WO2004030803A1 - Systeme de granulation et fabrication de poudre au moyen dudit systeme - Google Patents

Systeme de granulation et fabrication de poudre au moyen dudit systeme Download PDF

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Publication number
WO2004030803A1
WO2004030803A1 PCT/JP2003/012623 JP0312623W WO2004030803A1 WO 2004030803 A1 WO2004030803 A1 WO 2004030803A1 JP 0312623 W JP0312623 W JP 0312623W WO 2004030803 A1 WO2004030803 A1 WO 2004030803A1
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WIPO (PCT)
Prior art keywords
nozzle
granulation
powder
fluid
granulation chamber
Prior art date
Application number
PCT/JP2003/012623
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English (en)
Japanese (ja)
Inventor
Hiroyuki Tsujimoto
Toyokazu Yokoyama
Kazuo Takeshima
Masaharu Yamamoto
Hayao Inoue
Original Assignee
Hosokawa Powder Technology Research Institute
Shionogi & Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hosokawa Powder Technology Research Institute, Shionogi & Co., Ltd. filed Critical Hosokawa Powder Technology Research Institute
Priority to AU2003272911A priority Critical patent/AU2003272911A1/en
Publication of WO2004030803A1 publication Critical patent/WO2004030803A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
    • B01J2/16—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by suspending the powder material in a gas, e.g. in fluidised beds or as a falling curtain

Definitions

  • the present invention relates to a granulating apparatus and a method for producing powder using the granulating apparatus.
  • the present invention relates to an air-flow type granulating apparatus including a fluidized bed, a spouted bed, and an atomized granulator for charging a raw material into a sealed granulation chamber to granulate a target powdery / granular product, and an apparatus for the same.
  • the present invention relates to a method for producing a powder using a granulator.
  • airflow granulation device by spraying a variety of materials inside the granulation chamber. It is to produce a powdery-granular or granular product comprising the material (the granulator, pharmaceuticals When used in equipment that requires washing and sterilization such as manufacturing equipment and food manufacturing equipment, it is necessary to thoroughly wash and sterilize the inside of the granulation chamber after granulation.
  • Patent Document 1 Japanese Patent Laid-Open Publication (JP-A-5-22853: published date: September 7, 1993) describes a three-dimensional rotation in a granulation chamber. There is disclosed a granulating apparatus for cleaning a wall surface of a granulation chamber by using a nozzle which inverts and ejects a fluid to an inner wall surface of the granulation chamber.
  • the granulation chamber is impacted from outside the granulation chamber with an air knocker or the like, and adheres to the wall of the granulation chamber.
  • the company is trying to get rid of collected products and increase the product collection rate.
  • the granulating apparatus disclosed in Patent Document 1 has a structure in which the nozzle is driven to rotate three-dimensionally in the granulating chamber, so that it is usually necessary to store the nozzle in a position that does not interfere with the granulation. There is. That is, the nozzle moves between the cleaning position and the storage position.
  • the constituent elements of the granulation chamber for example, the joining flange portion and the like are rubbed by vibration, and the gasket forming the joining flange portion. Foreign matter may be generated from the flange and the like.
  • freeze-drying method the spray-drying method, and the like have been conventionally used as a method for producing the above-mentioned powder which refuses to contaminate foreign substances, particularly, aseptic powder.
  • freeze-drying method has many ancillary equipment such as refrigerators and vacuum pumps, so that initial capital investment, maintenance and operation costs are high, and production takes a long time.
  • Spray-drying can produce powder in a shorter time than freeze-drying.However, in order to obtain a powder with a low solvent content, drying at high temperatures is necessary. It is not suitable, and powder that has adhered to the equipment and has been thermally degraded may be mixed into the powder.
  • the present invention has been made in view of the above problems, and has as its object to provide a granulating apparatus in which no foreign matter is generated in a granulating chamber before and after washing, and no foreign matter is mixed into a product.
  • An object of the present invention is to provide a powder production method capable of producing aseptic and dust-free powder at a low temperature and in a short time by using a granulation apparatus. Disclosure of the invention
  • the granulation apparatus of the present invention is an airflow type granulation apparatus for charging a raw material into a closed granulation chamber to granulate a target powdery / granular product.
  • a plurality of nozzles for ejecting a fluid to the wall surface of the granulation chamber are provided, and a fluid ejection direction of each of the nozzles is fixed in a predetermined direction.
  • fluid is applied to the wall surface of the granulation chamber.
  • the fluid ejection direction of the nozzle is fixed in a predetermined direction, the fluid can be sprayed onto the wall surface of the granulation chamber without driving the nozzle such as rotation or movement. Accordingly, it is possible to eliminate generation of foreign matter in the granulation chamber due to driving such as rotation and movement of the nozzle.
  • the powder attached to the wall surface of the granulation chamber during granulation can be removed.
  • a liquid is used as the fluid, it is possible to clean the inner wall of the granulation chamber by including a cleaning component in the liquid.
  • high-temperature steam that can be sterilized is used as a fluid, the wall surface of the granulation chamber can be sterilized.
  • the nozzle itself is granulated because the direction in which the fluid flows out of the nozzle is fixed in a predetermined direction (the direction in which the inner wall surface can be cleaned). There is no need to rotate or move the inside of the room, and the wall of the granulation room can be washed. Thus, there is no problem that foreign matter generated by driving the nozzle such as rotation and movement enters the granulation chamber after cleaning. Therefore, no foreign matter is generated in the granulation chamber before and after the washing, so that it is possible to prevent foreign matter from being mixed into a product manufactured in the granulation chamber. As a result, it is possible to use the granulating apparatus having the above configuration as a granulating apparatus for granulating a product such as a preparation that extremely dislikes the incorporation of foreign substances into the product.
  • the granulation chamber is sterilized. It is easy to make the environment dust-free, and the granulation device with the above configuration should be used suitably for the preparation that needs to be granulated in such a sterile and dust-free environment, especially for the granulation of injections that are dissolved before use. Becomes possible.
  • dissolving injections for use include vaccines, antibiotics, interferons, various anticancer agents, and sterile preparations such as enzyme-based reagents.
  • a granulator that only performs automatic washing can be suitably used for a granulator that coats various high-performance oral preparations.
  • the fluid ejection direction of each of the nozzles may be fixed to a direction in which a swirling flow is generated in the granulation chamber by the fluid ejected to the wall surface of the granulation chamber. Good.
  • each nozzle since the fluid ejection direction of each nozzle is fixed in a direction in which a swirling flow is generated in the granulation chamber by the fluid ejected on the wall surface of the granulation chamber, the nozzle is ejected into the granulation chamber. Products adhering to the inner wall surface can be efficiently removed using a fluid. Therefore, it is possible to minimize the amount of fluid used from the removal of the product in the granulation chamber to the cleaning and sterilization, and to provide a granulation device capable of saving resources and energy. Can be.
  • the fluid may be ejected from the nozzle intermittently.
  • the auxiliary air from the nozzle introduced into the side of the main body or the inside of the apparatus is efficiently used, so that the adhesion of powder (powder) is reduced, and the efficiency is improved. It forms a fluidized bed well and can be dried in a short time.
  • the granulating apparatus having the above configuration, powder adhesion on the wall surface of the granulator can be reduced, and the powder recovery rate can be improved.
  • the particle size of the powder can be adjusted by the granulation function, the handling of the powder is improved compared to the freeze-dried product.
  • using the coating function after the powder is produced by this granulator, it is possible to coat the powder with a coating liquid, so that it is possible to control the powder properties by adjusting the surface properties. .
  • the present inventors conducted a granulation process using the granulation apparatus of the present invention at a temperature lower than the drying temperature of the spray drying method, and subsequently performed a fluidized bed. By conducting the drying process, it was found that a powder having the same chemical quality as a sterile preparation produced by the freeze-drying method could be produced in a short time.
  • a fluid dehumidification
  • a fluid dehumidification
  • the powder production method of the present invention is a powder production method for producing a target powder by using the granulator having the above-described configuration.
  • the above-mentioned powder production method may include a spray granulation step of subjecting a solution in which a target substance is dissolved or a suspension in which the target substance is suspended in a granulation chamber of the above-mentioned granulation apparatus to atomization granulation. .
  • the drying can be performed at a lower temperature as compared with the spray drying method, it is possible to use a heat-sensitive substance as a target substance, and to prevent mixing of a thermally degraded product.
  • sterile and dust-free powder can be produced at a low temperature in a short time.
  • the powder production method may include a drying step of performing fluidized-bed drying after the above-described atomization granulation step until the solvent content in the granulated powder reaches a target value.
  • the allowable solvent content in the powder varies depending on the type of drug produced as the powder. Therefore, when the solvent is water, it is defined as the solvent content that does not hydrolyze the drug, and when the solvent is an organic solvent, it has an effect on the human body. It is defined as a solvent content that is not possible (no residual solvent).
  • a powder having a desired solvent content can be obtained by performing fluidized-bed drying until the target value is reached using the above-mentioned allowable solvent content as the target value.
  • Powder Z products with a low content can be produced at lower temperatures than the spray dry method.
  • the inside of the granulation chamber of the above-mentioned granulation apparatus is sterilized, and a solution in which the gas introduced into the apparatus and the target substance are dissolved or a suspension containing the target substance is suspended.
  • the method may include a step of sterilizing the suspension by a sterilization method or an aseptic operation method, and the subsequent steps may be performed by an aseptic operation method.
  • the powder is produced by a series of aseptic processes after sterilization and / or from the raw material stage, not only is there no contamination from foreign substances, but also a sterile powder can be produced. In other words, sterile and dust-free powder can be obtained.
  • aseptic means conforming to the sterility test method described in the Japanese Pharmacopoeia
  • dustless refers to conforming to the insoluble particulate test method described in the Japanese Pharmacopoeia
  • sterilization and aseptic procedures are based on the Japanese Pharmacopoeia. It means what is specified.
  • the granulation apparatus of the present invention and the powder manufacturing method using the granulation apparatus are useful for producing sterile preparations that require sterility in the production process and the raw materials thereof.
  • it is suitably used for oral preparations, pulmonary administration preparations, and the like that require sterility at a low level without assurance of sterility in the production process.
  • a pharmaceutical preparation can be mentioned, and as the pharmaceutical preparation, an injection can be suitably mentioned.
  • an antibiotic may be contained as an active ingredient in the above pharmaceutical preparation.
  • the above antibiotic may be a cefem or oxacephem antibiotic, and this antibiotic may be flomoxeftonium ( flomoxefntrium is a chemical name: monosodium (6R, 7 R)-7-(2-difluoromethylsulfa-lucetylamino) 1-3-[1-1 (2-hydroxethyl) 1 1-H-tetrazone 1-5-ylsulfanylmethyl] 1-7-methoxy 8- Oxo-5-oxa-1-azabicyclo [4,2,0] oct-1-ene-2-carboxylate
  • the substance used as the powder Z formulation used in the present invention is: As long as they are not toxic when used as pharmaceuticals and foods, they are not particularly limited and can be applied to a very wide range of substances, except for substances that become liquid at the temperature in the spray granulation process and fluidized bed drying process. Applying the present invention alone is difficult in principle. Further, even if the temperature in the decom
  • compositions in the above-mentioned pharmaceutical preparations are not particularly limited.
  • flomoxeftonium for example, disodium (6R, 7R) -17- [2-carboxylate-12- (4-hi) Droxifenino) Aceta Mid] —— 7—Methoxy-3 — [((1-Methyl-1H—tetrazol-15—yl) thiomethyl] -18-oxo-1-5—oxar1-azabicyclo [4,2,0] oct-2 — 1-2 carboxylate (generic name: latamox cephnate), 7 ⁇ — [( ⁇ ) -2-(2-amino 4-thiazolyl) 1-2-hydroxyiminoacetamide] 1 3 — (1,2,3—triazole-4-ylthiomethylthio) 1-one-carper 3-sefumu 4 mono-rubonic acid, (+)-(6R, 7R) —7
  • cefcapene pivoxil hydrochloride cloxasilina sodium, cefazolinnatrium, cefapirinnatridium, cephalothinnadium, cephalodium Examples include lysine, cefotaximnadium, cephoperazone sodium and the like.
  • the additives in the above pharmaceutical preparations are not particularly limited, but include, for example, stabilizers, buffers, flavoring agents, tonicity agents, ⁇ -regulators, solubilizers, antioxidants, storage Agents, solubilizers, excipients, dispersants, soothing agents, etc.
  • ascorbic acid More specifically, ascorbic acid, L-arginine, sodium chloride, sodium bicarbonate, sodium carbonate, sterile sodium bicarbonate, sodium citrate, Sodium sodium citrate, trisodium phosphate, sodium hydrogen phosphate, dicalcium phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, fructose , Xylitol, D-sorbitol, lactose, sucrose, podo bran, maltose, D-mannitol, etc.
  • FIG. 1 is a schematic configuration diagram of a granulation chamber of a granulation apparatus of the present invention.
  • FIG. 2 is a schematic configuration diagram of a granulation system including the granulation device of FIG. 3 (a) to 3 (d) are schematic cross-sectional views of a joint portion of each cylinder of the granulation chamber shown in FIG. 1.
  • FIG. 4 is a schematic diagram showing an arrangement relationship between a first cylinder portion and a first nozzle which constitute the granulation chamber shown in FIG.
  • FIG. 5 is a cross-sectional view of a support member that supports the first nozzle provided in the first cylinder portion shown in FIG.
  • FIG. 6A is a longitudinal sectional view of the first nozzle.
  • FIG. 6B is a cross-sectional view taken along line AA of FIG. 6A.
  • FIG. 7 is a schematic configuration diagram showing a connection state between the first nozzle and the fluid introduction pipe.
  • FIG. 8 is a schematic diagram showing an arrangement relationship between a first cylindrical portion and a second nozzle which constitute the granulation chamber shown in FIG.
  • FIG. 9 is a cross-sectional view of a support member that supports the second nozzle provided in the first cylindrical portion shown in FIG.
  • FIG. 10 (a) is a longitudinal sectional view of the first nozzle.
  • FIG. 10 (b) is a sectional view taken along line BB of FIG. 10 (a).
  • FIG. 10 (c) is a sectional view taken along line CC of FIG. 10 (a).
  • FIG. 11 is a schematic diagram showing an arrangement relationship between a second cylindrical portion and a third nozzle constituting the granulation chamber shown in FIG.
  • FIG. 12 is a cross-sectional view of a support member that supports the third nozzle provided in the second cylindrical portion shown in FIG.
  • FIG. 13A is a longitudinal sectional view of the third nozzle.
  • FIG. 13 (b) is a front view of the third nozzle as viewed from the fluid ejection side.
  • FIG. 14 is a cross-sectional view taken along line DD of FIG. 13 (a).
  • FIG. 15 is a schematic configuration diagram showing a connection state between the third nozzle and the fluid introduction pipe.
  • FIG. 16 is a schematic diagram showing an arrangement relationship between a third cylindrical portion and a fourth nozzle constituting the granulation chamber shown in FIG.
  • FIG. 17 is a cross-sectional view of a support member that supports the fourth nozzle provided in the third cylindrical portion shown in FIG.
  • FIG. 18 (a) is a longitudinal sectional view of the fourth nozzle.
  • FIG. 18 (b) is a front view of the fourth nozzle viewed from the fluid ejection side.
  • FIG. 19 is a schematic configuration diagram showing a connection state between the fourth nozzle and the fluid introduction pipe.
  • FIG. 20 is a graph for comparing the degree of cleaning between the case where the side wall nozzle provided in the granulation chamber is used and the case where the side wall nozzle is not used.
  • the granulation system mainly includes a granulation device 1, a raw material supply unit 2 (first fluid supply device), a compressed air supply unit 3 (second fluid supply device). , Flowing air supply unit 4, Exhaust unit 5, First cleaning-Sterilizing unit 6 (Third cleaning device), Second cleaning and sterilizing unit 7 (Third cleaning device), Third cleaning and sterilizing unit 8 (First The cleaning device) and the fourth cleaning / sterilizing unit 9 (second cleaning device) are arranged.
  • the granulating apparatus 1 includes a substantially cylindrical granulating chamber 200 provided with a two-fluid spray nozzle 100 at a lower portion.
  • the two-fluid spray nozzle 100 mixes the liquid material 20 (first fluid) from the raw material supply unit 2 and the compressed air (second fluid) from the compressed air supply unit 3 to form a tip.
  • the granulation chamber 200 is sprayed from the opening 100a.
  • the granulation chamber 200 has an opening 200 a at a lower portion for taking in the flow air supplied from the flow air supply section 4, water accumulated in the granulation chamber 200, and the like.
  • An opening 200 c for draining the liquid is formed, and an opening 200 b for discharging the air in the granulation chamber 200 to the external exhaust unit 5 is formed in the upper part. I have.
  • the flowing air is blown upward from the flowing air supply section 4 into the granulating chamber 200, and the liquid material 20 is sprayed upward from the two-fluid spray nozzle 100 into the flowing air, and the fine particles of the atomized liquid material 20 are suspended in the inside of the granulation chamber 200 while the liquid is sprayed.
  • the water of the material 20 is evaporated and granulated.
  • the fine particles are intermittently layered and grown by the liquid material 20 atomized from the two-fluid spray nozzle 100. Such a process is repeated to produce particles having a predetermined particle size.
  • the two-fluid spray nozzle 100 A jacket that allows the fluid to flow is provided over substantially the entire outer peripheral portion.
  • the temperature and viscosity of the liquid material 20 to be atomized are optimized, and the sprayed liquid material 2 is The particle size of 0 is made uniform.
  • the degree of aggregation and growth of the sprayed liquid material 20 can be made uniform, and product particles having a narrow particle size distribution can be obtained.
  • a filter 206 in order to prevent particles and the like in the middle of granulation from being discharged from the opening 200b serving as an air discharge port, A filter 206, and a removing means for removing particles adhering to the filter 206, and a pressure applying means for instantaneously increasing the internal pressure of the granulation chamber 200. Is added.
  • the filter 206 By providing the filter 206, the discharge of particles can be prevented, so that the volume of the granulation chamber 200 can be made relatively small. Heavy product particles can be obtained by compacting particles in the middle of the particles.
  • individual members constituting the granulation system having the above configuration will be described.
  • the raw material supply unit 2 comprises a container 21 containing liquid material 20 and a pump 22 for extruding the liquid material 20 contained in the container 21 by air pressure. It is configured.
  • a regulator valve (not shown) of the pump 22
  • the liquid material 20 from the raw material supply unit 2 is supplied from the pump 22 through a filter (not shown) to the container 21.
  • Air is supplied into the liquid material 20, and the air causes a filter (shown in the drawing) provided between the switching pulp 10 and the container 21 to switch a common flow path with a third washing / sterilizing section 8 described later. ) Is supplied from the switching valve 10 to the two-fluid spray nozzle 100.
  • the compressed air supply unit 3 includes a compressor 31 to compress air taken in from the outside and supply the compressed air to the two-fluid spray nozzle 100 from the switching pulp 12 through a filter (not shown). It has become.
  • the compression conditions at this time are 0.6 MPa and 300 NLmin.
  • the liquid material 20 supplied from the raw material supply unit 2 and the compressed air supplied from the compressed air supply unit 3 are introduced into separate flow paths, The mixture is finally mixed and sprayed from the tip opening 100a.
  • the details of the two-fluid spray nozzle 100 will be described later.
  • the fluidizing air supply unit 4 is configured to supply fluidizing air, which has been set to a predetermined temperature and humidity, through a filter (not shown) upward from the opening 200 a to the granulating chamber 200. I'm familiar.
  • the temperature and humidity were measured mainly by a thermometer and a hygrometer (not shown) provided on the inner wall 200 d of the granulation chamber 200. Measure using
  • the flow air supply unit 4 includes a probe 41 for taking in air from outside, an air tank 42 for storing the air taken in by the blower 41, and drying the air stored in the air tank 42.
  • the dryer 43 includes a heater 43 for heating air dried by the dryer 43 to a predetermined temperature. That is, by adjusting the humidity of the air by the dryer 43 and adjusting the temperature of the air by the heater 44, the air set to the predetermined temperature and humidity is supplied to the granulation chamber 200. I'm wearing
  • the pressure of the fluidizing air is desirably such that the individual particles flow inside the granulation chamber 200.
  • an example is shown in which particles are grown inside the granulation chamber 200 only by spraying the liquid material 20, for example. Adjust the flow rate of the flow air to prevent agglomeration.
  • the temperature and humidity of the air for flow may be inconsistent, for example, if the drying of the particles is slow, the particles may easily aggregate and the resulting particles may become too large. Adjust appropriately according to the degree.
  • the blowing of the flow air is performed generally upward, but the blowing air may be blown upward in the vertical direction, or may be blown diagonally upward to form the granulation chamber 20.
  • a swirling flow of the flowing air may be formed inside the zero. When a swirling flow is formed, the particles are more actively wound up, so that the drying and solidification of the particles can be further promoted.
  • the exhaust part 5 is used for granulation in the granulation chamber 200 or during granulation.
  • An exhaust device 51 is provided for discharging the fuel.
  • the present granulating apparatus 1 when used for a pharmaceutical manufacturing apparatus or a food manufacturing apparatus, it is necessary to perform a sterilization process in addition to washing.
  • a fluid for introducing at least one of the cleaning liquid as a fluid, steam (water vapor), and clean air into the granulation chamber 200 is provided on the inner wall surface 200 d of the granulation chamber 200.
  • a first nozzle 201 to a fourth nozzle 204 for ejection are formed, and a filter 206 for washing and sterilizing the filter 206 is provided above the inside of the granulation chamber 200.
  • Nozzles 205 are provided.
  • the first nozzle 201 is disposed above the granulation chamber 200 more than the other nozzles, and is used for cleaning and sterilizing the filter 206 in the granulation chamber 200. You.
  • the second to fourth nozzles 202 to 204 are disposed below the first nozzle 201 and mainly wash the inner wall surface 200 d of the granulation chamber 200. Used for cleaning and sterilization.
  • washing nozzle 205 is used for washing and sterilizing the entire filter (air) inside surface of the filter 206 and the granulation chamber 200.
  • the first nozzle 201 to the fourth nozzle 204 are connected to the second cleaning / sterilizing unit 7, and the cleaning nozzle 205 is connected to the first cleaning / sterilizing unit 6. .
  • the detailed structure and structure of the first nozzle 201 to the fourth nozzle 204 The functions and functions will be described later.
  • the first cleaning / sterilization section 6 supplies a steam supply section 61 for supplying PS (pure steam), a pure water supply section 62 for supplying PW (pure water), and a PA (purified air). It consists of a clean air supply section 6 3.
  • the second cleaning / sterilization section 7 has basically the same configuration as the first cleaning / sterilization section 6, and includes a steam supply section 71, a pure water supply section 72, and a clean air supply section 13. Have been.
  • nitrogen may be used instead of PA, and a cleaning solution may be used instead of PW.
  • the third washing / sterilizing section 8 is connected to the first inlet 100b of the two-fluid spray nozzle 100 via the switching valve 10 and the two-fluid spray nozzle 1 after granulation. Cleaning and sterilization of the flow path (first flow path) of the liquid material 20 in 00 are performed.
  • the fourth washing / sterilizing section 9 includes a jet nozzle 100 as a second inlet of the two-fluid spray nozzle 100 via the switching valve 12.
  • the third cleaning / sterilizing unit 8 and the fourth cleaning / sterilizing unit 9 have the same configuration as the first cleaning / sterilizing unit 6 and the second cleaning / sterilizing unit 7, and the steam supply units 8 1 and 9 1 And pure water supply sections 82, 92 and clean air supply sections 83, 93.
  • Sterilization unit 6 the second cleaning / sterilization unit 7, the third cleaning 'sterilization unit 8, and the fourth cleaning. Sterilization unit 9 have the same configuration, they are provided separately. Instead, it may be common. By doing so, it is possible to save the space of the entire granulation system, and to unify the control of each supply unit in each washing / sterilizing unit, thereby reducing complicated operations.
  • the granulation chamber 200 has three cylindrical portions (first cylindrical portion 301, second cylindrical portion 302, and third cylindrical portion 303) connected vertically.
  • first cylindrical portion 301 the lid portion 3 0 4 with is provided, under the third cylindrical portion 3 0 3 of the lowermost portion two-fluid spray nozzle 1 Bottom with 0 0
  • the lid portion 304 is provided with the above-described cleaning nozzle 205 and a tube pole 302 for cleaning the inner surface of the tube sheet 303 and the inside of the cover portion 304. Have been.
  • a tube sheet 303 for ensuring airtightness in the granulation chamber 200 is provided. It is provided to cover the upper opening.
  • the tube sheet 303 is provided with a fixing portion 360 a for fixing the filter 206 ′ in the first cylindrical portion 301.
  • the lid 304 and the first cylindrical portion 301 are connected so as to secure the airtightness by sandwiching the tube sheet 303. Details of this connection portion will be described later.
  • a filter 206 is provided inside the first cylindrical portion 301, and a pipe 209 provided with a cleaning nozzle (not shown) for the filter 206 is provided. I have. Further, in addition to the first nozzle 201 and the second nozzle 202, the temperature inside the granulation chamber 200 is detected on the inner wall surface of the first cylindrical portion 301. For example, three temperature sensors 21 1 to 21 3 and one pressure sensor 2 14 for detecting the pressure in the granulation chamber 200 are provided.
  • an opening 302c for observing the inside of the granulation chamber 200 from the outside is provided on the inner wall surface of the second cylindrical portion 302 connected to the first cylindrical portion 301 on the side opposite to the connection side with the lid portion 304, other than the third nozzle 203.
  • a transparent plate glass 215 is fitted into the opening 302c to hermetically seal the inside of the second cylindrical portion 302.
  • connection structure The details of the connection between the first cylindrical portion 301 and the second cylindrical portion 302 will be described later.
  • the fourth nozzle 204 On the inner wall surface of the third cylindrical portion 303 connected to the opposite side of the second cylindrical portion 302 from the connection portion with the first cylindrical portion 301, the fourth nozzle 204 is provided. In addition, a temperature sensor 216 for detecting the temperature in the granulation chamber 200 is provided.
  • the bottom portion 305 is connected via a screen 307.
  • the screen 307 covers the lower opening of the third cylindrical portion 303 and is formed in a conically concave shape toward the center, and is granulated in the granulation chamber 200 at the center. Products are coming together. At the center of the screen 307, an opening 307a for product recovery is provided. The opening portion 307a is connected to a product collection pipe 308 provided at the bottom portion 305.
  • the product recovery pipe 308 is provided at the bottom portion 305, and the product recovery pipe 308 is provided.
  • a two-fluid spray nozzle 100 is provided so as to penetrate the inside of the condensate tube 308. The tip of the two-fluid spray nozzle 100 is disposed so as to protrude into the third cylindrical portion 303.
  • a jet nozzle 100 c for introducing air for flow into the granulation chamber 200 is provided at the bottom portion 300. .
  • the third cylindrical portion 303 and the bottom portion 305 are connected so as to have airtightness similarly to the connection between the second cylindrical portion 302 and the third cylindrical portion 303. However, the details will be described later.
  • FIGS. 3 (a) to 3 This is explained below with reference to (d).
  • the connecting portion (first connecting portion 311) between the first cylindrical portion 301 and the lid portion 304 is a flange 3 1 provided on the lid portion 304.
  • the la and the flange 311b provided in the first tubular portion 301 are connected to each other so as to sandwich the periphery of the tube sheet 303.
  • Grooves 311d on the tube sheet 303 side of the flange 311a above are formed with grooves 311d on the flange 311b side of the tubesheet 303.
  • An O-ring (not shown) having a diameter slightly larger than the size of the groove is fitted into the groove. This O-ring is designed to be crushed in the flange grooves 311c and 311d when the first cylindrical portion 301 and the lid portion 304 are connected. It works to improve the airtightness of 11.
  • connecting portion (second connecting portion 312) between the first tubular portion 301 and the second tubular portion 302, as shown in FIG. And a flange 312b provided on the second cylindrical portion 302.
  • a groove 312c is formed on the side of the flange 312a facing the flange 312b, and the groove 312c has a large size within the groove 312c.
  • An O-ring (not shown) having a diameter slightly larger than the size is fitted. This O-ring is designed to be crushed in the groove of the flange when connecting the first cylindrical portion 301 and the second cylindrical portion 302, thereby improving the airtightness at the second connecting portion 3122.
  • the connecting portion (third connecting portion 313) between the second tubular portion 302 and the third tubular portion 303 is, as shown in FIG.
  • the structure is such that a flange 313a provided on the second cylinder portion 02 and a flange 313b provided on the third cylindrical portion 303 are connected.
  • a groove 313c is formed on the side of the flange 313a opposite to the flange 313b, and a large portion of the groove 313c is formed in the groove 313c.
  • a ring (not shown) having a diameter slightly larger than the size is fitted. This O-ring is designed to be crushed in the groove of the flange when the second cylindrical portion 302 and the third cylindrical portion 303 are connected, thereby improving the airtightness of the third connection portion 313.
  • a connecting portion (fourth connecting portion 314) between the third cylindrical portion 303 and the bottom portion 305 is provided in the third cylindrical portion 303 as shown in FIG. 3 (d). and flange 3 1 4 a and the bottom 3 0 flange 3 provided in 5 1 4 c b and are in connected structure so as to sandwich the peripheral portion of the disk rie down 3 0 7 above
  • a groove 3 14 c is formed on the screen 3 07 side of the flange 3 14 a
  • a groove 3 14 d is formed on the flange 3 14 b side of the screen 3 07.
  • An O-ring ′ (not shown) having a diameter slightly larger than the size of the groove is fitted in each groove. This ring is crushed in the groove of the flange at the time of connection between the third cylindrical portion 303 and the bottom portion 305, and serves to increase the airtightness of the fourth connection portion 314. ing.
  • each connection portion has an airtight structure, it is possible to prevent foreign matter from being mixed into the granulation chamber 200 from each connection portion. It is possible to realize a sterile and dust-free environment in the granulation room 200.
  • the granulation room 200 is integrally molded.
  • the connecting portion is formed to have airtightness as described above, the connecting portion may be formed of a plurality of cylindrical portions.
  • a relatively large granulation chamber can be easily formed.
  • the degree of freedom in design is increased.
  • a large granulation chamber with an internal volume exceeding 100 liters should use an integrally molded cylinder. Although it is difficult to realize this, it can be easily realized by using a plurality of cylindrical portions as described above.
  • FIG. 4 is a view schematically showing the arrangement position of the first nozzle 201 in the first cylinder portion 301. As shown in FIG. 4
  • the first cylindrical portion 301 has four first nozzles 201 whose fluid ejection sides protrude toward the inner wall surface 301 a of the first cylindrical portion 301. Are arranged at equal intervals.
  • Each of the first nozzles 201 described above is a support member provided on the first cylindrical portion 301.
  • the support member 3 21 has a substantially cylindrical shape, and a through hole 3 2 1 a penetrating from the outer wall surface 301 b side of the first cylindrical portion 301 toward the inner wall surface 301 a side. Are arranged to form As shown in FIG. 5, the support member 3 21 has one end portion of the cylindrical portion joined to the outer wall surface 301 b of the first cylindrical portion 301 by welding or the like, while the other end portion has Is formed with a flange 3221b for joining to a flange 201e of a first nozzle 201 described later.
  • the inner diameter of the support member 321 is such that the main body portion of the first nozzle 201 can be inserted therein, and the airtightness in the first cylindrical portion 301 when the first nozzle 201 is inserted. It is set to a size that can secure the performance.
  • the first nozzle 201 has a substantially cylindrical shape, and has a through hole 201a for guiding a fluid therein.
  • FIG. 6A is a sectional view of the first nozzle 201
  • FIG. 6B is a front view of the first nozzle 201 as viewed from the fluid ejection side.
  • the through hole 201a has a structure in which one fluid introduction hole 201b at the rear end and four fluid intake holes 201c at the front end communicate with each other. These four fluid outlet holes 201c are directed in different directions, respectively, so that fluid can be blown to different regions of the inner wall surface 301a of the first cylindrical portion 301. ing.
  • a groove 201d is formed circumferentially at a position near the fluid outlet hole 201c.
  • An O-ring (not shown) fits into the groove 201d. That is, when the first nozzle 201 is inserted into the support member 321, with the O-ring fitted in the groove 201d of the first nozzle 201, The gap created between the surface of the first nozzle 201 and the surface of the through-hole 321a of the support member 321 is filled with the O-ring.
  • FIG. 7 is a diagram schematically showing a connection relationship between the first nozzle 201 and the fluid introduction pipe 401. As shown in FIG.
  • the fluid introduction pipe 401 is formed in a substantially arc shape so that the pipe extends along the outer periphery of the first cylindrical part 301, and is disposed in the first cylindrical part 301.
  • the branch pipes 410 a branched corresponding to each of the four first nozzles 201 This branch pipe 401 a is connected to the fluid introduction hole 201 b side of the first nozzle 201.
  • the connection between the branch pipe 401a and the first nozzle 201 is also structured to ensure airtightness.
  • a bent portion 401b is provided with a gentle R.
  • the bent portion 401b is formed so as not to have an acute portion, so that the fluid does not remain in the pipe.
  • the first nozzle 201 has high-temperature steam from the steam supply section 71 of the second cleaning / sterilization section 7 shown in FIG. 2, a cleaning liquid from the pure water supply section 72, and a clean air supply section 7 shown in FIG. Any fluid with the clean air from 3 is switched.
  • the fluid is introduced through the fluid introduction pipe 401. This switching is performed by a valve (switching means) not shown.
  • the timing of the ejection of the fluid from the first nozzle 201 is controlled by controlling the second washing and sterilizing unit 7 by a control circuit (control means) not shown.
  • FIG. 8 is a view schematically showing the arrangement position of the second nozzle 202 in the first cylindrical portion 301. As shown in FIG.
  • first nozzle 201 Like the first nozzle 201, four second nozzles 202 are provided in the first cylindrical portion 301. That is, as shown in FIG. 8, in addition to the first nozzle 201 shown in FIG. 4, a fluid ejection side is provided on the inner wall surface of the first cylindrical portion 301 in addition to the first nozzle 201 shown in FIG. Four second nozzles 202 projecting toward the 301a side are provided.
  • Each of the above-mentioned second nozzles 202 is provided with a support member provided on the first cylindrical portion 301. Supported by 3 2 2
  • the support member 3 2 2 has a substantially cylindrical shape, and a through hole 3 2 2 a penetrating from the outer wall surface 3 0 1 b side of the first cylindrical portion 3 1 1 toward the inner wall surface 3 0 1 a side. Are arranged to form
  • the support member 32 2 has substantially the same configuration as the support member 32 1. That is, as shown in FIG. 9, the support member 32 2 has one end portion of the cylindrical portion joined to the outer wall surface 301 b of the first cylindrical portion 301 by welding or the like, while the other end portion has A flange 32 b is formed for joining with a flange 202 e of a second nozzle 202 described later.
  • the inner diameter of the support member 322 is such that the main body of the second nozzle 202 can be inserted therein, and the airtightness inside the first cylindrical portion 301 when the second nozzle 202 is inserted. It is set to a size that can secure
  • the second nozzle 200 is substantially cylindrical and has a through hole 202 a for guiding a fluid therein.
  • FIG. 10 (a) shows a cross-sectional view of the second nozzle 202
  • FIG. 10 (b) shows a cross-sectional view taken along line BB of FIG. 10 (a)
  • FIG. ) Shows a cross-sectional view taken along line CC of FIG. 10 (a).
  • the through hole 202a has a structure in which one fluid introduction hole 202b on the rear end side and four fluid ejection holes 202c on the front end side communicate with each other. These four fluid ejection holes 202c are directed in different directions, and blow fluid to different regions of the inner wall surface 3Ola of the first cylindrical portion 301.
  • a groove 202d is formed circumferentially at a position near the fluid outlet hole 202c.
  • An O-ring (not shown) fits into the groove 202d.
  • the second nozzle 202 The surface of the second nozzle 202 and the support member 3 when inserted into the support member 322 with the ring fitted in the groove 202 d of the second nozzle 202 The gap formed between the surface of the through-hole 32 2 a and the through-hole 22 a is filled by the O-ring.
  • a flange 202e joined to the flange 32b of the support member 322 is formed on the surface of the second nozzle 202.
  • FIG. 11 is a diagram schematically showing the arrangement position of the third nozzle 203 in the second cylindrical portion 302. As shown in FIG.
  • the second cylinder portion 302 has two third nozzles 20 whose fluid ejection sides project toward the inner wall surface 302 a side of the second cylinder portion 302. 3 ⁇ are provided.
  • Each of the third nozzles 203 is supported by a support member 323 provided on the second cylindrical portion 302.
  • the support member 3 23 has a substantially cylindrical shape, and a through-hole 3 2 3 a penetrating from the outer wall surface 302 b side of the second cylindrical portion 302 to the inner wall surface 302 a side.
  • the support member 3 2 3 has one end portion of the cylindrical portion joined to the outer wall surface 302 b of the second cylindrical portion 302 by welding or the like, while the other end portion has A flange 32 b is formed for joining with a flange 203 f of a third nozzle 203 described later.
  • the inner diameter of the support member 323 is such that the main body of the third nozzle 203 can be inserted, and the airtightness in the second cylindrical portion 302 is inserted in a state where the third nozzle 203 is inserted. It is set to a size that can secure the property.
  • the third nozzle 203 has a substantially cylindrical shape, and has a through hole 203a for guiding a fluid therein.
  • FIG. 13A is a sectional view of the third nozzle 203
  • FIG. 13B is a front view of the third nozzle 203 as viewed from the fluid ejection side.
  • the through hole 203a has a structure in which one fluid introduction hole 203b on the rear end side and a fluid outlet hole 203c on the front end side communicate with each other. As shown in FIG. 14, the fluid introduction hole 203 b is further provided with a third nozzle 203. 20 20
  • Each of the fluid outlet holes 203 c and 203 d blows a fluid to a different region of the inner wall surface 302 a of the second cylindrical portion 302.
  • the fluid ejection hole 203 c is provided along the inner wall surface 302 a of the second cylindrical portion 302, so that the inner wall surface Fluid can be efficiently ejected to 2a.
  • a groove 203e is formed circumferentially at a position near the fluid ejection hole 203d.
  • An O-ring (not shown) fits into the groove 203e. That is, when the third nozzle 203 is inserted into the support member 321 in a state where the O-ring is fitted in the groove 203 e of the third nozzle 203, The gap created between the surface of the nozzle 201 and the surface of the through hole 323a of the support member 323 is filled with the O-ring.
  • a flange 203 f joined to the flange 32 b of the support member 323 is formed on the surface of the third nozzle 203.
  • the third nozzle 203 is joined so as to prevent the third nozzle 203 from entering the second cylindrical portion 302, and contributes to ensuring airtightness.
  • the fluid introduction hole 203 b of the nozzle 203 is a fluid introduction pipe to be described later.
  • FIG. 15 is a diagram schematically showing a connection relationship between the third nozzle 203 and the fluid introduction pipe 403.
  • the fluid introduction pipe 400 has a second cylindrical portion 302 as shown in FIG.
  • the two third nozzles 203 disposed in the second cylindrical portion 302 are connected to the respective distal end portions 400 a in such a manner as to be branched along the outer circumference of the cylinder. It's swelling. Note that the connection between the distal end portion 403a and the third nozzle 203 is also structured to ensure airtightness.
  • the distal end portion 4003a of the fluid introduction tube 403 has a bent portion 403b having a gentle radius.
  • the bent portion 4003b is formed such that there is no sharp angle portion, so that fluid does not remain in the pipe.
  • the third nozzle 203 has high-temperature steam from the steam supply section 71 of the second cleaning / sterilization section 7 shown in FIG. 2, a cleaning liquid from the pure water supply section 72, and a clean air supply section 7 as shown in FIG. Any fluid with the clean air from 3 is switched.
  • the fluid is introduced through the fluid introduction pipe 403. This switching is performed by pulp (switching means) not shown. Further, the timing of ejecting the fluid from the third nozzle 203 is controlled by controlling the second washing / sterilizing section 7 by a control circuit (control means) not shown.
  • FIG. 16 is a diagram schematically showing the arrangement position of the fourth nozzle 204 in the third tubular portion 303. As shown in FIG. 16
  • the third cylinder portion 303 has a fluid ejection side in the third cylinder portion 303.
  • Three fourth nozzles 204 protruding from the inner wall surface 303 a side of the three cylindrical portion 303 are arranged at regular intervals.
  • Each of the fourth nozzles 204 is supported by a support member 324 provided on the third cylindrical portion 303.
  • the support member 3 2 4 has a substantially cylindrical shape.
  • the third cylindrical portion 303 is disposed so as to form a through hole 324a penetrating from the outer wall surface 303b side to the inner wall surface 303a side.
  • the support member 3 2 4 has one end portion of the cylindrical portion joined to the outer wall surface 303 b of the third cylindrical portion 303 by welding or the like, while the other end portion has A flange 324b for joining with a flange 204e of a fourth nozzle 204 described later is formed.
  • the inner diameter of the support member 324 is such that the main body of the fourth nozzle 204 can be inserted, and the airtightness inside the third cylindrical portion 303 when the fourth nozzle 204 is inserted. It is set to a size that can secure
  • the fourth nozzle 204 has a substantially cylindrical shape, and has a through hole 204a for guiding a fluid therein.
  • FIG. 18 (a) is a cross-sectional view of the fourth nozzle 204
  • FIG. 18 (b) is a front view of the fourth nozzle 204 as viewed from the fluid ejection side.
  • the through hole 204a has a structure in which one fluid introduction hole 204b at the rear end and three fluid intake holes 204c at the front end communicate with each other.
  • the three fluid outlet holes 204c are directed in different directions, and blow fluid to different regions of the inner wall surface 303a of the third cylindrical portion 303. I have.
  • two fluid ejection holes 204c are shaped to eject fluid toward the fluid introduction hole 204b, as shown in Fig. 18 (a).
  • the other fluid ejection hole 204c has a shape that ejects fluid away from the inner wall surface 303a of the third cylindrical portion 303. ing.
  • the surface of the fourth nozzle 204 has a groove near the fluid outlet hole 204c. 204 d is formed in a circumferential shape. An O-ring (not shown) fits into the groove 204d. That is, when the fourth nozzle 204 is inserted into the support member 324 with the O-ring fitted in the groove 204 d of the fourth nozzle 204, the fourth nozzle 204 The gap formed between the surface of the nozzle 204 and the surface of the through hole 324a of the support member 324 is filled by the ring.
  • a flange 204 e joined to the flange 324 b of the support member 324 is formed on the surface of the fourth nozzle 204.
  • the fourth nozzle 204 is restricted so as not to enter the third cylindrical portion 303 by joining the second nozzle 204 and the fourth nozzle 204, and contributes to ensuring airtightness.
  • the fluid introduction hole 204 b of the nozzle 204 is connected to a fluid introduction pipe 404 (FIG. 19) described later.
  • FIG. 19 is a diagram schematically showing a connection relationship between the fourth nozzle 204 and the fluid introduction pipe 404. As shown in FIG.
  • the fluid introduction pipe 404 is formed in a substantially arc shape so that the pipe extends along the outer periphery of the third cylindrical portion 303, and is disposed in the third cylindrical portion 303.
  • a branched pipe 400a is formed corresponding to each of the three fourth nozzles 204 thus formed, and the branched pipe 400a is formed as a fluid introduction hole 204b of the fourth nozzle 204.
  • the connection between the branch pipe 404a and the fourth nozzle 204 also has a structure for ensuring airtightness.
  • a bent portion 404b is formed with a gentle R. Since the bent portion 404b is formed so as not to have an acute angle portion, The body is prevented from remaining in the tube.
  • the fourth nozzle 204 has high-temperature steam from the steam supply section 71 of the second cleaning / sterilization section 7 shown in FIG. 2, a cleaning liquid from the pure water supply section 72, and a clean air supply section 7 shown in FIG. Any fluid with the clean air from 3 is switched.
  • the fluid is introduced through the fluid introduction pipe 404. This switching is performed by a valve (switching means) not shown.
  • the timing of the ejection of the fluid from the fourth nozzle 204 is controlled by controlling the second washing / sterilizing unit 7 by a control circuit (control means) not shown.
  • Each of the first nozzle 201 to fourth nozzle 204 is set to such an amount that the tip of the fluid ejection side does not hinder granulation in the granulation chamber 200. ing.
  • the fluid ejection direction of each nozzle is fixed in a predetermined direction. In this case, the direction of fluid ejection is determined by the formation of the fluid ejection holes (201c, 202c, 203c, 203d, 204c) of each nozzle.
  • the fixed fluid ejection direction is set to a direction in which a swirling flow is generated by the fluid in the granulation chamber 200 when each nozzle is installed on the inner wall surface 200 d of the granulation chamber 200. Is preferred.
  • the fluid ejection direction of each nozzle is specified in this manner, the amount of ejected fluid can be minimized, so that resource saving and energy saving can be realized.
  • this is a granulation apparatus for producing target particles by charging raw materials into a closed granulation chamber 200, and the granulation chamber 200 has an inner wall surface 200d.
  • One or more nozzles (first nozzle 201 to fourth nozzle 204) for ejecting fluid are provided on the inner wall surface 200d of the granulation chamber 200. Therefore, it has the following advantages.
  • the powder adhering to the inner wall surface 200 d of the granulation chamber 200 during granulation can be reduced. It can be separated by the ejected fluid. That is, the powder adhering to the inner wall surface 200 d of the granulation chamber 200 can be peeled off without giving an impact to the granulation chamber 200.
  • the granulating chamber 200 having the above configuration can be applied to a granulating apparatus for granulating a product such as a preparation that extremely dislikes the incorporation of foreign substances into the product.
  • the inner wall surface 200 d of the granulation chamber 200 can be sterilized.
  • the flow of fluid from each nozzle is performed at predetermined time intervals. In this case, it is desirable to perform the granulation for a time that does not hinder the granulation. In particular, it is preferable to perform the operation intermittently and instantaneously.
  • the ejection timing may be shifted for each nozzle, or the ejection may be performed at each nozzle. You may adjust the timing. In addition, when the timing of ejection is shifted for each nozzle, the effect on granulation can be minimized.
  • the use of the granulator having the above-described configuration can provide a powder production method for producing aseptic and dust-free powder which is superior to freeze-drying and spray-drying methods.
  • the powder production method of the present invention comprises freeze-drying by performing a fine-granulation step performed at a lower temperature than the spray-drying method and a fluidized-bed drying step performed subsequently to the fine-granulation step. Powders with a chemical quality comparable to that of aseptic preparations produced by the process can be produced in a short time.
  • the adhesion of powder to the inner wall surface is reduced, and the formation of a fluidized bed is performed.
  • the produced powder can be dried in a short time, and the recovery rate can be improved.
  • the spray granulation step is a step in which a solution in which a target substance is dissolved or a suspension in which the target substance is suspended is used as a fluid in a granulation chamber of the granulator to perform spray granulation. .
  • the fluidized bed drying step is a drying step of performing fluidized bed drying after the above-mentioned atomization granulation step until the solvent content in the granulated powder reaches a target value.
  • the raw material of the powder and the apparatus are subjected to aseptic processing, so that not only foreign substances are not mixed but also aseptic powder can be produced. In other words, sterile and dust-free powder can be obtained.
  • the drying can be performed at a lower temperature as compared with the spray drying method, it is possible to use a heat-sensitive substance as a target substance, and to prevent mixing of a thermally degraded product.
  • Powder Z products with a low content can be produced at lower temperatures than the spray dry method.
  • the allowable solvent content in the powder varies depending on the type of drug produced as the powder. Therefore, when the solvent is water, it is defined as the solvent content that does not hydrolyze the drug, and when the solvent is an organic solvent, it is defined as the solvent content that does not affect the human body (no residual solvent). .
  • a powder Z formulation of a component unstable to heat By performing spray granulation at a low temperature in a range where powdering can be performed and fluidized bed drying at a low temperature, it is possible to manufacture a powder Z formulation of a component unstable to heat.
  • the use of a granulating device enables the production of a powder that does not exceed the allowable solvent content in the powder at a low temperature without thermal degradation.
  • a powder having excellent re-dissolvability can be obtained as compared with a bulk obtained by a freeze-drying method.
  • the capacity of the granulation chamber 200 of the granulation apparatus according to the present example was set to 800 L, the surface area was set to 10 m 2 , and a 30% solids aqueous solution of sorbic acid was used as a model raw material.
  • the inlet temperature of the raw material is 80 ° C
  • the outlet temperature is 50 ° C
  • the spray liquid speed is 120 g Zmin
  • the spray air volume is 300 LZ min (using 2 tubes)
  • 33.4 kg of liquid raw material (potassium sorbate aqueous solution) is blown (droplet diameter is 10 ⁇ m or less)
  • about 10 kg of fine particles of sorbic acid are introduced into the granulation chamber 200.
  • the inner wall 200 d of the granulation chamber 200 d after the fine particles were washed off was cleaned by the conventional method centering on the cleaning nozzle 205, and the unwashed portion (fine particles) (A portion where is attached).
  • a UV (ultraviolet) absorption method was used. This UV absorption method is a method in which an aqueous riboflavin solution is sprayed on the inner wall surface 200 d of the granulation chamber 200, washed, and then irradiated with a UV lamp to confirm residual fine particles.
  • the operating conditions of the first nozzle 201 to the fourth nozzle 204 are as follows.
  • Stop (OFF) time 30 seconds
  • the fine particles attached to the inner wall surface 200d were removed by injecting the fluid into the inner wall surface 200d of the granulation chamber 200.
  • the recovery rate when the removed fine particles were recovered as a product was 90% (about 9 kg) or more. That is, about 1 kg of fine particles remained on the inner wall surface 200 d of the granulation chamber 200.
  • the inside wall 200 d of the granulation chamber 200 was cleaned using the first nozzle 201 to the fourth nozzle 204.
  • the operating conditions of the first nozzle 201 to the fourth nozzle 204 are
  • Stop (OFF) time 90 seconds
  • the inside wall 200 d of the granulation room 200 was cleaned.
  • the above-mentioned UV (ultraviolet) absorption method was used to confirm the residual fine particles, but the residue could not be confirmed.
  • a smaller amount of the washing liquid can be used for the granulation chamber 200.
  • the entire inner wall surface of 200 d can now be cleaned.
  • FIG. 20 shows a comparison result of the cleaning degree under the above two conditions.
  • the degree of cleaning is expressed using the electrical conductivity of the wastewater discharged from the granulation chamber 200.
  • the higher the electrical conductivity of the wastewater the more the residue (potassium sorbate) is contained in the wastewater.
  • Figure 20 shows the results for each of the nozzles (first nozzle 2) shown in Figure 1 when the powder of potassium sorbate remaining on the inner wall 200d of the granulation chamber 200 was 2 kg.
  • first nozzle 2 When cleaning is performed using the 0-1 to 4th nozzles 204) (use of side wall nozzles: equivalent to the above condition (a)), these existing nozzles are not used, and only the existing cleaning nozzles are used.
  • ⁇ indicates the case where the side wall nozzle is used
  • ⁇ indicates the case where the side wall nozzle is not used
  • ⁇ indicates the amount of drainage
  • the first nozzle 201 to the fourth nozzle 204 are formed such that the vent hole is exposed on the inner wall surface 200 d of the granulation chamber 200. Accordingly, the granulation chamber 200 adheres to the inner wall surface 200 d without vibrating the granulation chamber 200 from outside or rotating the nozzle inside. The fine particles can be removed or washed without generating foreign matter, so that granulation can be performed in a dust-free state. Moreover, since the granulation chamber 200 can be maintained in a dust-free state, it is easy to make it sterile.
  • a solution containing a cleaning agent-high-temperature steam is automatically switched and ejected, sterile, dust-free, granulated, dried and washed off,
  • the process from cleaning to sterilization can be automated.
  • the granulating apparatus of the present invention enables automatic washing and automatic sterilization (automatic high-pressure steam sterilization). It can be applied to the dry powder manufacturing method that has been performed only by “lyophilization”.
  • the granulator with the above configuration can be sterilized and dust-free, so it can be used to generate microparticles with few agglomerations and micro-mouth coating with little aggregation in an environment without contamination. If it is easy to carry out and continues fluidized-bed drying (secondary drying) after spraying, it is not possible to obtain a dry product with the same low moisture content as freeze-dried products, which cannot be achieved with conventional spray dryers.
  • the granulation apparatus having the above configuration is more advantageous than the freeze-drying method in terms of economics (initial, running, maintenance cost).
  • the granulating apparatus may perform only automatic cleaning, or may perform automatic cleaning and automatic sterilization in combination.
  • the above-mentioned granulating apparatus is suitably used for coating, granulating, and drying of the preparation.
  • it is suitably used for drying and granulating the above-mentioned injection solution for use at the time of use.
  • a fluidized-bed granulator (Hosokin Co., Ltd .: AGM-2SD-S) manufactured by Microcron Co., Ltd. was used as the granulator shown in FIG.
  • a chemical indicator made by HOGY: AC detection force
  • a temperature sensor were placed at various locations inside the building.
  • the target product was granulated in a fluidized bed granulator (spray granulation process). Before the fluid is atomized into the fluidized-bed granulator, the inside of the fluidized-bed granulator is sterilized in advance (sterilization process). However, the degree of sterilization in the sterilization process performed here shall be set according to the quality of the product to be manufactured.
  • the main body of the fluidized bed granulator was From the 1 nozzles provided (Fig. 1, 4, 8, 11 and 16), from the 7 nozzles other than the nozzle that blows out the dehumidifying air, the ⁇ 1? & 0.22 m filter filtered nitrogen was spouted at 20 second intervals for 0.4 seconds to prevent powder from adhering to the wall and to promote the formation of a fluidized bed.
  • dehumidifying air is blown out from a nozzle provided on the inner wall surface, and water contained in the powder is discharged.
  • the drying in the fluidized bed drying step was performed for 1 hour after the completion of the spraying of the fluid.
  • a small-sized spray dryer manufactured by Niguchi Company was used to pulverize Moxafenadurime, an oxacephem antibiotic, into powder.
  • the liquid was sent to the spray dryer at a rate of 1 minute.
  • Nitrogen at an inlet temperature of 95 ° C (dew point: 80 ° C) was blown at 32 ⁇ 1 kg / h to powderize. The powder adhered to the drying cylinder of the spray dryer, but no thermal deterioration was observed.
  • the oxacephem antibiotic, puffer moxefnate was powdered using the same small spray dryer as in comparative example 1 (here, the same oxacephem antibiotic as in Example 1).
  • An aqueous solution containing 29.5 W / W% of Flomocef sodium and 1.5 W / W% of sodium chloride was sent to the spray dryer at a rate of 2.1 g / min.
  • Nitrogen at an inlet temperature of 95 ° C (dew point: 180 ° C) was blown into powder at 32 lkg Zh. Powder was attached to the drying cylinder of the spray dryer. No deterioration was observed.
  • Example 1 The powder produced in Example 1 was subjected to a test according to the test method of the Japanese Pharmacopoeia. Here, 1.1 g of the powder produced in Example 1 was dissolved in 100 mL of water for injection, and the insoluble fine particles were measured with a particle counter. It was confirmed that they were compatible.
  • the powder produced in each of the examples and comparative examples was examined for water content.
  • the water content of each powder is determined by the Karl Fischer method. Was measured. Table 1 shows the measurement results.
  • the allowable water content (target value) of flomoxef sodium as a drug product must be less than 0.5%.
  • the relative titers of the powders produced in Examples 1 and 2 with respect to the used raw material powders were measured by using a high performance liquid chromatography.
  • the measurement conditions of the high-speed liquid chromatography method are as follows.
  • Measuring device Waters 600E, 741, 712, 741
  • Table 2 shows the measurement results under the above measurement conditions.
  • the drug content in the preparation may be from 90 to 100%, preferably from 95 to: L00%, more preferably from 98 to 100%. Therefore, according to the powder production method of the present invention, the drug content in the preparation can be in the above range.
  • a sterile and dust-free solution or suspension can be used to remove the sterile and dust-free solution without impairing the chemical characteristics of the material to be dried (powder). It becomes possible to produce powder formulations.
  • the powder manufacturing method of the present invention can produce a dry powder / formulation in a shorter time than the freeze-drying method, and does not require auxiliary equipment such as a refrigerator and a vacuum pump. The operation cost can be reduced and it is economical.
  • the powder production method of the present invention can be dried at a lower temperature than the spray drying method, and can be made into a powder / formulation even with a substance that is weak to heat.
  • the powder manufacturing method of the present invention is characterized in It is safe because there is no risk of contamination.
  • a powder Z preparation having excellent powder properties, good fluidity, high strength, and industrially easy to handle can be obtained by using the coating function and the granulation function.
  • the granulation apparatus of the present invention is a granulation apparatus that granulates a desired powdery / granular product by introducing and / or spraying a raw material into a closed granulation chamber, A plurality of nozzles for ejecting a fluid to the wall of the granulation chamber are provided on the wall of the granulation chamber, and the direction of ejecting the fluid of each nozzle is fixed in a predetermined direction.
  • the fluid ejected by each nozzle adheres to the wall surface of the granulation chamber.
  • Powder and granular products can be peeled off. That is, it is possible to peel off the product adhering to the wall surface of the granulation chamber without giving an impact to the granulation chamber.
  • the fluid ejection direction of the nozzle is fixed in a predetermined direction, the fluid can be ejected to the wall surface of the granulation chamber without driving the nozzle such as rotation or movement. Accordingly, it is possible to eliminate generation of foreign matter in the granulation chamber due to driving such as rotation and movement of the nozzle.
  • the powder attached to the wall surface of the granulation chamber during granulation can be removed.
  • a liquid used as the fluid, it is possible to clean the wall of the granulation chamber by including a cleaning component in the liquid.
  • high-temperature steam that can be sterilized as a fluid If used, it is possible to sterilize the wall of the granulation chamber.
  • the product adhering to the inner wall surface can be wiped off by ejecting the fluid to the inner wall surface of the granulation chamber without giving an external impact to the granulation chamber. As a result, there is no danger of foreign matter entering the product to be recovered.
  • the nozzle itself When a liquid containing a cleaning component is used as the fluid, the nozzle itself is rotated or moved in the granulation chamber because the fluid ejection hole of the nozzle is fixed in a predetermined direction. There is no need to wash the granulation chamber wall. As a result, there is no problem that foreign matter generated by driving the nozzle by rotation, movement, or the like is mixed into the granulation chamber after cleaning.
  • the granulating apparatus having the above configuration as a granulating apparatus for granulating a product such as a preparation or the like in which foreign substances are extremely mixed into the product.
  • the granulation chamber is sterilized and free It is easy to use a granulation apparatus of the above configuration for granulation of a preparation that needs to be granulated in a sterile and dust-free environment, especially for granulation of a dissolution injection at the time of use. The effect that becomes possible To play.
  • the direction in which the fluid is ejected from each of the nozzles may be fixed in a direction in which a swirling flow is generated by the fluid ejected to the wall surface of the granulation chamber.
  • the ejection of the fluid from the nozzle may be performed intermittently.
  • the method for producing powder includes a spray granulation step of spray granulating a solution in which the target substance is dissolved or a suspension in which the target substance is suspended in the granulation chamber of the granulator. This has the effect that sterile and dust-free powder can be produced at a low temperature in a short time. Further, in the above-mentioned powder production method, it is preferable that the method further includes a drying step of performing fluidized-bed drying until the solvent content in the granulated powder reaches a target value after the above-mentioned atomization granulation step. This has the effect of obtaining a powder having a solvent content of
  • the granulation chamber of the above-mentioned granulation apparatus is sterilized, and a gas or target substance dissolved in a gas or a target substance introduced into the apparatus is dissolved.
  • the sterilization process or the aseptic operation method includes the step of sterilizing the suspension in which the powder is suspended and the aseptic treatment of the powder material and equipment. Not only is there no contamination, but also sterile powder can be produced. That is, there is an effect that sterile and dust-free powder can be obtained.
  • the granulating apparatus of the present invention and the method for producing powder using the granulating apparatus can be used not only for general powder production but also for aseptic preparations and sterile foods that require sterility in the production process, as well as for raw materials and sterile foods.
  • it can be suitably used for producing oral preparations, transpulmonary preparations, and the like that do not require sterility assurance in the production process but require a high level of sterility.

Abstract

Cette invention concerne un système de granulation disposé sur la paroi intérieure (200d) d'une chambre de granulation fermée (200), dans lequel quatre injecteurs, du premier (201) au quatrième (204), projettent un liquide contre la surface de la paroi intérieure (200d). Les directions du liquide projeté par les injecteurs (201) à (204) sont fixes comme spécifié. Une poudre est produite au moyen du système de granulation. Avec ce système de granulation, aucune matière étrangère n'est engendrée dans la chambre de granulation avant et après nettoyage et ne peut se mélanger au produit obtenu. On peut ainsi obtenir une poudre exempte de poussière, à basse température et en un bref laps de temps.
PCT/JP2003/012623 2002-10-03 2003-10-01 Systeme de granulation et fabrication de poudre au moyen dudit systeme WO2004030803A1 (fr)

Priority Applications (1)

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AU2003272911A AU2003272911A1 (en) 2002-10-03 2003-10-01 Granulation system and process for producing powder using granulation system

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JP2002291308 2002-10-03
JP2002-291308 2002-10-03
JP2003120612A JP3907605B2 (ja) 2002-10-03 2003-04-24 造粒装置およびこの造粒装置を用いた粉末製造方法
JP2003-120612 2003-04-24

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WO2004030803A1 true WO2004030803A1 (fr) 2004-04-15

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AU (1) AU2003272911A1 (fr)
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Cited By (1)

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CN114008816A (zh) * 2019-06-28 2022-02-01 壹久公司 具有动力喷射模块的系统及其方法

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GB0427568D0 (en) * 2004-12-16 2005-01-19 Resolution Chemicals Ltd Particle-size reduction apparatus, and the use thereof
DE102010043087A1 (de) * 2010-10-28 2012-05-03 Dürr Systems GmbH Prozesskammer mit Vorrichtung zum Einblasen von gasförmigen Fluid
EP3058299B1 (fr) 2013-10-18 2020-03-25 GEA Process Engineering A/S Procédé pour nettoyer un agencement de buses dans un appareil de séchage par pulvérisation, et appareil de séchage par pulvérisation pour mettre en oeuvre le procédé
JP6526502B2 (ja) * 2014-06-30 2019-06-05 株式会社パウレック 連続式粒子製造装置
JP5937161B2 (ja) * 2014-09-01 2016-06-22 株式会社パウレック 流動層装置
WO2017002694A1 (fr) * 2015-06-30 2017-01-05 株式会社パウレック Dispositif de fabrication continue de particules
EP3318319B1 (fr) 2015-06-30 2020-08-05 Kabushiki Kaisha Powrex Dispositif de fabrication continue de particules

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GB1289996A (fr) * 1968-09-09 1972-09-20
US3735792A (en) * 1970-06-01 1973-05-29 Asizawa Tekko Kk Spray drying method and apparatus for producing granular particles from stock liquids of solids
WO1993023129A1 (fr) * 1992-05-21 1993-11-25 Niro Holding A/S Procede et appareil pour reduire au minimum les depots dans une chambre de sechage
JPH08511335A (ja) * 1993-06-16 1996-11-26 ヘンケル・コマンディットゲゼルシャフト・アウフ・アクチェン 乾燥媒体中に過熱水蒸気を用いる改良された乾燥方法およびその使用
JPH11114027A (ja) * 1997-10-13 1999-04-27 Sumitomo Pharmaceut Co Ltd 充実スプレードライ粉末及びその製造方法

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GB1289996A (fr) * 1968-09-09 1972-09-20
US3735792A (en) * 1970-06-01 1973-05-29 Asizawa Tekko Kk Spray drying method and apparatus for producing granular particles from stock liquids of solids
WO1993023129A1 (fr) * 1992-05-21 1993-11-25 Niro Holding A/S Procede et appareil pour reduire au minimum les depots dans une chambre de sechage
JPH08511335A (ja) * 1993-06-16 1996-11-26 ヘンケル・コマンディットゲゼルシャフト・アウフ・アクチェン 乾燥媒体中に過熱水蒸気を用いる改良された乾燥方法およびその使用
JPH11114027A (ja) * 1997-10-13 1999-04-27 Sumitomo Pharmaceut Co Ltd 充実スプレードライ粉末及びその製造方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114008816A (zh) * 2019-06-28 2022-02-01 壹久公司 具有动力喷射模块的系统及其方法

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JP2004174481A (ja) 2004-06-24
JP3907605B2 (ja) 2007-04-18
AU2003272911A8 (en) 2004-04-23
AU2003272911A1 (en) 2004-04-23

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