Method for producing hydroxypropyl methylcellulose acetate succinate

Abstract

To provide a method for producing hydroxypropyl methylcellulose acetate succinate that suppresses an increase in particle density and shortens dissolution time.SOLUTION: Provided is a method for producing hydroxypropyl methylcellulose acetate succinate including at least a liquid removal step, a first drying step, and a second drying step, wherein in the first drying step, hydroxypropyl methylcellulose acetate succinate is dried by a fluidized bed dryer so that its water content becomes 30 mass% and its product temperature does not exceed 28°C.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing hydroxypropyl methylcellulose acetate succinate. [Background technology]

[0002] Hydroxypropyl methylcellulose acetate succinate (hereinafter also referred to as "HPMCAS") is a widely known enteric polymer. It is a polymer that has four types of substituents introduced into the cellulose backbone: two substituents, a methyl group (-CH3) and a hydroxypropyl group (-C3H6OH), to form an ether structure, and two substituents, an acetyl group (-COCH3) and a succinyl group (-COC2H4COOH), to form an ester structure.

[0003] HPMCAS is widely used in tablet coatings, drug release control applications, and in the preparation of solid dispersions of poorly water-soluble drugs by hot-melt extrusion or spray drying.

[0004] Generally, when coating or spray drying is performed, HPMCAS alone or both a drug and HPMCAS must first be dissolved in a solvent. However, the extremely long time required for dissolving HPMCAS presents a problem, and there has been a demand for the production of HPMCAS with improved solubility.

[0005] As a method for improving the solubility of HPMCAS, Patent Document 1 proposes a method that includes a step of continuously or intermittently adding a reaction solution containing HPMCAS to water to produce particles. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Special Publication No. 2017-501239 Summary of the Invention [Problem to be solved by the invention]

[0007] However, the method described in Patent Document 1 requires adding water to the reaction solution after the reaction in an amount 12 to 20 times the total weight of the reaction medium before the precipitation step, which generates a large amount of wastewater, resulting in problems in terms of production cost and environmental impact.In addition, there is room for improvement in the solubility of the HPMCAS particles obtained by this production method. The present invention has been made in view of the above circumstances, and aims to provide a method for producing hydroxypropyl methylcellulose acetate succinate in which an increase in particle density is suppressed, and a method for producing hydroxypropyl methylcellulose acetate succinate in which the dissolution time is shortened. [Means for solving the problem]

[0008] As a result of intensive research conducted by the present inventors to solve the above-mentioned problems, they discovered that by providing two drying steps, namely, a first drying step in which first dried HPMCAS is obtained by drying in a fluidized bed dryer while keeping the product temperature below 28°C until the moisture content reaches 30% by mass, and a second drying step in which the first dried HPMCAS is further dried to obtain HPMCAS, it is possible to suppress an increase in particle density after drying without requiring strict material control or production control, and the dissolution time of HPMCAS in a solvent is improved, which led to the completion of the present invention. According to the present invention, there is provided the following method for producing hydroxypropyl methylcellulose acetate succinate. [1] a deliquification step of reacting hydroxypropyl methylcellulose with an acetylating agent and a succinoylating agent in the presence of a catalyst, and then mixing the reaction solution with water to obtain a hydroxypropyl methylcellulose acetate succinate suspension, and then deliquifying the resulting suspension to obtain deliquified hydroxypropyl methylcellulose acetate succinate; a first drying step in which the deliquor-removed hydroxypropyl methylcellulose acetate succinate is dried in a fluidized bed dryer until the moisture content reaches 30% by mass, while keeping the product temperature at 28°C or less to obtain a first dried hydroxypropyl methylcellulose acetate succinate; a second drying step of further drying the first dried hydroxypropyl methylcellulose acetate succinate to obtain hydroxypropyl methylcellulose acetate succinate; A method for producing hydroxypropyl methylcellulose acetate succinate, comprising at least [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 temperature of the intake air 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 deliquor-dehydrated hydroxypropyl methylcellulose acetate succinate has a water content of 55 to 80 mass % immediately before being introduced into the first drying step. [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 invention, the increase in particle density of HPMCAS particles, a heat-weak material, can be suppressed simply by adjusting the product temperature during the drying process using a fluidized bed dryer. This allows HPMCAS with a low bulk density to be obtained by adjusting the product temperature during the first drying process. Furthermore, because the resulting HPMCAS has a low particle density, the dissolution time can be significantly shortened, improving the production capacity of HPMCAS solutions or mixed solutions of HPMCAS and drugs. Furthermore, since there is no need to modify existing manufacturing equipment, this method can be introduced immediately. DETAILED DESCRIPTION OF THE INVENTION

[0010] The method for producing HPMCAS of the present invention includes at least a deliquoring step, a first drying step, and a second drying step. The method for producing HPMCAS of the present invention may also include a washing step, if necessary.

[0011] [Deliquoring process] In the draining step, 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 step), then the reaction solution is mixed with water to produce a hydroxypropyl methylcellulose acetate succinate suspension (precipitation step), and the hydroxypropyl methylcellulose acetate succinate suspension is drained to obtain deliquified hydroxypropyl methylcellulose acetate succinate.

[0012] We will explain how to obtain hydroxypropyl methylcellulose (hereinafter also referred to as "HPMC"), the raw material for HPMCAS. HPMC may be obtained by a known method or may be a commercially available product. HPMC can be obtained, for example, by contacting pulp in the form of a sheet, chips, or powder with a solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide to form alkali cellulose, and then adding an etherifying agent such as methyl chloride and propylene oxide to react with the resulting cellulose.

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

[0014] After the alkali cellulose is produced, an etherifying agent such as methyl chloride and propylene oxide is added to the alkali cellulose in a conventional manner to cause an etherification reaction, thereby obtaining HPMC.

[0015] From the viewpoint of obtaining HPMC having a small number of non-dissolved fibers, the DS of the methoxy group in HPMC is preferably 1.10 to 2.20, more preferably 1.40 to 2.00, and even more preferably 1.60 to 2.00. From the viewpoint of obtaining HPMC having a small number of non-dissolved fibers, the MS of the hydroxypropoxy group in HPMC is preferably 0.10 to 1.00, more preferably 0.20 to 0.80, and even more preferably 0.20 to 0.65. Insoluble fiber refers to the portion of HPMC that does not dissolve in water. HPMC exhibits water solubility by partially etherifying the hydroxyl groups of cellulose, weakening the intramolecular and intermolecular hydrogen bonds of cellulose. Because completely uniform etherification is difficult industrially, HPMC may contain insoluble portions, i.e., insoluble fiber, due to insufficient or uneven ether group substitution. If the final HPMCAS contains a large amount of insoluble fiber, the enteric coating becomes nonuniform, reducing the yield of enteric-coated formulations and frequently clogging filters during the filtration process of the coating solution, reducing productivity. Therefore, it is preferable that the HPMC used as the raw material for HPMCAS contains a small amount of insoluble fiber. The amount of insoluble fiber can be determined by analyzing an aqueous HPMC solution using a device such as a Coulter counter. The DS of the methoxy group in HPMC represents the degree of substitution and is the average number of methoxy groups per unit of anhydroglucose, and the MS of the hydroxypropoxy group in HPMC represents the molar substitution and is the average number of moles of hydroxypropoxy groups per mole of anhydroglucose. The DS of the methoxy group and the MS of the hydroxypropoxy group in HPMC can be determined by converting values ​​obtained by measurement based on the 18th Edition of the Japanese Pharmacopoeia.

[0016] The viscosity of a 2% by mass aqueous solution of HPMC at 20°C is preferably 2.2 to 7.2 mPa·s, more preferably 3.0 to 3.5 mPa·s, from the viewpoint of kneading properties during the esterification reaction. The viscosity of a 2% by mass HPMC aqueous solution at 20°C is measured in accordance with the capillary viscometer method of the 18th edition of the Japanese Pharmacopoeia.

[0017] From the viewpoint of economy, the catalyst for the esterification step is preferably an alkali metal carboxylate such as sodium acetate. The amount of catalyst is preferably 0.1 to 1.5, more preferably 0.6 to 1.1, in terms of molar ratio relative to the starting HPMC, from the viewpoints of the composition (degree of substitution) and yield of the resulting HPMCAS.

[0018] Among the esterifying agents used in the esterification step, acetylating agents include acetic anhydride and acetyl chloride, with acetic anhydride being preferred from the viewpoint of economy. 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 relative to the raw material HPMC, from the viewpoints of the composition (degree of substitution) and yield of the resulting HPMCAS. Of the esterifying agents used in the esterification step, examples of the succinoylating agent include succinic anhydride and succinyl chloride, with succinic anhydride being preferred from the viewpoint of economy. The amount of succinoylating agent is preferably 0.1 to 1.0, more preferably 0.3 to 0.5, in terms of molar ratio relative to the starting HPMC, from the viewpoints of the composition (degree of substitution) and yield of the resulting HPMCAS.

[0019] The esterification step may be carried out in the presence of a solvent, preferably one that can dissolve HPMC, the esterifying agent, and the catalyst, and examples of the solvent include acetic acid, propionic acid, and butyric acid, with acetic acid being preferred from an economical viewpoint. From the viewpoint of reaction rate, the amount of the solvent used is preferably 1.0 to 3.0, more preferably 1.2 to 2.0, and even more preferably 1.5 to 1.8, in terms of mass ratio relative to HPMC. The reactor used for the esterification reaction in the esterification step may be a twin-shaft agitator capable of kneading a highly viscous fluid to form a uniform mixture. Specifically, agitators generally available on the market under the names of kneaders, internal mixers, etc. may be used. The reaction temperature in the esterification step is preferably 60 to 100° C., more preferably 80 to 90° C., from the viewpoint of increasing the reaction rate or viscosity. The reaction time in the esterification step is preferably 2 to 8 hours, more preferably 3 to 6 hours, from the viewpoint of obtaining HPMCAS with the desired degree of substitution.

[0020] After the esterification reaction, water may be added to the reaction solution to treat any unreacted acetylating agent and succinoylating agent (the treatment of mixing with water after the esterification reaction is also referred to as "post-treatment"). The amount of water added to the reaction solution 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 mass ratio relative to HPMC.

[0021] In the precipitation step, the reaction solution obtained in the esterification step is mixed with water to precipitate crude HPMCAS, thereby obtaining an HPMCAS suspension. The amount of water to be 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 the HPMC used in the esterification reaction, from the viewpoints of the degree of precipitation of HPMCAS and the treatment time. 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 size of the 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 size of the HPMCAS particles in the HPMCAS suspension.

[0022] The average particle size 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, and even more preferably 150 to 2000 μm, from the viewpoint of reducing the water content of the deliquified HPMCAS after the deliquifying step described below. The average particle size of the suspended particles can be adjusted to fall within the above range by carrying out the esterification step and the precipitation step under the above conditions.

[0023] The concentration of the HPMCAS suspension obtained in the precipitation step (the ratio of the mass of suspended particles per unit mass of suspension) is not particularly limited, but is preferably 20% by mass or less, more preferably 15% by mass or less, from the viewpoint of the tendency of suspended particles to aggregate in the subsequent deliquoring step. The lower limit of the concentration of the HPMCAS suspension obtained in the precipitation step is not particularly limited, but is 0.1% by mass from the viewpoint of productivity. The amount of water added in the precipitation step is appropriately adjusted so that the concentration of the HPMCAS suspension falls within the aforementioned range; however, the amount of water in the suspension may also be appropriately adjusted before the HPMCAS suspension is subjected to the deliquoring step so that the concentration of the HPMCAS suspension falls within the aforementioned range.

[0024] Furthermore, in consideration of factors such as the tendency for suspended particles to aggregate in the subsequent deliquoring step, it is preferable to adjust the temperature of the HPMCAS suspension obtained in the precipitation step to preferably 80° C. or lower, more preferably 60° C. or lower, and even more preferably 40° C. or lower before subjecting it to the deliquoring step. There are no particular restrictions on the lower limit of the temperature of the HPMCAS suspension, but from the viewpoint of operability and the like, it is 0° C.

[0025] The obtained HPMCAS suspension may contain residual impurities such as salts, free acetic acid, free succinic acid, etc. Therefore, a washing step can be included between the precipitation step and the deliquification step, if necessary, in which the crude HPMCAS in the HPMCAS suspension obtained in the precipitation step is washed to obtain an HPMCAS suspension to be used in the deliquification step. Examples of methods for washing an HPMCAS suspension include removing water from the HPMCAS suspension by filtration or other methods and then resuspending the HPMCAS in a clean solvent. In the washing step, the removal of a portion of the water from the HPMCAS suspension by filtration or other methods and resuspension in a solvent may be repeated multiple times. The solvent used to wash the HPMCAS includes water. Typically, this washing step involves washing the crude HPMCAS with, for example, water, using a filter such as a batch stirred filter, a continuous rotary pressure filter, a continuous horizontal vacuum filter, a horizontal table filter, or a horizontal belt filter.

[0026] The HPMCAS suspension obtained after the washing step preferably has the same average particle size of suspended particles, concentration, and temperature as the HPMCAS suspension obtained in the precipitation step. Furthermore, water may be added appropriately after the washing step so that the concentration of the HPMCAS suspension obtained after the washing step and used in the dewatering step falls within the above range.

[0027] In the deliquification step, the water content of the HPMCAS suspension is reduced and the drying load is reduced. The HPMCAS suspension is deliquified using a dehydrator between the washing step and the drying step, or between the precipitation step and the drying step if the washing step is not performed, to obtain deliquified HPMCAS. Generally, for this dehydration, a dehydrator such as a pressure dehydrator, a vacuum dehydrator, a centrifugal dehydrator, a compression type dehydrator, or a decanter type centrifugal separator can be used.

[0028] The moisture content of the deliquified HPMCAS obtained after the deliquifying 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 even more preferably 60 to 70 mass%. The moisture content of deliquified HPMCAS can be measured by the method described in "General Test Methods, 2. Physical Test Methods, Loss on Drying Test Method" in the Japanese Pharmacopoeia, 18th Edition. Specifically, the moisture content of HPMCAS is defined as {(Total Mass of HPMCAS - Bone-Dry Mass of HPMCAS) / (Total Mass of HPMCAS)} × 100%. Here, "Total Mass of HPMCAS" refers to the mass of HPMCAS precisely weighed according to the "Loss on Drying Test Method" in the Japanese Pharmacopoeia, 18th Edition. Furthermore, "Bone-Dry Mass of HPMCAS" refers to the mass of HPMCAS after drying according to the "Loss on Drying Test Method" in the Japanese Pharmacopoeia, 18th Edition. When measuring the "moisture content of deliquified HPMCAS," the "moisture content of deliquified HPMCAS" can be measured and calculated by replacing "HPMCAS" in the above with "deliquified HPMCAS." The moisture content of HPMCAS in each step, such as the moisture content of the first dried HPMCAS described below, can also be measured in the same manner. Furthermore, from the viewpoint of controlling the product temperature in the subsequent first drying step, the temperature of the deliquified HPMCAS used in the first drying step is preferably above 0°C and not higher than 28°C, more preferably 5°C to 28°C, even more preferably 10°C to 25°C, and most preferably 12°C to 20°C.

[0029] [Drying process] In the drying step, the deliquified HPMCAS obtained in the deliquifying step is dried to a target moisture content (for example, 0.1 to 5.0% by mass). The drying step comprises a first drying step in which a first dried HPMCAS is obtained using a fluidized bed dryer, and a second drying step in which the first dried HPMCAS is further dried using an optional dryer to obtain HPMCAS.

[0030] [First drying process] In the first drying step, the deliquified HPMCAS obtained in the deliquifying step is dried in a fluidized bed dryer until the moisture content reaches 30% by mass. The drying temperature is not particularly limited as long as the product temperature in the first drying step does not exceed 28°C. However, from the viewpoints of preventing an increase in the particle density of HPMCAS, which is a heat-labile material, and of drying efficiency, the drying temperature is preferably 5°C to 70°C, more preferably 5°C to 60°C, and even more preferably 30°C to 60°C. Here, the drying temperature refers to the temperature of the inlet air supplied to the fluidized bed. As described above, the product temperature in the first drying step is 28° C. or lower, preferably 0 to 28° C., more preferably 5 to 28° C., and even more preferably 15 to 25° C. If the product temperature exceeds 28° C., the particle density increases and the solubility deteriorates. If the time for the first drying step is too short, the deliquified HPMCAS may not be dried uniformly, resulting in localized increases in particle density. Therefore, the time is preferably 5 minutes or longer, more preferably 10 minutes or longer. Under constant drying conditions, such as drying temperature, the temperature of the deliquified HPMCAS used for drying rises during the preheating period after drying begins. Then, during the constant-rate drying period, the HPMCAS product temperature is maintained constant while the moisture content of the HPMCAS gradually decreases. Then, during the falling-rate drying period, the HPMCAS product temperature rises again. By monitoring the temperature and moisture content of the HPMCAS over time after the start of the first drying step, it is possible to confirm that the HPMCAS has transitioned to the second drying step when its moisture content reaches 30% by mass or less, and to confirm that the maximum product temperature during the first drying step does not exceed 28°C based on the temperature change.

[0031] [Second drying process] In the second drying step, the first dried HPMCAS obtained in the first drying step is dried to a 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, more preferably 50°C to 95°C. The dryer is not particularly limited as long as the target moisture content is achieved, but examples include a vacuum dryer, a fluidized bed dryer, and a flash dryer. A fluidized bed dryer is preferred from the viewpoint of efficient drying while suppressing adhesion between HPMCAS particles. The moisture content of the HPMCAS obtained in the second drying step is preferably more than 0% by mass and not more than 5% by mass, more preferably 0.1% to 4% by mass, and even more preferably 0.1% to 3% by mass.

[0032] The humidity (relative humidity) of the intake air in the first and second drying steps is preferably 0 to 50 RH%, more preferably 0 to 25 RH%, and even more preferably 0 to 10 RH%, from the viewpoint of suppressing an increase in the wet-bulb temperature during the constant rate drying period, i.e., an increase in product temperature, and from the viewpoint of increasing drying efficiency. The lower limit of the air velocity supplied to the fluidized bed dryer in the first and second drying steps is preferably high enough to visually confirm that the HPMCAS particles are sufficiently fluidized. The upper limit of the air velocity is preferably low enough to avoid particle collisions that result in particle size reduction or particle adhesion to the exhaust filter or the upper part of the dryer, thereby reducing the yield. Specific upper and lower limits are preferably 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 HPMCAS obtained by the production method of the present invention will now be described. The DS of the methoxy group in HPMCAS is preferably 1.10 to 2.20, more preferably 1.40 to 2.00, and even more preferably 1.60 to 2.00. The MS of the hydroxypropoxy group in HPMCAS is preferably 0.10 to 1.00, more preferably 0.20 to 0.80, and even more preferably 0.20 to 0.65. The DS of the acetyl group in HPMCAS is preferably 0.10 to 2.50, more preferably 0.10 to 1.00, and even more preferably 0.20 to 0.80. The DS of the succinyl group in HPMCAS is preferably 0.10 to 2.50, more preferably 0.10 to 1.00, and even more preferably 0.10 to 0.60. From the viewpoint of solubility, the ratio of the DS of the acetyl group to the DS of the succinyl group in HPMCAS (acetyl group / succinyl group) is preferably 0.50 to 4.00, more preferably 0.80 to 3.70. The DS of the methoxy, acetyl, and succinyl groups in HPMCAS represents the degree of substitution, which is the average number of methoxy, acetyl, and succinyl groups per unit of anhydroglucose, and the MS of the hydroxypropoxy groups in HPMCAS represents the molar substitution, which is the average number of moles of hydroxypropoxy groups per mole of anhydroglucose. The DS of the methoxy group, acetyl group, and succinyl group and the MS of the hydroxypropoxy group in HPMCAS can be calculated from the values ​​obtained by the method described in the pharmaceutical articles "Hypromellose acetate succinate" in the 18th Edition of the Japanese Pharmacopoeia.

[0034] The average particle size (D50) of the HPMCAS obtained in this manner is preferably 70 to 2000 μm, more preferably 150 to 1750 μm, and even more preferably 300 to 1500 μm, from the viewpoints of powder fluidity and miscibility with drugs. The average particle size (D50) of the HPMCAS can be measured by dry laser diffraction (for example, using a Mastersizer manufactured by Malvern Pharmaceuticals, UK).

[0035] The HPMCAS obtained by the production method of the present invention has a suppressed increase in particle density and a shortened dissolution time. The loose bulk density and packed bulk density of the HPMCAS thus obtained will now be described. The loose bulk density is preferably 0.1 to 0.5 g / cm from the viewpoint of increasing the dissolution rate of HPMCAS. 3 , more preferably 0.1 to 0.45 g / cm 3 "Loose bulk density" refers to the bulk density in a loosely packed state, and is measured by passing a sample through a 24-mesh sieve into a cylindrical container 5.03 cm in diameter and 5.03 cm in height (volume 100 mL) and uniformly feeding the sample from 23 cm above the cylindrical container, then leveling off the top surface and weighing the sample. The packed bulk density is preferably 0.1 to 0.6 g / cm from the viewpoint of accelerating the dissolution rate of HPMCAS. 3 , more preferably 0.1 to 0.5 g / cm 3 "Packed bulk density" is the bulk density when the sample is tightly packed by tapping. Tapping is a procedure in which a cylindrical container filled with the sample is repeatedly dropped from a certain height to apply a light impact to the bottom, causing the sample to be tightly packed. In practice, the sample is filled into a cylindrical container in the same manner as for measuring loose bulk density, and the top is leveled off and weighed. Then, a cap is placed on the cylindrical container, the sample is added up to the top edge, and tapping is performed 180 times at a tapping height of 1.8 cm. After tapping is complete, the cap is removed and the sample is leveled off at the top of the cylindrical container and weighed; the bulk density in this state is taken as the packed bulk density. The "packed bulk density" and the "loose bulk density" can be measured using a powder tester manufactured by Hosokawa Micron Corporation. [Example]

[0036] EXAMPLES The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited to these examples in any way. The moisture content, degree of substitution, loose bulk density, packed bulk density and average particle size (D50) of the HPMCAS obtained in each example were measured by the methods described above. The dissolution time of the HPMCAS obtained in each example in the solvent was measured by the following method. 3.0 g of HPMCAS was accurately weighed into a CC27 measuring cup (Anton Paar, CC27 / T200 / AL, a cylindrical aluminum container with a diameter of 29 mm and a height of 68 mm) of an MCR301 rheometer (Anton Paar). Distilled water at 25°C was added to the solution to achieve a final HPMCAS concentration of 10% by mass. The solution was thoroughly stirred using a blade-type measuring jig (Anton Paar, ST24-2D / 2V / 2V-30) to completely disperse the HPMCAS in the distilled water. The measuring cup and blade-type measuring jig were then placed in the rheometer, and the dispersion was stirred at 400 rpm for 2 minutes while maintaining the temperature at 25°C. After 2 minutes, a 10% aqueous ammonia solution sufficient to neutralize 100% of the carboxyl groups in the HPMCAS was added while continuing to maintain the temperature at 25°C and stir at 400 rpm. The time when the 10% aqueous ammonia solution was added was defined as 0 minutes, and torque was collected at one point every minute for 120 minutes. The maximum torque value over 120 minutes was determined, and the time when the torque reached 99% of the maximum torque value over 120 minutes was defined as the dissolution time. These results are shown in Tables 1 and 2.

[0037] Example 1 1,376 g of glacial acetic acid was weighed into a 5 L horizontal kneader reactor (PNV-5T model, manufactured by Irie Shokai Co., Ltd.) equipped with a biaxial stirring blade (PNV-5T Z-type stirring blade, made of SUS316L, manufactured by Irie Shokai Co., Ltd.), and 860 g of HPMC (having a methoxy group DS of 1.88, a hydroxypropoxy group MS of 0.24, and a viscosity of a 2 mass% aqueous solution at 20°C of 3.2 mPa s), 495.4 g of acetic anhydride, 262.3 g of succinic anhydride, and 415.0 g of sodium acetate were added, and an esterification reaction was carried out at 85°C for 5 hours to obtain a reaction solution. To the resulting reaction solution (75°C), water at 20°C was gradually added in an amount 5.0 times the mass of the reaction solution to obtain a suspension in which HPMCAS-1 precipitated. The precipitated HPMCAS-1 was filtered through an 80-mesh sieve to obtain crude HPMCAS-1. The obtained crude HPMCAS-1 was resuspended in water in an amount 10 times by mass relative to the raw material HPMC at 20°C, stirred for 10 minutes, and then filtered through an 80-mesh sieve. This procedure was repeated five times to obtain washed HPMCAS-1. The washed HPMCAS-1 was resuspended in water at 10 times the mass of the raw material HPMC at 20°C, and deliquified using a filtration-type centrifugal dehydrator (top-discharge centrifuge H-130A, manufactured by Kokusan Co., Ltd.) at a centrifugal effect of 600 G to obtain deliquified HPMCAS-1. The water content of the deliquified HPMCAS-1 was 67% by mass. 1 kg of deliquified HPMCAS-1 (moisture content 67% by mass, product temperature 8°C) was placed in a fluidized bed dryer (FD-LAB-1, manufactured by Powrex Corporation), and the first drying was initiated while maintaining an inlet air velocity of 2.8 m / sec and an inlet air temperature of 40°C. During drying, sampling was performed as appropriate to measure the moisture content. The product temperature reached 18°C ​​in 5 minutes after the start of the first drying and was maintained at 18°C ​​for 20 minutes. 20 minutes after the start of the first drying, the product temperature began to rise from 18°C, and after 40 minutes, the moisture content reached 27% by mass, confirming that the first drying had ended and the transition to the second drying had begun. 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 to the end of the first drying process. Subsequently, in the same fluidized bed dryer, a second drying step was continued under the same conditions as at the start of the first drying step, except that the inlet air temperature was changed to 80° C. 20 minutes after the inlet air temperature was changed, the product temperature reached 70° C., and the second drying step was terminated, resulting in the production of HPMCAS.

[0038] Example 2 First drying was started under the same conditions as in Example 1, except that 1 kg of deliquified HPMCAS-1 (moisture content 67% by mass, product temperature 8°C) was used, and the inlet air temperature of the fluidized bed dryer was changed to 60°C. During drying, sampling was performed as appropriate, and the moisture content was measured. Five minutes after the start of the first drying, the product temperature reached 23°C, and the product temperature was maintained at 23°C until 15 minutes. 15 minutes after the start of the first drying, the product temperature began to rise from 23°C, and 30 minutes later, the moisture content reached 22% by mass, confirming that the first drying had ended and the transition to the second drying had begun. The product temperature at this time was 26°C, and the product temperature did not exceed 26°C from the start of the first drying process until the end of the first drying process. Subsequently, in the same fluidized bed dryer, the second drying was continued under the same conditions as at the start of the first drying step, except that the inlet air temperature was changed to 80° C. 15 minutes after the inlet air temperature was changed, the product temperature reached 70° C., and the second drying was terminated, resulting in the production of HPMCAS.

[0039] Example 3 1,440 g of glacial acetic acid was weighed into a 5 L horizontal kneader reactor (PNV-5T model, manufactured by Irie Shokai Co., Ltd.) equipped with a biaxial stirring blade (Z-type stirring blade for PNV-5T, made of SUS316L, manufactured by Irie Shokai Co., Ltd.), and 900 g of HPMC (having a methoxy group DS of 1.88, a hydroxypropoxy group MS of 0.24, and a viscosity of 3.2 mPa s as a 2 mass% aqueous solution at 20°C), 460 g of acetic anhydride, 160 g of succinic anhydride, and 400 g of sodium acetate were added, and an esterification reaction was carried out at 85°C for 5 hours to obtain a reaction solution. To the resulting reaction solution (75°C), water at 20°C was gradually added in an amount 5.0 times the mass of the reaction solution to obtain a suspension in which HPMCAS-2 was precipitated. The precipitated HPMCAS-2 was filtered through an 80-mesh sieve to obtain crude HPMCAS-2. The obtained crude HPMCAS-2 was resuspended in water in an amount 10 times by mass relative to the raw material HPMC at 20°C, stirred for 10 minutes, and then filtered through an 80-mesh sieve. This procedure was repeated five times to obtain washed HPMCAS-2. The washed HPMCAS-2 was resuspended in water at 20°C in an amount 10 times the mass of the raw material HPMC, and deliquified using a filtration-type centrifugal dehydrator (top-discharge centrifuge H-130A, manufactured by Kokusan Co., Ltd.) at a centrifugal effect of 600 G to obtain deliquified HPMCAS-2. The water content of the deliquified HPMCAS-2 was 67% by mass. 1 kg of deliquified HPMCAS-2 (moisture content 67% by mass, product temperature 8°C) was placed in a fluidized bed dryer (FD-LAB-1, manufactured by Powrex Corporation), and the first drying was started while maintaining an inlet air velocity of 2.8 m / sec and an inlet air temperature of 40°C. During drying, sampling was performed as appropriate to measure the moisture content. The product temperature reached 18°C ​​in 5 minutes after the start of the first drying, and was maintained at 18°C ​​for 20 minutes. 20 minutes after the start of the first drying, the product temperature began to rise from 18°C, and after 40 minutes, the moisture content reached 28% by mass, confirming that the first drying had ended and the transition to the second drying had begun. 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 to the end of the first drying process. Subsequently, in the same fluidized bed dryer, the second drying was continued under the same conditions as at the start of the first drying step, except that the inlet air temperature was changed to 80° C. 20 minutes after the inlet air temperature was changed, the product temperature reached 70° C., and the second drying was terminated, resulting in the production of HPMCAS.

[0040] Comparative Example 1 Drying of 1 kg of deliquified HPMCAS-1 (moisture content 67% by mass, product temperature 8°C) was initiated under the same conditions as in Example 1, except that the inlet air temperature of the fluidized bed dryer was changed to 80°C. Five minutes after the start of drying, the product temperature reached 29°C and was maintained at 29°C for 10 minutes. The moisture content at this time was 61% by mass. Ten minutes after the start of drying, the product temperature began to rise from 29°C, and 25 minutes later, the moisture content reached 19% by mass. The product temperature at this time was 35°C. Drying was continued under the same conditions, and 40 minutes after the start of drying, the product temperature reached 70°C, at which point drying was terminated.

[0041] Comparative Example 2 First drying was started using 1 kg of deliquified HPMCAS-2 (moisture content 67% by mass, product temperature 8°C) under the same conditions as in Example 3, except that the inlet air temperature of the fluidized bed dryer was changed to 80°C. After the start of the first drying, the product temperature reached 29°C in 5 minutes and was maintained at 29°C for 10 minutes. The moisture content at this time was 63% by mass. 10 minutes after the start of the first drying, the product temperature began to rise from 29°C, and after 25 minutes, the moisture content reached 20% by mass, so the first drying was terminated. The product temperature at this time was 34°C. Subsequently, in the same fluidized bed dryer, a second drying was started under the same conditions as the first drying, without changing the inlet air temperature. 15 minutes after the start of the second drying, the product temperature reached 70°C, and the second drying was terminated.

[0042] [Table 1]

[0043] [Table 2]

[0044] The results of Examples 1 and 2 and the Comparative Example demonstrated that the first drying step, in which first dried HPMCAS having a moisture content of 30% by mass is obtained so that the product temperature does not exceed 28°C, and the HPMCAS obtained by further drying the first dried HPMCAS, have an excellent dissolution rate in a solvent. In particular, when fluidized bed drying is performed in the first drying step at a product temperature above 0°C and not higher than 20°C, the dissolution rate in a solvent is improved. Furthermore, the results of Example 3 revealed that the same effect was obtained even when the degree of substitution of HPMCAS was different.

Claims

1. a deliquification step of reacting hydroxypropyl methylcellulose with an acetylating agent and a succinoylating agent in the presence of a catalyst, and then mixing the reaction solution with water to obtain a hydroxypropyl methylcellulose acetate succinate suspension, and then deliquifying the resulting suspension to obtain deliquified hydroxypropyl methylcellulose acetate succinate; a first drying step in which the deliquor-removed hydroxypropyl methylcellulose acetate succinate is dried in a fluidized bed dryer so that the product temperature does not exceed 28°C until the moisture content reaches 30% by mass to obtain a first dried hydroxypropyl methylcellulose acetate succinate; a second drying step of further drying the first dried hydroxypropyl methylcellulose acetate succinate to obtain hydroxypropyl methylcellulose acetate succinate; A method for producing hydroxypropyl methylcellulose acetate succinate, comprising at least

2. The method for producing hydroxypropyl methylcellulose acetate succinate according to claim 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 claim 1, wherein the intake air temperature in the first drying step is 5 to 70°C.

4. 2. The method for producing hydroxypropyl methylcellulose acetate succinate according to claim 1, 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 claim 1, wherein the water content of the deliquor-dehydrated hydroxypropyl methylcellulose acetate succinate immediately before being introduced into the first drying step is 55 to 80% by mass.

6. 2. The method for producing hydroxypropyl methylcellulose acetate succinate according to claim 1, wherein the water content of the hydroxypropyl methylcellulose acetate succinate is 5% by mass or less.

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