Title of Invention	"A METHOD FOR PURIFICATION OF HYDROXYPROPYLMETHYL CELLULOSE PHTHALATE"
Abstract	The present invention relates to a purification method of hydroxypropylmethyl cellulose phthalate, more particularly to a method of preparing high-purity hydroxypropylmethyl cellulose phthalate through a simple crushing process which comprises: increasing fluidity of reaction product mixture by adding fluidization solvent as a post-treatment process; and spraying it into water through a spray nozzle. As a result, formation of fine granular hydroxypropylmethyl cellulose phthalate particles prevents inter-particle coagulation during the a post-treatment process, and phthalic anhydride reactant, free phthalic acid and remaining acetic acid solvent can be removed effectively.

Title of Invention

"A METHOD FOR PURIFICATION OF HYDROXYPROPYLMETHYL CELLULOSE PHTHALATE"

Abstract

The present invention relates to a purification method of hydroxypropylmethyl cellulose phthalate, more particularly to a method of preparing high-purity hydroxypropylmethyl cellulose phthalate through a simple crushing process which comprises: increasing fluidity of reaction product mixture by adding fluidization solvent as a post-treatment process; and spraying it into water through a spray nozzle. As a result, formation of fine granular hydroxypropylmethyl cellulose phthalate particles prevents inter-particle coagulation during the a post-treatment process, and phthalic anhydride reactant, free phthalic acid and remaining acetic acid solvent can be removed effectively.

Full Text	Field of the Invention The present invention relates to a method for purification of hydroxypropylmethyl cellulose phthalate. More particularly, the invention relates to a method of preparing high-purity hydroxypropylmethyl cellulose phthalate through a simple crushing process which comprises increasing fluidity of reaction product mixture by adding fluidization solvent as a post-treatment process; and spraying it into water through a spray nozzle. As a result, formation of fine granular hydroxypropylmethyl cellulose phthalate particles prevents inter-particle coagulation during the post-treatment process, and phthalic anhydride reactant, free phthalic acid and remaining acetic acid solvent can be removed effectively. Background of the invention: Generally, cellulose and its derivatives are used for pharmaceuticals, foods, cosmetics and construction additives. Among these, hydroxypropylmethyl cellulose phthalate is used as a filler of enteric coatings, because it is relatively stable in acidic condition. This hydroxypropylmethyl cellulose phthalate is prepared by esterification of hydroxypropylmethyl cellulose with phthalic anhydride in the presence of sodium acetate in acid solvent to bind phthalic acid to one end of the cellulose molecule. One of such examples is US Patent No. 3,629,237, which discloses a method of preparing hydroxypropylmethyl cellulose phthalate by mixing hydroxypropylmethyl cellulose phthalic anhydride and sodium acetate in acetic acid solvent, carrying out reaction at 80°C for 5hr, and making the product mixtures as slurry in water. In this method, it is more important to remove, free phthalic acid, and residual acetic_acid_s.olvent through a suitable post-treatment rather than the synthesis itself, in order to obtain pure granular hydipxypropy lmethyl cellulose phthalate. It is because if acetic acid and free phthalic acid are present in the reaction product mixture, it becomes very hard during drying process. As a result, crushing of final product becomes very difficult, and the product may be yellowed or it may smell of acetic acid. Also, when tablets or pellets are coated with a filler, the coating solution is not formed easily due to low solubility and the product stability becomes poor because of decomposition, due to acetic acid or free phthalic acid. Therefore, it is essential to entirely remove acetic acid and to reduce free phthalic acid content: Because free phthalic acid can be formed from decomposition of phthalyl group in HPMCP it is the most important to reduce free phthalic acid content at early stage. Standard for free phthalic acid regulated by pharmacopeias of many countries is less than 1.0%, and most pharmaceutical companies are demanding much lower standard. What is more, because hydroxypropylmethyl cellulose phthalate is an excipient used as filler like enteric coatings, high-purity product with low impurity level is highly required. In order to effectively remove these impurities, it is required to prevent coagulation of hydroxypropylmethyl cellulose phthalate particles, so that impurities like phthalic acid and acetic acid present between the particles can contact with water and be washed away. In the conventional preparing method of hydroxypropylmethyl cellulose phthalate, cold water was poured to the reaction product mixture in order to remove the impurities. However, from this method, hydroxypropylmethyl cellulose phthalate in fine powder or granule cannot be obtained because inter-particle coagulation is very severe. This inter-particle coagulation prevents water from penetrating between the particles, so that it becomes difficult to effectively remove phthalic acid and acetic acid. And, additional crushing process is required to obtain granular product. As described above, the conventional preparing method of hydroxypropylmethyl cellulose phthalate requires a crushing process in order to effectively remove impurities, which is troublesome in practice. Therefore, it is highly required to include this crushing process in a post-treatment method in a natural way. OBJECTS OF THE INVENTION: Accordingly, an object of the present invention is to provide a preparing method of high-purity hydroxypropylmethyl cellulose phthalate by forming fine-granular particles to prevent inter-particle coagulation and effectively removing free phthalic acid and acid solvent in the product. STATEMENT OF INVENTION: Accordingly, the invention provides a method for purification of hydroxypropylmethyl cellulose phthalate comprising the steps of: a) reacting hydroxypropylmethyl cellulose, alkali acetate, phthalic anhydride and alkali chlorate in an acetic acid. isolvent to obtain hydroxypropylmethyl celluloseMas reaction product mixture, b) adding 2-4 wt% of a fluidization solvent to the product of step (a) , the solvent being selected from water and a lower alcohol having C1-C5 carbon atoms, c) spraying the product of step (b) into 10-20 wt. % of water through a spray nozzle whose pressurization speed is 3-81/min to obtain fine particles, and d) hydroxypropylmethyl cellulose phthalate in high purity by stirring, filtering and drying. Hereunder is given a more detailed description of the invention. The present invention is a new technology, of purifying hydroxypropylmethyl cellulose phthalate in high purity for preparing hydroxypropylmethyl cellulose phthalate from low-molecular-weight cellulose or its derivatives wherein a suitable amount of fluidization solvent is added to the reaction product mixture to enhance fluidity of the,reaction product mixture, and it is sprayed into water through a spray nozzle in order to obtain fine-granular particles. In the present invention, hydroxypropylmethyl cellulose phthalate is prepared through synthesis and purification processes. Hereunder is given a more detailed description of each process. In the synthesis process, lwt.% of hydroxypropylmethyl cellulose is added to 3-6wt.% of cetic acid solvent and dissolved. Then, after adding 0.4-1wt.% of alkali acetate, 0.5-1.3wt.% of phthalic anhydride and 0.01-0.05wt.% of alkali chlorate, the mixture is stirred slowly at 60-85 °C for 4-6hr in order to obtain hydroxypropylmethyl cellulose phthalate. For said hydroxypropylmethyl cellulose, the one whose viscosity in 2%-aqueous solution 3-20 cps and whose chloride content is lower than 0.4% is recommended For said alkali acetate, sodium acetate or potassium acetate is recommended and, for said alkali chlorate, sodium chlorate or potassium chlorate is recommended] -not chearly worded In the purification process, remaining unreacted phthalic anhydride and phthalic acid_and.acetic..acid solvent are removed. This process is core of the present invention.. To the reaction product mixture obtained from the synthesis process, 2-4wt.% of fluidization solvent Cfor lwt.% of hydroxypropylmethyl cellulose) is. added and stirred to enhance fluidity_of the reaction product mixture. then. it is sprayed to 10-20wt.% of water through a spray nozzle, stirred for 2-10min, and dried for 4-6hr at 60-75 °C to obtain high-purity hydroxypropylmethyl cellulose phthalate. In this purification process, hydroxypropylmethyl cellulose phthalate dissolved in acetic acid becomes solid when it contacts with water to form fine granular particles, which prevent inter-particle coagulation of hydroxypropylmethyl cellulose phthalate. As a result, free phthalic acid and acetic acid solvent can be removed effectively. For said fluidization solvent, the one selected from water or G1-C5 low alcohols can be used. For said water, purified".water can be used; and for said C1-C5 low alcohols, methanol of ethanol can be used. If the amount of the fluidization solvent is below 2wt.%, impurities like acetic acid and free phthalic acid may remain in hydroxypropylmethyl cellulose phthalate particles; and if it exceeds 4wt.%, spraying becomes impossible due to solidification of hydroxypropylmethyl cellulose phthalate. Also, if the amount of water to which the reaction product mixture is sprayed is below 10wt.%, the high acetic acid concentration in the reaction product mixture renders dissolution of surface particles of the solid hydroxypropylmethyl cellulose phthalate, which causes re-coagulation of the particles. Otherwise, if it exceeds 20wt.%, a large amount of waste water is generated. For said spray nozzle, the one with 0.5-1.5mm of internal diameter and whose air or nitrogen gas pressurizatiori speed is 3-81/ min is recommended. If the internal diameter of the spray nozzle is smaller than 0.5mm, the productivity becomes poor because only small amount of reaction product mixture can be treated for unit time. Otherwise, if it exceeds 1.5mm, air or nitrogen gas pressurization speed should be increased. And, if the air or nitrogen gas pressurization speed is below 3£/min, the particle size is increased and impurities are held between the particles. Otherwise, if it exceeds 8C/min, an excess amount of nitrogen should be used and hydroxypropylmethyl cellulose phthalate sticks on the reactor wall, so that a large amount of product, is lost. Hydroxypropylmethyl cellulose phthalate obtained from this method contains 30-34% of phthalyl content and only 0.05-0.2% of free phthalic acid. And, particle size of the purified hydroxypropylmethyl cellulose phthalate is 50-300 meshes (300-50um). As explained above, the preparing method of purification method of hydroxypropylmethyl cellulose phthalate according to the present invention effectively removes free phthalic acid and reaction solvent remaining in the final product by preventing inter-particle coagulation of hydroxypropylmethyl cellulose phthalate. The following examples are intended to be illustrative of the present invention and should not be construed as limiting the scope of this invention. Example 1 25g of hydroxypropylmethyl cellulose (2% aqueous solution; viscosity: 4.25cps) was added in iDOg of acetic acid solvent and dissolved slowly. When hydroxypropylmethyl cellulose was spread uniformly in acetic acid, 25g of sodium acetate, 32.5g of phthalic anhydride and 0.25g of potassium chlorate were added. After raising temperature to S0-85°C, the mixture was stirred slowly for 5hr. After the reaction was completed,100g of water was added while keeping the temperature at 80-85°C, and the reaction product mixture was stirred for 30min. After fluidizing the reaction product mixture, it was sprayed into 500g of water through a spray nozzle. After spraying was completed, the reaction product mixture was stirred for five more minutes, and was filtered with pure water. Then the product was dried for 4-6hr at 60-75 °C to obtain pure dry granular hydroxypropylmethyl cellulose phthalate. Analysis of the prepared hydroxypropylmethyl cellulose phthalate according to methods proclaimed hi Korean Pharmacopoeia (KP7), United States Pharmacopoeia (USP24) and European Pharmacopoeia (EP348) showed that it contains 33.4% of phthalyl content and only 0.07% of free phthalic acid. Example 2 25g of hydroxypropylmethyl cellulose (2% aqueous solution; viscosity: 16cps) was added in 75g of acetic acid solvent and dissolved slowly. When hydroxypropylmethyl cellulose was spread uniformly in acetic acid, 25g of sodium acetate, 32.5g of phthalic anhydride and 0.5g of potassium chlorate were added. After raising temperature to 80-85 °C, the mixture was stirred slowly for 5hr. After the reaction was completed, 75g of water was added while keeping the temperature at 80-85°C, and the reaction product mixture was stirred for 30min.. After fluidizing the reaction product mixture, it was sprayed into 500g of water through a spray nozzle. After spraying was completed, the reaction product mixture was stirred for five more minutes, and was filtered with pure water. Then the product was dried for 4-6hr at 60-75 °C to obtain pure dry granular hydroxypropylmethyl cellulose phthalate. Analysis of the prepared hydroxypropylmethyl cellulose phthalate according to methods proclaimed in Korean Pharmacopoeia (KP7), United States Pharmacopoeia (USP24) and European Pharmacopoeia (EP348) showed that it contains 32.7% of phthalyl content and only 0.10% of free phthalic acid. Example 3 25g of hydroxypropylmethyl cellulose (viscosity: 6.25cps) was added in 125g of acetic acid solvent and dissolved slowly. When hydroxypropylmethyl cellulose ether was spread uniformly in acetic acid, 25g of sodium acetate, 32.5g of phthalic anhydride and 0.3g of potassium chlorate were added. After raising temperature to 80-85 °C, the mixture was stirred slowly for 5hr. After the reaction was completed, 50g of methanol was added while keeping the temperature at 80-85 °C, and the reaction product mixture was stirred for 30min. After fluidizing the reaction product mixture; it was sprayed into 500g of water through a spray nozzle." After spraying was completed, the reaction product mixture was stirred for five more minutes, and was filtered with pure water. Then the product was dried for 4-6hr at 60-75 "C to obtain pure dry granular hydroxypropylmethyl cellulose phthalate. Analysis of the prepared hydroxypropylmethyl cellulose phthalate according to methods proclaimed in Korean Pharmacopoeia (KP7), United States Pharmacopoeia (USP24) and European Pharmacopoeia (EP348) showed that it contains 33.1% of phthalyl contnet and only 0.12% of free phthalic acid. Example 4 100g of hydroxypropylmethyl cellulose (viscosity: 13.78cps) was added in 500g of acetic acid solvent and dissolved slowly. When hydroxypropylmethyl cellulose ether was spread uniformly in acetic acid, lOOg of sodium acetate, 130g of phthalic anhydride and 2.5g of potassium chlorate were added. After raising temperature to 80-85 °C, the mixture was stirred slowly for 5hr. After the reaction was completed, 250g of water was added while keeping the teinperature at 80-85 °C, and the reaction product mixture was stirred for 30min. After fluidizing the reaction product mixture, it was sprayed into 1000g of water through a spray nozzle. After spraying was completed, the reaction product mixture was stirred for five more minutes, and was filtered with pure water. Then the product was dried for 4-6hr at 60-75 "C to obtain pure dry granular hydroxypropylmethyl cellulose phthalate. Analysis of the prepared hydroxypropylmethyl cellulose phthalate according to methods proclaimed in Korean Pharmacopoeia (KP7), United States Pharmacopoeia (USP24) and European Pharmacopoeia (EP348) showed that it contains 33.7% of phthalyl content and only 0.08% of free phthalic acid. Comparative Example 50g of hydroxypropylmethyl cellulose (viscosity: 15-100cps) was added in 200g of acetic acid solvent and dissolved slowly. When hydroxypropylmethyl cellulose was spread uniformly in acetic acid, 50g of sodium acetate, 60g of phthalic anhydride and 5g of potassium chlorate were added. After raising temperature to 80-85°C, the mixture was stirred slowly for 5hr. After the reaction was completed, the reaction product mixture was sprayed into 200g of water. After spraying was completed, the reaction product mixture was stirred for five more minutes, and was filtered with pure water. Then the product was dried for 4-6hr at 60-75 °C to obtain hydroxypropylmethyl cellulose phthalate. Analysis of the prepared hydroxypropylmethyl cellulose phthalate showed that it contains 33.2% of phthalyl contnet. However, it also contained as much as 0.82% of free phthalic acid and 3% of remaining acetic acid. From these examples, it was confirmed that high-purity hydroxypropylmethyl cellulose phthalate can be obtained by, after synthesizing hydroxypropylmethyl cellulose phthalate, enhancing fluidity of the reaction product mixture with water or low alcohols and spraying it into water through a spray nozzle. As explained in detail above, the present invention provides a preparing method of high-purity hydroxypropylmethyl cellulose phthalate by reducing particle size through a special spraying method under a specific condition, which prevents inter-particle coagulation of hydroxypropylmethyl cellulose phthalate and effectively removes phthalic acid and acetic acid remaining in the final product. We claim: 1. A method for purification of hydroxypropylmethyl cellulose phthalate comprising the steps of: a) reacting hydroxypropylmethyl cellulose, alkali acetate, phthalic anhydride and alkali chlorate in an acetic acid solvent to obtain hydroxypropylmethyl cellulose phthalate as reaction product mixture, b) adding 2-4 wt% of a fluidization solvent to the product of step (a) , based on lwt% of hydroxypropylmethyl cellulose phthalate, the solvent being selected from water and a lower alcohol having C1-C5 carbon atoms, c) spraying the product of step (b) into 10-20 wt% % of water through a spray nozzle whose pressurization speed is 3-81/min to obtain fine particles of hydroxypropylmethyl cellulose phthalate in high purity, optionally stirring, filtering and drying to obtain the phthalate. 2. A method as claimed in claim 1, wherein the hydroxypropylmethyl cellulose phthalate has 3-20cps of 2% aqueous solution viscosity and less than 0.4% of chloride content. 3. A method as claimed in claim 1, wherein said alkali acetate is sodium acetate or potassium acetate. 4. A method as claimed in claim 1, wherein the alkali chlorate is sodium chlorate or potassium chlorate. 5. A method as claimed in claim 1, wherein the fluidization solvent is water. 6. A method as claimed in claim 1, wherein the alcohol is selected from methanol and ethanol. 7. A method as claimed in claim 1, wherein the internal diameter of said spray nozzle is 0.5-1.5mm. 8. A method as claimed in claim 1, wherein the particle size of purified hydroxypropylmethyl cellulose phthalate is of mesh size 50-300, corresponding to 300-50 um. 9. A method for purification of hydroxypropylmethyl cellulose phthalate, substantially as herein described and illustrated with reference to the examples.

Full Text

Field of the Invention
The present invention relates to a method for purification of hydroxypropylmethyl cellulose phthalate. More particularly, the invention relates to a method of preparing high-purity hydroxypropylmethyl cellulose phthalate through a simple crushing process which comprises increasing fluidity of reaction product mixture by adding fluidization solvent as a post-treatment process; and spraying it into water through a spray nozzle. As a result, formation of fine granular hydroxypropylmethyl cellulose phthalate particles prevents inter-particle coagulation during the post-treatment process, and phthalic anhydride reactant, free phthalic acid and remaining acetic acid solvent can be removed effectively.
Background of the invention:
Generally, cellulose and its derivatives are used for pharmaceuticals, foods, cosmetics and construction additives. Among these, hydroxypropylmethyl cellulose phthalate is used as a filler of enteric coatings, because it is relatively stable in acidic condition. This hydroxypropylmethyl cellulose phthalate is prepared by esterification of hydroxypropylmethyl cellulose with phthalic anhydride in the presence of sodium acetate in acid solvent to bind phthalic acid to one end of the cellulose molecule. One of such examples is US Patent No. 3,629,237, which discloses a method of preparing hydroxypropylmethyl cellulose phthalate by mixing hydroxypropylmethyl cellulose phthalic anhydride and sodium acetate in acetic acid solvent, carrying out reaction at 80°C for 5hr, and making the product mixtures as slurry in water.
In this method, it is more important to remove, free phthalic acid, and residual acetic_acid_s.olvent through a suitable post-treatment rather than the synthesis itself, in order to obtain pure granular hydipxypropy lmethyl cellulose phthalate. It is because if acetic acid and free phthalic acid are present in the reaction product mixture, it becomes very hard during drying process. As a result, crushing of final product becomes very difficult, and the product may be yellowed or it may smell of acetic acid. Also, when tablets or pellets are coated with a filler, the coating solution is not formed easily due to low solubility and the product stability becomes poor because of decomposition, due to acetic acid or free phthalic acid. Therefore, it is essential to entirely remove acetic acid and to reduce free phthalic acid content: Because free phthalic acid can be formed from decomposition of phthalyl group in HPMCP it is the most important to reduce free phthalic acid content at early stage. Standard for free phthalic acid regulated by pharmacopeias of many countries is less than 1.0%, and most pharmaceutical companies are demanding much lower standard. What is more, because hydroxypropylmethyl cellulose phthalate is an excipient used as filler like enteric coatings, high-purity product with low impurity level is highly required.
In order to effectively remove these impurities, it is required to prevent coagulation of hydroxypropylmethyl cellulose phthalate particles, so that impurities like phthalic acid and acetic acid present between the particles can contact with water and be washed away.
In the conventional preparing method of hydroxypropylmethyl cellulose phthalate, cold water was poured to the reaction product mixture in order to remove the impurities. However, from this method, hydroxypropylmethyl cellulose phthalate in fine powder or granule cannot be obtained because inter-particle coagulation is very severe. This inter-particle coagulation prevents water from penetrating between the particles, so that it becomes difficult to effectively remove phthalic acid and acetic acid. And,
additional crushing process is required to obtain granular product.
As described above, the conventional preparing method of hydroxypropylmethyl cellulose phthalate requires a crushing process in order to effectively remove impurities, which is troublesome in practice. Therefore, it is highly required to include this crushing process in a post-treatment method in a natural way.
OBJECTS OF THE INVENTION:
Accordingly, an object of the present invention is to provide a preparing method of high-purity hydroxypropylmethyl cellulose phthalate by forming fine-granular particles to prevent inter-particle coagulation and effectively removing free phthalic acid and acid solvent in the product. STATEMENT OF INVENTION:
Accordingly, the invention provides a method for purification of hydroxypropylmethyl cellulose phthalate comprising the steps of:
a) reacting hydroxypropylmethyl cellulose, alkali acetate, phthalic anhydride and alkali chlorate in an acetic acid. isolvent to obtain hydroxypropylmethyl celluloseMas reaction product mixture,
b) adding 2-4 wt% of a fluidization solvent to the product of step (a) , the solvent being selected from water and a lower alcohol having C1-C5 carbon atoms,
c) spraying the product of step (b) into 10-20 wt. % of water through a spray nozzle whose pressurization speed is 3-81/min to obtain fine particles, and
d) hydroxypropylmethyl cellulose phthalate in high purity by stirring, filtering and drying.
Hereunder is given a more detailed description of the invention.
The present invention is a new technology, of purifying hydroxypropylmethyl cellulose phthalate in high purity for preparing hydroxypropylmethyl cellulose phthalate from low-molecular-weight cellulose or its derivatives wherein a suitable amount of fluidization solvent is added to the reaction product mixture to enhance fluidity of the,reaction product mixture, and it is sprayed into water through a spray nozzle in order to obtain fine-granular particles.
In the present invention, hydroxypropylmethyl cellulose phthalate is prepared through synthesis and purification processes. Hereunder is given a more detailed description of each process.
In the synthesis process, lwt.% of hydroxypropylmethyl cellulose is added to 3-6wt.% of cetic acid solvent and dissolved. Then, after adding 0.4-1wt.% of alkali acetate, 0.5-1.3wt.% of phthalic anhydride and 0.01-0.05wt.% of alkali chlorate, the mixture is stirred slowly at 60-85 °C for 4-6hr in order to obtain hydroxypropylmethyl cellulose phthalate.
For said hydroxypropylmethyl cellulose, the one whose viscosity in 2%-aqueous solution 3-20 cps and whose chloride content is lower than 0.4% is recommended For said alkali acetate, sodium acetate or potassium acetate is recommended and, for said alkali chlorate, sodium chlorate or potassium chlorate is recommended] -not chearly worded
In the purification process, remaining unreacted phthalic anhydride and phthalic acid_and.acetic..acid solvent are removed. This process is core of the present invention.. To the reaction product mixture obtained from the synthesis process, 2-4wt.% of fluidization solvent Cfor lwt.% of hydroxypropylmethyl cellulose) is. added and stirred to enhance fluidity_of the reaction product mixture. then. it is sprayed to 10-20wt.% of water through a spray nozzle, stirred for 2-10min, and dried for 4-6hr at 60-75 °C to obtain high-purity hydroxypropylmethyl cellulose phthalate. In this purification process, hydroxypropylmethyl cellulose phthalate dissolved in acetic acid becomes solid
when it contacts with water to form fine granular particles, which prevent inter-particle coagulation of hydroxypropylmethyl cellulose phthalate. As a result, free phthalic acid and acetic acid solvent can be removed effectively. For said fluidization solvent, the one selected from water or G1-C5 low alcohols can be used. For said water, purified".water can be used; and for said C1-C5 low alcohols, methanol of ethanol can be used. If the amount of the fluidization solvent is below 2wt.%, impurities like acetic acid and free phthalic acid may remain in hydroxypropylmethyl cellulose phthalate particles; and if it exceeds 4wt.%, spraying becomes impossible due to solidification of hydroxypropylmethyl cellulose phthalate. Also, if the amount of water to which the reaction product mixture is sprayed is below 10wt.%, the high acetic acid concentration in the reaction product mixture renders dissolution of surface particles of the solid hydroxypropylmethyl cellulose phthalate, which causes re-coagulation of the particles. Otherwise, if it exceeds 20wt.%, a large amount of waste water is generated. For said spray nozzle, the one with 0.5-1.5mm of internal diameter and whose air or nitrogen gas pressurizatiori speed is 3-81/ min is recommended. If the internal diameter of the spray nozzle is smaller than 0.5mm, the productivity becomes poor because only small amount of reaction product mixture can be treated for unit time. Otherwise, if it exceeds 1.5mm, air or nitrogen gas pressurization speed should be increased. And, if the air or nitrogen gas pressurization speed is below 3£/min, the particle size is increased and impurities are held between the particles. Otherwise, if it exceeds 8C/min, an excess amount of nitrogen should be used and hydroxypropylmethyl cellulose phthalate sticks on the reactor wall, so that a large amount of product, is lost.
Hydroxypropylmethyl cellulose phthalate obtained from this method contains 30-34% of phthalyl content and only 0.05-0.2% of free phthalic acid. And, particle size of the purified hydroxypropylmethyl cellulose phthalate is 50-300 meshes (300-50um).
As explained above, the preparing method of purification method of hydroxypropylmethyl cellulose phthalate according to the present invention effectively removes free phthalic acid and reaction solvent remaining in the final product by preventing inter-particle coagulation of hydroxypropylmethyl cellulose phthalate.
The following examples are intended to be illustrative of the present invention and should not be construed as limiting the scope of this invention.
Example 1
25g of hydroxypropylmethyl cellulose (2% aqueous solution; viscosity: 4.25cps) was added in iDOg of acetic acid solvent and dissolved slowly. When hydroxypropylmethyl cellulose was spread uniformly in acetic acid, 25g of sodium acetate, 32.5g of phthalic anhydride and 0.25g of potassium chlorate were added. After raising temperature to S0-85°C, the mixture was stirred slowly for 5hr. After the reaction was completed,100g of water was added while keeping the temperature at 80-85°C, and the reaction product mixture was stirred for 30min. After fluidizing the reaction product mixture, it was sprayed into 500g of water through a spray nozzle. After spraying was completed, the reaction product mixture was stirred for five more minutes, and was filtered with pure water. Then the product was dried for 4-6hr at 60-75 °C to obtain pure dry granular hydroxypropylmethyl cellulose phthalate.
Analysis of the prepared hydroxypropylmethyl cellulose phthalate according to methods proclaimed hi Korean Pharmacopoeia (KP7), United States Pharmacopoeia (USP24) and European Pharmacopoeia (EP348) showed that it contains 33.4% of phthalyl content and only 0.07% of free phthalic acid.
Example 2
25g of hydroxypropylmethyl cellulose (2% aqueous solution; viscosity: 16cps) was added in 75g of acetic acid solvent and dissolved slowly. When
hydroxypropylmethyl cellulose was spread uniformly in acetic acid, 25g of sodium acetate, 32.5g of phthalic anhydride and 0.5g of potassium chlorate were added. After raising temperature to 80-85 °C, the mixture was stirred slowly for 5hr. After the reaction was completed, 75g of water was added while keeping the temperature at 80-85°C, and the reaction product mixture was stirred for 30min.. After fluidizing the reaction product mixture, it was sprayed into 500g of water through a spray nozzle. After spraying was completed, the reaction product mixture was stirred for five more minutes, and was filtered with pure water. Then the product was dried for 4-6hr at 60-75 °C to obtain pure dry granular hydroxypropylmethyl cellulose phthalate.
Analysis of the prepared hydroxypropylmethyl cellulose phthalate according to methods proclaimed in Korean Pharmacopoeia (KP7), United States Pharmacopoeia (USP24) and European Pharmacopoeia (EP348) showed that it contains 32.7% of phthalyl content and only 0.10% of free phthalic acid.
Example 3
25g of hydroxypropylmethyl cellulose (viscosity: 6.25cps) was added in 125g of acetic acid solvent and dissolved slowly. When hydroxypropylmethyl cellulose ether was spread uniformly in acetic acid, 25g of sodium acetate, 32.5g of phthalic anhydride and 0.3g of potassium chlorate were added. After raising temperature to 80-85 °C, the mixture was stirred slowly for 5hr. After the reaction was completed, 50g of methanol was added while keeping the temperature at 80-85 °C, and the reaction product mixture was stirred for 30min. After fluidizing the reaction product mixture; it was sprayed into 500g of water through a spray nozzle." After spraying was completed, the reaction product mixture was stirred for five more minutes, and was filtered with pure water. Then the product was dried for 4-6hr at 60-75 "C to obtain pure dry granular hydroxypropylmethyl cellulose phthalate.
Analysis of the prepared hydroxypropylmethyl cellulose phthalate according to methods proclaimed in Korean Pharmacopoeia (KP7), United States Pharmacopoeia (USP24) and European Pharmacopoeia (EP348) showed that it contains 33.1% of phthalyl contnet and only 0.12% of free phthalic acid.
Example 4
100g of hydroxypropylmethyl cellulose (viscosity: 13.78cps) was added in 500g of acetic acid solvent and dissolved slowly. When hydroxypropylmethyl cellulose ether was spread uniformly in acetic acid, lOOg of sodium acetate, 130g of phthalic anhydride and 2.5g of potassium chlorate were added. After raising temperature to 80-85 °C, the mixture was stirred slowly for 5hr. After the reaction was completed, 250g of water was added while keeping the teinperature at 80-85 °C, and the reaction product mixture was stirred for 30min. After fluidizing the reaction product mixture, it was sprayed into 1000g of water through a spray nozzle. After spraying was completed, the reaction product mixture was stirred for five more minutes, and was filtered with pure water. Then the product was dried for 4-6hr at 60-75 "C to obtain pure dry granular hydroxypropylmethyl cellulose phthalate.
Analysis of the prepared hydroxypropylmethyl cellulose phthalate according to methods proclaimed in Korean Pharmacopoeia (KP7), United States Pharmacopoeia (USP24) and European Pharmacopoeia (EP348) showed that it contains 33.7% of phthalyl content and only 0.08% of free phthalic acid.
Comparative Example
50g of hydroxypropylmethyl cellulose (viscosity: 15-100cps) was added in 200g of acetic acid solvent and dissolved slowly. When hydroxypropylmethyl cellulose was spread uniformly in acetic acid, 50g of sodium acetate, 60g of phthalic anhydride and 5g of potassium chlorate were added. After raising temperature to 80-85°C, the mixture was stirred slowly for
5hr. After the reaction was completed, the reaction product mixture was sprayed into 200g of water. After spraying was completed, the reaction product mixture was stirred for five more minutes, and was filtered with pure water. Then the product was dried for 4-6hr at 60-75 °C to obtain hydroxypropylmethyl cellulose phthalate.
Analysis of the prepared hydroxypropylmethyl cellulose phthalate showed that it contains 33.2% of phthalyl contnet. However, it also contained as much as 0.82% of free phthalic acid and 3% of remaining acetic acid.
From these examples, it was confirmed that high-purity hydroxypropylmethyl cellulose phthalate can be obtained by, after synthesizing hydroxypropylmethyl cellulose phthalate, enhancing fluidity of the reaction product mixture with water or low alcohols and spraying it into water through a spray nozzle.
As explained in detail above, the present invention provides a preparing method of high-purity hydroxypropylmethyl cellulose phthalate by reducing particle size through a special spraying method under a specific condition, which prevents inter-particle coagulation of hydroxypropylmethyl cellulose phthalate and effectively removes phthalic acid and acetic acid remaining in the final product.

We claim:
1. A method for purification of hydroxypropylmethyl cellulose phthalate comprising the steps of:
a) reacting hydroxypropylmethyl cellulose, alkali acetate, phthalic anhydride and alkali chlorate in an acetic acid solvent to obtain hydroxypropylmethyl cellulose phthalate as reaction product mixture,
b) adding 2-4 wt% of a fluidization solvent to the product of step (a) , based on lwt% of hydroxypropylmethyl cellulose phthalate, the solvent being selected from water and a lower alcohol having C1-C5 carbon atoms,
c) spraying the product of step (b) into 10-20 wt% % of water through a spray nozzle whose pressurization speed is 3-81/min to obtain fine particles of hydroxypropylmethyl cellulose phthalate in high purity, optionally stirring, filtering and drying to obtain the phthalate.
2. A method as claimed in claim 1, wherein the
hydroxypropylmethyl cellulose phthalate has 3-20cps of
2% aqueous solution viscosity and less than 0.4% of
chloride content.
3. A method as claimed in claim 1, wherein said alkali
acetate is sodium acetate or potassium acetate.
4. A method as claimed in claim 1, wherein the alkali
chlorate is sodium chlorate or potassium chlorate.
5. A method as claimed in claim 1, wherein the
fluidization solvent is water.
6. A method as claimed in claim 1, wherein the alcohol is selected from methanol and ethanol.
7. A method as claimed in claim 1, wherein the internal diameter of said spray nozzle is 0.5-1.5mm.
8. A method as claimed in claim 1, wherein the particle size of purified hydroxypropylmethyl cellulose phthalate is of mesh size 50-300, corresponding to 300-50 um.
9. A method for purification of hydroxypropylmethyl
cellulose phthalate, substantially as herein described and illustrated with reference to the examples.

Documents:

« Previous Patent

Next Patent »

Patent Number

217622

Indian Patent Application Number

1694/DELNP/2003

PG Journal Number

17/2008

Publication Date

25-Apr-2008

Grant Date

28-Mar-2008

Date of Filing

16-Oct-2003

Name of Patentee

SUMSUNG FINE CHEMICALS CO. LTD.,

Applicant Address

190, YEOCHEON-DONG, NAM-KU, ULSAN 680-090, REPUBLIC OF KOREA

Inventors:

#	Inventor's Name	Inventor's Address
1	CHO, KYU-IL	106-906 HYANGCHON APT., DOONSAN-DONG, DAEJEON 302-776, REPUBLIC OF KOREA

PCT International Classification Number

A61K 9/28

PCT International Application Number

PCT/KR02/00580

PCT International Filing date

2002-04-02

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2001-21076	2001-04-19	Republic of Korea