WO1993009867A1 - Process for coating small particles using a rotor fluidized bed apparatus - Google Patents

Process for coating small particles using a rotor fluidized bed apparatus Download PDF

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Publication number
WO1993009867A1
WO1993009867A1 PCT/US1992/008159 US9208159W WO9309867A1 WO 1993009867 A1 WO1993009867 A1 WO 1993009867A1 US 9208159 W US9208159 W US 9208159W WO 9309867 A1 WO9309867 A1 WO 9309867A1
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WO
WIPO (PCT)
Prior art keywords
particles
disk
product
chamber
longitudinal
Prior art date
Application number
PCT/US1992/008159
Other languages
French (fr)
Inventor
Isaac Ghebre-Sellassie
Original Assignee
Warner-Lambert Company
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Publication date
Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Publication of WO1993009867A1 publication Critical patent/WO1993009867A1/en

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Classifications

    • 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
    • B01J8/00—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes
    • B01J8/18—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes with fluidised particles
    • B01J8/24—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes with fluidised particles according to "fluidised-bed" technique
    • B01J8/38—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes with fluidised particles according to "fluidised-bed" technique with fluidised bed containing a rotatable device or being subject to rotation or to a circulatory movement, i.e. leaving a vessel and subsequently re-entering it
    • B01J8/382—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes with fluidised particles according to "fluidised-bed" technique with fluidised bed containing a rotatable device or being subject to rotation or to a circulatory movement, i.e. leaving a vessel and subsequently re-entering it with a rotatable device only
    • 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
    • B01J2/14—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic in rotating dishes or pans
    • 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

  • This invention relates to a process and apparatus for coating particles having an average equivalent diameter of less than 1000 ⁇ m using a rotor fluidized bed apparatus.
  • Rotor fluidized bed granulator ⁇ are reviewed in I. Ghebre-Sellassie, ed. , Pharmaceutical Pelletization Technol ⁇ ogy. Marcel Dekker, pp. 101-104, 109-116 (1989) , incorpo ⁇ rated herein by reference, and are described in detail below.
  • Such granulators are widely used in the pharmaceuti ⁇ cal industry to prepare granulations as well as to manufac ⁇ ture and coat relatively large pellets using various coating formulations.
  • Rotor fluidized bed granulators are characterized by a relatively short expansion chamber.
  • a short chamber is sufficient for the above applications, as the product bed does not expand to more than two or three times the static bed height and thus typically stays within the granulator's product chamber during processing.
  • the particle density is high, the large particles do not agglomerate since the breaking forces (i.e. centrifu ⁇ gal force, fluidizing force and gravitational force) are greater than the binding or agglomerating forces due to the heaviness of such particles.
  • the rotor fluidized bed apparatus has been used in the pharmaceutical industry to coat only relatively large parti ⁇ cles. Very small particles would agglomerate during the coating process since their light weight and high density in the region near the disk end of the product chamber results in the binding forces being greater than the breaking forces. This agglomeration is undesirable as it leads to increased particle size and a decrease in particle popula ⁇ tion.
  • Increasing the fluidization air velocity in the attempt to increase turbulence (i.e. increase breaking forces) and decrease particle density in the region of coat ⁇ ing and drying to decrease agglomeration causes the parti ⁇ cles to pass out of the product chamber and into the short expansion chamber where they contact the filter housing. This leads to filter clogging during the coating process, consequently generating variable and disorganized fluidiza ⁇ tion patterns resulting in drug particles with unpredictable release rates.
  • the present invention therefore meets a need in the art by solving the agglomeration problems experienced with small particle coating in a rotor fluidized bed apparatus.
  • the present invention relates to a process for coating small particles.
  • the process comprises coating a plurality of particles having an average equivalent diameter of less than about 1000 ⁇ m in a rotor fluidized bed apparatus.
  • This process is applicable to coating a plurality of particles having an average equivalent diameter of less than 750 ⁇ m, 500 ⁇ m, and even 250 ⁇ m, and is quite suitable for coating particles having an average equivalent diameter of 10 - 500 ⁇ m.
  • the equivalent diameter is the diameter of a sphere having the same volume as that of a particle.
  • the parts of the rotor fluidized bed apparatus cooperate to result in a process wherein small or fine particles can be coated.
  • the height to width ratio of tlae expansion chamber of the apparatus is increased to at least 0.5, preferably at least 1, and most preferably at least 2. This increase in volume enables the particles to have a longer residence time in the expansion chamber in which to dry.
  • the height of the spray inlet means typically a spray nozzle, should be increased so that it is disposed at least 20%, preferably at least 50%, and more preferably about 80% of the product chamber height from the disk end, so as to provide for coating in a region of lower particle density in the fluidized system.
  • Figure 1 is a side view of the rotor fluidized bed appa- ratus of the present invention with the disk in a loading position.
  • Figure 2 is the embodiment of Figure 1 during fluidizing operation.
  • Figures 1 and 2 depict a rotor fluidized bed apparatus which can be used for coating, without agglom ⁇ eration, particles having an average equivalent diameter of less than about 1000 ⁇ m according to the above process.
  • the apparatus comprises a product chamber 10 having a longitudinal axis 12.
  • the product chamber is defined by a longitudinal product surface 13, an open top end 14, and a disk end 15.
  • a rotatable disk 16 is positioned toward the disk end 15.
  • the disk 16 has a product chamber side 17, a gas inlet side 18, and a disk perimeter 19.
  • the apparatus also includes an expansion chamber 20 coax ⁇ ial with the longitudinal axis 12.
  • the expansion chamber 20 is defined by a longitudinal expansion surface 21, an open base end 22, and a gas outlet end 23.
  • the longitudinal product surface 13 at the open top end 14 of the product chamber 10 is attached to the longitudinal expansion surface 21 at the open base end 22, whereby the product chamber 10 communicates with the expansion chamber 20.
  • both the product chamber and expansion chamber are cylindrical.
  • the apparatus also has a gas inlet means 24 disposed to provide a fluidizing gas to the gas inlet side 18 of the disk 16.
  • a gas outlet means 25, typically a filter means, is located at the gas outlet end 23 of the expansion chamber 20.
  • At least one and typically up to nine spray inlet means 26 are located at the longitudinal product surface 13 directed to spray into the product chamber 10.
  • the above rotor fluidized bed apparatus can further com ⁇ prise a means to support the disk such as shaft 30 and a means to rotate the disk such as motor 31 having a motor shaft rotatably connected to support shaft 30.
  • the longitudinal product surface 13 preferably tapers toward the longitudinal axis 12 at the disk end 15 having a smaller perimeter than the disk.
  • the disk 16 can be lowered so that the disk perimeter 19 inter ⁇ sects the tapered product surface 13 to prevent particles from falling beneath the disk.
  • the disk In operation, the disk is raised longitudinally and fluidizing gas passes through annular gap 34 defined by the longitudinal product surface 13 and the disk perimeter 19.
  • the annular gap generally ranges in size from about 0.5 to about 10.0 mm wide. The gas prevents particles from falling beneath the disk.
  • Rotor fluidized bed apparatus are known in the pharmaceu ⁇ tical art which are designed for preparing granulations and for making and coating larger pellets.
  • the present inven ⁇ tion is directed to an improved rotor fluidized bed appara ⁇ tus useful for coating small, irregularly-shaped and variably-sized particles, particularly with a controlled release membrane.
  • the expansion chamber 20 of the apparatus of the present invention has been increased to provide sufficient volume in the chamber to permit the particles to expand resulting in a reduced particle density in the region of coating and the region of drying to allow the particles to be coated and dried without significant agglomeration.
  • the fluidizing air then exerts its fluidizing force to expand the particles not only within the product chamber but up into the expansion chamber, so that the particles are coated and dried before gravitational forces force them down into areas of increased particle density in the lower regions of the product chamber 10 near the disk product surface 17.
  • the expansion chamber of the present invention has a height to width ratio of at least 0.5, preferably, at least 1, and most preferably at least 2.
  • the spray inlet means i.e. nozzles
  • the spray inlet means are located at the longitudinally lower region of the product chamber 10 along the product surface 13. While this is satisfactory for coating larger pellets, small particles are dense at the disk surface 17. Spraying fluid in this region tends to agglomerate small particles. Load size is there ⁇ fore limited. It has been found that the spray inlet means 26, typically spray nozzles, can be elevated and accom o- date larger production-size loads of small particles. While nozzles placed too low can result in agglomeration, nozzles placed too high can result in some of the particles being left uncoated since a statistical amount of the particles
  • the nozzles therefore should be disposed in the product chamber, at least 20%, preferably at least 50%, more preferably at least 75% and most preferably about 80% of the product cham ⁇ ber height from the disk end 15 to the top end 14. Then, even with larger particle loads, substantially all of the particles are coated.
  • the number of spray inlet means or nozzles is variable depending on the particular details of the coating process being carried out. Generally, the number of nozzles is between 3 and 9, with 3 nozzles preferred, equally spaced (i.e. 120° apart) around the longitudinal product surface.
  • droplet size from the coating spray must be considered. Droplet size is dependent upon factors such as the width of the spray nozzle openings, coating fluid flow rate through the nozzles, and ato ization air pressure. As a general rule, droplets will agglomerate those particles smaller in size than the droplets and coat those particles of equal or greater size. Therefore, it is preferred to have the droplets of coating fluid smaller than the particles and preferably about ten times smaller than the average particle size, i.e. droplets with an average equivalent diameter ten times less than the average equiva ⁇ lent diameter of the particles.
  • the temperature of the incoming fluidizing air can vary depending upon the properties of the coating, particles, etc. Generally, the fluidizing air ranges from about 15 to about 80°C. Typically, it is important to the drying of the coating during the rotor fluidized bed process, for the humidity of the fluidizing air to be kept at a minimum. One way to accomplish this is to cool the air first so that the water in the air condenses out, and then warming the air to the desired production temperature before it enters the apparatus.
  • the coating process is conducted for a period of time sufficient to coat the particles to the extent desired. This will depend not only upon the particular machine used, but also on the particles to be coated, the coating composi ⁇ tion, etc. , and the release profile desired. Processing time can be determined and optimized with a minimum of experimentation. Generally, the amount of coating applied to the particles is at least about 15% by weight of the final formulation, with more coating applied if a slower release profile is desired, or if the pharmaceutical agent in the particles is particularly soluble.
  • the present invention also relates to a process for coat ⁇ ing small particles.
  • the process comprises coating a plurality of particles having an average equivalent diameter of less than about 1000 ⁇ m in a rotor fluidized bed appara- tus. This process is applicable to coating a plurality of particles having an average equivalent diameter of less than 750 ⁇ m, 500 ⁇ m, and even 250 ⁇ m, and is quite suitable for coating of particles having an average equivalent diameter of 10-500 ⁇ m.
  • the average equivalent diameter is the diame ⁇ ter of a sphere having the same volume as that of the average particle.
  • the above coating process involves the steps of feeding the particles onto a product chamber side of a rotor (disk) having a rotor diameter, with a product chamber defined by a longitudinal product surface, there being a gap between the rotor and the product surface, forcing a stream of a fluidizing gas through the gap, rotating the rotor to force the particles into the stream of fluidizing gas, spraying fluid droplets into the stream of fluidizing gas and particles, and expanding the stream of fluidizing gas, particles and droplets in an expansion chamber.
  • the feeding of the particles onto the rotor can be accomplished by vacuum or mechanical feed.
  • the number of feeders can be varied, and they should preferably be positioned between the spray inlet means.
  • the above process permits the maintenance of a predeter ⁇ mined particle population, rather than experiencing agglom- eration and a consequent decrease in particle population.
  • the particle population preferably remains relatively constant as should be with particle coating, with only insignificant changes resulting from the agglomeration of at least some of the particles having a diameter lower than the average equivalent diameter, and substantially below 100 ⁇ m. Such agglomeration is believed to be due to the fact that some of the particles actually are smaller than the fluid droplets sprayed into the apparatus to coat the particles.
  • the present invention also includes a process comprising the steps of forming granules comprising at least one phar ⁇ maceutical agent and a binder, comminuting the granules so formed to produce a plurality of particles having an average equivalent diameter of less than 1000 ⁇ m, and coating the particles in a rotor fluidized bed apparatus as discussed above.
  • This process may also include a drying step which involves drying the granules prior to comminuting.
  • the process of forming granules is known as "granulation", which is an agglomeration process where primary particles are randomly bound together with the help of binders to generate secondary particles of various shapes and sizes.
  • Granules prepared by conventional wet or dry granulation methods can be used. Also, crystals of the drug or pharmaceutical agent could alternatively be used.
  • Comminuting is typically accomplished by milling. Drying is typically accomplished in a drying oven.
  • the present invention therefore not only permits the coating of small particles, but also permits the coating of irregularly-shaped or random-shaped particles or granules which result from simple pharmaceutical granulation methods. Furthermore, the present invention is suitable for the coat ⁇ ing of a wide distribution of particle-sizes which often results from the preparation of granules. This is all, of course, in sharp contrast to the coating processes tradi ⁇ tionally performed in a rotor fluidized bed apparatus, that is, the coating of pellets, since, not only are pellets larger, but they also are by nature spherical and uniformly- sized.
  • the particles which are coated typically comprise at least one pharmaceutical agent and a binder.
  • the pharmaceu ⁇ tical agent or agents used can be any pharmaceutical agent.
  • the agent should be present in the final dosage form in a therapeutically effective amount.
  • Some possible agents include gemfibrozil, diphenhydramine hydrochloride, ascorbic acid, diltiazem, diazepam, etc. If gemfibrozil was included, for example, the amount of gemfibrozil included in the formulation should be an amount sufficient to provide for administration of the required daily dose, depending on the dosage regimen, which is typically 1200 g.
  • a binder is included to allow the particles to withstand the agitation (e.g. from fluidization) and frictional force (e.g. particle to particle, particle to wall) in the rotor fluidized bed apparatus during the coating process, so that the particles do not break up into a fine powder.
  • the binder selected is dependent upon the pharmaceutical agent being used and thus may be soluble or insoluble.
  • suitable binders include an acrylic resin, ethyl cellu ⁇ lose (e.g. Surelease , Aquacoat ) , and a plasticizer with hydroxypropyl cellulose or hydroxypropylmethyl cellu ⁇ lose.
  • suitable acrylic resins include pharma ⁇ ceutically acceptable acrylic and (meth)acrylic copolymers.
  • the copolymer may be derived from methyl and ethyl acrylate and methyl and ethyl methacrylate.
  • Other conventional comonomers may be present in the copolymers as long as they do not detract from the copolymer's usefulness in the present system.
  • Examples are those of the Eudragit R family, such as poly(methacrylic acid, ethylacrylate) , poly(methacrylic acid, methylmethacry- late), poly(ethylacrylate, methylmethacrylate) , poly(ethyl- acrylate, methylmethacrylate,-trimethylammonioethylmeth- acrylate chlorid) , and poly(butylmethacrylate, (2-dimethy- laminoethyl) methacrylate, methylmethacrylate) as discussed in Lehmann, "The Application and Processing of Acrylic Coat ⁇ ings in Form of Aqueous Dispersions Compared with Organic Solutions," Acta Pharm. Fenn. 91, 225-238 (1982).
  • suitable plasticizers used in the pharmaceutical art include propylene glycol, polyethylene glycol, and glycer- ine.
  • the pharmaceutical agent will be present in the particles to be coated in amounts of from about 80 to about 98% by weight and the binder will be present in amounts of from about 2 to about 20% by weight.
  • Modified release includes both extended or sustained release and delayed or enteric release.
  • the release profile of the coated particles will depend upon the controlled release membrane coating applied.
  • suitable coating compositions can include compounds such as dioxypropylmethyl cellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, cellulose acetate, ethyl cellulose, acrylic resins and waxes. Examples of suitable acrylic resins are as listed above. Examples of suitable waxes include carnauba wax, hydrogenated wax, or stearated wax.
  • the coating composition can also include one or more pharmaceutical excipients to reduce the tackiness of the coating composition and thereby diminish any opportunity for agglomeration.
  • coated granules can be used alone as sustained or enteric release granules, or these coated granules can be mixed with other excipients or even an immediate release granulation of the pharmaceutical agent, and can be placed in the desired dosage forms including tablets or capsules.
  • a Glatt Rotor Granulator Type GRG-200, is modified by increasing the height of the expansion chamber so that the height to width ratio is approximately 1, and by raising the coating spray nozzles toward the open top end of the product chamber, to approximately 80% of the product chamber height from the disk end.
  • a granulation is prepared from the following Components:
  • Purified water 6.0 *Eudragit E30D is a polymeric dispersion of a copolymer neutral in character based on poly(meth)acrylic acid ester and having a mean molecular weight of about 800,000.
  • This granulation is dried and milled to yield particles having an average equivalent diameter of about 300 ⁇ m, which are then coated with the following composition:
  • the coating conditions are as follows:
  • Particles with coating levels of 15, 17, 19 and 21% by weight are produced.

Abstract

A process and apparatus for coating a plurality of particles having an average equivalent diameter of less than about 1000 νm in a rotor fluidized bed apparatus. The rotor fluidized bed apparatus is improved to include an expansion chamber (20) having a height to width ratio at least sufficient to expand a fluidized particle bed of such particles to coat the particles without agglomeration, and spray inlet means disposed at least 20 % of the product chamber height from the disk end.

Description

PROCESS FOR COATING SMALL PARTICLES USING A ROTOR FLUIDIZED BED APPARATUS
Background of the Invention
Field of the Invention
This invention relates to a process and apparatus for coating particles having an average equivalent diameter of less than 1000 μm using a rotor fluidized bed apparatus.
Description of the Related Art
Rotor fluidized bed granulatorε are reviewed in I. Ghebre-Sellassie, ed. , Pharmaceutical Pelletization Technol¬ ogy. Marcel Dekker, pp. 101-104, 109-116 (1989) , incorpo¬ rated herein by reference, and are described in detail below. Such granulators are widely used in the pharmaceuti¬ cal industry to prepare granulations as well as to manufac¬ ture and coat relatively large pellets using various coating formulations. Rotor fluidized bed granulators are characterized by a relatively short expansion chamber. A short chamber is sufficient for the above applications, as the product bed does not expand to more than two or three times the static bed height and thus typically stays within the granulator's product chamber during processing. Although the particle density is high, the large particles do not agglomerate since the breaking forces (i.e. centrifu¬ gal force, fluidizing force and gravitational force) are greater than the binding or agglomerating forces due to the heaviness of such particles.
The rotor fluidized bed apparatus has been used in the pharmaceutical industry to coat only relatively large parti¬ cles. Very small particles would agglomerate during the coating process since their light weight and high density in the region near the disk end of the product chamber results in the binding forces being greater than the breaking forces. This agglomeration is undesirable as it leads to increased particle size and a decrease in particle popula¬ tion. Increasing the fluidization air velocity in the attempt to increase turbulence (i.e. increase breaking forces) and decrease particle density in the region of coat¬ ing and drying to decrease agglomeration causes the parti¬ cles to pass out of the product chamber and into the short expansion chamber where they contact the filter housing. This leads to filter clogging during the coating process, consequently generating variable and disorganized fluidiza¬ tion patterns resulting in drug particles with unpredictable release rates.
The present invention therefore meets a need in the art by solving the agglomeration problems experienced with small particle coating in a rotor fluidized bed apparatus.
Summary of the Invention
The present invention relates to a process for coating small particles. The process comprises coating a plurality of particles having an average equivalent diameter of less than about 1000 μm in a rotor fluidized bed apparatus. This process is applicable to coating a plurality of particles having an average equivalent diameter of less than 750 μm, 500 μm, and even 250 μm, and is quite suitable for coating particles having an average equivalent diameter of 10 - 500 μm. The equivalent diameter is the diameter of a sphere having the same volume as that of a particle.
The parts of the rotor fluidized bed apparatus cooperate to result in a process wherein small or fine particles can be coated. Preferably, the height to width ratio of tlae expansion chamber of the apparatus is increased to at least 0.5, preferably at least 1, and most preferably at least 2. This increase in volume enables the particles to have a longer residence time in the expansion chamber in which to dry. Additionally, the height of the spray inlet means, typically a spray nozzle, should be increased so that it is disposed at least 20%, preferably at least 50%, and more preferably about 80% of the product chamber height from the disk end, so as to provide for coating in a region of lower particle density in the fluidized system.
Brief Description of the Drawings
Figure 1 is a side view of the rotor fluidized bed appa- ratus of the present invention with the disk in a loading position.
Figure 2 is the embodiment of Figure 1 during fluidizing operation.
Description of the Preferred Embodiment
A preferred embodiment of the present invention will be apparent to those skilled in the art by references to Figures 1 and 2. Figures 1 and 2 depict a rotor fluidized bed apparatus which can be used for coating, without agglom¬ eration, particles having an average equivalent diameter of less than about 1000 μm according to the above process.
The apparatus comprises a product chamber 10 having a longitudinal axis 12. The product chamber is defined by a longitudinal product surface 13, an open top end 14, and a disk end 15. A rotatable disk 16 is positioned toward the disk end 15. The disk 16 has a product chamber side 17, a gas inlet side 18, and a disk perimeter 19.
The apparatus also includes an expansion chamber 20 coax¬ ial with the longitudinal axis 12. The expansion chamber 20 is defined by a longitudinal expansion surface 21, an open base end 22, and a gas outlet end 23. The longitudinal product surface 13 at the open top end 14 of the product chamber 10 is attached to the longitudinal expansion surface 21 at the open base end 22, whereby the product chamber 10 communicates with the expansion chamber 20. Preferably both the product chamber and expansion chamber are cylindrical.
The apparatus also has a gas inlet means 24 disposed to provide a fluidizing gas to the gas inlet side 18 of the disk 16. A gas outlet means 25, typically a filter means, is located at the gas outlet end 23 of the expansion chamber 20. At least one and typically up to nine spray inlet means 26 are located at the longitudinal product surface 13 directed to spray into the product chamber 10.
The above rotor fluidized bed apparatus can further com¬ prise a means to support the disk such as shaft 30 and a means to rotate the disk such as motor 31 having a motor shaft rotatably connected to support shaft 30. There can be a means such as piston 33 to move the disk 16 in a longitudinal direction. The longitudinal product surface 13 preferably tapers toward the longitudinal axis 12 at the disk end 15 having a smaller perimeter than the disk. During loading, i.e. by vacuum through feed line 35, the disk 16 can be lowered so that the disk perimeter 19 inter¬ sects the tapered product surface 13 to prevent particles from falling beneath the disk.
In operation, the disk is raised longitudinally and fluidizing gas passes through annular gap 34 defined by the longitudinal product surface 13 and the disk perimeter 19. The annular gap generally ranges in size from about 0.5 to about 10.0 mm wide. The gas prevents particles from falling beneath the disk.
Rotor fluidized bed apparatus are known in the pharmaceu¬ tical art which are designed for preparing granulations and for making and coating larger pellets. The present inven¬ tion is directed to an improved rotor fluidized bed appara¬ tus useful for coating small, irregularly-shaped and variably-sized particles, particularly with a controlled release membrane.
The expansion chamber 20 of the apparatus of the present invention has been increased to provide sufficient volume in the chamber to permit the particles to expand resulting in a reduced particle density in the region of coating and the region of drying to allow the particles to be coated and dried without significant agglomeration. Thus, when the rotor's centrifugal force forces the particles toward the longitudinal product surface and into the stream of fluidiz¬ ing air, the fluidizing air then exerts its fluidizing force to expand the particles not only within the product chamber but up into the expansion chamber, so that the particles are coated and dried before gravitational forces force them down into areas of increased particle density in the lower regions of the product chamber 10 near the disk product surface 17. The extra fluidizing force imparted by the increased flow of fluidizing air also enhances the breaking forces discussed earlier by increasing turbulence. Gener¬ ally, the expansion chamber of the present invention has a height to width ratio of at least 0.5, preferably, at least 1, and most preferably at least 2.
Typically, the spray inlet means, i.e. nozzles, are located at the longitudinally lower region of the product chamber 10 along the product surface 13. While this is satisfactory for coating larger pellets, small particles are dense at the disk surface 17. Spraying fluid in this region tends to agglomerate small particles. Load size is there¬ fore limited. It has been found that the spray inlet means 26, typically spray nozzles, can be elevated and accom o- date larger production-size loads of small particles. While nozzles placed too low can result in agglomeration, nozzles placed too high can result in some of the particles being left uncoated since a statistical amount of the particles
.are not pushed too high by the fluidization forces. The nozzles therefore should be disposed in the product chamber, at least 20%, preferably at least 50%, more preferably at least 75% and most preferably about 80% of the product cham¬ ber height from the disk end 15 to the top end 14. Then, even with larger particle loads, substantially all of the particles are coated.
The number of spray inlet means or nozzles is variable depending on the particular details of the coating process being carried out. Generally, the number of nozzles is between 3 and 9, with 3 nozzles preferred, equally spaced (i.e. 120° apart) around the longitudinal product surface.
During processing, droplet size from the coating spray must be considered. Droplet size is dependent upon factors such as the width of the spray nozzle openings, coating fluid flow rate through the nozzles, and ato ization air pressure. As a general rule, droplets will agglomerate those particles smaller in size than the droplets and coat those particles of equal or greater size. Therefore, it is preferred to have the droplets of coating fluid smaller than the particles and preferably about ten times smaller than the average particle size, i.e. droplets with an average equivalent diameter ten times less than the average equiva¬ lent diameter of the particles.
In processing, the temperature of the incoming fluidizing air can vary depending upon the properties of the coating, particles, etc. Generally, the fluidizing air ranges from about 15 to about 80°C. Typically, it is important to the drying of the coating during the rotor fluidized bed process, for the humidity of the fluidizing air to be kept at a minimum. One way to accomplish this is to cool the air first so that the water in the air condenses out, and then warming the air to the desired production temperature before it enters the apparatus.
The coating process is conducted for a period of time sufficient to coat the particles to the extent desired. This will depend not only upon the particular machine used, but also on the particles to be coated, the coating composi¬ tion, etc. , and the release profile desired. Processing time can be determined and optimized with a minimum of experimentation. Generally, the amount of coating applied to the particles is at least about 15% by weight of the final formulation, with more coating applied if a slower release profile is desired, or if the pharmaceutical agent in the particles is particularly soluble.
The present invention also relates to a process for coat¬ ing small particles. The process comprises coating a plurality of particles having an average equivalent diameter of less than about 1000 μm in a rotor fluidized bed appara- tus. This process is applicable to coating a plurality of particles having an average equivalent diameter of less than 750 μm, 500 μm, and even 250 μm, and is quite suitable for coating of particles having an average equivalent diameter of 10-500 μm. The average equivalent diameter is the diame¬ ter of a sphere having the same volume as that of the average particle.
Preferably, the above coating process involves the steps of feeding the particles onto a product chamber side of a rotor (disk) having a rotor diameter, with a product chamber defined by a longitudinal product surface, there being a gap between the rotor and the product surface, forcing a stream of a fluidizing gas through the gap, rotating the rotor to force the particles into the stream of fluidizing gas, spraying fluid droplets into the stream of fluidizing gas and particles, and expanding the stream of fluidizing gas, particles and droplets in an expansion chamber. The feeding of the particles onto the rotor can be accomplished by vacuum or mechanical feed. The number of feeders can be varied, and they should preferably be positioned between the spray inlet means.
The above process permits the maintenance of a predeter¬ mined particle population, rather than experiencing agglom- eration and a consequent decrease in particle population. The particle population preferably remains relatively constant as should be with particle coating, with only insignificant changes resulting from the agglomeration of at least some of the particles having a diameter lower than the average equivalent diameter, and substantially below 100 μm. Such agglomeration is believed to be due to the fact that some of the particles actually are smaller than the fluid droplets sprayed into the apparatus to coat the particles. The agglomeration of these very small particles -is pharmaceutically insignificant since the agglomeration will stop and the agglomerated particle will be coated by the fluid once the particle's size exceeded the droplet size which is usually adjusted to be less than the average parti- cle size. Therefore, there will be no effect on drug release. Furthermore, in production, where the droplet size will be set, the agglomeration of these very small particles will be consistent and reproducible which is important in the manufacture of pharmaceuticals.
The present invention also includes a process comprising the steps of forming granules comprising at least one phar¬ maceutical agent and a binder, comminuting the granules so formed to produce a plurality of particles having an average equivalent diameter of less than 1000 μm, and coating the particles in a rotor fluidized bed apparatus as discussed above. This process may also include a drying step which involves drying the granules prior to comminuting. The process of forming granules is known as "granulation", which is an agglomeration process where primary particles are randomly bound together with the help of binders to generate secondary particles of various shapes and sizes. Granules prepared by conventional wet or dry granulation methods can be used. Also, crystals of the drug or pharmaceutical agent could alternatively be used. Comminuting is typically accomplished by milling. Drying is typically accomplished in a drying oven.
The present invention therefore not only permits the coating of small particles, but also permits the coating of irregularly-shaped or random-shaped particles or granules which result from simple pharmaceutical granulation methods. Furthermore, the present invention is suitable for the coat¬ ing of a wide distribution of particle-sizes which often results from the preparation of granules. This is all, of course, in sharp contrast to the coating processes tradi¬ tionally performed in a rotor fluidized bed apparatus, that is, the coating of pellets, since, not only are pellets larger, but they also are by nature spherical and uniformly- sized.
The particles which are coated typically comprise at least one pharmaceutical agent and a binder. The pharmaceu¬ tical agent or agents used can be any pharmaceutical agent. The agent should be present in the final dosage form in a therapeutically effective amount. Some possible agents include gemfibrozil, diphenhydramine hydrochloride, ascorbic acid, diltiazem, diazepam, etc. If gemfibrozil was included, for example, the amount of gemfibrozil included in the formulation should be an amount sufficient to provide for administration of the required daily dose, depending on the dosage regimen, which is typically 1200 g.
A binder is included to allow the particles to withstand the agitation (e.g. from fluidization) and frictional force (e.g. particle to particle, particle to wall) in the rotor fluidized bed apparatus during the coating process, so that the particles do not break up into a fine powder. The binder selected is dependent upon the pharmaceutical agent being used and thus may be soluble or insoluble. Examples of suitable binders include an acrylic resin, ethyl cellu¬ lose (e.g. Surelease , Aquacoat ) , and a plasticizer with hydroxypropyl cellulose or hydroxypropylmethyl cellu¬ lose. Examples of suitable acrylic resins include pharma¬ ceutically acceptable acrylic and (meth)acrylic copolymers. The use of " eth" as a prefix in parenthesis indicates that the polymer molecule is derived from one or both of acrylic and methacrylic species. Thus, the copolymer may be derived from methyl and ethyl acrylate and methyl and ethyl methacrylate. Other conventional comonomers may be present in the copolymers as long as they do not detract from the copolymer's usefulness in the present system. Examples are those of the Eudragit R family, such as poly(methacrylic acid, ethylacrylate) , poly(methacrylic acid, methylmethacry- late), poly(ethylacrylate, methylmethacrylate) , poly(ethyl- acrylate, methylmethacrylate,-trimethylammonioethylmeth- acrylate chlorid) , and poly(butylmethacrylate, (2-dimethy- laminoethyl) methacrylate, methylmethacrylate) as discussed in Lehmann, "The Application and Processing of Acrylic Coat¬ ings in Form of Aqueous Dispersions Compared with Organic Solutions," Acta Pharm. Fenn. 91, 225-238 (1982). Examples of suitable plasticizers used in the pharmaceutical art include propylene glycol, polyethylene glycol, and glycer- ine.
Typically, the pharmaceutical agent will be present in the particles to be coated in amounts of from about 80 to about 98% by weight and the binder will be present in amounts of from about 2 to about 20% by weight.
The present invention is particularly suited to the manu¬ facture of modified release dosage formulations. Modified release includes both extended or sustained release and delayed or enteric release. The release profile of the coated particles will depend upon the controlled release membrane coating applied. For example, suitable coating compositions can include compounds such as dioxypropylmethyl cellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, cellulose acetate, ethyl cellulose, acrylic resins and waxes. Examples of suitable acrylic resins are as listed above. Examples of suitable waxes include carnauba wax, hydrogenated wax, or stearated wax.
The coating composition can also include one or more pharmaceutical excipients to reduce the tackiness of the coating composition and thereby diminish any opportunity for agglomeration.
The above coated granules can be used alone as sustained or enteric release granules, or these coated granules can be mixed with other excipients or even an immediate release granulation of the pharmaceutical agent, and can be placed in the desired dosage forms including tablets or capsules.
The following example will serve to further typify the nature of the invention but should not be construed as being a limitation on the scope thereof, which scope is defined solely by the appended claims.
EXAMPLE
A Glatt Rotor Granulator, Type GRG-200, is modified by increasing the height of the expansion chamber so that the height to width ratio is approximately 1, and by raising the coating spray nozzles toward the open top end of the product chamber, to approximately 80% of the product chamber height from the disk end. A granulation is prepared from the following Components:
INGREDIENT PARTS BY WEIGHT
Gemfibrozil 344.5
Eudragit E30D* 137.8
Polysorbate 80 2.8
Purified water 6.0 *Eudragit E30D is a polymeric dispersion of a copolymer neutral in character based on poly(meth)acrylic acid ester and having a mean molecular weight of about 800,000.
This granulation is dried and milled to yield particles having an average equivalent diameter of about 300 μm, which are then coated with the following composition:
INGREDIENT PARTS BY WEIGHT
Eudragit E30D* 349.70
Ethyl cellulose (30% aqueous dispersion) 103.40
The coating conditions are as follows:
Figure imgf000016_0001
Particles with coating levels of 15, 17, 19 and 21% by weight are produced.
The result in each case is a coated granulation. A slower release of gemfibrozil is seen as the coating level increases.

Claims

What is claimed is:
1. A process which comprises coating a plurality of particles having an average equivalent diameter of less than 1000 μm in a rotor fluidized bed apparatus.
2. The process according to claim 1 wherein the parti¬ cles have an average equivalent diameter of less than 750 μm.
3. The process according to claim 2 wherein the parti¬ cles have an average equivalent diameter of less than 500 μm.
4. The process according to claim 1 comprising:
feeding the particles onto a product chamber side of a rotor having a rotor diameter, with a product chamber defined by the rotor product chamber side and a longitudinal product surface, there being a gap between the rotor and the longitudinal product surface;
forcing a stream of fluidizing gas through the gap;
rotating the rotor to force the particles into the stream of fluidizing gas;
spraying fluid droplets into the stream of fluidizing gas and particles; and
expanding the stream of fluidizing gas, particles and droplets in an expansion chamber.
5. The process according to claim 4 further comprising maintaining a predetermined particle population.
6. The process according to claim 4 further comprising agglomeration of at least some particles having a diameter lower than the average equivalent diameter, and substan¬ tially below 100 μm.
1. The process according to claim 1 wherein the rotor fluidized bed apparatus comprises an expansion chamber having a height to width ratio which provides at least a sufficient volume to expand the particles to coat the parti¬ cles without agglomeration.
8. The process according to claim 7 wherein the height to width ratio of the expansion chamber is at least 1.
9. The process according to claim 1 wherein the rotor fluidized bed apparatus comprises a product chamber having a disk end, with a spray inlet means disposed at least 75% of the product chamber height from the disk end.
10. The process according to claim 9 wherein the spray inlet means is disposed about 80% of the product chamber height from the disk end.
11. The process according to claim 1 wherein the parti¬ cles are coated with a controlled release membrane.
12. The process according to claim 11 wherein the parti- cles are coated with a composition comprising a compound selected from the group consisting of hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, cellulose acetate, ethyl cellulose, acrylic resins and waxes.
13. The process according to claim 12 wherein the acrylic resin is poly(methacrylic acid, ethylacrylate) , poly
(methacrylic acid, methylmethacrylate) , poly(ethylaeryla e, methylmethacrylate) , poly(ethylacrylate, methylmethacrylate,
-trimethylammonioethylmethacrylate-chlorid) , poly(ethyl- acrylate, methylmethacrylate,-trimethylammonioethylmetha- acrylate-chlorid) , and poly(butylmethacrylate, (2-dimethyl- aminoethyl) methacrylate, methylmethacrylate) .
14. The process according to claim 12 wherein the wax is carnauba wax, hydrogenated wax or stearated wax.
15. The process according to claim 1 wherein the parti¬ cles comprise at least one pharmaceutical agent and a binder.
16. The process according to claim 15 wherein the phar¬ maceutical agent is gemfibrozil.
17. The process according to claim 15 wherein the binder is one selected from the group consisting of an acrylic resin, ethyl cellulose, and a plasticizer with hydroxypropyl cellulose or hydroxypropylmethyl cellulose.
18. A process comprising the steps of:
forming granules comprising at least one pharmaceuti¬ cal agent and a binder;
comminuting the granules to produce a plurality of particles having an average equivalent diameter of less than 1000 μm; and
coating the particles in a rotor fluidized bed appa¬ ratus.
19. The process according to claim 18 further comprising drying the granules prior to comminuting.
20. In a fluidized bed apparatus of the type having:
a product chamber, having a longitudinal axis, the product chamber defined by a longitudinal product surface, an open top end and a disk end; a rotatable disk toward the disk end having a product chamber side, a gas inlet side, and a disk perimeter;
an expansion chamber coaxial with the longitudinal axis, the expansion chamber defined by a longitudinal expan- * sion surface, an open base, and a gas outlet end, the longi¬ tudinal product surface at the open top end is attached to the longitudinal expansion surface at the open base end whereby the product chamber communicates with the expansion chamber;
a gas inlet means disposed to provide a fluidizing gas to the gas inlet side of the disk;
a gas outlet means at the gas outlet end of the expansion chamber; and
a spray inlet means at the longitudinal product sur- face directed to spray into the product chamber;
the improvement comprising:
the expansion chamber having a height to width ratio at least sufficient to expand a fluidized particle bed of particles having an average equivalent diameter of less than 1000 μm to coat the particles without agglomeration, and the spray inlet means disposed at least 20% of the product cham¬ ber height from the disk end.
21. The apparatus according to claim 20 wherein the height to width ratio of the expansion chamber is at least 0.5.
22. The apparatus according to claim 21 wherein the height to width ratio of the expansion chamber is at least 1.
23. The apparatus according to claim 22 wherein the height to width ratio of the expansion chamber is at least 2.
24. The apparatus according to claim 20 wherein the aver¬ age equivalent diameter of the particles is less than 750 μm.
25. The apparatus according to claim 24 wherein the average equivalent diameter of the particles is less than 500 μm.
26. The apparatus according to claim 20 wherein the spray inlet means is disposed at least 50% of the product chamber height from the disk end.
27. The apparatus according to claim 26 wherein the spray inlet means is disposed about 80% of the product chamber height from the disk end.
28. The apparatus according to claim 20 further com¬ prising:
a means to support the disk; and
a means to rotate the disk.
29. The apparatus according to claim 28 further corn-prising:
a means to move the disk in a longitudinal direction,
wherein the longitudinal product surface tapers toward the longitudinal axis at the disk end having a smaller perimeter than the disk.
30. The apparatus according to claim 20 wherein the expansion chamber is cylindrical.
31. The apparatus according to claim 20 wherein the product chamber is cylindrical.
32. The apparatus according to claim 20 wherein the gas outlet means further comprises a filter means.
33. A fluidized bed apparatus for coating, without agglomeration, particles having an average equivalent diame¬ ter of less than 1000 μm which comprises:
a product chamber, having a longitudinal axis, the product chamber defined by a longitudinal product surface, an open top end and a disk end;
a rotatable disk toward the disk end having a product chamber side, a gas inlet side, and a disk perimeter;
an expansion chamber coaxial with the longitudinal axis, the expansion chamber defined by a longitudinal expan- sion surface, an open base end, and a gas outlet end, the longitudinal product surface at the open top end is attached to the longitudinal expansion surface at the open base end, whereby the product chamber communicates with the expansion chamber, the expansion chamber having a height to width ratio of at least 0.5;
a gas inlet means disposed to provide a fluidizing gas to the gas inlet side of the disk;
a gas outlet means at the gas outlet end of the expansion chamber; and
spray inlet means at the longitudinal product surface directed to spray into the product chamber, the spray inlet means disposed at least 50% of the product chamber height from the disk end.
34. The apparatus according to claim 33 wherein the fluidizing gas passes through an annular gap defined by the longitudinal product surface and the disk perimeter.
35. The apparatus according to claim 34 wherein the annular gap is from about 0.5 to about 10.0 mm wide.
PCT/US1992/008159 1991-11-18 1992-09-24 Process for coating small particles using a rotor fluidized bed apparatus WO1993009867A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB962711A (en) * 1961-09-18 1964-07-01 Smith Kline French Lab Improvements in or relating to apparatus and method for coating discrete solids
US3394468A (en) * 1965-06-14 1968-07-30 Glatt Werner Container for the reception of a pulverulent or granular feed for treatment in a hot air dryer
FR2534488A1 (en) * 1982-10-18 1984-04-20 Freunt Ind Co Ltd GRANULATING AND COATING MACHINE
CH670053A5 (en) * 1986-11-06 1989-05-12 Aeromatic Ag Spray coat for small objects - has rotary disc with air-permeable rim round upstanding central cone in chamber contg. helical baffles
EP0423701A2 (en) * 1989-10-20 1991-04-24 Freund Industrial Co., Ltd. Granulating and coating method and apparatus therefor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB962711A (en) * 1961-09-18 1964-07-01 Smith Kline French Lab Improvements in or relating to apparatus and method for coating discrete solids
US3394468A (en) * 1965-06-14 1968-07-30 Glatt Werner Container for the reception of a pulverulent or granular feed for treatment in a hot air dryer
FR2534488A1 (en) * 1982-10-18 1984-04-20 Freunt Ind Co Ltd GRANULATING AND COATING MACHINE
CH670053A5 (en) * 1986-11-06 1989-05-12 Aeromatic Ag Spray coat for small objects - has rotary disc with air-permeable rim round upstanding central cone in chamber contg. helical baffles
EP0423701A2 (en) * 1989-10-20 1991-04-24 Freund Industrial Co., Ltd. Granulating and coating method and apparatus therefor

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