Method for producing hydroxypropyl methyl cellulose acetate succinate

Abstract

Provided is a method for producing hydroxypropyl methyl cellulose acetate succinate in which an increase in particle density is suppressed and dissolution time is shortened, said method comprising at least a liquid removal step, a first drying step, and a second drying step, and in the first drying step, the hydroxypropyl methyl cellulose acetate succinate is dried by a fluidized bed dryer so that the product temperature does not exceed 28 DEG C until the moisture content of the hydroxypropyl methyl cellulose acetate succinate is 30 mass%.

Description

TECHNICAL FIELD

[0001] The present application relates to a production method of hydroxypropyl methylcellulose acetate succinate. BACKGROUND

[0002] As an enteric polymer, in addition to introducing two substituents of methyl (-CH3) and hydroxypropyl (-C3H6OH) to form an ether structure on a cellulose skeleton, it is also known that hydroxypropyl methylcellulose acetate succinate (hereinafter also referred to as "HPMCAS") is a polymer in which two substituents of acetyl (-COCH3) and succinyl (-COC2H4COOH) are introduced to form an ether structure on a cellulose skeleton, a total of four substituents being introduced.

[0003] HPMCAS is widely used for coating of tablets, release control of drugs, and for use with poorly water-soluble drugs to prepare solid dispersions by a hot melt extrusion method or a spray drying method.

[0004] In general, when coating or spray drying is performed, it is first necessary to dissolve HPMCAS alone or both a drug and HPMCAS in a solvent. At this time, there is a problem that dissolution of HPMCAS requires a long time, and a production of HPMCAS having improved solubility is sought.

[0005] As a method for improving the solubility of HPMCAS, a method including a step of continuously or intermittently feeding a reaction liquid containing HPMCAS into water to generate particles is proposed in Patent Literature 1. PRIOR ART DOCUMENTS PATENT LITERATURE

[0006] Patent Literature 1: Japanese Patent Application Laid-Open No. 2017-501239 SUMMARY PROBLEMS TO BE SOLVED BY THE INVENTION

[0007] However, in the method described in Patent Literature 1, it is necessary to add water in an amount of 12 to 20 times the total weight of the reaction medium to the reaction liquid after the reaction before the precipitation step is performed, and since a large amount of water is discharged, there are problems in terms of manufacturing cost and environmental load. In addition, there is room for improvement in terms of the solubility of HPMCAS particles obtained by the production method. The present application was completed in view of the above circumstances, and aims to provide a production method of hydroxypropyl methylcellulose acetate succinate in which the increase in particle density is suppressed, and a production method of hydroxypropyl methylcellulose acetate succinate in which the dissolution time is shortened. SOLUTION TO PROBLEM

[0008] As a result of the intensive studies made by the present inventors in order to solve the above problems, it has been found that, as the drying step, two steps of a first drying step of drying the hydroxypropyl methylcellulose acetate succinate to a moisture content of 30 mass% by a fluidized bed dryer so that the product temperature does not exceed 28°C to obtain first dried HPMCAS and a second drying step of further drying the first dried HPMCAS to obtain HPMCAS, even if meticulous material management and manufacturing management are not performed, the increase in the particle density after drying can be suppressed, the dissolution time of HPMCAS in a solvent is improved, and thus the present invention has been completed. According to the present invention, there is provided a method for producing hydroxypropyl methylcellulose acetate succinate. [1] A method for producing hydroxypropyl methylcellulose acetate succinate, comprising at least: a de-liquoring step of de-liquoring a suspension of hydroxypropyl methylcellulose acetate succinate obtained by mixing the reaction solution with water after reacting hydroxypropyl methylcellulose with an acetylating agent and a succinylating agent in the presence of a catalyst to obtain de-liquored hydroxypropyl methylcellulose acetate succinate; a first drying step of drying the de-liquored hydroxypropyl methylcellulose acetate succinate by a fluidized bed dryer so that the product temperature does not exceed 28°C to a moisture content of 30 mass% to obtain first dried hydroxypropyl methylcellulose acetate succinate; and a second drying step of further drying the first dried hydroxypropyl methylcellulose acetate succinate to obtain hydroxypropyl methylcellulose acetate succinate. [2] The method for producing hydroxypropyl methylcellulose acetate succinate according to [1], wherein the product temperature of the hydroxypropyl methylcellulose acetate succinate in the first drying step is 5 to 28°C. [3] The method for producing hydroxypropyl methylcellulose acetate succinate according to [1] or [2], wherein the air supply temperature in the first drying step is 5 to 70°C. [4] The method for producing hydroxypropyl methylcellulose acetate succinate according to any one of [1] to [3], wherein the dryer used in the second drying step is a fluidized bed dryer. [5] The method for producing hydroxypropyl methylcellulose acetate succinate according to any one of [1] to [4], wherein the moisture content of the de-liquored hydroxypropyl methylcellulose acetate immediately before being introduced into the first drying step is 55 to 80 mass%. [6] The method for producing hydroxypropyl methylcellulose acetate succinate according to any one of [1] to [5], wherein The water content of the hydroxypropyl methylcellulose acetate succinate is 5% by mass or less. Effects of the Invention

[0009] According to the present application, by adjusting only the product temperature at the time of the drying process by the fluidized bed dryer, it is possible to suppress an increase in the particle density of the HPMCAS particles, which are a material weak to heat. Thus, by adjusting the product temperature at the time of the first drying process, it is possible to obtain HPMCAS having a low bulk density. In addition, since the obtained HPMCAS has a low particle density, it is possible to greatly shorten the dissolution time, and the production capacity of an HPMCAS solution or a mixed solution of a medicament and HPMCAS is improved. Furthermore, since there is no need to change the existing manufacturing equipment, it is possible to immediately introduce. DETAILED DESCRIPTION

[0010] The production method of the HPMCAS of the present application has at least a liquid-removing process, a first drying process, and a second drying process. The production method of the HPMCAS of the present application can also have a cleaning process as needed.

[0011] [LIQUID-REMOVING PROCESS] In the liquid-removing process, first, hydroxypropyl methylcellulose is reacted with an acetylating agent and a succinoylating agent in the presence of a catalyst to produce a reaction solution (esterification process), then the reaction solution is mixed with water to produce a hydroxypropyl methylcellulose acetate succinate suspension (precipitation process), and further the hydroxypropyl methylcellulose acetate succinate suspension is subjected to liquid removal to obtain a liquid-removed hydroxypropyl methylcellulose acetate succinate.

[0012] Hereinafter, a method for obtaining hydroxypropyl methylcellulose (hereinafter referred to as "HPMC") which is a raw material of HPMCAS will be described. The HPMC can be either HPMC obtained by a known method or a commercially available product. The HPMC can be obtained, for example, by forming alkali cellulose from a solution of an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide by bringing into contact with pulp in the form of a sheet, a fragment, or a powder, and then adding an etherifying agent such as methyl chloride and propylene oxide to perform a reaction.

[0013] The solution of an alkali metal hydroxide used in the production of alkali cellulose is not particularly limited as long as it can obtain alkali cellulose having a desired composition, but from the viewpoint of economy, an aqueous solution of sodium hydroxide or potassium hydroxide is preferred. In addition, from the viewpoint of stabilizing the composition of alkali cellulose and ensuring the transparency of cellulose ether, the aqueous solution concentration is 23 to 60% by mass, and more preferably 35 to 55% by mass.

[0014] After the production of the alkali cellulose, an etherifying agent such as methyl chloride and propylene oxide is added to the alkali cellulose in accordance with a conventional method to perform an etherification reaction, thereby obtaining HPMC.

[0015] The DS of the methoxyl group in the HPMC is preferably 1.10 to 2.20, more preferably 1.40 to 2.00, and further preferably 1.60 to 2.00 from the viewpoint of obtaining HPMC having a small number of non-dissolved fibers. The MS of the hydroxypropoxyl group in the HPMC is preferably 0.10 to 1.00, more preferably 0.20 to 0.80, and further preferably 0.20 to 0.65 from the viewpoint of obtaining HPMC having a small number of non-dissolved fibers. The non-dissolved fiber is a portion of the HPMC that is not dissolved in water. The HPMC exhibits water solubility by etherifying a portion of the hydroxyl group of cellulose to weaken the hydrogen bonds within and between the molecules of cellulose. Since it is industrially difficult to perform etherification completely uniformly, the HPMC can contain a portion that is not dissolved in water due to insufficient substitution degree of the ether group or uneven substitution of the ether group, that is, can contain non-dissolved fibers. If a large amount of non-dissolved fibers are contained in the finally obtained HPMCAS, the enteric coating film becomes uneven, the yield of the enteric coated preparation decreases, or the clogging of the filter frequently occurs in the filtration process of the coating solution, which leads to a decrease in the production rate, and therefore, the HPMC used as the raw material of the HPMCAS is preferably HPMC having a small number of non-dissolved fibers. The number of non-dissolved fibers can be obtained by analyzing an aqueous solution of the HPMC with a device such as a Coulter counter, for example. Note that the DS of the methoxyl group in the HPMC indicates the degree of substitution (Degree of Substitution) and is the average number of methoxyl groups per 1 unit of anhydrous glucose. The MS of the hydroxypropoxyl group in the HPMC indicates the molar substitution (Molar Substitution) and is the average number of moles of the hydroxypropoxyl group per 1 mole of anhydrous glucose. The DS of the methoxyl group and the MS of the hydroxypropoxyl group in the HPMC can be obtained by converting the values obtained by the determination based on the 18th revised edition of the Japanese Pharmacopoeia.

[0016] The viscosity of a 2 mass% aqueous solution of the HPMC at 20°C is preferably 2.2 to 7.2 mPa-s, and more preferably 3.0 to 3.5 mPa-s from the viewpoint of the kneadability at the time of performing the esterification reaction. The viscosity of a 2 mass% aqueous solution of the HPMC at 20°C can be measured in accordance with the capillary viscometer method of the 18th revised edition of the Japanese Pharmacopoeia.

[0017] From the viewpoint of economy, the catalyst for the esterification step is preferably a carboxylic acid alkali metal salt such as sodium acetate. From the viewpoint of the composition (degree of substitution) and yield of the obtained HPMCAS, the amount of the catalyst is preferably 0.1 to 1.5, more preferably 0.6 to 1.1, in terms of molar ratio to the raw material HPMC.

[0018] Among the esterifying agents used in the esterification step, as the acetylating agent, acetic anhydride and acetyl chloride, etc. can be exemplified, but from the viewpoint of economy, acetic anhydride is preferred. From the viewpoint of the composition (degree of substitution) and yield of the obtained HPMCAS, the amount of the acetylating agent is preferably 0.1 to 1.5, more preferably 1.1 to 1.3, in terms of molar ratio to the raw material HPMC. Among the esterifying agents used in the esterification step, as the succinylating agent, succinic anhydride and succinyl chloride, etc. can be exemplified, but from the viewpoint of economy, succinic anhydride is preferred. From the viewpoint of the composition (degree of substitution) and yield of the obtained HPMCAS, the amount of the succinylating agent is preferably 0.1 to 1.0, more preferably 0.3 to 0.5, in terms of molar ratio to the raw material HPMC.

[0019] The esterification step can also be performed in the presence of a solvent, which is preferably a solvent capable of dissolving HPMC, the esterifying agent and the catalyst, and acetic acid, propionic acid and butyric acid, etc. can be exemplified, but from the viewpoint of economy, acetic acid is preferred. The amount of the solvent used is preferably 1.0 to 3.0, more preferably 1.2 to 2.0, further preferably 1.5 to 1.8, in terms of mass ratio to HPMC, from the viewpoint of reaction rate. As the reactor for the esterification reaction in the esterification step, a double shaft mixer or the like capable of mixing a highly viscous fluid into a uniform mixture can be exemplified. Specifically, a mixer generally sold under the name of kneader, closed mixer, etc. can be used. The reaction temperature of the esterification step is preferably 60 to 100°C, more preferably 80 to 90°C, from the viewpoint of reaction rate or rise in viscosity. In addition, the reaction time of the esterification step is preferably 2 to 8 hours, more preferably 3 to 6 hours, from the viewpoint of obtaining HPMCAS having the desired degree of substitution.

[0020] After the esterification reaction, water can also be added to the reaction liquid for the purpose of treating unreacted acetylating agent and succinylating agent (the treatment of the reaction liquid after the esterification reaction with water is also referred to as "post-treatment"). The amount of water added to the reaction liquid in the esterification step for the purpose of post-treatment is preferably 0.8 to 1.5, more preferably 1.0 to 1.3, in terms of mass ratio to HPMC.

[0021] In the precipitation step, the reaction solution obtained in the esterification step and water are mixed, and HPMCAS suspension is obtained by precipitation of crude HPMCAS. From the viewpoint of the degree of precipitation of HPMCAS and the processing time, the amount of water mixed with the reaction solution in the precipitation step is preferably 3.0 to 50.0, more preferably 5.0 to 20.0, in terms of mass ratio, relative to HPMC used in the esterification reaction. In addition, the temperature of the water mixed with the reaction solution in the precipitation step is preferably 0 to 40°C, more preferably 0 to 30°C, from the viewpoint of controlling the particle diameter of HPMCAS particles in the HPMCAS suspension. The temperature of the reaction solution immediately before mixing with water is preferably 10 to 80°C, more preferably 10 to 50°C, from the viewpoint of controlling the particle diameter of HPMCAS particles in the HPMCAS suspension.

[0022] From the viewpoint of reducing the water content of the de-liquoring HPMCAS after the de-liquoring step described later, the average particle diameter of the suspended particles in the HPMCAS suspension obtained in the precipitation step is preferably 150 μm or more, more preferably 150 to 4000 μm, further preferably 150 to 2000 μm. In order to make the average particle diameter of the suspended particles within the above range, it is only necessary to perform the esterification step and the precipitation step under the conditions described above.

[0023] The concentration of the HPMCAS suspension obtained in the precipitation step (the proportion of the mass of the suspended particles in the suspension per unit mass) is not particularly limited, but from the viewpoint of the aggregation property of the suspended particles with each other in the de-liquoring step, it is preferably 20% by mass or less, more preferably 15% by mass or less. Note that the lower limit of the concentration of the HPMCAS suspension obtained in the precipitation step is not particularly limited, but from the viewpoint of productivity and the like, the lower limit of the concentration of the HPMCAS suspension is 0.1% by mass. The amount of water added in the precipitation step is appropriately adjusted so that the concentration of the HPMCAS suspension is within the range described above, but the amount of water in the suspension can also be appropriately adjusted so that the concentration of the HPMCAS suspension is within the range described above before being supplied to the de-liquoring step.

[0024] In addition, from the viewpoint of the aggregation property of the suspended particles with each other in the de-liquoring step, it is preferable to adjust the temperature of the HPMCAS suspension obtained in the precipitation step to be preferably 80°C or lower, more preferably 60°C or lower, further preferably 40°C or lower, before being supplied to the de-liquoring step. Note that the lower limit of the temperature of the HPMCAS suspension is not particularly limited, but from the viewpoint of operability and the like, it is 0°C.

[0025] In the obtained HPMCAS suspension, impurities such as salts, free acetic acid, free succinic acid, and the like can remain. Therefore, between the precipitation step and the liquid-removing step, a cleaning step of cleaning the crude HPMCAS in the HPMCAS suspension obtained in the precipitation step to obtain a HPMCAS suspension for the liquid-removing step can be included as necessary. As a method of cleaning the HPMCAS suspension, a method of resuspending the HPMCAS in a clean solvent after removing water from the HPMCAS suspension by filtration or the like can be exemplified. In the cleaning step, removal of a part of water from the HPMCAS suspension by filtration or the like and resuspension in a solvent can be repeated a plurality of times. As a solvent for cleaning the HPMCAS, water can be exemplified. Generally, this cleaning step uses a filter such as a batch stirring type filter, a continuous rotary type pressure filter, a continuous horizontal type vacuum filter, a horizontal plate type filter, or a horizontal belt filter, and the like, and, for example, the crude HPMCAS is cleaned with water.

[0026] The HPMCAS suspension obtained after the cleaning step also preferably has the same average particle diameter of the suspended particles, the same concentration of the HPMCAS suspension, and the same temperature as the HPMCAS suspension obtained in the precipitation step. In addition, water can be added as appropriate after the cleaning step so that the concentration of the HPMCAS suspension used in the liquid-removing step obtained after the cleaning step becomes the range described above.

[0027] In the liquid-removing step, in order to reduce the water content of the HPMCAS suspension and reduce the drying load, the HPMCAS suspension is subjected to liquid removal by using a dewatering machine between the cleaning step and the drying step, or between the precipitation step and the drying step without performing the cleaning step, to obtain a dewatered HPMCAS. Generally, this liquid removal can use a dewatering machine such as a pressure dewatering machine, a vacuum dewatering machine, a centrifugal dewatering machine, a press dewatering machine, a decanter type centrifugal separator, and the like.

[0028] The water content of the dewatered HPMCAS obtained after the liquid-removing step is not particularly limited, but from the viewpoint of drying efficiency and the like, it is preferably 55 to 80 mass%, more preferably 55 to 70 mass%, and further preferably 60 to 70 mass%. The moisture content of the de-liquated HPMCAS can be measured according to the method described in "General Tests 2. Physical Tests Drying Loss Test" of the Japanese Pharmacopoeia 18th Revision. Specifically, the moisture content of the HPMCAS is defined as {(total mass of the HPMCAS - absolute dry mass of the HPMCAS) / (total mass of the HPMCAS)} x 100%. Here, the "total mass of the HPMCAS" means the mass when the HPMCAS is accurately weighed according to the "Drying Loss Test" of the Japanese Pharmacopoeia 18th Revision. In addition, the "absolute dry mass of the HPMCAS" means the mass after the HPMCAS is dried according to the "Drying Loss Test" of the Japanese Pharmacopoeia 18th Revision. Here, in the case of measuring the "moisture content of the de-liquated HPMCAS", the "moisture content of the de-liquated HPMCAS" can be measured and calculated by replacing "HPMCAS" in the above with "de-liquated HPMCAS", and the moisture content of the HPMCAS in each step described later, such as the moisture content of the first dried HPMCAS, can also be measured in the same manner. In addition, from the viewpoint of controlling the product temperature in the subsequent first drying step, the temperature of the de-liquated HPMCAS supplied to the first drying step is preferably more than 0°C and 28°C or lower, more preferably 5°C to 28°C, further preferably 10 to 25°C, and most preferably 12°C to 20°C.

[0029] [Drying Step] In the drying step, the de-liquated HPMCAS obtained by the de-liquation step is dried to a target moisture content (for example, 0.1 to 5.0 mass%). The drying step is composed of a first drying step of obtaining a first dried HPMCAS by a fluidized bed dryer and a second drying step of further drying the first dried HPMCAS by an arbitrary dryer to obtain a HPMCAS.

[0030] [First Drying Step] In the first drying step, the de-liquated HPMCAS obtained by the de-liquation step is dried to a moisture content of 30 mass% by a fluidized bed dryer. The drying temperature is not particularly limited as long as the product temperature in the first drying step is not more than 28°C, but from the viewpoint of suppressing the increase in the particle density of the HPMCAS, which is a weakly thermal material, and the viewpoint of drying efficiency, it is preferably 5°C to 70°C, more preferably 5°C to 60°C, and further preferably 30°C to 60°C. Here, the drying temperature means the supply air temperature supplied into the fluidized bed. The product temperature in the first drying step is 28°C or less, preferably 0 to 28°C, more preferably 5 to 28°C, and further preferably 15 to 25°C. If the product temperature exceeds 28°C, the particle density increases and the solubility deteriorates. If the time of the first drying step is too short, uniform drying of the de-liquified HPMCAS can not be achieved, and the particle density can increase locally. Therefore, the time of the first drying step is preferably 5 minutes or more, and more preferably 10 minutes or more. Under conditions where the drying conditions such as the drying temperature are constant, after the start of drying, the temperature of the de-liquified HPMCAS provided for drying increases during the preheating period, and then the product temperature of the HPMCAS is maintained at a constant temperature while the moisture content of the HPMCAS gradually decreases during the constant-rate drying period. Thereafter, the product temperature of the HPMCAS increases again during the deceleration drying period. After the start of the first drying step, by monitoring the product temperature and the moisture content of the HPMCAS over time, the transition to the second drying step can be confirmed at the point when the moisture content of the HPMCAS becomes 30 mass% or less, and the maximum product temperature during the first drying step is confirmed to be 28°C or less based on the temperature change.

[0031] [Second Drying Step] In the second drying step, the first dried HPMCAS obtained by the first drying step is dried to the target moisture content. The drying temperature is not particularly limited as long as the target moisture content is achieved, but from the viewpoint of drying efficiency, it is preferably 30°C to 95°C, and more preferably 50°C to 95°C. The drying machine is not particularly limited as long as the target moisture content is achieved, and examples include a vacuum dryer, a fluidized bed dryer, an air flow dryer, and the like, and from the viewpoint of being able to effectively dry while suppressing the adhesion of HPMCAS particles to each other, a fluidized bed dryer is preferred. The moisture content of the HPMCAS obtained in the second drying step is preferably more than 0 mass% and 5 mass% or less, more preferably 0.1 mass% to 4 mass%, and further preferably 0.1 mass% to 3 mass%.

[0032] From the viewpoint of suppressing the increase in the wet bulb temperature (WBT) during the constant-rate drying period, i.e., suppressing the increase in the product temperature, and the viewpoint of improving the drying efficiency, the supply air humidity (relative humidity) in the first drying step and the second drying step is preferably 0 to 50 RH%, more preferably 0 to 25 RH%, and further preferably 0 to 10 RH%. The lower limit of the air velocity of the air supplied to the fluidized bed dryer in the first and second drying processes is preferably as fast as the air velocity at which the HPMCAS particles are sufficiently fluidized as confirmed by visual observation. The upper limit of the air velocity of the air supplied is preferably as slow as the air velocity at which the particles are not micronized due to collisions between the particles or the yield is not reduced due to the particles adhering to the exhaust filter or the upper portion of the tank. As specific upper and lower limits, 0.1 to 5.0 m / sec, more preferably 0.2 to 3.5 m / sec.

[0033] [Hydroxypropyl methylcellulose acetate succinate] The degree of substitution of the HPMCAS obtained by the production method of the present application is described. The DS of the methoxyl group in the HPMCAS is preferably 1.10 to 2.20, more preferably 1.40 to 2.00, further preferably 1.60 to 2.00. The MS of the hydroxypropoxyl group in the HPMCAS is preferably 0.10 to 1.00, more preferably 0.20 to 0.80, further preferably 0.20 to 0.65. The DS of the acetyl group in the HPMCAS is preferably 0.10 to 2.50, more preferably 0.10 to 1.00, further preferably 0.20 to 0.80. The DS of the succinyl group in the HPMCAS is preferably 0.10 to 2.50, more preferably 0.10 to 1.00, further preferably 0.10 to 0.60. The ratio of the DS of the acetyl group to the DS of the succinyl group (acetyl / succinyl) in the HPMCAS is preferably 0.50 to 4.00, more preferably 0.80 to 3.70, from the viewpoint of solubility. Note that the DS of the methoxyl group, the acetyl group, and the succinyl group in the HPMCAS indicates the degree of substitution (Degree of Substitution), which is the average number of methoxyl groups, acetyl groups, and succinyl groups per 1 unit of anhydrous glucose, and the MS of the hydroxypropoxyl group in the HPMCAS indicates the molar substitution (Molar Substitution), which is the average number of moles of hydroxypropoxyl groups per 1 mole of anhydrous glucose. Note also that the DS of the methoxyl group, the acetyl group, and the succinyl group, and the MS of the hydroxypropoxyl group in the HPMCAS can be converted from the values obtained by the method described in "Hydroxypropyl methylcellulose acetate succinate" in each item of pharmaceutical products in the Japanese Pharmacopoeia, 18th revised edition.

[0034] The average particle size (D50) of the HPMCAS thus obtained is preferably 70 to 2000 μm, more preferably 150 to 1750 μm, and even more preferably 300 to 1500 μm, from the viewpoint of the flowability of the powder and the miscibility with a drug. The average particle size (D50) of the HPMCAS can be measured by a dry laser diffraction method (for example, master sizer manufactured by Malvern Instruments Ltd. in England).

[0035] The HPMCAS obtained by the production method of the present application is HPMCAS in which the increase in the particle density is suppressed and the dissolution time is shortened. The bulk density and the tap density of the HPMCAS thus obtained are described below. The bulk density is preferably 0.1 to 0.5 g / cm 3 , and more preferably 0.1 to 0.45 g / cm 3 , from the viewpoint of accelerating the dissolution rate of the HPMCAS. The "bulk density" refers to the bulk density in a loosely packed state, which is measured by uniformly supplying a sample from the upper side (23 cm) of a cylindrical container having a diameter of 5.03 cm and a height of 5.03 cm (volume: 100 ml) through a 24-mesh sieve, and weighing the sample after scraping the upper surface flat. The tap density is preferably 0.1 to 0.6 g / cm 3 , and more preferably 0.1 to 0.5 g / cm 3 , from the viewpoint of accelerating the solubility of the HPMCAS. The tap density is the bulk density when the cylindrical container is tightly packed by applying tapping. The "tapping" refers to an operation of tightly packing a sample by repeatedly dropping the cylindrical container filled with the sample from a certain height, and applying a slight impact to the bottom. In practice, the sample is filled into the cylindrical container, and after the upper surface is scraped flat and weighed, the cylindrical container is further capped with a lid, and the sample is added to the upper edge of the lid, and then the tapping is performed 180 times with a free-fall height of 1.8 cm. After the completion of the tapping, the lid is removed, the sample is scraped flat at the upper surface of the cylindrical container, and weighed, and the bulk density in this state is taken as the tap density. The tap density and the bulk density can be measured by using a Powder Tester manufactured by Hosokawa Micron Ltd. [Examples]

[0036] The present application is described in detail below by way of examples and comparative examples, but the present application is not limited to any of these examples. Following the method described, the moisture content, degree of substitution, loose bulk density, compact bulk density, and average particle size (D50) of the HPMCAS obtained in each example were determined. In addition, the dissolution time of HPMCAS obtained in each example in the solvent was determined using the following method. Accurately weigh 3.0 g of HPMCAS and add it to the CC27 measuring cup (Anton Paar, CC27 / T200 / AL, 29 mm diameter and 68 mm height aluminum cylindrical container) of the MCR 301 rheometer (manufactured by Anton Paar). Add distilled water at 25°C to bring the HPMCAS concentration in the solution to 10% by mass. Then, use a blade-type measuring clamp (Anton Paar, ST24-2D / 2V / 2V-30) to thoroughly mix and completely disperse the HPMCAS in the distilled water. Place the measuring cup and blade-type measuring clamp on the apparatus and adjust the temperature of the dispersion at 25°C while stirring at 400 rpm for 2 minutes. After 2 minutes, while continuing to adjust the temperature to 25°C and stir at 400 rpm, add a 10% ammonia solution to neutralize 100% of the carboxyl groups in the HPMCAS. The point at which 10% ammonia solution is added is taken as minute 0. One torque value is collected every minute over 120 minutes. The maximum torque value within 120 minutes is calculated. The time when the torque reaches 99% of the maximum torque value within 120 minutes is taken as the dissolution time. The manufacturing conditions of HPMCAS in the examples and comparative examples are shown in Table 1, and the physical properties of the HPMCAS obtained in the examples and comparative examples are shown in Table 2.

[0037] Example 1 1376g of glacial acetic acid was weighed and placed into a 5L horizontal kneading reactor (PNV-5T type, manufactured by Irie Shokai Co., Ltd., Japan) equipped with biaxial stirring blades (Z-type stirring blades for PNV-5T, material SUS 316L, manufactured by Irie Shokai Co., Ltd., Japan). 860g of methoxy-based DS (1.88), hydroxypropoxy-based MS (0.24), 2% by mass aqueous solution of HPMC with a viscosity of 3.2 mPa·s at 20°C, 495.4g of acetic anhydride, 262.3g of succinic anhydride, and 415.0g of sodium acetate were added. The esterification reaction was carried out at 85°C for 5 hours to obtain the reaction solution. Water at 20°C was slowly added at a mass ratio of 5.0 times that of the reaction solution to the obtained reaction solution (75°C) to obtain a suspension in which HPMCAS-1 precipitated. The precipitated HPMCAS-1 was filtered out through an 80-mesh sieve to obtain crude HPMCAS-1. The obtained crude HPMCAS-1 was again suspended in water 10 times by mass relative to the raw material HPMC at 20°C, and after stirring for 10 minutes, the operation of filtering on a 80-mesh sieve was repeated 5 times to obtain the washed HPMCAS-1. The washed HPMCAS-1 was again suspended in water 10 times by mass relative to the raw material HPMC at 20°C, and using a filter-type centrifugal dehydrator (upper discharge type centrifuge H-130A, manufactured by KOKUSAN Corporation), dewatering was performed at a centrifugal effect of 600 G to obtain the dewatered HPMCAS-1. The moisture content of the dewatered HPMCAS-1 was 67 mass%. The 1 kg of the dewatered HPMCAS-1 (moisture content 67 mass%, product temperature 8°C) was put into a fluidized bed dryer (FD-LAB-1, manufactured by POWREX Corporation), and first drying was started under the conditions of maintaining the air supply rate at 2.8 m / sec and the air supply temperature at 40°C. During the drying, sampling was appropriately performed, and the moisture content was measured. After starting the first drying, the product temperature reached 18°C within 5 minutes, and the product temperature was maintained at 18°C until 20 minutes. After 20 minutes from the start of the first drying, the product temperature started to rise from 18°C, and the moisture content reached 27 mass% after 40 minutes, and it was confirmed that the first drying was completed and the second drying was shifted. At this time, the product temperature was 20°C, and the product temperature did not exceed 20°C from the start of the first drying to the end of the first drying. Next, in the same fluidized bed dryer, the second drying was continued under the same conditions as at the start of the first drying, except that the air supply temperature was changed to 80°C. After 20 minutes from the change of the air supply temperature, the product temperature reached 70°C, and the second drying was completed to obtain HPMCAS.

[0038] Example 2 The 1 kg of the dewatered HPMCAS-1 (moisture content 67 mass%, product temperature 8°C) was put into a fluidized bed dryer (FD-LAB-1, manufactured by POWREX Corporation), and first drying was started under the same conditions as in Example 1, except that the air supply temperature of the fluidized bed dryer was changed to 60°C. During the drying, sampling was appropriately performed, and the moisture content was measured. From the start of the first drying, the product temperature reached 23°C within 5 minutes, and the product temperature was maintained at 23°C until 15 minutes. After 15 minutes from the start of the first drying, the product temperature started to rise from 23°C, and the moisture content reached 22 mass% after 30 minutes, and it was confirmed that the first drying was completed and the second drying was shifted. At this time, the product temperature was 26°C, and the product temperature did not exceed 26°C from the start of the first drying to the end of the first drying. Next, in the same fluidized bed dryer, except that the supply air temperature was changed to 80°C, the second drying process was continued under the same conditions as at the start of the first drying process. After 15 minutes from the change in the supply air temperature, the product temperature reached 70°C, and the second drying was completed, and HPMCAS was obtained.

[0039] Example 3 A 5L horizontal kneader reactor (PNV-5T, manufactured by Nippon Gohsei Co., Ltd.) equipped with double shaft stirring blades (Z-shaped stirring blades for PNV-5T, SUS 316L, manufactured by Nishi Gohsei Co., Ltd.) was charged with 1440 g of glacial acetic acid, and 900 g of HPMC having a methoxyl group DS of 1.88, a hydroxypropoxyl group MS of 0.24, and a viscosity of 3.2 mPa-s at 20°C in a 2 mass% aqueous solution, 460 g of acetic anhydride, 160 g of succinic anhydride, and 400 g of sodium acetate, and an esterification reaction was performed at 85°C for 5 hours, and a reaction solution was obtained. Water at 20°C was slowly added to the obtained reaction solution (75°C) at 5.0 times the mass of the reaction solution, and a suspension in which HPMCAS-2 was precipitated was obtained. The precipitated HPMCAS-2 was filtered out on a 80 mesh sieve, and a crude HPMCAS-2 was obtained. The obtained crude HPMCAS-2 was again suspended in water at 10 times the mass of the raw material HPMC at 20°C, and after stirring for 10 minutes, the operation of filtering out on a 80 mesh sieve was repeated 5 times, and a washed HPMCAS-2 was obtained. The washed HPMCAS-2 was again suspended in water at 10 times the mass of the raw material HPMC at 20°C, and a centrifugal dewatering machine (top discharge type centrifugal separator H-130A, manufactured by KOKUSAN Co., Ltd.) was used to perform dewatering at a centrifugal effect of 600G, and a dewatered HPMCAS-2 was obtained. The water content of the dewatered HPMCAS-2 was 67 mass%. 1 kg of the dewatered HPMCAS-2 (water content 67 mass%, product temperature 8°C) was charged into a fluidized bed dryer (FD-LAB-1, manufactured by POWREX Co., Ltd.), and the first drying was started while maintaining the supply air velocity at 2.8 m / sec and the supply air temperature at 40°C. During the drying, sampling was appropriately performed, and the water content was measured. Within 5 minutes from the start of the first drying, the product temperature reached 18°C, and the product temperature was maintained at 18°C until 20 minutes. After 20 minutes from the start of the first drying, the product temperature started to rise from 18°C, and the water content reached 28 mass% after 40 minutes, and the end of the first drying was confirmed and the transition to the second drying was performed. The product temperature at this time was 20°C, and the product temperature did not exceed 20°C from the start of the first drying process until the end of the first drying process. Next, in the same fluidized bed dryer, except that the supply air temperature was changed to 80°C, the second drying process was continued under the same conditions as at the start of the first drying process. After 20 minutes from the change in the supply air temperature, the product temperature reached 70°C, and the second drying was completed, and HPMCAS was obtained.

[0040] Comparative Example 1 Except that the supply air temperature of the fluidized bed dryer was changed to 80°C, 1 kg of the de-liquefied HPMCAS-1 (water content 67 mass%, product temperature 8°C) was subjected to drying under the same conditions as in Example 1. After the start of drying, the product temperature reached 29°C within 5 minutes, and the product temperature was maintained at 29°C until 10 minutes. At this time, the water content was 61 mass%. After 10 minutes from the start of drying, the product temperature started to rise from 29°C, and the water content reached 19 mass% after 25 minutes, at which time the product temperature was 35°C. Drying was further continued under the same conditions, and after 40 minutes from the start of drying, the product temperature reached 70°C, and the drying was completed.

[0041] Comparative Example 2 Except that the supply air temperature of the fluidized bed dryer was changed to 80°C, 1 kg of the de-liquefied HPMCAS-2 (water content 67 mass%, product temperature 8°C) was subjected to the first drying under the same conditions as in Example 3. After the start of the first drying, the product temperature reached 29°C within 5 minutes, and the product temperature was maintained at 29°C until 10 minutes. At this time, the water content was 63 mass%. Since the product temperature started to rise from 29°C after 10 minutes from the start of the first drying, and the water content reached 20 mass% after 25 minutes, the first drying was completed. At this time, the product temperature was 34°C. Next, in the same fluidized bed dryer, without changing the supply air temperature, the second drying was started under the same conditions as the first drying. After 15 minutes from the start of the second drying, the product temperature reached 70°C, and the second drying was completed.

[0042] Table 1

[0043] Table 2

[0044] From the results of Examples 1 to 2 and Comparative Examples, it was found that HPMCAS obtained by a method having a first drying process for obtaining first dried HPMCAS having a moisture content of 30 mass% in such a manner that the product temperature does not exceed 28°C and a second drying process for further drying the first dried HPMCAS has an excellent dissolution rate in a solvent. In particular, in the first drying process, if fluidized bed drying is performed under conditions where the product temperature exceeds 0°C and is 20°C or lower, the dissolution rate in a solvent is improved. In addition, from the results of Example 3, it was found that the same effect is obtained even if the degree of substitution of HPMCAS is different.

Claims

1. A method for manufacturing hydroxypropyl methylcellulose acetate succinate, wherein, At least includes: In the dehydration process, hydroxypropyl methylcellulose is reacted with an acetylation agent and a succinylation agent in the presence of a catalyst, and then the hydroxypropyl methylcellulose acetate succinate suspension obtained by mixing the reaction solution with water is dehydrated to obtain dehydrated hydroxypropyl methylcellulose acetate succinate. In the first drying step, the dehydrated hydroxypropyl methylcellulose acetate succinate is dried in a fluidized bed dryer at a temperature not exceeding 28°C until the moisture content reaches 30% by mass, thereby obtaining first-dried hydroxypropyl methylcellulose acetate succinate; and The second drying step further dries the first dried hydroxypropyl methylcellulose acetate succinate to obtain hydroxypropyl methylcellulose acetate succinate.

2. The method for manufacturing hydroxypropyl methylcellulose acetate succinate as described in claim 1, wherein, The temperature of hydroxypropyl methylcellulose acetate succinate in the first drying process is 5–28°C.

3. The method for manufacturing hydroxypropyl methylcellulose acetate succinate as described in claim 1, wherein, The gas supply temperature in the first drying process is 5 to 70°C.

4. The method for manufacturing hydroxypropyl methylcellulose acetate succinate as described in claim 1, wherein, The dryer used in the second drying process is a fluidized bed dryer.

5. The method for manufacturing hydroxypropyl methylcellulose acetate succinate as described in claim 1, wherein, The water content of the dehydrated hydroxypropyl methylcellulose acetate, which is about to be introduced into the first drying process, is 55-80% by mass.

6. The method for manufacturing hydroxypropyl methylcellulose acetate succinate as described in claim 1, wherein, The water content of the hydroxypropyl methylcellulose acetate succinate is less than 5% by mass.

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