Hydroxypropylmethylcellulose acetate succinate and method for producing same

Abstract

Provided is an industrially efficient production method for hydroxypropyl methyl cellulose acetate succinate having a high dissolution rate in a solvent. The present invention relates to a method for producing hydroxypropyl methyl cellulose acetate succinate, which comprises at least a liquid removal step, a first drying step and a second drying step, the hydroxypropyl methyl cellulose acetate succinate is dried under reduced pressure until the moisture content of the hydroxypropyl methyl cellulose acetate succinate is more than 0% by mass and 30% by mass or less in a manner that the product temperature of the hydroxypropyl methyl cellulose acetate succinate is more than 0 DEG C and not more than 25 DEG C.

Description

Technical Field

[0001] This invention relates to hydroxypropyl methylcellulose acetate succinate and its manufacturing method. Background Technology

[0002] Hydroxypropyl methylcellulose acetate succinate (hereinafter also known as "HPMCAS"), a high molecular weight cellulose with four substituents introduced into it: methyl (-CH3), hydroxypropyl (-C3H6OH), acetyl (-COCH3), and succinyl (-COC2H4COOH), is widely used in solid dispersions to improve the dissolution of poorly soluble drugs and in enteric coatings for tablets.

[0003] One method for manufacturing solid dispersions using HPMCAS involves dissolving a mixture of a poorly soluble drug and HPMCAS in a solvent, followed by removing the solvent by spray drying. As a method for enteric coating of tablets using HPMCAS, the general procedure is to dissolve HPMCAS in a solvent to prepare a coating solution, and then spray it onto the tablet to form a film on the tablet surface.

[0004] However, since HPMCAS is used for solid dispersions and enteric coatings, the dissolution of HPMCAS in solvents requires a long time. Therefore, there is a need to improve productivity by shortening the dissolution time.

[0005] As a method to shorten the dissolution time of HPMCAS in a solvent, there is a method that focuses on the particle size distribution of HPMCAS powder and sets the fraction of particles with a size of 841 to 1190 μm to 25% by weight or more (Patent Document 1). Existing technical documents Patent documents

[0006] Patent Document 1: Japanese Patent Publication No. 2017-501239 Summary of the Invention The problem the invention aims to solve

[0007] In the method described in Patent Document 1, there is room for improvement regarding the dissolution rate of the obtained HPMCAS powder in the solvent. Furthermore, in the method of Patent Document 1, water, at a weight of 12 to 20 times the total weight of the solvent used in the esterification reaction step, is used to precipitate the HPMCAS particles from the reaction solution, thus generating a large amount of water discharge. In addition, since the fraction of particles with a size of 841 to 1190 μm in the HPMCAS powder is more than 25% by weight, it is difficult to extract impurities from the interior of the HPMCAS particles during the washing process precipitated in water, potentially requiring a long washing time; there is still room for improvement. The present invention was made in view of the above circumstances, and its object is to provide an industrially efficient manufacturing method for HPMCAS, which has a fast dissolution rate in solvents. Solution for solving the problem

[0008] In order to solve the above-mentioned problems, the inventors conducted careful research and found that by setting a first drying step of dehydrated HPMCAS under reduced pressure drying at a temperature above 0°C and below 25°C to obtain first dried HPMCAS with a water content of less than 30%, and a second drying step of further drying the first dried HPMCAS to obtain HPMCAS, even without using complex and inefficient precipitation methods, it is possible to manufacture HPMCAS with fast dissolution rate and excellent solubility in solvents in an industrially efficient manner, thus completing the present invention. According to the present invention, a method for manufacturing hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose acetate succinate are provided. [1] A method for manufacturing hydroxypropyl methylcellulose succinate, comprising at least: 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 under reduced pressure at a temperature exceeding 0°C and below 25°C until the moisture content is exceeding 0% by mass and below 30% by mass, to obtain 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 [1], wherein, The pressure inside the dryer in the first drying process is 0.5–3 kPa abs. [3] The method for manufacturing hydroxypropyl methylcellulose acetate succinate as described in [1] or [2], wherein, The heating temperature of the dryer in the first drying process is 50-120℃. [4] A method for manufacturing hydroxypropyl methylcellulose acetate succinate as described in any one of [1] to [3], wherein, The first drying step is performed using a dryer selected from container rotary dryers, internal stirring dryers, and vibratory dryers. [5] A method for manufacturing hydroxypropyl methylcellulose succinate as described in any one of [1] to [4], wherein, The water content of the dehydrated hydroxypropyl methylcellulose acetate, which is about to be introduced into the first drying process, is 40-80% by mass. [6] A method for manufacturing hydroxypropyl methylcellulose acetate succinate as described in any one of [1] to [5], wherein, The water content of the hydroxypropyl methylcellulose acetate succinate is greater than 0% by mass and less than 5% by mass. [7] A method for manufacturing hydroxypropyl methylcellulose acetate succinate as described in any one of [1] to [6], wherein, The temperature of hydroxypropyl methylcellulose acetate succinate at the end of the second drying process is 60–120°C. [8] A hydroxypropyl methylcellulose acetate succinate, wherein... The pore volume of fine pores with diameters of 0.01–3.0 μm, measured by mercury porosimetry, is 0.5–2.0 mL / g. Invention Effects

[0009] According to the present invention, HPMCAS with a fast dissolution rate relative to the solvent can be manufactured using an industrially efficient method. By using HPMCAS obtained by the manufacturing method, the dissolution time when dissolving HPMCAS in a solvent can be shortened, and solutions can be prepared in a short time. Detailed Implementation

[0010] The HPMCAS manufacturing method of the present invention includes at least a dehydration step, a first drying step, and a second drying step. The HPMCAS manufacturing method of the present invention may also include a cleaning step and / or a pre-dehydration step, as needed.

[0011] [Liquid removal process] In the dehydration process, firstly, hydroxypropyl methylcellulose is reacted with an acetylation agent and a succinylation 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 suspension of hydroxypropyl methylcellulose acetate succinate (precipitation process); then, the suspension of hydroxypropyl methylcellulose acetate succinate is dehydrated to obtain dehydrated hydroxypropyl methylcellulose acetate succinate.

[0012] The following describes the method for obtaining hydroxypropyl methylcellulose (hereinafter referred to as "HPMC"), which is used as a raw material for HPMCs. HPMC can be obtained using known methods or commercially available products. For example, HPMC can be obtained by contacting a solution of alkali metal hydroxides such as sodium hydroxide and potassium hydroxide with flake, fragment, or powdered pulp to form alkali cellulose, followed by an etherification reaction with etherifying agents such as chloromethane and propylene oxide.

[0013] The alkali metal hydroxide solution used in the preparation of alkali cellulose is not particularly limited as long as it can produce alkali cellulose with the desired composition, but from an economic point of view, an aqueous solution of sodium hydroxide or potassium hydroxide is preferred. From the viewpoint of obtaining HPMC with a low number of undissolved fibers, its concentration is 23–60% by mass, more preferably 35–55% by mass.

[0014] After the production of alkali cellulose, etherifying agents such as chloromethane and propylene oxide are added to the alkali cellulose according to conventional methods to cause an etherification reaction, thereby obtaining HPMC.

[0015] From the viewpoint of obtaining HPMC with a low 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 1.70 to 2.00. From the viewpoint of obtaining HPMC with a low 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 0.60, and even more preferably 0.20 to 0.30. Non-soluble fibers refer to the water-insoluble portions of HPMC. HPMC exhibits water solubility by partially etherifying the hydroxyl groups of cellulose, thereby weakening the intramolecular and intermolecular hydrogen bonds. Since complete and uniform etherification is difficult industrially, HPMC may contain water-insoluble portions due to insufficient or uneven substitution of the ether groups, i.e., it may contain non-soluble fibers. If the final HPMC contains a large amount of non-soluble fibers, the enteric coating becomes uneven, the yield of enteric-coated formulations decreases, or frequent filter clogging occurs during the filtration process of the coating solution, leading to reduced productivity. Therefore, HPMC used as a raw material for HPMC is preferably HPMC with a low number of non-soluble fibers. The number of non-soluble fibers can be determined, for example, by analyzing the HPMC aqueous solution using a device such as a Coulter counter. It should be noted that the DS of methoxy groups in HPMC represents the degree of substitution, which is the average number of methoxy groups per unit of anhydrous glucose. The MS of hydroxypropoxy groups in HPMC represents the molar substitution, which is the average number of moles of hydroxypropoxy groups per mole of anhydrous glucose. The DS of methoxy groups and the MS of hydroxypropoxy groups in HPMC can be calculated by converting values ​​obtained from determinations based on the 18th revision of the Japanese Pharmacopoeia.

[0016] From the viewpoint of the composability during the esterification reaction, 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. The viscosity of a 2% by mass aqueous solution of HPMC at 20°C can be determined according to the capillary viscometer method in the 18th revised edition of the Japanese Pharmacopoeia.

[0017] From an economic point of view, the catalyst for the esterification process is preferably an alkali metal salt of carboxylic acids such as sodium acetate. The amount of catalyst can be arbitrarily selected as long as the degree of substitution of the obtained HPMCs is taken into account, but from the point of view of reaction efficiency, the molar ratio relative to the raw material HPMC is preferably 0.1 to 1.5, more preferably 0.6 to 1.1.

[0018] Among the esterifying agents used in the esterification process, acetic anhydride and acetyl chloride can be cited as acetylation agents, but from an economic point of view, acetic anhydride is preferred. The amount of acetylation agent is not particularly limited as long as it is sufficient to obtain the desired degree of substitution of HPMCs. However, from the point of view of reaction efficiency, the molar ratio relative to the raw material HPMC is preferably 0.1 to 1.5, more preferably 0.8 to 1.3. Among the esterifying agents used in the esterification process, succinic anhydride and succinic chloride can be cited as succinic agents, but from an economic point of view, succinic anhydride is preferred. The amount of succinylating agent is not particularly limited as long as it is sufficient to obtain the desired degree of substitution HPMCs. However, from the point of view of reaction efficiency, the molar ratio relative to the raw material HPMC is preferably 0.1 to 1.0, more preferably 0.3 to 0.5.

[0019] The esterification process can also be carried out in the presence of a solvent, preferably one capable of dissolving HPMC, the esterifying agent, and the catalyst. Examples of solvents include acetic acid, propionic acid, and butyric acid, but from an economic point of view, acetic acid is preferred. From the viewpoint of reaction rate, the amount of solvent used, relative to HPMC, is preferably 1.0 to 3.0 by mass, more preferably 1.2 to 2.0, and even more preferably 1.5 to 1.8. As a reactor used for the esterification reaction in the esterification process, examples include twin-shaft mixers that can knead highly viscous fluids into a homogeneous mixture. Specifically, commercially available mixers, such as kneaders and closed mixers, can be used. From the viewpoint of reaction rate or viscosity increase, the reaction temperature of the esterification process is preferably 60–100°C, more preferably 80–90°C. Furthermore, from the viewpoint of obtaining the desired degree of substitution (HPMCAS), the reaction time of the esterification process is preferably 1–8 hours, more preferably 3–6 hours.

[0020] After the esterification reaction, water may be added to the HPMC reaction solution to treat unreacted acetylation and succinylation agents (this treatment of mixing with water after the esterification reaction is also called "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, by mass ratio relative to HPMC.

[0021] Next, the process of mixing the reaction solution obtained in the esterification process with water and obtaining an HPMCAS suspension by precipitation of crude HPMCAS will be described. From the viewpoint of controlling the particle size of HPMCs in the HPMCs suspension, the amount of water mixed with the reaction solution in the precipitation process is preferably 3.0 to 50.0 by mass relative to the HPMCs used in the esterification reaction, more preferably 5.0 to 20.0. In addition, from the viewpoint of controlling the particle size of HPMCAS particles in the HPMCAS suspension, the temperature of the water mixed with the reaction solution in the precipitation process is preferably 0 to 50°C, more preferably 5 to 30°C. From the viewpoint of controlling the particle size of HPMCAS particles in the HPMCAS suspension, the temperature of the reaction solution before mixing with water is preferably 10 to 80°C, more preferably 10 to 50°C.

[0022] The obtained HPMCAS suspension may contain impurities such as salts, free acetic acid, and free succinic acid. Therefore, between the precipitation and desliming processes, a washing process may be included, if necessary, to wash away the crude HPMCAS in the HPMCAS suspension obtained in the precipitation process to obtain an HPMCAS suspension for the desliming process. Examples of methods for cleaning HPMCAS suspensions include removing a portion of the water from the HPMCAS suspension through filtration or similar methods, and then resuspending the HPMCAS in a clean solvent. In the cleaning process, this process of removing a portion of the water from the HPMCAS suspension through filtration or similar methods and then resuspending it in a solvent can be repeated multiple times. Effluent can be cited as an example of a solvent used for HPMCAS cleaning. Typically, this cleaning process uses filters such as intermittent stirring filters, continuous rotary pressure filters, continuous horizontal vacuum filters, water platform filters, or horizontal belt filters, for example, to clean coarse HPMCAS with water.

[0023] Next, the dehydration process will be explained. In the dehydration process, with the aim of reducing the water content of the HPMCAS suspension and reducing the drying load, the HPMCAS suspension is dehydrated by a dehydrator between the washing and drying processes, or between the precipitation and drying processes without a washing process, to obtain dehydrated HPMCAS. Examples of devices for dehydrating HPMCAS suspensions include pressure dehydrators, vacuum dehydrators, filter dehydrators, press dehydrators, and decanter centrifuges.

[0024] From the viewpoint of obtaining HPMCAS with excellent dissolution rate in solvent, the water content of the dehydrated HPMCAS obtained after the dehydration process is preferably 40-80% by mass, more preferably 45-75% by mass, and even more preferably 50-70% by mass. The moisture content of dehydrated HPMCAS can be determined according to the method described in the 18th revised edition of the Japanese Pharmacopoeia, "General Test Method 2. Physical Test Method - Loss on Drying Test Method". Specifically, the moisture content of HPMCAS is defined as {(total mass of HPMCAS - oven-dry mass of HPMCAS) / (total mass of HPMCAS)} × 100%. Here, "total mass of HPMCAS" refers to the mass of HPMCAS accurately weighed according to the "Loss on Drying Test Method" in the 18th revised edition of the Japanese Pharmacopoeia. Furthermore, "oven-dry mass of HPMCAS" refers to the mass of HPMCAS after drying according to the "Loss on Drying Test Method" in the 18th revised edition of the Japanese Pharmacopoeia. Here, when measuring the moisture content of "dehydrated HPMCAS", by replacing "HPMCAS" with "dehydrated HPMCAS", the moisture content of "dehydrated HPMCAS" can be measured and calculated. The moisture content of HPMCAS in each process, such as the moisture content of the first drying HPMCAS described later, can also be measured in the same way.

[0025] Furthermore, from the viewpoint of controlling the product temperature in the subsequent first drying process, the temperature of the dehydrated HPMCAS provided in the first drying process is preferably above 0°C and below 35°C, more preferably 5°C to 30°C, further preferably 10°C to 25°C, and most preferably 12°C to 20°C.

[0026] [Drying Process] In the drying process, the dehydrated HPMCAS obtained by the dehydration process is dried to a target moisture content (e.g., 0.1 to 5.0% by mass) under reduced pressure. The drying process consists of a first drying process to obtain a first dried HPMCAS and a second drying process to further dry the first dried HPMCAS to obtain HPMCAS.

[0027] [First Drying Process] In the first drying process, the dehydrated HPMCAS obtained through the reduced pressure drying and dehydration processes is dried to obtain the first dried HPMCAS. Here, reduced pressure drying refers to a method of drying by using a vacuum pump or the like to expel the gas from the drying device, maintaining the pressure inside the drying device below atmospheric pressure. From the viewpoint of obtaining HPMCAS with excellent drying speed and solvent solubility, the temperature of HPMCAS in the first drying step is above 0°C and below 25°C, preferably 5°C to 23°C, more preferably 10°C to 20°C, and even more preferably 12°C to 19°C. When the temperature is below 0°C, the moisture in the HPMCAS may freeze, reducing the drying speed. On the other hand, when the temperature exceeds 25°C, the pore volume of the HPMCAS, measured by mercury intrusion porosimetry (MIP) with a diameter of 0.01 to 3.0 μm, becomes smaller, making it impossible to obtain HPMCAS with excellent solvent solubility. Examples of drying apparatuses used in the first drying step include rotary container dryers, internally stirred dryers, vibrating dryers, drum dryers, belt dryers, and shelf dryers. Rotary container dryers, internally stirred dryers, and vibrating dryers are particularly preferred. It should be noted that fluidized bed dryers are not used in the first drying step of this invention. The drying equipment can be either batch-type or continuous. Furthermore, multiple drying equipment can be used in combination in the first drying process. From the perspective of temperature control and drying time in HPMCAS, the heating temperature in the first drying step is preferably 50℃~120℃, more preferably 60℃~110℃, and most preferably 70℃~100℃. Here, the heating temperature refers to the temperature of the heat medium (water, steam, etc.) passing through the jacket of the dryer when heating is performed using the jacket; the temperature of the hot water bath when heating is performed by immersing the dryer in a hot water bath; and the temperature of the electric heater when heating is performed by an electric heater. The pressure inside the drying device in the first drying step is only required to control the temperature of the product in the HPMCAS in the first drying step, and there are no particular restrictions, but it is preferably 0.5 to 3.0 kPa absolute pressure (abs.), more preferably 0.6 to 2.8 kPa abs., and even more preferably 0.65 to 2.3 kPa abs. Heating in the first drying step is preferably started after the pressure inside the drying apparatus reaches the aforementioned pressure range. If heating begins before the pressure inside the drying apparatus reaches the aforementioned pressure range, the temperature of HPMCAS may rise sharply, which not only fails to produce HPMCAS with excellent dissolution rates in the solvent, but may also sometimes cause a large amount of adhesion to the drying apparatus. There is no particular limitation on the time of the first drying process, but it is preferably 5 minutes to 300 minutes, more preferably 10 minutes to 200 minutes, and even more preferably 15 minutes to 100 minutes. From the viewpoint of obtaining HPMCAS with excellent solubility in solvents, the moisture content of the first dried HPMCAS obtained in the first drying process is greater than 0% by mass and less than 30% by mass, preferably 5% to 30% by mass, and more preferably 10% to 30% by mass. When the moisture content of the first dried HPMCAS exceeds 30% by mass, the pore volume of the fine pores in the HPMCAS with a diameter of 0.01 to 3.0 μm as measured by mercury porosimetry becomes smaller, making it difficult to obtain HPMCAS with excellent solubility in solvents.

[0028] [Second drying process] In the second drying step, HPMCAS obtained from the first drying step is further dried to obtain HPMCAS. The second drying step can be carried out by vacuum drying, just like the first drying step, or by a drying method other than vacuum drying. In the second drying process, the temperature of HPMCAS increases as drying proceeds. From the viewpoint of removing moisture and volatile impurities from HPMCAS, the temperature of HPMCAS at the end of the second drying process is preferably 60–120°C, more preferably 65–115°C, and even more preferably 70–110°C. As for the drying apparatus used in the second drying step, examples of dryers include rotary container dryers, internally stirred dryers, vibrating dryers, drum dryers, belt dryers, and tray dryers when vacuum drying is performed, and fluidized bed dryers when fluidized bed drying is performed. Among these, rotary container dryers, internally stirred dryers, and vibrating dryers are particularly preferred. The drying apparatus can be a batch dryer or a continuous dryer. The apparatus in the second drying step can be the same as the apparatus in the first drying step, or a different apparatus can be used. Furthermore, multiple drying apparatuses can be used in combination in the second drying step. From the perspective of temperature control and drying time of HPMCAS, the heating temperature in the second drying process is preferably 65-140°C, more preferably 70-130°C, and most preferably 75-120°C. When vacuum drying is performed in the second drying process, the pressure inside the drying apparatus is only required to control the product temperature of HPMCAS at the end of the second drying process, and there are no particular restrictions, but it is preferably 0.5 to 3.0 kPa abs., more preferably 0.6 to 2.8 kPa abs., and even more preferably 0.65 to 2.4 kPa abs. The time for the second drying process is not particularly limited, but it is preferably 5 to 200 minutes, more preferably 8 to 100 minutes, and even more preferably 10 to 50 minutes. The moisture content of the HPMCAS obtained in the second drying process is preferably greater than 0% by mass and less than 5% by mass, more preferably 0.1% to 4% by mass, and even more preferably 0.2% to 3% by mass.

[0029] [Hydroxypropyl methylcellulose acetate succinate] The degree of substitution of HPMCAS obtained by the manufacturing method of the present invention will be explained. 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 1.70 to 2.00. The MS concentration of hydroxypropoxy in HPMCAS is preferably 0.10–1.00, more preferably 0.20–0.60, and even more preferably 0.20–0.30. 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 succinyl group in HPMCAS preferably has a DS of 0.10 to 2.50, more preferably 0.10 to 1.00, and even more preferably 0.10 to 0.60. The ratio of the DS of acetyl to DS of succinyl in HPMCAS (acetyl / succinyl) is preferably 0.50 to 4.00, more preferably 0.80 to 3.70, and even more preferably 0.80 to 2.40. It should be noted that in HPMCAS, DS for methoxy, acetyl, and succinyl groups represents the degree of substitution, which is the average number of methoxy, acetyl, and succinyl groups per unit of anhydrous glucose. In HPMCAS, MS for hydroxypropoxy groups represents the molar substitution, which is the average number of moles of hydroxypropoxy groups per mole of anhydrous glucose. It should also be noted that the DS values ​​for methoxy, acetyl, and succinyl groups, and the MS values ​​for hydroxypropoxy groups in HPMCAS can be converted from the values ​​obtained by the methods described in the pharmaceutical section of the 18th revised edition of the Japanese Pharmacopoeia for "Hydroxypropyl methylcellulose acetate succinate".

[0030] The pore volume of HPMCAS with a diameter of 0.01–3.0 μm, as measured by mercury porosimetry, is preferably 0.5–2.0 mL / g, more preferably 0.6–2.0 mL / g, and even more preferably 0.8–1.4 mL / g. When the pore volume of HPMCAS with a diameter of 0.01–3.0 μm, as measured by mercury porosimetry, is less than 0.5 mL / g, the dissolution rate of HPMCAS relative to the solvent may sometimes be slower. The upper limit of the pore volume of HPMCAS with a diameter of 0.01–3.0 μm, as measured by mercury porosimetry, is not particularly limited, but is preferably 2.0 mL / g or less. The pore volume of pores with diameters of 0.01 to 3.0 μm, measured by mercury porosimetry, can be determined, for example, by using a mercury porosimetry porosimeter (e.g., the Autopore V9020 pore distribution measurement device manufactured by MicroMeritics) as the measuring and analytical device, after taking a sample of about 0.05 g in a standard sample cell and measuring it under an initial mercury pressure of 4 kPa, and then calculating the volume of pores with diameters of 0.01 to 3.0 μm.

[0031] HPMCAs obtained by the manufacturing method of the present invention are suitable for use in enteric coating of tablets and in the preparation of solid dispersions for improving the dissolution of poorly soluble drugs due to their fast dissolution rate and excellent solubility in solvents. To prepare a solution for enteric coating (coating composition), examples of solvents for dissolving HPMCAS include a mixed solution of water and alcohols such as methanol, ethanol, and isopropanol in a ratio of 2 to 4:6 to 8 (in other words, 1:1.5 to 1:4) (mass ratio), and an aqueous solution of 0.01 to 1.0% by mass of ammonia. When using an aqueous ammonia solution as a solvent, for example, after dispersing HPMCAS powder in water at room temperature, an amount of ammonia (e.g., ammonia concentration: 5-30% by mass) required to neutralize the carboxyl groups in HPMCAS is added, and the mixture is stirred to dissolve. From the viewpoint of the solubility of HPMCAS and the acid resistance of the solid formulation coated with the coating composition, the amount of ammonia added is preferably 70-120%, more preferably 80-110%, and even more preferably 95-105% relative to the carboxyl groups. To prepare a solution for spray drying, examples of solvents for dissolving HPMCAS include acetone, methanol, ethanol, isopropanol, methyl ethyl ester, ethyl ethyl ester, tetrahydrofuran, dichloromethane, and mixtures thereof.

[0032] From the viewpoint of solubility relative to the solvent and flowability as a powder, the loose bulk density of HPMCAS is preferably 0.20–0.34 g / cm³. 3 More preferably, it is 0.21–0.33 g / cm³. 3The so-called "loose bulk density" refers to the bulk density of a loosely packed state. It is determined by feeding the sample through a 24-mesh sieve from the top (23cm) of a cylindrical container into a cylindrical container with a diameter of 5.03cm and a height of 5.03cm (volume of 100ml), and then weighing the sample after leveling the top surface. From the viewpoint of solubility relative to the solvent and flowability as a powder, the close packing density of HPMCAS is preferably 0.20–0.36 g / cm³. 3 More preferably, it is 0.22–0.32 g / cm³. 3 "Tight packing density" refers to the packing density of the cylindrical container after it has been compacted by tapping. Tapping refers to the process of repeatedly dropping the cylindrical container filled with the sample from a certain height, applying a slight impact to the bottom to achieve tight packing. In practice, similar to the determination of loose packing density, the sample is filled into the cylindrical container, the top surface is leveled, and the sample is weighed. A lid is then fitted over the container, and the sample is added to the top edge of the lid. The container is then subjected to 180 free-fall drops from a height of 1.8 cm. After tapping, the lid is removed, the sample is leveled on the top surface of the cylindrical container, and the sample is weighed. The packing density in this state is taken as the tight packing density. "Dense packing density" and "loose packing density" can be determined using a Powder Tester manufactured by Hosokawa Micron Ltd.

[0033] From the viewpoint of powder flowability, the compressibility of HPMCAS is preferably 0% to 12%, more preferably 2% to 10%, and even more preferably 5% to 10%. The compressibility is calculated using the following formula. Compressibility (%) = {(Closed packing density - Loose packing density) / Closed packing density} × 100

[0034] From the viewpoint of the dissolution rate of HPMCAS relative to the solvent and its cleanability in the manufacturing process of HPMCAS, the average particle size of HPMCAS is preferably 100 to 1000 μm, more preferably 200 to 800 μm, even more preferably 250 to 600 μm, and particularly preferably 300 to 540 μm. The average particle size of HPMCAS can be measured by dry sieving as described in JIS Z 8815.

[0035] The average value of the ratio (L / D) of the maximum diameter (L) to the minimum diameter (D) of HPMCAS is preferably more than 1.0 and less than 2.0, more preferably 1.1 to 1.8. If L / D is 2.0 or more, the fluidity of the powder deteriorates, and it becomes difficult to measure HPMCAS and to put it into a container during solution preparation. The ratio of the maximum diameter (L) to the minimum diameter (D) of HPMCAS can be measured and calculated as follows. Using a digital microscope VHX-2000 manufactured by KEYENCE Corporation, 10 mg of HPMCAS powder was dispersed in a petri dish, and the maximum diameter (L) and minimum diameter (D) of the particles were measured at a magnification of 50 times, and L / D was calculated from the ratio of the maximum diameter (L) to the minimum diameter (D) of each particle. The number of particles measured in one measurement was set to 30 or more, and this was repeated 10 times or more, and the average value of 300 or more particles in total was set. [Examples]

[0036] Hereinafter, the present invention will be described in detail by way of examples and comparative examples, but the present invention is not limited by any of these examples. It should be noted that the dissolution time of HPMCAS with respect to the solvent was measured by the method described below to evaluate the dissolution rate of HPMCAS. In addition, the average particle diameter of HPMCAS was measured by the method shown below. The water content, substitution degree, pore volume of pores with a diameter of 0.01 to 3.0 μm measured by mercury intrusion porosimetry, bulk density and tapped density, and the ratio (L / D) of the maximum diameter (L) to the minimum diameter (D) of HPMCAS were measured by the above methods. In addition, the degree of compression was calculated from the bulk density and the tapped density by the above method. The manufacturing conditions of HPMCAS in the examples and comparative examples are shown in Table 1, and the physical properties of HPMCAS obtained in the examples and comparative examples are shown in Table 2.

[0037] <Dissolution time of HPMCAS with respect to the solvent> Accurately weigh 3.0 g of HPMCAS and add it to the CC27 measuring cup (manufactured by Anton Paar, CC27 / T200 / AL, an aluminum cylindrical container with a diameter of 29 mm and a height of 68 mm) of the rheometer MCR 301 (manufactured by Anton Paar). Then add distilled water at 25°C to finally make the concentration of HPMCAS in the solution ............

[0038] <Average particle size of HPMCAS> Supply 50 g of HPMCAS (humidified at 40°C and 75% humidity to make the moisture content 5 - 6 mass%) to a Ro-TAP sieve shaker (manufactured by TanaKa tec) equipped with 8 sieves arranged from top to bottom in the order of inner diameters of 200 mm and pore sizes of 1000 μm, 710 μm, 500 μm, 355 μm, 250 μm, 180 μm, 150 μm, and 106 μm. Perform sieving under the conditions of vibration frequency: 250 rpm, hammer strike frequency: 67 times per minute, and vibration time: 20 minutes. After sieving, measure the weight of HPMCAS on each sieve and calculate the cumulative mass (%) of the oversize material. Take the horizontal axis as the sieve pore size (μm) and the vertical axis as the cumulative mass (%) of the oversize material. The value of the sieve pore size at the intersection of the straight line connecting the two plotted points sandwiching the cumulative mass of the oversize material of 50% when plotting the graph of each sieve pore size and the cumulative mass (%) of the oversize material of each sieve pore is taken as the average particle size of HPMCAS particles.

[0039] 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), and 2% by mass aqueous solution of HPMC with a viscosity of 3.2 mPa·s at 20°C were added. 495.4g of acetic anhydride, 262.3g of succinic anhydride, and 415.0g of sodium acetate were also added. The esterification reaction was carried out at 85°C for 5 hours to obtain the reaction solution. 963.2% water was added to the obtained reaction solution and mixed to obtain a post-treated reaction solution. Water at 20°C, at a mass ratio of 3.0 times that of the post-treated reaction solution (35°C), was slowly added to the post-treated reaction solution to obtain a suspension in which HPMCAS precipitated. The precipitated HPMCAS was then filtered through an 80-mesh sieve to obtain coarse HPMCAS. The obtained crude HPMCs were resuspended in water at 20°C with a mass of 10 times that of the raw material HPMC. After stirring for 10 minutes, the process of filtering through an 80-mesh sieve was repeated 5 times to obtain the cleaned HPMCs. The cleaned HPMCAS was resuspended in water at 20°C at a mass ratio of 10 times that of the raw material HPMC, and then dehydrated using a filter-type centrifugal dewatering machine (top-discharge type H-130A centrifuge, manufactured by KOKUSAN) at a centrifugal force of 600G to obtain dehydrated HPMCAS. The water content of the dehydrated HPMCAS was 67% by mass. 400g of dehydrated HPMCAS (67% by mass moisture content) was added to a 1L flask, and the pressure inside the flask was reduced to 2kPa abs. While maintaining the pressure at 2kPa abs., the flask was immersed in a 90°C hot water bath and rotated at 30 rpm to begin the first drying process (rotary container dryer). The temperature remained constant at 20°C for 35 minutes after the start of the first drying. After 35 minutes, the temperature began to rise from 20°C, reaching 25°C after 40 minutes, thus ending the first drying process. According to another experiment, the moisture content of the HPMCAS at the end of the first drying process was 27% by mass. The first drying time was 40 minutes. Next, in the same flask, under the same conditions as the first drying, including pressure, hot water bath temperature, and rotation speed, a second drying process was initiated. The initial temperature of the sample at the start of the second drying was 25°C, and it rose to 80°C 18 minutes after the start of the second drying. Rotation of the flask was stopped, and the flask was removed from the hot water bath. Nitrogen gas was introduced into the flask to restore it to atmospheric pressure, and 125g of HPMCAS was recovered from the flask. The second drying time was 18 minutes. When the ratio (L / D) of the maximum diameter (L) to the minimum diameter (D) of the obtained HPMCAS was measured, its value was 1.7.

[0040] Examples 2-4 HPMCAS was obtained in the same manner as in Example 1, except that the pressure and temperature in the first drying and the pressure in the second drying were changed as shown in Table 1.

[0041] Example 5 Except that the amounts of acetic anhydride were adjusted to 436 g, succinic anhydride to 163 g, and sodium acetate to 376 g in the esterification reaction, HPMCAS was obtained by the same method as in Example 3.

[0042] Comparative Example 1 400 g of dehydrated HPMCAS (67% by mass) was added to a fluidized bed dryer and dried at a gas supply temperature of 80°C. The temperature of the HPMCAS remained constant at 33°C for 30 minutes from the start of the first drying process. The first drying process ended when the moisture content of the HPMCAS reached 30% by mass. Then, a second drying process was carried out at a gas supply temperature of 80°C until the temperature reached 75°C, yielding the final HPMCAS.

[0043] Comparative Example 2 Except for changing the pressure and temperature in the first drying and the pressure in the second drying as shown in Table 1, HPMCAS was obtained using the same method as in Example 1. It should be noted that in the first drying, the drying process ended when the moisture content of the HPMCAS reached 30% by mass.

[0044] Table 1 Table 2

[0045] As can be seen from the results of Examples 1-4 and Comparative Examples 1 and 2, HPMCAS obtained by a method comprising a first drying step of performing vacuum drying at a temperature exceeding 0°C and below 25°C to obtain HPMCAS with a moisture content exceeding 0% and below 30%, and a second drying step of further drying the first-dried HPMCAS, exhibits excellent dissolution rates in solvents. In particular, in the first drying step, performing vacuum drying at a temperature exceeding 0°C and below 20°C further increases the dissolution rate of HPMCAS in solvents. Furthermore, the results of Example 5 show that the same effect is achieved even with different degrees of substitution of HPMCAS.

Claims

1. A method for manufacturing hydroxypropyl methylcellulose acetate succinate, wherein, At least including: 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 under reduced pressure at a temperature exceeding 0°C and below 25°C until the moisture content is exceeding 0% by mass and below 30% by mass, to obtain 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 pressure inside the dryer in the first drying process is 0.5–3 kPa abs.

3. The method for manufacturing hydroxypropyl methylcellulose acetate succinate as described in claim 1, wherein, The heating temperature of the dryer in the first drying process is 50-120℃.

4. The method for manufacturing hydroxypropyl methylcellulose acetate succinate as described in claim 1, wherein, The first drying step is performed using a dryer selected from container rotary dryers, internal stirring dryers, and vibratory dryers.

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 40-80% 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 greater than 0% by mass and less than 5% by mass.

7. The method for manufacturing hydroxypropyl methylcellulose acetate succinate as described in claim 1, wherein, The temperature of hydroxypropyl methylcellulose acetate succinate at the end of the second drying process is 60–120°C.

8. A hydroxypropyl methylcellulose acetate succinate, wherein, The pore volume of fine pores with diameters of 0.01–3.0 μm, measured by mercury porosimetry, is 0.5–2.0 mL / g.

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