JPH06100601A - Lowly substituted hydroxypropylcellulose highly soluble in aqueous alkali solution and production thereof - Google Patents

Abstract

PURPOSE:To obtain a compound excellent in film formability, etc., by regulating the degree of hydroxypropylation of cellulose and the viscosity of a solution of the cellulose in an aqueous NaOH solution under given conditions each to a spicified volve. CONSTITUTION:This compound has a degree of hydroxypropylation of 0.2-0.9 and a 2wt.% solution thereof in an 8wt.% aqueous NaOH solution has a viscosity (at 25 deg.C) of 1,000cP or higher. It can be obtained preferably by reacting cellulose (e.g. linter) with 0.8-1.5mol of an alkali (e.g. NaOH) per mol of the anhydroglucose units in a medium consisting of 85-92wt.% t-butyl alcohol and water, the amount of the medium being 10-20 times by weight the amount of the cellulose, and reacting the resulting alkali cellulose with 1.1-5.0mol of propylene oxide per mol of the anhydroglucose units at 50-70 deg.C for 2-5hr.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a low-substituted hydroxypropyl cellulose which is extremely soluble in an alkaline aqueous solution, has excellent transparency, and can easily form a film or coating film, and a process for producing the same.

[0002]

2. Description of the Related Art There are numerous studies on cellulose ethers in the past. In particular, for the production method for hydroxyalkyl cellulose, a huge number of proposals have been made because their derivatives are extremely useful for various applications.

Hydroxypropyl cellulose (hereinafter referred to as HP
(Abbreviated as C) is no exception, and many proposals have been made regarding the manufacturing method. Generally, cellulose ether is water-soluble and is used for producing a thickening effect of a water solution and a protective colloid effect, but this HPC is not only water-soluble but also soluble in an organic solvent, and has excellent film forming ability. Therefore, it has been used for coating tablets and the like.
However, conventional HPC is soluble in organic solvents,
The hydroxypropyl substitution degree is 3 or more, preferably 3.
It must be 5 or more, and naturally, the proposal regarding the manufacturing method was also for the HPC having these substitution degrees.

However, in recent years, it has been found that HPC, which is insoluble in organic solvents and water, is suitable for coating tablets and has excellent disintegration properties of tablets. Has been proposed to use. However, regarding the manufacturing method of low substitution degree HPC, Japanese Patent Publication No.
It is only described in 59857. The content is that the degree of substitution is 0.05 to 0.40 and the water-soluble part at 20 ° C is
It relates to an HPC having a content of 10% by weight or less, a content of 8% sodium hydroxide aqueous solution soluble at 20 ° C of 90% by weight or more, and a 2% concentration of 8% sodium hydroxide aqueous solution having a viscosity at 20 ° C of 5 to 500 centipoise. is there. Certainly,
Although the low substitution degree HPC disclosed in this publication is excellent in tablet disintegration, it does not exhibit coating strength due to its poor solubility in a solvent during coating formation. Since the uniformity of the film does not appear, HPC with a high degree of substitution when used
Means such as using together with were taken.

[0005]

Means for Solving the Problems As a result of intensive studies to solve these problems, the present inventors have adjusted the concentration of alkali used as a reaction catalyst in the production of low substitution degree HPC, and used it as a reaction solvent. By using tertiary butyl alcohol in a specific ratio with respect to cellulose, excellent solubility in an alkaline solvent during coating film formation,
Moreover, they have found that a low substitution degree HPC having good tablet disintegration can be obtained, and completed the present invention.

That is, the present invention has a hydroxypropyl substitution degree in the range of 0.2 to 0.9, and the viscosity of a 2 wt% solution in an 8 wt% sodium hydroxide aqueous solution at 25 ° C.
A low-substituted hydroxypropylcellulose having a high solubility in an alkaline aqueous solution of 1000 centipoise or more, and a mixed medium consisting of 85 to 92% by weight of tertiary butyl alcohol and the balance of water is 10 to 20 times by weight the weight of cellulose. And 0.8-1 per anhydroglucose unit of cellulose.
It is characterized in that 5 mol of alkali is reacted with cellulose to give alkali cellulose, and then 1.1 to 5.0 mol of propylene oxide per anhydrous glucose unit of cellulose is reacted at 50 to 70 ° C. for 2 to 5 hours. The present invention provides a method for producing the above low-substituted hydroxypropyl cellulose.

The cellulose used in the present invention may be any of wood pulp, linter and the like which are commonly used in chemical reactions. In addition, it is preferable to use cellulose that has been crushed by a hammer mill or the like prior to the reaction.

In the present invention, cellulose is first added to the third
Alkali cellulose is generated by reacting an alkali in a mixed medium composed of tertiary butyl alcohol and water (mercerization), but the composition of the mixed medium used is tertiary butyl alcohol of tertiary butyl alcohol and water. A ratio of 85 to 92% of the total is preferable. This mixed medium is used in an amount of 10 to 20 times the weight of cellulose.

Various alkalis such as caustic soda, potassium hydroxide and lithium hydroxide can be used, but caustic soda is preferably used industrially.
The concentration of alkali is extremely important in the present invention. In order to obtain the low degree of substitution HPC according to the present invention, the alkali needs 0.8 mol or more per anhydroglucose unit of cellulose, and the target degree of hydroxypropyl substitution is
In the range of 0.2 to 0.9, it is sufficient to use 1.5 mol or less of alkali per anhydroglucose unit of cellulose used for the reaction. That is, if the amount of alkali is 0.8 mol or less per anhydroglucose unit of cellulose, the effect of the present invention cannot be obtained, while if it is 1.5 mol or more, the effect is not changed, but a large amount of salt is generated during neutralization, Cleaning is labor-intensive and uneconomical. The preferred amount of alkali used is 1.0-
It is 1.4 mol. Further, mercerization is preferably carried out at 10 to 15 ° C. for 1 to 4 hours.

Next, the alkali cellulose obtained as described above is reacted with propylene oxide. The propylene oxide used in the present invention is 1.1 to 5.0 mol per anhydroglucose unit of cellulose. Also,
The reaction needs to be carried out at 50 to 75 ° C. for 2 to 5 hours in order to adjust the degree of hydroxypropyl substitution to 0.2 to 0.9. When the reaction time is less than 2 hours, a sufficient degree of substitution of HPC having a low degree of substitution cannot be obtained, and the solubility in an alkaline aqueous solution becomes poor.

After completion of the reaction, it is necessary to neutralize caustic soda with an inorganic acid and wash the product with an aqueous acetone solution or water. Drying at 105 ° C for several hours is sufficient.

The low degree of substitution HPC thus obtained is
Having 0.2 to 0.9 mol of hydroxypropyl group per anhydrous glucose unit, extremely good film forming ability, film strength,
It has the disintegration property of tablets. JP-B-57-59857 mentioned above describes that an HPC having a hydroxypropyl group number of 0.05 to 0.4 per glucose unit is good. The reason is that if it is 0.05 or less, the solubility in an alkaline aqueous solution becomes poor, while if it is 0.4 or more, the solubility in water increases, and the function as a disintegrant is impaired. However, the low substitution degree HPC obtained by the present inventors does not increase the solubility in water even when the substitution degree of the hydroxypropyl group is 0.4 or more, while it is almost completely dissolved in the alkaline aqueous solution. A phenomenon was seen. This is considered to be related to the distribution of substituents resulting from the production method of the present invention. That is, in the production method of the present invention, since the alkali concentration is high, it is presumed that the hydroxyl group at the 6-position of glucose selectively reacts, resulting in a difference in solubility.

[0013]

The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

Example 1 20 parts by weight of a linter crushed with a cutting mill was placed in a separable flask, and 268 parts by weight of t-butyl alcohol and 20 parts by weight of water were added to form a slurry. An aqueous solution of caustic soda in which caustic soda was dissolved in 12 parts by weight of water was added, and mercerization was performed for 1 hour while stirring. At this time, the ratio of t-butyl alcohol to the total of t-butyl alcohol and water was 89%. After mercerization, propylene oxide was added in an amount of 5 mol per anhydroglucose unit and reacted at 70 ° C. for 3 hours. After the reaction, the mixture was cooled, neutralized with nitric acid, drained, and washed 4 times with 400 parts by weight of a 70% by weight aqueous acetone solution. After washing, it was dried at 105 ° C.

The properties of the low-substituted HPC thus obtained are shown in Table 1. Incidentally, it is a property of low substitution degree HPC.
The methods for measuring (1) hydroxypropyl substitution (MS), (2) aqueous solution viscosity, and (3) aqueous solution transparency are as follows. (1) Substitution degree: Measured by oxidatively decomposing a hydroxypropyl group with chromium trioxide, or liberating and iodifying a hydroxypropyl group with hydroiodic acid, and quantifying these decomposition products. (2) Aqueous solution viscosity: A sample was dissolved in an 8% aqueous sodium hydroxide solution at a concentration of 2% and measured at 25 ° C using a B-type viscometer. Hereinafter, in the table, simply referred to as viscosity. (3) Transparency of aqueous solution: height 350 mm, inner diameter 25 mm, thickness 2 mm, glass bottom made by closely adhering 2 mm thick good quality glass plate to outer tube, height 300 mm, inner diameter 15 mm, thickness The inner tube consists of a 2 mm thick glass plate adhered to the bottom of a 2 mm glass cylinder, and the outer tube is filled with the test solution.
Place 15 parallel lines with 1mm spacing and 1mm spacing on a black sheet of white paper, and measure the height to the lower end of the inner pipe when you cannot see the lines when you move the inner pipe up and down and see through from above. To do.
The average value obtained by repeating this operation three times is expressed in mm.
In addition, in the table, it is simply described as transparency.

Example 2 and Comparative Example 1 A low-substituted HPC was prepared in the same manner as in Example 1 except that the hydroxypropylation time was as shown in Table 1 below. The properties of the obtained low-substituted HPC are shown in Table 1 together with the results of Example 1, and the hydroxypropylation was 1
In Comparative Example 1 carried out over a period of time, a sufficient degree of substitution could not be obtained, and the transparency of the alkaline aqueous solution was very poor.

[0017]

[Table 1]

Examples 3 to 5 and Comparative Example 2 Hydroxypropylation reaction was carried out at 60 ° C. for 1 hour and then 70
Low substitution degree HPC was performed in exactly the same manner as in Example 1 except that the reaction time was changed to that shown in Table 2 below.
Was manufactured. The properties of the obtained low substitution degree HPC are shown in Table 2.
As shown in Table 1, a sufficient degree of substitution was not obtained only by carrying out the reaction at 60 ° C. for 1 hour as in Comparative Example 2, and the product was hardly dissolved in the alkaline aqueous solution.

[0019]

[Table 2]

Examples 6 to 8 and Comparative Example 3 During the hydroxypropylation reaction, the amount of propylene oxide charged was as shown in Table 3 below, and the reaction was carried out at 60 ° C. for 1 hour and then at 70 ° C. for 2 hours. In the same manner as in Example 1, a low-substituted HPC was manufactured. The properties of the obtained low-substituted HPC are shown in Table 3. However, when the reaction was carried out at a charged amount of propylene oxide of 1 mol per anhydroglucose unit as in Comparative Example 3, a sufficient degree of substitution was not obtained and the product was obtained. Was hardly dissolved in the alkaline aqueous solution.

[0021]

[Table 3]

Comparative Example 4 The amount of caustic soda charged was 0.75 per unit of anhydrous glucose.
Low substitution degree HP in the same manner as in Example 1 except that the molar ratio is
C was manufactured. The degree of substitution of the obtained low degree of substitution HPC is
The product was hardly dissolved in the alkaline aqueous solution because 0.14 was not a sufficient degree of substitution.

Comparative Example 5 The amount of caustic soda charged was 1.8 per anhydrous glucose unit.
Low substitution degree HP in the same manner as in Example 1 except that the molar ratio is
C was manufactured. The degree of substitution of the obtained low degree of substitution HPC is
The product was hardly dissolved in the alkaline aqueous solution because 0.18 was not a sufficient degree of substitution.

Comparative Example 6 A low-substituted HPC was manufactured in exactly the same manner as in Example 1 except that the ratio of tertiary butyl alcohol to the total amount of tertiary butyl alcohol and water was 80%. The low degree of substitution HPC thus obtained had a degree of substitution of 0.07, which was not a sufficient degree of substitution, and therefore the product was hardly dissolved in the alkaline aqueous solution.

Comparative Example 7 A low-substituted HPC was produced in the same manner as in Example 1 except that the reaction medium was only tertiary butyl alcohol and no water was added. The degree of substitution of the obtained low degree of substitution HPC was 0.04, which was not a sufficient degree of substitution, and therefore the product was hardly dissolved in the alkaline aqueous solution.

Examples 9 and 10 The solubility of the low-substituted HPC of the present invention obtained in Examples 3 and 4 in water was compared. The results are shown in Table 4.

[0027]

[Table 4]

Comparative Example 8 Commercially available low-substituted HPC (L-HP manufactured by Shin-Etsu Chemical Co., Ltd.)
For C and grade LH21), the degree of substitution, the viscosity of the aqueous solution, the transparency of the aqueous solution, and the solubility in water were measured in the same manner as in Example 1. The results are the low substitution degree HP of Examples 3 and 4.
It shows in Table 5 with the result of C.

[0029]

[Table 5]

From Table 5, the low-substituted HPC obtained by the present invention has a low degree of substitution as compared with the commercially available low-substituted HPC, but the water-soluble content thereof is slightly higher than that of the commercially available low-substituted HPC. It can be seen that the solubility in the alkaline aqueous solution is very excellent.

Example 11 and Comparative Examples 9 and 10 The low substitution degree HPC shown in the above-mentioned Examples 3, Comparative Example 2 and Comparative Example 8 was added to an 8% aqueous sodium hydroxide solution to a concentration of 7%.
And then left to cool to a temperature of 0 ° C., cast on a glass plate, coagulated in a 20% aqueous ammonium sulfate solution, and washed with water to remove salts,
A film was prepared by drying at 70 ° C. The film thickness, appearance and transparency of the obtained film were evaluated. The film thickness was measured with a micro gauge. Also the appearance of the film,
In the transparency evaluation, ⊚ means good, Δ means normal, and × means bad. The results are shown in Table 6.

[0032]

[Table 6]

From Table 6, it can be seen that the film made of the low substitution degree HPC of the present invention is superior in transparency and uniformity to the film of Comparative Example.

Example 12 and Comparative Examples 11 and 12 Tablets were produced using the low substitution degree HPC shown in the above-mentioned Example 3, Comparative Example 2 and Comparative Example 8 as a disintegrant, and a tableting test was conducted. The composition and formulation conditions of the tablets are as shown below. (2) Formulation conditions-Tabletting machine: Kikusui Seisakusho, Clean Press Collect 19-Molding conditions: Tablet diameter 8 mmφ, tablet thickness 2 mm, weight 250 mg The tablet physical properties were measured by the following methods. The results are shown in Table 7. -Hardness: Using a Sunmont hardness tester-Disintegration: According to the test method of the Japanese Pharmacopoeia, water (22 ± 1 ° C) was used as the test solution.

[0035]

[Table 7]

From Table 7, it can be seen that the tablets of Example 12 are superior in disintegration and hardness to the tablets of Comparative Examples 11 and 12.

Claims (2)

[Claims] 1. The degree of hydroxypropyl substitution is 0.2 to 0.9.
And a low-substituted hydroxypropyl cellulose having a high solubility in an alkaline aqueous solution in which the viscosity of a 2% by weight solution in an 8% by weight sodium hydroxide aqueous solution at 25 ° C. is 1000 centipoise or more. 2. A mixed medium composed of 85 to 92% by weight of tertiary butyl alcohol and the balance of water, based on the weight of cellulose.
After 10 to 20 times by weight and 0.8 to 1.5 mol of alkali per anhydrous glucose unit of cellulose are reacted with cellulose to give alkali cellulose, 1.1 to 5.0 mol of propylene oxide per 50 to anhydrous glucose unit of cellulose is added to this. The method for producing a low-substituted hydroxypropyl cellulose according to claim 1, wherein the reaction is carried out at -70 ° C for 2-5 hours.