JPS59166503A - Carboxymethylcellulose derivative and its preparation - Google Patents

Abstract

PURPOSE:To produce the titled novel derivative useful as a disintegration agent capable of giving a tablet having excellent property, by reacting CMC having substituent group with calcium carbonate in wet state. CONSTITUTION:The objective derivative of formula II (M is Ca; a part of M may be H) is obtained by reacting (A) a substituted carboxymethylcellulose of formula I (Gul is skeleton of anhydrous glucose unit C6H7O2 of cellulose; OR and OR' are ether, ester, etc.; n is >=50) with (B) calcium carbonate in wet state. The component A is prepared preferably by synthesizing a carboxymethylcellulose Na salt having substituent group by conventional process, and converting the product to the free acid with an aqueous solution of an acid.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel cellulose derivatives having two or three types of ether or ester substituents, one of which is a calcium carboxymethyl group which may contain a free acid, and their preparation. It is about the method.

Calcium salts of carboxymethyl cellulose are insoluble in water, but have the property of swelling and dispersing in water, making it easier to disintegrate solids containing this in water. However, due to its poor binding properties, it has the disadvantage of being prone to capping during tablet compression depending on the active ingredient and other physical properties. As a result of various studies, the present inventors found that carboxymethylcellulose calcium The present invention was achieved by discovering that the above-mentioned drawbacks could be improved by introducing a different type of ester group or ether group into the salt. Carboxymethylcellulose calcium salts having such substituents have not been known at all so far.

That is, the present invention relates to the general formula (where Gul represents an anhydroglucose unit skeleton of cellulose 06H702, and OR and OR' are the same as -
or a different ether group, ester group or hydroxyl group (
However, the case where both OR and OR' are hydroxyl groups is excluded), and M is Oa or H (however, all M are H
), n represents a number of 50 or more. ) Substituted carboxymethylcellulose calcium salt represented by:

The present invention also provides a general formula (where Gum represents an anhydroglucose unit skeleton of cellulose C6H702, and OR and OR' are the same as -
or different ether, ester or hydroxyl groups (
However, the case where both OR and OR' are hydroxyl groups is excluded), and n indicates a number of 50 or more. ) In the general formula (1), OR, OR' As the substituent represented by, an alkyl ether group having 5 or less carbon atoms,
A hydroxyalkyl ether group and an alkyl ester group having 5 or less carbon atoms are included, and these two types may be present as substituents at the same time.

In implementing the method for producing a substituted carboxymethylcellulose 5-scalcium salt of the present invention, first, a carboxymethylcellulose sodium salt having a substituent is synthesized. The synthesis method includes, for example,
No. 8751, Special Publication No. 18586, Special Publication No. 18586, Special Publication No. 18586-
Methods shown in prior patent documents such as No. 15678 and USF2476551 can be used.

Next, the carboxymethylcellulose sodium salt having a substituent is treated with an acid aqueous solution to form a free acid. Suitable acids to be used include mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, and phosphoric acid, and lower fatty acids such as acetic acid. When using a mineral acid, it is desirable to treat it at a low concentration of 15 chloride or less and at a temperature of 20C or less in order to avoid side reactions. The acid treatment is followed by washing with water to remove the generated salt and excess acid to obtain the free acid of carboxymethyl cellulose in a wet state. The free acid is once dried and re-wetted by adding water until the moisture content in the wet material is 30~30%.
After adjusting the concentration to 80%, powdered calcium carbonate is mixed and a neutralization reaction is performed with 30 to 40 U to obtain a calcium salt. When the quantitative relationship of moisture can be determined separately, the step of drying and rewetting the wet free acid can be omitted. In this case, the amount of calcium carbonate is preferably equivalent to or less than the equivalent amount to the free acid of carboxymethyl cellulose. In this case, a portion of the carboxymethyl group will remain in the free acid form.

When the thus obtained substituted carboxymethylcellulose calcium salt is used as a disintegrant for pharmaceutical tablets, it enables tablet formulations with better tablet physical properties than conventional unsubstituted carboxymethylcellulose calcium salts. It's something.

The present invention will be explained below with reference to Examples, but the present invention is not limited thereto.

Example 1 Powdered carboxymethyl cellulose sodium salt (degree of carboxymethyl substitution DS 0.49.1 part Viscosity 118 c
ps) 50 t to t-butanol 528.9? After dispersing the mixture in a mixed system of 63.5 r of water, 21.9 f of a 50% sodium chloride aqueous solution was added and stirred at 15 tl' for 45 minutes. Thereafter, 24.5 f of propylene oxide was added, and the mixture was reacted at 50C for 1 hour and then at 70C for 1 hour.

After the reaction was completed, the caustic soda was neutralized with acetic acid, washed twice with 80% methanol, and dried. The degree of substitution (MS) of hydroxypropyl group per anhydroglucose unit of the produced carboxymethylhydroxypropyl cellulose is 0.20
Met. Next, this derivative was treated with 10-thiosulfuric acid, washed with water, deliquified, the moist water was replaced with acetone, and the mixture was vacuum-dried. After drying, 55 parts of water was added to 40 parts of the powdered sample (by weight, same hereinafter), and after mixing well, 4 parts of calcium carbonate powder was added, and the mixture was stirred and reacted at a temperature of 50 to 40 C for 2 hours. After the reaction was completed, the mixture was dried and ground. This product is a carboxymethyl hydroxypropylcellulose calcium salt, and the degree of substitution of carboxymethyl is D80.4.
9. The degree of substitution of hydroxypropyl was MS 0.20. The infrared absorption spectrum (TER spectrum) of this product is shown in FIG. For comparison, the second R spectrum of commercially available carboxymethyl cellulose calcium salt was
Shown in the figure.

Example 2 Powdered carboxymethyl cellulose sodium salt (degree of substitution DSO 849, viscosity 118 cps) 50 g!
and t-butanol 52B, 91. After dispersing in a mixed system of 66.52% water, add 5oq6 caustic soda aqueous solution 21.9%
f was added and stirred at 15C for 45 minutes. After that, 5.5f of ethylene oxide was added and the mixture was reacted at 60C for 1.5 hours. After the reaction was completed, the caustic soda was neutralized with acetic acid, washed twice with 80-thimethanol, and dried. The degree of substitution (MS) of hydroxyethyl groups per anhydroglucose unit of the produced carboxymethyl hydroxyethyl cellulose was 0.25. Next, this derivative was treated with 1096 sulfuric acid, washed with water, deliquified, wet water was replaced with a7ton, and vacuum dried. After drying, 80 parts of water was added to 50 parts of the powdered sample, and after mixing well, 4.9 parts of calcium carbonate powder was added, and the mixture was stirred at 30 to 40 C for 2 hours to react. After the reaction was completed, it was dried and pulverized. The product was a carboxymethyl hydroxyethyl cellulose calcium salt, with a carboxymethyl substitution degree DS of 0.49 and a hydroxyethyl substitution degree MS of 0.25. The R spectrum of this product is shown in FIG.

Example 5 After dispersing powdered carboxymethyl cellulose sodium salt (degree of substitution DB 0.64.1, viscosity 1850 cps) 4952 in 2264 t of toluene in an autoclave,
While stirring, 320v of 50% ethanol aqueous solution was gradually added. Thereafter, after adding flaky caustic soda 1421 and stirring well, the autoclave was purged with nitrogen, 260 V of methyl chloride was added, the autoclave was closed, and the reaction was carried out for 1 hour at aOC and 2 hours at 90C. After the reaction was completed, the mixture was neutralized with acetic acid, the liquid was removed, and the mixture was washed three times with 80-thimethanol. The degree of substitution DS of the methoxyl 10-group of the produced carboxymethylmethyl cellulose was 0.7. Next, add this derivative to 1
After treating with 0% sulfuric acid and washing with water, the solution was dehydrated, directly replaced with acetone, and dried in vacuum. After drying, add 80 parts of water to 50 parts of the powdered sample, mix well, and add 5 parts of calcium carbonate powder.
．． 7 parts were added, and the mixture was stirred and reacted at a temperature of 50 to 40C for 2 hours. After the reaction was completed, it was dried and pulverized. The product is carboxymethyl methylcellulose calcium salt, with a carboxymethyl substitution degree DS of 0.64 and a methoxyl substitution degree D of 80.
．． It was 7. The R spectrum of this product is shown in FIG. Mock tablets were molded using the carboxymethylmethyl cellulose calcium salt obtained in this example as a disintegrant.

The tablet composition is as follows.

Lactose: 100 parts Disintegrant: 10 Calcium sularate: 0.5 Talc: 0.5 Tablets with a diameter of B mm and a thickness of 4 mm were molded by a direct compression method under a compression pressure of 2000 kg. For comparison, tablets using a commercially available carboxymethyl cellulose calcium salt as a disintegrant were compressed. Monsando hardness is 2.2 for the product of the present invention
kg, compared with 1.4 plums, and there was no significant difference in the rate of disintegration in water.

Example 4 Degree of carboxymethyl substitution (DS) 0.65 Nocarboxymethylcellulose sodium salt 50f was added to 20 sulfuric acid 1
．． After soaking in 5 barrels at room temperature for 2 hours and washing with water, acetic acid 1.5 IQ
The sample was washed three times with acetic acid and the moist water was replaced with acetic acid to make it wet with acetic acid.

After removing the liquid, put it into a small kneader and add 250 g of acetic acid and 5.6 g of sulfuric acid. , add acetic anhydride 1501, 48-50C
It reacted for 4 hours. As the reaction progressed, the raw materials dissolved in the reaction medium and became a homogeneous system. The reaction solution was added to water and the resulting precipitate was thoroughly washed with water and dried under vacuum. The degree of diacetylation of the product was measured by a saponification method and found to be DS 2.54. After drying, 15 parts of water was added to 10 parts of the powdered sample, and after mixing well, 0.8 parts of calcium carbonate powder was added and reacted at a temperature of 60 to 40C for 2 hours. After the reaction was completed, it was dried and pulverized. The product was carpoquine methyl acetylcellulose calcium salt, with a carboxymethyl substitution degree DS of 0.63 and an acetyl substitution degree D of 82.54. The R spectrum of this product is shown in FIG.

Example 5 514 vol (containing 23 ml of water) of carboxymethylcellulose sodium salt having a degree of carboxymethyl substitution (DB) of 0.52 was added to an autoclave together with 2194 t of toluene, and while stirring, 460 t of an aqueous 50% ethanol solution was added, followed by flaky caustic soda. After adding 4042,
After adding 1005r of ethyl chloride and purging with nitrogen, the autoclave was sealed and reacted at 120C for 6 hours. After the reaction, the mixture was cooled to around room temperature, and further added with flaky caustic soda 2252, and reacted at 120C for 6 hours. After the reaction was completed, the solution was deliquified and the wet solvent was evaporated, treated with 10elD sulfuric acid, thoroughly washed with water, and deliquified. The dehydrated sample was vacuum dried. The degree of ethoxyl substitution Ds of this carboxymethylethylcellulose 15- was 2.0. After drying,
Add 100 parts of water to 100 parts of the powdered sample, mix well, add 8 parts of calcium carbonate powder, and heat at a temperature of 30 to 4.
The mixture was stirred at 0°C for 2 hours to react. After the reaction was completed, it was dried and pulverized. The product is a carboxymethyl ethylcellulose calcium salt with a degree of carboxymethyl substitution DsO, 52
, the degree of ethoxyl substitution D82.0. The R spectrum of this product is shown in FIG.

[Brief explanation of the drawing]

FIG. 1 is the product of Example 1, FIG. 2 is the commercially available carboxymethyl cellulose calcium salt, and FIGS. 3-6 are the R spectra of the products of Examples 2-5, respectively. Applicant's agent Kaoru Furuya 14-

Claims (1)

[Claims] 1 General formula (in the formula, Gul represents an anhydroglucose unit skeleton of cellulose, C6H702, and OR and OR' are the same -
or different ether, ester or hydroxyl groups (
However, the case where both OR and OR' are hydroxyl groups is excluded), and M is Oa or H (however, all M are H
), n represents a number of 50 or more. ) Substituted carboxymethylcellulose calcium salt represented by: 2. The substituted carboxymethylcellulose calcium salt according to claim 1, wherein the ether group or ester group represented by 0R, OR' is an alkyl ether group, hydroxyalkyl ether group, or haalkyl ester group having 5 or less carbon atoms. . 5 general formula (in the formula, Gul represents the anhydroglucose unit skeleton of cellulose 06H, 02, and OR and OR' are the same -
or different ether, ester or hydroxyl groups (
However, ○R and OR' are both hydroxyl groups), and n is a number of 50 or more. ) A patent characterized in that substituted carboxymethyl cellulose represented by is H) A method for producing a substituted carboxymethylcellulose calcium salt represented by: