Preparation process of industrialized medicinal cellulose diacetate

Abstract

The invention relates to a preparation process of medicinal cellulose diacetate, which comprises the following steps: A, activating 1 part by weight of cellulose by using 8-15 parts by weight of glacial acetic acid and 0.005-0.05 part by weight of catalyst at 20-50 DEG C; b, 3-6 parts by weight of acetic anhydride is added into the solution obtained in the step A for esterification, the esterification temperature is 40-75 DEG C, and the esterification time is 2-5 hours; c, at the esterification temperature, adding 0.004-0.008 part by weight of a neutralizing agent for neutralization, so that the residual sulfuric acid is completely neutralized; d, after the neutralization is finished, adding a hydrolysis catalyst and purified water, heating to 105-115 DEG C, and hydrolyzing for 5-10 hours; e, adding 20-25 parts by weight of purified water at the temperature of 60-90 DEG C into the reaction liquid in the step D, precipitating and centrifuging; respectively carrying out alkali washing, water washing and alcohol washing on the obtained solid; and F, dissolving the solid in the step E with an organic solution, filtering, adding purified water for precipitation, centrifuging, and drying to obtain the product cellulose diacetate. The process is easy to operate, the product quality is controllable, and the viscosity is low.

Description

Technical Field

[0001] The invention belongs to the technical field of polymer chemistry, relates to the preparation of cellulose acetate, and specifically provides a cellulose diacetate used as a semipermeable membrane material in the medical field, a preparation method and the prepared cellulose diacetate. Background Art

[0002] Cellulose Acetate (CA) is a cellulose ester obtained by acetylation of natural cellulose. It is an extremely important organic cellulose ester. According to the degree of acetic acid binding, it is divided into: 48.5-58.8% is called di-cellulose acetate (DCA); 60.0-62.5% is called tri-cellulose acetate (TCA). Among them, di-cellulose acetate can be used in textiles, plastics, semi-permeable membranes, and cigarette filters. In 2005, the global sales of cigarette filters reached 2.45 billion US dollars.

[0003] There are three homogeneous reaction methods reported for the preparation of cellulose acetate:

[0004] 1. Non-aqueous solution system: that is, dissolve cellulose and then acylate to obtain the required amount of cellulose ester with acetic acid. The systems include DMAc / LiCl, DMF / N2O4, DMSO / TBAF, NMMO, LiClO4.3H2O, etc. The above reaction systems have been reported, but these solvents are more or less toxic, expensive, and difficult to recycle in actual use, making it difficult to achieve industrialization. The only industrialized NMMO system is only used in regenerated cellulose fiber technology. The reagent has poor thermal stability, high price, strong oxidizing properties, and the disadvantages of cellulose being easily degraded during the dissolution process limit its application.

[0005] 2. Ionic liquid system: Swatloski [J.Am.Chem.Soc.2002,124,4974] systematically studied the use of substituted imidazolate ionic liquids as reaction media, dissolving cellulose and then acetylation. This study has led to a boom in the synthesis of cellulose acetate using ionic liquid systems. Currently, ionic liquids of different substituents and their anions such as imidazoles [Chem.Commun.2011,47,1405], quaternary ammonium salts [Green Chem.2008,10,696], phosphonium ions [Biomacromolecules 2007,8,.2629], and pyridinium ions [Macromol.Biosci.2005,5,520] have been reported. Patent CN1958616 discloses the use of plant fibers, substituted imidazolate ionic liquids as reaction media, and acetic anhydride as acylating agent to obtain cellulose triacetate. The embodiment is laboratory-scale, and the ratio of ionic liquid to cellulose is large, and vigorous stirring is required to dissolve cellulose, and the quality requirements of the recovered ionic liquid are unknown, so it is not suitable for large-scale production; Patent CN103509123 discloses the use of cellulose as raw material, replacing imidazole salt ionic liquid as reaction medium, acetic anhydride or acetyl chloride as acetylation reagent, sulfonated solid acid Amberlyst15 as catalyst for synthesizing cellulose diacetate, which is complicated to operate in the post-processing process, and needs to be dissolved repeatedly, and unreacted raw materials or by-products are filtered out, and the solvent is removed and the post-processing is obtained. The embodiment shows that the amount of ionic liquid required for dissolving cellulose is large (cellulose and ionic liquid ratio is 1g / 30mL), and the time for ionic liquid to dissolve cellulose is not indicated, and the product is not easy to separate. From the embodiment, it is limited to laboratory research and is not suitable for large-scale production. This is also an important reason why ionic liquids have not yet been industrialized.

[0006] 3. The ester acid method is a traditional method for producing cellulose acetate, which has been widely used in industrial practice. The process includes activation reaction, esterification reaction, hydrolysis reaction, neutralization reaction, and precipitation washing of cellulose. Patent CN102180975 reported a method for low-temperature hydrolysis to obtain cellulose triacetate used in polarizing films in optical components; CN102153659 reported a method for using excess acetate to improve the transparency of cellulose triacetate; CN1995066 reported a method for preparing tricellulose acetate by high-temperature esterification to make the product substitution more uniform, and low-temperature hydrolysis to prevent local hydrolysis, so as to obtain a more uniform acetylation.

[0007] CN112225823A discloses a method for preparing high-stability cellulose diacetate, including cellulose pretreatment, mixed acid preparation, acetylation reaction, adding desalted water for molding, washing and drying, etc. However, the cellulose diacetate obtained by this method has a high viscosity, 70-125 mPa.s in 6% acetone, which can be used for liquid crystal display screens but is not suitable for medicinal use.

[0008] So far, there is an urgent need for a method for industrially preparing medicinal cellulose diacetate. Summary of the invention

[0009] In view of the above technical status, the present invention provides a method for industrially preparing medicinal cellulose diacetate, and the specific invention is as follows:

[0010] The present invention provides a preparation process of medicinal cellulose diacetate, comprising the following steps:

[0011] A. Cellulose activation: 1 part by weight of cellulose is activated with 8 to 15, preferably 10 to 12 parts by weight of glacial acetic acid and 0.005 to 0.05, preferably 0.005 to 0.01 parts by weight of a catalyst at 20 to 50° C., preferably 25 to 35° C.;

[0012] As an exemplary illustration, the temperature can be 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, or 35°C; the amount of glacial acetic acid can be 10 parts, 11 parts, or 12 parts; the amount of the catalyst can be 0.005, 0.006, 0.008, 0.009, or 0.01 parts by weight.

[0013] B. Esterification reaction: adding 3 to 6 parts by weight of acetic anhydride to the solution obtained in step A for esterification at a temperature of 40 to 75° C., preferably 55 to 65° C., for a time of 2 to 5 hours, preferably 3 to 4 hours;

[0014] As an exemplary illustration,

[0015] The amount of acetic anhydride ester can be 3, 4, 5 or 6 parts by weight;

[0016] The esterification temperature may be 40°C, 41°C, 42°C, 43°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C, 74°C or 75°C;

[0017] The esterification time may be 2 hours, 3 hours, 4 hours or 5 hours.

[0018] C. Neutralization reaction: at the esterification temperature, add 0.004 to 0.001, preferably 0.008 to 0.01 parts by weight of a neutralizing agent to completely neutralize the residual sulfuric acid;

[0019] As an exemplary illustration,

[0020] The amount of the neutralizing agent may be 0.004, 0.005, 0.006, 0.007, 0.008, 0.009 or 0.01 parts by weight.

[0021] D. Hydrolysis reaction: After neutralization, add a hydrolysis catalyst and purified water, heat to 105-115°C, preferably 108-112°C, and hydrolyze for 5-10 hours, preferably 6-8 hours;

[0022] As an exemplary illustration,

[0023] The hydrolysis temperature can be 105°C, 106°C, 107°C, 108°C, 109°C, 110°C, 111°C, 112°C, 113°C, 114°C, 115°C; the hydrolysis time can be 5, 6, 7, 8, 9 or 10 hours.

[0024] E. Add 20 to 25 parts by weight of purified water at 60 to 90° C. to the reaction solution of step D, precipitate, and centrifuge; the obtained solid is washed with alkali, water, and alcohol respectively;

[0025] F. The solid in step E is dissolved in an organic solution and then filtered, purified water is added for precipitation, centrifuged and dried to obtain the product cellulose diacetate.

[0026] In the process for preparing cellulose diacetate of the present invention, as one of the embodiments, the step A further comprises immersing at 25 to 35° C. for 2 to 4 hours for activation.

[0027] In the process for preparing cellulose diacetate of the present invention, as one of the embodiments, in step A, the catalyst is 98% concentrated sulfuric acid.

[0028] In the process for preparing cellulose diacetate of the present invention, as one of the embodiments, in step C, the neutralizing agent is selected from sodium acetate or potassium acetate.

[0029] In the preparation process of cellulose diacetate of the present invention, as one of the embodiments, in the step D, the hydrolysis catalyst is selected from concentrated sulfuric acid, phosphoric acid, sodium bisulfate or potassium bisulfate, preferably sodium bisulfate or potassium bisulfate, and the amount used is 0.005-0.05 parts by weight, preferably 0.005-0.01 parts by weight; the concentrated sulfuric acid is 98% concentrated sulfuric acid.

[0030] In the process for preparing cellulose diacetate of the present invention, as one of the embodiments, in the step D, the amount of purified water added is 1.8 to 2.4 parts by weight, preferably 1.9 to 2.1 parts by weight.

[0031] In the cellulose diacetate preparation process of the present invention, as one of the embodiments, in the step E, the alkali washing solution is selected from the group consisting of sodium carbonate solution, sodium bicarbonate solution, potassium carbonate solution, potassium bicarbonate solution, preferably sodium bicarbonate solution.

[0032] In the process for preparing cellulose diacetate of the present invention, as one of the embodiments, in step E, the concentration of the alkaline washing solution is 8-10%.

[0033] In the process for preparing cellulose diacetate of the present invention, as one of the embodiments, in step E, the alcohol washing solution is selected from methanol or ethanol solution, preferably methanol solution.

[0034] In the process for preparing cellulose diacetate of the present invention, as one of the embodiments, the organic solvent used in step F is acetone.

[0035] The process for preparing cellulose diacetate of the present invention, as one of the embodiments, further comprises the following steps:

[0036] A. Cellulose activation: 1 part by weight of cellulose is activated with 10 to 12 parts by weight of glacial acetic acid and 0.005 to 0.01 parts by weight of concentrated sulfuric acid at 25 to 35°C for 2 to 4 hours;

[0037] B. Esterification reaction: 3-6 parts by weight of acetic anhydride are slowly added dropwise to the reaction system at the activation temperature while stirring, and the temperature is slowly raised to the esterification temperature of 55-65°C; the esterification reaction time is 3-4 hours; the reaction mixture is a uniform transparent viscous liquid;

[0038] C. Neutralization reaction: at the esterification temperature, add 0.008-0.01 parts by weight of a neutralizing agent, sodium acetate, to completely neutralize the residual sulfuric acid;

[0039] D. Hydrolysis reaction: After neutralization, add 0.005-0.01 parts by weight of sodium bisulfate as a hydrolysis catalyst to the reaction solution; add 1.9-2.1 parts by weight of water required for hydrolysis; heat the reaction solution to 108-112° C., and react for 6-8 hours;

[0040] E. Precipitation and washing: add 20-25 parts by weight of purified water at 60-90°C for precipitation, centrifuge, alkali wash, water wash, and alcohol wash; the alkali solution is preferably 8-10% sodium bicarbonate, and the alcohol solution for washing is preferably methanol;

[0041] F. Dissolving, filtering and precipitating: The obtained solid is dissolved in an organic solvent and then filtered, and the organic solvent is preferably acetone; purified water is added at room temperature for precipitation, and the product cellulose diacetate is obtained by centrifugation and drying. The product yield is 1.05 to 1.2 times the weight of cellulose.

[0042] In the process for preparing cellulose diacetate of the present invention, as one of the embodiments, in step A, the cellulose is selected from cotton cellulose.

[0043] The present invention also provides a cellulose diacetate prepared by a preparation process, wherein the acetic acid binding amount is 53% to 57%, the weight average molecular weight is 95000 to 105000, and the molecular weight distribution is 1.8 to 2.1.

[0044] The invention also provides a preparation process of cellulose diacetate and application of cellulose diacetate in the medical field.

[0045] In the application of the present invention, as one of the embodiments, the cellulose diacetate is used as a semipermeable membrane material.

[0046] In the application of the present invention, as one of the embodiments, the cellulose diacetate is used as a functional film coating of a sustained-release preparation.

[0047] The invention provides an industrializable preparation process of medicinal cellulose diacetate, which is easy to operate, has controllable product quality and low viscosity.

[0048] The process of the present invention can obtain cellulose diacetate with an acetic acid binding amount of 53% to 57%, a number average molecular weight of 3.5 to 4.5w (weight average molecular weight of 95,000 to 100,000), a molecular weight distribution of 1.8 to 2.1, and a viscosity of 22.8 to 38.0 mPa.s.

[0049] Through the present invention, cellulose diacetate with product quality that meets the 2015 edition Pharmacopoeia standard can be obtained industrially and stably. The present invention can reduce product degradation, improve product molecular weight distribution and product solution transparency. The product has good water permeability and can be used in the medical field, specifically as a functional film coating for sustained-release preparations.

[0050] The process parameters of the present invention are optimized, especially the hydrolysis process and reaction temperature of the present invention, the catalyst with appropriate acidity and the amount of water effectively control the acetyl (i.e. acetic acid) content, molecular weight and its distribution; and at the same time solve the problem of ignition residue and insoluble particles. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 : Molecular weight spectrum of cellulose diacetate product batch 18010401 in test 1;

[0052] Figure 2: Molecular weight spectrum of cellulose diacetate product batch 18010402 in test 1;

[0053] Figure 3 : Molecular weight spectrum of cellulose diacetate product batch 18010403 in test 1;

[0054] Figure 4 : Dissolution stability of different batches of products in test 2 after 6 months of accelerated release;

[0055] Figure 5 : The dissolution stability of different batches of products in Test 2 after 24 months. DETAILED DESCRIPTION

[0056] The following examples are used to further illustrate the present invention, but are not intended to limit the effective scope of the present invention in any way.

[0057] In the following embodiments and effect verification examples, the detection method of the product is as follows:

[0058] According to the guidance of GB / T 21863-2008 and GB / T 21864-2008, the molecular weight value is used to assist in monitoring the viscosity of the product (the range of molecular weight values ​​is guided by the molecular weight data of multiple batches of commercially available Eastman cellulose acetate).

[0059] Molecular weight (HPLC) detection method:

[0060] Chromatographic conditions:

[0061] Chromatographic columns: SepaxMono GPC-500 (guard column), SepaxMono GPC-500, SepaxMono GPC-300;

[0062] Mobile phase: tetrahydrofuran;

[0063] Flow rate: 0.5 ml / min; column temperature: 40°C, detection wavelength: 212 nm; injection volume: 20 μl.

[0064] Preparation of reference solution: Take 10 mg each of polystyrene standards with molecular weight of 3000, 10000, 20000, 30000, 70000, 150000, and 300000, accurately weigh, dissolve and dilute with tetrahydrofuran to a solution containing 10 μg of the standard per 1 ml, filter with a 0.45 μm syringe filter (PTFE), and take the filtrate to obtain the reference solution.

[0065] Preparation of test solution: Take about 250 mg of the product, accurately weigh it, put it in a 25 ml volumetric flask, add an appropriate amount of tetrahydrofuran, shake and stir to dissolve, dilute to the scale with tetrahydrofuran, shake well, filter with a 0.45 μm needle filter (PTFE), and take the filtrate to obtain the solution.

[0066] Determination method:

[0067] Accurately measure 20μl of each reference solution, inject it into the liquid chromatograph, record the chromatogram, and use the GPC workstation to fit the cubic equation curve between the retention time and peak molecular weight (MP) of the main peak of each reference solution. Accurately measure 20μl of the test solution, inject it into the liquid chromatograph, record the chromatogram, and calculate the molecular weight with the GPC workstation. The weight average molecular weight (Mw) should be between 83,000 and 103,000.

[0068] According to the guidance of the 2015 edition of the Pharmacopoeia, the free acid, ignition residue, heavy metals, loss on drying, molecular weight, solvent residue and content of the product are determined.

[0069] Example 1

[0070] 10 kg of pretreated cotton cellulose was placed in a 300L reactor, and a mixture of 100 kg of glacial acetic acid and 0.05 kg of concentrated sulfuric acid was added, and the mixture was soaked at 25°C for 3 hours for activation. After activation, 40 kg of acetic anhydride was slowly added to the mixture in the reactor under stirring, and the drop rate was controlled so that the reaction temperature could be controlled to rise without exceeding the esterification temperature. After the drop addition was completed, the temperature was raised to 60°C, the esterification temperature, and the reaction was carried out for 2 hours to obtain a uniform reaction solution. 0.084 kg of sodium acetate was added as a neutralizing agent to neutralize the residual sulfuric acid. After neutralization, 0.05 kg of sodium bisulfate and 19 kg of purified water were added, and the temperature was raised to 110°C for hydrolysis for 7 hours to complete the hydrolysis. The temperature was lowered to 80-90°C, and 200 kg of purified water at 80°C was added to precipitate the product. The centrifuged solid was washed with 10% sodium bicarbonate aqueous solution, 50°C purified water, and 100 kg of methanol, respectively. The obtained solid was dissolved in an appropriate amount of acetone and filtered, and the filtrate was dropwise added with purified water at room temperature to precipitate a solid, which was dried and stored. The weight yield was 115%.

[0071] After chemical analysis, the product has an acetic acid binding capacity of 55.1%, free acid <0.1%, ignition residue <0.1%, heavy metal <10ppm, and meets the pharmacopoeia quality standards. The weight average molecular weight is 100000 (number average molecular weight 4.4w), the viscosity is 37mPa·s, and the molecular weight distribution is 1.9.

[0072] Example 2

[0073] 10 kg of pretreated cotton cellulose was placed in a 300L reactor, and a mixture of 110 kg of glacial acetic acid and 0.05 kg of concentrated sulfuric acid was added, and the mixture was soaked at 35°C for 2 hours for activation. After activation, 50 kg of acetic anhydride was slowly added to the mixture in the reactor under stirring, and the drop rate was controlled so that the reaction temperature could be controlled to rise without exceeding the esterification temperature. After the drop addition was completed, the temperature was raised to 55°C, the esterification temperature, and the reaction was carried out for 3 hours to obtain a uniform reaction solution. 0.1 kg of potassium acetate was added as a neutralizing agent to neutralize the residual sulfuric acid. After neutralization, 0.06 kg of potassium hydrogen sulfate and 20 kg of purified water were added, and the temperature was raised to 110°C for hydrolysis for 6 hours to complete the hydrolysis. The temperature was lowered to 80-90°C, and 200 kg of purified water at 80°C was added to precipitate the product. The centrifuged solid was washed with 10% potassium bicarbonate aqueous solution, 50°C purified water, and methanol, respectively. The obtained solid was dissolved in an appropriate amount of acetone and filtered, and the filtrate was dropwise added with purified water at room temperature to precipitate a solid, which was dried and stored. The weight yield was 105%.

[0074] After chemical analysis, the product has an acetic acid binding capacity of 56.5%, free acid <0.1%, ignition residue <0.1%, heavy metal <10ppm, and meets the pharmacopoeia quality standards. The weight average molecular weight is 98000 (number average molecular weight 4w), the viscosity is 30mPa·s, and the molecular weight distribution is 1.9.

[0075] Example 3

[0076] 10 kg of pretreated cotton cellulose was placed in a 300L reactor, and a mixture of 120 kg of glacial acetic acid and 0.05 kg of concentrated sulfuric acid was added, and the mixture was soaked at 25°C for 3 hours for activation. After activation, 40 kg of acetic anhydride was slowly added to the mixture in the reactor under stirring, and the drop rate was controlled so that the reaction temperature could be controlled to rise without exceeding the esterification temperature. After the drop addition was completed, the temperature was raised to 65°C, the esterification temperature, and the reaction was carried out for 2 hours to obtain a uniform reaction solution. 0.084 kg of sodium acetate was added as a neutralizing agent to neutralize the residual sulfuric acid. After neutralization, 0.1 kg of sodium bisulfate and 21 kg of water were added, and the temperature was raised to 110°C for hydrolysis for 6 hours to complete the hydrolysis. The temperature was lowered to 80-90°C, and 200 kg of purified water at 80°C was added to precipitate the product. The centrifuged solid was washed with 10% sodium bicarbonate aqueous solution, 50°C purified water, and methanol, respectively. The obtained solid was dissolved in an appropriate amount of acetone and filtered, and the filtrate was dropwise added with purified water at room temperature to precipitate a solid, which was dried and stored. The weight yield was 108%.

[0077] After chemical analysis, the product has an acetic acid binding capacity of 53.2%, free acid <0.1%, ignition residue <0.1%, heavy metal <10ppm, and meets the pharmacopoeia quality standards. The weight average molecular weight is 95,000 (number average molecular weight 3.8w), the viscosity is 25mPa·s, and the molecular weight distribution is 2.0.

[0078] Example 4

[0079] 10 kg of pretreated cotton cellulose was placed in a 300L reactor, and a mixture of 100 kg of glacial acetic acid and 0.05 kg of concentrated sulfuric acid was added, and the mixture was soaked at 25°C for 3 hours for activation. After activation, 40 kg of acetic anhydride was slowly added to the mixture in the reactor under stirring, and the drop rate was controlled so that the reaction temperature could be controlled to rise without exceeding the esterification temperature. After the drop addition was completed, the temperature was raised to 60°C, the esterification temperature, and the reaction was carried out for 2 hours to obtain a uniform reaction solution. 0.084 kg of sodium acetate was added as a neutralizing agent to neutralize the residual sulfuric acid. After neutralization, 0.05 kg of concentrated sulfuric acid and 19 kg of purified water were added, and the temperature was raised to 110°C, the hydrolysis temperature, and the hydrolysis was completed for 11 hours. The temperature was lowered to 80-90°C, and 80°C and 200 kg of purified water were added to precipitate the product. The centrifuged solid was washed with 10% sodium bicarbonate aqueous solution, 50°C purified water, and 100 kg of methanol, respectively. The obtained solid was dissolved in an appropriate amount of acetone and filtered, and the filtrate was dropwise added with purified water at room temperature to precipitate a solid, which was dried and stored. The weight yield was 110%.

[0080] After chemical analysis, the product has an acetic acid binding capacity of 54.8%, free acid <0.1%, ignition residue <0.1%, heavy metal <10ppm, and meets the pharmacopoeia quality standards. The weight average molecular weight is 96000 (number average molecular weight 4w), viscosity is 28mPa·s, and molecular weight distribution is 1.8.

[0081] Example 5

[0082] 10 kg of pretreated cotton cellulose was placed in a 300L reactor, and a mixture of 100 kg of glacial acetic acid and 0.05 kg of concentrated sulfuric acid was added, and the mixture was soaked at 25°C for 3 hours for activation. After activation, 40 kg of acetic anhydride was slowly added to the mixture in the reactor under stirring, and the drop rate was controlled so that the reaction temperature could be controlled to rise without exceeding the esterification temperature. After the drop addition was completed, the temperature was raised to 60°C, the esterification temperature, and the reaction was carried out for 2 hours to obtain a uniform reaction solution. 0.084 kg of sodium acetate was added as a neutralizing agent to neutralize the residual sulfuric acid. After neutralization, 0.1 kg of phosphoric acid and 19 kg of purified water were added, and the temperature was raised to 110°C for hydrolysis for 12 hours to complete the hydrolysis. The temperature was lowered to 80-90°C, and 200 kg of purified water at 80°C was added to precipitate the product. The centrifuged solid was washed with 10% sodium bicarbonate aqueous solution, 50°C purified water, and 100 kg of methanol, respectively. The obtained solid was dissolved in an appropriate amount of acetone and filtered, and the filtrate was dropwise added with purified water at room temperature to precipitate a solid, which was dried and stored. The weight yield was 116%.

[0083] After chemical analysis, the product has an acetic acid binding capacity of 55.3%, free acid <0.1%, ignition residue <0.1%, heavy metal <10ppm, and meets the pharmacopoeia quality standards. The weight average molecular weight is 97,000 (number average molecular weight 4.2w), the viscosity is 33mPa·s, and the molecular weight distribution is 1.7.

[0084] Example 6

[0085] 10 kg of pretreated cotton cellulose was placed in a 300L reactor, and a mixture of 100 kg of glacial acetic acid and 0.05 kg of concentrated sulfuric acid was added, and the mixture was soaked at 25°C for 3 hours for activation. After activation, 40 kg of acetic anhydride was slowly added to the mixture in the reactor under stirring, and the drop rate was controlled so that the reaction temperature could be controlled to rise without exceeding the esterification temperature. After the drop addition was completed, the temperature was raised to 60°C, the esterification temperature, and the reaction was carried out for 2 hours to obtain a uniform reaction solution. 0.084 kg of sodium acetate was added as a neutralizing agent to neutralize the residual sulfuric acid. After neutralization, 0.05 kg of sodium bisulfate and 19 kg of purified water were added, and the temperature was raised to 100°C for hydrolysis for 14 hours to complete the hydrolysis. The temperature was lowered to 80-90°C, and 200 kg of purified water at 80°C was added to precipitate the product. The centrifuged solid was washed with 10% sodium bicarbonate aqueous solution, 50°C purified water, and 100 kg of methanol, respectively. The obtained solid was dissolved in an appropriate amount of acetone and filtered, and the filtrate was dropwise added with purified water at room temperature to precipitate a solid, which was dried and stored. The weight yield was 122%.

[0086] After chemical analysis, the product has an acetic acid binding capacity of 55.9%, free acid <0.1%, ignition residue <0.1%, heavy metal <10ppm, and meets the pharmacopoeia quality standards. The weight average molecular weight is 99,000 (number average molecular weight 4.3w), the viscosity is 36mPa·s, and the molecular weight distribution is 1.8.

[0087] Test Example 1: Test results of properties of different batches of products

[0088] Take batches 18010401, 18010402, and 18010403 of products, and prepare and measure the molecular weight spectra according to Example 1 (such as Figures 1 to 3 The free acid, ignition residue, heavy metals, loss on drying, molecular weight, solvent residue and content of the product were tested respectively. The results are shown in Table 1. Figure 1 to Figure 3 :

[0089] Table 1: Test results of properties of different batches of products

[0090]

[0091] Experimental Example 2 Comparative experiment on stability and dissolution of different batches of products and Eastman's marketed products

[0092] Take 16112402, 16120103 and 16120204 batches of products, the three batches of products are prepared according to Example 1 respectively, with Eastman listed product (lot number AC-01971NF) as contrast, respectively dissolved in acetone with porogen as coating slurry, felodipine sustained-release tablets II core (lot number 170401) is subjected to controlled release film coating, punching and aluminum-plastic blister, and then the dissolution stability test under accelerated and long-term conditions is carried out, and the results are shown in Tables 2 to 3. Figure 4-5 :

[0093] Table 2 Dissolution stability test results of different batches of products after 6 months of accelerated release

[0094]

[0095] Table 3 Dissolution stability test results of different batches of products after 24 months

[0096]

Claims

1. A process for preparing medicinal cellulose diacetate, characterized in that: The following steps are involved: A. Cellulose activation: 1 part by weight of cellulose is activated with 8 to 15, preferably 10 to 12 parts by weight of glacial acetic acid and 0.005 to 0.05, preferably 0.005 to 0.01 parts by weight of a catalyst at 20 to 50° C., preferably 25 to 35° C.; B. Esterification reaction: adding 3 to 6 parts by weight of acetic anhydride to the solution obtained in step A for esterification at a temperature of 40 to 75° C., preferably 55 to 65° C., for a time of 2 to 5 hours, preferably 3 to 4 hours; C. Neutralization reaction: at the esterification temperature, add 0.004-0.01, preferably 0.008-0.01 parts by weight of a neutralizing agent to completely neutralize the residual sulfuric acid; D. Hydrolysis reaction: After neutralization, add a hydrolysis catalyst and purified water, heat to 105-115°C, preferably 108-112°C, and hydrolyze for 5-10 hours, preferably 6-8 hours; E. Add 20 to 25 parts by weight of purified water at 60 to 90° C. to the reaction solution of step D, precipitate, and centrifuge; the obtained solid is washed with alkali, water, and alcohol respectively; F. The solid in step E is dissolved in an organic solution and then filtered, purified water is added for precipitation, centrifuged and dried to obtain the product cellulose diacetate.

2. The process for preparing cellulose diacetate according to claim 1, characterized in that: The step A further comprises immersing at 25 to 35° C. for 2 to 4 hours for activation.

3. The process for preparing cellulose diacetate according to claim 1, characterized in that: In the step A, the catalyst is 98% concentrated sulfuric acid.

4. The process for preparing cellulose diacetate according to claim 1, characterized in that: In step C, the neutralizing agent is selected from sodium acetate or potassium acetate.

5. The process for preparing cellulose diacetate according to claim 1, characterized in that: In the step D, the hydrolysis catalyst is selected from concentrated sulfuric acid, phosphoric acid, sodium bisulfate or potassium bisulfate, preferably sodium bisulfate or potassium bisulfate, and the amount used is 0.005 to 0.05 parts by weight, preferably 0.005 to 0.01 parts by weight.

6. The process for preparing cellulose diacetate according to claim 1, characterized in that: In the step D, the amount of purified water added is 1.8 to 2.4 parts by weight, preferably 1.9 to 2.1 parts by weight.

7. The process for preparing cellulose diacetate according to claim 1, characterized in that: In the step E, the alkaline washing solution is selected from sodium carbonate solution, sodium bicarbonate solution, potassium carbonate solution, potassium bicarbonate solution, preferably sodium bicarbonate solution.

8. The process for preparing cellulose diacetate according to claim 1, characterized in that: In the step E, the concentration of the alkaline washing solution is 8-10%.

9. The process for preparing cellulose diacetate according to claim 1, characterized in that: In the step E, the alcohol washing solution is selected from methanol or ethanol solution, preferably methanol solution.

10. The process for preparing cellulose diacetate according to claim 1, characterized in that: The organic solvent used in step F is acetone.

11. The process for preparing cellulose diacetate according to any one of claims 1 to 10, characterized in that: Further comprising the steps of: A. Cellulose activation: 1 part by weight of cellulose is activated with 10 to 12 parts by weight of glacial acetic acid and 0.005 to 0.01 parts by weight of concentrated sulfuric acid at 25 to 35°C for 2 to 4 hours; B. Esterification reaction: 3-6 parts by weight of acetic anhydride are slowly added dropwise to the reaction system at the activation temperature while stirring, and the temperature is slowly raised to the esterification temperature of 55-65°C; the esterification reaction time is 3-4 hours; the reaction mixture is a uniform transparent viscous liquid; C. Neutralization reaction: at the esterification temperature, add 0.008-0.01 parts by weight of a neutralizing agent, sodium acetate, to completely neutralize the residual sulfuric acid; D. Hydrolysis reaction: After neutralization, add 0.005-0.01 parts by weight of sodium bisulfate as a hydrolysis catalyst to the reaction solution; add 1.9-2.1 parts by weight of water required for hydrolysis; heat the reaction solution to 108-112° C., and react for 6-8 hours; E. Precipitation and washing: add 20-25 parts by weight of purified water at 60-90°C for precipitation, centrifuge, alkali wash, water wash, and alcohol wash; the alkali solution is preferably 8-10% sodium bicarbonate, and the alcohol solution for washing is preferably methanol; F. Dissolving, filtering and precipitating: The obtained solid is dissolved in an organic solvent and then filtered, and the organic solvent is preferably acetone; purified water is added at room temperature for precipitation, and the product cellulose diacetate is obtained by centrifugation and drying. The product yield is 1.05 to 1.2 times the weight of cellulose.

12. The process for preparing cellulose diacetate according to claim 11, characterized in that: In the step A, the cellulose is selected from cotton cellulose.

13. Cellulose diacetate prepared according to the process for preparing cellulose diacetate according to any one of claims 1 to 12, wherein the acetic acid binding amount is 53% to 57%, the weight average molecular weight is 95,000 to 105,000, and the molecular weight distribution is 1.8 to 2.

1.

14. The process for preparing cellulose diacetate according to any one of claims 1 to 12, or the use of cellulose diacetate according to claim 12 in the medical field.

15. The use according to claim 14, characterized in that: The cellulose diacetate is used as a semipermeable membrane material.

16. The use according to claim 14, characterized in that The application of the cellulose diacetate as a functional film coating for a sustained-release preparation.

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