KR20000062186A - Preparation of a Low Substituted Hydroxypropylcellulose - Google Patents

Abstract

In the production of low-substituted hydroxypropyl cellulose, the water content of the low-substituted hydroxypropyl cellulose, particularly after the cleaning and purification process after the completion of the reaction, is reduced, while reducing the amount of heat required in the subsequent drying step, Detergency can be improved.

Provided is a method for producing low-substituted hydroxypropyl cellulose, characterized in that the temperature at the time of dissolution neutralization is 60 ° C. or higher in the process of dissolving and neutralizing the reaction product during the production of low-substituted hydroxypropyl cellulose.

Description

Preparation method of low-substituted hydroxypropyl cellulose {Preparation of a Low Substituted Hydroxypropylcellulose}

The present invention relates to a method for producing low-substituted hydroxypropyl cellulose which is added to impart disintegrating or binding property to a pharmaceutical or food preparation.

Solid formulations, such as granules or tablets in the pharmaceutical or food sectors, are formulated with only the main pharmaceutical components, which do not achieve sufficient disintegration even when the drug is administered, and thus do not exhibit sufficient drug efficacy or poor binding properties. There is a problem such as not being able to. In order to solve this problem, the addition of low-substituted hydroxypropyl cellulose during formulation has imparted disintegration or binding properties. For this purpose, in addition to the low-substituted hydroxypropyl cellulose, for example, carboxymethyl cellulose and its calcium salt, cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, carboxymethyl starch and the like are used. Among these, low-substituted hydroxypropyl cellulose is nonionic, and thus has the advantage of less deterioration due to interaction with ionic chemicals and the like.

Therefore, the preparation such as granules or tablets, using the above-described advantages, dry-mixing the powder of low-substituted hydroxypropyl cellulose with the active ingredient or other excipients of the medicine and then tableting or kneading with an aqueous solution of water or water-soluble binder It is formulated by assembling.

In order to prepare a low-substituted hydroxypropyl cellulose added to impart disintegration or binding property in such a formulation, first, the raw pulp is immersed in an aqueous solution of caustic soda, and then the alkali cellulose obtained by pressing is reacted with propylene oxide. Or an alkali cellulose obtained by adding an aqueous solution of caustic soda to pulverized pulp in an organic solvent such as isopropyl alcohol, tert-butyl alcohol, hexane, or propylene oxide. Subsequently, the obtained crude reaction product is dispersed and dissolved in water, and the remaining alkali is neutralized with an acid.

In addition, the apparent density of the low-substituted hydroxypropyl cellulose can be adjusted by neutralizing and dissolving some of the residual alkali before the neutralization reaction (see Japanese Patent Publication No. 57-53100).

Finally, in order to remove salts and other impurities generated in the above-described process steps, washing and purification using water or hot water are carried out, and the purified products are compressed to remove moisture and then dried and pulverized. Finally, low-substituted hydroxypropyl cellulose is obtained.

However, such low-substituted hydroxypropyl cellulose is insoluble in water, collapses by absorbing and swelling in water, and has a peculiar property that is excellent in water-retaining property. For this reason, the conventional low-substituted hydroxypropyl cellulose production method has a problem in that the water content of the product after washing and purifying with water or hot water is high, so that a large amount of heat is required in the subsequent drying process and productivity is lowered.

The present invention has been made in view of the above circumstances, and an object thereof is to reduce the water content of low-substituted hydroxypropyl cellulose in the production of low-substituted hydroxypropyl cellulose, particularly after the cleaning and purification step after the completion of the reaction.

According to an aspect of the present invention for achieving the above object, the low substitution degree, characterized in that the temperature at the time of dissolution neutralization in the process of dissolving and neutralizing the reaction product in the production of low-substituted hydroxypropyl cellulose A method for producing hydroxypropyl cellulose is provided. According to the method of the present invention, since the moisture content of the low-substituted hydroxypropyl cellulose decreases, the amount of heat required in the subsequent drying step is reduced, and the reduction rate of ash per unit water content is improved. In addition, the filtration time is also shortened, thereby reducing the production cost by improving the detergency of the low-substituted hydroxypropyl cellulose.

EMBODIMENT OF THE INVENTION Hereinafter, embodiment of this invention is described. In addition, this invention is not limited only to the following embodiment.

As the low-substituted hydroxypropyl cellulose of the present invention, the number of substituted moles of hydroxypropoxyl groups per anhydroglucose unit is preferably 0.1 to 0.5. If the number of substituted moles of the hydroxypropoxy group is less than 0.1, the desired bondability is not exhibited. On the other hand, if the number of substituted moles of the hydroxypropoxy group exceeds 0.5, the desired disintegration property is not exhibited. There is a fear that the time required for collapse will be too long.

Referring to the method of producing a low-substituted hydroxypropyl cellulose of the present invention in detail. First, the raw material pulp is immersed in 10 to 50% by weight of a caustic soda aqueous solution, and then the alkali cellulose and propylene oxide obtained by pressing are reacted at 20 to 90 ° C for about 2 to 8 hours. Alternatively, the powdered pulp is dissolved in an organic solvent such as isopropyl alcohol, tert-butyl alcohol, hexane, an aqueous solution of caustic soda is added to prepare an alkali cellulose, and propylene oxide is added to the alkali cellulose for reaction. This gives a crude reaction product.

Thereafter, hot water of 60 ° C. or higher is added to a known dissolution apparatus such as a kneader-type mixer or a vertical mixer, and the crude reaction product is dissolved therein for a predetermined time while being maintained at 60 ° C. or higher, and then neutralized with an acid. Here, since the low-substituted hydroxypropyl cellulose is precipitated in the form of spouting water by treating the alkaline solution of the low-substituted hydroxypropyl cellulose at a high temperature of 60 ° C or higher, the water content of the dehydrated purified product is lowered, and at the time of washing As water drainage improves, washing | cleaning property also improves.

The temperature at the time of the said neutralization of a solution is 60 degreeC or more, Preferably 60-100 degreeC is suitable. If the temperature at the time of melt | dissolution neutralization is less than 60 degreeC, the water content of the dehydrated refined | purified product will be high and water drainage at the time of washing will worsen. On the other hand, if the temperature at the time of dissolution neutralization exceeds 10 ° C., there may be a problem such that the degree of polymerization of the low-substituted hydroxypropyl cellulose is lowered or discoloration of the final product occurs.

The amount of water or hot water used in dissolving the low-substituted hydroxypropyl cellulose of the present invention is preferably 2 to 20 parts by weight, particularly 4 to 10 parts by weight, per 1 part by weight of anhydrous cellulose. When the amount of the dissolved water is less than 2 parts by weight, the solution of the reactant becomes highly viscous, so that it is difficult to uniformly dissolve low-substituted hydroxypropyl cellulose, and when the amount of the dissolved water exceeds 20 parts by weight, the device necessary for dissolution is At the same time, there is a problem that the water content of the dehydrated purified product increases.

In addition, the solubility of low-substituted hydroxypropyl cellulose can also be adjusted by neutralizing and dissolving a part of residual alkali before adding the acid separately before neutralization.

The acid used in the neutralization step is not particularly limited, and any acid can be used, and examples thereof include organic acids such as acetic acid, formic acid and propionic acid, and inorganic acids such as hydrochloric acid and sulfuric acid. The use concentration of such acid is not particularly limited and can be freely selected, but a range of 10 to 50% by weight is preferable.

Thereafter, the precipitate obtained in the above step is diluted with water or hot water to obtain a slurry, and the slurry is washed according to a conventional method such as vacuum filtration or pressure filtration. The purified product thus obtained is compressed, dried and pulverized according to a conventional method. That is, the low substituted hydroxypropyl cellulose powder which is a final product can be obtained by carrying out compression dehydration by pressure compression, drying with a stationary oven or a fluidized bed dryer, and then pulverizing using an impact mill, a ball mill, or the like.

The obtained low-substituted hydroxypropyl cellulose powder is formulated into granules or tablets by dry mixing with active ingredients of pharmaceuticals or other excipients and the like, or by granulating by mixing with an aqueous solution of water or a water-soluble binder.

Hereinafter, although an Example and a comparative example demonstrate this invention further in detail, this invention is not limited to these Examples.

Example 1

The raw material pulp was immersed in 43 wt% caustic soda solution, and then compressed to obtain alkaline cellulose having a composition of 22.2 wt% sodium hydroxide, 44.8 wt% cellulose, and 33.0 wt% moisture. 350 g of alkaline cellulose was charged into a 5 liter reactor in terms of cellulose, and the reactor was replaced with nitrogen gas. After substitution, 79 g of propylene oxide (0.226 parts by weight relative to cellulose) was added to the reactor, followed by reaction at 45 ° C. for 2 hours at 65 ° C. for 30 minutes, and low substitution having hydroxypropoxy group substitution mole number of 0.25 per anhydroglucose unit. 860 g of crude reaction product of hydroxypropyl cellulose were obtained.

Thereafter, 1925 g of hot water (5.5 parts by weight based on cellulose) at 65 ° C. was added to the kneader, 52 g of glacial acetic acid (0.2 moles based on alkali) was added, and then all the reaction products were dispersed therein. Subsequently, the reaction product was dissolved for 30 minutes while maintaining the temperature at 65 ° C, and then, while maintaining the same temperature, 631 g of 33% by weight of acetic acid was added for 30 minutes to neutralize and precipitate. The following dehydration test and washing test were performed on the precipitated low-substituted hydroxypropyl cellulose, and the results are shown in Table 1.

1. Dehydration test

The obtained low-substituted hydroxypropyl cellulose was diluted with hot water at 60 ° C. so as to be a 4 wt% slurry, compressed with a strength tester (manufactured by Makagawa Co., Ltd.) for 1 t and 1 minute to perform dehydration operation. Thereafter, the dehydrated product was dried at 105 ° C. for 4 hours, and its weight change yielded the water content after dehydration of the product.

2. Cleaning test

The obtained low-substituted hydroxypropyl cellulose was diluted with hot water at 60 ° C. so as to obtain a 4 wt% slurry, and the slurry was pressurized at 49 kPa with a pressure filter to perform a dehydration operation. Thereafter, 50 g of hot water at 80 ° C. was added to carry out the same dehydration operation. This dehydration operation was performed three times, and the washability was evaluated by calculating the average filtration time and the ash content for the third purified product in these three dehydration operations.

Example 2

The alkali cellulose used in Example 1 was reacted with propylene oxide in the same manner as in Example 1 to obtain a low-substituted hydroxypropyl cellulose having a number of moles of hydroxypropoxy group substitution per unit of anhydroglucose. Thereafter, 1925 g of hot water at 55 ° C. (5.5 parts by weight based on cellulose) was added to Kneader, and 52 g of glacial acetic acid (0.2 mol based on alkali) was added thereto, and then all the reaction products were dispersed therein. Subsequently, the reaction product was dissolved for 30 minutes while maintaining the temperature at 70 ° C, followed by neutralization precipitation by adding 33% by weight of 631 g of acetic acid over 30 minutes while maintaining the same temperature. The dehydrated test and the washing test were carried out in the same manner as in Example 1 on the precipitated low-substituted hydroxypropyl cellulose, and the results are shown in Table 1.

Example 3

The alkali cellulose used in Example 1 was reacted with propylene oxide in the same manner as in Example 1 to obtain a low-substituted hydroxypropyl cellulose having a number of moles of hydroxypropoxy group substitution per unit of anhydroglucose. Thereafter, 1925 g of hot water (5.5 parts by weight based on cellulose) at 80 ° C. was added to the kneader, 52 g of glacial acetic acid (0.2 moles based on alkali) was added, and then all the reaction products were dispersed therein. Subsequently, the reaction product was dissolved for 30 minutes while maintaining the temperature at 80 ° C., and then, while maintaining the same temperature, 631 g of acetic acid at 33% by weight was added over 30 minutes to neutralize it. The dehydrated test and the washing test were carried out in the same manner as in Example 1 on the precipitated low-substituted hydroxypropyl cellulose, and the results are shown in Table 1.

Example 4

The raw pulp was immersed in 43 wt% caustic soda solution and then compressed to obtain alkaline cellulose having a composition of 24.1 wt% sodium hydroxide, 40.9 wt% cellulose, and 35.0 wt% moisture. 350 g of alkaline cellulose was charged into a 5 liter reactor in terms of cellulose, and the reactor was replaced with nitrogen gas. After substitution, 41 g of propylene oxide (0.116 parts by weight relative to cellulose) was added to the reactor, followed by reaction at 45 ° C. for 2 hours at 65 ° C. for 30 minutes, and low substitution having a number of moles of hydroxypropoxy group substitution per 0.1 g of anhydroglucose. 896 g of crude reaction product of hydroxypropyl cellulose were obtained. Thereafter, 2520 g of hot water at 65 ° C. (7.2 parts by weight based on cellulose) were placed in a kneader, and all the reaction products were dispersed therein. Subsequently, the reaction product was dissolved for 30 minutes while maintaining the temperature at 65 ° C, and then neutralized was precipitated by adding 33% by weight of 937 g of acetic acid over 30 minutes while maintaining the same temperature. The dehydrated test and the washing test were carried out in the same manner as in Example 1 on the precipitated low-substituted hydroxypropyl cellulose, and the results are shown in Table 1.

Example 5

The alkaline cellulose used in Example 1 was placed in a 5 liter reactor in an amount of 350 g in terms of cellulose, and the reactor was replaced with nitrogen gas. After substitution, 56 g of propylene oxide (0.116 parts relative to cellulose) was added to the reactor and reacted at 45 ° C. for 2 hours at 65 ° C. for 30 minutes to form a low-substituted hydride having 0.17 moles of hydroxypropoxy group substitution per anhydroglucose unit. 837 g of crude reaction product of oxypropyl cellulose were obtained. Thereafter, 2450 g of hot water at 65 ° C. (7.0 parts by weight based on cellulose) was added to the kneader, and all the reaction products were dispersed therein. Subsequently, the reaction product was dissolved for 30 minutes while maintaining the temperature at 65 ° C, and then neutralized was precipitated by adding 33% by weight of 937 g of acetic acid over 30 minutes while maintaining the same temperature. About the precipitated low substituted hydroxypropyl cellulose, the dehydration test and the washing test were performed like Example 1, and the result is shown in Table 1.

Example 6

The alkaline cellulose used in Example 1 was placed in a 5 liter reactor in an amount of 350 g in terms of cellulose, and the reactor was replaced with nitrogen gas. After substitution, 118.3 g of propylene oxide (0.338 parts by weight relative to cellulose) were added to the reactor, and the reaction was carried out at 45 ° C for 2 hours and at 65 ° C for 30 minutes. 899 g of crude reaction product of hydroxypropyl cellulose were obtained. Thereafter, 1750 g of hot water (5.0 parts by weight based on cellulose) at 80 ° C. was placed in the kneader, and all the reaction products were dispersed therein. Subsequently, the reaction product was dissolved for 30 minutes while maintaining the temperature at 80 ° C, and then neutralized was precipitated by adding 20% by weight of 778 g of hydrochloric acid over 30 minutes while maintaining the same temperature. The dehydrated test and the washing test were carried out in the same manner as in Example 1 on the precipitated low-substituted hydroxypropyl cellulose, and the results are shown in Table 1.

Comparative Example 1

The alkali cellulose used in Example 1 was reacted with propylene oxide in the same manner as in Example 1 to obtain a low-substituted hydroxypropyl cellulose having a number of moles of hydroxypropoxy group substitution per unit of anhydroglucose. Thereafter, 1925 g of water (5.5 parts by weight based on cellulose) at 30 ° C. was added to the kneader, and 52 g of glacial acetic acid (0.2 moles based on alkali) was added thereto, and then all the reaction products were dispersed therein. Subsequently, the reaction product was dissolved for 30 minutes while maintaining the temperature at 30 ° C, and then, while maintaining the same temperature, 631 g of acetic acid at 33% by weight was added over 30 minutes to neutralize the precipitate. The dehydrated test and the washing test were carried out in the same manner as in Example 1 on the precipitated low-substituted hydroxypropyl cellulose, and the results are shown in Table 1.

Comparative Example 2

The alkali cellulose used in Example 1 was reacted with propylene oxide in the same manner as in Example 1 to obtain a low-substituted hydroxypropyl cellulose having a number of moles of hydroxypropoxy group substitution per unit of anhydroglucose. Then, 1925 g of 40 degreeC water (5.5 weight part with respect to cellulose) was put into kneader, 52 g of glacial acetic acid (0.2 mol with respect to alkali) was added, and all the said reaction products were disperse | distributed here. Subsequently, the reaction product was dissolved for 30 minutes while maintaining the temperature at 40 ° C, and then, while maintaining the same temperature, 631 g of 33% by weight of acetic acid was added for 30 minutes to neutralize and precipitate. The dehydrated test and the washing test were carried out in the same manner as in Example 1 on the precipitated low-substituted hydroxypropyl cellulose, and the results are shown in Table 1.

Comparative Example 3

The alkali cellulose used in Example 4 was reacted with propylene oxide in the same manner as in Example 4 to obtain a low-substituted hydroxypropyl cellulose having a mole number of hydroxypropoxy group substitution mole per 0.1 g of anhydroglucose units. Thereafter, 2520 g of water at 25 ° C. (7.2 parts by weight based on cellulose) were added to Kneader, 52 g of glacial acetic acid (0.2 mole based on alkali) was added, and then all the reaction products were dispersed therein. Subsequently, the reaction product was dissolved for 30 minutes while maintaining the temperature at 25 ° C, and then neutralized was precipitated by adding 33% by weight of 937 g of acetic acid over 30 minutes while maintaining the same temperature. The dehydrated test and the washing test were carried out in the same manner as in Example 1 with respect to the precipitated low-substituted hydroxypropyl cellulose, and the results are shown in Table 1.

[Comparative Example 4]

The alkali cellulose used in Example 5 was reacted with propylene oxide in the same manner as in Example 5 to obtain a low-substituted hydroxypropyl cellulose having a mole number of hydroxypropoxy group substitution mole per 0.1 g of anhydroglucose units. Thereafter, 2450 g of water at 25 ° C. (7.0 parts by weight based on cellulose) were added to the kneader, and all the reaction products were dispersed therein. Subsequently, the reaction product was dissolved for 30 minutes while maintaining the temperature at 25 ° C, followed by neutralization precipitation by adding 33% by weight of 937 g of acetic acid over 30 minutes while maintaining the same temperature. About the precipitated low substituted hydroxypropyl cellulose, the dehydration test and the washing test were performed like Example 1, and the result is shown in Table 1.

Dehydration test Cleaning test Moisture content (% by weight) Filtration time Ash (% by weight) Example 1 69.2 32 0.33 Example 2 68.8 25 0.28 Example 3 67.4 23 0.26 Example 4 64.7 5 0.13 Example 5 66.5 8 0.19 Example 6 69.9 10 0.41 Comparative Example 1 80.8 140 3.82 Comparative Example 2 79.7 138 1.22 Comparative Example 3 75.3 60 0.65 Comparative Example 4 76.8 80 0.89

As can be seen from Table 1, in Examples 1 to 6, both the dehydration and the detergency of the final product were superior to the comparative example by reacting the reaction at a high temperature at the time of neutralization of dissolution.

As is clear from the above description, according to the present invention, since the water content of the low-substituted hydroxypropyl cellulose decreases during the production of the low-substituted hydroxypropyl cellulose, especially after the completion of the washing and purification process, the amount of heat required in the subsequent drying step Can be reduced. In addition, the production cost can be reduced by reducing the ash content per unit water content, shortening the filtration time, and improving the washability of the low-substituted hydroxypropyl cellulose.

Claims (1)

A method for producing low-substituted hydroxypropyl cellulose, characterized in that the temperature at the time of dissolution neutralization is 60 ° C. or higher in the step of dissolving and neutralizing the reaction product during the production of low-substituted hydroxypropyl cellulose.