Hydroxypropyl methylcellulose acetate succinate and method for producing the same

Abstract

To provide an efficient industrial method for producing hydroxypropyl methylcellulose acetate succinate that exhibits a rapid dissolution rate in a solvent.SOLUTION: 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 vacuum-dried so that its water content becomes more than 0 mass% and 30 mass% or less, and its product temperature becomes more than 0°C and 25°C or less.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Hydroxypropyl methylcellulose acetate succinate (hereinafter referred to as "HPMCAS") is a polymer in which four types of substituents, namely, methyl group (-CH3), hydroxypropyl group (-C3H6OH), acetyl group (-COCH3), and succinyl group (-COC2H4COOH), have been introduced into cellulose. It is widely used in applications such as solid dispersions for improving the dissolution of poorly soluble drugs and enteric coating for tablets.

[0003] One method for producing a solid dispersion using HPMCAS involves dissolving a mixture of a poorly soluble drug and HPMCAS in a solvent, followed by spray drying to remove the solvent. The most common method for enteric coating tablets with HPMCAS is to dissolve HPMCAS in a solvent to prepare a coating solution, which is then sprayed onto tablets to form a film on the tablet surface.

[0004] However, when HPMCAS is dissolved in a solvent for use in solid dispersions or enteric coatings, it takes a long time to dissolve HPMCAS, and there is a need to improve productivity by shortening the dissolution time.

[0005] One method for shortening the time required to dissolve HPMCAS in a solvent focuses on the particle size distribution of the HPMCAS powder, and sets the fraction of particles having a size of 841 to 1,190 μm to 25% by weight or more (Patent Document 1). [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] The method described in Patent Document 1 leaves room for improvement in the dissolution rate of the resulting HPMCAS powder in the solvent. Furthermore, the method described in Patent Document 1 involves precipitating HPMCAS particles from the reaction solution using water in an amount 12 to 20 times the total weight of the solvent used in the esterification reaction stage, resulting in the generation of a large amount of wastewater. Furthermore, because the proportion of particles with a size of 841 to 1,190 μm in the HPMCAS powder is as high as 25% by weight or more, impurities are difficult to extract from the interior of the HPMCAS particles during the washing process of the HPMCAS particles precipitated in water, potentially resulting in a long washing time, leaving room for improvement. The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an industrially efficient method for producing HPMCAS, which has a high dissolution rate in a solvent. [Means for solving the problem]

[0008] As a result of intensive research to solve the above-mentioned problems, the present inventors have found that HPMCAS that dissolves quickly in solvents and has excellent solubility can be produced industrially and efficiently by a first drying step in which deliquified HPMCAS is dried under reduced pressure at a product temperature of above 0°C but not exceeding 25°C to obtain first dried HPMCAS having a moisture content of 30% or less, and a second drying step in which the first dried HPMCAS is further dried to obtain HPMCAS, without using a complicated and inefficient precipitation method, and have thereby completed the present invention. According to the present invention, there are provided the following method for producing hydroxypropyl methylcellulose acetate succinate and 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 deliquorized hydroxypropyl methylcellulose acetate succinate is dried under reduced pressure at a product temperature of more than 0°C and not more than 25°C until the moisture content is more than 0% by mass and not more than 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 [1], wherein the pressure inside the dryer in the first drying step is 0.5 to 3 kPa abs. [3] The method for producing hydroxypropyl methylcellulose acetate succinate according to [1] or [2], wherein the heating temperature of the dryer in the first drying step is 50 to 120°C. [4] The method for producing hydroxypropyl methylcellulose acetate succinate according to any one of [1] to [3], wherein the first drying step is carried out using a dryer selected from a container rotary dryer, an internal stirring dryer, and a vibration dryer. [5] The method for producing hydroxypropyl methylcellulose acetate succinate according to any one of [1] to [4], wherein the water content of the deliquor-dehydrated hydroxypropyl methylcellulose acetate succinate immediately before being introduced into the first drying step is 40 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 more than 0 mass% and 5 mass% or less. [7] The method for producing hydroxypropyl methylcellulose acetate succinate according to any one of [1] to [6], wherein the product temperature of the hydroxypropyl methylcellulose acetate succinate at the end of the second drying step is 60 to 120°C. [8] Hydroxypropyl methylcellulose acetate succinate, having a pore volume of 0.5-2.0 mL / g for pores with diameters of 0.01-3.0 μm as measured by mercury intrusion porosimetry. [Effects of the Invention]

[0009] According to the present invention, HPMCAS, which has a rapid dissolution rate in solvents, can be produced industrially and efficiently. By using HPMCAS obtained by the above production method, the dissolution time when dissolving HPMCAS in a solvent can be shortened, and a solution can be prepared in a short time. DETAILED DESCRIPTION OF THE INVENTION

[0010] The method for producing HPMCAS of the present invention comprises 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 comprise a washing step and / or a preliminary deliquoring step, as 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] This section explains 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 commercially available. 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 cause an etherification reaction.

[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 is 23 to 60% by mass, more preferably 35 to 55% by mass, from the viewpoint of obtaining HPMC with a small number of undissolved fibers.

[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 1.70 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 0.60, and even more preferably 0.20 to 0.30. 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 may be selected as desired taking into consideration the degree of substitution of the resulting HPMCAS, but from the viewpoint of reaction efficiency, the molar ratio of the catalyst 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 step, acetylating agents include acetic anhydride and acetyl chloride, with acetic anhydride being preferred from the viewpoint of economy. The amount of acetylating agent is not particularly limited as long as HPMCAS with the desired degree of substitution is obtained, but from the viewpoint 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. 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 not particularly limited as long as HPMCAS with the desired degree of substitution is obtained, but from the viewpoint of reaction efficiency, the molar ratio relative to the starting HPMC is preferably 0.1 to 1.0, more preferably 0.3 to 0.5.

[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 1 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 HPMCAS reaction solution to treat any unreacted acetylating agent and succinoylating agent (the process 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, by mass ratio relative to the HPMC.

[0021] Next, the step of mixing the reaction solution obtained in the esterification step with water to precipitate crude HPMCAS and obtain a suspension of HPMCAS will be described. 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 mass ratio relative to the HPMC used in the esterification reaction, from the viewpoint of controlling the particle size of the HPMCAS particles in the HPMCAS suspension. The temperature of the water mixed with the reaction solution in the precipitation step is preferably 0 to 50°C, more preferably 5 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 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. The HPMCAS suspension may be washed by removing a portion of the 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.

[0023] Next, the liquid removal step will be described. 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. Examples of devices used for dehydrating the HPMCAS suspension include pressure dehydrators, vacuum dehydrators, filtration-type centrifugal dehydrators, compression-type dehydrators, decanter-type centrifuges, and the like.

[0024] The water content of the deliquified HPMCAS obtained after the deliquification step is preferably 40 to 80% by mass, more preferably 45 to 75% by mass, and most preferably 50 to 70% by mass, from the viewpoint of obtaining HPMCAS with an excellent dissolution rate in a solvent. 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.

[0025] 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 35°C, more preferably 5°C to 30°C, even more preferably 10°C to 25°C, and most preferably 12°C to 20°C.

[0026] [Drying process] In the drying step, the deliquified HPMCAS obtained in the deliquifying step is dried under reduced pressure to a desired moisture content (for example, 0.1 to 5.0% by mass). The drying step comprises a first drying step for obtaining a first dried HPMCAS, and a second drying step for further drying the first dried HPMCAS to obtain HPMCAS.

[0027] [First drying process] In the first drying step, the deliquified HPMCAS obtained in the deliquifying step is dried under reduced pressure to obtain first dried HPMCAS. Here, reduced pressure drying refers to a method in which gas is evacuated from a drying apparatus using a vacuum pump or the like to maintain the pressure inside the drying apparatus at or below atmospheric pressure. From the viewpoint of obtaining HPMCAS with a high drying rate and a high dissolution rate in a solvent, the product temperature of the HPMCAS in the first drying step is above 0°C and not higher than 25°C, preferably 5°C to 23°C, more preferably 10°C to 20°C, and even more preferably 12°C to 19°C. If the product temperature is below 0°C, the water in the HPMCAS may freeze, resulting in a decrease in the drying rate. On the other hand, if the product temperature exceeds 25°C, the pore volume of pores in the HPMCAS with a diameter of 0.01 to 3.0 μm measured by mercury intrusion porosimetry will be small, and HPMCAS with a high dissolution rate in a solvent will not be obtained. Drying apparatuses used in the first drying step include container rotary dryers, internal stirring dryers, vibration dryers, drum dryers, belt dryers, and tray dryers. Among these, container rotary dryers, internal stirring dryers, and vibration dryers are particularly preferred. Note that the use of a fluidized bed dryer is excluded in the first drying step of the present invention. The drying apparatus may be of a batch type or a continuous type. In the first drying step, a plurality of drying apparatuses may be used in combination. From the viewpoints of controlling the HPMCAS product temperature and drying time, the heating temperature in the first drying step is preferably 50° C. to 120° C., more preferably 60° C. to 110° C., and most preferably 70° C. to 100° C. 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 water bath when heating is performed by immersing the dryer in a water bath, etc., and the temperature of the electric heater when heating is performed using an electric heater, etc. The pressure inside the dryer in the first drying step is not particularly limited as long as the product temperature of the HPMCAS in the first drying step can be controlled, but 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 2.3 kPa abs. Heating in the first drying step is preferably initiated after the pressure inside the dryer reaches the above-mentioned pressure range. If heating is initiated before the pressure inside the dryer reaches the above-mentioned pressure range, the product temperature of the HPMCAS will rise rapidly, which will not only prevent HPMCAS from dissolving quickly in a solvent, but may also result in a large amount of adhesion to the dryer. The time for the first drying step is not particularly limited, but is preferably 5 to 300 minutes, more preferably 10 to 200 minutes, and even more preferably 15 to 100 minutes. The water content of the first dried HPMCAS obtained in the first drying step is greater than 0% by mass and not more than 30% by mass, preferably 5% to 30% by mass, and more preferably 10% to 30% by mass, from the viewpoint of obtaining HPMCAS with a high dissolution rate in solvents. If the water content of the first dried HPMCAS exceeds 30% by mass, the pore volume of pores in the HPMCAS with diameters of 0.01 to 3.0 μm measured by mercury intrusion porosimetry will be small, and HPMCAS with a high dissolution rate in solvents will not be obtained.

[0028] [Second drying process] In the second drying step, the first dried HPMCAS obtained in the first drying step is further dried to obtain HPMCAS. The second drying step may be carried out by drying under reduced pressure, as in the first drying step, or by a drying method other than drying under reduced pressure. In the second drying step, the product temperature of the HPMCAS increases as the drying progresses. From the viewpoint of removing moisture and volatile impurities in the HPMCAS, the product temperature of the HPMCAS at the end of the second drying step is preferably 60 to 120°C, more preferably 65 to 115°C, and even more preferably 70 to 110°C. Examples of drying apparatuses used in the second drying step include container rotary dryers, internal stirring dryers, vibration dryers, drum dryers, belt dryers, and tray dryers when performing reduced pressure drying, and fluidized bed dryers when performing fluidized bed drying. Among these, container rotary dryers, internal stirring dryers, and vibration dryers are particularly preferred. The drying apparatus may be a batch type or a continuous type. The apparatus used in the second drying step may be the same as or different from the apparatus used in the first drying step. Furthermore, a combination of multiple drying apparatuses may be used in the second drying step. The heating temperature in the second drying step is preferably 65°C to 140°C, more preferably 70°C to 130°C, and most preferably 75°C to 120°C, from the viewpoints of controlling the product temperature of HPMCAS and drying time. When reduced-pressure drying is performed in the second drying step, the pressure inside the drying apparatus is not particularly limited as long as the product temperature of the HPMCAS at the end of the second drying step can be controlled, but 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 step is not particularly limited, but 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 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 0.2% to 3% by mass.

[0029] [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 1.70 to 2.00. The MS of the hydroxypropoxy group in HPMCAS is preferably 0.10 to 1.00, more preferably 0.20 to 0.60, and even more preferably 0.20 to 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 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. 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, and even more preferably 0.80 to 2.40. 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.

[0030] The pore volume of HPMCAS pores having a diameter of 0.01 to 3.0 μm as measured by mercury intrusion porosimetry is preferably 0.5 to 2.0 mL / g, more preferably 0.6 to 2.0 mL / g, and even more preferably 0.8 to 1.4 mL / g. If the pore volume of pores having a diameter of 0.01 to 3.0 μm as measured by mercury intrusion porosimetry is less than 0.5 mL / g, the dissolution rate of HPMCAS in the solvent may be slow. There is no particular upper limit to the pore volume of pores having a diameter of 0.01 to 3.0 μm as measured by mercury intrusion porosimetry, but it is preferably 2.0 mL / g or less. The pore volume of pores with a diameter of 0.01 to 3.0 μm measured by mercury intrusion porosimetry is measured, for example, by placing approximately 0.05 g of sample in a standard cell using a mercury intrusion porosimeter (e.g., Micromeritics' Autopore V9020 pore size distribution analyzer). The volume can be determined by taking a sample, 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 production method of the present invention has a rapid dissolution rate in solvents and excellent solubility, and is therefore suitable for use in enteric coating of tablets and in preparing solid dispersions to improve the dissolution of poorly soluble drugs. Examples of solvents for dissolving HPMCAS to prepare an enteric coating solution (coating composition) include a mixture of water and an alcohol such as methanol, ethanol, or isopropanol in a mass ratio of 2-4:6-8 (in other words, 1:1.5 to 1:4), and a 0.01-1.0% by mass aqueous ammonia solution. When an aqueous ammonia solution is used as the solvent, for example, HPMCAS powder is dispersed in water at room temperature, and then an amount of aqueous ammonia (e.g., ammonia concentration: 5 to 30% by mass) required to neutralize the carboxyl groups in the HPMCAS is added and the mixture is stirred and dissolved. From the viewpoints of the solubility of HPMCAS and the acid resistance of the solid preparation coated with the coating composition, the amount of ammonia added is preferably 70 to 120%, more preferably 80 to 110%, and even more preferably 95 to 105% of the carboxyl groups. Solvents in which HPMCAS can be dissolved to prepare a solution for spray drying include acetone, methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, tetrahydrofuran, dichloromethane, and mixtures thereof.

[0032] The loose bulk density of HPMCAS is preferably 0.20 to 0.34 g / cm from the viewpoint of solubility in a solvent and flowability as a powder. 3 , more preferably 0.21 to 0.33 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 of HPMCAS is preferably 0.20 to 0.36 g / cm from the viewpoint of solubility in a solvent and flowability as a powder. 3 , more preferably 0.22 to 0.32 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.

[0033] From the viewpoint of flowability as a powder, the compressibility of HPMCAS is preferably 0% to 12%, more preferably 2% to 10%, and even more preferably 5% to 10%. The compression ratio was calculated using the following formula: Compressibility (%) = {(packed bulk density - loose bulk density) / packed bulk density} x 100

[0034] 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, from the viewpoints of the dissolution rate of HPMCAS in a solvent and the washability in the manufacturing process of HPMCAS. The average particle size of HPMCAS can be measured by dry sieving as described in JIS Z 8815.

[0035] The average ratio (L / D) of the maximum diameter (L) to the minimum diameter (D) of HPMCAS is preferably greater than 1.0 and less than 2.0, more preferably 1.1 to 1.8. If the L / D is 2.0 or greater, the flowability of the powder deteriorates, making HPMCAS difficult to handle when measuring it out or pouring it into a container to prepare a solution. 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, 10 mg of HPMCAS powder is dispersed in a petri dish φ90×15, and the maximum diameter (L) and minimum diameter (D) of the particles are measured at a magnification of 50 times. The ratio L / D is determined by the ratio of the maximum diameter (L) to the minimum diameter (D) of each particle. The number of particles measured in one measurement is 30 or more, and this is repeated 10 or more times, and the average value of 300 or more particles is taken.

Example

[0036] Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples. Note that the dissolution rate of HPMCAS in a solvent was evaluated by measuring the dissolution time by the method shown below. Also, the average particle diameter of HPMCAS was measured by the method shown below. The water content, degree of substitution, pore volume of pores with a diameter of 0.01 to 3.0 μm measured by mercury intrusion porosimetry, bulk density in the loose state and bulk density in the compacted state, and the ratio (L / D) of the maximum diameter (L) to the minimum diameter (D) were measured by the above-mentioned methods. Also, the degree of compression was calculated from the bulk density in the loose state and the bulk density in the compacted state by the above-mentioned method. These results are shown in Tables 1 to 2.

[0037] <Dissolution time of HPMCAS in a solvent> Accurately weigh 3.0 g of HPMCAS into a CC27 measuring cup (manufactured by Anton Paar, model CC27 / T200 / AL, an aluminum cylindrical container with a diameter of 29 mm and a height of 68 mm) of a rheometer MCR301 (manufactured by Anton Paar). Finally, add distilled water at 25°C so that the HPMCAS concentration in the solution is 10% by mass, and use a blade-type measuring jig (manufactured by Anton Paar, model ST24-2D / 2V / 2V-30) to stir and mix well to completely disperse HPMCAS in distilled water. Set the measuring cup and the blade-type measuring jig on the device, and stir the dispersion at 400 rpm for 2 minutes while maintaining the temperature at 25°C. After 2 minutes, while continuing to maintain the temperature at 25°C and stir at 400 rpm, add a 10% aqueous ammonia solution necessary to neutralize 100% of the carboxyl groups in HPMCAS. Taking the time when the 10% aqueous ammonia solution is added as 0 minutes, collect the torque every minute for 120 minutes, find the maximum value of the torque in 120 minutes, and define the time when the torque reaches 99% of the maximum value of the torque in 120 minutes as the dissolution time.

[0038] <Average particle size of HPMCAS> Subject 50 g of HPMCAS (humidity-adjusted at 40°C and 75% humidity so that the moisture content is 5 - 6% by mass) to a Ro-Tap sieve shaker (manufactured by Tanaka Tech) with eight sieves having inner diameters of 200 mm and mesh openings of 1000 μm, 710 μm, 500 μm, 355 μm, 250 μm, 180 μm, 150 μm, and 106 μm installed in this order from the top. Perform sieving under the conditions of a shaking frequency of 250 rpm, a hammering frequency of 67 times per minute, and a shaking time of 20 minutes. After sieving, measure the weight on each sieve and determine the cumulative sieve residue mass (%). Taking the horizontal axis as the mesh opening (μm) and the vertical axis as the cumulative sieve residue mass (%), the value of the mesh opening at the intersection of the straight line connecting two points sandwiching the cumulative sieve residue mass of 50% when plotting the cumulative sieve residue mass (%) of each mesh opening and the cumulative sieve residue mass (%) of the sieve of each mesh opening is defined as the average particle size of HPMCAS.

[0039] 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, 963.2 g of water was added and mixed to obtain a post-treated reaction solution. To the post-treated reaction solution (35°C), 3.0 times the mass of water at 20°C was gradually added to obtain a suspension in which HPMCAS was precipitated. The precipitated HPMCAS was filtered through an 80-mesh sieve to obtain crude HPMCAS. The obtained crude HPMCAS 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. The washed HPMCAS was resuspended in water at 20°C in an amount 10 times the mass of the raw 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. The water content of the deliquified HPMCAS was 67% by mass. 400 g of deliquified HPMCAS (water content 67% by mass) was placed in a 1-L flask, and the pressure inside the flask was reduced to 2 kPa abs. using a pump. While maintaining the pressure inside the flask at 2 kPa abs., the flask was immersed in a water bath at 90°C and rotated at 30 rpm to initiate primary drying (container rotary dryer). The product temperature remained constant at 20°C for 35 minutes after the start of primary drying. 35 minutes after the start of primary drying, the product temperature began to rise from 20°C, and after 40 minutes, the product temperature reached 25°C, and primary drying was terminated. A separate experiment revealed that the moisture content of the HPMCAS at the end of primary drying was 27% by mass. The primary drying time was 40 minutes. Subsequently, a second drying was started in the same flask while maintaining the same conditions as the first drying: pressure inside the flask, water bath temperature, and flask rotation speed. The product temperature was 25°C when the second drying started, and 18 minutes after the start of the second drying, the product temperature had risen to 80°C. The rotation of the flask was stopped, and the flask was removed from the water bath. Nitrogen gas was introduced into the flask to return it to atmospheric pressure, and 125 g of HPMCAS was recovered from the flask. The second drying time was 18 minutes. The ratio (L / D) of the maximum diameter (L) to the minimum diameter (D) of the obtained HPMCAS was measured and found to be 1.7.

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

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

[0042] Comparative Example 1 400 g of deliquified HPMCAS (moisture content 67% by mass) was placed in a fluidized bed dryer and dried at an inlet air temperature of 80°C. The product temperature of the HPMCAS was constant at 33°C for 30 minutes after the start of the first drying. The first drying was terminated when the moisture content of the HPMCAS in the first drying reached 30% by mass. Next, a second drying was performed at an inlet air temperature of 80°C until the product temperature reached 75°C, yielding HPMCAS.

[0043] Comparative Example 2 HPMCAS was obtained in the same manner as in Example 1, except that the pressure and product temperature in the first drying and the pressure in the second drying were changed as shown in Table 1. The first drying was terminated when the moisture content of the HPMCAS reached 30% by mass.

[0044] [Table 1] [Table 2]

[0045] The results of Examples 1 to 4 and Comparative Examples 1 and 2 demonstrated that the first drying step, in which first dried HPMCAS having a moisture content of more than 0% and not more than 30% is obtained by drying under reduced pressure at a product temperature of more than 0°C and not more than 25°C, and the HPMCAS obtained by further drying the first dried HPMCAS, have excellent dissolution rates in solvents. In particular, when drying under reduced pressure at a product temperature of more than 0°C and not more than 20°C in the first drying step is performed, the dissolution rate in solvents is improved. Furthermore, the results of Example 5 revealed that the same effect was obtained even if 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 deliquorized hydroxypropyl methylcellulose acetate succinate is dried under reduced pressure at a product temperature of more than 0°C and not more than 25°C until the moisture content is more than 0% by mass and not more than 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. 2. The method for producing hydroxypropyl methylcellulose acetate succinate according to claim 1, wherein the pressure inside the dryer in the first drying step is 0.5 to 3 kPa abs.

3. The method for producing hydroxypropyl methylcellulose acetate succinate according to claim 1, wherein the heating temperature of the dryer in the first drying step is 50 to 120°C.

4. 2. The method for producing hydroxypropyl methylcellulose acetate succinate according to claim 1, wherein the first drying step is carried out using a dryer selected from the group consisting of a container rotary dryer, an internal stirring dryer, and a vibration 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 40 to 80% by mass.

6. The method for producing hydroxypropyl methylcellulose acetate succinate according to claim 1, wherein the water content of the hydroxypropyl methylcellulose acetate succinate is more than 0 mass% and 5 mass% or less.

7. The method for producing hydroxypropyl methylcellulose acetate succinate according to claim 1, wherein the product temperature of the hydroxypropyl methylcellulose acetate succinate at the end of the second drying step is 60 to 120°C.

8. Hydroxypropyl methylcellulose acetate succinate having a pore volume of 0.5 to 2.0 mL / g for pores having a diameter of 0.01 to 3.0 μm as measured by mercury intrusion porosimetry.

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