Hydroxypropyl methylcellulose and production method thereof

Abstract

The invention relates to the technical field of medicinal high polymer material synthesis, in particular to hydroxypropyl methylcellulose (HPMC) and a preparation method thereof, the method comprises the following steps: (1) pre-swelling treatment: mixing cotton powder with an isopropanol aqueous solution with the mass concentration of 10-20% according to the mass ratio of 1: (4-6), and pre-swelling at 20-25 DEG C for 30-60 minutes to obtain pre-swelled cotton powder; and (2) alkalization. (3) etherification: adding the etherification reagent into a reaction kettle, and enabling the etherification reagent to react with the alkalized refined cotton powder. (4) separating and drying; and (5) crushing: performing multi-stage gradient freeze-dried powder crushing on the dried material. And (6) obtaining a final product: mixing and packaging the crushed product. The HPMC product which is low in bulk density, fine in particle size and extremely small in batch-to-batch difference is prepared through the method, and it is ensured that the HPMC product has excellent and stable slow release performance when serving as a slow release framework material.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of synthesis of pharmaceutical polymers, in particular to a hydroxypropyl methyl cellulose (HPMC) and a preparation method thereof. BACKGROUND

[0002] Hydroxypropyl methyl cellulose (Hyroxypropyl methyl cellulose, HPMC) is used as a pharmaceutical excipient, mainly as a sustained-release material, a film-coating material, a thickening agent, a stabilizer, an emulsifying agent and an adhesive. When used as a sustained-release material, it is mainly used for the preparation of 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.

[0003] At present, the main concern about hydroxypropyl methyl cellulose is its sustained-release effect. For example, the patent application No. 201510150104.5 discloses a hydroxypropyl methyl cellulose and a preparation method and use thereof. The method for preparing the hydroxypropyl methyl cellulose comprises: contacting methyl cellulose with epichlorohydrin to cause etherification reaction of the methyl cellulose so as to obtain the hydroxypropyl methyl cellulose. The method can prepare hydroxypropyl methyl cellulose with high viscosity and solubility, and the obtained hydroxypropyl methyl cellulose product can significantly improve the sustained-release ability when used as a sustained-release agent.

[0004] However, the above method for preparing hydroxypropyl methyl cellulose has poor stability, and the existing technology often controls the bulk density, particle size and degree of substitution as independent indexes, ignoring the internal correlation among them. It is difficult to simultaneously achieve low bulk density, fine particle size and high sustained-release consistency. SUMMARY

[0005] The purpose of the present application is to provide a production method of hydroxypropyl methyl cellulose, which can prepare HPMC products with low bulk density, fine particle size and little batch difference, and ensure that the products have excellent and stable sustained-release performance when used as sustained-release matrix materials.

[0006] To achieve the above purpose, the present application provides a production method of hydroxypropyl methyl cellulose, comprising the following steps: (1) Pre-swelling treatment: crushing refined cotton, screening out cotton powder with a mesh size of 80-120, mixing the cotton powder with isopropyl alcohol aqueous solution with a mass concentration of 10-20% at a mass ratio of 1:(4-6), and pre-swelling treatment at 20-25℃ for 30-60 minutes to obtain pre-swelling cotton powder.

[0007] (2) Alkalization: the prepared toluene and isopropyl alcohol mixed solvent is pressed into the reaction kettle; the sodium hydroxide aqueous solution with a mass concentration of 45-65% is pressed into the mixed solvent in the reaction kettle; nitrogen is opened, and the air in the reaction kettle is replaced for multiple times; the pre-swollen cotton powder obtained in step (1) is added into the reaction kettle while stirring; the temperature of the system in the reaction kettle is maintained at 20-25°C, and the alkalization reaction is performed for 1-2 hours.

[0008] (3) Etherification: the etherification reagent is added into the reaction kettle to react with the alkalized refined cotton powder.

[0009] (4) Separation and drying: after the reaction is completed, the residual alkali is neutralized with glacial acetic acid, the material is pressed into a desolventizing kettle, and the solvent is separated; the mixture after desolventization is subjected to BHS steam pressure filter pressing, the material is separated, and drying is performed. (5) Crushing: the dried material is subjected to multi-stage gradient freeze-drying and crushing.

[0010] (6) Final product: the crushed product is mixed and packaged.

[0011] The obtained product has a bulk density of 0.20-0.30 g / cm3, a particle size D70≤75 μm, and a batch-to-batch bulk density RSD≤3% and a particle size D70 RSD≤5%.

[0012] In the above scheme, the cotton powder is subjected to pre-swelling treatment before alkalization, and isopropyl alcohol aqueous solution is used as the pre-swelling agent, and the polarity of isopropyl alcohol aqueous solution is between that of water and pure organic solvent. The low-concentration isopropyl alcohol with a concentration of 10-20% can effectively penetrate the cellulose bundle, destroy the internal hydrogen bond network, realize mild and uniform preliminary swelling, and open the microporous structure of cellulose, thereby providing a channel for subsequent alkalization and etherification.

[0013] Further, the alkalization temperature is controlled at 20-25°C in the present application, and the pre-swelling treatment is combined, so that the low-temperature environment can maximize the adsorption amount and swelling degree of cellulose to alkali, and minimize the hydrolysis reaction of cellulose. The synergistic effect of the channel provided by pre-swelling and low-temperature high adsorption ensures that the alkalization reaction is carried out deeply and uniformly in the cellulose, and highly uniform alkali cellulose is generated, which is the key to realizing the high consistency of the final product. It is generally believed that increasing the alkalization temperature is beneficial to the reaction, but the present application adopts low-temperature alkalization combined with pre-swelling, and unexpected synergistic effect is achieved.

[0014] As a preferred embodiment, the etherification reaction includes four stages, a first low-temperature etherification stage at 50-55°C for 60-90 min, a first high-temperature etherification stage at 85-90°C for 60-90 min, a second low-temperature etherification stage at 50-55°C for 60-90 min, and a second high-temperature etherification stage at 85-90°C for 60-90 min. The segmented etherification ensures that the etherification reaction is carried out stably and controllably, and avoids side reactions caused by excessively high local concentration.

[0015] As preferred, in step (3), a 5-10 minute holding and standing period is arranged between the first low-temperature etherification section and the second low-temperature etherification section, and between the first high-temperature etherification section and the second high-temperature etherification section As preferred, the multi-stage gradient freeze-drying and crushing process comprises: first-stage crushing: -40℃~-30℃, 5-10 min; intermediate cooling: -30℃~-20℃, 5 min; second-stage crushing: -60℃~-50℃, 10-15 min; intermediate cooling: -50℃~-40℃, 5 min; third-stage crushing: -80℃~-70℃, 15-20 min.

[0016] Single low-temperature crushing may result in "incomplete crushing" or "excessive crushing" due to uneven one-time brittle of the material. The multi-stage gradient of the present application, by gradually deepening the low-temperature environment, each stage of crushing is applied to a more stable and more brittle material state, thereby achieving a more fine and uniform crushing effect, effectively controlling the particle size distribution, reducing the generation of fine powder and large particles, and ensuring D70≤75μm and narrow distribution.

[0017] As preferred, in the alkalization step, the mass ratio of toluene: isopropyl alcohol: water is 4.0: (0.8-1.0): (0.2-0.4).

[0018] As preferred, the mass ratio of the mixed solvent: cotton powder is (8-10): 1.

[0019] As preferred, the mass ratio of chloromethane to propylene oxide in the etherification reagent is (3.0-3.5): 1.

[0020] As preferred, the mass ratio of the refined cotton powder to the total amount of etherification reagent is 1: (1.0-1.5) The present application also provides a hydroxypropyl methyl cellulose prepared by the above method. The hydroxypropyl methyl cellulose has a bulk density of 0.20-0.30 g / cm3, a particle size D70≤75μm, a batch-to-batch bulk density RSD≤3%, a particle size D70 RSD≤5%, a methoxyl content of 20.5%-21.5%, and a hydroxypropoxy content of 10.0%-11.0%.

[0021] The hydroxypropyl methyl cellulose is used as a matrix material for preparing an oral sustained-release preparation, and the prepared sustained-release tablets have a drug dissolution RSD≤5% in 600 minutes.

[0022] By implementing the above technical solution, compared with the prior art, the present application has the following beneficial effects: The present application ensures high uniformity of the alkalization and etherification reactions by optimizing the preparation method, fundamentally solves the problem of large batch difference, and the prepared HPMC has low bulk density, fine particle size and narrow distribution, the prepared sustained-release tablets have high consistency in dissolution behavior, and the RSD is less than or equal to 5%, which is much better than the prior art. DETAILED DESCRIPTION

[0023] Embodiment 1 The present embodiment provides a production method of hydroxypropyl methyl cellulose for sustained-release matrix, comprising the following steps: 1. Crush the refined cotton, and pass the cotton powder passing through an 80-mesh sieve to a reaction kettle, mix the cotton powder 100 kg with isopropyl alcohol aqueous solution 500 kg (mass ratio 1:5) with a mass concentration of 15%, and pre-swelling at 22 ℃ for 45 minutes to obtain pre-swollen cotton powder.

[0024] 2. Add toluene 400 kg, isopropyl alcohol 90 kg, and 55% NaOH aqueous solution 50 kg (containing water 45 kg) into the reaction kettle, replace the air with nitrogen for 3 times, add the pre-swollen cotton powder into the reaction kettle while stirring, and control the system temperature at 22 ℃ for 1.5 hours of alkalization reaction.

[0025] 3. Stepwise gradient etherification: add etherification reagent (chloromethane: propylene oxide = 3.3:1) with a total mass of 130 kg, and refined cotton: etherification reagent = 1:1.3. Perform four-stage etherification: First low-temperature etherification stage: 50 ℃ for 75 min, and stand for 8 min (stop stirring) First high-temperature etherification stage: 88 ℃ for 75 min, and stand for 8 min (stop stirring) Second low-temperature etherification stage: 50 ℃ for 75 min, and stand for 8 min (stop stirring) Second high-temperature etherification stage: 88 ℃ for 75 min.

[0026] 4. After the reaction is completed, neutralize the remaining alkali with glacial acetic acid to pH = 7; 5. Press the material into a desolventizing kettle to separate out the solvent; 6. Separate out the material from the desolventized mixture through a BHS steam pressure filter; 7. Granulate and dry the material, and introduce the material into a freeze-drying pulverizer for pulverization after the material temperature in the bin approaches room temperature: First-stage pulverization: -35 ℃, 8 min, and rotation speed 900 rpm; Intermediate cooling: -25 ℃, 5 min; Second-stage pulverization: -55 ℃, 12 min, and rotation speed 1300 rpm; Intermediate cooling: -45 ℃, 5 min; Third pulverization: -75℃, 18min, 1700rpm.

[0027] 8. Mixing, packing into final product.

[0028] Finished product requirements: bulk density: 0.20-0.30g / cm3, particle size: D70≤75μm.

[0029] Five independent batches were performed.

[0030] Test results (n=5 batches): Example 2 The present example provides a production method of hydroxypropyl methyl cellulose for sustained-release matrix, comprising the following steps: 1. Pulverize refined cotton, and mix the cotton powder passing through a 100-mesh sieve with 500 kg of 10% isopropyl alcohol aqueous solution (mass ratio 1:5) through pipeline airflow delivery to a reaction kettle, and pre-swelling at 22℃ for 45 minutes to obtain pre-swollen cotton powder.

[0031] 2. Add 400 kg of toluene, 90 kg of isopropyl alcohol, and 50 kg of 55% NaOH aqueous solution (containing 45 kg of water) to the reaction kettle. Replace the air with nitrogen gas for 3 times. Add the pre-swollen cotton powder to the reaction kettle while stirring. Control the system temperature at 20℃, and alkalization for 1.5 hours.

[0032] 3. Stepwise gradient etherification: add a total of 130 kg of etherification reagent (chloromethane: propylene oxide = 3.3:1), and the refined cotton: etherification reagent = 1:1.3. Perform four-stage etherification: First low-temperature etherification stage: 50℃ for 75 min, and stand for 8 min (stop stirring) First high-temperature etherification stage: 88℃ for 75 min, and stand for 8 min (stop stirring) Second low-temperature etherification stage: 50℃ for 75 min, and stand for 8 min (stop stirring) Second high-temperature etherification stage: 88℃ for 75 min.

[0033] 4. After the reaction is completed, neutralize the remaining alkali with glacial acetic acid to pH=7; 5. Press the material into a desolventizing kettle to separate out the solvent; 6. The desolventized mixture is separated into materials through a BHS steam pressure filter; 7. The materials are granulated, dried, and introduced into a freeze-drying pulverizer for pulverization after the material temperature in the bin approaches room temperature: Primary grinding: -35°C, 8 min, 900 rpm; Intermediate cooling: -25°C, 5 min; Secondary grinding: -55°C, 12 min, 1300 rpm; Intermediate cooling: -45°C, 5 min; Tertiary grinding: -75°C, 18 min, 1700 rpm.

[0034] 8. Mixing, packaging into final product.

[0035] Finished product requirements: bulk density: 0.20-0.30 g / cm3, particle size: D70≤75 μm.

[0036] Five independent batches were performed.

[0037] Test results (n=5 batches): Example 3 The present example provides a production method of hydroxypropyl methyl cellulose for sustained-release matrix, comprising the following steps: 1. Pulverize refined cotton, and pass the cotton powder passing through an 80-mesh sieve to a reaction kettle, and mix 100 kg of the cotton powder with 500 kg of isopropyl alcohol aqueous solution with a mass concentration of 15% (mass ratio 1:5) to obtain pre-swollen cotton powder at 22°C for 45 minutes.

[0038] 2. Add toluene 400 kg, isopropyl alcohol 90 kg, and 50 kg of 55% NaOH aqueous solution (containing 45 kg of water) to the reaction kettle. Replace the air with nitrogen gas for 3 times. Add the pre-swollen cotton powder to the reaction kettle while stirring. Control the system temperature at 22°C, and alkalize for 1.5 hours.

[0039] 3. Stepwise gradient etherification: add a total of 130 kg of etherification reagent (chloromethane: propylene oxide = 3.0:1), and the refined cotton: etherification reagent = 1:1.3. Perform four-stage etherification: First low-temperature etherification stage: 50°C for 75 min, and stand for 8 min (stop stirring) First high-temperature etherification stage: 88°C for 75 min, and stand for 8 min (stop stirring) Second low-temperature etherification stage: 50°C for 75 min, and stand for 8 min (stop stirring) Second high-temperature etherification stage: 88°C for 75 min.

[0040] 4. After the reaction is completed, neutralize the remaining base with glacial acetic acid to pH=7; 5. The material is pressed into the desolventizing kettle, and the solvent is separated out; 6. The mixture after desolventizing is filtered by a BHS steam filter, and the material is separated out; 7. The material is granulated and dried, and after the material temperature in the bin approaches room temperature, it is introduced into a freeze-drying pulverizer for pulverization: First-stage pulverization: -35°C, 8 min, rotation speed 900 rpm; Intermediate cooling: -25°C, 5 min; Second-stage pulverization: -55°C, 12 min, rotation speed 1300 rpm; Intermediate cooling: -45°C, 5 min; Third-stage pulverization: -75°C, 18 min, rotation speed 1700 rpm.

[0041] 8. Mixing and packaging into the final product.

[0042] The finished product has a bulk density of 0.20-0.30 g / cm3 and a particle size of D70≤75 μm.

[0043] Five independent batches are performed.

[0044] Test results (n=5 batches): Example 4 The present example provides a production method of hydroxypropyl methyl cellulose for sustained-release matrix, comprising the following steps: 1. The refined cotton is pulverized, and the cotton powder passing through an 80-mesh sieve is taken, 100 kg of which is conveyed by pipeline air flow to a reaction kettle, mixed with 500 kg of isopropyl alcohol aqueous solution with a mass concentration of 15% (mass ratio 1:5), and pre-swelled at 22°C for 45 minutes to obtain pre-swelled cotton powder.

[0045] 2. Toluene 400 kg, isopropyl alcohol 90 kg, and 55% NaOH aqueous solution 50 kg (containing water 45 kg) are added to the reaction kettle. Nitrogen is used to replace air for 3 times. The pre-swelled cotton powder is added to the reaction kettle while stirring. The system temperature is controlled at 22°C, and the alkalization reaction is carried out for 1.5 hours.

[0046] 3. Stepwise gradient etherification: a total of 130 kg of etherification reagent (chloromethane: propylene oxide = 3.3:1) is added, and the refined cotton: etherification reagent = 1:1.3. Four-stage etherification is carried out: First low-temperature etherification stage: 50°C for 75 min, and standing for 8 min (stopping stirring) First high-temperature etherification stage: 88°C for 75 min, and standing for 8 min (stopping stirring) Second low temperature etherification section: 50℃ for 75min, keep standing for 8min (stop stirring) Second high temperature etherification section: 88℃ for 75min.

[0047] 4. After the reaction, the remaining base is neutralized with glacial acetic acid to pH = 7; 5. The material is pressed into a desolventizing kettle to separate the solvent; 6. The desolventized mixture is separated by a BHS steam pressure filter; 7. The material is granulated, dried, and then introduced into a freeze-drying crusher for crushing when the material temperature in the bin approaches room temperature: First crushing: -40℃, 10min, speed 800rpm; Intermediate cooling: -30℃, 5min; Second crushing: -60℃, 15min, speed 1200rpm; Intermediate cooling: -50℃, 5min; Third crushing: -80℃, 20min, speed 1600rpm.

[0048] 8. Mixing and packaging into the final product.

[0049] The finished product requires a bulk density of 0.20-0.30g / cm3 and a particle size of D70≤75μm.

[0050] Five independent batches were performed.

[0051] Test results (n=5 batches): Comparative Example 1 The difference from Example 1 is only that the pre-swelling treatment is not performed, and the sieved cotton powder 100kg is directly conveyed to the reaction kettle by pipeline air flow, and then step 2 is performed.

[0052] Five independent batches were performed.

[0053] Test results (n=5 batches): Compared with Example 1, the bulk density RSD of Comparative Example 1 significantly increases, indicating that the product has a large fluctuation in density. This shows that without pre-swelling treatment, the initial swelling state of cellulose is not uniform, resulting in differences in the depth and uniformity of subsequent alkalization and etherification reactions between batches, which ultimately manifests as inconsistencies in macroscopic physical properties.

[0054] Comparative Example 2 The difference from Example 1 is only that in step 2, the alkalization temperature is 38℃.

[0055] Five independent batches were performed.

[0056] Test results (n=5 batches): Compared with Example 1, the bulk density RSD and particle size RSD of Comparative Example 2 were both significantly higher. This indicates that even with pre-swelling treatment, higher alkalization temperature still exacerbates the local hydrolysis and uneven swelling of cellulose, destroying the uniformity brought by pre-swelling, resulting in a decrease in the consistency of the final product.

[0057] Comparative Example 3 The only difference from Example 1 is that the etherification step in this comparative example is: Segmented gradient etherification: add a total of 130 kg of etherification reagent (chloromethane: propylene oxide = 3.3:1), refined cotton: etherification reagent = 1:1.3. Perform four segments of etherification: First low-temperature etherification segment: 50°C for 75 min; First high-temperature etherification segment: 88°C for 75 min; Second low-temperature etherification segment: 50°C for 75 min; Second high-temperature etherification segment: 88°C for 75 min.

[0058] Five independent batches were performed.

[0059] Test results (n=5 batches): Compared with Example 1, the bulk density RSD and particle size RSD of Comparative Example 3 were significantly higher. This indicates that without a holding and resting period, the temperature and concentration gradients in the reaction system cannot be effectively eliminated, resulting in differences in reaction conditions in different batches or different regions within the same batch, and ultimately a decrease in the consistency of the final product.

Claims

1. A method for producing hydroxypropyl methylcellulose, characterized by, The method comprises the following steps: (1) Pre-swelling treatment: the refined cotton is crushed, and cotton powder with a mesh size of 80-120 is screened out, and the cotton powder is mixed with isopropyl alcohol aqueous solution with a mass concentration of 10-20% at a mass ratio of 1:(4-6), and pre-swelling treatment is carried out at 20-25°C for 30-60 min to obtain pre-swollen cotton powder; (2) Alkalization: the prepared toluene-isopropyl alcohol mixed solvent is pressed into a reaction kettle; the sodium hydroxide aqueous solution with a mass concentration of 45-65% is pressed into the mixed solvent in the reaction kettle; nitrogen is opened, and the air in the reaction kettle is replaced for multiple times; the pre-swollen cotton powder obtained in step (1) is added into the reaction kettle while stirring; the temperature of the system in the reaction kettle is maintained at 20-25°C, and the alkalization reaction is carried out for 1-2 h; (3) Etherification: the etherification reagent is added into the reaction kettle to react with the refined cotton powder after alkalization; (4) Separation and drying: after the reaction is completed, the remaining alkali is neutralized with glacial acetic acid, the material is pressed into a desolventizing kettle, and the solvent is separated out; the mixture after desolventization is subjected to BHS steam pressure filtration, the material is separated out, and drying is carried out; (5) Crushing: the dried material is subjected to multi-stage gradient freeze-drying crushing; (6) Final product: the crushed product is mixed and packaged.

2. The production method of hydroxypropyl methylcellulose according to claim 1, characterized by, The etherification reaction comprises four stages in sequence, the first low-temperature etherification stage is 50-55°C for 60-90 min; the first high-temperature etherification stage is 85-90°C for 60-90 min; the second low-temperature etherification stage is 50-55°C for 60-90 min; and the second high-temperature etherification stage is 85-90°C for 60-90 min.

3. The production method of hydroxypropyl methylcellulose according to claim 1, characterized by, In step (3), a heat preservation and standing period of 5-10 min is arranged between the first low-temperature etherification stage and the second low-temperature etherification stage, and between the first high-temperature etherification stage and the second high-temperature etherification stage.

4. The production method of hydroxypropyl methylcellulose according to claim 1, characterized by, The multi-stage gradient freeze-drying crushing process comprises: first-stage crushing: -40°C to -30°C, 5-10 min; intermediate cooling: -30°C to -20°C, 5 min; second-stage crushing: -60°C to -50°C, 10-15 min; intermediate cooling: -50°C to -40°C, 5 min; and third-stage crushing: -80°C to -70°C, 15-20 min.

5. The method of producing hypromellose according to claim 1, characterized by, In the alkalization step, the mass ratio of toluene to isopropyl alcohol is 4.0:(0.8-1.0).

6. The production method of hydroxypropyl methylcellulose according to claim 1, characterized by, The mass ratio of the mixed solvent to the cotton powder is (8-10):

1.

7. The method of producing hypromellose according to claim 1, characterized by, The mass ratio of chloromethane to propylene oxide in the etherification reagent is (3.0-3.5):

1.

8. The method of producing hypromellose according to claim 1, characterized by, The mass ratio of the refined cotton powder to the total amount of the etherification reagent is 1:(1.0-1.5).

9. Hypromellose characterized in that, The product is prepared by the method of any one of claims 1-8.

10. The hydroxypropyl methylcellulose of claim 1, wherein, The hydroxypropyl methyl cellulose has a bulk density of 0.20-0.30 g / cm3, a particle size D70≤75 μm, a batch-to-batch bulk density RSD≤3%, a particle size D70 RSD≤5%, a methoxyl content of 20.5%-21.5%, and a hydroxypropoxy content of 10.0%-11.0%.

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