CN115626957A - Production method of hydroxypropyl methylcellulose for skeleton slow release - Google Patents
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Abstract
The invention relates to a production method of hydroxypropyl methylcellulose, in particular to a production method of hydroxypropyl methylcellulose for skeleton slow release, belonging to the technical field of cellulose ether production. A production method of hydroxypropyl methylcellulose for skeleton slow release comprises the following steps: 1) Crushing the refined cotton; 2) Performing nitrogen replacement; 3) Adding refined cotton powder, a mixed solvent and an alkalizer into an alkalization kettle, and controlling reaction alkalization reaction conditions; 4) Adding an etherification reagent into the reaction kettle for a plurality of periods to react with the alkalized refined cotton powder, and controlling the reaction etherification reaction conditions; 5) Neutralizing with glacial acetic acid; 6) Desolventizing; 7) And centrifugally separating, granulating, drying, mixing and packaging to obtain the final product. The hydroxypropyl methylcellulose prepared by the method has the advantages of stable quality and small batch difference.
Description
Technical Field
The invention relates to a production method of hydroxypropyl methylcellulose, in particular to a production method of hydroxypropyl methylcellulose for skeleton slow release, belonging to the technical field of cellulose ether production.
Background
Hypromellose is used as a pharmaceutic adjuvant and mainly used as a slow release material, a film coating material, a thickening agent, a stabilizing agent, an emulsifying agent and an adhesive. When used as a sustained-release material, the compound is mainly used for preparing insoluble matrix sustained-release tablets, hydrophilic gel matrix sustained-release tablets, coated sustained-release tablets, sustained-release pellets, multi-layer sustained-release tablets and sustained-release capsules. The annual demand of the hydroxypropyl methylcellulose for the sustained release of the medicinal skeleton at present in China is about 1000 tons. With the rapid development of the pharmaceutical industry, especially the modernization of traditional Chinese medicine, the hydroxypropyl methylcellulose for skeleton slow release has wider and wider application prospect in the field of pharmaceutical industry.
The hydroxypropyl methyl fiber is divided into different specifications according to different contents of hydroxypropyl and methoxyl, and the different specifications correspond to different properties and different purposes. In the Chinese pharmacopoeia 2020 edition, hydroxypropyl methylcellulose is divided into four substitution types, 1828, 2208, 2906 and 2910. The designation of the type is 2208, 22 means that the content of methoxyl group is about 22%, 08 means that the content of hydroxypropoxyl group is about 8%. It is common in the art to use form 1828 as a binder and disintegrant for tablets, form 2208 as a matrix material for sustained and controlled release preparations, form 2906 as a coating material for enteric preparations, and form 2910 as a film coating material.
The gelling temperature is an important characteristic of hypromellose. Generally, the gelation temperature of hypromellose decreases with increasing methoxy content. Generally, the hypromellose can only be dissolved in cold water, but the hypromellose with low gelation temperature can be dissolved in organic solvents besides being used in cold water, which significantly improves the practical value and economic value thereof. At present, the domestic market divides hypromellose into K series, F series and E series according to the gelation temperature. The E series roughly corresponds to 2910 type, the F series roughly corresponds to 2906 type, and the K series roughly corresponds to 2208 type.
Although the Chinese pharmacopoeia provides the type and the corresponding series on the market, in practice, the molecular weight of the hypromellose is not provided. The research on the influence of physical and chemical property characterization of hydroxypropyl methylcellulose from different manufacturers on the slow release effect, which is published by the institute of medicine and university of Qingdao, of the Jamai Nu and the like indicates that the hydroxypropyl methylcellulose produced from different manufacturers has differences in physical and chemical properties, which are specifically shown in the following steps: the particle size is different, the bulk density is different, the physical properties are different, whether a crystallization peak and the content difference of hydroxypropoxyl exist or not is different, and the slow release effect caused by the crystallization peak and the hydroxypropoxyl is different. The final study results were: the differences among the hydroxypropyl methylcellulose batches produced by the same manufacturer are large, and the differences among the hydroxypropyl methylcellulose produced by different manufacturers are larger, so that the differences are great when the hydroxypropyl methylcellulose is used as a skeleton slow-release material. If publication numbers are: CN 109336985 a, the present invention discloses a method for producing high viscosity hypromellose, as shown above, the hypromellose prepared by the method has unstable quality and large batch-to-batch difference.
Disclosure of Invention
The invention aims to solve the problems and provides a production method of hydroxypropyl methylcellulose for skeleton slow release. The hydroxypropyl methylcellulose prepared by the method has the advantages of stable quality and small batch difference.
The technical scheme for solving the problems is as follows:
a production method of hydroxypropyl methylcellulose for skeleton slow release comprises the following steps:
1) Crushing the refined cotton, screening cotton powder of 200-120 meshes, and conveying the cotton powder to a storage tank through a pipeline airflow;
2) Performing nitrogen replacement in a storage tank to obtain deoxidized cotton powder;
3) Starting nitrogen to replace the air in the reaction kettle; then pressing toluene and isopropanol into a reaction kettle to form a mixed solvent; pressing a sodium hydroxide aqueous solution with the mass concentration of 40-60% into a mixed solvent of a reaction kettle; adding the deoxidized cotton powder, stirring while adding the cotton powder, keeping the temperature of a system in the tank at 25-30 ℃ after uniformly stirring, and standing for 1-2 hours; mass ratio, toluene: isopropyl alcohol: water =6.0: (1.0-1.2): (0.4-0.5); mixing solvent: deoxidized cotton powder = (8-12): 1; in this step, the water is the solvent part of the aqueous sodium hydroxide solution;
4) Dividing the etherification reagent into a plurality of periods, adding the periods into a reaction kettle, and reacting the etherification reagent with the alkalized refined cotton powder, wherein each reaction period comprises low-temperature etherification and high-temperature etherification; the ratio of methyl chloride to propylene oxide in the etherification reagent is (3.0-3.5): 1, the mass ratio of the refined cotton powder to the total amount of the etherification reagent is 1 (1.2-1.5); the low-temperature etherification is carried out at the temperature of 45-55 ℃, and the high-temperature etherification is carried out at the temperature of 85-90 ℃;
5) After the reaction is finished, neutralizing the residual alkali by using glacial acetic acid;
6) Pressing the materials into a desolventizing kettle, starting stirring of the desolventizing kettle, adding hot water at the top while stirring, and introducing water vapor from the bottom of the desolventizing kettle to prevent the temperature from being lower than 80 ℃; the adding amount of the hot water is 0.6 to 1.0 time of the volume of the solvent; continuously stirring for more than 10 minutes, and standing for more than 20 minutes to form a solid-liquid-gas three phase; leading most of liquid solvent into a water diversion tank from a pipeline at the waist position of a desolventizing kettle, and then, standing and layering to recover the solvent; then the residual solvent is recovered through a condensation way;
7) And the mixture after desolventizing is centrifugally separated by a horizontal sedimentation centrifuge, and then is granulated, dried, mixed and packaged to form the final product.
In the technical scheme of the invention, cotton powder of 200-120 meshes is firstly selected and roughly corresponding to the particle size of 80-120 mu m, so that the raw material basis of hydroxypropyl methylcellulose for skeleton slow release production is met. Because the fineness of the crushed cotton powder can influence the degree of polymerization, and the degree of polymerization cannot meet the requirement due to the excessively fine crushing; and too coarse pulverization makes it difficult to reduce the crystallinity between the celluloses. The reduction of crystallinity is beneficial to improving the reactivity of the cellulose. That is, the present invention first adopts a crushing and sieving method to reduce the crystallinity of cellulose as much as possible and improve the reactivity of cellulose while satisfying the requirement of polymerization degree.
Secondly, the invention further improves the activity of the cellulose by means of alkalization. The inventors have found that alkali cellulose can be produced by reacting cellulose with sodium hydroxide solutions of various concentrations. The alkali cellulose has different NaOH contents and H according to different alkali concentrations 2 O content, e.g. C 6 H 7 O 2 (OH) 3 ·NaOH·H 2 O、C 6 H 7 O 2 (OH) 3 ·NaOH·3H 2 O、C 6 H 7 O 2 (OH) 3 ·NaOH·5H 2 O、C 6 H 7 O 2 (OH) 3 ·NaOH·12H 2 O、C 6 H 7 O 2 (OH) 3 ·NaOH·20H 2 O, and the like. The alkalization of the invention further optimizes the technical parameters on the basis of the prior art by researching the influence of the solvent, alkali and temperature on the alkalization. Such as alkalization temperature, the prior art generally controls the alkalization temperature to be above 35 ℃; in the present application, the inventors have found, through research, that the adsorption amount of cellulose to alkali in a sodium hydroxide solution having a certain concentrationAnd the degree of swelling increases with a decrease in the treatment temperature, so that the alkali liquor concentration for producing alkali cellulose can be decreased by decreasing the treatment temperature, which is of great significance for production. The temperature is high, the adsorption quantity of the cellulose to alkali is reduced, and the hydrolysis reaction of the cellulose is greatly increased. However, the viscosity of the cotton powder is high due to the low temperature, and the equipment is difficult to start, so the alkalization temperature is controlled to be 25-30 ℃.
The invention further researches the influence of alcohol on alkalization, and the existence of the alcohol can increase the disorder degree of the fiber and is beneficial to alkalization and subsequent etherification. The water molecules form temporary hydrogen bond crosslinking among the molecular chains of the swelling cellulose, and the alcohol is a monofunctional compound, so that the hydrogen bonds are formed less and no crosslinking is formed, so that the use amount of alkali liquor and free alkali in a system during alkalization can be reduced, the water content is adjusted, and the alkalization and etherification are facilitated. In the alkalization process, the more polar the solution medium, the lower the R value (the number of hydroxyl groups that react with sodium hydroxide per 100 anhydroglucose units) of the resulting alkali cellulose; the higher the value of R, the greater the number of activated-ONa groups, which is advantageous for the subsequent etherification. The alcohol and water form a mixed solvent and significantly reduce the polarity of water, so that the R value of the alkali cellulose can be increased. The function of the invention is that isopropanol is more than propanol and more than ethanol, so the invention selects the isopropanol as the component of the ternary mixed solvent.
The concentration of the alkali liquor, the total concentration of the alkali liquor is usually controlled to be about 10 percent in the prior art; as mentioned above, the invention effectively improves the effective utilization rate of alkali through parameter optimization, and can control the total concentration of the alkali liquor to be about 6%.
Preferably, in step 3), after the sodium hydroxide solution is introduced, the mixed solvent is continuously introduced to flush the pipeline conveying the sodium hydroxide, and then the deoxidized cotton powder is added.
In the above-described aspect of the present invention, the carrying of oxygen improves the hydrolyzability of cellulose, and thus the degree of polymerization of cellulose is disadvantageously reduced, so that the present invention removes oxygen in two ways. Firstly, carry out the replacement of nitrogen gas in the storage tank of cellulose raw materials, secondly in reation kettle, before solvent and material are put into, carry out the replacement of nitrogen gas to reation kettle inside. Thereby trying to remove the adverse effect of oxygen on the reaction.
Preferably, in the step 4), the reaction period is divided into two reaction periods, wherein in the first reaction period, half of propylene oxide is added for low-temperature etherification, half of methyl chloride is added after the low-temperature etherification reaction is completed, then the temperature is raised for high-temperature etherification, and the second reaction period is repeated for the first reaction period; in each reaction period, the low-temperature etherification time is 20-40 min, and the high-temperature etherification time is 40-60 min.
In the scheme of the invention, the method divides the total reaction into two periods, about half of etherifying agent is added in each period for reaction, and each period is divided into two steps of low-temperature etherification and high-temperature etherification, so that the whole etherification reaction is divided into four steps, namely low-temperature etherification, high-temperature etherification, low-temperature etherification and high-temperature etherification. Theoretically, the etherification reaction can be divided into more cycles, and on one hand, the substitution degree of cellulose can be improved by segmental etherification, namely the contents of hydroxypropoxyl and methoxyl are improved; and secondly, the occurrence of side reactions is reduced, so that the etherifying agent is maintained at a relatively average level in the whole reaction process, and the occurrence of related side reactions caused by overhigh concentration of the etherifying agent is avoided. However, in actual production, the system temperatures required in different steps are different, so that the two steps need to be connected with each other, and temperature rise and fall cannot be completed instantly, and if the etherification reaction is divided into too many periods, a large amount of time is consumed in the temperature rise and fall process, so that the production efficiency is reduced, and a negative effect is achieved, so that the two periods are more suitable for selection.
It should be noted that "one-half" as referred to above and hereinafter is not particularly limited to precise data as long as the amount added is around this value, and for example, when 50kg of the total amount of the raw materials is added, one-half may be 20 to 30kg.
As the optimization of the technical scheme, in the step 6), after the material is pressed into the desolventizing kettle, the stirring of the desolventizing kettle is started firstly, hot water at the top is added while stirring, and meanwhile, water vapor is introduced from the bottom of the desolventizing kettle to prevent the temperature from being lower than 80 ℃; the solvent is then separated off.
In the scheme of the invention, the production of the product is actually finished in the step 6), but the hypromellose needs to be separated. As a known property, hypromellose is soluble in cold water, but gels in hot water. And this gelation is reversible. By utilizing the property, the invention prevents the hydroxypropyl methylcellulose dispersed in water from being discharged along with the discharge of the solvent by adding hot water at the top and keeping the hot water above 80 ℃.
Preferably, the adding amount of the top hot water is 0.6 to 1.0 time of the volume of the solvent; continuously stirring for more than 10 minutes, and standing for more than 20 minutes to form a solid-liquid-gas three phase; most of the liquid solvent is discharged and recovered from the pipeline at the waist position of the desolventizing kettle, and the liquid solvent is guided into the water diversion tank after being discharged from the pipeline at the waist position of the desolventizing kettle, and then is subjected to static stratification to discharge water; and part of the liquid solvent and the gaseous solvent are recovered through a condensation path.
In the technical scheme of the invention, the gaseous solvent does not mean a solvent which is completely gaseous at normal temperature; since the solvents are volatile, especially at higher temperatures. The invention maintains the internal temperature of the desolventizing kettle to be more than 80 ℃, so that a considerable part of toluene, isopropanol and water are in a gaseous state, and the technical proposal relates to the concept of gaseous solvents.
Preferably, in the step 5), the pH after neutralization is from 6.5 to 7.5.
Preferably, in the step 2), nitrogen gas replacement is specifically performed by inputting nitrogen gas from the bottom of the storage tank, injecting the nitrogen gas into the storage tank, and stirring the cotton powder by means of nitrogen gas flow.
Preferably, in the step 5), the average adding speed of the glacial acetic acid is 2-5L/min.
Preferably, the rotation speed during stirring is controlled to be 1200-1600 rpm, and the stirring time is controlled to be 20-30 min.
Preferably, when the solvent is discharged, if the solvent is opaque, contains a large amount of materials and is continuous, the solvent discharge must be stopped in time, a valve and a solvent pump are closed, then a small amount of elevated tank solvent is used for proper backflushing, and then the solvent is properly kept still for a period of time and then discharged.
In conclusion, the invention has the following beneficial effects:
1. the invention removes oxygen by two aspects; firstly, replacing nitrogen in a storage tank of the cellulose raw material, and secondly, replacing nitrogen in the reaction kettle before putting the solvent and the material into the reaction kettle; thereby eliminating the adverse effect of oxygen on the reaction as much as possible; the polymerization degree of the hydroxypropyl methylcellulose is high, the viscosity measured value is more than 100000mPa & S and is stabilized at 100000-130000 mPa & S, and the stability among batches is ensured;
2. the invention effectively improves the effective utilization rate of alkali by optimizing parameters, and can control the concentration of alkali liquor to be about 6 percent;
3. the invention reduces the hydrolysis of the cellulose by controlling the temperature, thereby ensuring the polymerization degree of the cellulose;
4. according to the invention, the isopropanol is added, so that the polarity of water is obviously reduced, the R value of the alkali cellulose is improved, and the later etherification is facilitated;
5. according to the invention, the etherification reaction is divided into two periods, so that on one hand, the substitution degree of cellulose can be improved, namely, the contents of hydroxypropoxyl and methoxyl are improved; secondly, the occurrence of side reactions is reduced, so that the etherifying agent is maintained at a relatively average level in the whole reaction process, and the occurrence of related side reactions caused by overhigh concentration of the etherifying agent is avoided;
6. the reactants recovered by the method of the invention participate in the separation process by heating water, so that compared with the HPMC prepared by the prior art, the material of the invention has higher purity of the crude product, and the processing difficulty of the HPMC at the later stage is reduced.
Detailed Description
This detailed description is to be construed as illustrative only and is not limiting, since modifications will occur to those skilled in the art upon reading the preceding specification, and it is intended to be protected by the following claims.
Example 1
1) Pretreatment of cellulosic raw material
Crushing the refined cotton into refined cotton blocks with the diameter of about 1-3 cm by a cotton opener, then feeding the refined cotton blocks into a crusher, and crushing the refined cotton blocks into refined cotton powder with the size of 200-120 meshes by high-speed shearing; subsequently conveyed in a gas stream to a storage tank through a pipe connected to the pulverizer;
the existing HPMC production process completes the pretreatment process of the cellulose raw material, namely refined cotton, through the steps of opening, crushing, cyclone separation, bag type dust removal packaging and the like.
The main pollution source of the process is dust pollution, and the main source of the dust is dust pollution of air caused by cellulose tiny particles generated in the crushing process.
The dust generated in the two steps of unpacking and crushing in the whole pretreatment process is less. And in the opening step, the manually opened flaky refined cotton is placed on an opener and is torn into loose small pieces of 3 cm. Dust is easily generated in the step because the feeding is generally open, and the degree and the quantity of the generated dust are greatly different due to the difference of the sealing performance of feeding devices of different manufacturers and the difference of the operation of workers.
2) Pretreatment of cellulose powder
Performing nitrogen replacement in a storage tank to obtain deoxidized cotton powder; during specific operation, nitrogen is input from the bottom of the storage tank and is sprayed into the tank, and cotton powder is stirred by means of nitrogen airflow;
the process is carried out in a closed container, and no dust pollution is generated.
3) Alkalization, etherification, solvent recovery and washing process
This process is the main reaction stage in HPMC production.
The process comprises the following steps:
3.1 starting nitrogen to replace the air in the reaction kettle; then pressing toluene and isopropanol into a reaction kettle to form a mixed solvent; pressing a sodium hydroxide aqueous solution with the mass concentration of 50% into a mixed solvent in a reaction kettle; adding the deoxidized cotton powder, stirring while adding the cotton powder, keeping the temperature of a system in the tank at 15-18 ℃ after uniformly stirring, and standing for 1h; in the step, the mass ratio of the materials is as follows: isopropyl alcohol: water =6.0:1.0:0.5, mixed solvent: deoxidized cotton powder =10:1; in this step, the water is the solvent part of the aqueous sodium hydroxide solution; controlling the temperature of the alkalization reaction to be 25-30 ℃;
3.2 dividing the etherification reagent into two periods and adding the two periods into a reaction kettle to enable the etherification reagent to react with the alkalized refined cotton powder, wherein each reaction period comprises low-temperature etherification and high-temperature etherification; the ratio of methyl chloride to propylene oxide in the etherification reagent is 3.0:1, the mass ratio of the refined cotton powder to the total amount of the etherification reagent is 1.3;
in a first reaction cycle: firstly, adding half of propylene oxide, controlling the temperature to be about 50 ℃, and carrying out low-temperature etherification;
after the low-temperature etherification reaction is finished, adding half of chloromethane, and then heating to 88 ℃ for high-temperature etherification;
and a second reaction period: repeating the first reaction cycle;
in each reaction period, the low-temperature etherification time is 30min, and the high-temperature etherification time is 50min;
3.3 after the reaction is finished, neutralizing the residual alkali by glacial acetic acid;
3.4 pressing the materials into the desolventizing kettle, starting stirring of the desolventizing kettle, adding hot water at the top while stirring, and introducing steam from the bottom of the desolventizing kettle to prevent the temperature from being lower than 80 ℃; the amount of top hot water added is 0.8 times the volume of the solvent; continuously stirring for more than 10 minutes, and then standing for more than 20 minutes to form a solid-liquid-gas three phase; most of the liquid solvent is discharged and recovered from the pipeline at the waist position of the desolventizing kettle, the liquid solvent is discharged from the pipeline at the waist position of the desolventizing kettle, then the liquid solvent is led into a water diversion tank, and then the water is discharged after static layering; and part of the liquid solvent and the gaseous solvent are recovered through a condensation path.
In the whole process, alkalization and etherification are important points. The degree of alkalization determines the reactivity of the alkali cellulose, and has great influence on the subsequent etherification; etherification is a key step for generating hydroxypropoxyl and methoxyl, directly influences the height of the substitution degree, and directly influences the content of the substituent of the product; that is, this step can be said to determine the model of the product.
Solvent recovery is also an issue. The organic solvent is not only a valuable production material, but also causes pollution to the environment and pollutes water, soil and air when being improperly treated.
In the prior art, the recovery of the organic solvent adopts a direct distillation method, so that the treatment energy consumption is higher.
In the invention, after the reaction is finished, water is heated and stirred simultaneously, then the solvent is separated from the reactant by precipitation, most of the liquid solvent is discharged through a pipe positioned at the waist of a desolventizing kettle, and the rest of the solvent is recovered by a conventional distillation way; compared with the prior art of direct distillation, the energy consumption is obviously reduced.
4) HPMC post-treatment
And (4) the mixture after desolventizing is subjected to centrifugal separation by a horizontal sedimentation centrifuge, and then is granulated, dried, mixed and packaged to form a final product.
Examples 2 to 6
This example is the same as example 1, except for the parameter control, see in particular the table below.
The inventor carries out the content determination of methoxyl and hydroxypropoxyl according to the Chinese pharmacopoeia 2020 edition-the fourth part-the pharmaceutic adjuvant-hypromellose [ 9004-65-3 ].
Taking the methoxyl group, and determining according to methoxyl group, ethoxyl group and hydroxypropoxyl group determination method (general rule 0712). After heating at 130 ℃. + -. 2 ℃ for 30 minutes by the first method (gas chromatography), it was vigorously shaken for 5 minutes, and heating at 130 ℃. + -. 2 ℃ was continued for 30 minutes.
Hydroxypropoxyl the product was taken and measured by methoxy, ethoxy, and hydroxypropoxyl assays (general rule 0712). After heating at 130 ℃ and 2 ℃ for 30 minutes by the first method (gas chromatography), the mixture was vigorously shaken for 5 minutes, and heating at 130 ℃ and 2 ℃ was continued for 30 minutes.
The results are as follows:
| methoxy group content | Hydroxypropoxy group content | |
| Example 1 | 20.8％ | 10.6％ |
| Example 2 | 21.2％ | 10.5％ |
| Example 3 | 19.6％ | 8.1％ |
| Example 4 | 19.0％ | 7.9％ |
| Example 5 | 23.6％ | 9.3％ |
| Example 6 | 23.3％ | 9.5％ |
The inventor carries out the determination of viscosity according to the Chinese pharmacopoeia 2020 edition-fourth part-pharmaceutic adjuvant-hydroxypropyl methylcellulose [ 9004-65-3 ].
Taking a proper amount of the product (calculated according to a dry product), adding water at 90 ℃ to prepare a solution of 2.0 percent (g/g), fully stirring for about 10 minutes until the particles are completely and uniformly dispersed and wetted and no undissolved sample particles exist on the inner wall of a bottle, cooling in an ice bath, continuously stirring uniformly in the cooling process to remove bubbles, adjusting the weight by using cold water if necessary, and removing all foams to be used as a test solution.
The measurement was carried out at 20 ℃. + -. 0.1 ℃ using a suitable single column rotary viscometer (Brookfield type LV model) with a rotor type of 4, 3rpm, 2 minutes rotation, 2 minutes reading, 2 minutes rest, and the experiment was repeated 2 times, taking the average of three experiments (third method, general rule 0633).
The results are as follows:
| viscosity of the mixture | |
| Example 1 | 108854 |
| Example 2 | 118542 |
| Example 3 | 111253 |
| Example 4 | 120236 |
| Example 5 | 109856 |
| Example 6 | 128512 |
Claims (10)
1. A production method of hydroxypropyl methylcellulose for skeleton slow release comprises the following steps:
1) Crushing the refined cotton, screening out cotton powder of 200-120 meshes, and conveying the cotton powder to a storage tank through pipeline airflow;
2) Performing nitrogen replacement in a storage tank to obtain deoxidized cotton powder;
3) Opening nitrogen to replace the air in the reaction kettle; then pressing toluene and isopropanol into a reaction kettle to form a mixed solvent; pressing a sodium hydroxide aqueous solution with the mass concentration of 40-60% into a mixed solvent in a reaction kettle; adding the deoxidized cotton powder, stirring while adding the cotton powder, uniformly stirring, maintaining the system temperature in the reaction kettle at 25 to 30 ℃, and standing for 1 to 2h; in the step, the mass ratio of the materials is as follows: isopropyl alcohol: water =6.0: (1.0 to 1.2): (0.4 to 0.5), mixed solvent: deoxidized cotton powder = (8 to 12): 1; in this step, the water is the solvent part of the aqueous sodium hydroxide solution;
4) Dividing the etherification reagent into a plurality of periods, adding the periods into a reaction kettle, and reacting the etherification reagent with the alkalized refined cotton powder, wherein each reaction period comprises low-temperature etherification and high-temperature etherification; the ratio of methyl chloride to propylene oxide in the etherification reagent is (3.0 to 3.5): 1, the mass ratio of the refined cotton powder to the total amount of the etherification reagent is 1 (1.2 to 1.5); the low-temperature etherification is carried out at a temperature of 45 to 55 ℃, and the high-temperature etherification is carried out at a temperature of 85 to 90 ℃;
5) After the reaction is finished, neutralizing the residual alkali by using glacial acetic acid;
6) Pressing the materials into a desolventizing kettle, and separating out the solvent;
7) And the mixture after desolventizing is centrifugally separated by a horizontal sedimentation centrifuge, and then is granulated, dried, mixed and packaged to form the final product.
2. The method for producing hypromellose for skeleton sustained release according to claim 1, characterized in that: in the step 3), after the sodium hydroxide solution is introduced, the mixed solvent is continuously introduced to wash a pipeline which conveys the sodium hydroxide, and then the deoxidized cotton powder is added.
3. The method for producing hypromellose for skeleton sustained release according to claim 1, wherein: in the step 4), two reaction cycles are divided, in the first reaction cycle, half of propylene oxide is added for low-temperature etherification, half of methyl chloride is added after the low-temperature etherification reaction is finished, then the temperature is raised for high-temperature etherification, and in the second reaction cycle, the first reaction cycle is repeated; in each reaction period, the low-temperature etherification time is 20 to 40min, and the high-temperature etherification time is 40 to 60min.
4. The method for producing hypromellose for skeleton sustained release according to claim 1, wherein: step 6), after pressing the materials into the desolventizing kettle, starting stirring of the desolventizing kettle, adding top hot water while stirring, and introducing water vapor from the bottom of the desolventizing kettle to prevent the temperature from being lower than 80 ℃; the solvent is then separated off.
5. The method for producing hypromellose for skeleton sustained release according to claim 4, wherein: the adding amount of the hot water at the top is 0.6 to 1.0 time of the volume of the solvent; continuously stirring for more than 10 minutes, and standing for more than 20 minutes to form a solid-liquid-gas three phase; leading most of liquid solvent into a water diversion tank from a pipeline at the waist position of a desolventizing kettle, and then, standing and layering to recover the solvent; and part of the liquid solvent and the gaseous solvent are recovered through a condensation path.
6. The method for producing hypromellose for skeleton sustained release according to claim 1, characterized in that: in the step 5), the pH value after neutralization is 6.5 to 7.5.
7. The method for producing hypromellose for skeleton sustained release according to claim 1, wherein: and 2) specifically performing nitrogen replacement, namely inputting nitrogen from the bottom of the storage tank, spraying the nitrogen into the storage tank, and stirring cotton powder by virtue of nitrogen airflow.
8. The method for producing hypromellose for skeleton sustained release according to claim 1, wherein: in the step 5), the average adding speed of the glacial acetic acid is 2 to 5L/min.
9. The method for producing hypromellose for skeleton sustained release according to claim 4, characterized in that: the rotation speed is controlled within 1200 to 1600rpm during stirring, and the stirring time is controlled within 20 to 30min.
10. The method for producing hypromellose for skeleton sustained release according to claim 4, characterized in that: when the solvent is discharged, if the solvent is opaque, contains a large amount of materials and is continuous, the solvent discharge must be stopped in time, a valve and a solvent pump are closed, then a small amount of elevated tank solvent is used for proper backflushing, and then the solvent is properly kept still for a period of time for discharge.
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| CN116375390A (en) * | 2023-03-31 | 2023-07-04 | 美信佳中维药业股份有限公司 | Hydroxypropyl methyl cellulose modified additive for plastering gypsum |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107098982A (en) * | 2017-05-03 | 2017-08-29 | 浙江中维药业股份有限公司 | The production method of hydroxypropyl methylcellulose |
| CN112694536A (en) * | 2021-02-04 | 2021-04-23 | 浙江中维药业股份有限公司 | Preparation method of hydroxypropyl methyl cellulose |
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| CN107098982A (en) * | 2017-05-03 | 2017-08-29 | 浙江中维药业股份有限公司 | The production method of hydroxypropyl methylcellulose |
| CN112694536A (en) * | 2021-02-04 | 2021-04-23 | 浙江中维药业股份有限公司 | Preparation method of hydroxypropyl methyl cellulose |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116375390A (en) * | 2023-03-31 | 2023-07-04 | 美信佳中维药业股份有限公司 | Hydroxypropyl methyl cellulose modified additive for plastering gypsum |
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