Hydroxypropyl methylcellulose having high film elongation at break and method of making and use thereof

Abstract

The application belongs to the technical field of cellulose ether materials, and discloses hydroxypropyl methyl cellulose with high film breaking elongation, a preparation method and application thereof. The hydroxypropyl methyl cellulose with high film breaking elongation is prepared by adopting a mixed reaction system composed of a polar solvent and a non-polar solvent to perform alkalization treatment on methyl cellulose, and performing epoxypropane etherization, neutralization, hot water washing and drying treatment. The hydroxypropyl methyl cellulose with high film breaking elongation has the controllable characteristic of hydroxypropoxy substitution structure, the formed film has high breaking elongation, and the problem of insufficient flexibility of the existing hydroxypropyl methyl cellulose film and easy brittle fracture can be effectively improved.

Description

Technical Field

[0001] This invention belongs to the field of cellulose ether materials technology, specifically relating to a hydroxypropyl methylcellulose with high film breaking elongation, its preparation method, and its application. Background Technology

[0002] Hydroxypropyl methyl cellulose (HPMC) is a cellulose ether polymer material prepared by etherification modification of natural cellulose, containing methoxy and hydroxypropoxy substituents in its molecular structure. Due to its excellent water solubility, film-forming properties, biocompatibility, and good processing performance, HPMC is widely used in pharmaceutical film coating, plant capsules, food packaging films, and functional coating materials. In the field of plant capsules, HPMC, as a primary encapsulation material, needs to form capsule shell structures with good formability, mechanical strength, and suitable toughness to meet the requirements of capsule production processes such as molding, demolding, transportation, and storage. Simultaneously, the capsule shell also needs to possess certain barrier properties and stability to protect the contents and ensure the capsule maintains its structural integrity under different storage conditions. Therefore, the mechanical properties of HPMC films, especially elongation at break, have a significant impact on their practical application performance.

[0003] Currently, the industrial preparation of HPMC typically involves alkalization, etherification, neutralization, washing, and drying of cellulose raw materials. Specifically, cellulose is first activated using alkaline substances such as sodium hydroxide, transforming the hydroxyl groups on the cellulose molecular chains into more reactive structures. Then, an etherification reagent is added to introduce methoxy and hydroxypropoxy substituents into the cellulose molecular chains, ultimately obtaining HPMC products with a certain degree of substitution. Since the type, degree, and distribution of substituents in the HPMC molecular structure affect the intermolecular forces, chain segment mobility, and molecular arrangement during film formation, the preparation process of HPMC directly impacts the mechanical properties of its films.

[0004] In existing technologies, to improve the overall performance of HPMC films, the product performance is typically controlled by adjusting the methoxy content, hydroxypropoxy content, and molecular weight. However, in actual production, the cellulose etherification reaction is a heterogeneous reaction system. The cellulose molecular chain structure is complex, and the degree of alkalization, the composition of the reaction medium, and the diffusion efficiency of the etherification reagent all affect the introduction of hydroxypropoxy groups. Films prepared using traditional processes for HPMC exhibit poor flexibility, low elongation at break, and are prone to brittleness under external forces, making it difficult to meet the high toughness requirements of the plant capsule industry.

[0005] Chinese patent application number 2022114437047 discloses a method for preparing ultra-low viscosity hydroxypropyl methylcellulose. This patented method uses medium-to-high viscosity hydroxypropyl methylcellulose as raw material, and then adds steps such as material swelling, degradation and decolorization, and pressure filtration to the purification process between centrifugal solid-liquid separation and drying. Finally, the product is obtained through spray drying. This method is not only complex in its steps, but also uses spray drying technology, resulting in high energy consumption, low yield, and high cost.

[0006] In summary, the existing technology for preparing hydroxypropyl methylcellulose inevitably results in the hydroxypropoxy terminal hydroxyl group being blocked by the methoxy group, which makes the product structure more complex. Moreover, the research on quality properties mainly focuses on meeting the pharmacopoeia inclusion standards, while neglecting the research on the key material properties required for its use as a film-forming material. Summary of the Invention

[0007] The purpose of this invention is to provide hydroxypropyl methylcellulose with high film breaking elongation and its preparation method. The hydroxypropyl methylcellulose has good film-forming properties and film flexibility, which can improve the breaking elongation of the film formed therefrom, thereby meeting the application requirements of the film coating field for materials with high mechanical strength and high deformation resistance.

[0008] The present invention also aims to provide an application of hydroxypropyl methylcellulose with high film breaking elongation at break in the film formation of plant capsules, so as to improve the problem of insufficient flexibility or easy breakage under external force of existing film coating materials.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0010] This invention provides a method for preparing hydroxypropyl methylcellulose with high film elongation at break, the method comprising the following steps:

[0011] 1) Disperse methylcellulose in a mixed solvent and add liquid alkali for alkalization treatment;

[0012] 2) The product from step 1) is added to propylene oxide for etherification;

[0013] 3) Neutralize the product from step 2) to a pH of 6-7;

[0014] 4) The product from step 3) is washed, dried, dispersed and sieved to obtain hydroxypropyl methylcellulose with high film breaking elongation.

[0015] In step 1), the mixed solvent is a mixture of polar and non-polar solvents, wherein the polar solvent includes one or more of methanol, ethanol, isopropanol or acetone; the non-polar solvent includes one or more of toluene, benzene or chloroform, and the mass ratio of the non-polar solvent to the polar solvent is 4.6-5.4:1-1.2.

[0016] In step 1), the alkali used in the liquid alkali is one or more of sodium hydroxide or potassium hydroxide, the mass fraction of the liquid alkali is 20-40%, and the mass ratio of methylcellulose to liquid alkali is 1:1.3-1.8.

[0017] In step 1), the alkalization treatment is carried out at room temperature for 2-4 hours.

[0018] In step 2), the mass ratio of propylene oxide to methylcellulose in step 1) is 1.5-3:1.

[0019] In step 2), the etherification reaction is carried out at a temperature of 50-70°C for 2-4 hours.

[0020] According to a specific embodiment of the present invention, preferably, in step 3), the acid used for neutralization is acetic acid.

[0021] In step 4), the washing process is performed using hot water with a temperature ≥90℃, and the mass ratio of hot water to methylcellulose in step 1) is 40-60:1.

[0022] In step 4), the drying temperature is 80-130℃ and the sieve mesh size is 100 mesh.

[0023] The present invention provides a hydroxypropyl methylcellulose with high film breaking elongation obtained by the above preparation method, wherein the film breaking elongation of the hydroxypropyl methylcellulose with high film breaking elongation is ≥6.5%.

[0024] This invention provides an application of the above-mentioned hydroxypropyl methylcellulose with high film breaking elongation at break in the film-forming of plant capsules.

[0025] Compared with the prior art, the present invention has the following advantages:

[0026] 1. This scheme uses methylcellulose as a pre-substituted cellulose raw material and then introduces hydroxypropoxy, avoiding the competing reactions and side reactions caused by multiple substitution reactions occurring simultaneously. This makes the hydroxypropylation process more selective and controllable. At the same time, under this reaction pathway, the hydroxypropoxy-terminal hydroxyl group will not be further replaced by methoxy, thus preserving the hydroxypropoxy-terminal structure and achieving precise control of the hydroxypropyl methylcellulose substitution structure.

[0027] 2. Using methylcellulose as a raw material to prepare hydroxypropyl methylcellulose results in a product with molecular structure characteristics that differ from products prepared by traditional processes. This is beneficial for improving the intermolecular forces and chain segment mobility during film formation, thereby enhancing the mechanical properties of the film.

[0028] 3. The hydroxypropyl methylcellulose prepared by this invention has a high film breaking elongation, which can form a capsule film layer with good flexibility, reduce the types of capsule film excipients and formula adjustment steps, simplify the production process, and improve product stability and consistency. Attached Figure Description

[0029] Figure 1 This is the chromatogram of the first standard solution test;

[0030] Figure 2 The chromatogram for the second standard solution test;

[0031] Figure 3 This is the chromatogram for the third standard solution test;

[0032] Figure 4 The test chromatogram of the product obtained in Example 1 is shown. Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0034] Unless otherwise specified, all test materials and reagents used in the following examples are commercially available.

[0035] The methoxyl content of the methylcellulose used in the examples and comparative examples below is 29.9%.

[0036] Example 1

[0037] A method for preparing hydroxypropyl methylcellulose with high film breaking elongation includes the following steps:

[0038] 1) Add 50 g of methylcellulose to a mixed solvent consisting of 250 g of isopropanol and 1250 g of toluene, stir thoroughly to disperse it evenly, then add 165 g of sodium hydroxide aqueous solution with a mass fraction of 40 wt%, and perform alkalization treatment at 20 ℃ for 2 h.

[0039] 2) Add 150 g of propylene oxide to the above-mentioned alkalized reaction system, stir and mix evenly, and then heat to 60°C to carry out the etherification reaction for 4 h.

[0040] 3) After the reaction is complete, add glacial acetic acid to the reaction system to neutralize it and adjust the pH to 7;

[0041] 4) The above-mentioned neutralized reaction system is distilled to recover the organic solvent; then, 90 °C hot water is added to the obtained material for washing, and the washing is repeated 3 times. The total amount of hot water used is 2 kg to remove residual salt and impurities. After washing, the product is dried at 100 °C, then crushed and passed through a 100-mesh sieve to obtain the hydroxypropyl methylcellulose with high film breaking elongation.

[0042] Example 2

[0043] A method for preparing hydroxypropyl methylcellulose with high film breaking elongation includes the following steps:

[0044] The only difference between this embodiment and Example 1 is that the temperature of the etherification reaction in step 2) is 50 °C, and the rest is the same as in Example 1.

[0045] Example 3

[0046] A method for preparing hydroxypropyl methylcellulose with high film breaking elongation includes the following steps:

[0047] The only difference between this embodiment and Example 1 is that the reaction time for the etherification reaction in step 2) is 3 hours, while the rest is the same as in Example 1.

[0048] Comparative Example 1

[0049] A method for preparing hydroxypropyl methylcellulose specifically includes the following steps:

[0050] 1) Add 50g of pulverized refined cotton cellulose to a mixed solvent consisting of 250g isopropanol and 1250g toluene, stir thoroughly to disperse it evenly, then add 165g of sodium hydroxide aqueous solution with a mass fraction of 40 wt%, and perform alkalization treatment at 20 ℃ for 2 h.

[0051] 2) Add 25 g of propylene oxide and 75 g of chloromethane to the above-mentioned alkalized reaction system, stir and mix evenly, then raise the temperature to 50°C in the first stage and keep it at that temperature for 1 hour, and raise the temperature to 90°C in the second stage and keep it at that temperature for 2 hours to carry out the etherification reaction.

[0052] 3) After the reaction is complete, add glacial acetic acid to the reaction system to neutralize it and adjust the pH to 7;

[0053] 4) The above-mentioned neutralized reaction system was distilled to recover the organic solvent; then, 90 °C hot water was added to the obtained material for washing, and the washing was repeated 3 times. The total amount of hot water used was 2 kg to remove residual salt and impurities. After washing, the product was dried at 100 °C, then pulverized and passed through a 100-mesh sieve to obtain hydroxypropyl methylcellulose.

[0054] Comparative Example 2

[0055] A method for preparing hydroxypropyl methylcellulose specifically includes the following steps:

[0056] The only difference between this comparative example and Example 1 is that the alkalization treatment time in step 1) is 1 hour, and the rest is the same as in Example 1.

[0057] Comparative Example 3

[0058] The only difference between this comparative example and Example 1 is that the etherification reaction in step 1) takes 1 hour and is carried out at a temperature of 60°C. The rest is the same as in Example 1.

[0059] Test Example 1

[0060] 1. Gelation temperature:

[0061] Take 0.5g of the hydroxypropyl methylcellulose sample prepared in each example and comparative example, disperse it evenly in 50ml of boiling water, and stir it with electromagnetic stirring to form an insoluble slurry; cool the slurry to 10°C under electromagnetic stirring to form a clear or slightly turbid solution, add 50ml of water, stir electromagnetically and heat at the same time, and record the temperature at which turbidity occurs.

[0062] 2. Tensile strength of the film:

[0063] Prepare 15% (w / w) aqueous solutions of hydroxypropyl methylcellulose (HPMC) as described in the examples and comparative examples. Use a coating tester to prepare films. After drying, select HPMC sample films with uniform thickness and cut them into small pieces of 1.5cm × 15cm. Fix the small pieces of samples on a tensile strength tester, set the test speed to 30.000mm / min, and perform three parallel tests, recording the tensile strength.

[0064] 3. Film breaking elongation test

[0065] Prepare 15% hydroxypropyl methylcellulose (HPMC) aqueous solution as described in each example and comparative example. Prepare films using a coating tester. After drying, select HPMC sample films with uniform thickness and cut them into small pieces of 1.5cm × 15cm. Fix the small pieces of samples on a material tensile strength tester, set the test speed to 30.000mm / min, and perform three parallel tests. Record the elongation at break of the film.

[0066] ;

[0067] in:

[0068] L0 is the initial gauge length of the sample, in mm;

[0069] L1 is the gauge length at which the specimen breaks, in mm.

[0070] 4. Methoxyl content, hydroxypropoxyl content

[0071] Referencing the 2025 edition of the Chinese Pharmacopoeia, Part IV, General Rules <0712> The first method involves using gas chromatography with an internal standard method to determine the content of methoxy and hydroxypropoxy compounds in the HPMC prepared in Example 1. The same standard solution is injected three times consecutively to obtain the average peak area of ​​the methoxy and hydroxypropoxy derivatives, which is used for sample content calculation.

[0072] Methoxy conversion factor F1

[0073]

[0074] Hydroxypropoxy conversion factor F2

[0075]

[0076] calculate:

[0077]

[0078] In the formula: QT and QS are the ratios of the peak areas of the test sample and the reference sample to the peak areas of their corresponding internal standard substances, respectively; WS is the sampling amount of the reference sample, in mg.

[0079] W represents the weight of the test sample on a dry basis, in mg.

[0080] The calculation process for Example 1 is as follows:

[0081] ;

[0082] ;

[0083] The test results are shown in Table 1 below:

[0084] Table 1

[0085]

[0086] The hydroxypropoxy group content in the hydroxypropyl methylcellulose of each embodiment was lower than that of Comparative Example 1. This may be because the C6 hydroxyl group, which is the most reactive in the methylcellulose molecule, has been largely replaced by methoxy groups, resulting in significant steric hindrance to propylene oxide during the subsequent etherification reaction, thus limiting the introduction of hydroxypropoxy groups. Simultaneously, due to the presence of steric hindrance, the alkalization activation process and the etherification reaction process must be strictly controlled. After adjusting the reaction conditions in Comparative Examples 2 and 3, the hydroxypropoxy group content was extremely low, failing to meet the requirements of the Chinese Pharmacopoeia for the hydroxypropoxy group content of hydroxypropyl methylcellulose, and therefore lacking application value in the pharmaceutical field. Furthermore, the embodiments and comparative examples showed a trend of lower gelation temperature with lower hydroxypropoxy group content. The mechanism is that hydroxypropoxy groups are hydrophilic substituents that can form a stable hydrated layer with water molecules. When the hydroxypropoxy group content decreases, the overall hydrophilicity of the molecule weakens, the stability of the hydrated layer decreases, and dissociation occurs at lower temperatures, making it easier for hydrophobic segments to be exposed and aggregate, thereby accelerating the thermo-gelation process, manifested as a decrease in gelation temperature.

[0087] The films prepared in each embodiment exhibit significantly higher tensile strength and elongation at break than those in Comparative Example 1, indicating superior flexibility and stronger resistance to breakage. Especially in the preparation of plant capsules, traditional hydroxypropyl methylcellulose (HPMC) typically requires the addition of plasticizers and gelling agents compared to Comparative Example 1 to improve film-forming flexibility, reduce brittleness, and prevent breakage. However, the HPMC prepared in this invention can be directly used for plant capsule film formation without any added excipients, simplifying the formulation system and production process, significantly reducing process steps and complexity, and substantially improving production efficiency and product consistency.

[0088] It should be noted that the above embodiments are merely some preferred embodiments of the present invention, and not all embodiments. Obviously, based on the above embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

[0089] The above description of the embodiments is intended to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A method for preparing hydroxypropyl methylcellulose with high film breaking elongation, characterized in that, The preparation method includes the following steps: 1) Disperse methylcellulose in a mixed solvent and add liquid alkali for alkalization treatment; 2) The product from step 1) is added to propylene oxide for etherification; 3) Neutralize the product from step 2) to a pH of 6-7; 4) The product from step 3) is washed, dried, dispersed and sieved to obtain hydroxypropyl methylcellulose with high film breaking elongation.

2. The preparation method according to claim 1, characterized in that, In step 1), the mixed solvent is a mixture of polar and non-polar solvents, wherein the polar solvent includes one or more of methanol, ethanol, isopropanol or acetone; the non-polar solvent includes one or more of toluene, benzene or chloroform, and the mass ratio of the non-polar solvent to the polar solvent is 4.6-5.4:1-1.

2.

3. The preparation method according to claim 1, characterized in that, In step 1), the alkali used in the liquid alkali is one or more of sodium hydroxide or potassium hydroxide, the mass fraction of the liquid alkali is 20-40%, and the mass ratio of methylcellulose to liquid alkali is 1:1.3-1.

8.

4. The preparation method according to claim 1, characterized in that, In step 1), the alkalization treatment is carried out at room temperature for 2-4 hours.

5. The preparation method according to claim 1, characterized in that, In step 2), the mass ratio of propylene oxide to methylcellulose in step 1) is 1.5-3:

1.

6. The preparation method according to claim 1, characterized in that, In step 2), the etherification reaction is carried out at a temperature of 50-70°C for 2-4 hours.

7. The preparation method according to claim 1, characterized in that, In step 4), the washing process is performed using hot water with a temperature ≥90℃, and the mass ratio of hot water to methylcellulose in step 1) is 40-60:

1.

8. The preparation method according to claim 1, characterized in that, In step 4), the drying temperature is 80-130℃ and the sieve mesh size is 100 mesh.

9. A hydroxypropyl methylcellulose with high film elongation at break prepared by the preparation method according to any one of claims 1-8, characterized in that, The hydroxypropyl methylcellulose with high film elongation at break has a film elongation at break of ≥6.5%.

10. The application of hydroxypropyl methylcellulose with high film breaking elongation as described in claim 9 in the formation of plant capsules.

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