] 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 another embodiment, KOH is used as the alkalizing agent. In the latter case, the residual K in the produced CMC is + The ions are preferably replaced by Na + Ion exchange.

[0026] The monohaloacetic acid can be used as a free acid or in the form of a salt thereof. Preferably, monochloroacetic acid or a salt thereof is used in the process of the present invention (including all preferred embodiments described below).

[0027] According to the present invention, it is important to observe the molar ratio of each of the above components during the preparation of CMC.

[0028] The alkalizing agent (including the preferred alkalizing agents described above) is used in an amount of 2.5 to 10 mol, preferably 3.1 to 10 mol, more preferably 3.5 to 8 mol, most preferably 4 to 7 mol based on 1 mol of anhydroglucose unit of cellulose.

[0029] Monohaloacetic acid, preferably monochloroacetic acid, is used in an amount of 0.2 to 2 mol of monohaloacetic acid or a salt thereof, preferably in an amount of 0.3 to 1.5 mol, more preferably in an amount of 0.4 to 1 mol, more preferably in an amount of 0.5 to 0.8 mol, each based on 1 mol of anhydroglucose units of cellulose. These preferred amounts of monohaloacetic acid are preferably used in combination with the preferred amounts of the above-mentioned alkalizing agents.

[0030] The alkalizing agent / monohalogenated acetic acid ratio is preferably between 2.4 and 20, more preferably between 2.6 and 20, and most preferably between 2.8 and 20. The alkalizing agent / monohalogenated acetic acid ratio is further preferably between 3.0 and 15, more preferably between 3.5 and 14, and most preferably between 4.0 and 13.

[0031] Water is used in the alkalization step (a) in an amount of preferably less than 15 mol of water based on 1 mol of anhydroglucose units of the cellulose. In another embodiment, water is used in the alkalization step (a) in an amount of preferably greater than or equal to 15 mol of water based on 1 mol of anhydroglucose units of the cellulose. In another embodiment, water is used in the alkalization step (a) in an amount of preferably 10 to 14.95 mol, more preferably 12 to 14.92 mol, most preferably 14 to 14.9 mol, based on 1 mol of anhydroglucose units of the cellulose. In another embodiment, water is used in the alkalization step (a) in an amount of preferably 15 to 45 mol, more preferably 15.5 to 45 mol, more preferably 20 to 45 mol, most preferably 30 to 45 mol, based on 1 mol of anhydroglucose units of the cellulose.

[0032] These preferred amounts of water are preferably used in combination with the alkalizing agent and monohaloacetic acid indicated above in preferred amounts. Isopropyl alcohol is usually used in the alkalization step (a) in an amount of 100 to 10 mol, preferably 80 to 20 mol, more preferably 60 to 30 mol, and most preferably 55 to 32 mol, based on 1 mol of cellulosic anhydroglucose units respectively. These preferred amounts of isopropyl alcohol are preferably used in combination with the alkalizing agent, monohaloacetic acid, and water indicated above in preferred amounts.

[0033] In a preferred embodiment of the present invention, the non-regenerated cellulose is reacted with the alkalizing agent in the presence of water and isopropanol and an additional amount of methanol. Methanol, if present, is preferably used in the alkalization step (a) in an amount of 10 to 1 mol, more preferably 9 to 2 mol, even more preferably 8 to 3 mol, and most preferably 7 to 4 mol, each based on 1 mol of anhydroglucose units of the cellulose. These preferred amounts of methanol are preferably used in combination with the preferred amounts of the alkalizing agent, monohaloacetic acid, water and isopropanol indicated above.

[0034] It will be appreciated that the solvent (i.e., water, isopropanol, and optionally methanol) introduced in the alkalization step (a) is typically not intentionally removed prior to or during the reaction of the alkalized cellulose with the monohaloacetic acid, and that the solvent therefore also constitutes the reaction medium of step (b). However, it should be noted that the amounts of water, isopropanol, and optionally methanol specified above refer only to the amounts present during the alkalization in step (b), and do not include any additional amounts of the solvent that may optionally be added later in the process (e.g., during the reaction with the monohaloacetic acid in step (b)).

[0035] In some embodiments (including those using the preferred amounts of the components as indicated above), the alkalizing agent and the 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.

[0036] The process of the present invention for preparing CMC as described above produces a new type of CMC.

[0037] Typically, the novel CMC according to the present invention has a degree of substitution equal to or lower than 0.25, preferably equal to or lower than 0.2, more preferably equal to or lower than 0.19 and a turbidity equal to or lower than 1500 NTU, preferably equal to or lower than 1200 NTU, such as equal to or lower than 1000 NTU, more preferably equal to or lower than 700 NTU, most preferably equal to or lower than 500 NTU, measured as a 2 wt% aqueous solution.

[0038] The degree of substitution is the average number of OH groups substituted in one anhydroglucose unit. It is determined according to ASTM D1439-03 "Standard Test Methods for Sodium Carboxymethylcellulose; Degree of Etherification, Test Method B: Nonaqueous Titration." Treatment of a solid sample of CMC with glacial acetic acid at boiling temperature releases an amount of acetate ions equal to the number of sodium carboxymethyl groups. These acetate ions can be titrated as a strong base in anhydrous acetic acid using a standard perchloric acid solution. The titration endpoint is determined potentiometrically. Alkaline salts of other carboxylic acids, such as sodium glycolate and disodium diglycolate, behave similarly and are co-titrated.

[0039] Quite surprisingly, the novel CMCs according to the invention form highly viscous solutions or gels in aqueous media, despite their low to moderate degrees of substitution.

[0040] In one aspect of the invention, novel CMCs (including those with the preferred degrees of substitution as described above) typically have 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, as measured as a 2 wt % aqueous solution as described below. The viscosity is typically up to 30,000 mPa·s, preferably up to 25,000 mPa·s, more preferably up to 20,000 mPa·s, as measured as a 1 wt % aqueous solution as described below.

[0041] In order to determine the viscosity, a 2% solution (the total amount of the solution is 300g) is prepared as follows. 294g of deionized water (minus the water in the CMC) is placed in a 500ml screw-top bottle thermostated at 25°C. The CMC of 6g (dry weight) is then stirred evenly at a rotating speed of approximately 1300 to prepare the solution. Afterwards, the solution is stirred for 1 hour and 30 minutes at a constant rotating speed (approximately 1000-1500rpm) and at a temperature of 25°C. The agitator is then turned off and the solution is kept at 25°C for 30 minutes without stirring, and the viscosity is then determined. The viscosity of the solution is measured using a Brookfield LVT viscometer, 30rpm, 25°, where Example A is Spindle No. 3, Example B is Spindle No. 2, and Examples C, D, E are Spindle No. 3 and Examples F, G and H are Spindle No. 1.

[0042] Not only are aqueous solutions of CMC according to the invention highly viscous, but further, quite surprisingly, the clarity of the aqueous CMC solutions is good, ie much better than would be expected based on the relatively low degree of substitution.

[0043] In another aspect of the invention, novel CMCs (including those preferred CMCs described above) wherein the carboxymethyl cellulose 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, such as 1000 NTU or less, more preferably 700 NTU or less, most preferably 500 NTU or less, measured as a 2 wt% aqueous solution.

[0044] Preferably, a 2 wt% aqueous solution of a novel CMC according to the invention (including those preferred CMCs described above) has a transmittance value of 100% to 5%, more preferably 100% to 5%, even more preferably 100% to 8%, measured as indicated below.

[0045] A 2 wt % aqueous solution of CMC was prepared as described above in conjunction with the viscosity analysis and was additionally rolled on a rolling apparatus for 24 h. Transmittance and turbidity were analyzed using a Turbidimeter 2100AN using a tungsten lamp (Hach Company, Loveland, Colorado, USA) emitting light with a wavelength of 300 to 1000 nm. Transmittance is a photometric analysis of the transmitted light through a sample cell (diameter: 24 mm) at a given wavelength (here 610 nm). It is given in % transmitted light. The system was calibrated with water (100% transmittance). The result is the average of eight measurements. Turbidity is an analysis of scattered light through a sample cell (diameter: 24 mm) according to USEPA method 180.1 and is given in NTU (scattered turbidity units). The control range was from <0.1 NTU to 7500 NTU of formazin standards (StablCalTM , catalog number 2659505). USEPA method 180.1 filter block (catalog number 3031200, 400 to 600 nm) was used. The results are the average of ten measurements.

[0046] Within the meaning of the present application, the term "high viscosity CMC" or "CMC with high or low viscosity" or similar expressions refers to the viscosity of an aqueous CMC solution.

[0047] The type of non-regenerated cellulose used to prepare the CMC is not essential to the present invention and is determined by the intended end use of the CMC. Conventional non-regenerated starting materials are natural celluloses such as cotton linters and wood pulp, for example hardwood pulp or softwood pulp. Typically, cotton linters or wood pulp is used, depending on the desired application of the CMC. The pulp according to the present invention has an intrinsic viscosity value of 50 to 300 mL / g, preferably 1000 to 3000 mL / g, and more preferably 300 to 1000 mL / g, as measured according to ISO 5351:2010.

[0048] Thanks to the present invention, it is now also possible to prepare food-grade CMC derived from wood pulp, which can be used as a powerful thickener in the food industry due to its excellent viscosity and gel-forming properties. Although wood pulp is the preferred raw material in the process of the present invention for economic reasons, of course, cotton linters can also be used if a CMC with a very high viscosity is desired for some reason.

[0049] The basic steps of the method for preparing carboxymethyl cellulose are alkalizing cellulose by reacting with an alkalizing agent (alkalization step (a)) and adding monohaloacetic acid to cause etherification of the alkali cellulose (carboxymethylation step (b)).

[0050] At first in alkalization step (a), cellulose is alkalized in the presence of water and isopropyl alcohol and methyl alcohol alternatively, and then in the carboxymethylation step, add monohaloacetic acid.In the alkalization step, single component (for example cellulose, water, isopropyl alcohol, alkalizing agent and methyl alcohol alternatively) can be added in any order.Yet preferably, in first step, cellulose and water, isopropyl alcohol and methyl alcohol combination alternatively, and then in subsequent step, add alkalizing agent.If use methyl alcohol, then can before adding monohaloacetic acid, simultaneously or afterwards methyl alcohol is added in the reaction mixture soon, but preferably by it individually or as with water and / or isopropyl alcohol mixture and water and / or isopropyl alcohol add simultaneously.

[0051] How to contact cellulose with alkalizing agent has various options. Preferably, cellulose powder is used as starting material. Typically, before the alkalizing agent is added as a solid or as an aqueous solution, the cellulose powder is suspended (pulped) in a solvent / water mixture comprising water, isopropyl alcohol and optionally methanol. However, the total amount of the water used in the alkalization step should be the amount of less than 15 moles of water based on the cellulose anhydroglucose units of 1mol. In another embodiment, the amount of water is greater than or equal to 15 moles of water based on the cellulose anhydroglucose units of 1mol. In another embodiment, the amount of water is 10 to 14.95 mol, more preferably 12 to 14.92, most preferably 14 to 14.9 mol, based on the cellulose anhydroglucose units of 1mol. In another embodiment, the amount of water is 15 to 45 mol, more preferably 15.5 to 45 mol, more preferably 20 to 45, most preferably 30 to 45 mol, based on the cellulose anhydroglucose units of 1mol. The amount of cellulose in the starting slurry of cellulose in a solvent / water mixture is preferably in the range of 1 to 14 wt%, more preferably 3 to 12 wt%, and most preferably 4 to 10 wt%, each based on the total weight of cellulose and solvent / water mixture.

[0052] According to the preferred slurry method, the alkalization step (a) is typically carried out at a temperature in the range of 10°C to 40°C, preferably 15°C to 40°C, more preferably 15°C to 30°C, even more preferably 18°C to 25°C, and most preferably at about 20°C. Typical reaction times for the alkalization step range from 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.

[0053] In the carboxymethylation step (b), a monohaloacetic acid or a salt thereof, preferably a sodium salt, may be added alone or as a solution, preferably as an aqueous solution or as a solution in water and isopropanol and optionally methanol. The carboxymethylation step is typically carried out at a temperature in the range of 40°C to 100°C, preferably 50°C to 90°C, more preferably 60°C to 80°C, and most preferably at about 70°C. In a preferred embodiment, the monohaloacetic acid is added to the reaction mixture before the carboxymethylation temperature is reached; more preferably, the monohaloacetic acid is added before the start of the heating phase or within the first minute of the heating phase, typically at the temperatures described above for the alkalization step, for example, at 15°C to 40°C. Early addition of the monohaloacetic acid at a lower temperature can avoid undesirable degradation of the cellulose (resulting in a decrease in viscosity) that may occur at higher temperatures in the absence of the monohaloacetic acid. After reaching the desired temperature (carboxymethylation temperature) for the carboxymethylation step as mentioned above, the carboxymethylation temperature is typically maintained for a period of 0 to 180 minutes, preferably 20 to 140 minutes.

[0054] The product obtained from the carboxymethylation step (i.e. etherification) is a sodium salt or potassium salt of carboxymethyl cellulose, depending on which alkalizing agent is 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). "Neutralization" herein means adjusting the pH value to a value of 6 to 9, preferably 7 to 8. The CMC is then separated from the reaction mixture and purified (if necessary, according to the intended end use), and dried. Purification is carried out according to standard methods well known to those skilled in the art. For example, the CMC can be washed with an organic solvent comprising a mixture of an organic solvent and one or more solvent / water mixtures (such as methanol, acetone, methanol / water mixtures, acetone / methanol mixtures and methanol / isopropanol / water mixtures).

[0055] An outstanding property of the CMCs according to the present invention is their ability to form highly viscous aqueous solutions or gels having low turbidity in combination with a low to moderate degree of substitution of the cellulose. Furthermore, in contrast to currently commercially available CMCs, the CMCs according to the present invention having a DS below 0.5 (e.g., a DS between 0.4 and 0.5) are also biodegradable.

[0056] It has been found that the use of KOH as alkalizing agent in the process of the present invention produces CMC with even superior gel forming properties (higher viscosity and clarity) compared to the use of NaOH. + ions have been Na +After the CMC is separated from the reaction mixture by washing it thoroughly with, for example, methanol containing about 20 weight percent saturated aqueous sodium chloride solution, the K content of the resulting CMC is maintained. + Ions can be Na + Ion exchange. + Ion exchange K + After purification, the CMC can be purified according to known procedures, for example as described above or in the Examples below.

[0057] The CMCs according to the present invention are promising candidates for many different applications. For example, they can be used as thickeners and / or gelling agents, adhesives, stabilizers, emulsifiers, film formers, suspending agents, protective colloids, or crystallization inhibitors. Their beneficial properties make the CMCs of the present invention useful in a variety of technical fields, including their use in drilling fluids, such as oil drilling fluids; pharmaceutical dosage forms, such as capsules, tablets, solutions, suspensions, emulsions, creams, and lotions; food products, such as processed meat products, dairy products, baked goods, structured, extruded, or coated food products, like meat substitutes, condiments, sauces, marinades, soups, and spreads; cosmetic applications, such as hair styling products, toothpastes, lotions, creams, and lotions; detergents; paper coatings or paper bonding; welding electrodes; textile applications, such as textile printing and dyeing; ceramic applications, such as clay body and tile production; adhesives; paints; and construction applications, such as gypsum- or cement-based dry mortar applications.

[0058] While some dosage forms are effective if released immediately into the bloodstream, it may be advantageous to slowly release the active ingredient or target the release to a specific area of the body. CMC according to the present invention is a promising candidate for use as a modified-release coating for solid dosage forms. Modified-release can be delayed-release or extended-release.

[0059] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims that follow.Unless otherwise indicated, all parts and percentages are by weight.

[0060] Examples

[0061] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims that follow.Unless otherwise indicated, all parts and percentages are by weight.

[0062] Cellulose starting material

[0063] For Examples A, B, and C, a milled cellulose pulp with an intrinsic viscosity of 660 ml / g (Biofloc 96 from Tartas) was used. For Examples D and E, a milled cotton pulp with an intrinsic viscosity of 1740 ml / g (PCS2400 from Gaomi) was used. For Examples F, G, and H, a milled wood pulp with an intrinsic viscosity of 410 ml / g (Cellunier F from Rayonier) was used.

[0064] In all examples, 129.7 g of dry cellulose (corresponding to 0.8 mol of anhydroglucose units (AGU)) was used with varying amounts of isopropyl alcohol (IPA), methanol (MeOH), water, NaOH or KOH, and monochloroacetic acid (MCA) as indicated in the table. MCA was added as an 80% solution in water.

[0065] First, cellulose powder was introduced into a dry, 3-liter laboratory reactor, and then a solvent mixture of isopropanol, methanol, and water was added under a nitrogen atmosphere. NaOH (as pellets) or KOH (as pellets) was added at 20°C with stirring, and stirring was continued for 15 minutes. Afterwards, hydrogen peroxide (Example DH) was added at a concentration of 3% in water; stirring was continued at 20°C for a total of 60 minutes. The reaction mixture was then heated to 70°C over 40 minutes, and monochloroacetic acid was added as an 80% by weight aqueous solution during the first few minutes of the heating phase. During the carboxymethylation step, the temperature of 70°C was maintained for 120 minutes, and the reaction mixture was then cooled to 20°C over approximately 60 minutes. The pH of the cooled reaction mixture was adjusted to 7.5 with acetic acid, and the solution was then filtered. The filter residue was then washed at least five times with 2 liters of an isopropanol / methanol / water mixture (5:3:2 weight ratio) until no chloride ions were detected in the filtrate. This was followed by a final wash step with pure methanol. The washed samples were dried in a drying cabinet at 55° C. overnight and then ground in a laboratory grinder.

[0066] The degree of substitution of the obtained CMC was determined as described in the general section of the specification. 2 wt% solutions of CMC samples were also prepared and their viscosity, turbidity and transmittance were determined as described in the general section of the specification. The results are given in the table below.

[0067]

[0068] 1 Amount used in the alkalization step

[0069] 2 Degree of substitution

[0070] Two kinds (samples D and E) in the above CMC synthesis are carried out with water and high concentration of sodium hydroxide (>4mol / mol AGU) with concentration lower than 15mol / molAGU, produce CMC with DS lower than 0.5.Solutions from these CMCs show very low turbidity and high transmittance.Synthesize as described on page 11 of WO 2011 / 120533, except using reactants and solvents according to the respective amounts of the above table.Sample D has 0.4 DS and 3.1NTU turbidity, which is lower turbidity than the CMC (it has 0.4 DS and 14NTU turbidity) from Example 5 of WO 2011 / 120533.Sample E has 0.34 DS and 3NTU turbidity, which is lower turbidity than the CMC (it has 0.36 DS and 10NTU turbidity) from Example 18 of WO 2011 / 120533.

[0071] The turbidity of the sample of WO 2011 / 120533 was measured at a lower concentration (1%) than the turbidity of sample D / E (measured at 2%). The higher the concentration, the higher the turbidity of the solution. However, even at a concentration of 2%, sample D / E showed lower turbidity than the prior art.

[0072] The CMC synthesis for samples A, B and C produced CMC with DS of 0.19, 0.16 and 0.22 respectively. All solutions were turbid, but viscous. The film was cast from a 2% solution on a glass plate several times and dried at room temperature. The film cast from the solution was uniform, strong and elastic, which shows that CMC still works. The film contains a large amount of fibers that do not prevent film formation or have a negative impact on film properties. The film is a uniform film and is not a non-woven type. A piece of film (123 μm) of sample A was placed in a Franz cell diffusion cell and paracetamol (APAP) was diffused through at 37°C in HCl during 2h. The film remained stable in gastric juice and allowed to continue drug release over time.

[0073] Sample H is a CMC with a DS of 0.6, synthesized with a high concentration of base but with a water concentration of <15 mol / mol AGU.

[0074] The film from sample H (165 μm thickness) disintegrated in HCl within 15 min in a Franz cell.

[0075] Sample F is a CMC with a DS of 0.33, which was synthesized with a high concentration of base but with water having a concentration of >15 mol / mol AGU. The film (155 μm thickness) from sample F cast from a 4% solution remained intact in a Franz cell. The acid resistance did not meet the USP requirements, but met the nutritional drug requirements. See Figure 2A slightly higher film thickness should be sufficient to ensure that USP requirements are met, as shown for Sample G (see table above for Sample G).

[0076] Sample G has a DS of 0.33 and was synthesized using a high concentration of base but with water containing >15 mol / mol AGU. The film was cast several times from a 7.5% solution onto a glass plate and dried at room temperature. One piece of film (1 cm x 1 cm) (189 μm thickness) remained intact in the Franz cell. Drug release after 2 h was 0.2 mg of APAP, which is the USP limit. The film passed the USP test. See Figure 3 .

[0077] All publications mentioned in the above description are incorporated herein by reference. Various modifications and variations of the described methods and systems of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. Although the present invention has been described in conjunction with certain preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for practicing the present invention that would be apparent to those skilled in the biochemistry and biotechnology or related fields are intended to fall within the scope of the following claims.

Claims

1. A method for preparing carboxymethyl cellulose, comprising the steps of: a) suspending non-regenerated cellulose powder in a solvent / water mixture comprising water and isopropanol, adding an alkalizing agent in the form of a solid or aqueous solution, and reacting the non-regenerated cellulose with the alkalizing agent in the presence of isopropanol and water; and b) then adding a 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, wherein more than 2.5 mol of an alkalizing agent is used in step a), and wherein 0.2 to 2 mol of a monohaloacetic acid or a salt thereof is used in step b); each based on 1 mol of anhydroglucose units of the cellulose.

2. The method according to claim 1, wherein The ratio of alkalizing agent to monohaloacetic acid is between 2.4-20, preferably between 2.6-20; more preferably between 2.8-20.

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

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

5. The method according to any one of claims 1 to 4, wherein In step a), 100 to 10 mol of isopropanol is used based on 1 mol of anhydroglucose units of the cellulose.

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

7. The method according to any one of claims 1 to 6, wherein The method is carried out in the presence of greater than or equal to 15 moles of water based on 1 mole of anhydroglucose units of the cellulose.

8. The method according to any one of claims 1 to 6, wherein The process is carried out in the presence of water in an amount of 10 to 14.95 mol, more preferably in an amount of 12 to 14.92, most preferably in an amount of 14 to 14.9 mol, each based on 1 mol of anhydroglucose units of the cellulose.

9. The method according to any one of claims 1 to 5 or 7, wherein The process is carried out in the presence of water in an amount of 15 to 45 mol, more preferably 15.5 to 45 mol, more preferably 20 to 45, most preferably 30 to 45 mol, each based on 1 mol of anhydroglucose units of the cellulose.

10. A method according to any one of the preceding claims, wherein The alkalizing agent is used in an amount of 2.5 to 10 mol, preferably 3.1 to 10 mol, more preferably 3.5 to 8 mol, most preferably 4 to 7 mol, each based on 1 mol of the anhydroglucose unit of the cellulose.

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

12. The method according to claim 11, wherein When KOH is used as the alkalizing agent, K + ions are replaced by Na + Ion exchange.

13. A method according to any one of the preceding claims, wherein The monohaloacetic acid or its salt is used in an amount of 0.3 to 1.5 mol, preferably 0.4 to 1 mol, more preferably 0.5 to 0.8 mol, each based on 1 mol of the anhydroglucose unit of the cellulose.

14. A method according to any one of the preceding claims, wherein The monohaloacetic acid or its salt is monochloroacetic acid or its salt.

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

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

17. Carboxymethyl cellulose obtained or obtainable by a process according to any one of the preceding claims.

18. A carboxymethyl cellulose, wherein the carboxymethyl cellulose 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, more preferably 700 NTU or less, most preferably 500 NTU or less, measured as a 2 wt% aqueous solution.

19. Use of the carboxymethyl cellulose according to any one of claims 17-18 as a modified release coating.

20. The use according to claim 19, wherein The modified release is delayed release.

21. The use according to claim 19, wherein The modified release is extended release.

22. Use of the carboxymethyl cellulose according to any one of claims 17-18 as a thickener and / or gelling agent, binder, stabilizer, emulsifier, film former, suspending agent, protective colloid, crystallization inhibitor, or as an enteric coating.

23. Use of the carboxymethyl cellulose according to any one of claims 17-18 in drilling fluids, such as oil drilling fluids; pharmaceutical dosage forms, such as capsules, tablets, solutions, suspensions, emulsions, creams and lotions; food products, such as processed meat products, dairy products, bakery products, structured, extruded or coated food products, like meat substitutes, condiments, sauces, marinades, soups and spreads; cosmetic applications, such as hair styling products, toothpastes, lotions, creams and lotions; detergents; paper coatings or paper bonding; welding electrodes; textile applications, such as textile printing and dyeing; home care applications like laundry and dishwashing; Ceramic applications such as clay body and tile production; adhesives; paints; and construction applications such as dry mortar applications based on gypsum or cement; The polymer components in the capsules are formed as cross-linked interfaces.

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