Hydroxypropyl methylcellulose phthalate, its production method and composition for hot melt extrusion

Abstract

Provided is a method for efficiently producing hydroxypropyl methylcellulose phthalate (HPMCP) having excellent fluidity, in which acetic acid in a reaction product mixture through washing and recovery steps can be reduced. More specifically, provided is a method for producing HPMCP, which includes an esterification step of esterifying hydroxypropyl methylcellulose (HPMC) with phthalic anhydride in acetic acid as a solvent to obtain a reaction product solution containing HPMCP; a water addition step of adding water to the reaction product solution to obtain a water-added reaction product solution; an acetic acid removal step of removing at least a part of acetic acid from the water-added reaction product solution to obtain a mixture with a reduced acetic acid content; and a washing and recovery step of washing the mixture and recovering HPMCP.

Description

Technical Field

[0001] The present invention relates to hydroxypropyl methylcellulose phthalate, a method for producing the hydroxypropyl methylcellulose phthalate, and a composition for hot melt extrusion. Background Art

[0002] Hydroxypropyl methylcellulose phthalate (hereinafter also referred to as "HPMCP") is a cellulose derivative having a methoxy group (-OCH3), a hydroxypropoxy group (-OC3H6OH), and a carboxybenzyloxy group (-COC6H4COOH), and is produced by chemically modifying cellulose.

[0003] HPMCP is used as an enteric polymer base material in coating applications, or as a solid dispersion containing a poorly water-soluble drug, and is thus particularly widely used in the pharmaceutical field.

[0004] Examples of methods for producing HPMCP include methods for producing a carboxylic acid ester cellulose derivative, including a step of esterifying cellulose with a polyvalent carboxylic anhydride in acetic acid as a solvent in the presence of an alkali metal carboxylate as a catalyst, while stirring with a twin-screw mixer, wherein the amount of acetic acid as a solvent is 1 to 2 times the weight of cellulose (JPH05-0339301A). Summary of the Invention

[0005] In conventional methods for producing HPMCP (for example, the method in JPH5-339301A), water is added to the reaction product solution to obtain a suspension in which HPMCP is precipitated, and the HPMCP in the suspension is washed with water to remove impurities. The suspension contains a large amount of acetic acid used as a solvent in the esterification step. Since it is difficult to recover, the acetic acid contained in the washing water is discarded together with the water. However, acetic acid is a factor that increases the chemical oxygen demand (COD) of wastewater. Acetic acid is also a factor that lowers the pH of wastewater. Acetic acid is also a factor of odor.

[0006] Therefore, after the washing and recovery steps of the suspension containing a large amount of acetic acid, it is necessary to perform wastewater treatment, such as biological treatment, on the washing water. The amount of acetic acid in the mixture after the washing and recovery steps is desirably small to reduce the load of wastewater treatment.

[0007] In order to reduce the acetic acid in the mixture after the washing and recovery steps, consideration is given to reducing the amount of acetic acid used in the esterification step. However, as described in JPH05-339301A, a reduction in the amount of acetic acid may make it difficult for cellulose to be uniformly dissolved in a high-concentration acetic acid solvent.

[0008] As described above, there is room for improvement in the conventional methods for producing HPMCP. There is also room for improvement in the fluidity of conventional HPMCP with respect to problems such as hopper clogging due to fluidity issues and hygiene problems caused by residual HPMCP in the hopper and pipelines.

[0009] To solve the above problems, extensive research has been carried out. As a result, the inventors have found that removing acetic acid from the reaction product solution containing HPMCP can reduce the acetic acid in the mixture through the washing and recovery steps and effectively produce HPMCP with excellent fluidity, thus completing the present invention.

[0010] In one aspect of the present invention, there is provided a method for producing hydroxypropyl methylcellulose phthalate, the method comprising:

[0011] an esterification step of esterifying hydroxypropyl methylcellulose with phthalic anhydride in acetic acid as a solvent to obtain a reaction product solution containing hydroxypropyl methylcellulose phthalate;

[0012] a water addition step of adding water to the reaction product solution to obtain a water-added reaction product solution;

[0013] an acetic acid removal step of removing at least a part of acetic acid from the water-added reaction product solution to obtain a mixture with a reduced acetic acid content; and

[0014] a washing and recovery step of washing the mixture and recovering hydroxypropyl methylcellulose phthalate.

[0015] In another aspect of the present invention, there is provided a hydroxypropyl methylcellulose phthalate, wherein the volume fraction of spherical particles is 70.0% or more with respect to all hydroxypropyl methylcellulose phthalate particles, and all hydroxypropyl methylcellulose phthalate particles are classified into fine particles, spherical particles, and fibrous particles based on dynamic image analysis

[0016] wherein

[0017] the fine particles have a fiber length of less than 40 μm;

[0018] the spherical particles have a length of 40 μm or more and are composed of a first spherical particle and a second spherical particle, wherein the first spherical particle has an elongation ratio (the ratio of fiber diameter to fiber length) of 0.5 or more, and the second spherical particle has an elongation ratio of less than 0.5, an aspect ratio (the ratio of the minimum Feret diameter to the maximum Feret diameter) of 0.5 or more, and a roundness (the ratio of the perimeter (P EQPC ) of a circle having the same area as the projected area of the particle to the true perimeter (P real ) of the particle) of 0.7 or more;

[0019] The fibrous particles are composed of long fibrous particles and short fibrous particles;

[0020] The long fibrous particles have a fiber length of 200 μm or greater and an elongation rate of less than 0.5, and are composed of first long fibrous particles and second long fibrous particles, where the first long fibrous particles have an aspect ratio of less than 0.5, and the second long fibrous particles have an aspect ratio of 0.5 or greater and a roundness of less than 0.7; and

[0021] The short fibrous particles have a fiber length of 40 μm or greater and less than 200 μm, an elongation rate of less than 0.5, and are composed of first short fibrous particles and second short fibrous particles, where the first short fibrous particles have an aspect ratio of less than 0.5, and the second short fibrous particles have an aspect ratio of 0.5 or greater and a roundness of less than 0.7.

[0022] According to the present invention, since at least a part of acetic acid is removed from the reaction product solution containing HPMCP, the amount of acetic acid in the mixture to be subjected to the washing and recovery steps can be reduced. In view of this, the burden in wastewater treatment is expected to be reduced, and the cost can be reduced by reusing the removed acetic acid.

[0023] In addition, HPMCP with excellent fluidity can be produced. In view of this, the mixing uniformity of HPMCP and a drug in a composition for hot melt extrusion can be improved, and the bridge formed by the mixed powder of HPMCP and the drug in the hopper can be reduced. Improvement in the uniformity of the drug content, the mass ratio of HPMCP to the drug, quantitative supply, and continuous operation can be expected. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 A flowchart showing the classification of "all particles" of HPMCP into four types of particles: "fine particles", "long fibrous particles (LF1 and LF2)", "short fibrous particles (SF1 and SF2)", and "spherical particles (S1 and S2)". DETAILED DESCRIPTION

[0025] Regarding the method for producing HPMCP, an esterification step of esterifying hydroxypropyl methylcellulose with phthalic anhydride in acetic acid as a solvent to obtain a reaction product solution containing HPMCP will be described.

[0026] Hydroxypropyl methylcellulose (hereinafter also referred to as "HPMC") is a nonionic water-soluble cellulose ether. HPMC synthesized by a known method or commercially available HPMC can be used.

[0027] From the perspective of HPMC that provides a reduced number of undissolved fibers, the DS of the methoxy group of HPMC is preferably from 1.10 to 2.20, more preferably from 1.3 to 2.10, still more preferably from 1.60 to 2.00, and particularly preferably from 1.80 to 2.00. From the perspective of HPMC that provides a reduced number of undissolved fibers, the MS of the hydroxypropyl group of HPMC is preferably from 0.10 to 1.00, more preferably from 0.10 to 0.80, still more preferably from 0.15 to 0.60, and particularly preferably from 0.20 to 0.50.

[0028] The DS of the methoxy group of HPMC represents the degree of substitution of the methoxy group and means the average number of methoxy groups per glucoside unit. The MS of the hydroxypropyl group of HPMC represents the molar degree of substitution of the hydroxypropyl group and means the average number of moles of hydroxypropyl groups per mol of glucoside. The DS of the methoxy group and the MS of the hydroxypropyl group of HPMC can be determined by conversion of the values obtained by measurement according to the 17th Edition of the Japanese Pharmacopoeia.

[0029] From the perspective of kneadability in the esterification step, the viscosity of a 2 mass% aqueous solution of HPMC at 20 °C is preferably from 1.0 mPa·s to 30.0 mPa·s, more preferably from 2.0 mPa·s to 20.0 mPa·s. The viscosity of a 2 mass% aqueous solution of HPMC at 20 °C can be measured using an Ubbelohde viscometer according to the method described in the monograph "Hydroxypropylmethylcellulose" of the 17th Edition of the Japanese Pharmacopoeia.

[0030] From the perspective of dissolving HPMC and increasing the reaction rate, the amount of acetic acid to be used is preferably from 3.5 to 10.0 mol, more preferably from 4.5 to 7.0 mol, and still more preferably from 5.0 to 6.5 mol, per 1 mol of HPMC.

[0031] The amount of phthalic anhydride to be used is not particularly limited as long as HPMCP having the desired degree of substitution is obtained. From the perspective of reaction efficiency, it is preferably from 0.2 to 3.0 mol, more preferably from 0.4 to 1.8 mol, per 1 mol of HPMC.

[0032] The esterification reaction can be carried out in the presence of a catalyst. As the catalyst, from an economic perspective, an alkali metal carboxylate such as sodium acetate is preferred. Optional catalysts can be used alone or in combination of two or more. Commercially available catalysts can be used.

[0033] The amount of the optional catalyst to be used can be selected according to the degree of substitution of HPMCP. From the perspective of reaction efficiency, it is preferably from 0.1 to 3.0 mol, more preferably from 0.3 to 2.0 mol, per 1 mol of HPMC.

[0034] Esterification can be carried out in the presence of a depolymerizing agent. From an economic perspective, alkali metal chlorates (such as sodium chlorate) are preferred as the depolymerizing agent. Optional depolymerizing agents can be used alone or in combination of two or more. Commercially available depolymerizing agents can be used.

[0035] The amount of the optional depolymerizing agent to be used can be selected according to the degree of polymerization of HPMCP. From the perspective of preventing a significant decrease in viscosity, it is preferably 0.01 to 0.20 mol, more preferably 0.02 to 0.10 mol, relative to 1 mol of HPMC.

[0036] From the perspective of reaction efficiency, it is preferred to use a kneader reactor or the like for the esterification reaction. From the perspective of reaction rate, the reaction temperature in the esterification step is preferably 60°C to 120°C, more preferably 60°C to 100°C. From the perspective of obtaining HPMCP with a desired degree of substitution, the reaction time in the esterification step is preferably 2 to 8 hours, more preferably 3 to 6 hours.

[0037] Next, a water addition step of adding water to the reaction product solution containing HPMCP to obtain a water-added reaction product solution will be described.

[0038] The water addition step allows for the treatment of unreacted phthalic anhydride.

[0039] From the perspective of preventing deterioration of transferability due to precipitation of HPMCP, water is added in an amount that does not cause precipitation of HPMCP. The amount of water to be added is preferably not more than 250 parts by mass, more preferably 1 to 200 parts by mass, and still more preferably 3 to 190 parts by mass, relative to 100 parts by mass of the starting HPMC used in the esterification reaction. From the perspective of continuing to perform the acetic acid removal step after water addition, the temperature of the reaction product solution containing HPMCP to which water is to be added is preferably 60°C to 100°C.

[0040] Next, an acetic acid removal step of removing at least a part of acetic acid from the water-added reaction product solution to obtain a mixture with a reduced acetic acid content will be described. When sodium acetate is used as a catalyst, it is in the following equilibrium state, so acetic acid derived from sodium acetate is not considered.

[0041] CH3COONa + CH3COOH = CH3COOH + CH3COONa

[0042] The method of removing at least a part of acetic acid from the water-added reaction product solution is not particularly limited. From the perspective of effectively removing and recovering acetic acid, the acetic acid removal step preferably includes evaporating acetic acid by heating and stirring the water-added reaction product solution under reduced pressure to recover acetic acid.

[0043] For example, the acetic acid removal step can be carried out by using a device capable of stirring a high-viscosity aqueous reaction product solution and ensuring a sealed state for heating and decompression or for decompression only. Examples of such a device include a reactor capable of heating and reducing the internal pressure and equipped with stirring blades that rotate; a reactor capable of heating and reducing the internal pressure and equipped with stirring blades that rotate and revolve. The device is preferably a reactor capable of heating and reducing the internal pressure and equipped with stirring blades that rotate and revolve. For example, a 5L vertical kneader reactor (Trimix TX-5 manufactured by INOUE MFG., Inc.) having three frame-shaped stirring blades that rotate and revolve. From the perspective of stirring uniformity in the acetic acid removal step, the circumferential speed of the rotational movement of one stirring blade is preferably 0.01 m / s to 2.00 m / s. When a revolving movement is also used, the circumferential speed of the revolving movement of one stirring blade is preferably 0.001 m / s to 2.00 m / s. As used herein, the term "circumferential speed in rotational movement" refers to the speed of the fastest part (i.e., the outermost circumference) of one stirring blade that rotates in the device used. The "circumferential speed in revolving movement" refers to the speed of the fastest part (i.e., the outermost circumference) of one stirring blade that revolves along an orbit in the device used.

[0044] From the perspective of acetic acid evaporation, the acetic acid removal temperature in the acetic acid removal step is preferably 60°C to 100°C. From the perspective of acetic acid evaporation, the decompression in the acetic acid removal step is preferably -0.10 MPaG to -0.02 MPaG. The decompression in the acetic acid removal step can be carried out using a suction device or the like.

[0045] From the perspective of productivity, the acetic acid removal time in the acetic acid removal step is preferably 0.1 to 5 hours.

[0046] The evaporated acetic acid can be recovered in a cold trap or the like connected to the device. The trap is preferably cooled by ice or the like. The recovered acetic acid may contain water.

[0047] The ratio of the amount of acetic acid removed in the acetic acid removal step to the amount of acetic acid added as a solvent is called the acetic acid removal percentage. From the perspective of the fluidity of HPMCP, the acetic acid removal percentage is preferably 10.0% or higher, more preferably 20.0% to 95.0%, still more preferably 40.0% to 90.0%, and particularly preferably 70.0% to 85.0%.

[0048] Considering that the removed acetic acid is a mixture of acetic acid and water added in the water addition step, the acetic acid removal percentage in the acetic acid removal step is determined by the following formula.

[0049] Acetic acid removal percentage (%) = { (C × D / 100) / A} × 100

[0050] In the above formula, "A" means the mass ratio of acetic acid used as a solvent to the starting HPMC; "C" means the mass ratio of the recovered mixture containing acetic acid to the starting HPMC; and "D" means the acetic acid concentration in the recovered mixture, where the recovered mixture also contains the water added in the water addition step.

[0051] From the perspective of the fluidity of HPMCP, the mixture with reduced acetic acid content after the washing and recovery steps is preferably in solid form. When the mixture with reduced acetic acid content is in the form of a liquid with high viscosity, the solid mixture can be obtained by cooling the liquid mixture to room temperature.

[0052] From the perspective of effectively washing the mixture with reduced acetic acid content in solid form, an optional pulverization step of pulverizing the solid mixture can be carried out between the acetic acid removal step and the washing and recovery steps described later to obtain a pulverized mixture with reduced acetic acid content.

[0053] Pulverization can be carried out using a pulverizer. Examples of pulverizers include high-speed rotary pulverizers such as hammer mills and pin mills; high-shear devices such as homogenizing mixers and high-shear mills; roll pulverizers such as roll mills; pulverizers with grinding media such as vibration mills and planetary mills; and fluidized pulverizers such as jet mills.

[0054] When the mixture with reduced acetic acid content is a non-sticky solid, it can be pulverized as it is (i.e., dry pulverization). When the mixture with reduced acetic acid content is a sticky solid, water can be added to the mixture and then pulverized (i.e., wet pulverization). Generally, when the mixture with reduced acetic acid content is in solid form, as the removal percentage of acetic acid becomes higher and the acetic acid content becomes smaller, the stickiness becomes weaker. From the perspective of pulverizing HPMCP, the temperature of the water to be added is preferably 5°C to 40°C. The amount of water to be added is preferably 100 to 1000 parts by mass relative to 100 parts by mass of the solid mixture with reduced acetic acid content.

[0055] Next, the washing and recovery steps of washing the mixture with reduced acetic acid and recovering hydroxypropyl methylcellulose phthalate will be described.

[0056] The method of washing and recovery is not particularly limited. Examples of the method include the following methods: a method including mixing a mixture with a reduced acetic acid content with water to obtain an aqueous mixture, subjecting the aqueous mixture to centrifugation, filtration, decantation, etc. to obtain crude HPMCP, dispersing the crude HPMCP in water and washing while stirring with a stirrer to obtain a dispersion, and subjecting the dispersion to centrifugation, filtration, etc. to remove the washing water; a method including subjecting the mixture with a reduced acetic acid content or the crude HPMCP to a continuous water flow; and a method including repeatedly replacing a part of the liquid in the aqueous mixture with water.

[0057] From the perspective of washing, the aqueous mixture containing the mixture with a reduced acetic acid content and water is preferably a suspension.

[0058] From the perspective of effectively removing impurities contained in HPMCP, the water temperature to be used for washing is preferably 5°C to 40°C. The amount of water to be used for washing varies depending on the washing method. For example, when washing the crude HPMCP obtained by centrifugation or filtration, from the perspective of obtaining HPMCP with reduced impurities, the amount of water to be used for washing is preferably 200 to 20000 parts by mass relative to 100 parts by mass of the mixture with a reduced acetic acid content.

[0059] The amount of water to be used for washing, combined with the amount of water added in the water addition step, can preferably be selected to fall within the above range.

[0060] The obtained HPMCP can be optionally dried. From the perspective of preventing aggregation of HPMCP, the drying temperature is preferably 40°C to 100°C, more preferably 40°C to 80°C. From the perspective of preventing aggregation of HPMCP, the drying time is preferably 1 to 20 hours, more preferably 3 to 15 hours.

[0061] The obtained HPMCP can be selectively sieved to obtain the desired average particle size.

[0062] The viscosity of a 10% by mass HPMCP solution obtained by dissolving HPMCP in a mixed solvent of methanol and dichloromethane (mass ratio of methanol to dichloromethane is 1:1) at 20°C is preferably 10.0 mPa·s to 300.0 mPa·s, more preferably 15.0 mPa·s to 250.0 mPa·s, and still more preferably 15.0 mPa·s to 220.0 mPa·s. The viscosity of a 10% by mass HPMCP solution obtained by dissolving HPMCP in a mixed solvent of methanol and dichloromethane (mass ratio of methanol to dichloromethane is 1:1) at 20°C can be measured using an Ubbelohde viscometer according to the method described in the 17th Edition of the Japanese Pharmacopoeia, Monograph "Hydroxypropyl Methylcellulose Phthalate".

[0063] The DS of the methoxy group of HPMCP is preferably from 1.10 to 2.20, more preferably from 1.30 to 2.10, still more preferably from 1.60 to 2.00, and most preferably from 1.80 to 2.00.

[0064] The MS of the hydroxypropoxy group of HPMCP is preferably from 0.10 to 1.00, more preferably from 0.10 to 0.80, still more preferably from 0.15 to 0.60, and most preferably from 0.20 to 0.50.

[0065] The DS of the carboxybenzoyl group of HPMCP is preferably from 0.10 to 2.50, more preferably from 0.10 to 1.00, and still more preferably from 0.40 to 0.80.

[0066] The DS of the methoxy group of HPMCP, the DS of the carboxybenzoyl group, and the MS of the hydroxypropoxy group can be obtained by conversion of the values obtained by the methods according to the 17th Edition of the Japanese Pharmacopoeia, Monographs "Hydroxypropylmethylcellulose" and "Hydroxypropylmethylcellulose Phthalate". The DS of the methoxy group or the carboxybenzoyl group of HPMCP represents the degree of substitution and means the average number of methoxy groups or carboxybenzoyl groups per glucoside unit. In addition, the MS of the hydroxypropoxy group of HPMCP represents the molar substitution and means the average number of moles of hydroxypropoxy groups per glucoside unit.

[0067] The particle size D at which 50% is cumulative in the particle size distribution of HPMCP can be appropriately selected according to the application. 50 From the viewpoint of the fluidity of HPMCP, it is preferably from 50 μm to 700 μm, more preferably from 100 μm to 600 μm, and still more preferably from 300 μm to 500 μm.

[0068] D 90 The particle size ratio of D 10 to D 90 , that is, the ratio of the particle size at which 90% is cumulative in the particle size distribution to the particle size at which 10% is cumulative, is preferably 40.0 or less, more preferably from 0.5 to 10.0, still more preferably from 1.0 to 4.0, and particularly preferably from 1.0 to 3.5. The particle size ratio of D 10 to D

[0069] represents the width of the particle size distribution. 10 D 50 and D 90Measurements can be carried out using a dry laser diffraction particle size distribution analyzer (Mastersizer 3000 manufactured by Malvern Panalytic Ltd.) under a dispersion pressure of 2 bar. A dry laser diffraction particle size distribution analyzer is a device that ejects a powder sample with compressed air, irradiates it with a laser beam, and measures the volume equivalent spherical diameter through the diffraction intensity. Examples thereof include Mastersizer manufactured by Malvern Panalytical Ltd. in the UK and HELOS device manufactured by Sympatec GmbH in Germany.

[0070] From a processing perspective, the bulk density of HPMCP in the loose state is preferably 0.30 g / cm 3 to 0.60 g / cm 3 , more preferably 0.35 g / cm 3 to 0.55 g / cm 3 , and even more preferably 0.40 g / cm 3 to 0.53 g / cm 3 . The bulk density in the loose state means the bulk density in the loose packing state. It is measured by a method including the following steps: uniformly feeding a sample of more than 23 cm into a cylindrical container with a volume of 100 mL, a diameter of 5.03 cm, and a height of 5.03 cm; then leveling the upper surface of the container; and weighing the container.

[0071] As described in the general information of the 17th edition of the Japanese Pharmacopoeia, the flow rate of HPMCP through the orifice can be determined by flow rate measurement. From a processing perspective, the flow rate of HPMCP is preferably 1.50 g / second to 3.50 g / second, and more preferably 1.60 g / second to 3.00 g / second. The flow rate depends to a great extent on the measurement method used as described in the general information of the 17th edition of the Japanese Pharmacopoeia. Therefore, it is necessary to compare the flow rates measured under the same conditions. Details of the measurement conditions will be described in the examples.

[0072] In this specification, HPMCP particles are divided into four types of particles: "long fibrous particles", "short fibrous particles", "spherical particles", and "fine particles". Figure 1 The flowchart showing the method of summarizing "all particles" of HPMCP into four types of particles: "fine particles", "long fibrous particles (LF1 and LF2)", "short fibrous particles (SF1 and SF2)", and "spherical particles (S1 and S2)" is shown.

[0073] The volume fraction of each type of HPMCP particle can be calculated by measuring shape parameters such as fiber length (LEFI), fiber diameter (DIFI), elongation, aspect ratio, and roundness based on dynamic image analysis. Dynamic image analysis is a method in which images of particles dispersed in a fluid (such as a gas or a solvent) are continuously taken, binarized, and analyzed to obtain particle diameters or particle shapes. For example, analysis can be performed using a dynamic image analysis type particle size distribution analyzer QICPIC / R16 (manufactured by Sympatec GmbH).

[0074] All particle A is divided into particle C with a fiber length (LEFI) of 40 or greater and fine particle B with a fiber length less than 40 μm. LEFI is defined as the length of the longest direct path connecting the endpoints of the particle within the particle contour. The detection limit of QICPIC / R16 equipped with an M7 lens is 4.7 μm, so particles with a LEFI less than 4.7 μm cannot be detected. However, the volume of particles with a LEFI less than 4.7 μm is very small relative to all particles of HPMCP, so it can be ignored for the purposes of this invention.

[0075] Particle C with a LEFI of 40 μm or greater is divided into first spherical particle (S1) with an elongation of 0.5 or greater and particle D with an elongation less than 0.5, where elongation is the ratio of the fiber diameter (DIFI) to the particle's LEFI (DIFI / LEFI). DIFI is defined as the small diameter of the particle, calculated by dividing the projected area of the particle by the sum of all lengths of the fiber branches of the particle.

[0076] Particle D with a LEFI of 40 μm or greater and an elongation less than 0.5 is divided into particle E with an aspect ratio less than 0.5 and particle F with an aspect ratio of 0.5 or greater, where the aspect ratio is the ratio of the minimum Feret diameter (Fmin) to the maximum Feret diameter (Fmax) (Fmin / Fmax). Each particle has an aspect ratio greater than 0 and not greater than 1. The Feret diameter is the distance between two parallel tangents between which the particle is placed. The maximum Feret diameter (Fmax) is the maximum distance between pairs of tangents of the particle considering all possible directions by changing the direction from 0° to 180°, and the minimum Feret diameter (Fmin) is the minimum distance between pairs of tangents of the particle considering all possible directions by changing the direction from 0° to 180°.

[0077] Fibrous particle E with a LEFI of 40 μm or greater, an elongation less than 0.5, and an aspect ratio less than 0.5 is divided into first long fibrous particle (LF1) with a LEFI of 200 μm or greater and first short fibrous particle (SF1) with a LEFI less than 200 μm.

[0078] Particles F having a LEFI of 40 μm or greater, an elongation ratio of less than 0.5, and an aspect ratio of 0.5 or greater are classified into second spherical particles (S2) having a roundness of 0.7 or greater and fibrous particles G having a roundness of less than 0.7. Roundness is the ratio of the circumference (P P ) of a circle having the same area as the projected area (A EQPC ) of the particle to the true circumference (P real ) of the particle, and is defined by the following equation. The roundness of each particle is greater than 0 and not greater than 1. The smaller the roundness of a particle, the more irregular its shape. EQPC is the diameter of a circle of equal projected area and is defined as the diameter of a circle having the same area as the projected area of the particle, also known as the Heywood diameter.

[0079]

[0080] Fibrous particles G having a LEFI of 40 μm or greater, an elongation ratio of less than 0.5, an aspect ratio of 0.5 or greater, and a roundness of less than 0.7 are classified into second long fibrous particles (LF2) having a LEFI of 200 μm or greater and second short fibrous particles (SF2) having a LEFI of less than 200 μm.

[0081] The volume (V m ) of the fine particles of HPMCP can be calculated by the following equation, assuming that each fine particle is a sphere with a diameter of EQPC.

[0082] V m = (π / 6) × (EQPC) 3 × N m

[0083] where N m is the number of fine particles in the sample, and EQPC is the median EQPC corresponding to the 50% cumulative value on the number-based cumulative particle size distribution curve of the fine particles.

[0084] In this specification, particles having a LEFI of 40 μm or greater (particles other than fine particles having a LEFI of less than 40 μm among all particles) are classified into "long fibrous particles", "short fibrous particles", and "spherical particles", which are distinct from each other. This classification or categorization is based on the above-mentioned shape parameters of the particles, including LEFI, elongation ratio, aspect ratio, and roundness.

[0085] <Long fibrous particles>

[0086] Particles that satisfy the following definition of LF1 or LF2 are classified as "long fibrous particles".

[0087] LF1: Particles having an elongation rate of less than 0.5, an aspect ratio of less than 0.5, and a LEFI (length of the fiber) of 200 μm or greater, and

[0088] LF2: Particles having an elongation rate of less than 0.5, an aspect ratio of 0.5 or greater, a roundness of less than 0.7, and a LEFI (length of the fiber) of 200 μm or greater.

[0089] The volume (V LF ) of the long fibrous particles of HPMCP can be calculated by the following equation, where each long fibrous particle is assumed to be a cylinder with a bottom diameter of DIFI and a height of LEFI.

[0090] V LF = (π / 4) × (DIFI) 2 × (LEFI) × N LF

[0091] where N LF is the number of long fibrous particles in the sample, DIFI is the median DIFI corresponding to the 50% cumulative value on the number-based cumulative particle size distribution curve for the long fibrous particles, and LEFI is the median LEFI corresponding to the 50% cumulative value on the number-based cumulative particle size distribution curve for the long fibrous particles.

[0092] The volume of the particles satisfying the definition of LF1 and the volume of the particles satisfying the definition of LF2 are calculated according to the above equation respectively, and the sum of these volumes means the volume of the long fibrous particles of HPMCP.

[0093] <Short fibrous particles>

[0094] Particles satisfying the following definition of SF1 or SF2 are classified as "short fibrous particles".

[0095] SF1: Particles having an elongation rate of less than 0.5, an aspect ratio of less than 0.5, and a LEFI (length of the fiber) of 40 μm or greater and less than 200 μm, and

[0096] SF2: Particles having an elongation rate of less than 0.5, an aspect ratio of 0.5 or greater, a roundness of less than 0.7, and a LEFI (length of the fiber) of 40 μm or greater and less than 200 μm.

[0097] The volume (V SF ) of the short fibrous particles of HPMCP can be calculated by the following equation in the same manner as for the above long fibrous particles, where each short fibrous particle is assumed to be a cylinder with a bottom diameter of DIFI and a height of LEFI.

[0098] V SF = (π / 4) × (DIFI) 2×(LEFI)×N SF

[0099] where N SF is the number of short fibrous particles in the sample, DIFI is the median DIFI corresponding to the 50% cumulative value on the number-based cumulative particle size distribution curve for short fibrous particles, and LEFI is the median LEFI corresponding to the 50% cumulative value on the number-based cumulative particle size distribution curve for short fibrous particles.

[0100] The volume of particles satisfying the SF1 definition and the volume of particles satisfying the SF2 definition are calculated according to the above equations respectively, and the sum of these volumes means the volume of short fibrous particles of HPMCP.

[0101] <Spherical particles>

[0102] Particles satisfying the definition of S1 or S2 are classified as "spherical particles".

[0103] S1: Particles having an elongation ratio of 0.5 or greater and a LEFI (fiber length) of 40 μm or greater, and

[0104] S2: Particles having an elongation ratio of less than 0.5, an aspect ratio of 0.5 or greater, a roundness of 0.7 or greater, and a LEFI (fiber length) of 40 μm or greater.

[0105] The volume (V S ) of spherical particles of HPMCP can be calculated by the following equation, where each spherical particle is assumed to be a sphere with a diameter of EQPC.

[0106] V S = (π / 6) × (EQPC) 3 × N S

[0107] where N S is the number of spherical particles in the sample, and EQPC is the median EQPC corresponding to the 50% cumulative value on the number-based cumulative particle size distribution curve for spherical particles.

[0108] The volume of particles satisfying the definition of S1 and the volume of particles satisfying the definition of S2 are calculated according to the above equations respectively, and the sum of these volumes means the volume of spherical particles of HPMCP.

[0109] The volume fraction of each type of particle of HPMCP can be calculated according to the volumes defined above, V m 、V LF 、V SF and V S by the following corresponding equations.

[0110] Volume fraction of fine particles = {Vm / (V m +V LF +V SF +V S )}×100

[0111] Volume fraction of long fibrous particles = {V LF / (V m +V LF +V SF +V S )}×100

[0112] Volume fraction of short fibrous particles = {V SF / (V m +V LF +V SF +V S )}×100

[0113] Volume fraction of spherical particles = {V S / (V m +V LF +V SF +V S )}×100

[0114] The volume fraction of each type of particle (long fibrous particles, short fibrous particles, spherical particles, and fine particles) is measured as follows. A dynamic image analysis type particle size distribution analyzer QICPIC / R16 (manufactured by Sympatec GmbH) equipped with a quantitative feeder VIBRI / L, an air flow type disperser RODOS / L, and an M7 lens is used under the conditions of a frame rate of 500 Hz, an injector of 4 mm, and a dispersion pressure of 1 bar. The images of the particles are analyzed by analysis software WINDOX5 version 5.9.1.1 to determine the number-based median EQPC, number-based median LEFI, number-based median DIFI, elongation ratio, aspect ratio, and roundness of each type of particle. The volume fraction of each type of particle is calculated by the above equation based on the measured values. It should be noted that M7 is used as the division for analysis.

[0115] From the perspective of obtaining HPMCP with excellent fluidity, the volume fraction of spherical particles in HPMCP is 70.0% or higher, preferably 75.0% to 99.0%, and more preferably 83.0% to 97.0%.

[0116] From the perspective of the fluidity of HPMCP, the volume fraction of long fibrous particles in HPMCP is preferably 30.0% or less, more preferably 1.0% to 25.0%, and still more preferably 3.0% to 20.0%.

[0117] From the viewpoint of the fluidity of HPMCP, the volume fraction of the short fibrous particles of HPMCP is preferably 2.5% or less, more preferably from 0.0% to 1.5%, and still more preferably from 0.0% to 0.5%.

[0118] From the viewpoint of the fluidity of HPMCP, the volume fraction of the fine particles of HPMCP is preferably 2.5% or less, more preferably from 0.0% to 1.5%, and still more preferably from 0.0% to 0.5%.

[0119] Next, a composition for hot melt extrusion containing the above-mentioned hydroxypropyl methylcellulose phthalate and a drug will be described.

[0120] By using the above-mentioned HPMCP having good fluidity, the mixing uniformity of HPMCP and a drug in the composition for hot melt extrusion, and the formation of a bridge of the mixed powder of HPMCP and a drug in a hopper can be improved. Uniformity of drug content, improvement of the mass ratio of HPMCP to a drug, quantitative feeding, and continuous operation are also expected.

[0121] The drug is not particularly limited as long as it can be orally administered. Examples of the drug include drugs for the central nervous system, drugs for the cardiovascular system, drugs for the respiratory system, drugs for the digestive system, antibiotics, antitussives and expectorants, antihistamines, antipyretics and anti-inflammatory analgesics, diuretics, autonomic nerve drugs, antimalarials, antidiarrheals, psychotropic drugs, and vitamins and their derivatives.

[0122] Examples of drugs for the central nervous system include diazepam, idebenone, naproxen, piroxicam, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen (another name: paracetamol), ethenzamide, and chlordiazepoxide.

[0123] Examples of drugs for the cardiovascular system include molsidomine, vinpocetine, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nifedipine, atenolol, spironolactone, metoprolol, pindolol, captopril, isosorbide dinitrate, delapril hydrochloride, meclofenoxate hydrochloride, diltiazem hydrochloride, etilefrine hydrochloride, digitoxin, and alprenolol hydrochloride.

[0124] Examples of drugs for the respiratory system include amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol, and guaifenesin.

[0125] Examples of drugs for the digestive system include benzimidazole drugs with anti-ulcer effects, such as 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl]benzimidazole and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole; cimetidine; ranitidine; pirenzepine hydrochloride; pancreatin; bisacodyl; and 5-aminosalicylic acid.

[0126] Examples of antibiotics include talampicillin hydrochloride, bacampicillin hydrochloride, cefaclor, and erythromycin.

[0127] Examples of antitussive and expectorant agents include noscapine hydrochloride, pentoxyverine citrate, 4-dimethylamino-2,2-diisopropylphenylvaleronitrile, and dimemorfan phosphate.

[0128] Examples of antihistamines include chlorpheniramine maleate, diphenhydramine hydrochloride, and promethazine hydrochloride.

[0129] Examples of antipyretics, anti-inflammatory and analgesic drugs include ibuprofen, diclofenac sodium, flufenamic acid, surolan, aspirin, and ketoprofen.

[0130] An example of a diuretic is caffeine.

[0131] Examples of autonomic nervous system drugs include codeine phosphate, dl-methylephedrine hydrochloride, atropine sulfate, acetylcholine chloride, and neostigmine.

[0132] An example of an antimalarial agent is quinine hydrochloride.

[0133] An example of an antidiarrheal agent is loperamide hydrochloride.

[0134] An example of a psychotropic drug is chlorpromazine.

[0135] Examples of vitamins and their derivatives include vitamin A, vitamin B1, fursultiamine, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, calcium pantothenate, and tranexamic acid.

[0136] In particular, when HPMCP according to the present invention is used as a carrier for a solid dispersion containing a poorly water-soluble drug, the solubility of the poorly water-soluble drug can be increased. A poorly water-soluble drug refers to a drug that is "slightly soluble", "very slightly soluble", or "almost insoluble or insoluble" in water as listed in the 17th Edition of the Japanese Pharmacopoeia. The term "slightly soluble" means that when 1 g or 1 mL of a solid drug product is placed in a beaker and shaken vigorously for 30 seconds every 5 minutes at 20°C ± 5°C, it dissolves in 100 mL or more and less than 1000 mL of water within 30 minutes. The term "very slightly soluble" means that 1 g or 1 mL of a solid drug product dissolves in 1000 mL or more and less than 10,000 mL of water in the same manner within 30 minutes. The term "almost insoluble or insoluble" means that 1 g or 1 mL of a solid drug product dissolves in 10,000 mL or more of water within 30 minutes.

[0137] In the above-mentioned drug test, the dissolution of a poorly water-soluble drug means that the drug dissolves in water or is miscible with water, and also means that fibers or the like are not present or are present in a very small amount.

[0138] Examples of poorly water-soluble drugs include azole compounds such as itraconazole, ketoconazole, fluconazole, and methoconazole; dihydropyridine compounds such as nifedipine, nitrendipine, amlodipine, nicardipine, nilvadipine, ferrodipine, and efonidipine; propionate compounds such as ibuprofen, ketoprofen, and naproxen; indoleacetic acid compounds such as indomethacin and acemetacin; griseofulvin; phenytoin; carbamazepine; and dipyridamole.

[0139] The mass ratio of HPMCP to the drug is not particularly limited. From the perspective of storage stability in the amorphous state, it is preferably 1:0.1 to 1:10, more preferably 1:0.2 to 1:5.

[0140] In addition, the composition for hot melt extrusion may contain optional additives such as plasticizers and surfactants for improving moldability during hot melt extrusion and the like.

[0141] Examples of plasticizers include higher alcohols preferably having 10 to 20 carbon atoms such as cetyl alcohol and stearyl alcohol; polyhydric alcohols preferably having 2 to 6 valences such as mannitol, sorbitol, and glycerol; spermaceti wax; triethyl citrate; polyalkylene glycols such as polyethylene glycol and polypropylene glycol; glyceryl triacetate; dibutyl sebacate; glyceryl monostearate; and glyceryl monoacetate.

[0142] From the perspective of storage stability, the content of the plasticizer in the composition for hot melt extrusion is preferably 0.1% by mass to 30% by mass.

[0143] Examples of surfactants include anionic surfactants such as sodium dodecyl sulfate; nonionic surfactants such as diglycerides, poloxamers, polyoxyethylene sorbitan fatty acid esters (Tween 20, 60, and 80), glycerol fatty acid esters, and propylene glycol fatty acid esters; and natural surfactants such as lecithin and sodium taurocholate.

[0144] From the perspective of storage stability, the content of the surfactant in the composition for hot melt extrusion is preferably 0.1% by mass to 10% by mass.

[0145] The composition for hot melt extrusion can be prepared by a method including the step of mixing HPMCP, a drug, an optional plasticizer, and an optional surfactant to obtain the composition for hot melt extrusion. The prepared composition for hot melt extrusion can be introduced into a hot melt extruder through a hopper and extruded into a desired shape such as a circle, square, column, or film to obtain an extrudate.

[0146] The hot melt extruder is not particularly limited as long as it is an extruder capable of melting and kneading HPMCP and the drug while heating and applying a shearing force using a piston or a screw and then extruding them from a die. It is preferably a twin-screw extruder to obtain a more uniform extrudate. Specific examples include Capilograph (single-screw piston extruder) produced by Toyo Seiki Seisaku-sho, Ltd.; NANO 16 (twin-screw extruder) produced by Leistritz Extrusionstechnik GmbH; Mini Lab (twin-screw extruder) and Pharma Lab (twin-screw extruder) produced by Thermo Fisher Scientific Inc.

[0147] The hot melt temperature is not particularly limited. Preferably, the composition for hot melt extrusion is melted and reasonably extruded while avoiding the temperature at which the drug and HPMCP thermally decompose as much as possible. Considering the melting points of the drug and HPMCP and the melting point of the composition for hot melt extrusion, the hot melt temperature is preferably 50°C to 250°C, more preferably 60°C to 200°C, and still more preferably 90°C to 190°C.

[0148] The conditions for hot melt extrusion can be appropriately selected according to the properties of the composition for hot melt extrusion in a conventional manner.

[0149] The hot melt extrudate after extrusion is cooled at the die outlet or later at room temperature (1°C to 30°C) by natural cooling or cold blowing. In order to minimize the thermal decomposition of the drug and inhibit the recrystallization of the amorphous drug, the hot melt extrudate is desirably cooled to 50°C or lower, more preferably 30°C or lower.

[0150] The cooled hot melt extrudate can optionally be granulated into small pellets of 0.1 mm to 5 mm by a cutter, or pulverized into granules or powder for particle size adjustment. It is preferred to use an impact mill (such as a jet mill, chopper or pin mill) for pulverization because its structure hardly raises the product temperature. When the temperature in the cutter and pulverizer rises, HPMCP thermally softens and the particles adhere to each other. Therefore, pulverization is preferably carried out under cold air purge.

[0151] Example

[0152] Hereinafter, the present invention will be described in detail with reference to the examples and comparative examples. It should not be construed that the present invention is limited by or restricted to them.

[0153] In the acetic acid removal step, under the following conditions, the concentration of acetic acid in the recovered mixture containing at least the removed acetic acid and water was determined by liquid chromatography.

[0154] Equipment: Liquid chromatograph LC-20AB manufactured by Shimadzu Corporation.

[0155] Column: ODS-3 (inner diameter 4.6 mm, length 15 cm, particle size 5 μm, manufactured by GL Science Inc.)

[0156] Column temperature: 30 °C, constant

[0157] Detector: Ultraviolet-visible absorption photometer (measured at 215 nm, SPD-20AV manufactured by Shimadzu Corporation)

[0158] Mobile phase: 0.02 mol / L aqueous potassium dihydrogen phosphate solution, and the solution was adjusted to pH 2.8 by adding phosphoric acid.

[0159] Flow rate: 1 mL / min

[0160] In the acetic acid removal step, the recovered mixture containing at least the removed acetic acid and water was diluted 500-fold (by volume) with water, and then further diluted 6.25-fold (by volume) with the mobile phase to prepare a measurement sample.

[0161] Under the following conditions, the flow rate of HPMCP flowing through the orifice was measured by a flowability tester BEP2 (Copley Scientific Ltd.) to obtain the average value of two measurements.

[0162] Orifice size: 8 mm

[0163] Feeding of HPMCP: 30 g

[0164] Standing time: 30 seconds

[0165] Container: Cylindrical (diameter 57 mm)

[0166] Example 1

[0167] Place 600 g of HPMC with a DS of 1.88 for methoxy groups, an MS of 0.24 for hydroxypropoxy groups, and a viscosity of 6.0 mPa at 20 °C (measured as a 2 mass% aqueous solution), 960.0 g of glacial acetic acid, 498 g of phthalic anhydride, 253.0 g of sodium acetate, and 9.5 g of sodium chlorate in a 5 L vertical kneading reactor (Trimix TX-5 manufactured by INOUE MFG., Ltd.) equipped with a frame-shaped stirring blade with three self-rotations and orbital revolutions; and stir at 85 °C for 4.5 hours to obtain 2320.5 g of a reaction product solution containing HPMCP.

[0168] Next, while maintaining 85 °C, add 27.0 g of water to the reaction product solution containing HPMCP in the same reactor and stir to obtain 2347.5 g of a water-added reaction product solution. The equivalent relationship of the esterification reaction is shown in Table 1.

[0169] Table 1

[0170]

[0171] Subsequently, use a suction pump (A-1000S manufactured by Tokyo Rika Kikai Co., Ltd.) to reduce the internal pressure in the same kneading reactor to -0.09 MPaG and stir at 85 °C for 30 minutes to recover acetic acid into an ice trap. The recovered acetic acid contains water, and the amount of the recovered mixture containing at least acetic acid and water is 253.8 g. Then, by cooling the inside of the kneading machine reactor to room temperature, a viscous solid-like mixture containing HPMCP with a reduced acetic acid content is obtained.

[0172] In the esterification step, the water-adding step, and the acetic acid removal step, the circumferential speed of the self-rotation movement of each frame-shaped stirring blade is 0.050 m / s, and the circumferential speed of the revolution movement is 0.019 m / s. The ratio of the circumferential speed of the self-rotation movement to the circumferential speed of the revolution movement is 2.6. In addition, the circumferential speeds of the self-rotation movements of all three frame-shaped stirring blades that rotate and revolve along an orbit are the same.

[0173] Next, 300 parts by mass of water at 20°C was added to 100 parts by mass of the viscous solid-like mixture, and the mixture was pulverized in a homogenizer (Homomixer MARK II 2.5 manufactured by PRIMIX Corporation; rotor diameter 30.0 mm) at a rotational speed of 8000 rpm and a circumferential speed of 12.57 m / s to obtain a suspension of the pulverized mixture. Then, the pulverized mixture was filtered to obtain crude HPMCP.

[0174] Thereafter, washing was carried out by repeating the sequence of dispersing the crude HPMCP in water, stirring, and filtering 10 times to obtain washed HPMCP. The temperature of the washing water was 20°C, and the amount of water used in each sequence for washing was 500 parts by mass relative to 100 parts by mass of the solid-like mixture with reduced acetic acid content. The washed HPMCP was dried at a temperature of 80°C for 2 hours and sieved through a sieve with an opening of 0.5 mm to obtain HPMCP.

[0175] Table 2 shows the mass ratio (A) of glacial acetic acid used as a solvent to HPMC, the mass ratio (B) of water added in the water addition step after completion of the esterification step to HPMC, the mass ratio (C) of the recovered mixture containing at least acetic acid and water in the acetic acid removal step to HPMC, the concentration (D) of acetic acid in the recovered mixture containing at least acetic acid and water, the percentage of acetic acid removal, and the form of the mixture with reduced acetic acid content before performing the washing and recovery steps. Table 3 shows various properties of the obtained HPMCP.

[0176] Example 2

[0177] A non-viscous solid-like mixture containing HPMCP with reduced acetic acid content was obtained in the same manner as in Example 1, except that the stirring time in the acetic acid removal step was 60 minutes and the amount of the recovered mixture containing at least the removed acetic acid and water was 775.0 g.

[0178] Next, the solid-like mixture with reduced acetic acid content was pulverized in a Feather Mill FM-1F (manufactured by Hosokawa Micron Corporation; rotor diameter 266.4 mm) equipped with a knife-type grinding blade and a sieve with an opening of 0.8 mm at a rotational speed of 4000 rpm and a circumferential speed of 55.79 m / s. Then, 300 parts by mass of water at 20°C was added to 100 parts by mass of the pulverized mixture with reduced acetic acid content, and the mixture was mixed to obtain an aqueous mixture of the pulverized mixture and water. The aqueous mixture was filtered to obtain crude HPMCP.

[0179] Thereafter, washing was carried out by repeating the sequence of dispersing the crude HPMCP in water, stirring, and filtering 10 times to obtain the washed HPMCP. The temperature of the washing water was 20°C, and with respect to 100 parts by mass of the solid-like mixture with reduced acetic acid content, the amount of water used in each washing sequence was 500 parts by mass. Thereafter, the washed HPMCP was dried and sieved in the same manner as in Example 1 to obtain HPMCP. The results are shown in Tables 2 and 3.

[0180] Example 3

[0181] HPMCP was obtained in the same manner as in Example 1, except that the amount of water added to the reaction product solution containing HPMCP was 1104.0 g, the stirring time in the acetic acid removal step was 60 minutes, and the amount of the recovered mixture containing at least acetic acid and water was 1230.2 g. It should be noted that a viscous solid-like mixture containing HPMCP with reduced acetic acid content was obtained in the acetic acid removal step. The results are shown in Tables 2 and 3.

[0182] Example 4

[0183] HPMCP was obtained in the same manner as in Example 1, except that the amount of water added to the reaction product solution containing HPMCP was 1104.0 g, the stirring time in the acetic acid removal step was 120 minutes, and the amount of the recovered mixture containing at least acetic acid and water was 1719.5 g. It should be noted that a viscous solid-like mixture containing HPMCP with reduced acetic acid content was obtained in the acetic acid removal step. The results are shown in Tables 2 and 3.

[0184] Comparative Example 1

[0185] HPMCP was obtained in the same manner as in Example 1, except that the amount of water added to the reaction product solution containing HPMCP was 1104.0 g, and the water-added reaction product solution was placed in a homogenizer without an acetic acid removal step. The results are shown in Tables 2 and 3.

[0186] Table 2

[0187]

[0188] Table 3

[0189]

[0190] *1 "Viscosity" means the viscosity of a 10 mass% HPMCP solution in a mixed solvent of methanol and dichloromethane (mass ratio 1:1) at 20°C. "MeO" means a methoxy group, "HPO" means a hydroxypropoxy group, and "Cbz" means a carboxybenzoyl group.

[0191] Table 3 (continued)

[0192] Spherical particles (%) Long fibrous particles (%) Short fibrous particles (%) Fine particles (%) Example 1 80.7 19.1 0.1 0.1 Example 2 94.0 5.9 0.1 0.0 Example 3 83.0 16.9 0.1 0.0 Example 4 88.7 11.2 0.1 0.0 Comparative Example 1 27.6 69.7 2.1 0.6

[0193] By performing the acetic acid removal step, HPMCP having a volume fraction of spherical particles of 70.0% or more is obtained. It shows a good particle size ratio D 90 :D 10 , good bulk density and good flow rate. In addition, by reducing the wastewater treatment burden and reusing the recovered acetic acid, the cost can be reduced. Furthermore, the mixing uniformity of HPMCP and the drug in the composition for hot melt extrusion, and the formation of bridges of the mixed powder of HPMCP and the drug in the hopper can be improved. Uniformity of drug content, improvement of the mass ratio of HPMCP to the drug, quantitative feeding, and continuous operation can be expected.

Claims

1. A method for producing hydroxypropyl methylcellulose phthalate, the method comprising: An esterification step of esterifying hydroxypropyl methylcellulose with phthalic anhydride in acetic acid as a solvent to obtain a reaction product solution containing hydroxypropyl methylcellulose phthalate; A water addition step of adding water to the reaction product solution in an amount that does not precipitate hydroxypropyl methylcellulose phthalate to obtain a water-added reaction product solution; An acetic acid removal step of removing at least a part of acetic acid from the water-added reaction product solution to obtain a mixture with a reduced acetic acid content; and A washing and recovery step of washing the mixture and recovering the hydroxypropyl methylcellulose phthalate, wherein the acetic acid removal step includes evaporating acetic acid by heating and stirring the water-added reaction product solution under reduced pressure, and the amount of acetic acid removed in the acetic acid removal step is equivalent to 10.0% or more of the solvent acetic acid, and wherein the mixture with a reduced acetic acid content is in solid form, and the method further includes a pulverization step of pulverizing the mixture in solid form between the acetic acid removal step and the washing and recovery step.

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