Low-substituted hydroxypropyl cellulose and method for producing the same

Abstract

To provide a method for producing L-HPC having high flowability and favorable compactibility.SOLUTION: A method for producing low-substituted hydroxypropyl cellulose at least includes the steps of: bringing a powder pulp into contact with alkali metal hydroxide solution to obtain alkali cellulose; allowing the alkali cellulose to react with propylene oxide to obtain a reaction product; mixing the reaction product with water, as a solubilization step, without adding any acid; neutralizing the alkali metal hydroxide contained in the reaction product; washing, dewatering and drying the reaction product of after the neutralization step to obtain dried low-substituted hydroxypropyl cellulose; and pulverizing the dried low-substituted hydroxypropyl cellulose.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to low-substituted hydroxypropyl cellulose and a method for producing the same. [Background technology]

[0002] Solid preparations such as pharmaceuticals and health foods disintegrate when the disintegrant contained therein absorbs water and swells. Examples of disintegrants include low-substituted hydroxypropyl cellulose, carboxymethyl cellulose and its calcium salt, starch and its derivatives, etc. Among them, low-substituted hydroxypropyl cellulose (hereinafter also referred to as "L-HPC"), a nonionic disintegrant and binder, is widely used in the pharmaceutical field.

[0003] Among solid dosage forms, tablets are made by compressing powder into a specific shape using a tablet press. To prevent clogging of the hopper of the tablet press used in this production, it is desirable to use L-HPC, which has high fluidity, for tablet production.

[0004] A known method for producing highly fluid L-HPC is to immerse wood pulp in caustic soda, squeeze it, and then subject the resulting alkali cellulose to an etherification reaction, dissolve the reaction product in acid-free water, and then completely neutralize the alkali with an acid (Patent Document 1). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 11-322802 Summary of the Invention [Problem to be solved by the invention]

[0006] However, it was found that although the L-HPC obtained by the method described in Patent Document 1 has high fluidity, its moldability when formed into tablets, i.e., the bonding strength between L-HPC particles in the tablet, is poor. On the other hand, when attempting to produce L-HPC with high bonding strength, there is also the problem of reduced fluidity. As such, since fluidity and bonding strength are contradictory properties, it has been difficult to achieve both high fluidity and good bonding strength. The present invention has been made to overcome the drawbacks of the prior art, and aims to provide a method for producing L-HPC having high fluidity and good bonding properties. [Means for solving the problem]

[0007] As a result of extensive research conducted by the present inventors to achieve the above object, they have surprisingly found that L-HPC having good binding properties despite having high fluidity can be obtained by carrying out an etherification reaction using alkali cellulose obtained by contacting powdered pulp with an alkali metal hydroxide solution, and then mixing the reaction product with water in the dissolution step without adding an acid, thereby achieving the present invention. According to the present invention, there are provided the following method for producing low-substituted hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose. [1] contacting the powdered pulp with an alkali metal hydroxide solution to obtain alkali cellulose; reacting the alkali cellulose with propylene oxide to obtain a reaction product; a dissolving step of mixing the reaction product with water without adding an acid; a step of neutralizing alkali metal hydroxide contained in the reaction product; a step of washing, dehydrating and drying the reaction product after the neutralization step to obtain dry low-substituted hydroxypropyl cellulose; grinding the dried low-substituted hydroxypropyl cellulose; A method for producing low-substituted hydroxypropyl cellulose, comprising at least [2] The method for producing low-substituted hydroxypropyl cellulose according to [1], wherein the amount of water used in the dissolving step is 2.0 to 3.5 as a mass ratio of water to cellulose in the powdery pulp. [3] The method for producing low-substituted hydroxypropyl cellulose according to [1] or [2], wherein the mixing temperature in the dissolving step is 30 to 40°C. [4] A low-substituted hydroxypropyl cellulose having a hydroxypropoxy group content of 5 to 16% by mass, wherein, when all particles are classified by dynamic image analysis into fine particles, spherical particles consisting of first spherical particles and second spherical particles, and fibrous particles consisting of long fibrous particles and short fibrous particles, the volume fraction of the spherical particles to all particles is 60 to 90%, and the volume fraction ratio of the second spherical particles to the first spherical particles (second spherical particles / first spherical particles) is 0.90 to 1.35, The fine particles have a fiber length of less than 40 μm, The spherical particles are selected from the group consisting of first spherical particles having an elongation ratio, which is the ratio of fiber diameter to fiber length, of 0.5 or more, and second spherical particles having an elongation ratio of less than 0.5, an aspect ratio, which is the ratio of minimum Feret diameter to maximum Feret diameter, of 0.5 or more, and a perimeter (P EQPC ) and the actual particle perimeter (P real and second spherical particles having a circularity of 0.7 or more, the circularity being a ratio of the long fibrous particles are particles having a fiber length of 200 μm or more and an elongation ratio of less than 0.5, and include first long fibrous particles having an aspect ratio of less than 0.5 and second long fibrous particles having an aspect ratio of 0.5 or more and a circularity of less than 0.7; The short fibrous particles have a fiber length of 40 μm or more but less than 200 μm and an elongation ratio of less than 0.5, and the short fibrous particles are composed of first short fibrous particles having an aspect ratio of less than 0.5 and second short fibrous particles having an aspect ratio of 0.5 or more and a circularity of less than 0.7. [Effects of the Invention]

[0008] The present invention provides L-HPC that has both high fluidity and good binding properties. When the L-HPC obtained by the production method of the present invention is used to produce pharmaceutical tablets, the high fluidity of the L-HPC obtained by the production method of the present invention can prevent clogging of the powder in a hopper. Furthermore, the high binding properties of the L-HPC obtained by the production method of the present invention allow for a reduction in the amount of L-HPC added to the tablets, enabling the tablets to be made smaller. [Brief explanation of the drawings]

[0009] [Figure 1] The flowchart below shows how to classify the "total particles" of L-HPC into seven types of particles: "fine particles," "first long fiber particles," "second long fiber particles," "first short fiber particles," "second short fiber particles," "first spherical particles," and "second spherical particles." DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention will be described in detail below. As used herein, the term "binding ability" refers to an index of the binding of L-HPC molecules when the L-HPC is formed into a tablet. High binding ability indicates that the L-HPC tablet has the property of easily maintaining its shape against external forces, whereas low binding ability indicates that the L-HPC tablet has the property of not easily maintaining its shape against external forces. The method for producing L-HPC of the present invention includes at least the steps of: contacting powdered pulp with an alkali metal hydroxide solution to obtain alkali cellulose; reacting the alkali cellulose with propylene oxide to obtain a reaction product; dissolving the reaction product in water without adding an acid; neutralizing the alkali metal hydroxide contained in the reaction product; washing, dehydrating, and drying the neutralized reaction product to obtain dry low-substituted hydroxypropyl cellulose; and pulverizing the dry low-substituted hydroxypropyl cellulose.

[0011] <Step for obtaining alkali cellulose> Alkali cellulose is obtained by contacting powdered pulp with an alkali metal hydroxide solution.

[0012] Both wood pulp and non-wood pulp such as linter pulp can be used as the raw material powdered pulp, but wood-derived pulp is preferred from the viewpoint of being GMO (genetically modified organism)-free. Wood species that can be used include conifers such as pine, spruce, and hemlock, as well as broad-leaved trees such as eucalyptus and maple. Powdered pulp typically consists of cellulose and water. Therefore, in the present invention, the solid components in pulp are converted into cellulose content. The solid components in pulp, i.e., the cellulose content, can be calculated from the dry matter content determined by the JIS P8203:2010 Pulp - Dry Matter Content Test Method. The dry matter content is the ratio of the mass of a sample dried at 105±2°C to the mass before drying, and is expressed in mass%.

[0013] The alkali metal hydroxide solution is not particularly limited as long as it can convert pulp into alkali cellulose, but an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution is preferred for economic reasons. The concentration of the alkali metal hydroxide in the alkali metal hydroxide solution is preferably 20 to 60 mass %, more preferably 20 to 50 mass %, from the viewpoints of uniformity of the alkali cellulose and reaction efficiency. The content of alkali metal hydroxide in the alkali cellulose is preferably 5 to 35 mass % from the viewpoint of the reaction efficiency of propylene oxide. The content of alkali metal hydroxide in the alkali cellulose can be measured by neutralization titration of the alkali cellulose with an acid such as sulfuric acid having a known concentration. The temperature at which the pulp powder is brought into contact with the alkali metal hydroxide solution is preferably 20 to 80° C. The time for which the pulp powder is brought into contact with the alkali metal hydroxide solution is preferably 5 to 120 minutes.

[0014] After the preparation of alkali cellulose, it is preferable to replace the atmosphere in the reactor with an inert gas (preferably nitrogen gas or helium gas). Alternatively, the atmosphere in the reactor may be replaced with an inert gas before the preparation of alkali cellulose, and then replaced with an inert gas again after the preparation of alkali cellulose.

[0015] <Step of Obtaining Reaction Product> Next, the step of reacting the alkali cellulose obtained in the previous step with propylene oxide to obtain a reaction product will be described. The amount of propylene oxide added is preferably 0.05 to 0.5 parts by mass per part by mass of anhydrous cellulose. The propylene oxide may be added in any of the following ways: adding a predetermined amount of propylene oxide all at once, adding it in several portions, or adding it continuously. The reaction temperature in this step is preferably 40 to 80°C. The reaction time in this step is preferably 1 to 5 hours. This step is preferably carried out under an inert gas (nitrogen gas or helium gas) atmosphere.

[0016] <Dissolution process> Next, a process for dissolving the reaction product obtained in the previous process by mixing it with water without adding an acid will be described. In this step, the reaction product obtained in the previous step and water are placed in a mixer and mixed to dissolve L-HPC. To obtain L-HPC with both high fluidity and good binding properties, the amount of water mixed with the reaction product is preferably 2.0 to 3.5, more preferably 2.5 to 3.5, in mass ratio relative to the cellulose in the powdered pulp used to produce the reaction product to be subjected to the dissolution step. If the mass ratio of water mixed is less than 2.0, the fluidity of L-HPC may decrease. On the other hand, if the mass ratio of water mixed exceeds 3.5, the binding properties of L-HPC may decrease. The mixing temperature is preferably 30 to 40° C. The mixing temperature here refers to the jacket temperature of the mixer. The mixing time is preferably 10 minutes to 5 hours. The mixer is not particularly limited as long as the jacket temperature can be controlled, and for example, a jacketed twin-screw kneader, a jacketed reactor with an internal stirrer, etc. can be used.

[0017] <Neutralization process> Next, the step of neutralizing the alkali metal hydroxide contained in the reaction product will be described. In this step, an acid is added to the reaction product obtained in the dissolution step to neutralize the alkali metal hydroxide contained in the reaction product, thereby precipitating L-HPC. The acid to be used may be an inorganic acid such as hydrochloric acid, sulfuric acid, or nitric acid, or an organic acid such as formic acid or acetic acid, but hydrochloric acid or acetic acid is preferred from the viewpoint of corrosiveness and toxicity. The amount of acid used is the equivalent amount required to neutralize the alkali metal hydroxide contained in the alkali cellulose used to produce the reaction product. The acid may be used in the form of a mixed liquid (aqueous solution) mixed with water. The neutralization temperature is preferably 30 to 40° C. This step may be carried out in the same mixer as the dissolving step, and therefore the neutralization temperature refers to the jacket temperature of the reactor or the mixer.

[0018] <Washing, dehydration and drying process> Next, the step of washing, dehydrating and drying the reaction product after the neutralization step to obtain dry low-substituted hydroxypropyl cellulose will be described.

[0019] The washing and dehydration can be carried out, for example, by contacting the precipitate with water and then dehydrating it using a dehydrator. From the viewpoint of washability, the temperature of the water used for washing is preferably 50° C. or higher. From the viewpoint of economy, the amount of water used is preferably 30 to 300 times by mass the amount of cellulose in the powdery pulp used to produce the reaction product subjected to the dissolution step. The dehydrator may be a batch-type centrifugal dehydrator, a compression-type dehydrator, etc. The centrifugal effect of the batch-type centrifugal dehydrator may be sufficient to achieve sufficient dehydration, but from the viewpoint of productivity, a centrifugal acceleration of 500 G or more is preferred.

[0020] Next, the L-HPC obtained by washing and dehydration is dried to obtain dry low-substituted hydroxypropyl cellulose. Drying can be carried out using a dryer. Examples of dryers include a fluidized bed dryer, flash dryer, box dryer, vibration dryer, natural convection low-temperature dryer, low-temperature blower dryer, and tray dryer. From the viewpoint of drying efficiency, the drying temperature is preferably 60°C to 120°C. From the viewpoint of productivity, the drying time is preferably 0.5 to 36 hours.

[0021] <Crushing process> Next, the step of pulverizing the dried low-substituted hydroxypropyl cellulose will be described. The pulverization can be carried out using a pulverizer. Examples of the pulverizer include impact pulverizers such as a hammer mill, impact mill, and victory mill, and compaction pulverizers such as a roller mill and ball mill. From the viewpoint of energy efficiency, impact pulverizers are preferred. Furthermore, it is preferable to sieve the pulverized L-HPC to remove insufficiently pulverized coarse powder. The sieve used has an opening size of preferably 45 to 250 μm, more preferably 75 to 150 μm.

[0022] The L-HPC obtained by the production method of the present invention will now be described. The hydroxypropoxy group content of L-HPC is 5 to 16% by mass, preferably 6 to 15% by mass, and more preferably 7 to 14% by mass. If the hydroxypropoxy group content is less than 5% by mass, the swelling ratio of L-HPC will be low, and disintegration properties may be insufficient when used in tablets, etc. On the other hand, if the hydroxypropoxy group content exceeds 16% by mass, L-HPC may become water-soluble. The hydroxypropoxy group content of L-HPC can be measured by the method described in the pharmaceutical monograph "Low-substituted hydroxypropyl cellulose" in the 18th edition of the Japanese Pharmacopoeia.

[0023] In this specification, low-substituted hydroxypropyl cellulose is classified into four types of particles: "long fiber particles," "short fiber particles," "spherical particles," and "fine particles." The long fiber particles are further classified into "first long fiber particles" and "second long fiber particles," the short fiber particles into "first short fiber particles" and "second short fiber particles," and the spherical particles into "first spherical particles" and "second spherical particles." A flowchart summarizing the classification method is shown in Figure 1.

[0024] The volume fraction of each particle in L-HPC can be calculated by measuring the following shape parameters, such as fiber length (LEFI), fiber diameter (DIFI), elongation ratio, aspect ratio, and circularity, using dynamic image analysis. Dynamic image analysis is a method for determining particle size and shape by continuously capturing images of particles dispersed in a fluid such as a gas or solvent, binarizing the images, and analyzing them. For example, measurements can be made using a dynamic image analysis particle size distribution analyzer, QICPIC / R16 (manufactured by Sympatec Co., Ltd.).

[0025] All particles A are divided into particles C with a fiber length (LEFI) of 40 μm or more and fine particles B with a fiber length of less than 40 μm. LEFI is defined as the length between both ends of a particle, which is the longest path from one side of the particle's outline to the other. Since the detection limit of the QICPIC / R16 equipped with the M7 lens is 4.7 μm, particles less than 4.7 μm are not detected. However, since the volume of particles with a LEFI less than 4.7 μm accounts for only a small proportion of the total volume of L-HPC, they can be ignored for the purposes of this invention.

[0026] Particles C with a LEFI of 40 μm or more are divided into first spherical particles S1 with an elongation ratio (DIFI / LEFI), which is the ratio of the diameter of fiber (DIFI) to LEFI, of 0.5 or more, and particles D with an elongation ratio of less than 0.5. DIFI is defined as the minor axis of a particle and is calculated by dividing the projected area of ​​the particle by the sum of the lengths of all the fiber branches.

[0027] Particles D with a LEFI of 40 μm or more and an elongation ratio of less than 0.5 are divided into particles E with an aspect ratio (Fmin / Fmax) of less than 0.5, which is the ratio of the maximum Feret diameter (Fmax) to the minimum Feret diameter (Fmin), and particles F with an aspect ratio of 0.5 or more. For both types of particles, the aspect ratio is greater than 0 and less than 1. The Feret diameter is the distance between two parallel tangents that sandwich a particle. The maximum Feret diameter (Fmax) is the maximum diameter when the direction of the two tangents that sandwich the particle is changed from 0° to 180°, and the minimum Feret diameter (Fmin) is the smallest diameter when the direction of the two tangents that sandwich the particle is changed from 0° to 180°.

[0028] Particles E having a LEFI of 40 μm or more, an elongation ratio 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 more and first short fibrous particles SF1 having a LEFI of less than 200 μm.

[0029] Particles F having a LEFI of 40 μm or more, an elongation ratio of less than 0.5, and an aspect ratio of 0.5 or more are divided into second spherical particles S2 having a circularity of 0.7 or more and particles G having a circularity of less than 0.7. The circularity is determined by the projected area (A p ) the perimeter of a circle with the same area (P EQPC ) and the actual particle perimeter (P real ) and is defined by the following formula:

number

[0030] Particles G having a LEFI of 40 μm or more, an elongation ratio of less than 0.5, an aspect ratio of 0.5 or more, and a circularity of less than 0.7 are divided into second long fibrous particles LF2 having a LEFI of 200 μm or more and second short fibrous particles SF2 having a LEFI of less than 200 μm.

[0031] <Volume of fine particles> The volume of particles in L-HPC (V m ) can be calculated by the following formula, assuming that the microparticles are spheres with a diameter of EQPC. V m =(π / 6)×(EQPC) 3 ×N m where N m is the number of particles in the sample, and EQPC is the median EQPC corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of particles.

[0032] <Volume of first long fibrous particle> The volume of the first long fibrous particles in L-HPC (V LF1 ) can be calculated by the following formula by assuming that the first long fibrous particle is a cylinder with a base diameter of DIFI and a height of LEFI. V LF1 =(π / 4)×(DIFI) 2 ×(LEFI)×N LF1 where N LF1 is the number of first long fibrous particles in the sample, DIFI is the median DIFI corresponding to the 50% cumulative value on the cumulative particle size distribution curve based on the number of first long fibrous particles, and LEFI is the median LEFI corresponding to the 50% cumulative value on the cumulative particle size distribution curve based on the number of first long fibrous particles.

[0033] <Volume of second long fibrous particles> The volume of the second long fibrous particles in L-HPC (V LF2) can be calculated by the following formula by assuming that the second long fibrous particles are cylinders with a base diameter of DIFI and a height of LEFI. V LF2 =(π / 4)×(DIFI) 2 ×(LEFI)×N LF2 where N LF2 is the number of second long fibrous particles in the sample, DIFI is the median DIFI corresponding to the 50% cumulative value on the cumulative particle size distribution curve based on the number of second long fibrous particles, and LEFI is the median LEFI corresponding to the 50% cumulative value on the cumulative particle size distribution curve based on the number of second long fibrous particles.

[0034] <Volume of first short fibrous particle> The volume of the first short fibrous particles in L-HPC (V SF1 ) can be calculated by the following formula by assuming that the first short fibrous particle is a cylinder with a base diameter of DIFI and a height of LEFI. V SF1 =(π / 4)×(DIFI) 2 ×(LEFI)×N SF1 where N SF1 is the number of first short fibrous particles in the sample, DIFI is the median DIFI corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of first short fibrous particles, and LEFI is the median LEFI corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of first short fibrous particles.

[0035] <Volume of second short fibrous particles> The volume of the second short fibrous particles in L-HPC (V SF2 ) can be calculated by the following formula by assuming that the second short fibrous particles are cylinders with a base diameter of DIFI and a height of LEFI. V SF2 =(π / 4)×(DIFI) 2 ×(LEFI)×N SF2 where N SF2is the number of second short fibrous particles in the sample, DIFI is the median DIFI corresponding to the 50% cumulative value on the cumulative particle size distribution curve based on the number of second short fibrous particles, and LEFI is the median LEFI corresponding to the 50% cumulative value on the cumulative particle size distribution curve based on the number of second short fibrous particles.

[0036] <Volume of first spherical particle> The volume of the first spherical particle in L-HPC (V S1 ) can be calculated by the following formula by assuming that the first spherical particles are spheres with a diameter of EQPC. V S1 =(π / 6)×(EQPC) 3 ×N S1 where N S1 is the number of first spherical particles in the sample, and EQPC is the median EQPC corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of first spherical particles.

[0037] <Volume of second spherical particle> The volume of the second spherical particle in L-HPC (V S2 ) can be calculated by the following formula by assuming that the second spherical particles are spheres with a diameter of EQPC. V S2 =(π / 6)×(EQPC) 3 ×N S2 where N S2 is the number of second spherical particles in the sample, and EQPC is the median EQPC corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of second spherical particles.

[0038] <Volume of all particles> Volume of all particles in L-HPC V total is the volume V defined above. m , V LF1 , V LF2 , V SF1 , V SF2 , V S1 and V S2 It can be calculated using the following formula: V total =V m +VLF1 +V LF2 +V SF1 +V SF2 +V S1 +V S2

[0039] <Volume fraction of each particle> The volume fraction of each particle in L-HPC relative to the total particles is defined as the volume of each particle, V m , V LF1 , V LF2 , V SF1 , V SF2 , V S1 , V S2 and the volume of all particles V total can be calculated using the following formulas: Volume fraction of fine particles R m (%)=V m / V total ×100 Volume fraction R of first long fibrous particles LF1 (%)=V LF1 / V total ×100 Volume fraction R of second long fiber particles LF2 (%)=V LF2 / V total ×100 Volume fraction R of first short fibrous particles SF1 (%)=V SF1 / V total ×100 Volume fraction R of second short fibrous particles SF2 (%)=V SF2 / V total ×100 Volume fraction R of the first spherical particle S1 (%)=V S1 / V total ×100 Volume fraction R of the second spherical particles S2 (%)=V S2 / V total ×100

[0040] When all particles of L-HPC are classified into fine particles, spherical particles consisting of first and second spherical particles, and fibrous particles consisting of long fibrous particles and short fibrous particles, the volume fraction of the spherical particles to all particles is preferably 60 to 90%, more preferably 66 to 88%. If the volume fraction of the spherical particles to all particles is less than 60%, the fluidity of L-HPC will be poor, and if it exceeds 90%, the binding strength of L-HPC will be insufficient. The ratio of the volume fraction of the second spherical particles to the first spherical particles (second spherical particles / first spherical particles, i.e., R S2 / R S1 ) is 0.90 to 1.35. If the volume fraction ratio of the second spherical particles to the first spherical particles (second spherical particles / first spherical particles) is less than 0.90, the binding strength of L-HPC will be insufficient, and if it exceeds 1.35, the flowability will be poor.

[0041] The volume-based average particle size of L-HPC measured by a dry laser method is preferably 10 to 100 μm, more preferably 30 to 90 μm, and even more preferably 40 to 70 μm, from the viewpoints of binding property and flowability. The average particle size refers to the diameter corresponding to the 50% cumulative value on the volume-based cumulative particle size distribution curve, and can be measured, for example, using a laser diffraction particle size distribution analyzer, Mastersizer 3000 (manufactured by Malvern).

[0042] From the viewpoint of fluidity, the uniformity of L-HPC is preferably 2.0 to 2.9, more preferably 2.1 to 2.8, and even more preferably 2.2 to 2.7. The uniformity is determined by the diameter (D 60 ) and the diameter corresponding to 10% of the cumulative value of the volume-based cumulative particle size distribution curve (D 10 ) can be measured and calculated using the following formula. Uniformity=D 60 / D 10 In addition, D 60 and D 10 can be measured using, for example, a laser diffraction particle size distribution analyzer, Mastersizer 3000 (manufactured by Malvern). The smaller the degree of uniformity, the more excellent the fluidity of the powder.

[0043] From the viewpoint of fluidity, the compressibility of L-HPC is preferably 20 to 29%, more preferably 21 to 28%, and even more preferably 22 to 27%. The compressibility is determined by the loose bulk density (BD L ) and packed bulk density (BD T ) can be calculated using the following formula: Compression rate (%) = {(BD T -BD L ) / BD T}×100 The smaller the degree of compression, the more fluid the powder is.

[0044] The loose bulk density refers to the bulk density in a loosely packed state, and can be measured, for example, using a powder property evaluation device, Powder Tester PT-S (manufactured by Hosokawa Micron Corporation), by uniformly supplying the material from above (23 cm) into a cylindrical container (material: stainless steel) with a diameter of 5.05 cm and a height of 5.05 cm (volume 100 mL), and then leveling the top surface and weighing it. The packed bulk density is the bulk density when the cylindrical container is tapped to make it densely packed. Tapping is an operation in which a cylindrical container filled with a sample is repeatedly dropped from a certain height to apply a light impact to the bottom, causing the sample to be densely packed. In practice, the sample is filled into a cylindrical container in the same manner as in measuring the loose bulk density, and the top surface is leveled off and weighed. Then, a cap is placed on the cylindrical container, the sample is added up to the top edge, and tapping is performed 180 times at a tapping height of 1.8 cm. After tapping is completed, the cap is removed, and the sample is leveled off at the top of the cylindrical container and weighed. The bulk density in this state is taken as the packed bulk density.

[0045] From the viewpoint of fluidity, the angle of repose of L-HPC is preferably 20 to 55°, more preferably 25 to 50°, and even more preferably 30 to 45°. The angle of repose can be calculated, for example, using a powder property evaluation device, Powder Tester PT-S (manufactured by Hosokawa Micron Corporation), by pouring the powder from a height of 75 mm onto an 80 mm disc-shaped table and measuring the angle between the table and the deposited powder. The smaller the angle of repose, the better the fluidity of the powder.

[0046] From the viewpoint of fluidity, the spatula angle of L-HPC is preferably 40 to 60°, more preferably 45 to 55°. The spatula angle is measured, for example, using a powder property evaluation device, Powder Tester PT-S (manufactured by Hosokawa Micron Corporation). A 22 mm wide metal spatula is gently lifted from a layer filled with powder, and the angle between the spatula and the powder remaining on the spatula is measured. After that, an impact is applied to the spatula, and the angle between the spatula and the powder remaining on the spatula is measured again. The spatula angle can be calculated using these values ​​according to the following formula: Spatula angle = (angle before impact + angle after impact) / 2 The smaller the spatula angle, the better the fluidity of the powder.

[0047] The fluidity index of L-HPC is preferably 70 or higher. The fluidity index is an index for evaluating fluidity proposed by Carr (RL Carr, Chem. Eng., 72, Jan. 18, 163, Feb. 1, 69 (1965), 76 Oct. 13, 7 (1969)). Details are described in "Revised and Enlarged Illustrated Guide to Powder Properties" [edited by the Society of Powder Technology and the Japan Powder Industry and Technology Association, Nikkei Gijutsu Tosho, 1985], p. 151. The fluidity index can be calculated by measuring the aforementioned uniformity, compressibility, angle of repose, and spatula angle, calculating an index for each from the measured values, and then summing them. The higher the fluidity index, the higher the fluidity.

[0048] The binding strength of L-HPC is preferably 85N or more from the viewpoint of reducing the amount of L-HPC added to pharmaceutical tablets. The binding strength of L-HPC in the present invention can be measured by storing L-HPC in a desiccator (relative humidity: approximately 11%) containing a saturated lithium chloride solution at 25°C for one week to adjust the moisture content so that the loss on drying (moisture content) is 2.8 to 4.0% by mass, and then compressing the L-HPC into 450 mg tablets at a tableting pressure of 10 kN (approximately 88.5 MPa) using a tabletop tableting machine (e.g., HANDTAB200 (Ichihashi Seiki Co., Ltd.)) equipped with a 12 mm diameter circular flat punch. The hardness of the tablets can be measured using a tablet hardness tester (e.g., TBH-125 (ERWEKA)) to apply a load in the diameter direction of the tablet at a rate of 1 mm / sec, and measuring the maximum breaking strength at which the tablet breaks.

[0049] The loss on drying (water content) of L-HPC can be measured by the method described in "General Test Method 2.41 Loss on Drying Test Method" of the 18th Edition of the Japanese Pharmacopoeia. [Example]

[0050] EXAMPLES The present invention will be specifically explained below with reference to examples and comparative examples, but the present invention is not limited to the following examples.

[0051] Example 1 8,402 g of powdered pulp (cellulose content: 8,000 g) was charged into a 150 L reactor equipped with an internal stirrer, and the reactor was thoroughly purged with nitrogen by reducing the pressure and sealing in nitrogen. Then, 6,300 g of a 35 mass % aqueous sodium hydroxide solution was charged into the reactor and stirred for 5 minutes at an internal temperature of 60°C to obtain alkali cellulose containing 15 mass % sodium hydroxide (the mass ratio of sodium hydroxide to anhydrous cellulose in the alkali cellulose was 0.276). Next, the inside of the reactor was thoroughly purged with nitrogen gas by reducing the pressure and filling it with nitrogen gas, and then 1504 g of propylene oxide was charged and reacted for 75 minutes at an internal temperature of 60° C. with stirring to obtain 16206 g of a reaction product. Next, 671 g of water at 35°C was placed in a 5 L kneader equipped with a twin-shaft stirrer, and 680 g of the reaction product (333.5 g as anhydrous cellulose content) was dispersed therein. The mixture was then mixed for 30 minutes at a jacket temperature of 35°C to dissolve the L-HPC. The amount of water used in the dissolution step was 2.0 as the mass ratio of water to cellulose in the powdery pulp. Thereafter, while maintaining the jacket temperature at 35°C, 420.4 g of a 33% by mass aqueous solution of acetic acid was added to the kneader to completely neutralize the sodium hydroxide contained in the reaction product, thereby precipitating crude L-HPC. The entire amount of crude L-HPC obtained was dispersed in 15,000 g of hot water at approximately 90°C, washed and dehydrated using a batch centrifuge at 2,000 rpm, and then the entire amount of the dehydrated product was dispersed again in 15,000 g of hot water at approximately 90°C, washed and dehydrated using a batch centrifuge at 2,500 rpm. The dehydrated product was dried in a tray dryer at 80°C for 18 hours, and the dried product was crushed in an impact crusher (Victory Mill VP-1, manufactured by Hosokawa Micron Corporation) and sieved through a 91 μm mesh sieve to obtain L-HPC. The hydroxypropoxy group content of the resulting L-HPC was measured, and the average particle size, uniformity, compressibility, angle of repose, spatula angle, volume fraction of each type of particle (first long fibrous particles, second long fibrous particles, first short fibrous particles, second short fibrous particles, first spherical particles, second spherical particles, and fine particles), fluidity index, and bonding were measured as described below. The fluidity index was calculated from the uniformity, compressibility, angle of repose, and spatula angle. The results are shown in Table 1.

[0052] <Measurement of average particle size> The average particle size was measured using a laser diffraction particle size distribution analyzer Mastersizer 3000 (manufactured by Malvaern) in a dry method according to the Fraunhofer diffraction theory, at a dispersion pressure of 2 bar and a scattering intensity of 2 to 10%, as the diameter corresponding to the 50% cumulative value on the volume-based cumulative particle size distribution curve. <Measurement of uniformity> The degree of uniformity was measured using a laser diffraction particle size distribution analyzer, Mastersizer 3000 (manufactured by Malvaern), in a dry method according to the Fraunhofer diffraction theory, under conditions of a dispersion pressure of 2 bar and a scattering intensity of 2 to 10%, by determining the diameter (D 60 ) and the diameter corresponding to 10% of the cumulative value of the volume-based cumulative particle size distribution curve (D 10 ) was measured and calculated using the following formula: Uniformity=D 60 / D 10

[0053] <Measurement of compression degree> The degree of compression was calculated from the loose bulk density and the packed bulk density using the following formula. Compressibility (%) = {(packed bulk density - loose bulk density) / packed bulk density} x 100 Loose bulk density refers to the bulk density in a loosely packed state, and was measured using a powder property evaluation device, Powder Tester PT-S (manufactured by Hosokawa Micron Corporation), by uniformly supplying the material from above (23 cm) into a cylindrical container (material: stainless steel) with a diameter of 5.05 cm and a height of 5.05 cm (volume 100 mL), and then leveling the top surface and weighing it. The packed bulk density is the bulk density when the cylindrical container is tapped to make it densely packed. Tapping is a procedure in which a cylindrical container filled with a sample is repeatedly dropped from a certain height to apply a light impact to the bottom, causing the sample to be densely packed. In practice, the sample was filled into the cylindrical container in the same manner as in the measurement of loose bulk density, and the top surface was leveled off and weighed. Then, a cap was placed on the cylindrical container, and the sample was added up to the top edge of the cap, and tapping was performed 180 times at a tapping height of 1.8 cm. After tapping was completed, the cap was removed, and the sample was leveled off at the top of the cylindrical container and weighed. The bulk density in this state was taken as the packed bulk density.

[0054] <Measurement of angle of repose> The angle of repose was calculated by using a powder property evaluation device, Powder Tester PT-S (manufactured by Hosokawa Micron Corporation), to pour the powder onto an 80 mm disc-shaped table from a height of 75 mm and measure the angle between the deposited powder and the table.

[0055] <Spatula angle measurement> The spatula angle was measured using a powder property evaluation device, Powder Tester PT-S (manufactured by Hosokawa Micron Corporation), by gently lifting a 22 mm wide metal spatula from a layer filled with powder, measuring the angle between the spatula and the powder remaining on the spatula, then impacting the spatula and measuring the angle between the spatula and the powder remaining on the spatula again.The spatula angle was calculated using these values ​​using the following formula. Spatula angle = (angle before impact + angle after impact) / 2

[0056] <Measurement of volume fraction of various particles> The volume fractions of each type of particle (first long fiber particles, second long fiber particles, first short fiber particles, second short fiber particles, first spherical particles, second spherical particles, and fine particles) were measured using a dynamic imaging particle size analyzer QICPIC / R16 (Sympatec) equipped with a VIBRI / L quantitative feeder, a RODOS / L airflow disperser, and an M7 lens at a frame rate of 500 Hz, a 4 mm injector, and a dispersion pressure of 1 bar. The captured particle images were analyzed using 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 circularity of each type of particle. These values ​​were then used to calculate the values ​​using the formulas described above. Note that M7 was used as the classification for the analysis.

[0057] <Calculation of Liquidity Index> The fluidity index was calculated by measuring the uniformity, compressibility, angle of repose, and spatula angle, calculating an index for each from the measured values, and then summing them. The larger the fluidity index, the higher the fluidity. In the present invention, a fluidity index of 70 or more is considered to be good.

[0058] <Binding Measurement> The binding strength was measured by storing L-HPC in a desiccator (relative humidity: approximately 11%) containing saturated lithium chloride solution at 25°C for one week to adjust the loss on drying (moisture content) to 2.8 to 4.0% by mass. Then, 450 mg tablets were produced by compression molding using a HANDTAB200 tabletop tableting machine (manufactured by Ichihashi Seiki Co., Ltd.) equipped with a 12 mm diameter circular flat punch at a tableting pressure of 10 kN (approximately 88.5 MPa). The hardness of the tablets was measured using a tablet hardness tester (manufactured by ERWEKA) by applying a load in the diametric direction of the tablet at a rate of 1 mm / sec, and the maximum breaking strength at which the tablet broke was measured. The higher the maximum breaking strength, the better the binding strength. In the present invention, a maximum breaking strength of 85 N or greater is considered to be good binding strength.

[0059] Example 2 L-HPC was obtained in the same manner as in Example 1, except that the mass ratio of water to cellulose in the powdered pulp used in the dissolution step was changed to 2.5. The hydroxypropoxy group content, average particle size, uniformity, compressibility, angle of repose, spatula angle, volume fraction of various particles (first long fibrous particles, second long fibrous particles, first short fibrous particles, second short fibrous particles, first spherical particles, second spherical particles, and fine particles), fluidity index, and connectivity of the obtained L-HPC were measured. The fluidity index was calculated from the uniformity, compressibility, angle of repose, and spatula angle. The results are shown in Table 1.

[0060] Example 3 L-HPC was obtained in the same manner as in Example 1, except that the mass ratio of water to cellulose in the powdered pulp used in the dissolution step was changed to 3.0. The hydroxypropoxy group content, average particle size, uniformity, compressibility, angle of repose, spatula angle, volume fraction of various particles (first long fibrous particles, second long fibrous particles, first short fibrous particles, second short fibrous particles, first spherical particles, second spherical particles, and fine particles), fluidity index, and connectivity of the obtained L-HPC were measured. The fluidity index was calculated from the uniformity, compressibility, angle of repose, and spatula angle. The results are shown in Table 1.

[0061] Example 4 L-HPC was obtained in the same manner as in Example 1, except that the mass ratio of water to cellulose in the powdered pulp used in the dissolution step was changed to 3.5. The hydroxypropoxy group content of the obtained L-HPC was measured, as well as the average particle size, uniformity, compressibility, angle of repose, spatula angle, volume fraction of various particles (first long fibrous particles, second long fibrous particles, first short fibrous particles, second short fibrous particles, first spherical particles, second spherical particles, and fine particles), fluidity index, and connectivity. The fluidity index was calculated from the uniformity, compressibility, angle of repose, and spatula angle. The results are shown in Table 1.

[0062] Comparative Example 1 L-HPC was obtained in the same manner as in Example 2, except that in the dissolution step, 84.1 g of a 33% by mass aqueous acetic acid solution was added to the water before dispersing the reaction product in water. The hydroxypropoxy group content, average particle size, uniformity, compressibility, angle of repose, spatula angle, volume fraction of various particles (first long fibrous particles, second long fibrous particles, first short fibrous particles, second short fibrous particles, first spherical particles, second spherical particles, and fine particles), fluidity index, and connectivity of the obtained L-HPC were measured. The fluidity index was calculated from the uniformity, compressibility, angle of repose, and spatula angle. The results are shown in Table 1.

[0063] Comparative Example 2 The sheet-like pulp (moisture content 7.27% by mass) was immersed in a 35% by mass aqueous solution of sodium hydroxide at 20°C, and then squeezed to remove excess sodium hydroxide solution, yielding a sheet-like alkali cellulose containing 16.9% by mass of sodium hydroxide (the mass ratio of sodium hydroxide to anhydrous cellulose in the alkali cellulose was 0.353). This sheet-like alkali cellulose was cut using a slitter cutter to obtain alkali cellulose chips. Next, 625.9 g of this chip-form alkali cellulose (cellulose content: 300 g) was charged into a rotary reactor, and the inside of the reactor was thoroughly replaced with nitrogen gas by reducing the pressure and sealing in nitrogen gas. Then, 68.7 g of propylene oxide was charged and reacted for 180 minutes at an internal temperature of 50°C while stirring, yielding 694.6 g of reaction product. Next, 734.3 g of water at 35°C was placed in a 5 L kneader equipped with a twin-shaft stirrer, and 680 g of the reaction product (293.7 g as anhydrous cellulose content) was dispersed therein. The mixture was mixed for 30 minutes at a jacket temperature of 35°C to dissolve the L-HPC. The amount of water used in the dissolution step was 2.5 as the mass ratio of water to cellulose in the pulp sheet. Thereafter, while maintaining the jacket temperature at 35°C, 471.0 g of a 33% by mass aqueous solution of acetic acid was added to the kneader to completely neutralize the sodium hydroxide contained in the reaction product, thereby precipitating crude L-HPC. The washing, dehydration, and drying steps were carried out in the same manner as in Example 1 to obtain L-HPC. The obtained L-HPC was measured for its hydroxypropoxy group content, average particle size, uniformity, compressibility, angle of repose, spatula angle, volume fraction of various particles (first long fibrous particles, second long fibrous particles, first short fibrous particles, second short fibrous particles, first spherical particles, second spherical particles, and fine particles), fluidity index, and bonding property. The fluidity index was calculated from the uniformity, compressibility, angle of repose, and spatula angle. The results are shown in Table 1.

[0064] Comparative Example 3 The sheet pulp (moisture content: 8.86% by mass) was immersed in a 43% by mass aqueous solution of sodium hydroxide at 33.5°C, and then squeezed to remove excess sodium hydroxide solution, yielding a sheet alkali cellulose containing 24.0% by mass of sodium hydroxide (the mass ratio of sodium hydroxide to anhydrous cellulose in the alkali cellulose was 0.594). This sheet alkali cellulose was cut using a slitter cutter to obtain alkali cellulose chips. Next, 495.8 g of this alkali cellulose chips (cellulose content: 200 g) were charged into a rotary reactor, and the reaction was carried out in the same manner as in Comparative Example 2, to obtain 551.8 g of a reaction product. Next, 1,432.8 g of water at 33.5°C was placed in a 5 L kneader equipped with a twin-shaft stirrer, and 549.3 g of the reaction product (199.0 g as anhydrous cellulose content) was dispersed therein. The mixture was mixed for 70 minutes at a jacket temperature of 33.5°C to dissolve the L-HPC. The amount of water used in the dissolution step was 7.2 as the mass ratio of water to cellulose in the pulp sheet. Thereafter, while maintaining the jacket temperature at 33.5°C, 537.4 g of a 33% by mass aqueous solution of acetic acid was added to the kneader to completely neutralize the sodium hydroxide contained in the reaction product, thereby precipitating crude L-HPC. The washing, dehydration, and drying steps were carried out in the same manner as in Example 1 to obtain L-HPC. The obtained L-HPC was measured for its hydroxypropoxy group content, average particle size, uniformity, compressibility, angle of repose, spatula angle, volume fraction of various particles (first long fibrous particles, second long fibrous particles, first short fibrous particles, second short fibrous particles, first spherical particles, second spherical particles, and fine particles), fluidity index, and bonding property. The fluidity index was calculated from the uniformity, compressibility, angle of repose, and spatula angle. The results are shown in Table 1.

[0065] [Table 1]

[0066] The L-HPCs of Examples 1 to 4 were good in both fluidity and binding property, whereas the L-HPCs of Comparative Examples 1 and 2 were poor in fluidity, and the L-HPC of Comparative Example 3 was poor in both fluidity and binding property. The L-HPC of Examples 1 to 4 used powdered pulp as the raw pulp and was mixed with water without adding acid in the dissolution process. This likely resulted in a greater loss of fibrous L-HPC morphology, an increased proportion of spherical particles, and improved fluidity. Furthermore, the L-HPC of Examples 1 to 4 had an increased volume fraction of second spherical particles relative to first spherical particles, while maintaining the overall proportion of spherical particles, compared with Comparative Examples 1 to 3. Because the second spherical particles have a slightly more fibrous morphology than the first spherical particles, the increased volume fraction of the second spherical particles relative to the first spherical particles is likely to have contributed to the improved binding properties. In Comparative Example 2, chip-like pulp was used as the raw pulp, and although the amount of water mixed in the dissolution process was the same as in Example 2, the reaction product on the chips remained undissolved during the dissolution process, resulting in a decreased proportion of spherical particles and a decrease in fluidity. Furthermore, Examples 1 to 4 showed that increasing the amount of water mixed in the dissolving step tends to improve fluidity, while decreasing the amount of water tends to improve binding properties.

Claims

1. contacting the powdered pulp with an alkali metal hydroxide solution to obtain alkali cellulose; reacting the alkali cellulose with propylene oxide to obtain a reaction product; a dissolving step of mixing the reaction product with water without adding an acid; a step of neutralizing alkali metal hydroxide contained in the reaction product; a step of washing, dehydrating and drying the reaction product after the neutralization step to obtain dry low-substituted hydroxypropyl cellulose; grinding the dried low-substituted hydroxypropyl cellulose; A method for producing low-substituted hydroxypropyl cellulose, comprising at least

2. 2. The method for producing low-substituted hydroxypropyl cellulose according to claim 1, wherein the amount of water used in the dissolving step is 2.0 to 3.5 as a mass ratio of water to cellulose in the powdery pulp.

3. The method for producing low-substituted hydroxypropyl cellulose according to claim 1 or 2, wherein the mixing temperature in the dissolving step is 30 to 40°C.

4. A low-substituted hydroxypropyl cellulose having a hydroxypropoxy group content of 5 to 16% by mass, wherein, when all particles are classified by dynamic image analysis into fine particles, spherical particles consisting of first spherical particles and second spherical particles, and fibrous particles consisting of long fibrous particles and short fibrous particles, the volume fraction of the spherical particles to all particles is 60 to 90%, and the volume fraction ratio of the second spherical particles to the first spherical particles (second spherical particles / first spherical particles) is 0.90 to 1.35, The fine particles have a fiber length of less than 40 μm, The spherical particles include first spherical particles having an elongation ratio, which is a ratio of fiber diameter to fiber length, of 0.5 or more among the particles having a fiber length of 40 μm or more, and second spherical particles having an elongation ratio of less than 0.5, an aspect ratio, which is a ratio of a minimum Feret diameter to a maximum Feret diameter, of 0.5 or more, and a perimeter (P EQPC ) and the actual particle perimeter (P real and second spherical particles having a circularity, which is a ratio of the circularity of the particles to the spherical particles, of 0.7 or more, the long fibrous particles are particles having a fiber length of 200 μm or more and an elongation ratio of less than 0.5, and include first long fibrous particles having an aspect ratio of less than 0.5 and second long fibrous particles having an aspect ratio of 0.5 or more and a circularity of less than 0.7; The short fibrous particles have a fiber length of 40 μm or more but less than 200 μm and an elongation ratio of less than 0.5, and the short fibrous particles are composed of first short fibrous particles having an aspect ratio of less than 0.5 and second short fibrous particles having an aspect ratio of 0.5 or more and a circularity of less than 0.7.

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