A method for preparing an ultra-low viscosity hydroxypropyl methylcellulose

Abstract

The application belongs to the technical field of pharmaceutical excipients, and particularly relates to a preparation method of super-low viscosity hydroxypropyl methyl cellulose. The method comprises the following steps: S1, alkalization; S2, aging; S3, etherification reaction; S4, neutralization, washing and drying; and S5, post-treatment. The production process provided by the application directly obtains the super-low viscosity hydroxypropyl methyl cellulose product with a 2% aqueous solution viscosity of 3-15 mPa.s, without needing to first obtain the medium-high viscosity hydroxypropyl methyl cellulose, and then obtaining the super-low viscosity hydroxypropyl methyl cellulose product through degradation. The preparation process is shortened, the equipment investment of the degradation process is reduced, the occurrence of the phenomenon of serious equipment corrosion and great safety hazards caused by the acid gas degradation in the existing degradation process is avoided, the product quality is obviously improved, and the application range is more extensive.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical excipients, and particularly relates to a preparation method of super-low-viscosity hydroxypropyl methyl cellulose. BACKGROUND

[0002] Hydroxypropyl methyl cellulose (HPMC), also known as hydroxypropyl methylcellulose, is a non-ionic cellulose mixed ether, which is white or white-like fibrous or granular powder, non-toxic, odorless, and odorless, and has strong stability to heat, light, and humidity. Hydroxypropyl methyl cellulose is a semi-synthetic, inactive, viscoelastic polymer. Its chemical inertness does not affect the nature of the drug itself, and it also has good anti-allergic properties. It is widely used as various pharmaceutical excipients in drug preparation, such as coating film-forming materials, sustained-release or controlled-release matrix materials, adhesives or disintegrants, etc.

[0003] Hydroxypropyl methyl cellulose has different viscosities due to different degrees of polymerization. According to the size of the viscosity, it can be divided into high-viscosity, low-viscosity and super-low-viscosity hydroxypropyl methyl cellulose. Among them, super-low-viscosity hydroxypropyl methyl cellulose refers to the viscosity range of 3-15 mPa·s of a 2% HPMC material (mass number) aqueous solution at 20℃. In the prior art, the methods for preparing super-low-viscosity hydroxypropyl methyl cellulose mainly include: 1) first, the super-low-viscosity α-cellulose is obtained by alkalization and aging treatment of wood pulp or refined cotton, and then the super-low-viscosity hydroxypropyl methyl cellulose is prepared by etherification reaction; 2) the super-low-viscosity hydroxypropyl methyl cellulose is obtained by degradation of high-viscosity hydroxypropyl methyl cellulose. Since the directly produced super-low-viscosity HPMC has the problem of difficulty in solid-liquid separation of particles, the current main production method is still to synthesize a semi-finished product of medium-high viscosity HPMC first, and then prepare it by degradation treatment, such as the preparation method of a super-low-viscosity hydroxypropyl methyl cellulose disclosed in the invention patent with the application number 202211443704.7. The method increases the steps of material swelling, degradation and decolorization treatment and pressure filtration impurity removal operation between centrifugal solid-liquid separation and drying treatment in the later purification process after the synthesis of medium-high viscosity HPMC in the early stage, and finally obtains the product by spray drying. Although this method improves the quality of HPMC product, the super-low-viscosity hydroxypropyl methyl cellulose obtained still has problems such as poor clarity, poor material whiteness, and many yellow and black spots in the product, resulting in poor applicability of the product. SUMMARY

[0004] To address the problems existing in the prior art, the present invention aims to provide a method for preparing ultra-low viscosity hydroxypropyl methylcellulose (HPMC). By optimizing the synthesis process parameters, the method solves the problem of solid-liquid separation difficulties in the direct production of ultra-low viscosity HPMC. Furthermore, since this preparation method does not require secondary degradation, it also avoids affecting product quality.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] A method for preparing ultra-low viscosity hydroxypropyl methylcellulose includes the following steps:

[0007] S1. Alkali treatment: The wood pulp is immersed in an alkaline solution for alkalization, and then the excess alkaline solution is pressed off.

[0008] S2. Aging: Transfer the alkalized wood pulp to an aging room for aging.

[0009] S3, Etherification: The aged wood pulp is put into the reactor, and then solid sodium hydroxide and propylene oxide are added in sequence to carry out the first etherification reaction; after the first etherification reaction is completed, dimethyl ether and chloromethane are added to the reactor in sequence to carry out the second etherification reaction.

[0010] S4. Neutralization, washing, and drying: The etherified material is put into a three-in-one washing machine, hydrochloric acid is added for neutralization, and then the material is filtered, washed, and dried.

[0011] S5. Post-processing: The dried material is crushed and sieved to obtain ultra-low viscosity hydroxypropyl methylcellulose.

[0012] As a preferred embodiment of the above technical solution, in step S1, the alkaline solution is a 30-60 wt% sodium hydroxide or potassium hydroxide solution, the alkaline solution temperature is 45-60°C, and the alkalization time is 2-5 minutes. Preferably, the alkaline solution is a 40-50 wt% sodium hydroxide solution.

[0013] As a preferred embodiment of the above technical solution, in step S2, the aging process parameters are: temperature 50-60℃, time 8-48 hours.

[0014] As a preferred embodiment of the above technical solution, in step S3, the mass ratio of wood pulp to solid sodium hydroxide and propylene oxide in the first etherification reaction is 1:(0.05~0.15):(0.25~0.3); and the mass ratio of wood pulp to dimethyl ether and chloromethane in the second etherification reaction is 1:(1.7~2):(1.7~2).

[0015] As a preferred embodiment of the above technical solution, in step S3, the temperature of the first etherification reaction is 40-60°C and the time is 1-3 hours; the temperature of the second etherification reaction is 80-110°C and the time is 0.5-2.5 hours.

[0016] As the preferred technical solution, in step S4, the concentration of hydrochloric acid is 30-35wt%, and the pH of the solution is neutralized to 3.0-5.0; the temperature of the neutralization is 80-95℃; the washing refers to washing with water above 95℃; and the drying refers to drying with heated compressed air.

[0017] As the preferred technical solution, in step S4, the three-in-one washing machine is produced by Jiangsu Yihuan Group Co., Ltd., and the model is FW-800.

[0018] In summary, the present application has the following advantages:

[0019] 1. The solid sodium hydroxide is added first in the etherification reaction process, which can promote the reaction and increase the particle size of the product, which is beneficial to the subsequent washing;

[0020] 2. The washing process uses a three-in-one washing machine, which has more precise filtering performance and can achieve zero material loss. The washing process uses filter pressing to remove the washing liquid, which can reduce the number of washing and the generation of wastewater. The equipment has a drying function, which can reduce the investment in production equipment.

[0021] 3. The production process provided by the present application directly obtains an ultra-low viscosity hydroxypropyl methyl cellulose product with a 2% aqueous solution viscosity of 3-15 mPa·s, without first obtaining a medium-high viscosity hydroxypropyl methyl cellulose and then obtaining an ultra-low viscosity hydroxypropyl methyl cellulose product by degradation. The preparation process is shortened, the equipment investment of the degradation process is reduced, and the occurrence of serious equipment corrosion and the occurrence of a large safety hazard phenomenon caused by the use of acidic gas for degradation in the existing degradation process are avoided. At the same time, the product quality is significantly improved, and the application range is more extensive. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 is the preparation process route of the present application. DETAILED DESCRIPTION

[0023] The technical solution of the present application will be further described below with specific examples, but the specific details of the examples are only for illustration of the present application, and do not represent all technical methods under the concept of the present application. Therefore, it should not be understood as a limitation on the general technical solution of the present application.

[0024] Example 1

[0025] Alkali treatment: add a 42wt% sodium hydroxide solution to the alkali immersion machine, control the temperature to 55℃, slowly immerse 5kg of wood pulp in the alkali immersion machine for 2 minutes, and then press off the excess alkali solution;

[0026] Ageing: Put the alkalized wood pulp into the shelf and transfer to the ageing room, control the temperature of the ageing room at 55℃, and age for 8 hours;

[0027] Etherification: Put the aged wood pulp into the reactor, add 0.5kg of solid sodium hydroxide, then add 1.3kg of propylene oxide, control the temperature at 50℃, and react for 2 hours; then add 8.5kg of dimethyl ether and 8.5kg of chloromethane into the reactor, control the temperature at 100℃, and react for 1.5 hours; after the reaction is completed, recover the dimethyl ether and chloromethane;

[0028] Neutralization, washing, and drying: Put the etherified material into the three-in-one washing machine, add 32wt% hydrochloric acid, and neutralize at 90℃ until the pH of the material solution is 3.0; after the neutralization is completed, press out the mother liquor with compressed air, then wash twice with water at a temperature higher than 95℃, and finally dry with heated compressed air for 2 hours;

[0029] Post-treatment: Put the dried material into the pulverizer to be pulverized, and then sieve the pulverized material through the rotary vibrating screen to obtain the finished hydroxypropyl methyl cellulose.

[0030] Example 2

[0031] Alkalization: Add a 45% sodium hydroxide solution into the alkali immersion machine, control the temperature at 50℃, slowly immerse 5kg of wood pulp into the alkali immersion machine for alkalization for 3 minutes, and then press out the excess alkali solution;

[0032] Ageing: Put the alkalized wood pulp into the shelf and transfer to the ageing room, control the temperature of the ageing room at 50℃, and age for 21 hours;

[0033] Etherification: Put the aged wood pulp into the reactor, add 0.5kg of solid sodium hydroxide, then add 1.3kg of propylene oxide, control the temperature at 55℃, and react for 2 hours; then add 8.5kg of dimethyl ether and 8.5kg of chloromethane into the reactor, control the temperature at 105℃, and react for 1.5 hours; after the reaction is completed, recover the dimethyl ether and chloromethane;

[0034] Neutralization, washing, and drying: Put the etherified material into the three-in-one washing machine, add 32wt% hydrochloric acid, and neutralize at 85℃ until the pH of the material solution is 4.0; after the neutralization is completed, press out the mother liquor with compressed air, then wash twice with water at a temperature higher than 95℃, and finally dry with heated compressed air for 2 hours;

[0035] Post-treatment: Put the dried material into the pulverizer to be pulverized, and then sieve the pulverized material through the rotary vibrating screen to obtain the finished hydroxypropyl methyl cellulose.

[0036] Example 3

[0037] Alkali: 5 kg of wood pulp is slowly immersed in the alkali machine to be alkali for 3 minutes, and the temperature is controlled at 45℃. The excess alkali is pressed out;

[0038] Aging: The alkali-treated wood pulp is placed on a shelf and transferred to an aging room, with the temperature controlled at 60℃. The aging time is 29 hours;

[0039] Etherification: The aged wood pulp is put into a reaction kettle, 0.5 kg of solid sodium hydroxide is added, followed by the addition of 1.3 kg of propylene oxide. The temperature is controlled at 60℃ for 2 hours of etherification reaction. Then, 8.5 kg of dimethyl ether and 8.5 kg of chloromethane are added to the reaction kettle, and the temperature is controlled at 90℃ for 1.5 hours of reaction. After the reaction is completed, the dimethyl ether and chloromethane are recovered;

[0040] Neutralization, washing, and drying: The etherified material is put into a three-in-one washing machine, 32wt% hydrochloric acid is added, and the temperature is controlled at 80℃ for neutralization. The pH of the material liquid is adjusted to 5.0. After the neutralization is completed, the mother liquor is pressed out with compressed air. Then, the material is washed twice with water at a temperature above 95℃. Finally, the material is dried with heated compressed air for 2 hours;

[0041] Post-treatment: The dried material is put into a pulverizer for pulverization. The pulverized material is sieved through a rotary vibrating screen to obtain the finished hydroxypropyl methyl cellulose.

[0042] Example 4

[0043] Alkali: 5 kg of wood pulp is slowly immersed in the alkali machine to be alkali for 3 minutes, and the temperature is controlled at 45℃. The excess alkali is pressed out;

[0044] Aging: The alkali-treated wood pulp is placed on a shelf and transferred to an aging room, with the temperature controlled at 60℃. The aging time is 29 hours;

[0045] Etherification: The aged wood pulp is put into a reaction kettle, 0.5 kg of solid sodium hydroxide is added, followed by the addition of 1.3 kg of propylene oxide. The temperature is controlled at 60℃ for 2 hours of etherification reaction. Then, 8.5 kg of dimethyl ether and 8.5 kg of chloromethane are added to the reaction kettle, and the temperature is controlled at 90℃ for 1.5 hours of reaction. After the reaction is completed, the dimethyl ether and chloromethane are recovered;

[0046] Neutralization, washing, and drying: The etherified material is put into a three-in-one washing machine, 32wt% hydrochloric acid is added, and the temperature is controlled at 80℃ for neutralization. The pH of the material liquid is adjusted to 5.0. After the neutralization is completed, the mother liquor is pressed out with compressed air. Then, the material is washed twice with water at a temperature above 95℃. Finally, the material is dried with heated compressed air for 2 hours;

[0047] Post-processing: After drying, the material is put into a pulverizer for pulverization. The pulverized material is sieved through a rotary vibrating screen to obtain the finished product of hydroxypropyl methyl cellulose.

[0048] Comparative Example 1

[0049] Alkali treatment: In the alkali immersion machine, a 42wt% sodium hydroxide solution is added, the temperature is controlled at 55℃, and 5kg of wood pulp is slowly immersed in the alkali immersion machine for 2 minutes, and then the excess alkali solution is pressed out;

[0050] Aging: The alkali-treated wood pulp is placed on a shelf and transferred to an aging room, the temperature of the aging room is controlled at 55℃, and the aging time is 8 hours;

[0051] Etherification: The aged wood pulp is put into a reaction kettle, 1.3kg of propylene oxide is added, the temperature is controlled at 50℃, and the etherification reaction is carried out for 2 hours; then 0.5kg of solid sodium hydroxide, 8.5kg of dimethyl ether and 8.5kg of chloromethane are added to the reaction kettle, the temperature is controlled at 100℃, and the reaction is carried out for 1.5 hours. After the reaction is completed, the dimethyl ether and chloromethane are recovered;

[0052] Neutralization, washing and drying: The etherified material is put into a three-in-one washing machine, 32wt% hydrochloric acid is added, and the neutralization is carried out at 90℃ until the pH of the solution is 3.0. After the neutralization is completed, the mother liquor is pressed out with compressed air, then the material is washed twice with water at a temperature of 95℃ or above, and finally the material is dried with heated compressed air for 2 hours;

[0053] Post-processing: After drying, the material is put into a pulverizer for pulverization. The pulverized material is sieved through a rotary vibrating screen to obtain the finished product of hydroxypropyl methyl cellulose.

[0054] Comparative Example 2

[0055] First, hydroxypropyl methyl cellulose with medium-high viscosity is synthesized according to the method of Example 1 in the application number 201910771042.8, and then the degradation process is treated according to the steps of Example 1 in the application number 201611018242.9, to prepare the same 2910 type hydroxypropyl methyl cellulose as the above examples. The specific preparation method is as follows:

[0056] Synthesis of hydroxypropyl methyl cellulose with medium-high viscosity: N2 was introduced into the reaction kettle to replace oxygen until the oxygen content was ≤0.3% (by volume), and the pressure of the reaction kettle was 0.1 MPa by continuously introducing N2. 18 parts of 100-mesh wood pulp was mixed with 12 parts of lye to perform an alkalization reaction in the reaction kettle; 10 parts of dimethyl ether, 6 parts of propylene oxide, 14 parts of chloromethane and pure water were mixed to prepare an etherification agent; the etherification agent was added to the reaction kettle by a high-pressure constant-flow pump in a starved continuous feeding mode to perform an etherification reaction. The lye was one of sodium hydroxide, potassium hydroxide and lithium hydroxide aqueous solution, and the concentration of the lye was 45%; the alkalization and etherification reactions occurred in the reaction kettle in sequence, the alkalization temperature was 60°C, the reaction time was 2 h, the etherification temperature was 90°C, and the reaction time was 5 h to obtain product A. Hydrochloric acid, liquid alkali and sodium hypochlorite were mixed to prepare a washing liquid, which was placed in a washing kettle, and product A was washed in the washing kettle at a temperature of 85°C. The washed product A was filtered, washed, dried and crushed to prepare hydroxypropyl methyl cellulose.

[0057] Degradation: high-purity hydrochloric acid vapor was introduced into an HCL-resistant reactor, the above hydroxypropyl methyl cellulose powder was added, and then a degradation reaction was performed at 78°C to obtain hydroxypropyl methyl cellulose

[0058] The final hydroxypropyl methyl cellulose product obtained in the above examples was type 2910 hydroxypropyl methyl cellulose, and the following performance detection indexes were used to detect the hydroxypropyl methyl cellulose prepared in each example, and the results are shown in Table 1.

[0059] Viscosity: 8.0 g (calculated as dry product) of the sample was weighed by an electronic balance, placed in a high beaker (the high beaker was pre-weighed), 2% (g / g) of the suspension was prepared by using hot water at 90°C, and fully stirred for 10 minutes until the particles were completely uniformly dispersed and wetted, cooled in an ice bath, and continuously stirred for 40 minutes during the cooling process to remove bubbles, and the weight was adjusted by cold water if necessary, and the viscosity value was measured by a digital viscometer at 20±0.1°C.

[0060] Transmittance: the transmittance of the instrument was corrected to 100% by using distilled water as a blank solution, 2% (g / g) of the aqueous solution of the sample under the item of "viscosity" was taken, and the transmittance was measured at 580 nm by using a TU-1901 double-beam ultraviolet visible spectrophotometer.

[0061] Whiteness: Put the black cylinder on the sample seat according to the slide cylinder pressure plate, then let the slide cylinder rise to the measuring orifice, wait for a while until the displayed value is stable, then press the zero button to make the displayed value automatically return to zero (tolerance ±0.1); take off the black cylinder, put the working standard white plate on the sample seat, wait for the displayed value to be stable, then press the correction button to make the displayed value consistent with the whiteness value on the working standard white plate (tolerance ±0.1); put the sample to be measured on the sample seat, and record the whiteness value when the displayed value is stable. The whiteness is determined by using a WSB-2 whiteness tester.

[0062] Ignition residue: first place a 30ml porcelain crucible in a high temperature furnace at 500-600°C for 30 minutes, turn off the furnace gate to make the temperature in the furnace drop below 200°C, then take out the crucible and place it in a desiccator to cool for 20-30 minutes, weigh and keep constant. Weigh 1.0g of sample on an analytical balance, place the weighed sample in the crucible, place the sample and crucible on an electric furnace to carbonize, cool to room temperature, add 0.5-1.0ml of sulfuric acid, and then place it on an electric furnace to carbonize until complete. Move to a high temperature furnace and ignite at 500-600°C until constant weight.

[0063] Table 1:

[0064] Viscosity (mPa-s) Transmittance (%) Whiteness (%) Ignition residue (%) Example 1 10.8 96.1％ 87.2 0.19％ Example 2 5.7 96.8％ 86.8 0.25％ Example 3 4.2 98.5％ 86.7 0.18％ Example 4 3.7 97.7％ 87.3 0.11％ Comparative Example 1 11.6 97.5％ 85.7 0.26％ Comparative Example 2 5.2 90.8％ 75.5 0.85％

Claims

1. A method for preparing ultra-low viscosity hydroxypropyl methylcellulose, characterized in that, Includes the following steps: S1. Alkali treatment: The wood pulp is immersed in an alkaline solution for alkalization, and then the excess alkaline solution is pressed off. S2. Aging: The alkalized wood pulp is transferred to an aging room for aging. The aging process parameters are: temperature 50~60℃, time 8~48 hours. S3. Etherification: The aged wood pulp is put into a reaction vessel, and then solid sodium hydroxide and propylene oxide are added in sequence to carry out the first etherification reaction. After the first etherification reaction is completed, dimethyl ether and chloromethane are added to the reaction vessel in sequence to carry out the second etherification reaction. The temperature of the first etherification reaction is 40~60℃ and the time is 1~3 hours. The temperature of the second etherification reaction is 80~110℃ and the time is 0.5~2.5 hours. S4. Washing: The etherified material is put into a three-in-one washing machine, hydrochloric acid is added for neutralization, and then filtered, washed and dried. The three-in-one washing machine is produced by Jiangsu Yihuan Group Co., Ltd., and the model is FW-800. S5. Post-processing: The dried material is crushed and sieved to obtain ultra-low viscosity hydroxypropyl methylcellulose; The alkaline solution is a 30-60 wt% sodium hydroxide or potassium hydroxide solution, the temperature of the alkaline solution is 45-60℃, and the alkalization time is 2-5 minutes.

2. The method for preparing ultra-low viscosity hydroxypropyl methylcellulose according to claim 1, characterized in that, The alkaline solution is a 40-50 wt% sodium hydroxide solution.

3. The method for preparing ultra-low viscosity hydroxypropyl methylcellulose according to claim 1, characterized in that, In step S3, the first step of the etherification reaction has a mass ratio of wood pulp to solid sodium hydroxide and propylene oxide of 1:(0.05~0.15):(0.25~0.3); the second step of the etherification reaction has a mass ratio of wood pulp to dimethyl ether and chloromethane of 1:(1.7~2):(1.7~2).

4. The method for preparing ultra-low viscosity hydroxypropyl methylcellulose according to claim 1, characterized in that, In step S4, the concentration of hydrochloric acid is 30~35wt%, and it is neutralized to the pH of the feed solution = 3.0-5.

0.

5. The method for preparing ultra-low viscosity hydroxypropyl methylcellulose according to claim 1, characterized in that, In step S4, the neutralization temperature is 80~95℃; the washing refers to washing with water at a temperature above 95℃; and the drying refers to drying with heated compressed air.

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