Hydropropylmethylcellulose phthalate, method for the production thereof and composition for hot melt extrusion

Abstract

Provided is a method for efficiently producing hydroxypropyl methyl cellulose phthalate (HPMCP) having excellent flowability, in which acetic acid in a reaction product mixture that has undergone washing and recovery steps can be reduced. More specifically, provided is a method for producing HPMCP, the method comprising an esterification step of esterifying hydroxypropyl methyl cellulose (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 portion of the acetic acid from the water-added reaction product solution to obtain a mixture having a reduced acetic acid content; and a washing and recovery step of washing the mixture and recovering the HPMCP.

Description

[0001] This application is a divisional application. The application number of the original application is 202111151356.1, the application date is September 29, 2021, and the name of the invention is "Hydroxypropyl methylcellulose phthalate, its production method and composition for hot melt extrusion". Technical Field

[0002] 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

[0003] 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.

[0004] HPMCP is particularly widely used in the pharmaceutical field as an enteric polymer-based material in coating applications or as a solid dispersion containing poorly water-soluble drugs.

[0005] Examples of methods for producing HPMCP include a method for producing a carboxylate-containing cellulose derivative, comprising the steps of esterifying cellulose with a polyvalent carboxylic acid anhydride in acetic acid as a solvent in the presence of an alkali metal carboxylate as a catalyst, while stirring by a biaxial stirrer, wherein the amount of acetic acid as a solvent is 1 to 2 times the weight of the cellulose (JPH05-0339301A). Summary of the Invention

[0006] In conventional methods for producing HPMCP (e.g., the method disclosed in JPH5-339301A), water is added to the reaction product solution to obtain a suspension containing a precipitated HPMCP. The HPMCP in the suspension is then washed with water to remove impurities. The suspension contains a large amount of acetic acid, which is used as a solvent in the esterification step. Because it is difficult to recycle, the acetic acid contained in the washing water is discarded along with the water. However, acetic acid increases the chemical oxygen demand (COD) of the wastewater. It also lowers the pH of the wastewater and contributes to odor.

[0007] Therefore, after washing and recovering the suspension containing a large amount of acetic acid, it is necessary to subject the washing water to wastewater treatment, such as biological treatment. The amount of acetic acid in the mixture after the washing and recovery steps is ideally low to reduce the load on wastewater treatment.

[0008] To reduce the acetic acid in the mixture after washing and recovery, it is considered to reduce the amount of acetic acid used in the esterification step. However, as described in JPH05-339301A, reducing the amount of acetic acid may make it difficult to uniformly dissolve cellulose in a high-concentration acetic acid solvent.

[0009] As mentioned above, the traditional method of producing HPMCP has room for improvement. The flowability of traditional HPMCP also has room for improvement, such as fluidity issues such as hopper blockage and sanitation issues caused by residual HPMCP in the hopper and pipeline.

[0010] After extensive research to solve the above problems, the inventors found that removing acetic acid from the reaction product solution containing HPMCP can reduce acetic acid in the mixture after washing and recovery steps and efficiently produce HPMCP with excellent fluidity, thereby completing the present invention.

[0011] In one aspect of the present invention, there is provided a method for producing hydroxypropyl methylcellulose phthalate, the method comprising:

[0012] 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;

[0013] a water-adding step of adding water to the reaction product solution to obtain a water-added reaction product solution;

[0014] an acetic acid removal step of removing at least a portion of the acetic acid from the aqueous reaction product solution to obtain a mixture having a reduced acetic acid content; and

[0015] A washing and recovery step of washing the mixture and recovering the hydroxypropyl methylcellulose phthalate.

[0016] 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 relative 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.

[0017] in

[0018] Fine particles have a fiber length of less than 40 μm;

[0019] The spherical particles have a length of 40 μm or more and are composed of first spherical particles and second spherical particles, wherein the first spherical particles have an elongation (ratio of fiber diameter to fiber length) of 0.5 or more, and the second spherical particles have an elongation of less than 0.5, an aspect ratio (ratio of minimum Feret diameter to maximum Feret diameter) of 0.5 or more, and a circularity (circumference of a circle having the same area as the projected area of ​​the particle (P EQPC ) and the true perimeter of the particle (P real ) ratio) is 0.7 or greater;

[0020] Fibrous particles consist of long fibrous particles and short fibrous particles;

[0021] The long fibrous particles have a fiber length of 200 μm or more and an elongation of less than 0.5, and are composed of first long fibrous particles and second long fibrous particles, wherein 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 more and a roundness of less than 0.7; and

[0022] The short fibrous particles have a fiber length of 40 μm or greater and less than 200 μm, an elongation of less than 0.5, and are composed of first short fibrous particles and second short fibrous particles, wherein 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.

[0023] According to the present invention, since at least a portion of the acetic acid is removed from the HPMCP-containing reaction product solution, the amount of acetic acid in the mixture to be subjected to the washing and recovery steps can be reduced. Consequently, the burden on wastewater treatment is expected to be reduced, and costs can be reduced by reusing the removed acetic acid.

[0024] Furthermore, HPMCP with excellent flowability can be produced. This improves the mixing uniformity of HPMCP and drugs in compositions for hot-melt extrusion, and reduces bridges formed in the hopper by the mixed powder of HPMCP and drugs. This can lead to improved drug content uniformity, an improved HPMCP to drug mass ratio, quantitative supply, and continuous operation. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 A flow chart is shown for classifying “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

[0026] Regarding the method for producing HPMCP, the esterification step of esterifying hypromellose with phthalic anhydride in acetic acid as a solvent to obtain a reaction product solution containing HPMCP will be described.

[0027] 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.

[0028] From the perspective of providing HPMC with a reduced number of undissolved fibers, the DS of the methoxyl group of HPMC is preferably 1.10 to 2.20, more preferably 1.3 to 2.10, even more preferably 1.60 to 2.00, and particularly preferably 1.80 to 2.00. From the perspective of providing HPMC with a reduced number of undissolved fibers, the MS of the hydroxypropoxyl group of HPMC is preferably 0.10 to 1.00, more preferably 0.10 to 0.80, even more preferably 0.15 to 0.60, and particularly preferably 0.20 to 0.50.

[0029] The DS of the methoxy group of HPMC represents the degree of substitution of the methoxy group and refers to the average number of methoxy groups per glucoside unit. The MS of the hydroxypropoxy group of HPMC represents the molar substitution of the hydroxypropoxy group and refers to the average number of moles of hydroxypropoxy groups per mol of glucoside. The DS of the methoxy group of HPMC and the MS of the hydroxypropoxy group of HPMC can be determined by converting the values ​​obtained by measurement according to the Japanese Pharmacopoeia, 17th edition.

[0030] From the viewpoint of kneadability in the esterification step, the viscosity of a 2% by mass HPMC aqueous solution at 20° C. is preferably 1.0 to 30.0 mPa·s, more preferably 2.0 to 20.0 mPa·s. The viscosity of a 2% by mass HPMC aqueous solution at 20° C. can be measured using an Ubbelohde viscometer according to the method described in the monograph "Hydroxypropylmethylcellulose" in the Seventeenth Edition of the Japanese Pharmacopoeia.

[0031] The amount of acetic acid to be used is preferably 3.5 to 10.0 mol, more preferably 4.5 to 7.0 mol, and still more preferably 5.0 to 6.5 mol relative to 1 mol of HPMC from the viewpoint of dissolving HPMC and increasing the reaction rate.

[0032] The amount of phthalic anhydride to be used is not particularly limited as long as HPMCP having a desired degree of substitution is obtained. From the viewpoint of reaction efficiency, it is preferably 0.2 to 3.0 mol, more preferably 0.4 to 1.8 mol, relative to 1 mol of HPMC.

[0033] The esterification reaction can be carried out in the presence of a catalyst. As a catalyst, from an economic point of view, 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.

[0034] The amount of the optional catalyst to be used can be selected according to the degree of substitution of HPMCP. From the viewpoint of reaction efficiency, it is preferably 0.1 to 3.0 mol, more preferably 0.3 to 2.0 mol, relative to 1 mol of HPMC.

[0035] The esterification can be carried out in the presence of a depolymerizing agent. As the depolymerizing agent, alkali metal chlorates (such as sodium chlorate) are preferred from an economical point of view. The optional depolymerizing agents can be used alone or in combination of two or more. Commercially available depolymerizing agents can be used.

[0036] The amount of the optional depolymerizing agent to be used can be selected according to the degree of polymerization of the 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.

[0037] From the perspective of reaction efficiency, the esterification reaction is preferably carried out using a kneader reactor or the like. 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 an HPMCP having a desired degree of substitution, the reaction time in the esterification step is preferably 2 to 8 hours, more preferably 3 to 6 hours.

[0038] Next, the water-adding step of adding water to the reaction product solution containing HPMCP to obtain a water-added reaction product solution will be described.

[0039] The water addition step allows for the disposal of unreacted phthalic anhydride.

[0040] To prevent HPMCP precipitation and the resulting deterioration of transferability, water is added in an amount that does not cause HPMCP precipitation. The amount of water added is preferably no more than 250 parts by mass, more preferably 1 to 200 parts by mass, and even more preferably 3 to 190 parts by mass, relative to 100 parts by mass of the starting HPMC used in the esterification reaction. To facilitate the subsequent acetic acid removal step after water addition, the temperature of the HPMCP-containing reaction product solution to which water is added is preferably between 60°C and 100°C.

[0041] Next, the acetic acid removal step of removing at least a portion of the acetic acid from the water-added reaction product solution to obtain a mixture having 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.

[0042] CH3 COONa+CH3COOH=CH3COOH+CH3COONa

[0043] The method for removing at least a portion of the acetic acid from the aqueous reaction product solution is not particularly limited. From the perspective of effectively removing and recovering the acetic acid, the acetic acid removal step preferably includes evaporating the acetic acid by heating and stirring the aqueous reaction product solution under reduced pressure to recover the acetic acid.

[0044] For example, the acetic acid removal step can be performed by using an apparatus capable of stirring the high-viscosity water-added reaction product solution and ensuring a sealed state for heating and decompression or for decompression. Examples of such apparatus include a reactor capable of heating and reducing internal pressure and equipped with a stirring blade that rotates; a reactor capable of heating and reducing internal pressure and equipped with a stirring blade that rotates and orbits. The apparatus is preferably a reactor capable of heating and reducing internal pressure and equipped with a stirring blade that rotates and orbits, for example, a 5L vertical kneader reactor (Trimix TX-5 produced by INOUE MFG., Inc.), which has three frame-shaped stirring blades that rotate and orbit. From the perspective of stirring uniformity in the acetic acid removal step, the circumferential speed of the rotational motion of one stirring blade is preferably 0.01 m / s to 2.00 m / s. When revolution motion is also used, the circumferential speed of the revolution motion of one stirring blade is preferably 0.001 m / s to 2.00 m / s. As used herein, the term "circumferential speed in rotational motion" refers to the speed of the fastest portion (i.e., the outermost circumference) of a stirring blade rotating in the device used. The term "circumferential speed in revolution motion" refers to the speed of the fastest portion (i.e., the outermost circumference) of a stirring blade orbiting along an orbit in the device used.

[0045] 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 reduced pressure in the acetic acid removal step is preferably -0.10 MPaG to -0.02 MPaG. The reduced pressure in the acetic acid removal step can be performed using an aspirator or the like.

[0046] From the viewpoint of productivity, the acetic acid removal time in the acetic acid removal step is preferably 0.1 to 5 hours.

[0047] The evaporated acetic acid can be recovered in a cooling trap or the like connected to the apparatus. The trap is preferably cooled by ice or the like. The recovered acetic acid may contain water.

[0048] 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 referred to as the acetic acid removal percentage. From the perspective of HPMCP fluidity, the acetic acid removal percentage is preferably 10.0% or higher, more preferably 20.0% to 95.0%, even more preferably 40.0% to 90.0%, and particularly preferably 70.0% to 85.0%.

[0049] Considering that the removed acetic acid is a mixture of acetic acid and water added in the water adding step, the removal percentage of acetic acid in the acetic acid removing step is determined by the following formula.

[0050] Acetic acid removal percentage (%) = {(C × D / 100) / A} × 100

[0051] 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, wherein the recovered mixture also includes water added in the water-adding step.

[0052] From the perspective of HPMCP fluidity, the mixture with reduced acetic acid content and subjected to the washing and recovery steps is preferably in solid form. When the mixture with reduced acetic acid content is in a liquid form with high viscosity, a solid mixture can be obtained by cooling the liquid mixture to room temperature.

[0053] From the perspective of effectively washing the mixture with reduced acetic acid content in solid form, an optional pulverizing step of pulverizing the mixture in solid form may be performed between the acetic acid removal step and the washing and recovery steps described later to obtain a pulverized mixture with reduced acetic acid content.

[0054] The pulverization can be performed using a pulverizer. Examples of pulverizers include high-speed rotating pulverizers such as hammer mills and pin mills; high shear equipment such as homogenizers and high shear mills; roller pulverizers such as roller mills; pulverizers with grinding media such as vibration mills and planetary mills; and fluid pulverizers such as jet mills.

[0055] When the mixture with reduced acetic acid content is a non-sticky solid, it can be crushed as it is (i.e., dry crushing). When the mixture with reduced acetic acid content is a sticky solid, water can be added to the mixture and then crushed (i.e., wet crushing). Generally speaking, when the mixture with reduced acetic acid content is in solid form, as the percentage of acetic acid removal increases and the acetic acid content decreases, the viscosity becomes weaker. From the perspective of HPMCP crushing, 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 mixture in solid form with reduced acetic acid content.

[0056] Next, the washing and recovery steps of washing the acetic acid-reduced mixture and recovering hydroxypropylmethylcellulose phthalate will be described.

[0057] The method for washing and recovering is not particularly limited. Examples of the method include the following: a method comprising mixing the mixture with 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 for 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 comprising subjecting the mixture with reduced acetic acid content or the crude HPMCP to a continuous flow of water; and a method comprising repeatedly replacing a portion of the liquid in the aqueous mixture with water.

[0058] From the viewpoint of washing, the aqueous mixture containing the mixture with reduced acetic acid content and water is preferably a suspension.

[0059] From the perspective of effectively removing impurities contained in the HPMCP, the temperature of the water used for washing is preferably 5°C to 40°C. The amount of water used for washing varies depending on the washing method. For example, when washing crude HPMCP obtained by centrifugation or filtration, from the perspective of obtaining HPMCP with reduced impurities, the amount of water used for washing is preferably 200 to 20,000 parts by mass per 100 parts by mass of the mixture with reduced acetic acid content.

[0060] The amount of water to be used for washing in combination with the amount of water added in the water adding step may preferably be selected to fall within the above range.

[0061] The obtained HPMCP may be optionally dried. From the perspective of preventing HPMCP aggregation, the drying temperature is preferably 40°C to 100°C, more preferably 40°C to 80°C. From the perspective of preventing HPMCP aggregation, the drying time is preferably 1 to 20 hours, more preferably 3 to 15 hours.

[0062] The obtained HPMCP can be optionally sieved to obtain a desired average particle size.

[0063] The viscosity of a 10% by mass HPMCP solution obtained by dissolving HPMCP in a mixed solvent of methanol and dichloromethane (methanol and dichloromethane having a mass ratio of 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 even 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 (methanol and dichloromethane having a mass ratio of 1:1) at 20° C. can be measured using an Ubbelohde viscometer according to the method described in the monograph "Hydroxypropylmethylcellulose Phthalate" in the 17th edition of the Japanese Pharmacopoeia.

[0064] The DS of the methoxy group of HPMCP is preferably 1.10 to 2.20, more preferably 1.30 to 2.10, still more preferably 1.60 to 2.00, and most preferably 1.80 to 2.00.

[0065] 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.

[0066] 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.

[0067] The DS of the methoxyl group, the DS of the carboxybenzoyl group, and the MS of the hydroxypropoxyl group of HPMCP can be obtained by converting the values ​​obtained according to the method described in the monographs "Hydroxypropyl methylcellulose" and "Hydroxypropyl methylcellulose phthalate" in the 17th edition of the Japanese Pharmacopoeia. The DS of the methoxyl group or carboxybenzoyl group of HPMCP represents the degree of substitution and refers to the average number of methoxyl groups or carboxybenzoyl groups per glucoside unit. Furthermore, the MS of the hydroxypropoxyl group of HPMCP represents molar substitution and refers to the average number of moles of hydroxypropoxyl groups per glucoside unit.

[0068] The particle size D that represents 50% of the cumulative particle size distribution in HPMCP can be appropriately selected according to the application. 50 From the viewpoint of fluidity of HPMCP, it is preferably 50 μm to 700 μm, more preferably 100 μm to 600 μm, and still more preferably 300 μm to 500 μm.

[0069] D 90 With D 10The particle size ratio, that is, the ratio of the cumulative 90% particle size to the cumulative 10% particle size in the particle size distribution is preferably 40.0 or less, more preferably 0.5 to 10.0, further more preferably 1.0 to 4.0, and particularly preferably 1.0 to 3.5. 90 With D 10 The particle size ratio indicates the width of the particle size distribution.

[0070] D in HPMCP particle size distribution 10 、D 50 and D 90 The measurement can be performed using a dry laser diffraction particle size distribution analyzer (Mastersizer 3000 manufactured by Malvern Panalytic Ltd.) at a dispersion pressure of 2 bar. A dry laser diffraction particle size distribution analyzer is an apparatus that sprays a powder sample with compressed air, irradiates it with a laser beam, and measures the volume equivalent spherical diameter based on the diffraction intensity. Examples include the Mastersizer manufactured by Malvern Panalytical Ltd. in the UK and the HELOS apparatus manufactured by Sympatec GmbH in Germany.

[0071] From the perspective of processing, the loose bulk density of HPMCP is preferably 0.30 g / cm 3 to 0.60g / cm 3 , more preferably 0.35g / cm 3 to 0.55g / cm 3 , and more preferably 0.40 g / cm 3 to 0.53g / cm 3 The loose bulk density refers to the bulk density in a loosely packed state. It is measured by a method comprising the following steps: uniformly placing a sample over 23 cm in a cylindrical container having 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.

[0072] As described in the general information of the Japanese Pharmacopoeia, 17th edition, the flow rate of HPMCP flowing through the orifice can be determined by flow rate measurement. From the perspective of processing, 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 Japanese Pharmacopoeia, 17th edition. Therefore, it is necessary to compare the flow rates measured under the same conditions with each other. The details of the measurement conditions will be described in the Examples.

[0073] In this specification, HPMCP particles are classified into four types of particles: "long fibrous particles", "short fibrous particles", "spherical particles" and "fine particles". Figure 1A flow chart summarizing the method of classifying “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.

[0074] 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 circularity 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 solvent) are continuously captured and binarized and analyzed to obtain the particle diameter or particle shape. For example, the dynamic image analysis type particle size distribution analyzer QICPIC / R16 (manufactured by Sympatec GmbH) can be used for analysis.

[0075] All particles A are divided into particles C with a fiber length (LEFI) of 40 or greater and fine particles B with a fiber length of less than 40 μm. LEFI is defined as the length of the longest direct path connecting the particle endpoints within the particle contour. The QICPIC / R16 equipped with an M7 lens has a detection limit of 4.7 μm, so particles with a LEFI of less than 4.7 μm cannot be detected. However, the volume of particles with a LEFI of less than 4.7 μm is very small relative to the total volume of the HPMCP particles and can therefore be ignored for the purposes of this invention.

[0076] Particles C having a LEFI of 40 μm or more are divided into first spherical particles (S1) having an elongation of 0.5 or more and particles D having an elongation of less than 0.5, where the elongation is the ratio of the diameter of the fiber (DIFI) to the LEFI of the particle (DIFI / LEFI). DIFI is defined as the minor diameter of the particle and is calculated by dividing the projected area of ​​the particle by the sum of all lengths of the fiber branches of the particle.

[0077] Particles D having a LEFI of 40 μm or greater and an elongation of less than 0.5 are divided into particles E having an aspect ratio of less than 0.5 and particles F having an aspect ratio of 0.5 or greater, where the aspect ratio is the ratio (Fmin / Fmax) of the minimum Feret diameter (Fmin) to the maximum Feret diameter (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 a pair of tangents of the particle by changing the direction from 0° to 180°, taking into account all possible directions, and the minimum Feret diameter (Fmin) is the minimum distance between a pair of tangents of the particle by changing the direction from 0° to 180°, taking into account all possible directions.

[0078] Fibrous particles E having a LEFI of 40 μm or greater, an elongation of less than 0.5, and an aspect ratio of less than 0.5 are divided into first long fibrous particles (LF1) having a LEFI of 200 μm or greater and first short fibrous particles (SF1) having a LEFI of less than 200 μm.

[0079] Particles F having a LEFI of 40 μm or more, an elongation of less than 0.5, and an aspect ratio of 0.5 or more are divided into second spherical particles (S2) having a roundness of 0.7 or more and fibrous particles G having a roundness of less than 0.7. Roundness is the ratio of the area to the projected area (A) of the particle. P )The circumference of the same circle (P EQPC ) and the true perimeter of the particle (P real ) 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, the more irregular the particle 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.

[0080]

[0081] Fibrous particles G having a LEFI of 40 μm or greater, an elongation of less than 0.5, an aspect ratio of 0.5 or greater, and a roundness of less than 0.7 are divided 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.

[0082] The volume of fine particles of HPMCP (V m ) can be calculated by the following equation, where each fine particle is assumed to be a sphere with a diameter of EQPC.

[0083] V m =(π / 6)×(EQPC) 3 ×N m

[0084] where N m is the number of fine particles in the sample, and EQPC is the median EQPC corresponding to 50% of the cumulative values ​​on the number-based cumulative particle size distribution curve of the fine particles.

[0085] In this specification, particles having a LEFI of 40 μm or greater (excluding fine particles having a LEFI of less than 40 μm among all particles) are classified as "long fibrous particles," "short fibrous particles," and "spherical particles," which are distinguished from each other. This division or classification is based on the above-mentioned shape parameters of the particles, including LEFI, elongation, aspect ratio, and roundness.

[0086] <Long fibrous particles>

[0087] Particles that meet the definition of LF1 or LF2 below are classified as "long fibrous particles."

[0088] LF1: particles having an elongation of less than 0.5, an aspect ratio of less than 0.5 and a LEFI (length of fiber) of 200 μm or more, and

[0089] LF2: particles having an elongation of less than 0.5, an aspect ratio of 0.5 or more, a circularity of less than 0.7, and a LEFI (length of fiber) of 200 μm or more.

[0090] The volume of HPMCP long fibrous particles (V LF ) can be calculated by the following equation, where each long fibrous particle is assumed to be a cylinder with a base diameter of DIFI and a height of LEFI.

[0091] V LF =(π / 4)×(DIFI) 2 ×(LEFI)×N LF

[0092] where N LF is the number of long fibrous particles in the sample, DIFI is the median DIFI corresponding to 50% of the cumulative values ​​on the cumulative particle size distribution curve based on the number of long fibrous particles, and LEFI is the median LEFI corresponding to 50% of the cumulative values ​​on the cumulative particle size distribution curve based on the number of long fibrous particles.

[0093] The volume of particles meeting the definition of LF1 and the volume of particles meeting the definition of LF2 were calculated according to the above equations, respectively, and the sum of these volumes means the volume of the long fibrous particles of HPMCP.

[0094] <Short fibrous particles>

[0095] Particles that meet the definition of SF1 or SF2 below are classified as "short fibrous particles."

[0096] SF1: particles having an elongation of less than 0.5, an aspect ratio of less than 0.5, and a LEFI (length of fiber) of 40 μm or more and less than 200 μm, and

[0097] SF2: particles having an elongation of less than 0.5, an aspect ratio of 0.5 or more, a circularity of less than 0.7, and a LEFI (length of fiber) of 40 μm or more and less than 200 μm.

[0098] The volume of short fibrous particles of HPMCP (V SF) 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 base diameter of DIFI and a height of LEFI.

[0099] V SF =(π / 4)×(DIFI) 2 ×(LEFI)×N SF

[0100] where N SF is the number of short fibrous particles in the sample, DIFI is the median DIFI corresponding to 50% of the cumulative values ​​on the cumulative particle size distribution curve based on the number of short fibrous particles, and LEFI is the median LEFI corresponding to 50% of the cumulative values ​​on the cumulative particle size distribution curve based on the number of short fibrous particles.

[0101] The volume of particles meeting the definition of SF1 and the volume of particles meeting the definition of SF2 were calculated according to the above equations, respectively, and the sum of these volumes means the volume of short fibrous particles of HPMCP.

[0102] <Spherical particles>

[0103] Particles that meet definition S1 or S2 are classified as "spherical particles".

[0104] S1: particles having an elongation of 0.5 or more and a LEFI (length of fiber) of 40 μm or more, and

[0105] S2: particles having an elongation of less than 0.5, an aspect ratio of 0.5 or more, a circularity of 0.7 or more, and a LEFI (length of fiber) of 40 μm or more.

[0106] The volume of HPMCP spherical particles (V S ) can be calculated by the following equation, where each spherical particle is assumed to be a sphere with a diameter of EQPC.

[0107] V S =(π / 6)×(EQPC) 3 ×N S

[0108] where N S is the number of spherical particles in the sample, and EQPC is the median EQPC corresponding to 50% of the cumulative values ​​on the number-based cumulative particle size distribution curve of spherical particles.

[0109] The volume of particles satisfying Definition S1 and the volume of particles satisfying Definition S2 are calculated according to the above equations, respectively, and the sum of these volumes means the volume of the spherical particles of HPMCP.

[0110] The volume fraction of each type of HPMCP particle can be calculated based on the volume defined above, V m 、V LF 、V SF and V S Calculate using the following corresponding equation.

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

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

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

[0114] Volume fraction of spherical particles = {V S / (V m +V LF +V SF +V S )}×100

[0115] The volume fraction of each type of particle (long fibrous particles, short fibrous particles, spherical particles and fine particles) is measured as follows. The dynamic image analysis type particle size distribution analyzer QICPIC / R16 (manufactured by Sympatec GmbH) equipped with quantitative feeder VIBRI / L, airflow disperser RODOS / L and M7 lens is used under the condition that frame rate is 500Hz, injector is 4mm, dispersion pressure is 1 bar. The graphic of imaging particle is analyzed by analysis software WINDOX5 5.9.1.1 version to determine the median EQPC based on number, the median LEFI based on number, the median DIFI based on number, elongation, aspect ratio and the roundness of each type of particle. The volume fraction of each type of particle is calculated by above-mentioned equation based on measured value. It should be noted that M7 is used as the division of analysis.

[0116] From the viewpoint of obtaining HPMCP having excellent fluidity, the volume fraction of the spherical particles of the HPMCP is 70.0% or more, preferably 75.0% to 99.0%, and more preferably 83.0% to 97.0%.

[0117] From the viewpoint of the fluidity of HPMCP, the volume fraction of the long fibrous particles of HPMCP is preferably 30.0% or less, more preferably 1.0% to 25.0%, and still more preferably 3.0% to 20.0%.

[0118] 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 0.0% to 1.5%, and still more preferably 0.0% to 0.5%.

[0119] 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 0.0% to 1.5%, and still more preferably 0.0% to 0.5%.

[0120] Next, a composition for hot melt extrusion containing the above-mentioned hydroxypropyl methylcellulose phthalate and a drug will be described.

[0121] The use of this HPMCP with excellent flowability improves the mixing uniformity of the HPMCP and drug in the composition for hot-melt extrusion, as well as the bridge formation of the HPMCP-drug mixed powder in the hopper. This also leads to improved drug content uniformity, an improved HPMCP-to-drug mass ratio, quantitative feeding, and continuous operation.

[0122] The drug is not particularly limited as long as it can be taken orally. 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, antitussive expectorants, antihistamines, antipyretic and anti-inflammatory analgesics, diuretics, autonomic drugs, antimalarials, antidiarrheals, psychotropic drugs, and vitamins and their derivatives.

[0123] Examples of drugs used for the central nervous system include diazepam, idebenone, naproxen, piroxicam, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen (another name: paracetamol), ethenzamide, and chlordiazepoxide.

[0124] Examples of drugs for the cardiovascular system include molsidomide, 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.

[0125] Examples of drugs for the respiratory system include amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol, and guaifenesin.

[0126] Examples of drugs for the digestive system include benzimidazole drugs having an antiulcer effect, 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.

[0127] Examples of antibiotics include talampicillin hydrochloride, bacancillin hydrochloride, cefaclor, and erythromycin.

[0128] Examples of the antitussive expectorant include narcotine hydrochloride, pentoxyverine citrate, 4-dimethylamino-2,2-isopropylphenylvaleronitrile, and dimethorphan phosphate.

[0129] Examples of antihistamines include chlorpheniramine maleate, diphenhydramine hydrochloride, and promethazine hydrochloride.

[0130] Examples of antipyretic, anti-inflammatory, and analgesic drugs include ibuprofen, diclofenac sodium, flufenamic acid, sulpheniramine, aspirin, and ketoprofen.

[0131] Examples of diuretics include caffeine.

[0132] Examples of autonomic drugs include dihydrocodeine phosphate, dl-methylephedrine hydrochloride, atropine sulfate, acetylcholine chloride, and neostigmine.

[0133] Examples of antimalarial agents include quinine hydrochloride.

[0134] Examples of antidiarrheal agents include loperamide hydrochloride.

[0135] Examples of psychotropic drugs include chlorpromazine.

[0136] Examples of vitamins and derivatives thereof 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.

[0137] In particular, using the HPMCP according to the present invention as a carrier for solid dispersions containing poorly water-soluble drugs can improve the solubility of poorly water-soluble drugs. Poorly water-soluble drugs are those listed in the 17th edition of the Japanese Pharmacopoeia as "slightly soluble," "very slightly soluble," or "practically insoluble or insoluble" in water. The term "slightly soluble" means that when 1 gram or 1 mL of the solid drug 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 gram or 1 mL of the solid drug dissolves in 1000 mL or more and less than 10,000 mL of water in the same manner within 30 minutes. The term "practically insoluble or insoluble" means that 1 gram or 1 mL of the solid drug dissolves in 10,000 mL or more of water within 30 minutes.

[0138] In the above-mentioned drug test, dissolution of a poorly water-soluble drug means that the drug is dissolved in water or miscible with water, and also means that fibers and the like are found to be absent or present in a very small amount.

[0139] Examples of poorly water-soluble drugs include azole-based compounds such as itraconazole, ketoconazole, fluconazole, and methoconazole; dihydropyridine-based compounds such as nifedipine, nitrendipine, amlodipine, nicardipine, nilvadipine, ferrodipine, and efonidipine; propionic acid-based compounds such as ibuprofen, ketoprofen, and naproxen; indoleacetic acid-based compounds such as indomethacin and acemetacin; griseofulvin; phenytoin; carbamazepine; and dipyridamole.

[0140] The mass ratio of HPMCP to the drug is not particularly limited. From the perspective of storage stability in an amorphous state, it is preferably 1:0.1 to 1:10, more preferably 1:0.2 to 1:5.

[0141] Furthermore, the composition for hot-melt extrusion may contain optional additives such as plasticizers and surfactants for improving moldability during hot-melt extrusion, among other things.

[0142] Examples of the plasticizer 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; pearl wax; triethyl citrate; polyalkylene glycols such as polyethylene glycol and polypropylene glycol; triacetin; dibutyl sebacate; glyceryl monostearate; and glyceryl monoacetate.

[0143] From the viewpoint of storage stability, the content of the plasticizer in the composition for hot-melt extrusion is preferably from 0.1% by mass to 30% by mass.

[0144] Examples of the surfactant include anionic surfactants such as sodium lauryl 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.

[0145] The content of the surfactant in the composition for hot-melt extrusion is preferably 0.1% by mass to 10% by mass from the viewpoint of storage stability.

[0146] The composition for hot melt extrusion can be prepared by a method comprising mixing HPMCP, a drug, an optional plasticizer, and an optional surfactant to obtain a step of the composition for hot melt extrusion. The composition for hot melt extrusion prepared can be introduced into a hot melt extruder through a hopper and squeezed into a desired shape, such as a circle, square, column, or film, to obtain an extrudate.

[0147] The hot melt extruder is not particularly limited as long as it is an extruder capable of melting and kneading the HPMCP and the drug while heating and applying shearing force using a piston or screw and then extruding them from a die. It is preferably a twin-screw extruder to obtain a more uniform extrudate. Specific examples include the Capilograph (single-screw piston extruder) produced by Toyo Seiki Seisaku-sho, Ltd.; the NANO 16 (twin-screw extruder) produced by Leistritz Extrusionstechnik GmbH; the MiniLab (twin-screw extruder) and the Pharma Lab (twin-screw extruder) produced by Thermo Fisher Scientific Inc.

[0148] The hot melt temperature is not particularly limited. It is preferred that the composition for hot melt extrusion be melted and extruded appropriately while avoiding as much as possible a temperature at which the drug and HPMCP thermally decompose. Taking into account 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 even more preferably 90°C to 190°C.

[0149] The conditions for hot melt extrusion can be appropriately selected according to the properties of the composition for hot melt extrusion in accordance with a conventional method.

[0150] The hot melt extrudate after extrusion is cooled at the die outlet or thereafter cooled by natural cooling or cold blowing at room temperature (1° C. to 30° C.). 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.

[0151] The hot-melt extrudate after the cooling can optionally be granulated into the granules of 0.1mm to 5mm by cutter, or is ground into particles or powder to adjust particle size.Preferably use impact mill (such as jet mill, shredder or pin mill) to pulverize, because its structure can hardly raise product temperature.When the temperature in cutter and pulverizer increases, HPMCP heat softens, and particles adhere to each other.Therefore, pulverizing is preferably carried out under cold air purge.

[0152] Example

[0153] Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples, but it should not be construed that the present invention is restricted thereto or to them.

[0154] In the acetic acid removal step, the concentration of acetic acid in the recovered mixture containing at least the removed acetic acid and water was measured by liquid chromatography under the following conditions.

[0155] Equipment: Liquid chromatograph LC-20AB manufactured by Shimadzu Corporation.

[0156] Column: ODS-3 (inner diameter 4.6 mm, length 15 cm, particle size 5 μm, manufactured by GL Science Inc.)

[0157] Column temperature: 30°C, constant

[0158] Detector: UV-visible absorption spectrophotometer (measured at 215 nm, SPD-20AV manufactured by Shimadzu Corporation)

[0159] Mobile phase: 0.02 mol / L potassium dihydrogen phosphate aqueous solution, adjusted to pH 2.8 by adding phosphoric acid.

[0160] Flow rate: 1mL / min

[0161] In the acetic acid removal step, the recovered mixture containing at least the removed acetic acid and water was diluted 500 times (by volume) with water and then further diluted 6.25 times (by volume) with the mobile phase to prepare a measurement sample.

[0162] The flow rate of the HPMCP through the orifice was measured by a flow tester BEP2 (Copley Scientific Ltd.) under the following conditions to obtain an average value of two measurements.

[0163] Orifice size: 8mm

[0164] HPMCP feed: 30g

[0165] Standing time: 30 seconds

[0166] Container: cylindrical (diameter 57mm)

[0167] Example 1

[0168] 600 g of HPMC having a DS of 1.88 for a methoxy group, an MS of 0.24 for a hydroxypropoxy group, and a viscosity of 6.0 mPa (measured as a 2% by mass aqueous solution) at 20° C., 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 were placed in a 5 L vertical kneading reactor (Trimix TX-5 manufactured by INOUE MFG., Ltd.) equipped with three rotating and orbiting frame-shaped stirring blades; and stirred at 85° C. for 4.5 hours to obtain 2320.5 g of a reaction product solution containing HPMCP.

[0169] Next, 27.0 g of water was added to the reaction product solution containing HPMCP in the same reactor while maintaining 85° C. and stirred to obtain 2347.5 g of the water-added reaction product solution. The equivalent relationship of the esterification reaction is shown in Table 1.

[0170] Table 1

[0171]

[0172] Subsequently, the internal pressure in the same kneading reactor was reduced to -0.09 MPaG using an aspirator (A-1000S, manufactured by Tokyo Rika Kikai Co., Ltd.), and the mixture was stirred at 85°C for 30 minutes to recover acetic acid in an ice-cold trap. The recovered acetic acid contained water, and the amount of the recovered mixture containing at least acetic acid and water was 253.8 g. The interior of the kneading reactor was then cooled to room temperature to obtain a viscous, solid-like mixture containing HPMCP and having a reduced acetic acid content.

[0173] The circumferential speed of each frame-shaped stirring blade during the esterification step, the water addition step, and the acetic acid removal step was 0.050 m / s for self-rotation and 0.019 m / s for orbital motion. The ratio of the self-rotational speed to the orbital speed was 2.6. Furthermore, the self-rotational speed of all three frame-shaped stirring blades, which rotated and orbited along the orbit, was the same.

[0174] Next, 300 parts by mass of 20°C water was added to 100 parts by mass of the viscous solid-like mixture, and the mixture was pulverized in a homomixer (Homomixer MARKII 2.5 manufactured by PRIMIX Corporation; rotor diameter 30.0 mm) at a rotation speed of 8000 rpm and a peripheral speed of 12.57 m / s to obtain a suspension of the pulverized mixture. The pulverized mixture was then filtered to obtain crude HPMCP.

[0175] Afterwards, the crude HPMCP was washed by repeating a 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 washing sequence was 500 parts by mass per 100 parts by mass of the solid-like mixture with reduced acetic acid content. The washed HPMCP was dried at 80°C for 2 hours and sieved through a sieve with an opening of 0.5 mm to obtain HPMCP.

[0176] Table 2 shows the mass ratio of glacial acetic acid to HPMC used as a solvent (A), the mass ratio of water added in the water-addition step after the esterification step to HPMC (B), the mass ratio of the recovered mixture containing at least acetic acid and water to HPMC in the acetic acid removal step (C), the acetic acid concentration in the recovered mixture containing at least acetic acid and water (D), the percentage of acetic acid removed, and the form of the mixture with reduced acetic acid content before the washing and recovery steps. Table 3 shows various properties of the resulting HPMCP.

[0177] Example 2

[0178] A non-sticky solid-like mixture containing HPMCP and having a 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.

[0179] 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 screen with an opening of 0.8 mm at a rotation speed of 4000 rpm and a peripheral speed of 55.79 m / s. Then, 300 parts by mass of 20°C water was added to 100 parts by mass of the pulverized mixture with reduced acetic acid content, and mixed to obtain an aqueous mixture of the pulverized mixture and water. The aqueous mixture was filtered to obtain crude HPMCP.

[0180] The crude HPMCP was then washed 10 times by dispersing it in water, stirring it, and filtering it. This process produced washed HPMCP. The temperature of the washing water was 20°C, and the amount of water used in each washing process was 500 parts by mass per 100 parts by mass of the solid-like mixture with reduced acetic acid content. The washed HPMCP was then dried and sieved in the same manner as in Example 1 to produce HPMCP. The results are shown in Tables 2 and 3.

[0181] Example 3

[0182] HPMCP was obtained in the same manner as in Example 1, except that the amount of water added to the HPMCP-containing reaction product solution was 1104.0 g, the stirring time during 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 and having a reduced acetic acid content was obtained during the acetic acid removal step. The results are shown in Tables 2 and 3.

[0183] Example 4

[0184] HPMCP was obtained in the same manner as in Example 1, except that the amount of water added to the HPMCP-containing reaction product solution was 1104.0 g, the stirring time during 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 and having a reduced acetic acid content was obtained during the acetic acid removal step. The results are shown in Tables 2 and 3.

[0185] Comparative Example 1

[0186] 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 homomixer without the acetic acid removal step. The results are shown in Tables 2 and 3.

[0187] Table 2

[0188]

[0189] Table 3

[0190]

[0191] *1 “Viscosity” means the viscosity of a 10% by mass HPMCP solution in a mixed solvent of methanol and dichloromethane (mass ratio of 1:1) at 20°C. “MeO” means a methoxy group, “HPO” means a hydroxypropoxy group, and “Cbz” means a carboxybenzoyl group.

[0192] Table 3 (continued)

[0193] 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

[0194] By performing the acetic acid removal step, HPMCP having a volume fraction of spherical particles of 70.0% or more was obtained. 90 :D 10 , good loose bulk density, and good flow rate. Furthermore, by reducing the wastewater treatment burden and reusing recovered acetic acid, costs can be reduced. Furthermore, the mixing uniformity of HPMCP and drug in the composition for hot-melt extrusion can be improved, as can the bridge formation of the HPMCP and drug mixed powder in the hopper. Improved drug content uniformity, improved HPMCP to drug mass ratio, quantitative feeding, and continuous operation are anticipated.

Claims

1. Hydroxypropyl methylcellulose phthalate having a volume fraction of spherical particles relative to all hydroxypropyl methylcellulose phthalate particles of 70.0% or more, all hydroxypropyl methylcellulose phthalate particles being classified as fine particles, spherical particles, and fibrous particles based on dynamic image analysis; The fine particles have a fiber length of less than 40 μm; The spherical particles have a length of 40 μm or greater and are composed of a first spherical particle and a second spherical particle, wherein the first spherical particle has an elongation of 0.5 or greater, the elongation being the ratio of the fiber diameter to the fiber length, and the second spherical particle has an elongation of less than 0.5, an aspect ratio of 0.5 or greater, the aspect ratio being the ratio of the minimum Feret diameter to the maximum Feret diameter, and a roundness of 0.7 or greater, the roundness being the circumference P of a circle having the same area as the projected area of ​​the particle. EQPC The true perimeter P of the particle real ratio; The fibrous particles are composed of long fibrous particles and short fibrous particles; The long fibrous particles have a fiber length of 200 μm or more and an elongation of less than 0.5, and are composed of first long fibrous particles and second long fibrous particles, wherein 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 more and a roundness of less than 0.7; and The short fibrous particles have a fiber length of 40 μm or greater and less than 200 μm and an elongation of less than 0.5, and are composed of first short fibrous particles and second short fibrous particles, wherein 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.

2. The hydroxypropyl methylcellulose phthalate according to claim 1, wherein in the particle size distribution curve of the hydroxypropyl methylcellulose phthalate, the cumulative 50% particle size D 50 50μm to 700μm, and the cumulative 90% particle size D 90 With cumulative 10% particle size D 10 The ratio (D 90 / D 10 ) is 40.0 or less.

3. A composition for hot melt extrusion, comprising: The hydroxypropyl methylcellulose phthalate according to claim 1 or claim 2; and a drug.

Images