JP2003001091A - Fluidized bed granulating and coating method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To make the time for treatment shorter and the liquid rate of spraying lower. SOLUTION: Raw material particles of 20 to 150 μm in the average grain size having a wide grain size distribution are fed into a treating vessel of fluidized bed equipment and while particulates below an average grain size are mainly granulated by using binders, etc., dissolved, dispersed and suspended to a concentration at which the binders, etc., are sprayable to an aqueous liquid (water: >=50%), the granulation of the particles above the average grain size is suppressed and the particles of 50 to 200 μm in the average grain size are manufactured. The particles are thereafter subjected to the treatment to smooth the surface shapes of the particles by using the binders, etc., dissolved, dispersed and suspended to the aqueous liquid (water: >=50%) and other materials (containing chief agent in some case), by which the nuclear particles are manufactured. The nuclear particles are thereafter subjected to coating treatment by using the film agent liquids, etc., dissolved, dispersed and suspended in the aqueous liquid (water: >=50%).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a fluidized bed granulation / coating method used for producing fine particles, granules and the like of pharmaceuticals, agricultural chemicals, foods and the like.

[0002]

2. Description of the Related Art Generally, a fluidized bed apparatus forms a fluidized bed of granular particles in a processing vessel by means of fluidized air introduced from the bottom of the processing vessel, while spraying a spray liquid (binding solution, film) from a spray gun. Granulation or coating treatment is performed by spraying a mist of a chemical liquid or the like). Among this type of fluidized bed apparatus, one that involves one or more of rolling, jetting, and stirring of powder particles is called a composite fluidized bed apparatus. Also,
As the spray method, a method of spraying the spray liquid from above the fluidized bed downward (top spray method), a method of spraying the spray liquid upward from the bottom of the processing container (bottom spray method), and side parts of the processing container There is a method (tangential spray method) of spraying the spray liquid in a tangential direction from the side (closer to the bottom).

FIG. 4 illustrates a structural example (commonly called “Wurster”) of a composite type fluidized bed apparatus involving a jet flow of powder particles. In this fluidized bed apparatus, a draft tube 5'is installed in the center of a processing container 3 ', and an upward flow (jet flow) is generated in the granular particles by placing the draft tube 5'on the rising air flow. A spray gun 6'installed at the center of the bottom of the processing container 3'sprays a spray solution such as a film agent solution or a drug solution upward toward the powder particles in the tube 5'for coating. Is (bottom spray method).

A filter chamber 7'is provided above the processing container 3 '.
The fluidized air introduced into the processing container 3'from the air supply duct 8'contributes to the flow and jet of the granular particles, and then rises in the processing chamber 3'and rises in the filter chamber. 7 ', and is further exhausted to the exhaust duct 10' through the bag filter 9'installed in the filter chamber 7 '. At that time, the fine powder particles mixed in the exhaust gas (such as the abrasive powder of the raw material powder and the fine powder generated by drying and solidifying the solid components in the spray liquid) are captured by the bag filter 9 ′, and are prevented from being discharged to the outside. It

According to this fluidized bed apparatus, a large amount of powder particles can be fed into the coating zone at a high speed, so that a so-called spray drying phenomenon (the mist of the spray liquid is dried without adhering to the powder particles). Phenomenon of dusting)
The secondary agglomeration of particles and particles is unlikely to occur, and the coating treatment with good yield can be performed on the particles.

[0006]

In the manufacturing site of pharmaceuticals and the like, the handling of raw material fine particles has the following important problems.

The fine powder has a strong adhesion and cohesive property, and problems such as handling and non-uniform content are likely to occur, and improvement is desired.

It is desired to coat / coat the surface of a compound having a strong bitterness or a high activity with another substance, but fine particles having an average particle diameter of 150 μm or less have a large surface area and are Due to its strong cohesiveness, its treatment was difficult.

For example, if the weight of 300 μm particles is the same as that of 30 μm particles, the surface area is 10 times different. Since the purpose of drug coating is to control the elution of the coated drug, the thickness of the coated membrane agent is the standard, but when the surface area increases, the membrane agent increases in proportion to it. Therefore, the amount of film agent required for particles having a particle diameter of 1/10 is 10 times.

At the industrial production site, an increase in the amount of filming agent is directly linked to the production efficiency, which leads to a decrease in productivity.

[0011] For example, it is extremely difficult to coat or modify the surface of fine drug powders such as theophylline, caffeine, acetaminophen, aspirin, ascorbic acid, trimebutine maleate / ibuprofen maleate, etc. having a mean particle size of 150 µm or less. Met.

The present invention aims to solve the above problems.

[0013]

In order to solve the above-mentioned problems, according to the present invention, a mist of a spray liquid is sprayed from a spray gun while forming a fluidized bed of granular particles in a processing container of a fluidized bed apparatus. In a fluidized bed granulation / coating method of performing granulation or coating treatment, raw material particles having a wide particle size distribution and an average particle diameter of 20 μm to 150 μm are put into a treatment container of the fluidized bed apparatus, and in the treatment container, Water-based liquid (water: 50% or more), focusing on fine particles with an average particle size or less
While granulating using a binder that has been dissolved / dispersed / suspended to a sprayable concentration, granulation of particles having an average particle size or more is suppressed, and particles having an average particle size of 50 μm to 200 μm are produced. After that, the surface shape of the particles is made smooth by using a binder or the like dissolved in, dispersed in, or suspended in an aqueous liquid (water: 50% or more) and other materials (which may include the main ingredient). To produce the core particles, and then using the membrane agent solution or the like dissolved / dispersed / suspended in an aqueous solution (water: 50% or more) in the same processing container as described above. Provided is a fluidized bed granulation / coating method, which comprises performing coating treatment on.

Further, the present invention is a fluidized bed granulation in which a fluidized bed of powder and granule particles is formed in a processing container of a fluidized bed apparatus and a mist of a spray liquid is sprayed from a spray gun to perform granulation or coating treatment. In the coating method, 50 μm as a pretreatment for coating raw material particles having a complicated surface shape and a wide particle size distribution (the ratio of fine particles is large)
A fluidized bed granulation / coating method characterized by producing core particles by making particles grow using an aqueous binder (dissolution / dispersion / suspension) with a focus on the following fine particles and further smoothing the surface shape. provide.

In the above constitution, when the raw material particles are difficult to flow, 0 to 5% of a fluidization aid may be added to crush and size the particles to promote the initial flow.

Further, as the above fluidized bed apparatus, a composite type fluidized bed apparatus involving one or more types of rolling, stirring, and jet can be adopted.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described below with reference to the drawings.

FIG. 1 shows a main part of a fluidized bed apparatus (composite type fluidized bed apparatus: commonly known as Wurster) used in this embodiment.

The processing container 3 has, for example, a cylindrical upper part,
The lower portion has a conical tubular shape (the upper portion may have a conical tubular shape, and the lower portion may have a cylindrical shape), and a filter chamber (see FIG. 5) not shown is installed in the upper space of the processing chamber 3a. A gas dispersion plate 4 made of a perforated plate such as punching metal is arranged at the bottom of the processing chamber 3a. Usually, a wire net or the like is attached to the upper surface of the gas dispersion plate 4 (not shown) so that the powder particles in the processing chamber 3a do not fall from the opening of the gas dispersion plate 4. Further, a draft tube (guide tube) 5 is installed at a predetermined distance from the gas dispersion plate 4, and a spray gun 6 is installed upward through the center of the gas dispersion plate 4.

As shown in FIG. 2, the gas dispersion plate 4 has a through hole 4a for inserting the spray gun 6 in the central portion thereof, and an aperture ratio (occupies the total area of the region) on the outer periphery of the through hole 4a. A central region 4b having a large ratio of the total area of the openings) and a peripheral region 4c having a small opening ratio are provided on the outer periphery of the central region 4b. The outer diameter of the through hole 4a is D1, and the outer diameter of the central region 4b is D.
2, the outer diameter of the peripheral region 4c is D3. The aperture ratio of the central region 4b is, for example, 16 to 55%, and the aperture ratio of the peripheral region 4c is, for example, 1.5 to 16%.

As shown in FIG. 1, the draft tube 5
Has a cylindrical portion 5a in the upper portion and a conical cylindrical lower end opening 5b in the lower portion which expands downward. The diameter of the cylindrical portion 5a is D4, and the maximum diameter of the lower end opening 5b (opening 5
The diameter of b1) is D5. Cross-sectional area A4 of the cylindrical portion 5a
(= ΠD4 ² ) and the maximum cross-sectional area A5 of the lower end opening 5b
(Area of opening 5b1 = πD5 ² ) is, for example, 1.5 ≦ A
It is set to have a relationship of 5 / A4 ≦ 3.

The draft tube 5 is supported by the processing container 3 by a leg member (not shown), and has a lower end opening 5b.
Are opposed to the central region 4b of the gas dispersion plate 4 at a predetermined distance. The draft tube 5 is installed so that the distance between the lower end opening 5b and the gas dispersion plate 4 can be freely adjusted according to processing conditions and the like.

The maximum sectional area A5 (= πD5 ² ) of the lower end opening 5b of the draft tube 5 and the area A2 of the central region 4b of the gas dispersion plate 4 {= π (D2 ² -D1 ² )} are A2 <
A5, for example, 0.4 ≦ A2 / A5 ≦ 0.9 is set.

The fluidized air is introduced into the processing chamber 3a from the bottom through the gas dispersion plate 4. In this embodiment, fluidized air is supplied to the central area 4b and the peripheral area 4c of the gas dispersion plate 4 from independent air supply paths 7 and 8, respectively. That is, the central region 4 of the gas dispersion plate 4
Fluidizing air is supplied to b through the air supply path 7, and fluidizing air is supplied to the peripheral region 4c through the air supply path 8.
The air supply conditions such as the temperature and the air volume of the fluidized air are the air supply path 7,
Each of 8 is independently controlled. The air supply paths 7 and 8 may be a common path.

The fluidized air supplied from the air supply path 7 is
The lower end opening 5 is ejected from the central region 4b of the gas dispersion plate 4.
It flows into the draft tube 5 through the opening 5b1 of b,
An updraft is generated in the tube 5. An ejector effect is generated by a large amount of fluidized air flowing into the draft tube 5, and the powder particles in the peripheral portion are generated in the lower end opening portion 5b.
Is drawn into the tube 5 through the opening 5b1 thereof, and rides on the rising airflow in the tube 5 to form a spouted bed. on the other hand,
The fluidized air supplied from the air supply path 8 is the gas dispersion plate 4
However, since the aperture ratio of the peripheral region 4c is small, the volume and velocity of the fluidized air discharged from this region 4c are smaller than those of the fluidized air discharged from the central region 4b. Therefore, the particulate material particles flowing out from the upper end opening of the draft tube 5 ascend to some extent in the processing chamber 3a and then descend, and pass through the space between the draft tube 5 and the wall surface of the processing container 3 to disperse the gas. It reaches the vicinity of the plate 4 and is drawn into the draft tube 5 again from the opening 5b1 of the lower end opening 5b by the ejector effect.
In this way, the fluid circulation of the powder particles is performed in the processing container 3.

Further, in this embodiment, in order to effectively prevent particles from accumulating at the bottom of the processing chamber 3a, the gas ejection means 10 is provided on the outer periphery of the bottom of the processing chamber 3a. The gas ejection means 10 includes, for example, an outer ring 10a, an inner ring 10b, an annular chamber 10c formed between the outer ring 10a and the inner ring 10b, and an annular slit formed below the inner ring 10b. 10d,
Air supply pipe 10e for supplying compressed air to the chamber 10c
And a pressure regulator (not shown) that regulates the supply pressure of the compressed air. The compressed air supplied to the chamber 10c via the air supply pipe 10e is jetted from the slit 10d to the bottom of the processing chamber 3a, and disperses the agglomerated particles retained outside the draft tube 5 into the draft tube 5. Promote circulation. In addition, the compressed air ejected from the slit 10d disperses the particles that have undergone the secondary aggregation, and further effectively prevents the generation of aggregated particles. The chamber 10
The compressed air may be supplied to c continuously, but may be intermittently supplied using, for example, a timer and a solenoid valve.
Further, the slit 10d is not limited to the annular shape and may be divided in the circumferential direction (the same applies to the chamber 10c).

The spray gun 6 sprays a spray liquid (a film liquid, a drug liquid, etc.) from the lower side to the upper side toward the powder particles that rise by riding on the rising air current (jet flow) in the draft tube 5. Is. The base material component in the mist of the spray liquid sprayed from the spray gun 6 adheres to the surfaces of the granular particles to form a coating layer.

Instead of the fluidized bed apparatus shown in FIG. 1, the fluidized bed apparatus shown in FIG. 3 (composite type fluidized bed apparatus: Wurster) may be used. This fluidized bed apparatus is different from the configuration shown in FIG. 1 in that it has a guide tube 15 and a partition collar 16.

In this fluidized bed apparatus, the guide tube 15 is in the shape of a short conical cylinder that is contracted upward. The lower end opening of the guide tube 15 has an inner diameter equal to (or approximately equal to) the outer diameter D2 of the central region 4b of the gas dispersion plate 4, and is fixed to the upper surface of the gas dispersion plate 4 by an appropriate means. The upper end opening of the guide tube 15 is located at a position facing the opening 5b1 of the lower end opening 5b of the draft tube 5. By disposing the guide tube 15, the directionality of the flow toward the lower end opening 5b of the draft tube 5 is given to the fluidized air ejected from the central region 4b of the gas dispersion plate 4. Therefore, the ejector effect is further enhanced, and the concentration of particles drawn into the draft tube 5 is further enhanced. The guide tube 15 may be in the shape of a short conical tube that is enlarged upward, or a short cylindrical shape. Further, it is preferable to install the device so that the height dimension can be freely adjusted.

The partition collar 16 is, for example, of a cylindrical shape, and is installed so as to surround the outer periphery of the spray gun 6 with a predetermined interval. The lower end opening of the partition collar 16 is fixed to the upper surface of the central region 4b of the gas dispersion plate 4 by an appropriate means. The upper end opening of the partition collar 16 is at the same height as the tip (spout) of the spray gun 6 or at a position above it. By disposing the partition collar 16, an annular gas passage 16 is provided between the spray gun 6 and the outer periphery thereof.
a is formed. The air flow rising along the gas passage 16a prevents pulverization of particles by the high-speed flow of atomized air in the peripheral region of the tip of the spray gun 6, and the spray liquid mist is not sufficiently atomized. The occurrence of agglomeration (agglomeration) due to contact of particles with particles is prevented. Further, since the tip of the spray gun 6 is constantly covered with the air flow rising along the gas passage 16a, the spray outlet of the spray gun 6 is unlikely to be contaminated or clogged due to particle adhesion, and a stable processing operation can be performed for a long time. Is possible. The partition collar 16 is preferably installed so that the height dimension can be freely adjusted.

In the above fluidized bed apparatus, the draft tube may have a cylindrical shape similar to that shown in FIG.

[0032]

[Examples] Theophylline, caffeine, acetaminophen, aspirin, ascorbic acid, trimebutine maleate / ibuprofen maleate, etc., or bulk drug particles of a drug such as lactose, having an average particle size of 150 μm or less have extremely poor fluidity. , Smooth coating operation is difficult.

For example, as shown in FIG. 5 (upper), theophylline has an average particle size of 30 to 50 μm and has a complicated surface shape such as needle crystals, so that it has a large surface area and is suitable for uniform elution control. A large amount of film agent is required. Therefore, the coating time is 30 to 8 using an ethanol-based film agent (film agent: ethyl cellulose 5% solution) having a high evaporation rate.
The fact is that the coating treatment is performed for 0 hours to produce sustained-release particles. The amount of the ethanol-based membrane agent used here is 7 kg to 1 kg per 1 kg of theopherline.
I use 1 kg. Ethanol is expensive and requires explosion-proof electrical equipment. Further, there is a problem of environmental load.

In this example, using the above-mentioned fluidized bed apparatus, HPMC (T
Preliminary granulation was performed by adding (dissolving) 200 g of a polysaccharide (trehalose) to 1000 g of a 5% aqueous solution of C-5E), and
The core particles shown in (bottom) were obtained with a treatment time of 3 hours. The average particle size of the core particles thus obtained is 150 μm and is 75 μm.
Fine particles of m or less were 5% or less. Further, the surface area was about 1/3 to 1/5 of that of the raw material powder, the surface condition was smooth, core particles suitable for coating were obtained, and the required amount of filming agent was small.

Even if ethanol having a high evaporation rate is used,
When the solid content concentration of ethyl cellulose is about 5% (when the solid content concentration is higher than this, the viscosity is high and it is difficult to spray with a mist diameter necessary for coating.), And the spray rate is as high as 15 to 20 g / min. However, the adhered amount of the solid content of the film agent per unit time is small.

In the present embodiment, the obtained surface area is about 1/3 to
With 1/5 core particles, 2300 g of a 20% solid concentration K ethylcellulose-based aqueous dispersion (Aquacoat) was spray-added at a spray rate of 7 to 8 g / mim and a spray time of 5 hours. Although the apparent spray speed is slow, the solid content concentration is as high as 20%, and thus the solid deposition rate is high. Then, heat treatment + drying + cooling were carried out for 1 hour to obtain sustained release particles having an equivalent elution rate. As a result, the total process time could be shortened significantly.

The bitterness is strong, and fine particles of 75 μm or less are added to 25
%, An average particle diameter of 150 μm acetaminophen (Mallin Clot Co., Ltd .: high-density powder) is also sprayed with 5% solid content against acetaminophen using TC-5E (aqueous solution having a solid content concentration of 5%). Pre-granulate by addition,
3% or less of fine powder of 75 μm or less and an average particle diameter of 18
The bitterness could be suppressed in the oral cavity for about 40 hours by adjusting core particles of 0 μm and performing spray coating using an aqua coat having a solid content concentration of 20%.

Other particles that have been dissolved, dispersed and suspended in a water-based liquid together with a polymer binder, a filming agent and the like are, for example, polysaccharides such as mannitol and trehalose, talc, lactose and sugar. It is selected according to the physical properties of the raw material powder. By adding these liquids by spraying, particles with an average particle size (50% particle size) or less in the raw material particles are grown, the surface of the particles is smoothed, and a nucleus with a sharp particle size distribution is obtained. Adjust the particles. The core particles are coated with a polymer film agent or the like to impart a bitterness mask and sustained release of the drug.

HPMC (hydroxypropyl methylcellulose), HPC (polypinyl alcohol), etc. are dissolved in an aqueous solution of these bulk powders of medicines, and if necessary, other substances (eg, polysaccharide, talc, lactose, etc.) are added to the solution. ,
In some cases, the main ingredient is dissolved or dispersed / suspended and spray-added to the above particles, and the flow state of the raw material particles, spray speed, spray droplet diameter, and operating temperature are adjusted to focus on the fine particles in the raw material particles. Then, mutual adhesion and the like are performed to grow the particles. Here, by appropriately controlling the operating conditions, the growth of large particles in the raw material particles can be suppressed, and only the fine particles can be grown. Then, by smoothing the surface shape of the granulated product in the subsequent process, the coating time in the subsequent process can be significantly shortened.

[0040]

The present invention has the following effects.

(1) Since an aqueous spray liquid is used,
The safety is high, the price of the device and the spray liquid is low, and the environmental load can be reduced.

(2) The fine particles have a large surface area, and the amount of film material required for elution control increases. Also, the fine powder has a low chance of circulating in the spray zone, and the coating rate is poor.
In the present invention, preliminary granulation is performed in the step before coating to reduce the surface area of the raw material powder, so that elution control can be performed with a small amount of film agent.

(3) The coating time can be shortened and the manufacturing cost can be reduced by reducing the amount of the film forming agent.

(4) The complicated surface shape has an unstable film thickness and requires a large amount of a film-forming agent. However, by smoothing the surface of the core particles, the film thickness is homogenized and eluted. Easy to control.

[Brief description of drawings]

FIG. 1 is a partial cross-sectional view showing a main part of a fluidized bed apparatus used in an embodiment.

FIG. 2 is a plan view of a gas dispersion plate.

FIG. 3 is a partial cross-sectional view showing a main part of another fluidized bed apparatus used in the embodiment.

FIG. 4 is a cross-sectional perspective view showing a general structural example of a fluidized bed apparatus.

FIG. 5: Bulk powder of theophylline (top) and pre-granulated product (bottom)
It is an electron micrograph of.

[Explanation of symbols]

3 processing vessels 6 spray guns

Claims (4)

[Claims] 1. A fluidized bed granulation / coating method in which a fluidized bed of powdery or granular particles is formed in a processing container of a fluidized bed apparatus and a mist of a spray liquid is sprayed from a spray gun to perform granulation or coating treatment. , Raw material particles having a wide particle size distribution and an average particle diameter of 20 μm to 150 μm are put into the processing container of the fluidized bed apparatus, and in the processing container, an aqueous liquid (water: water: (50% or more), while granulating using a binder or the like dissolved, dispersed, and suspended to a concentration capable of being sprayed, the granulation of particles having an average particle size or more is suppressed, and the average particle size is 50 μm.
~ 200 μm particles are produced, and then an aqueous solution (water: 5
(0% or more) dissolved, dispersed, and suspended in a binder or other material (which may also contain the main ingredient) to smooth the surface shape of the particles to produce core particles. Then, in the same treatment container as described above, an aqueous solution (water: 5
A fluidized bed granulation / coating method characterized in that the core particles are coated with a membrane agent solution or the like dissolved, dispersed or suspended in 0% or more). 2. A fluidized bed granulation / coating method in which a fluidized bed of powdery or granular particles is formed in a processing container of a fluidized bed apparatus and a mist of a spray liquid is sprayed from a spray gun to perform granulation or coating treatment. As a pretreatment for coating raw material particles having a complicated surface shape and a wide particle size distribution (the content ratio of fine particles is high), an aqueous binder (dissolution / dispersion / suspension) is focused on fine particles of 50 μm or less. A fluidized bed granulation / coating method comprising the steps of: growing particles using the same, smoothing the surface shape, and producing core particles. 3. The method according to claim 1, wherein the raw material particles are hardly flowable, and 0 to 5% of a fluidization aid is added to crush and size the particles to promote initial flow. Fluidized bed granulation / coating method. 4. The fluidized bed granulation device according to claim 1, wherein the fluidized bed device is a composite fluidized bed device that includes one or more of rolling, stirring, and jet flow. -Coating method.