WO2003033126A1

WO2003033126A1 - Multifunction fluid bed apparatus and method for processing of material in a fluid bed apparatus

Info

Publication number: WO2003033126A1
Application number: PCT/FI2002/000810
Authority: WO
Inventors: Jukka-Pekka Mannermaa; Jouko Yliruusi; Seppo Lehtonen
Original assignee: Ariacon Oy
Priority date: 2001-10-19
Filing date: 2002-10-18
Publication date: 2003-04-24
Also published as: FI20012034A; FI20012034A0

Abstract

The invention relates to a fluidized bed apparatus (100). Said fluidized bed apparatus (100) comprises one or more module(s) (110) for treating materials and an optional air/gas treatment unit (130), each module (110) for treating materials containing 1 - 32, preferably 1 - 16 and particularly preferably 2 - 4 fluidizing units (120) operating independently and each fluidizing unit (120) comprising an integrated or exchangeable fluidizing chamber (50), a means (10) for controlling and measuring the air/gas flow, said means being an electronic hot wire sensor device or a device based on a static pressure difference, and optionally a heating/cooling means (51) for the air/gas. Further, the invention relates to a method for processing material in a fluidized bed apparatus (100). In said fluidized bed apparatus (100), one or several unit operations are carried out simultaneously, the materials in each of the fluidizing chambers being identical or different, and the amounts thereof in each of the fluidizing chambers being equal or different.

Description

Multifunction fluid bed apparatus and method for processing of material in a fluid bed apparatus

The invention relates to a multifunctional fluidized bed apparatus for controlled processing of a material, the apparatus also enabling to carry out several similar or different processing procedures independently. With this fluidized bed apparatus, it is for example possible to coat moist powders and particles, and it may be used as a coating apparatus. The apparatus is also particularly suitable for small batch sizes. This fluid- ized bed apparatus comprises an apparatus for treating materials consisting of one or more modules made of fluidizing units. This fluidized bed apparatus combines multi- functionality with modularity and with small size. For instance drugs, pharmaceutical adjuvants, medicaments for inhalation, peptides, oligonucleotides and active agents of functional food products may be processed in this fluidized bed apparatus. The inven- tion is further directed to a method for processing material in a fluidized bed apparatus.

Prior art

Conventional fluidized bed apparatuses are disclosed for instance in documents CH 390153, CH 403646, CH 455652 and DE 3137540. The patent application DE 3323418 presents a fluidized bed apparatus having several ascending pipes in the same device. The patent application EP 0 403 820 discloses a fluidized bed apparatus combined with a device for generating microwaves. This arrangement allows for in- stance the continuous measuring of the water content of a powder being treated.

Known fluidized bed apparatuses are used for drying mixtures of gases and solids, and for producing granules. They are also used in various testing arrangements for instance to study the properties of powders, liquids or coatings. The fluidized bed apparatus normally comprises a fluidizing chamber, through which an air stream or another air/gas stream is passed upwards from below. On the basis of the behaviour of the material, for instance a powder in the chamber, conclusions con- cerning the properties thereof may be drawn.

As for the fluidized bed apparatuses used at present, the batch size typically varies between 50 g and 1000 kg, and all existing apparatuses have a single chamber. Due to the batch size, a quick modification of the physical properties of the material is not possible in a few seconds, and accordingly, neither quick cyclic wetting/drying processes nor quick drying or wetting may actually be performed. With the existing single chamber apparatuses, it is very time consuming to carry out extensive tests, for instance series of tests based on systematic study design methods, the number of the tests being sufficiently high to make the study reliable, and typically, it takes several weeks to carry out such a series of tests. For these reasons, it is very hard to scale up such fluidized processes using the already existing apparatuses.

Granule samples of 1 - 5 g are conventionally taken from the fluidized bed apparatus, and dried in heat cabinets. In such heat cabinets, temperature and humidity distribu- tions are considerable, in dried samples the particles agglomarate and sometimes form only a single lump. These large lumps are broken manually and often in a totally uncontrolled manner. Finally, the particle sizes are measured by means of a sieve analysis, laser diffraction, image analysis or with another suitable method. The reliability of the results thus obtained may be considered as questionable.

Drawbacks of known fluidized bed apparatuses include the lack of precision and the fact that low material amounts may not be used for research purposes. The apparatuses in use being generally rather bulky, it is almost impossible to precisely fluidize and treat low amounts of materials, particularly when low air/gas flow rates are used. Lack of precision in the fluidized bed apparatuses is mainly due to the fact that the air/gas flow rates used for fluidizing vary widely. In a prior art apparatus with a capacity of 5 kg, the air/gas flow rate is normally between 3 and 180 1/s. The error made in the measurement of the fluidizing air/gas stream is generally about 30 - 50 %. An uncertainty of tens of percents in said measurement of the fluidizing air/gas amount impedes the accurate control of the processes and their reproducibility, and moreover, the precise thermodynamic modelling of the processes is not possible. Known instruments commonly used to measure flow rates are not able to give accurate results in such a wide measuring range. Thus, the prior art fluidized bed apparatuses are gen- erally meant for batches with sizes limited to a narrow range ± 50 %, the batch sizes for the apparatuses, however, varying between 50 g and 1000 kg.

Passing an air stream having precisely a desired volumetric flow rate to the subject material is a problem particularly in cases where the air streams to be directed to the material are minimal. For instance, if the volumetric flow rates of air vary between the values of 0.1 and 3 1/s, precise measuring and control is not possible with a single device according to the prior art. The reason for this is particularly the fact that there are no such flowmeters enabling the precise measuring of air or gas streams having volumetric flow rates that vary between very low and high values.

Volumetric flow rates of air or gas are generally measured using an orifice flange placed in a conduit. The flow rate may be determined from the difference between the pressures of the flow measured respectively upstream and downstream of the orifice flange. Such a measurement is, however, relatively accurate only for some values of the flow rate. For low flow rates, the orifice flange is not sufficiently precise to carry out accurate measurements. For volumetric flow rates, a venturi tube is a more precise meter than an orifice flange, also measuring the difference between the pressures in the flow channel and the throat part of the venturi tube. It is however evident that high volumetric flow rates may not be passed through the channel due to the tapering of the venturi tube, since this would increase the flow resistance substantially.

The accurate measuring range of volumetric flow rates is relatively narrow for known flowmeters. Particularly for the lower values of said range, the measuring error is considerable.

Several drugs such as drugs for inhalation, hormones and peptides are typically used in extremely low amounts, and accordingly, small scale devices are necessary in the research of such drugs and medical products. After the synthesis, the drug is almost always first available only in small amounts, and thus the unit price thereof is high. In practice, it is often not possible to produce high amounts, say some kilograms of the drug until the synthesis method of the drug is sufficiently well developed. It is expected that several novel drug families such as peptide drugs will be provided in the near future, the dosage of which is only a fraction of those of the medicaments in use at present. Thus, precise small scale production equipment will then be needed to produce them.

Granulation of powder material aims at increasing the particle size of the powder and accordingly, improving the properties thereof in processing, for instance improving the flowability, reducing static charges and compacting the material, as well as reduc- ing dust formation therefrom, improving the preservability, and controlling the release of the active agent from the granules.

In the production of pharmaceuticals, granulation is always a batch process due to drug safety requirements and legislative regulations. In the production of pharmaceu- ticals, typical production batch sizes being granulated in fluidized granulating devices are between 100 and 500 kg. In research laboratories such batch sizes are normally between 500 g and 10 kg. The newest fluidized granulating devices allow the processing of batches having sizes that are as low as 50 g. In air suspension granulation, i.e. fluidized granulation, the powder mass being granulated is introduced into a granulating chamber. The mass is fluidized with a depressurized or pressurized air stream flowing upwards from below, depressurization being preferable in pharmaceutical industry for safety reasons. Granulating liquid having a droplet size of about 30 - 80 μm is sprayed to the fluidized mass through nozzles using pressurized air or high pressures. This granulating liquid acts as a adhesive making the powder particles to adhere to each other.

On the basis of the above findings it is clear that there is an obvious need for a fluidized bed apparatus that is substantially more precise than the prior art apparatuses, this fluidized bed apparatus allowing the controlled and reproducible processing of a material and a reliable and reproducible handling of even very low amounts of materials while permitting to carry out several independent processing procedures simultaneously.

Object of the invention

The object of the invention is to provide a multifunctional modular fluidized bed apparatus that is substantially more precise than the prior art apparatuses and allows the controlled and reproducible processing of materials even in small scale and also dif- ferent substances simultaneously, allowing for instance the drying, granulating and coating of powders and particles. Another object of the invention is further a method for processing materials such as powders and particles reproducibly, with high precision and even in small scale in a fluidized bed apparatus. Characteristic features of the fluidized bed apparatus and method of the invention

The characteristic features of the modular multifunctional fluidized bed apparatus and the method for processing material in said fluidized bed apparatus are presented in the claims.

Description of the invention

It has been surprisingly found that the problems and drawbacks of the prior art solutions may be avoided or substantially reduced by means of the fluidized bed apparatus and method of the invention. The fluidized bed apparatus of the invention is an apparatus for treating materials, combining modularity with multifunctionality and optionally with small size. The apparatus and method are useful for treating powdery, granular and finely divided materials, and small single pieces such as tablets. The material may be porous, sponge-like or solid and have a regular or irregular shape. The apparatus and method are particularly suited for processing drugs, other biologically active agents, intermediates, pharmaceutical adjuvants, drugs for inhalation, proteins, peptides, oligonucleotides, pesticides, fertilizers, and active agents of functional food products and food additives.

Fluidized bed apparatus of the invention

The fluidized bed apparatus of the invention (100) comprises one or more module(s) (110) for treating materials. Each module (1 10) for treating materials contains 1 - 32, preferably 1 - 16 and particularly preferably 2 - 4 fluidizing units (120) operating independently. Preferably 1 - 5 and particularly preferably 1 - 3 module(s) (1 10) for treating materials may be connected to one air/gas treatment unit (130). In this way, identical conditions with respect to the air/gas feed may provided for all modules (1 10) for treating materials. This air/gas treatment unit (130) is optional, in some cases air may be taken from the ambient atmosphere in the room.

Each fluidizing unit (120) comprises an integrated or exchangeable fluidizing chamber (50), a means (10) for controlling and measuring the air/gas flow to measure the air/gas throughput, placed on the inlet side or outlet side relative to this fluidizing chamber (50), preferably on the outlet side, the measuring error of said means (10) being preferably no more than 5 % based on the air/gas throughput for the measuring range from 0.1 ml/s to 2 1/s when three elements, preferably venturi tubes (20) are used for measuring the volumetric flow rate of the air/gas, and for the measuring range from 0.1 ml/s to 8 1/s when four elements, preferably venturi tubes (20) are used for measuring the volumetric flow rate of the air/gas, a blower (30) as the mobilizing system for the fluidizing air/gas (providing suction or blowing) operating at a low or a high pressure, and optionally a heating/cooling device (51) for the air/gas.

Fluidizing units (120) are independent of each other and may be individually con- trolled, suitably by means of any suitable control device. Thus in each fluidizing unit (120), the temperature and the humidity of the fluidizing chamber (50), the amount of the fluidizing air/gas passing therethrough, the solvent content therein etc. may be individually controlled either manually, semiautomatically or automatically.

The mobility of the particles such as the fluidization and mixing thereof in the chamber may be improved by causing the fluidizing chamber to vibrate using for instance mechanical means, a shaker or ultrasound. In case the scale of the apparatus is small, handling of the material may be assisted or the properties thereof may be modified with an external energy field such as electric field, magnetic field or microwave field using a suitable field device (55).

Air may be introduced into the fluidizing chamber (50) of each fluidizing unit (120), or the medium may be another gas such as nitrogen, carbon dioxide or a mixture of gases containing water vapour or another mixture of gases. A gas contributing to the reaction such as oxygen may also be used as the fluidizing air/gas. The amount and quality of the useful fluidizing air/gas may be controlled; the air or gas having controlled water and solvent contents is obtained from the air/gas treatment unit (130) and may be used for instance for drying and mixing.

In the fluidized bed apparatus (100), each fluidizing chamber (50) may be accurately controlled as a separate thermodynamic system. This is made possible above all by the fact that fluidizing air/gas throughput, moisture or solvent content (0 - 100 %) of the feed air/gas and exhaust air/gas, and additional moisture or solvent feed are known precisely. Suitable solvents are organic solvents such as alcohols, e.g. ethanol, butanol, propanol, and acetone, chloroform and mixtures thereof. If organic solvents are used in the system, a suitable solvent recovery means may then be connected therewith (such as an adsorbent or back distillation of the solvents).

The fluidizing chambers (50) may have identical or different shapes and sizes. The fluidizing chambers (50) need not be symmetrical cylinders, and in some cases it is preferable that they are asymmetric. This improves the mixing of the particles being treated or enables the plastic deformation thereof as they are made to rotate against the wall of the fluidizing chamber (50).

The fluidizing chambers (50) may suitably be made of glass, plastic or metal. The wall material is preferably electrically conducting, and the whole apparatus is earthed. It is also possible not to earth the fluidizing chamber (50), and accordingly, the accu- mulation of charges thereto may be used as a measure of the static charges of the powder. The walls of the metal chamber may be maintained clean for instance with ultrasonic cleaning.

The fluidizing chamber (50) may be connected to the remaining apparatus with connections (58) using conventional technique or preferably with air/gas proof magnetic connections that enable the convenient exchange of the fluidizing chambers (50). The construction of the apparatus may preferably be such that the fluidizing chambers (50) are situated on the operating side, while separated from the air/gas treatment unit (130) and control and measuring means (10) therefor, placed on the technical side.

The state of the apparatus may readily be monitored on-line for instance with fiber optics by mean of a single external instrument (56), such as spectrometrically using NIR, FT-Raman, CCD-Raman and NMR spectrometers. Thus, even very expensive special instruments may be used, since no separate instrument is necessary for each fluidizing unit, but only e.g. sensoring with multiplexer technique is adequate. The sensors of the instrument may be designed to read the measuring signal automatically and successively from each chamber for instance using an optical cable, uniting the data from each chamber with computer technology to their respective files.

In each of the fluidizing units (120), identical or different materials in equal or different amounts may be processed, the amount of the material in the fluidizing chamber (50) of the respective fluidizing unit (120) varying in the range from 1 mg to 500 g, preferably from 1 mg to 40 g, particularly preferably from 0.1 to 20 g per fluidizing chamber (50). The material being processed may be a powdery, particulate, granule, tablet-like, corn-like or grainy material, including natural materials. In each of the fluidizing units (120), identical or different unit operations may be carried out simultaneously. The fluidizing chamber (50) of each of the fluidizing units (120) is connected with:

• an air/gas distributing grid (57) through which the air/gas/vapour fluidizing the material is introduced to the fluidizing chamber,

• a filter (52), through which the air/gas/vapour leaves the chamber, and • optionally a nozzle (54), through which granulating or coating liquid for granulation or coating may be introduced into the fluidizing chamber.

The fluidized bed apparatus (100) of the invention is depressurized or pressurized ac- cording to a method of the prior art to achieve the fluidization. Fluidizing gas or air is introduced into the apparatus optionally directly from the ambient atmosphere or through the air/gas treatment unit (130), the amount and moisture content thereof being controlled accurately to control the surface properties of the particles such as static charges, wetting, drying, recrystallization of the surfaces and fluidization. The air/gas treatment unit (130) comprises a common control chamber (60) and a blower (30), a means (34) for controlling the rotation speed, an additional feed line (32), a control valve (31) and optionally a drying means (61), a cooling means (62), a heating means (63) and a wetting means (64) permitting the full control and regulation of the air/gas entering the treatment chamber independent of the external parameters, thus a separate unit enabling the controlled adjustment of the humidity and temperature values.

The means (10) for controlling and measuring the air/gas flow allows to measure and control the air/gas flow very accurately, reliably and continuously. The means (10) for controlling and measuring the air/gas flow comprises a control means (35) and a volumetric flow metering means (36), situated downstream or upstream relative to this fluidizing chamber (50), preferably both of them being situated downstream of this fluidizing chamber (50). The measuring of the volumetric flow rate of the air or gas may be conveniently carried out with electronic hot wire flow sensor means or devices/means based on static pressure differences such as with an orifice flange or venturi tube, provided that the measuring error for the volumetric flow rate is sufficiently low. At least on the long run, measurements carried out using static meters are generally more reliable, since such meters will not be changed. The precision of hot wire flow sensor means are influenced for instance by the properties of the environment and air/gas being measured, such as the temperature, humidity and contamination thereof.

A preferable (apparatus) means (10) for controlling and measuring the air/gas flow, based on static pressure differences, comprises the following components: a blowing or sucking means (30), a conduit (11) to pass the air/gas to and from the target, preferably several parallel conduits (11), in which the air/gas flow is measured, thus obtaining an apparatus operating in a wide measuring range,

- control means (35) to adjust the volumetric flow rate of the air/gas passing to and leaving the target, means (36) for measuring the volumetric flow rate of the air/gas.

The conduit (11) of the means (10) for controlling and measuring the air/gas flow is connected to at least two, preferably three pressure difference meters (22) operating in a different pressure range. The pressure difference meters (22) are preferably connected in parallel. The pressure difference meters are employed to cover only part of the measuring range thereof. The inaccurate lower end of the measuring range is not used, this pressure difference range being covered with another pressure difference meter having a more suitable measuring range for these values.

The control (apparatus) means (35) to adjust the volumetric flow rate of the air/gas comprises: a blowing or sucking means (30) associated with a means (34) for adjusting the rotation speed and an additional inlet line (32) for air/gas having a control valve (31), and the means (34) for controlling the rotation speed of the blowing or suck- ing means (30), the additional inlet line (32) for air/gas, the closing valves

(12) and the pressure difference meters (22) in parallel of the partial conduits (1 1) of the air/gas streams being arranged to co-operate to measure the desired air/gas flow and to pass it to the target or to remove it therefrom.

The (apparatus) means (36) for measuring the volumetric flow rate of the air/gas comprises at least two parallel partial conduits (1 1 ) to measure the air/gas flow and to pass it to the target or to remove it therefrom, at least some of the partial conduits (1 1) having closing means (12) to close and open the particular partial conduit for passing the air/gas stream either through only a single partial conduit at a time, or simultaneously through two or more parallel partial conduits, respectively, and the partial conduit (1 1) of the air/gas stream is connected to at least two pressure difference meters (22) each operating in a different pressure range.

This is illustrated with example in the following:

The volumetric flow range of the measuring means used as a measuring device of the volumetric flow rate of air/gas, in this case a venturi tube (20), is divided into three partial ranges, three pressure difference meters (22) being connected thereto in paral- lei, having the following measuring ranges and the 0.5 % measuring errors thereof based on the measurable maximum value are: Measuring range Measuring error pressure difference meter no. 1 0 - 50 Pa 0.25 Pa pressure difference meter no. 2 0 - 200 Pa 2.5 Pa pressure difference meter no. 3 0 - 1000 Pa 5 Pa

The measuring errors in the selected operating ranges of the pressure difference meters, at the lower and upper ends thereof, are then as follows:

pressure difference meter no. 1 10 Pa ± 2.5 % - 50 Pa ± 0.5 % pressure difference meter no. 2 50 Pa ± 2 % - 200 Pa ± 0.5 % pressure difference meter no. 3 200 Pa ± 2.5 % - 1000 Pa ± 0.5 %

The maximum measuring error of the volumetric flow rate is thus V2,5 % = about 1 ,6 % for the whole operation range of the venturi tube.

The means (10) for controlling and measuring the air/gas flow preferably comprises at least two parallel partial conduits (1 1) to measure the air/gas flow and to pass it to and from the target, at least some of the partial conduits having closing means (12) to close and open the particular partial conduit (1 1) for passing the air/gas stream either through only a single partial conduit (1 1) at a time, or simultaneously through two or more parallel partial conduits (1 1), respectively, and the partial conduit (1 1) of the air/gas flow being connected to at least two pressure difference meters (22) each operating in a different range.

Due to the fact that the means (10) for controlling and measuring the air/gas flow comprises parallel partial conduits (1 1), the air flow to or from the target may be readily multiplied by opening and closing said partial conduits (1 1), while the air/gas flow rate may however still be measured precisely without the flow resistance or measuring error becoming adversely high in any of the partial conduits.

The means (10) for controlling and measuring the air/gas flow preferably comprises two or more parallel partial conduits (1 1) having different cross-sections. The partial conduits (1 1) having different sizes may be opened separately, thus providing for the air/gas flow to or from the target always a conduit with a desired size. Moreover, the partial conduits having different sizes may be opened in different combinations, thus making it possible to vary even more the total cross-section of the partial conduits (11).

The means may comprise three parallel partial conduits (11) having different cross- sections and having devices for measuring the air/gas volumetric flow rates such as venturi tubes (20), said two measuring devices being connected through measuring conduits to two or more parallel pressure difference meters (22).

In addition, in the means (10) for controlling and measuring the air/gas flow, the devices (20) for measuring the volumetric flow rates of the three partial conduits (11) having a different size are preferably connected through measuring conduits (21) to three parallel pressure meters (22).

Further, the blower or suction means (30) of the means (10) for controlling and measuring the air/gas flow are associated with a means (34) for controlling the rotation speed and an additional feed line (32) for air/gas provided with control valves (31). The means (34) for controlling the rotation speed of the blower or suction means (30), the additional feed line (32) for air/gas, the closing valves (12) and the parallel pressure difference meters (22) of the partial conduits of the air/gas flow are arranged to co-operate to measure the desired air/gas flow and to pass it to or from the target. APPLICATION EXAMPLES

The invention will be illustrated in the following with some examples, referring to the appended drawings wherein:

LIST OF THE FIGURES

Figure 1 shows a schematical presentation of the fluidizing unit of the fluidized bed apparatus of the invention having a means for controlling and measuring the air/gas flow.

Figure 2 shows the operation curves of the means for controlling and measuring the air/gas flow. Figure 3 shows a schematical presentation of the fluidized bed apparatus of the invention having one module for treating material with four fluidizing units.

Figure 4 shows a schematical presentation of the fluidized bed apparatus of the invention having three modules for treating material. Figure 5 shows a schematical presentation of the fluidizing chamber of the fluidized bed apparatus of the invention.

Figure 1 shows a fluidizing unit 120 having a fluidizing chamber 50 being mainly controlled with a means 10 for controlling and measuring the air/gas flow. This controlling and measuring means 10 comprises three partial conduits 11a, l ib and l ie having a different size for the air/gas flow, the partial conduits being provided with closing valves 12b and 12c. Each partial conduit 11a, l ib and l ie comprises a venturi tube 20a, 20b, 20c being connected with measuring conduits 21a, 21b and 21c for pressure difference. The means 10 for controlling and measuring the air/gas flow further comprises a blower 30 provided with a means 34 for controlling the rotation speed, the blower 30 being connected to an additional feed line 32 having a control valve 31.

In this means 10 for controlling and measuring the air/gas flow, the blower 30 provided with a means for controlling the rotation speed, the additional feed line 32 for diluting the air/gas flow, the venturi tubes 20a, 20b and 20c, and the pressure difference meters 22a, 22b and 22c are co-operating to obtain an air/gas stream having a volumetric flow rate precisely controlled in a very wide range. Partial conduits 11a, 1 lb and 1 lc may be used independently of each other or they may be combined to co-operate in various combinations. If always for each volumetric flow the most preferable combination of the venturi tubes (20a or 20a and 20b together or 20a and 20b and 20c together) and the pressure difference meter 22a, 22b and 22c corresponding best to the developed pressure difference are selected, the measuring and controlling precision of the apparatus will stay very good for the whole volumetric flow rate range thereof.

The blower 30 is accompanied with an additional feed line 32 provided with a control valve 31 for optional dilution of the air/gas stream. The apparatus further comprises a heater/cooler 51 and a filter 52.

Figure 2 shows the operation diagram of the means 10 for controlling and measuring the air/gas flow, the abscissa showing the volumetric flow rate V of the air/gas stream passed through one or more partial conduits and the venturi tube, and the ordinate showing the pressure difference. Each of the partial curves A, B and C of the diagram shows the flow situation of one partial conduit combination.

The curve A corresponds to the lower end of the flow range and shows the air/gas stream passed through the smallest or the first partial conduit 1 la, and the pressure difference 20a of the venturi tube. The partial conduit 1 la is always open. The closing valves 12b and 12c of the other partial conduits l ib and l ie are closed. The measuring channels 21a starting from the venturi tube 20a are then connected with pressure difference meters 22a, 22b and 22c.

The air/gas flow VI at the lower end of the volumetric flow curve A is very low, even as low as 0.05 ml/s. To produce such a low air flow, the rotation speed of the blower 30 is only a fraction of its maximum value and also the control valve 31 of the additional feed line 32 is nearly open. As the rotation speed of the blower 30 is raised and the air/gas flow increased along the curve A upwards from the pressure value pi, the precise measuring range of the first pressure difference meter 22a ends at the latest at the pressure p3. The measuring is then taken over by the pressure difference meter 22b having a precise measuring range varying between the pressure p2 upwards to the value of p5. Similarly, the measuring is then taken over by the pressure difference meter 22c to raech the upper end of the curve A, corresponding to a volumetric flow rate V2 of e.g. 30 ml/s.

Thereafter, the combination of the partial conduits is changed by opening the closing valve 12b of the next, bigger partial conduit l ib, in addition to the partial conduit 11a. The air/gas now passes simultaneously through both of the partial conduits 21a and 21b to a common air channel and further for instance to a fluidizing apparatus.

The rotation speed of the blower 30 is dropped and the control valve 31 of the additional feed line 32 is opened to again achieve a sufficient dilution of the air/gas stream, thus moving along the curve B upwards. First the meter of the lowest pressure difference is read, ascending along the curve B in a similar manner as for the curve A. The rotation speed of the blower is slowly increased with a frequency modulator, and as the pressure difference increases, the measuring is again taken over by the next pressure difference meter. Further switching to the curve C happens correspondingly, the same steps being carried out therefor. In this manner the volumetric flow rate may be controlled and measured very accurately in a wide range.

Figure 3 shows a module 1 10 for treating materials, comprising four fluidizing units 120a - 120d connected together, all of them having the means 10a - lOd according to Figure 1 for measuring and controlling the air/gas flow and fluidizing chambers 50a- 50d. Process gas such as air is introduced to the fluidizing units 120a - 120d through a common line 66 optionally from the unit 130 for treating air/gas 130, whereas in some cases air from the ambient atmosphere may be used.

Figure 4 shows a fluidized bed apparatus 100 having three modules 110a- 110c for treating materials, each of them having four fluidizing units 120a - 120d according to Figure 1 and each of them having the means 10a - lOd according to Figure 1 for measuring and controlling the air/gas flow, respectively. Fluidizing gas/air is is intro- duced to the modules 1 lOa-1 10c for treating materials through lines 66a-66c from the unit 130 for treating air/gas 130 having a control chamber 60, blower 30 and the control means 34 of the rotation speed, additional feed line 32, control valve 31, filter 52, dryer 61, cooler 62, heater 63 and wetting means 64, by means of which the precisely defined desired conditions may always be provided in all fluidizing units 120. This is important with respect to reproducible experiments.

Figure 5 shows a fluidizing chamber 50 connected to one or more field device(s) 55, one or more external instrument(s) 56 and a nozzle 54 for a granulation and coating liquid. In addition, the chamber comprises a distribution grid 57 for air and connect- ing elements 58.

The volumetric flow rate measuring unit of the means for controlling and measuring the air/gas flow of the fluidized bed apparatus according to the invention preferably comprises two or more parallel conduits provided with a flow rate meter such as a venturi tube or another flow rate meter preferably based on the measurement of the pressure difference, said lines being provided with valves enabling the selection of the conduit through which the air/gas is passed, the venturi tubes or other sensors provided at least in two conduits being connected to at least one or two, preferably to three pressure difference transmitter(s) operating in a different pressure difference range. Since there are several parallel conduits, the flow rate range measured by one conduit may be rather narrow. Thus, each separate channel is very precise. The whole fluidized bed apparatus is made very precise in a wide operating range by connecting thereto a sufficiently high number of parallel conduits.

The pressure difference measuring the flow rate is measured in the fluidized bed apparatus in a conduit, in which the pressure difference stays in a preferable range for the pressure difference meters used. If the gradual sizing of the conduits and venturi tubes connected thereto is suitable, then the measured pressure range of the pressure meters used for the conduits may be selected, by closing and opening the valves in the conduits, to lie in the most percise range of the meter. The fluidized bed apparatus may thus be extremely precise even in a very wide flow rate range.

The fluidized bed apparatus according to the invention is useful for carrying out the following operations:

• mixing of powders, granules, pellets or other particles,

• drying of powders, granules, pellets, tablets or other particles,

• wetting of powders, granules, pellets, tablets or other particles,

• control of the surface properties of powders, granules, pellets, tablets or other particles, by utilizing the adsorption in gas phase or vapour phase,

• coating of powders, granules, pellets, tablets or other particles by spraying a suitable coating liquid into the treatment chamber, • agglomeration of powders or other particles to form granules by spraying a suitable granulating liquid into the treatment chamber.

A single operation at a time may be carried out in the fluidized bed apparatus of the invention, for instance drying in each fluidizing unit thereof, or different operations such as coating, granulation and drying may be run simultaneously in different fluidizing units.

Scale changes are possible and the amount of the material being processed may vary in ratio of 1 :20 in each fluidizing unit of the apparatus. It is crucial to be able to perform scale changes while the precision and the apparatus are still the same, thus avoiding the need to change apparatuses and the problems associated thereto. Accordingly, scale-up experiments may be carried out in the same basic apparatus.

In this respect, the apparatus is not limited to a small scale, but the amount of the material may vary considerably in each modular apparatus owing to the precise control of the air or gas flow.

In case the air/gas flow and properties are under control, then • mixing without breaking the particles

• wetting and drying of the particles

• partial dissolution of the surface and recrystallization may be performed in a precisely controlled manner.

In case very high heating rates or drying rates or cooling rates are desired, it is necessary to use a scale that is as small as possible (batch size from 0.1 to 20 g per fluidizing chamber). Then, droplets of the granulation and coating liquid are generally formed without pressurized air, for instance by means of ultrasound waves or high pressure. The formation of droplets may, however, be performed utilizing a suitable shape of the chamber (for instance a cylinder broadening very slightly) and pressurized air. In apparatuses having a larger scale, the droplet formation may be readily carried out by spraying with pressurized air.

Also a closed circuit may be used in one or more chambers of the apparatus. Moreover, vacuum may be used in one or more chambers of the apparatus.

Fluidization may be monitored visually, with pressure difference measurements and with video camera technique.

The apparatus is very versatile enabling rapid and effective performance of powder technological processes. Some powder technological processes suitable for the apparatus of the invention are described below in more detail.

Use of the apparatus for drying

In the apparatus, controlled drying of a material such as wet granules may be carried out by using air/gas flowing therethrough, the air/gas being optionally heated with microwaves by means of an external microwave field or with another energy source, or by using a combination of heated/non-heated air/gas and an external energy source. For the controlled drying of a wet granule mass it is necessary that the succesive treatments of said granule mass are as identical as possible. This is not possible with the apparatuses of prior art, whereas the apparatus of the invention is excellently suited for such identical treatments. Exact control of the temperature, air or gas flow and moisture content guarantees the desired drying result. Use of the apparatus for controlling surfaces

To obtain a desired adhesion, surface charge humidity, and the like, carrier of charges or a surface active agent is introduced with the fluidizing air/gas. Wetting is performed either by spraying or with adsorbing vapour. Saturated vapour (water or a suitable solvent) is adsorbed by the surfaces of the powder particles, thus causing micro level dissolution. Thereafter, a quick drying for instance with microwaves recrys- tallizing the material is carried out. As a result, the quality of the powder surface, for instance for flowability is improved, the particle size of the powder remaining, however, substantially unchanged. The process may be reproduced step by step. The apparatus and method of the invention may thus be used for instance to produce the particles needed for inhalation medication.

Use of the apparatus for wetting

The material being treated may be wetted with a suitable liquid. Wetting may be achieved by producing moisture in vapour form among the air/gas throughput, or by spraying moisture directly to the fluidizing chamber. Both wetting methods may also be used together.

Use of the apparatus for coating

If the spraying rate of the liquid is sufficiently low and the size of the droplets being formed during spraying is suitable and the temperature of the air/gas passed through is sufficiently high, the particles will not adhere to one another, but the material being treated is coated. The material being coated may be powdery, granular material or a single tablet or pellet. Use of the apparatus for mixing

Mixing of materials is achieved by passing air/gas therethrough, while shaking the apparatus to make the mixing more effective.

Use of the apparatus for granulation

The apparatus of the invention may be used to granulate powdery material first by carrying out wetting/spraying with granulating liquid or coating liquid and then dry- ing by elevating the temperature of the incoming air/gas or using microwaves or another external energy source. Especially in apparatuses having a small scale, the processes may be readily run in a cyclic manner, that is by repeating the procedure several times. Granulating liquid such as water, aqueous solution of polyvinyl pyr- rolidone or another known granulating liquid is introduced into the fluidizing cham- ber using a suitable dispersion method.

In the fluidized bed apparatus of the invention, any of the above methods for treating material may be associated to each fluidizing unit.

Method of the invention

The method of the invention is directed to the processing of materials in the fluidized bed apparatus of the invention. According to said method, in said fluidized bed apparatus, one or several unit operations are carried out simultaneously, the amount of the material being processed varying in the range from 1 mg to 500 g, preferably from 1 mg to 40 g, and particularly preferably from 0.1 to 20 g per fluidizing chamber, the error of the air/gas flow measurement is preferably below 5 %, and the temperature of the air/gas being controlled with an accuracy of ± 3 %. The operation temperature of the processes is preferably between 10 °C and 90 °C, and the temperature change may be achieved even in 10 seconds. Said unit operations are selected from the group consisting of the following basic processes: drying, mixing, wetting, control of the surfaces, granulation and coating. Said material being treated may be powdery, gran- ule or finely divided material or small separate pieces like tablets. Said material may be porous, sponge-like or solid and may have a regular or irregular shape. The method is particularly suited for the processing of drugs, other biologically active agents, intermediates, pharmaceutical adjuvants, drugs for inhalation, proteins, pep- tides, oligonucleotides, pesticides, fertilizers, and active agents of functional food products, and food additives.

Advantages of the apparatus and method of the invention

The modularity and versatility of the apparatus of the invention are provided by the above solution for measuring and controlling the air/gas flow. This fluidized bed apparatus operating in wide measuring and operation ranges as well as apparatuses and processing methods for special applications for very small batch sizes are obtained by utilizing the above means for controlling and measuring the air/gas flow, having several parallel air/gas passages wherein the volumetric measuring of the air/gas flow takes place. A small size of the apparatus is a special advantage at the beginning of the drug research when the new substance is not yet available in substantial amounts or the substance is so expensive or the biological activity thereof is so high that it is in practice never available in such high amounts as several kilograms.

The precise controllability of the process is a substantial feature of the present invention. In the apparatus, it is possible to control accurately:

• the air/gas flow rate

• the air/gas temperature • the water or other solvent content of the air/gas.

Moreover, in successive treatments are known and reproducible:

• the water or other solvent content of the material being treated • the mobility of the material

The apparatus is very versatile and allows a quick and effective running of several powder technology processes. Further, due to the small size of the apparatus, the quality of the material being treated is always constant.

The modular character of the apparatus enables the running of high sample amounts and the quick generation of extensive testing charts, which is not possible using an apparatus with a single unit. Moreover, scaling-up runs may be carried out quickly and simultaneously (in parallel treatment units, batches of e.g. 0.5, 2, 10 and 20 grams may be readily run at the same time). It is also substantial, that there may be several small scale units operating independently. These units are automatically controlled by a computer. If necessary, the processes may be monitored via Internet in any place with an Internet connection.

The modularity and precise controllability of the apparatus may be utilized in processes: by using an apparatus having several small scale treatment units, it is easy to design a testing arrangement for testing the effects of for instance several process variables (such as temperature and gas flow rate) and/or material parameters (such as the particle size, polymorphic form, moisture content of the material) on the proper- ties of the material being processed.

Further, the modularity and the precise operation of the apparatus make it possible to carry out parallel experiments easily and quickly in separate treatment chambers. If the state of all of the treatment chambers is accurately known, then experiments carried out in different chambers may be used as reproductions of each other.

A small treatment chamber for materials may readily be surrounded by a functional and homogenous external (static or dynamic) magnetic field, external electric field and a microwave field provided with an external magnetron. The homogeneity of an external field - being easily generated in a small scale - always ensures the identical physical state of the materials being produced, and accordingly, the basic properties thereof (crystallinity, solubility, dissolution rate, surface structure) are sufficiently identical. The molecular orientation of the materials being processed (drying) and thus the properties thereof may be influenced by a magnetic and electrical fields. Using a fluidizing chamber having a diameter below 20 mm, it is possible to readily generate a homogenous magnetic field having a sufficient magnetic flux density, preferably at least 0.5 Tesla. The behaviour of all polar molecules may be influenced by a microwave field. The effect may not only be seen as an improved volatility of a polar solvent, but also as a control of the disorder of even weakly polar molecules in a solid dry phase. It is thus possible to endow the drying (and partly crystallizing) materials with ideal solubility characteristics.

In case the batch size of the material being treated is small, it is easy to carry out an extremely quick drying of partly moist material using microwaves, which is not possible in large scale apparatuses.

Preformulation studies as well as stability and compatibility studies and drying of granule samples may also be performed using a small batch size. The behaviour of substances may be modelled in large scale apparatuses using a small batch size in cases the substance is not available in high amounts. The small size will accelerate the process bringing about savings in space, material and operation costs like e.g. energy savings. The homogeneity of the chamber space and accordingly, the constant quality of the product obtained are made possible by a small fluidizing chamber and low material amounts used. The small size further allows a very quick and precise modification of the conditions of said fluidizing chamber such as the temperature, solvent content, surface moisture thereof, and the like. Treatment of materials that has so far been impossible in large apparatus may now be performed.

Using a small batch size in the treatment, it is possible to attain quick changes of the conditions in the fluidizing chamber. As a result of the small batch size, the condi- tions in the whole chamber (temperature, humidity, mean impact energy of the particles) are very identical. Such a state is in principle not achievable if high material amounts are used.

In a small apparatus, the distribution of the momentum of the particles is narrower, and the path the particle may move without collision to other particles is much shorter than in larger apparatuses. Thus the erosion of individual particles is less pronounced during the process than in larger apparatuses. It has been found out that the erosion of the particles for instance during drying tends to ruin the flow characteristics of the whole particle population in the apparatuses of prior art.

As a result of the small batch size of the material being treated, for instance heating, cooling and mixing of the material may be carried out much faster in the apparatus of the invention than in apparatuses needing a large batch size. With a quick, precisely controlled heating or quick cooling it is possible to endow the material being treated with new kinds of positive properties. For instance quick cooling produces amorphous structure, and thus the solubility and the dissolution rate of the material are higher compared to a fully crystalline material. The apparatus of the invention will now be illustrated with the following example, without intending to limit the invention thereto.

Example 1

For instance with an apparatus having 12 modules (12 treatment chambers), the following testing arrangements, among others, may be carried out, the testing variables being e.g. the compositions of the materials being treated or process conditions or both.

1) Two variables may be varied on two value levels (4 tests) and the third variable on three value levels.

2) Testing diagram of three variables on two value levels (8 tests), and thereafter, still 4 tests may be used for test repetitions.

3) It is also possible to perform a complete testing arrangement of two variables on three value levels (9 tests), and 3 tests may be used for test repetitions (for instance for mid- point repetitions)

4) Correspondingly, a Central Composite Desing -testing diagram of two variables may be performed.

5) Mixture Desing -testing diagram of three substances (1 1 tests + 1 test repetition). In this case, only material amounts serve as variables.

Each treatment chamber operating with a respective control, a process may be started and finished without interfering with the operation of the other chambers. Thus, a cyclic operation may be carried out quickly and effectively. A small size is a significant advantage in certain applications, since quick and precisely controlled changes may then be provided keeping all particles of the powder in the treatment chamber under very similar temperature, humidity and the like conditions. If for instance local temperature or humidity differences exist in the system, then there is a great risk for the treated material to be endowed with properties unacceptable for use. The precise control of the powder state is necessary when treating thermally sensitive substances such as peptides. Correspondingly, precise control of humidity is a requirement when treating hygroscopic substances.

Small size allows very quick heating, drying and cooling. Thus, the temperature, solvent content or for instance surface humidity of the material being treated may be quickly and accurately controlled. It is also possible to carry out the treatments in a cyclic manner. Thus, for instance cyclic coating may be performed. For instance, the material batch being treated is coated for 15 seconds. Thereafter, a quick drying of 15 seconds is carried out either by elevating the temperature of the incoming gas/air or by using a microwave field. For instance 10 such coating-drying cycles may be readily combined.

Owing to the small size, for instance an external microwave field with necessary protection measures may be easily combined to the apparatus. A strong homogenous magnetic field may be applied to the apparatus. The apparatus may be subjected to an external continuous or suitably oscillating microwave or magnetic field.

It is clear to those skilled in the art that various embodiments of the invention may be modified without departing from the scope of the appended claims. Reference number listing

10 a means for controlling and measuring the air/gas flow

11 conduit

12 closing valve

20 elements for measuring the volumetric flow rate of the air/gas, preferably a venturi tube

22 pressure difference meter

30 blower

31 control valve

32 additional feed line

34 means for controlling the rotation speed

35 control device

36 means for measuring the volumetric flow rate

50 fluidizing chamber

51 heater/cooler of air/gas

52 filter

54 nozzle

55 field device

56 measuring device

57 air/gas distribution grid

58 connection

60 control chamber

61 dryer

62 cooling means

63 heating means

64 wetting means

100 fluidized bed apparatus

110 module for treating materials 120 fluidizing unit

130 air/gas treatment unit

Claims

1. Fluidized bed apparatus (100), characterized in that said fluidized bed apparatus (100) comprises one or more module(s) (110) for treating materials and an optional air/gas treatment unit (130), each module (110) for treating materials containing 1 - 32, preferably 1 - 16 and particularly preferably 2 - 4 fluidizing units (120) operating independently and each fluidizing unit (120) comprising an integrated or exchangeable fluidizing chamber (50), a means (10) for controlling and measuring the air/gas flow, said means being an electronic hot wire sensor device or a device based on a static pressure difference, and optionally a heating/cooling means (51) for the air/gas.

2. Fluidized bed apparatus (100) of Claim 1, characterized in that from 1 to 5, preferably from 1 to 3 module(s) (110) for treating materials is/are connected to the air/gas treatment unit (130).

3. Fluidized bed apparatus (100) of Claim 1 or 2, characterized in that said means (10) for controlling and measuring the air/gas flow comprises: a blower or sucking means (30),

- a conduit (11), preferably at least two parallel conduits (11), - control means (35),

- means (36) for measuring the volumetric flow rate of the air/gas.

4. Fluidized bed apparatus (100) of Claim 3, characterized in that in said control means (35) of the air/gas flow: - the blowing or sucking means (30) are associated with a means (34) for adjusting the rotation speed and an additional inlet line (32) for air/gas having control valves (31),

- and the means (34) for controlling the rotation speed of the blowing or sucking means (30), the additional inlet line (32) for air/gas, the closing valves (12) of the partial conduits (11) of the air/gas streams and the measuring element for volumetric rate (20) in parallel are arranged to co-operate to measure the desired air/gas flow and to pass it to the target or to remove it therefrom.

5. Fluidized bed apparatus (100) of Claim 3 or 4, characterized in that the means (36) for measuring the volumetric flow rate of the air/gas comprises at least two parallel partial conduits (11) to measure the air/gas flow and to pass it to the target or to remove it therefrom, at least some of the partial conduits (11) are provided with closing means (12) to close and open said particular partial conduit for passing the air/gas stream either through only a single partial conduit at a time, or simultaneously through two or more parallel partial conduits, respectively, - and the partial conduit (11) of the air/gas stream is connected to at least two pressure difference meters (22) each operating in a different pressure range.

6. Fluidized bed apparatus (100) according to any of the Claims 1 - 5, characterized in that the amount of the material being processed varies in the range from 1 mg to 500 g per fluidizing chamber (50), preferably from 1 mg to 40 g per fluidizing chamber (50), particularly preferably from 0.1 to 20 g per fluidizing chamber (50), the ma- terial being identical or different in each of the fluidizing chambers (50), and the amount of the material being equal or different in each of the fluidizing chambers (50)

7. Fluidized bed apparatus (100) according to any of the Claims 1 - 6, characterized in that the measuring error of said means (10) for controlling and measuring the air/gas flow is no more than 5 % based on the air/gas throughput for the measuring range from 0.1 ml/s to 2 1/s when three measuring elements (20) are used, and for the measuring range from 0.1 ml/s to 8 1/s when four measuring elements (20) are used.

8. Fluidized bed apparatus (100) according to any of the Claims 1 - 4, characterized in that each of the fluidizing units (120) comprises at least one fluidizing chamber (50) connected to:

- an air/gas distributing grid (57), through which the air/gas/vapour fluidizing the material is introduced to the treatment chamber, a filter (52), through which the air/gas/vapour leaves the chamber, and optionally a nozzle (54), through which granulating or coating liquid for granulation or coating may be introduced into the fluidizing chamber, optionally one or more measuring device(s) (56), - optionally one or more field device(s) (55).

9. Method for processing material with the fluidized bed apparatus (100) according to any of the Claims 1 - 8, characterized in that in said fluidized bed apparatus (100), one or several unit operations are carried out simultaneously the amount of the mate- rial being processed varying in the range from 1 mg to 500 g, preferably from 1 mg to 40 g, particularly preferably from 0.1 to 20 g per fluidizing chamber, the materials in each of the fluidizing chambers being identical or different, and the amounts thereof in each of the fluidizing chambers being equal or different.

10. Method of Claim 9, characterized in that said unit operation is selected from the group consisting of: drying, mixing, wetting, control of the surfaces, granulation and coating.

11. Method of Claim 9 or 10, characterized in that said material is powdery, granule or finely divided material or small separate pieces.

12. Method according to any of the Claims 9 - 11, characterized in that said material is porous, sponge-like or solid and has a regular or irregular shape.

13. Method according to any of the Claims 9 - 12, characterized in that said material is selected from a group consisting of drugs, other biologically active agents, intermediates, pharmaceutical adjuvants, drugs for inhalation, proteins, peptides, oligonu- cleotides, pesticides, fertilizers, and active agents of functional food products, and food additives.