JP5866342B2 - Method for producing fine powder for pharmaceutical preparation of loxoprofen sodium dihydrate - Google Patents

Description

  The present invention relates to a method for producing a fine powder for preparation of loxoprofen sodium dihydrate, and more specifically, the volume average particle size is in the range of 20 to 120 μm when measured with a laser diffraction particle size distribution meter. The present invention relates to a method for producing a fine powder of loxoprofen sodium dihydrate with high productivity.

  Loxoprofen sodium (generic name) (sodium 2- [4- (2-oxocyclopentan-1-ylmethyl) phenyl] propionate (chemical name)) is a non-steroidal anti-inflammatory, analgesic and antipyretic agent, and rheumatoid arthritis It is widely used for the treatment of osteoarthritis, low back pain, etc.

  Normally, the drug substance powder used in drug formulation must be ground to an appropriate particle size. Examples of this include the following i) to iii). i) Uniform mixing with excipients and the like is facilitated by adjusting the particle size to an appropriate size. ii) The surface is clean and smooth when molding tablets. iii) Keep the absorption of active ingredients in the body constant.

  In general, there are dry pulverization, wet pulverization, freeze pulverization and the like as pulverization methods, but dry pulverization is most suitable in terms of cost and the like for pharmaceutical pulverization. The force used for pulverization includes compression force (crushing), shearing force (cutting with a cutter or knife), impact force (high-speed rotating hammer or pin or collision between particles), grinding force (grinding), etc. However, a pulverizer using an impact force is suitable for producing fine powder (usually several μm to several hundred μm in volume average particle diameter) used in pharmaceutical preparations. This type of pulverizer has the following three types, each having its own characteristics.

1) Pin mill pulverizer: Fine pulverization is performed between a disk pin or plate beater (plate-shaped hammer) that rotates at high speed and a disk pin on the stationary door side. The particle size and particle size distribution are adjusted according to the number of pins and the rotation speed.
2) Jet mill pulverizer: Also called a jet air pulverizer. High-pressure air or nitrogen gas injected from a nozzle is caused to collide with particles as an ultrahigh-speed jet, and fine particles are obtained by impact between the particles.
3) Impact type pulverizer with a built-in airflow classifying mechanism and using a pin hammer: pulverization is performed by the rotation of the pin hammer type pulverizing rotor and the impact between the liners on the inner wall of the pulverizing chamber. Since the classification rotor is mounted, the particles pulverized to a certain particle size are sent to the classification chamber, and over-pulverization can be prevented. This type of pulverizer includes a pulverizer type pulverizer that has almost the same structural principle as the atomizer, but has a small number of hammers and is suitable for processing a large lump by increasing the gap with the lining. This kind of pulverizer is easy to disassemble and clean.

  Loxoprofen sodium is usually a dihydrate crystalline powder, and a fine powder having a volume average particle size of about several tens of μm may be used in the preparation (Patent Document 1). When the particle size suitable for the preparation is measured with a laser diffraction particle size distribution analyzer, it is usually preferred that the volume average particle size is in the range of 20 to 120 μm.

However, as described in Patent Documents 1 to 4, loxoprofen sodium dihydrate powder has adhesion and adhesion specific to this substance, and adheres and adheres to drugs, devices, containers, etc. Thus, it is well known that it has the property of significantly hindering processing. Therefore, in order to grind loxoprofen sodium to the required particle size and particle size distribution as a raw material for preparation, to prevent clogging of the grinder due to adhesion and sticking of loxoprofen sodium and the resulting deterioration due to melting due to frictional heat, etc. In particular, loxoprofen sodium fine powder must be produced even at the expense of productivity.
Thus, a technique that can efficiently produce fine loxoprofen sodium powder while avoiding adhesion and fixation of loxoprofen sodium to the inside of the pulverizer and to the pulverization unit during pulverization has not yet been established.

JP 62-242616 A Japanese Patent No. 2711528 Japanese Patent Laid-Open No. 9-255569 Japanese Patent Laid-Open No. 11-21236

  The pulverization operation for obtaining a crystalline fine powder of loxoprofen sodium dihydrate used in the preparation is significantly hindered by the adhesion / sticking property which is a characteristic of the present compound, resulting in a decrease in productivity. The present invention avoids adhesion and fixation of the compound to the inside of the pulverizer and to the pulverization unit at the time of pulverization of loxoprofen sodium dihydrate by applying such a pulverization method considering the adhesion and adhesion characteristics. It is an object of the present invention to obtain a fine powder of loxoprofen sodium dihydrate having a desired particle size and particle size distribution while preventing deterioration of quality under high productivity.

  As a result of diligent research and examination of various pulverizers, the present inventor has found that only an impact pulverizer that incorporates an airflow classification mechanism and uses a pin hammer is useful for the above purpose. The invention has been completed. Further, it has been found that among impact type pulverizers using a pin hammer, those equipped with an airflow classification mechanism are suitable, and among them, a pulverizer type pulverizer is particularly suitable. Pulverizer pulverizers are available from Dalton Co., Tokyo Atomizer Manufacturing Co., Ltd. and Hosokawa Micron Co., Ltd. That is, the present invention incorporates an airflow classification mechanism and uses an impact-type pulverizer using a pin hammer, preferably a pulverizer-type pulverizer with a built-in airflow classification mechanism, to produce loxoprofen sodium dihydrate fine powder, It is characterized by avoiding a decrease in productivity due to the adhesion and sticking properties of loxoprofen sodium dihydrate. By this method, when measuring with a laser diffraction particle size distribution meter, particles having a volume average particle diameter in the range of 20 to 120 μm can be efficiently and continuously produced. Loxoprofen sodium dihydrate fine particles having such a particle size are used in various pharmaceutical preparations, particularly tablets; coating agents such as creams and ointments; patches such as plasters, tapes, patches, and poultices. It is suitable for manufacturing such as.

The results of the examination are shown in more detail below.
When trying to grind loxoprofen sodium dihydrate crystals with a pin mill grinder, the fine powder adheres to and adheres to the pin, which is the grinder unit, and grows. Occurrence of clogging caused the crystal to melt due to frictional heat, making it impossible to grind.
By thinning the pins of the pin disc, the situation was not improved even if the pin spacing was increased. Loxoprofen sodium dihydrate usually loses water of crystallization at 58 to 77 ° C., and therefore, during pin mill pulverization, the water of crystallization is desorbed due to heat generated due to adhesion / fixation / clogging to the pulverizer, and the composition changes. Therefore, the use of pin mill grinding, which cannot ensure product uniformity when increasing the amount of loxoprofen sodium dihydrate supplied to the grinder, is unsuitable for efficient production of loxoprofen sodium dihydrate fine powder. It is judged that there is.

  Next, an attempt was made to grind loxoprofen sodium dihydrate crystals with a jet mill grinder. In this case, although the pulverization was possible when the pulverization pressure was lowered to the lowest level, the particle size became too fine and the specific volume was increased, so that only a material suitable as a drug substance was obtained. In addition, due to the structure of this pulverizer, if the pretreatment pulverization is not performed in advance by another pulverizer (cutter mill or the like) before pulverization, the supply nozzle is blocked, so that productivity is lowered. In addition, when the amount of processing increases, the capital investment (such as a bag filter) increases compared to other pulverizers, and the use of a compressor increases the power running cost. Therefore, it was found that the jet mill grinder is not suitable as a method for efficiently grinding loxoprofen sodium dihydrate.

Production of fine powder of loxoprofen sodium dihydrate had a problem in productivity in the above-described pin mill grinder and jet mill grinder. On the other hand, when an attempt was made to use an impact-type pulverizer with a built-in airflow classification mechanism and a pin hammer, particularly a pulverizer-type pulverizer with a built-in airflow classification mechanism, a surprising improvement was observed. Ie:
1) No clogging of the crusher due to adhesion / adherence of fine powder was observed even when pulverization was performed under the supply amount per unit time of loxoprofen sodium dihydrate assuming actual production. .
2) There was no significant heat generation during pulverization, and no cooling operation was required. This is because loxoprofen sodium dihydrate did not stay in the pulverizer or in the pulverization rotor due to adhesion / fixation. Moreover, since the classification rotor was built in, overpulverization was suppressed, the particle size distribution of the pulverized product became sharper, and a fine powder that was easier to formulate could be obtained.
3) Since the classifying rotor is built-in, there is no need for pretreatment grinding, and the pulverized product does not need to be further sieved. Therefore, productivity has been greatly improved.
4) The running cost was the lowest compared with the pin mill and jet mill grinder.
5) From the above, commercial continuous production of fine powder of loxoprofen sodium dihydrate can be achieved by using an impact pulverizer with a built-in airflow classification mechanism and an impact pulverizer using a pin hammer, especially a pulverizer pulverizer with a built-in airflow classification mechanism. It turned out to be possible.

  The above results are summarized as shown in Table 1 below. When a fine powder of loxoprofen sodium dihydrate is built with an impact pulverizer with a built-in airflow classification mechanism and a pin hammer, preferably a pulverizer-type pulverizer, the pulverization ability is dramatically higher than other pulverizers. It is clear that productivity is greatly improved without the need for pre- and post-grinding treatments.

That is, the present invention relates to the following (1) to (4).
(1) When loxoprofen sodium dihydrate crystals or crystalline powders are pulverized using an impact pulverizer equipped with an airflow classification mechanism and using a pin hammer and measured with a laser diffraction particle size distribution meter A method for producing a fine powder of loxoprofen sodium dihydrate for pharmaceutical preparation, characterized by continuously producing a fine powder of loxoprofen sodium dihydrate having an average particle size in the range of 20 to 120 µm.
(2) The production method according to (1), wherein the impact type pulverizer having a built-in airflow classification mechanism and using a pin hammer is a pulverizer type pulverizer.
(3) When the fine powder of loxoprofen sodium dihydrate is measured with a laser diffraction particle size distribution meter, the volume average particle diameter is in the range of 20 to 120 μm, and the fine powder of loxoprofen sodium dihydrate is one The production method according to (1) or (2), wherein 40 Kg or more is continuously produced per hour.
(4) The above-mentioned (1) to (1), wherein the air pulverization mechanism is incorporated and the pulverization by the impact type pulverizer using the pin hammer is performed under the conditions of the rotational speed of the pin hammer rotor of 6000 to 9000 rpm and the rotational speed of the classification rotor of 2000 to 5000 rpm. The production method according to any one of 3).

  According to the method of the present invention, it is possible to avoid adhesion and sticking of the compound to the inside of the pulverizer and to the pulverizing unit at the time of pulverization to obtain fine powder of loxoprofen sodium dihydrate. Productivity can be dramatically improved. According to the method of the present invention, loxoprofen sodium dihydrate suitable for the production of various preparations, particularly tablets; coating agents such as creams and ointments; plasters, tapes, patches, patches, etc. A fine powder of a product can be produced continuously and efficiently.

  In the method for producing fine powder for pharmaceutical preparation of loxoprofen sodium dihydrate according to the present invention, an impact pulverizer using a pin hammer with a loxoprofen sodium dihydrate crystal or crystalline powder incorporated with an airflow classification mechanism Is used, and a fine powder of loxoprofen sodium dihydrate having a volume average particle size in the range of about 20 to 120 μm is continuously produced when measured with a laser diffraction particle size distribution analyzer. When loxoprofen sodium dihydrate crystals or crystalline powder is measured by a laser diffraction particle size distribution meter by pulverization using the above-mentioned impact pulverizer, the volume average particle size is about 20 to 120 μm. A fine powder of loxoprofen sodium dihydrate within the range can be produced continuously and efficiently.

  Loxoprofen sodium dihydrate crystals and crystalline powder can be produced, for example, according to the method described in J. Med. Chem., 1984, 27 (2), pp 212-216.

  In the present invention, the synthesized loxoprofen sodium dihydrate crystals or crystalline powder is incorporated into an airflow classification mechanism as it is without being pre-processed and supplied to an impact type pulverizer using a pin hammer for pulverization. be able to.

  The impact type pulverizer incorporating the airflow classification mechanism used in the present invention and using a pin hammer is preferably a pulverizer type pulverizer. When such a pulverizer is used, it is not necessary to further sieve the pulverized particles. For this reason, productivity is significantly improved. The pulverizer type pulverizer having a built-in airflow classification mechanism is sold by a plurality of manufacturers and is not particularly limited. For example, an apparatus having a processing capacity per hour (a pulverizable raw material amount) of about 40 kg or more is preferable.

  In the production method of the present invention, the above-mentioned fine powder of loxoprofen sodium dihydrate is incorporated into an airflow classification mechanism, and is an impact pulverizer using a pin hammer, preferably about 30 kg or more per hour by a pulverizer pulverizer. It is preferable to produce continuously, and it is more preferred to produce continuously about 40 kg or more per hour.

  The conditions of pulverization by an impact pulverizer that incorporates an airflow classification mechanism and uses a pin hammer can be adjusted, for example, by adjusting the rotational speed of the pin hammer rotor and the rotational speed of the classification rotor in the impact pulverizer. .

In the present invention, pulverization by an impact pulverizer using a pin hammer, for example, a pulverizer pulverizer, is preferably performed at a rotational speed of the pin hammer rotor of about 12000 rpm or less. That is, it is preferable to set the rotational speed of the pin hammer rotor of the impact type pulverizer used, preferably the pulverizer type pulverizer, in this way. It is preferable that the pulverization by the impact pulverizer using the pin hammer with the airflow classification mechanism is performed under the condition that the rotational speed of the classification rotor is about 6000 rpm or less. By setting the rotational speed of the pin hammer rotor and the rotational speed of the classification rotor within such ranges, adhesion and sticking of loxoprofen sodium dihydrate to the inside of the grinding machine and to the grinding unit can be more effectively suppressed. A fine powder having a particle size of 20 to 120 μm can be produced more efficiently. When the loxoprofen sodium dihydrate fine powder having a volume average particle size of 20 to 120 μm is continuously produced for 40 kg or more per hour, the maximum rotation speed of the pin hammer rotor and the maximum rotation speed of the classification rotor are set. The above range is preferable.
In pulverization by an impact type pulverizer that incorporates an airflow classification mechanism and uses a pin hammer, the rotation of the pin hammer rotor preferably has a lower limit of about 4000 rpm or more. More preferably, the rotational speed of the pin hammer rotor is about 6000 to 9000 rpm. Furthermore, the lower limit of the rotational speed of the classification rotor is preferably about 2000 rpm or more. The rotation speed of the classification rotor is more preferably about 2000 to 5000 rpm.

  The temperature at the time of pulverization by an impact pulverizer using a pin hammer with a built-in airflow classification mechanism is preferably, for example, pulverization at about 0 to 50 ° C., and more preferably at about 10 to 40 ° C. preferable.

  Loxoprofen sodium dihydrate crystals and crystalline powder airflow classification mechanism built-in, impact type mill using pin hammer, for example, supply rate to the pulverizer type mill, or supply rate per hour is determined by rotation of the feeder What is necessary is just to set suitably by adjusting a number. When preparing loxoprofen sodium dihydrate fine powder continuously, the loxoprofen sodium dihydrate crystal or crystalline powder, which is the raw material, has a built-in airflow classification mechanism and impact using a pin hammer It is preferable to supply to a type pulverizer, for example, a pulverizer type pulverizer.

  According to the present invention, when measuring with a laser diffraction particle size distribution meter, a fine powder of loxoprofen sodium dihydrate having a volume average particle size in the range of about 20 to 120 μm can be continuously produced.

The production method of the present invention is suitably used for the production of fine powder of loxoprofen sodium dihydrate which is a particle having a volume average particle diameter in the range of about 20 to 120 μm when measured by a laser diffraction particle size distribution analyzer. .
That is, according to the production method of the present invention, such fine powder of loxoprofen sodium dihydrate can be produced continuously with high productivity. In a more preferred embodiment, a fine powder of loxoprofen sodium dihydrate having a volume average particle diameter in the range of about 40 to 90 μm can be continuously produced as measured by a laser diffraction particle size distribution analyzer. That is, the production method of the present invention is particularly suitable as a method for producing fine powder of loxoprofen sodium dihydrate having a volume average particle diameter in the range of about 40 to 90 μm when measured with a laser diffraction particle size distribution analyzer.

  As an example of a preferred embodiment of the present invention, loxoprofen sodium having a volume average particle diameter of about 20 to 120 μm (preferably a volume average particle diameter of about 40 to 90 μm) as measured by a laser diffraction particle size distribution meter. It is mentioned that a dihydrate fine powder is continuously produced for about 40 kg or more per hour. According to the present invention, such a fine powder of loxoprofen sodium dihydrate can be produced continuously at a productivity of about 40 kg or more per hour, usually for about 5 hours per time. Preferably, it is continuously produced for about 1 to 3 hours at a time.

  In the present specification, unless otherwise specified, the “volume average particle diameter” is a volume average particle diameter as measured by a laser diffraction particle size distribution meter.

  As the laser diffraction particle size distribution meter used for measuring the volume average particle size in the present invention, model number MASTERSIZER2000 manufactured by Sysmex is suitable.

  The fine powder of loxoprofen sodium dihydrate obtained by the production method of the present invention has a volume average particle diameter in the range of about 20 to 120 μm, and can be used to produce various internal preparations or external preparations as fine powders for pharmaceutical preparations. Can be suitably used. Examples of pharmaceutical preparations in which the fine powder produced according to the present invention is suitably used include, for example, internal preparations such as tablets; coating agents such as creams and ointments; patches such as plasters, tapes, patches, and poultices Etc. The manufacturing method of the pharmaceutical formulation which uses the fine powder of loxoprofen sodium dihydrate is not specifically limited, A well-known method is employable. The excipient used for the preparation of the preparation is not particularly limited, and a known one can be appropriately selected and used.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in more detail, these do not limit this invention at all.

Example 1
Pulverization by a pulverizer type pulverizer, which is an impact pulverizer that uses a pin hammer and incorporates an airflow classification mechanism.
Crystals of loxoprofen sodium dihydrate (manufactured by Yonezawa Hamari Chemical Co., Ltd.) were pulverized by ACM Pulverizer 2EC (trade name) manufactured by Hosokawa Micron Corporation.

Test machine: ACM Pulverizer 2EC (trade name, manufactured by Hosokawa Micron)
Pin hammer grinding rotor: Maximum rotation speed 12,000rpm
Classification rotor: Maximum rotation speed 6,000rpm
Liner: Smooth liner
Classification rotor: Short type Cold air was not passed through the pulverizer (room temperature: about 27 ° C.).

  The amount of loxoprofen sodium dihydrate used for pulverization with the ACM Pulverizer 2EC pulverizer (the amount of powder used) was 0.7 kg for the first test (Run. No. 001) and the second test (Run. No.). 002) was 50 kg.

  As for the grinding conditions, in the first test (Run. No. 001), the rotational speed of the grinding rotor was set to 7500 rpm, and the rotational speed of the classification rotor was set to 3000 rpm. Under these conditions, 0.7 kg of loxoprofen sodium dihydrate was used, and the powder supply amount per hour was set to 46.7 kg to produce fine powder of loxoprofen sodium dihydrate.

  In the second test (Run. No. 002), the rotational speed of the grinding rotor was set to 8500 rpm, and the rotational speed of the classification rotor was set to 3000 rpm. Under these conditions, 50 kg of loxoprofen sodium dihydrate was used, and a fine powder of loxoprofen sodium dihydrate was produced by setting the powder supply amount per hour by the feeder to 46.7 kg. .

  The volume-based median diameter and volume-average particle diameter of loxoprofen sodium dihydrate crystals before pulverization, and the volume-based median diameter and volume-average particle diameter of fine powder obtained by pulverization using an ACM Pulverizer 2EC pulverizer were measured by Sysmex. It was measured with a laser diffraction type particle size distribution meter MASTERSIZER2000 (model number). Further, the crude specific volume and the full specific volume of the fine powder of loxoprofen sodium dihydrate obtained were measured according to the method described in the Japanese Pharmacopoeia.

The results are shown in Table 2. In Table 2, “100 μm pass” indicates what percentage of the whole passes through a sieve having a coarseness of 100 μm.
From Table 2, when the pulverization rotor rotation speed and the classification rotor rotation speed were set almost constant, reproducibility was obtained with respect to the volume average particle diameter, particle size distribution, throughput, and specific volume. Further, in both the first test (Run. No. 001) and the second test (Run. No. 002), the crusher was not clogged due to adhesion and adhesion of fine powder during the test period. Although the room temperature was about 27 ° C., there was no remarkable heat generation during the pulverization, and no special cooling operation was required. This is presumably because there was no retention of fine powder due to adhesion and sticking inside the pulverizer. Since the test machine used has a built-in classification unit, the particles are not excessively pulverized and the particle size distribution of the pulverized product is sharper than those of other machine pulverized products. Since the classification unit is built in, pre-treatment pulverization is not necessary, and the pulverized product does not need to be further sieved. Therefore, productivity has been greatly improved. The running cost was considered to be the cheapest compared with the pin mill and jet mill. From the above, it was found that the use of ACM pulverizer 2EC enables continuous production of fine powder of loxoprofen sodium dihydrate.

Comparative Example 1
Pin mill pulverization Crystals of loxoprofen sodium dihydrate (manufactured by Yonezawa Hamari Chemical Co., Ltd.) were pulverized using the following test machine (pin mill pulverizer).
Test machine: Fine impact mill UPZ160 (trade name, manufactured by Hosokawa Micron Corporation)

The test was performed three times, tests 3 to 5 (Run. No. 003 to Run. No. 005).
Table 3 shows the amount of loxoprofen sodium dihydrate crystals used for grinding in each test (the amount of powder used), the state of use of the pin disk, the number of rotations, and the volume average particle size of the fine particles obtained. . The apparatus used for the measurement of the volume average particle diameter and the median diameter (D50) on the volume basis is the same laser diffraction particle size distribution analyzer (model number MASTERSIZER2000, manufactured by Sysmex) as in Example 1.

  In the pulverization by the pin mill, the pulverized material adheres and adheres to the pin and grows, so that the interval between the pins is gradually narrowed and closes in a short time. This compound (loxoprofen sodium dihydrate) is a dihydrate having water of crystallization, and the results of differential thermal analysis show that dehydration occurs at about 58-77 ° C. In this pulverizer, it is conceivable that crystal water comes off due to clogging and heat generation due to adhesion or sticking.

  The same phenomenon was observed even if the pin spacing was increased by thinning the pins of the pin disc. If the number of pins was reduced too much, the desired particle size could not be pulverized. It was judged that there was a problem in production capacity and product uniformity.

  Although the hammer was replaced with a plate beater (plate-shaped hammer), satisfactory results were not obtained (Run. No. RUN-1, Run. No. RUN-4 and Run. No. RUN-6). The results are shown in Table 4.

Comparative Example 2
Jet mill pulverization Loxoprofen sodium dihydrate crystals (manufactured by Yonezawa Hamari Chemical Co., Ltd.) were pulverized using the following test machine ( jet mill pulverizer).

The test was performed five times of Tests 7 to 11 (Run. No. 006 to Run. No. 0010).
Table 5 shows the amount of the loxoprofen sodium dihydrate crystals used for grinding in each test (the amount of powder used), the grinding conditions, and the volume average particle diameter of the fine particles obtained. The apparatus used for the measurement of the volume average particle diameter is the same laser diffraction type particle size distribution analyzer as in Example 1 (manufactured by Sysmex, model number MASTERSIZER2000).

  In pulverization using a jet mill, pulverization was possible by lowering the pulverization pressure to the lowest level, but the average particle size became too fine and the specific volume increased, resulting in a fine powder unsuitable for the preparation. Due to the structure of this machine, the feed nozzle was blocked if it was not pre-processed by a crusher such as a cutter mill before crushing. Moreover, it was thought that the capital investment of bug filters and the like increased as the amount of processing increased. Since this machine uses a compressor, the power cost is relatively high and it is considered disadvantageous for commercial production.

Formulation Example 1 (Manufacture of tablets)
(1) 112 g of fine powder of loxoprofen sodium dihydrate produced in Example 1
(2) Hydroxypropylcellulose 100g
(3) 2400 g of crystalline cellulose
(4) Carmellose calcium 400g
(5) Magnesium stearate 40g
(1) to (4) are kneaded with water, dried in vacuum, and then sized. (5) is mixed with this sized powder and tableted with a tableting machine. By this method, 1600 tablets containing 250 mg of loxoprofen sodium dihydrate at 250 mg per tablet are obtained.

Formulation Example 2 (Manufacture of adhesive for patch preparation)
(1) Fine powder of loxoprofen sodium dihydrate produced in Example 1 18 g
(2) Styrene-isoprene-styrene block copolymer 100 g
(3) 120 g of alicyclic saturated hydrocarbon resin
(4) Liquid paraffin 240g
After mixing (2) to (4), the fine powder of loxoprofen sodium dihydrate produced in Example 1 of (1) is added and mixed to obtain a uniform adhesive.

  The present invention is useful in the field of medicine and the like.

Claims (4)

  When loxoprofen sodium dihydrate crystals or crystalline powders are pulverized using an impact pulverizer equipped with an airflow classification mechanism and using a pin hammer and measured with a laser diffraction particle size distribution meter, the volume average particle size A method for producing a fine powder of loxoprofen sodium dihydrate for pharmaceutical preparation, characterized by continuously producing a fine powder of loxoprofen sodium dihydrate having a diameter of 20 to 120 μm.   The manufacturing method according to claim 1, wherein the impact type pulverizer having a built-in airflow classification mechanism and using a pin hammer is a pulverizer type pulverizer.   When the fine powder of loxoprofen sodium dihydrate is measured with a laser diffraction particle size distribution meter, the volume average particle diameter is in the range of 20 to 120 μm, and the fine powder of loxoprofen sodium dihydrate is 40 kg per hour. The manufacturing method of Claim 1 or 2 produced continuously above.   The pulverization by the impact type pulverizer having a built-in airflow classification mechanism and using a pin hammer is performed under the conditions of a rotational speed of the pin hammer rotor of 6000 to 9000 rpm and a rotational speed of the classification rotor of 2000 to 5000 rpm. The production method according to item.