JP3059004B2 - Low-substituted hydroxypropylcellulose having high solubility in aqueous alkali solution and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a low-substituted hydroxypropylcellulose which is extremely soluble in an aqueous alkali solution, has excellent transparency, and can easily form films and coatings, and a method for producing the same.

[0002]

2. Description of the Related Art There are numerous studies on cellulose ethers following past studies. In particular, an enormous number of proposals have been made on production methods for hydroxyalkylcellulose because their derivatives are extremely useful for various uses.

[0003] Hydroxypropylcellulose (hereinafter HP)
C) is no exception, and a number of proposals have been made regarding the production method. Generally, cellulose ether is water-soluble, and is used for producing a thickening effect of an aqueous solution and a protective colloid effect. However, 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 HPCs are soluble in organic solvents,
Its hydroxypropyl substitution degree is 3 or more, preferably 3.
5 or more, and of course, the proposal for the production method was also for HPC having these degrees of substitution.

However, in recent years, HPC insoluble in organic solvents and water has been found to be suitable for tablet coating and excellent in disintegration of tablets. There has been a proposal to use. However, regarding the production method of low substitution HPC,
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
An HPC having a viscosity of 5 to 500 centipoise at 20 ° C. at a concentration of 10% by weight or less, an 8% aqueous solution of sodium hydroxide at 20 ° C. of 90% or more, and a 2% by weight aqueous solution of 8% aqueous sodium hydroxide at 20 ° C. is there. Certainly,
The low-substitution HPC disclosed in this publication has excellent tablet disintegration properties, but does not have sufficient film strength due to poor solubility in a solvent at the time of film formation. HPC with a high degree of substitution is used when the film is used because the film is not uniform.
And other measures were taken.

[0005]

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

That is, in the present invention, the degree of hydroxypropyl substitution is in the range of 0.2 to 0.9, and the viscosity of a 2% by weight solution in an 8% by weight aqueous sodium hydroxide solution at 25 ° C.
A low-substituted hydroxypropylcellulose having high solubility in an aqueous alkali solution of 1000 centipoise or more, and a mixed medium comprising 85 to 92% by weight of tertiary butyl alcohol and the balance of water are 10 to 20 times the weight of cellulose by weight. And 0.8-1 per anhydroglucose unit of cellulose.
After reacting 5 mol of alkali with cellulose to obtain alkali cellulose, 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. It is intended to provide a method for producing the above low-substituted hydroxypropylcellulose.

[0007] The cellulose used in the present invention may be any of wood pulp, linter and the like usually used in chemical reactions. 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, first, cellulose is added to the third
An alkali is allowed to act in a mixed medium composed of tertiary butyl alcohol and water to produce alkali cellulose (mercerization). However, the composition of the mixed medium used is a mixture of tertiary butyl alcohol of tertiary butyl alcohol and water. Those having a ratio to the total in the range of 85 to 92% are preferred. This mixed medium is used in an amount of 10 to 20 times the weight of the cellulose.

As the alkali, various alkalis such as caustic soda, potassium hydroxide and lithium hydroxide can be used, but industrially, caustic soda is preferably used.
The concentration of the alkali is very important in the present invention. In order to obtain the low-substitution HPC according to the present invention, the alkali requires 0.8 mol or more per anhydroglucose unit of cellulose, and the desired hydroxypropyl substitution degree is required.
In the range of 0.2 to 0.9, it is sufficient that the alkali is used in an amount of 1.5 mol or less per anhydroglucose unit of cellulose used in 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.On the other hand, if the amount is 1.5 mol or more, the effect does not change, but a large amount of salt is generated at the time of neutralization. Cleaning is laborious and uneconomical. The preferred amount of alkali used is 1.0 to 1.0 units per anhydroglucose unit of cellulose.
1.4 moles. The mercerization is preferably performed at 10 to 15 ° C. for 1 to 4 hours.

Next, propylene oxide is reacted with the alkali cellulose obtained as described above. The propylene oxide used in the present invention is from 1.1 to 5.0 moles per anhydrous glucose unit of cellulose. Also,
The reaction needs to be carried out at 50 to 75 ° C. for 2 to 5 hours in order to obtain a hydroxypropyl substitution degree of 0.2 to 0.9. If the reaction time is less than 2 hours, a sufficient degree of substitution of the low-substitution HPC cannot be obtained, resulting in poor solubility in an aqueous alkali solution.

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-substituted HPC thus obtained is
It has 0.2 to 0.9 mole of hydroxypropyl group per anhydroglucose unit, and has very good film forming ability, film strength,
Has tablet disintegration properties. JP-B-57-59857 describes that HPC having a hydroxypropyl group number of 0.05 to 0.4 per glucose unit is preferable. The reason is that if it is 0.05 or less, the solubility in an aqueous alkali solution is deteriorated, while if it is 0.4 or more, the solubility in water is increased, so that the function as a disintegrant is impaired. However, the low-substituted HPC obtained by the present inventors shows that even when the hydroxypropyl group substitution degree is 0.4 or more, the solubility in water does not increase, while it is almost completely dissolved in an aqueous alkaline 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, it is presumed that since the alkali concentration is high, the hydroxyl group at the 6-position of glucose reacts selectively, resulting in a difference in solubility.

[0013]

EXAMPLES 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 linter pulverized by 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 the mixture was mercerized for 1 hour with stirring. At this time, the ratio of t-butyl alcohol to the total of t-butyl alcohol and water was 89%. After mercerization, 5 mol of propylene oxide was added per anhydrous glucose unit, and the reaction was carried out at 70 ° C. for 3 hours. After the reaction, the mixture was cooled, neutralized with nitric acid, drained, and washed four times with 400 parts by weight of a 70% by weight acetone aqueous solution. After washing, it was dried at 105 ° C.

The properties of the low-substitution HPC thus obtained are shown in Table 1. In addition, it is the property of HPC with a low degree of substitution.
The methods for measuring (1) hydroxypropyl substitution degree (MS), (2) aqueous solution viscosity and (3) aqueous solution transparency are as follows. (1) Degree of substitution: Determined by oxidatively decomposing a hydroxypropyl group using chromium trioxide or liberating and iodinating a hydroxypropyl group using 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, it is simply described as viscosity in the table. (3) Transparency of aqueous solution: A high-quality glass plate with a thickness of 2 mm adhered to the bottom of a glass cylinder with a height of 350 mm, an inner diameter of 25 mm and a thickness of 2 mm as an outer tube, a height of 300 mm, an inner diameter of 15 mm, and a thickness A 2 mm thick glass cylinder with a 2 mm thick good quality glass plate attached to the bottom is used as the inner tube.
When 15 parallel lines with 1 mm spacing are placed on a white sheet of black paper and the upper tube is moved up and down to see through from the top, measure the height to the lower end of the inner tube when lines cannot be identified. I do.
The average value obtained by repeating this operation three times is expressed in mm.
In the table, it is simply described as transparency.

Example 2 and Comparative Example 1 A low-substitution HPC was produced in exactly 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-substitution HPC are shown in Table 1 together with the results of Example 1.
In Comparative Example 1 performed for a long time, a sufficient degree of substitution was not obtained, and the transparency of the alkaline aqueous solution was very poor.

[0017]

[Table 1]

Examples 3 to 5 and Comparative Example 2 After the hydroxypropylation reaction was carried out at 60 ° C. for 1 hour,
° C and the reaction time was changed as shown in Table 2 below, except that the low-substitution HPC was changed in exactly the same manner as in Example 1.
Was manufactured. Table 2 shows the properties of the obtained low-substitution HPC.
As shown in Comparative Example 2, when the reaction was carried out at 60 ° C. for 1 hour as in Comparative Example 2, a sufficient degree of substitution was not obtained, and the product was hardly dissolved in the aqueous alkaline solution.

[0019]

[Table 2]

Examples 6 to 8 and Comparative Example 3 During the hydroxypropylation reaction, the amounts of propylene oxide charged were 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. Produced a low-substitution HPC in exactly the same manner as in Example 1. The properties of the obtained low-substitution HPC are shown in Table 3. 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. Hardly dissolved in the aqueous alkali solution.

[0021]

[Table 3]

COMPARATIVE EXAMPLE 4 A charged amount of caustic soda was 0.75 per anhydroglucose unit.
Except for the molar amount, the low substitution HP
C was produced. The substitution degree of the obtained low substitution degree HPC is
Since 0.14 was not a sufficient degree of substitution, the product hardly dissolved in the aqueous alkali solution.

COMPARATIVE EXAMPLE 5 The amount of caustic soda was adjusted to 1.8 per anhydroglucose unit.
Except for the molar amount, the low substitution HP
C was produced. The substitution degree of the obtained low substitution degree HPC is
Since 0.18 was not a sufficient degree of substitution, the product was hardly dissolved in the aqueous alkali solution.

Comparative Example 6 A low-substitution HPC was produced in the same manner as in Example 1 except that the ratio of tertiary butyl alcohol to the total of tertiary butyl alcohol and water was changed to 80%. Since the degree of substitution of the obtained low-degree of substitution HPC was 0.07, which was not a sufficient degree of substitution, the product was hardly dissolved in the aqueous alkali solution.

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

Examples 9 and 10 The solubility of the low-substitution HPCs of the present invention obtained in Examples 3 and 4 in water was compared. Table 4 shows the results.

[0027]

[Table 4]

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

[0029]

[Table 5]

From Table 5, it can be seen that the low-substituted HPC obtained by the present invention has a slightly higher water-soluble content than the commercially available low-substituted HPC even though the low-substituted HPC has a lower degree of substitution than the commercially available low-substituted HPC. It can be seen that the solubility in an aqueous alkali solution is extremely excellent.

Example 11 and Comparative Examples 9 and 10 The low-substitution HPC shown in Examples 3 and 2 and Comparative Example 8 was dissolved in an 8% aqueous sodium hydroxide solution at a concentration of 7%.
And then left to cool to a temperature of 0 ° C., cast on a glass plate, coagulate in a 20% ammonium sulfate aqueous solution, and remove salts by washing with water.
The film was dried at 70 ° C. to produce a film. The 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 evaluation of transparency, ◎ means good, Δ means normal, and × means bad. Table 6 shows the results.

[0032]

[Table 6]

From Table 6, it can be seen that the film comprising the low-substitution HPC of the present invention is superior in transparency and uniformity to the film of the comparative example.

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

[0035]

[Table 7]

Table 7 shows that the tablet of Example 12 is superior in disintegration and hardness to the tablets of Comparative Examples 11 and 12.

Claims (2)

(57) [Claims] (1) a hydroxypropyl substitution degree of 0.2 to 0.9;
Low-substituted hydroxypropylcellulose having high solubility in an alkaline aqueous solution having a viscosity at 25 ° C. of a 2% by weight solution in an 8% by weight aqueous sodium hydroxide solution of not less than 1000 centipoise. 2. A mixed medium comprising 85 to 92% by weight of tertiary butyl alcohol and the balance of water is mixed with respect to the weight of cellulose.
After reacting 10 to 20 times by weight and 0.8 to 1.5 mol of alkali per anhydrous glucose unit of cellulose with cellulose to obtain alkali cellulose, 1.1 to 5.0 mol of propylene oxide per anhydrous glucose unit of cellulose is added to 50%. The method for producing low-substituted hydroxypropylcellulose according to claim 1, wherein the reaction is carried out at -70 ° C for 2-5 hours.