JPH09301851A - Crystalline medicine particle excellent in compression molding property and production of the same compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain medicine crystal particles having secondary physical properties, e.g. crystal structure of medicine, excellent fluidity and extremely ready feeding in tableting and improved in compression molding properties and provide a method for producing the compound. SOLUTION: The crystalline medicine particles are obtained by suspending or dissolving a medicine such as acetoaminophenone in a medium and spraying and drying the suspension or solution. The particles has secondary physical properties, e.g. crystal structure of medicine, excellent fluidity and extremely ready feeding in tableting and is improved in compression molding properties. This method for producing the compound is provided.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a crystalline drug particle having excellent compression moldability and a method for producing the compound.
More specifically, the present invention relates to particles of a crystalline drug having excellent compression moldability and a method for producing the compound, which utilizes a spray drying method.

[0002]

2. Description of the Related Art Tableting of powder having poor compression moldability (tabletting)
In this case, generally, a method (granulation) in which a molding aid or a binder is blended to enhance the bonding force between particles is often used.
In the case of pharmaceutical preparations (formulations below), it is preferable that the amount of such additives is as small as possible in consideration of the miniaturization of the preparations, or the development of a particle design method that enhances the compression moldability of the powder itself without additives. Is expected. As means for improving the compression moldability of the powder itself, it is possible to increase the number of contact points of the particles in the molded body by pulverizing the powder, or to amorphize the powder to increase the plasticity,
It has been reported that the contact area between particles is increased in the compression process to increase the binding force. However, in the above case, the flowability of the powder is remarkably impaired due to the refinement, and it is difficult to supply the powder during tableting, and the cost is increased due to the crushing. Further, the above-mentioned amorphized powder has a defect such as poor stability over time.

[0003]

SUMMARY OF THE INVENTION It is an object of the present invention to provide drug crystal particles having excellent compression moldability and a method for producing the compound. More specifically, the number of contact points between particles increases when compressed with fine crystals, and the bonding force between particles is strong,
Further, it has an excellent flowability, and an object thereof is to provide a drug crystal particle having improved compression moldability, which has secondary physical characteristics such as extremely easy supply during tableting, and a method for producing the compound. To do.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a drug powder having poor compression moldability is converted into a crystalline form by using a spray drying method. It was found that the compression moldability was remarkably improved. The present invention has been made based on such findings. As a characteristic of the spray-drying method utilized by the present inventors, when a drug solution is dried by using the spray-drying method, the drying speed is high, and thus the drug is expected to be obtained as fine crystals. Depending on the molecular structure of the drug or the spray-drying conditions, the drug can be obtained as an amorphous substance or crystalline polymorph in the particles. The spray-dried particles tend to be spherical and have excellent fluidity. The present inventors have succeeded in obtaining crystalline drug particles having improved compression moldability without using an additive, by utilizing such characteristics of the spray drying method.

That is, the first aspect of the present invention is stable and crystalline crystalline drug particles having improved compression moldability, which are obtained by dissolving a drug in a medium and then spray-drying the drug. The second aspect of the present invention is stable crystalline drug particles obtained by suspending a drug in a medium and then spray-drying it, and improving compression moldability. The spray-dried particles of the present invention are characterized by being crystalline consisting of fine crystals, having excellent fluidity, and being extremely easy to supply during tableting. The reason why the compression moldability of the crystalline drug particles obtained by spray-drying the solution of the first drug of the present invention is improved is that spray-drying is due to its rapid drying rate, and thus the drug has very fine crystals. Has been recrystallized as
It is considered that the binding force became stronger due to the increase in the number of contact points between drug crystals during compression. Further, the second aspect of the present invention
The reason why the moldability of the crystalline drug particles obtained by spray-drying the drug suspension is improved is that the finely ground particles in the starting material are selectively dissolved during the suspension preparation. It is considered that fine crystals were deposited on the surface of the coarsely pulverized product, which was not processed, and the bonding force became stronger due to the increase in the number of contact points between drug crystals during compression.

Preferred examples of the above drug include acetaminophen, aspirin, etenzamid and phenacetin, and more preferably acetaminophen. Examples of the medium include water, alcohols such as methanol, ethanol and isopropanol, one selected from the group of organic solvents such as dimethylformamide, methylene chloride, acetone and ethyl acetate, or a mixture of water and the above organic solvent. be able to. Examples of more preferable medium of the present invention include water and alcohols. More preferably, methanol or ethanol that is easily removed during spray drying and has a finer crystal form is suitable.

The feed liquid used for spray drying may be either a solution or a suspension, but by comparison in the present invention, spray drying the solution produces finer crystal particles than the case where a suspension is used. It is preferable because it can be obtained as aggregated spherical particles. The concentration of the supply liquid varies depending on the type of medium, the difference in suspension or solution, or the processing temperature, and is not particularly limited. For example, at 40 ° C., when water is used as the medium, the solution is 1-3% for suspension, 5-15 for suspension
% Is preferable.

The spray drying is carried out according to a conventional method, for example, by appropriately setting the spray drying conditions such as a temperature range such as an inlet temperature and an outlet temperature and the number of revolutions of the atomizer.
Although the temperature range such as the inlet temperature is not particularly limited, finer crystals can be obtained when the inlet temperature is higher. The rotation speed of the atomizer is also within the range used in ordinary spray drying.

The third aspect of the present invention is to dissolve a drug in a medium,
Then, the method is a method for producing spherical crystalline drug particles having stable and improved compression moldability, which is characterized by spray drying. A fourth aspect of the present invention is a method for producing crystalline drug particles which is stable and has improved compression moldability, which comprises suspending the drug in a medium and then spray-drying.

The improvement of the usefulness of the crystalline drug particles of the present invention, that is, the compression moldability, will be described in detail below.
Since acetaminophen has a layered structure consisting of a monoclinic crystal, it is known that it has poor compression moldability and hardly molds. Therefore, it is necessary to devise a formulation method such as adding a large amount of molding aids and binders. It is one of the representative drugs.

The average particle diameter of each particle obtained by the production method of the present invention is the kind and size of the drug used for spray drying, the method for preparing the feed solution, the spray dryer model, the atomizer rotation speed, Although it depends on conditions such as a drying temperature, it is not particularly limited.

The crystalline drug particles of the present invention have improved compression moldability and can be directly tableted. In addition, if necessary, it can be used in various pharmaceutical forms using various pharmaceutical carriers according to a conventional method.

The invention is described in more detail in the examples below. In the following examples and comparative examples, acetaminophen used was Fine Powder (manufactured powder) manufactured by Marin Clot Chemical Co., Ltd., and ethanol was manufactured by Wako Pure Chemical Industries, Ltd. .

[0014]

【Example】

Example 1 A feed solution was prepared by dissolving 0.4 kg of acetaminophen (bulk powder) in 3.6 kg of 95% ethanol. Next, for spray drying, a spray dryer MM type (manufactured by Niro) is used, the inlet temperature is about 220 ° C, the outlet temperature is about 90 ° C, and the atomizer is used.
The rotation speed was set to 25,000 rpm. The average particle size of the obtained powder was 41.5 μm.

Example 2 Acetaminophen (bulk powder) 0.4 kg was dissolved in purified water 19.6 kg kept at 40 ° to prepare a feed solution. Thereafter, spray drying was performed in the same manner as in Example 1. The average particle size of the obtained powder was 31.6 μm.

Example 3 Acetaminophen (powder powder) (0.4 kg) was suspended in purified water (3.6 kg) kept at 40 ° and uniformly dispersed by a colloid mill to prepare a feed solution. Thereafter, spray drying was performed in the same manner as in Example 1. The average particle size of the obtained powder was 27.1 μm.

Comparative Example 1 Preparation of Water Recrystallized Product A water recrystallized product was prepared by cooling an aqueous solution in which acetaminophen (original powder) was dissolved by a conventional recrystallization method.

The crystal forms and powder characteristics of the powders obtained in Examples 1 to 3 and Comparative Example 1 of the present invention were evaluated using various instrumental analysis methods 1) to 6) shown below. .

1) Powder X-ray Diffraction Measurement A powder X-ray diffractometer [X'Pert-MPD, manufactured by Nippon Phillips KK] was used, and a voltage of 40 KV was obtained using a Monochro filter, a CuKα ray, and a scintillation counter. Current 55mA, scan speed 2 ° /
It was carried out under the condition of minutes.

2) Differential calorimetry Differential scanning calorimeter [DSC8230C, Rigaku Denki Co., Ltd.
Manufactured by the above method) at an initial temperature of 20 ° C. and a temperature rising rate of 5 ° C./min.

3) Electron Microscope Observation A sample is subjected to ion sputtering (JFL-1100,
JEOL Co., Ltd., using a vacuum coating of 10 ⁻³ Torr, a voltage of 1.2 KV, and a current of 5 mA for 10 minutes, after gold coating, a scanning electron microscope (JSM-T200, JSM).
Photographs were taken under the condition of 10 to 15 KV by EOL Co., Ltd.

4) Measurement of particle size The particle size is measured by a laser scattering dry particle size distribution analyzer (LDS).
(A, Tohnichi Computer). The measurement is
The average particle size was determined 4 times.

5) Measurement of the angle of repose Using a device for measuring the angle of repose (Powder tester, manufactured by Hosokawa Micron Co., Ltd.), a predetermined amount of the sample was dropped on the measuring table while gently shaking, and the periphery of the table was measured. When the sample started to spill from, the shaking was stopped and the angle of repose was measured with a protractor.

6) Measurement of Loose Apparent Density and Consolidation Apparent Density A predetermined amount of sample was put into a 100 ml graduated cylinder, and a shaking specific volume measuring device (KRS-406, Kuramochi Kagaku Co., Ltd.) was used.
Manufactured), and the loose apparent density before tapping and 240
The compacted apparent density after repeated tapping filling was measured.

Formulation Example 1 Tablets were prepared by the following method. 1% magnesium stearate was added to each of the spray-dried particles obtained in Examples 1 to 3 of the present invention, and a tableting / compressibility measuring device [tabletting tester, manufactured by Sankyo Piotech Co., Ltd.] was used. Tablets were tabletted under the conditions of one tablet of 400 mg, punch diameter of 11.5 mm, and tableting speed of 2.5 mm / min. As the release method, two types of methods of normal release and pressure release were used. The hardness of the tablets and the thickness of the tablets of the 10 tablets thus obtained were measured with this apparatus.

For comparison with the tablet of the present invention, a comparative sample was prepared in the same manner as in Formulation Example 1 using acetaminophen (bulk powder) and the water recrystallized product of Comparative Example 1.

Stability of spray-dried particles over time in moldability: The acetaminophen bulk powder and the spray-dried particles after storage at 20 ° C. for 3 months were subjected to pressure-release compression molding to obtain a compression pressure of 2000 kg / cm ^2. The tablet was compressed under the conditions of 10 and the hardness of 10 tablets thus obtained was measured, and the hardness was compared with the hardness of a tablet produced in the same manner immediately after the preparation by t-test.

The particles obtained by the production method of Example 1 of the present invention were spherical particles having a very smooth surface. On the other hand, the particles obtained by the production method of Example 2 were also similar spherical particles, but the diameter thought to be drug crystals was about 1 to 2 μm on the particle surface.
Plates of m were observed. These were all clearly different from the shapes of the bulk powder and the particles of Example 3. Electron micrographs of the spray-dried particles of Examples 1 and 2 were as shown in FIGS. 1 and 2 described later.

The shape of the particles obtained in Example 3 of the present invention was a plate-like particle having a relatively uniform particle size without finely pulverized material found in the bulk powder. This can be presumed to be because the fine powder was selectively dissolved at the time of preparing the suspension and was taken in (deposited) on the surface of the coarsely pulverized product at the time of spray drying. The electron micrograph of the particles obtained in Example 3 was as shown in FIG. On the other hand, the shape of the bulk powder used as a control product is a mixture of a plate-like finely pulverized product having a diameter of about 5 to 10 μm and a coarsely pulverized product having a diameter of about 50 to 100 μm mixed in a randomly aggregated state. It was something that was.
The electron micrograph of the above-mentioned bulk powder was as shown in FIG.

Powder Secondary Physical Properties Table 1 shows the powder characteristics of acetaminophen (bulk powder) and each spray-dried particle obtained by the production method of Examples 1 to 3 or Comparative Example 1 of the present invention.

[0031]

[Table 1]

From the results shown in Table 1, the angle of repose decreases in the order of acetaminophen bulk powder> particles of Example 3> particles of Example 1 ≧ particles of Example 2, and particles of Example 1 and Examples It was clarified that all of the particles of No. 2 had better fluidity than the above-mentioned bulk powder.

Crystallinity of spray-dried particles of acetaminophen: The crystallinity of the drug in the particles considered to affect the compression moldability, which is the object of the present invention, was investigated. (1) Powder X-ray Diffraction Powder X-ray diffraction patterns of powder, water recrystallized product and each spray-dried particle are shown in FIG. 5 described later. As can be seen from this figure, it was confirmed that all the spray-dried particles were X-ray crystalline.

Considering together the observation results of the electron microscope photograph shown above, each particle obtained by the manufacturing method of Example 1 and Example 2 was very fine due to its rapid drying rate during the drying process of the solution. It is considered that drug crystals were deposited and aggregated to form spherical particles. Further, the difference in the surface shape between these particles is considered to be due to the fact that the drying rate of ethanol (particles of Example 1) is faster than that of water (particles of Example 2). Can be presumed to have been formed by finer crystal particles than the particles of Example 2.

The diffraction pattern of the particles of Example 3 is the same as in Example 1.
And the particles of Example 2 were the same, but the diffraction intensity was broader than these. As described above, it is considered that the finely pulverized product of the particles of Example 3 was dissolved during the preparation of the aqueous suspension, and the finely pulverized product was deposited on the surface of the coarsely pulverized particles during the spray drying process. Since the crystal particles deposited on the surface of the coarsely pulverized particles are ungrown and very small, the peak of the X-ray diffraction pattern is blown.
It was thought to have become

(2) Differential thermal analysis (DSC measurement) The DSC measurement results of acetaminophen (bulk powder), the water recrystallized product of Comparative Example 1 and the spray-dried particles of Examples 1 to 3 are as shown in Table 2. And the melting point is 170.2 ° C to 171.2
It was between 0 ° C and almost the same. No other peak was observed up to the melting point, and it was confirmed that all had the same crystal structure. The heat of fusion was almost the same.

[0037]

[Table 2]

Compression Moldability of Spray-Dried Particles of Acetaminophen Tensile Strength of Molded Body: The compression-moldability of each spray-dried particle, water recrystallized product and bulk powder was evaluated by tablet hardness. The results were as shown in Table 3 below.

[0039]

[Table 3]

As is clear from the results shown in Table 3, the particles of Examples 1 to 3 of the present invention were able to obtain a good compact at a compression pressure of 1500 kg / cm ² . On the other hand, both the bulk powder and the water recrystallized particles used as controls had poor moldability,
A compact could not be obtained at a compression pressure of 1500 kg / cm ² . The hardness of the tablets using the particles of Examples 1 to 3 was 4.4 kg, 4.0 kg and 1.5 kg, respectively. When compared in the present invention, more preferable compression pressure is 500 kg / cm ^{2 according} to a usual molding method.
The particles of Examples 1 and 2 exhibit excellent moldability. From the above results, it was revealed that the spray-dried particles of the present invention have improved compression moldability as compared with the bulk powder.

The reason why the acetaminophen crystals were converted into particles having excellent compression moldability by forming the particles from the solution by the spray drying method as described above in terms of the particle characteristics. It is considered that fine crystals were recrystallized during the drying process depending on the drying speed, the number of contact points between particles increased during compression, and the bonding force increased. Further, the reason why the particles C produced from the suspension were superior in compression moldability to the bulk powder was that 20% of acetaminophen dissolved in the aqueous suspension was spray-dried and It was thought that this was due to the deposition as fine crystal particles.

Stability of spray-dried particles with respect to moldability with time: The crystalline drug particles obtained by spray-drying of the present invention are extremely stable, and physical properties such as moldability hardly change even after storage for a long period of time. There was no problem at all. In the long-term storage test, the above particles were stored at 20 ° C. for 3 months, and then the bulk powder and the spray-dried particles were subjected to pressure release type compression molding under a compression pressure of 2000 kg / cm ² , and the hardness of the obtained tablets was sprayed. It was carried out by a method of comparing with the physical properties immediately after drying. As a result, in the spray-dried product of the present invention, no significant difference was observed between the physical properties of the sample at the start of the long-term storage test and the physical properties of the sample after 3 months when comparing the average values.

[0043]

INDUSTRIAL APPLICABILITY According to the present invention, a drug is crystalline, has excellent fluidity, and has a secondary physical property such that it is extremely easy to supply to a die during tableting. It was possible to provide an improved drug crystal particle and a method for producing the compound. In the spray-dried particles of the present invention, the drug is almost completely crystallized and the compression moldability is improved. The reason for this is considered to be that it can be dried quickly by spray drying, and that the drug became very fine crystal particles to form particles, so that the bonding force became stronger due to the increase in the number of contact points between drug crystals during compression. To be The drug crystal particles of the present invention have extremely improved compression moldability and can be directly tableted, and thus are extremely useful in the pharmaceutical industry.

[Brief description of drawings]

FIG. 1 is an electron micrograph of particles obtained in Example 1. The white one scale shown in the lower part of the photograph shows 10 μm.

FIG. 2 is an electron micrograph of particles obtained in Example 2. The white one scale shown in the lower part of the photograph shows 10 μm.

FIG. 3 is an electron micrograph of particles obtained in Example 3. The white one scale shown in the lower part of the photograph shows 100 μm.

FIG. 4 is an electron micrograph of a bulk powder of acetaminophen. The white one scale shown in the lower part of the photograph shows 100 μm.

FIG. 5 shows X-ray diffraction patterns of the powders obtained in Examples 1 to 3 of the present invention and Comparative Example 1. In order to compare Examples 1 to 3 and Comparative Example 1, the vertical axis (peak intensity) has an arbitrary scale for each Example.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location B01J 2/04 7419-4H C07B 63/00 E C07B 63/00 A61K 9/14 C (72) Invention Tatsuo Murakami 55 Hoyoji Temple, Kami-shi, Nakashingawa-gun, Toyama Prefecture

Claims (6)

[Claims] 1. Stable and crystalline crystalline drug particles having improved compression moldability obtained by dissolving a drug in a medium and then spray-drying the drug. 2. A method for producing spherical crystalline drug particles which is stable and has improved compression moldability, which comprises dissolving the drug in a medium and then spray-drying. 3. Stable and improved compression moldability of crystalline drug particles obtained by suspending a drug in a medium and then spray drying. 4. A method for producing crystalline drug particles which is stable and has improved compression moldability, which comprises suspending a drug in a medium and then spray-drying. 5. The crystalline drug particle according to claim 1 or 3, wherein the drug is acetaminophen. 6. The method for producing crystalline drug particles according to claim 2, wherein the drug is acetaminophen.