EP2101131A1 - Gefriertrocknungsverfahren sowie System dafür - Google Patents

Gefriertrocknungsverfahren sowie System dafür Download PDF

Info

Publication number
EP2101131A1
EP2101131A1 EP07425840A EP07425840A EP2101131A1 EP 2101131 A1 EP2101131 A1 EP 2101131A1 EP 07425840 A EP07425840 A EP 07425840A EP 07425840 A EP07425840 A EP 07425840A EP 2101131 A1 EP2101131 A1 EP 2101131A1
Authority
EP
European Patent Office
Prior art keywords
particles
equipment
nebulization
mixture
chamber
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP07425840A
Other languages
English (en)
French (fr)
Inventor
designation of the inventor has not yet been filed The
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Terruzzi Fercalx SpA
Original Assignee
Terruzzi Fercalx SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Terruzzi Fercalx SpA filed Critical Terruzzi Fercalx SpA
Priority to EP07425840A priority Critical patent/EP2101131A1/de
Publication of EP2101131A1 publication Critical patent/EP2101131A1/de
Ceased legal-status Critical Current

Links

Images

Classifications

    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
    • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
    • F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
    • F26B5/065—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing the product to be freeze-dried being sprayed, dispersed or pulverised

Definitions

  • the object of the present invention is a lyophilization method for substances such as, in general, food or pharmaceutical substances and, in particular, a method for the continuous lyophilization of said substances.
  • the invention relates to a system for the production of lyophilized substances which is designed such as to be capable of being operated in an essentially continuous manner.
  • any lyophilization method is carried out by following a batch operational scheme.
  • the lyophilization comprises a deposition step of a solution or suspension into special vessels, called trays, so as to form a layer having a thickness which can range between 1 and 3 cm in relation to the substance to be lyophilized.
  • the trays content is deep-frozen at temperatures usually ranging between -40° C and -60° C, according to the type of product to be processed.
  • the cryostatic stability Once the cryostatic stability has been reached, one starts to generate a micrometric vacuum and, concomitantly, to supply heat to the frozen mass which is contained in the trays.
  • the heat is conventionally provided by means of thermostated plates which the trays rest on.
  • the heat supplying step to the trays is of crucial significance, since it must take place in an accurately controlled manner so as to ensure the vehicle substance sublimation, without affecting the molecular structure of the substance of interest.
  • the sublimation beside depending on the known intrinsic characteristics of the product to be processed, also depends on external factor, such as the heat conduction from the tray bottom plate and, therefrom, to the product, on the heat radiance from a plate towards the inferiorly arranged tray, and on the heat conduction inside the product to be processed or, in other terms, on the particle-to-particle heat transmission between those particles which are contained in the trays.
  • the latter condition is particularly slow due to the particle arrangement on the trays plane which undergoes the heating.
  • the trays are so shaped as to contain a solution or suspension layer to be processed having a reduced thickness (1 to 3 cm), in any case, due to the slow heating process, the heat takes a considerable period of time in order to pass through said thickness and cause the vehicle substance sublimation in all the particles, also in those which are immersed in the solution or suspension, that is those particles which are far both from the bottom and the surface of the tray. All these conditions make the duration of the lyophilization operation possibly ranging between 12 and 24 hours.
  • the whole process is further burdened with batch operations such as the restoration of the atmospheric pressure conditions in the freeze-dryer, with optional heating of the substance of interest to a near-room temperature to recover the lyophilizate from the equipment without damaging it, the trays drawing from the lyophilization chamber, and the discharge of the lyophilizate they contain into special vessels intended for a successive processing, the cleaning of each tray, of the lyophilization chamber, and the plates, as well as the waiting time for the unfreezing of the condensers for successive operations.
  • batch operations such as the restoration of the atmospheric pressure conditions in the freeze-dryer, with optional heating of the substance of interest to a near-room temperature to recover the lyophilizate from the equipment without damaging it, the trays drawing from the lyophilization chamber, and the discharge of the lyophilizate they contain into special vessels intended for a successive processing, the cleaning of each tray, of the lyophilization chamber, and the plates, as well as the waiting time for the unfreezing of the condensers for successive operations.
  • the technical problem underlying the present invention is to devise a lyophilization method which allows considerably accelerating the production times, while allowing simplifying the processing steps as well as the production equipment.
  • a first object of the present invention is a continuous lyophilization method for substances such as food, flavours, and pharmaceutical industry products.
  • a second object of the invention is a system for the continuous production of lyophilized substances.
  • the thought underlying the present invention is the observation that, in order to be able to considerably increase the lyophilization process productivity, it is important to intervene during the heating step of the frozen products. In fact, as previously mentioned, this step is particularly crucial and slow.
  • mixture is meant both a homogeneous liquid phase and a suspension liquid phase, in other terms, it indicates both a solution and a suspension.
  • the method in accordance with the invention comprises the following consecutive steps:
  • the mixture which has to undergo the inventive method can be any mixtures which are usually employed in a lyophilization method.
  • the mixture can be a solution or a suspension of one or more pharmaceutical, food, cosmetic substances, fragrances, preservatives, substances for veterinary or agronomic use.
  • the mixture can be a solution or suspension of substances such as: antibiotics, enzymatic derivatives, fruit juices, natural extracts, substances in a vehicle substance, such as the commonest solvents, for example, water, alcohols, aromatic derivatives.
  • substances such as: antibiotics, enzymatic derivatives, fruit juices, natural extracts, substances in a vehicle substance, such as the commonest solvents, for example, water, alcohols, aromatic derivatives.
  • the mixture is provided under stirring before the nebulization step, so as to keep the best homogeneity possible during all the drawing time for the nebulization.
  • the lyophilized end product can continuously ensure a high degree of homogeneity.
  • the method of the invention can further comprise a pre-cooling step before undergoing the nebulization.
  • Aim of this step is to decrease the mixture temperature by bringing it nearer to that of start freezing at the cost of the cold nitrogen gas stream exiting the freezing chamber, resulting in an energetic recovery.
  • said step will be performed by means of a recovery chamber in which the mixture supply tube is lapped by the exiting nitrogen gas stream, as it will be better described herein below with reference to the equipment.
  • the nebulization step can be carried out also through any one of the methods which are known in the art. For example, it can be carried out by nozzle nebulization with spraying through compressed gas, nebulization through rotating dynamic heads where small toothed rotor and stator turbines cause the dispersion as droplets of the liquid passing through the gaps of the toothing (the more the cutting actions for each rotation of the turbine, the smallest the droplets), or sonic or ultrasonic energy nozzles in which a ultrasonic head, such as the one manufactured by the Austrian firm DUMAG, comprises a resonance chamber which is passed through by a spraying compressed gas while exerting a variable pressure power at the typical 20 KHz frequency, so as to atomize the liquid into micrometric droplets.
  • a ultrasonic head such as the one manufactured by the Austrian firm DUMAG, comprises a resonance chamber which is passed through by a spraying compressed gas while exerting a variable pressure power at the typical 20 KHz frequency, so as to atomize the liquid into micro
  • atomizers may be employed such as those described in the U.S. patent 5,707,636 , herein incorporated by reference in its entirety. Briefly, the atomizer exploits the vibrations of resonant metallic members, or suitable nozzles, so as to produce droplets having a diameter ranging between 5 and 500 microns.
  • resonant metallic members or suitable nozzles, so as to produce droplets having a diameter ranging between 5 and 500 microns.
  • Such members may comprise an axially-perforated nozzle, a member without nozzle with an angulated reflecting end, a member with vibrating planar plate.
  • the freezing step can be implemented in accordance with any one of the technologies which are known to those of ordinary skill in the art.
  • the freezing takes place by free fall of the mixture droplets inside a freezing chamber, during which said droplets are hit, usually countercurrently, by a cooling fluid.
  • the most commonly used cooling fluid is, without limitations, the nitrogen gas which is employed at a temperature of about -60° C.
  • gases for cryogenic system can be suitable to this aim, such as, for example, CO 2 .
  • the treatment must be carried out so as to allow the formation of solid particles having discrete dimensions in which one or more substances to be lyophilized and one or more vehicle substances to be sublimed are contained, according to the type of mixture which has been prepared for the lyophilization treatment.
  • the particles which have to be produced will also depend on the nebulization step which, as previously explained, can take place in accordance with conventional nebulization or atomization methods.
  • the frozen particles being composed by constituents which not necessarily are spherical, and small enough to ensure, in the successive heating step for the sublimation, an increase of the heating speed inside each member compared to the heating speed inside the solution or suspension layer which is usually deposited on the conventional trays.
  • the sublimation step can be carried out with any one of the conventional methods.
  • the discrete solid frozen particles fall by gravity inside a chamber under high vacuum and are passed through by thermal and/or electromagnetic energy, so that, upon falling, the particles are invested with a suitable energy dose such as to induce the heating and, therefore, the vehicle substance sublimation without damaging the molecular structure of the substance of interest.
  • the sublimation can take place horizontally on the conventional trays, or within structures which are designed so as to further accelerate the sublimation method, as it will be explained herein below.
  • the particles are subjected to a suitable heating in a sublimation, or lyophilization, chamber under high vacuum.
  • the first one consists in the free fall, under the action of the force of gravity only, the discrete frozen particles along the cavity of the lyophilization chamber, and recovering the lyophilized product essentially consisting in said at least one substance of interest on the same chamber bottom.
  • the second approach consists in the treatment of the particles along a guided vertical path in which the particles slide on a sloped plane under the action of the force of gravity.
  • the inner part of the lyophilization chamber will be provided with a guided path for the particles which is such as to increase their residing time therein.
  • the advantage of such approach is to ensure a higher degree of lyophilization, moreover for those particles which comprise substances which are particularly slow to be sublimed.
  • the third approach provides for a treatment which takes place also along a vertically guided path, but, in addition, such path undergoes a vibration in order to allow a higher agitation for the particles and, therefore, to further promote the same particles exposure to the heated and vacuumed environment, thus still improving the sublimation extent.
  • a first approach simply consists in the exploitation of the conventional technology, that is the lyophilization chambers in which the products to be processed are deposited on the trays.
  • the sublimation statically occurs on a horizontal plane.
  • the treatment can be carried out by sliding on a sloped plane so as to reduce the thickness of the product to be sublimed, in order to promote the exposure of the particles to the heat source and to the vacuum.
  • Such solution will be able to be efficiently adopted when particularly flowable or rotatable particles must be processed.
  • a further variation can be represented by a sliding and vibrational treatment in which the particles, beside sliding or rotating down along a more or less sloped plane, are also subjected to a vibrational motion, so as to make the particles jump upon sliding along the plane.
  • the advantage conferred by this variation is the fact that the particles are subjected to an agitated motion, which causes the continuous turnover thereof in order to avoid their build-up and ensure the maximum exposure to the heat of the whole surface of the particles.
  • the vehicle substance is dammed inside the particle structure, the more is the exposure extent of the particle to the heated environment, or, in other terms, the less is the obstacle on the particle surface, the higher is the possibility or ease to come out from the same particle.
  • a further variation is represented by a treatment on a conveyor belt which the particles are deposited on.
  • This variation has the advantage to be able to very easily adjust the residing time for the lyophilization, in the event that the sublimation is particularly troublesome.
  • a system for the production of lyophilized substances is indicated with the reference numeral 1.
  • the system 1 comprises a nebulization or atomization and freezing equipment 2 of a mixture comprising at least one substance to be lyophilized, and at least one vehicle substance to be sublimed, which is coupled to a lyophilization equipment 3 of the particles produced by said nebulization or atomization and freezing equipment so as to essentially continuously perform a lyophilization.
  • the nebulization and freezing equipment 2 can be any equipments which are known in the art such as, for example, the one which is described in the previously mentioned U.S. patent.
  • the nebulization and freezing equipment 2 comprises a closed container 22 equipped with an inlet 20 to allow the inlet of a mixture of substance to be processed, and an outlet 21 to discharge the mixture transformed into fine frozen droplets.
  • the equipment 2 further comprises a nebulization or atomization device 23 so arranged at said inlet 20 as to receive the mixture and continuously dispense it inside the container in the form of minute droplets.
  • the device 23 can be represented by any nebulizing or atomizing nozzle which is known in the art.
  • the vessel 22 can be arranged along a vertical axis X-X, as represented in Fig. 1 , so that the freezing of the droplets produced by the nebulizer or atomizer 23 can occur simply by falling.
  • the container 22 may comprise therein a path (not shown) along which the droplets are constrained in order to extend the residing time thereof in the nebulization and freezing equipment 2, thus promoting a better freezing degree or, anyhow, allowing a more accurate checking for the method.
  • the path can be represented by a helical plate on which the mixture droplets are sprayed which slide upon the plane thereof, while being run over by the cooling fluid.
  • a helical plate can be subjected to a vibration, so as to stir the droplets during the fall thereof in order to allow a homogeneous freezing extent for each droplet.
  • Vibrating means (not shown) allowing such agitation can be represented by conventional vibrating means which confer a sussultatory movement with longitudinal and vertical component to the plate, so that the material is induced to go forward and, concomitantly, to vertically jump.
  • the vibrating means will typically comprise, without limitations, an eccentric driving system.
  • Such vibrating means can be omitted in the case that the mixture to be frozen turns out to be easily processable.
  • the nebulization and freezing equipment 2 may comprise a recovery chamber (16).
  • the recovery chamber is a kind of jacket covering a variable length of the mixture feeding line, as already described, having the function to recover the cooling gas and sending it along the feeding line in order to pre-cool the mixture to be frozen.
  • a conventional system for an even distribution of the cooling gas in the chamber 22 beneath can be provided.
  • the lyophilization equipment 3 may comprise, as illustrated in Figs. 1 , 2A, and 2B , a container or chamber 30 which extends along a horizontal axis Y-Y inside which handling means 31 for the frozen particles to be processed are housed.
  • the handling means 31 can comprise a support 32 which the frozen particles coming from the nebulization and freezing equipment 2 are discharged on.
  • a support 32 which the frozen particles coming from the nebulization and freezing equipment 2 are discharged on.
  • Such support can be composed, as represented in Fig. 2A , by one or more trays 33 suitably shaped and arranged in series upon handling, for example, by a conveyor belt 34.
  • the support can be a single plane with adjustable sloping (not shown) which extends almost for the entire container 30 length so as to receive the frozen particles at a first end and let them slide towards the opposite end, simply under the action of gravity.
  • the support 32 can be subjected to a vibration, thanks to vibrating means 35 which confer a sussultatory movement with longitudinal and vertical components to the receiving and transporting surface 36 of the frozen particles of said support, so that the material is forced to go forward and, concomitantly, to vertically jump.
  • the vibrating means 35 will typically comprise an electromagnetic transmission system or an eccentric transmission system similar to the one described with reference to the nebulization and freezing equipment 2 helical plate.
  • the equipment 300 comprises a container 310 similar to that of the equipment 3, but arranged along a vertical axis Z-Z.
  • handling means 311 comprising a support 321 which extends essentially along the whole container so as to support the frozen particles during the fall thereof are housed inside said container.
  • Such support can be a helical plate.
  • Such plate also can be handled by vibration, as previously explained in order to advantageously improve the lyophilization treatment quality.
  • the vibration which is conferred to the particles by vibrating means allows exposing the individual particles as more as possible to the environment inside the container 310 in which thermal or electromagnetic energy is applied, so as to induce the heating of the frozen particles and, therefore, the desired sublimation.
  • the lyophilization equipment in the two variations 3 and 300 is so designed as that the container 30, 310 inner surface is electrolytically polished.
  • connection points to the several devices and equipments are provided with a high vacuum connection of the smooth surface type, and with "O"-rings if a static seal is necessary, and a rotating one if a double mechanical seal is required.
  • quartz infrared-transparent accesses both to supply of the electromagnetic energy from outside, and to allow the control of the particle surface temperature by means of contactless readers; visible spectrum transparent accesses for the visual check of the evolution of the process inside; vacuum sealing connections for instruments necessary to the sensing of operative parameters such as room temperature, inner pressure, microwave field data are also provided (not shown).
  • the nebulization and freezing equipment 2 is advantageously coupled to the lyophilization equipment 3 by means of a continuously transferring device 4 of the discrete frozen particles produced in said equipment 2.
  • the transferring device 4 comprises in turn a vacuum generating chamber 5 and a collection and continuous, gradual release device 6 of the particles.
  • the vacuum generating chamber 5 can be advantageously represented by a channel which is continuous with the outlet 21 of the nebulization and freezing equipment 2, and closed in the proximity of said outlet by a first controllably openable gate or lid 51 to allow the fall therein of the discrete frozen particles. Furthermore, the chamber 5 is closed at its end opposite said outlet by a second controllably openable gate or lid 52 to allow the discharge of the particles inside the collection and release device 6.
  • the vacuum generating chamber 5 is divided in a number of sectors or compartments 50 by further gates or lids 53.
  • the vacuum chamber 5 can be divided in a number of sectors inside which the vacuum is increased to increasingly higher values upon reaching the lyophilization equipment 3. Therefore, the sector which is more proximate to the equipment 2 will not have very high vacuum pressure values, while the sector which is more proximate to the equipment 3 will have values which are equal to or near the high vacuum generated in said equipment.
  • a vacuum chamber 5 has the advantage to prepare the discrete frozen particles in the best way for the reception by the equipment 3 and already treated in the suitable conditions.
  • the particles were forced to directly pass through the slightly overpressurized environment of the equipment due to the presence of the nitrogen which is inputted for the countercurrent freezing 2 to a high vacuum environment, such as the inner part of the heated equipment 3, they will undergo, by one hand, a pressure and thermal shock which could cause alterations to the aggregative structure of the particles and, on the other hand, it would result in a so-called "blow-by effect".
  • the blow-by effect consists in a continuous inflow of the inert gases which are used for the freezing step in the vacuum chamber, consequently having to oversize the vacuum generation system power because of the excess of said inert gases.
  • the collection and gradual continuous release device 6 of the particles can be represented, for example, by a simple funnel or hopper (not shown) in which a collecting portion is relatively large, so as to collect the particles coming from the vacuum chamber 5, while a discharge portion is restricted, so as to allow a constant, continuous release of said particles inside the lyophilization chamber 30.
  • said device comprises collecting means 60 of the particles coming from the vacuum chamber 5, and discharge means 7 so as to discharge said particles in the lyophilization chamber 30.
  • the collecting means 60 consist in valve means such as, for example, controlled flow rate rotative valves. These types of valves can be implemented so as to allow a further removal of optional gas residues by suction at these valves.
  • the discharge means 7 can be represented by any member which is able to receive the particles which are collected by the collecting means 6, and to deposit them in an essentially continuous manner inside the freeze-dryer.
  • said means 7 comprise a chamber 71 sealingly connected at one end to the discharge means 6 and, at the other end, to the lyophilization equipment 3, a coil 72, and a movement system 73 adapted to control the movement of said coil.
  • Such means not only continuously operate, but also so as to move a constant amount of particles.
  • the means consist in a open coil screw, the movement of which allows meeting the requirement of an essentially continuous deposition of prefixed amounts of material.
  • the system 1 of the invention can further comprise a discharge device 8 for the lyophilized material.
  • the device preferably comprises a "diverter" valve 81 to direct the exiting lyophilizate flow to two alternately operating collecting volumes/tanks 91 and 92.
  • Two closures 82 and 83 arranged in series on the two valve 81 outlets ensure a perfect sealing against the room pressure.
  • the system 1 Downstream said closures 82 and 83, the system 1 is equipped with two collecting tanks 91 and 92 for the lyophilized product.
  • the tanks 91 and 92 are kept at a constant temperature with dry, optionally sterile, air or nitrogen atmosphere blanketing during the lyophilizate collecting step.
  • the tanks 91 and 92 can be dimensioned so as to have such a volume that allows performing suitable quality tests by drawing samples from the mass without interrupting the whole process or parts thereof.
  • the device can be equipped with systems with a single tank having the function to allow the above-mentioned test and dosing operations for the supply of successive manufacturing processes directly connected to the production line.
  • processes can comprise the packaging step.
  • a pressurized tank 13 is connected to the freezing device 2 for the liquid nitrogen which is employed as a freezing fluid, or other cryogenic liquid, as stated before.
  • a container 15 is in communication with the inlet 20 of the device 2 so as to continuously supply it with the mixture of the substances to be lyophilized and to be sublimed.
  • the mixture is kept under agitation by means of conventional stirrers 14.
  • the system 1 of the invention can be equipped with a cooling unit 10, a powering unit 11, and a vacuum unit 12.
  • the nebulization and freezing equipment 2 can be coupled to a cooling unit 10 of the conventional type so as to receive a cooling fluid which countercurrently run over the mixture nebulized particles which fall by gravity from the inlet 20 to the outlet 21 of said equipment 2.
  • the powering unit 11 is employed to supply energy to the particles to be subjected to sublimation.
  • the powering unit can be connected to several energy sources for the transmission to the particles, so as to induce the heating thereof and the sublimation of the vehicle substances. Powering units of this type are broadly known, therefore they will not be set forth in detail herein.
  • the thermal energy is the most spread.
  • the thermal energy can be supplied by plates or electric resistances (not shown) which are superiorly, inferiorly, and/or laterally arranged in relation to the trays or any of the support and handling systems of the discrete frozen particles previously described.
  • the employed energy can be energy from electromagnetic waves, such as microwaves or infrared waves.
  • electromagnetic waves such as microwaves or infrared waves.
  • the above-mentioned upper, lower, and/or side arrangement can be adopted also in the case of said alternative sources.
  • the microwave energy can be generated by a magnetron with adjustable power, 10% to 100%, according to the type, flow rate, and characteristics of the vehicle substance which must be treated.
  • the magnetron is sized according to the geometric parameters of the lyophilization device 3 and the specific consumption for the vehicle substance sublimation. These equipments are available in the market from specialized firms. Furthermore, the employment thereof on the basis of the above-mentioned substance types is within the skill of those of ordinary skill in the art.
  • infrared energy it can be used by itself, or associated to microwaves.
  • the infrared radiations can be employed to heat the particles surface, thus allowing the sublimation of the surface molecules of the vehicle substance, while the microwaves heat more quickly the inner part of the particles, thus allowing the sublimation of the vehicle substance entrapped after that the surface has been at least partially cleared.
  • Appliances for infrared radiation emission of are well known, such as, for example, lamps provided with power adjusting means in order to meet different needs.
  • the transferring equipment 4 of the mixture discrete frozen particles is handled in each of the components thereof by conventional handling means (not shown) of the hydraulic or pneumatic type and which are synchronically controlled in order to ensure the proper continuous operation of the whole lyophilization method, as it will be explained herein below.
  • the vacuum unit 12 may comprise a conventional vacuum pump such as a mechanic, fluid jet, condensation, adsorption, or ionization pump. Such unit is mainly connected to the lyophilization equipment 3 for the generation of vacuum therein, but also to the vacuum chamber 5 of the transferring device 4 of the particles from the nebulization and freezing device 2 to the lyophilization equipment 3.
  • a conventional vacuum pump such as a mechanic, fluid jet, condensation, adsorption, or ionization pump.
  • the operation of the whole system 1 of the invention is controlled and operated by means of a system comprising a controlling and operative unit (UCC) which is connected, through electrical cables lines, or wireless transmissions, to sensors (not shown) which are mounted at each handling device or member.
  • UCC controlling and operative unit
  • the connections are implemented through dedicated lines, which are adapted both to receive and send electrical signals for each system equipment or device which needs to be checked.
  • the line L1 connects the controlling and operative unit to the freezing unit 10, the line L2 to the nitrogen tank 13, the line L3 to the nebulization and freezing equipment 2, the line L4 to the vacuum unit 12, the line L5 to the vacuum chamber 5 and to each correposnding compartment and gates, the line L6 to the collecting device 6 of the frozen particles, the line L7 to the discharge device 7 of the frozen particles, the line L8 to the valve 81, the closures 82 and 83 of the discharge device 8, the line L9 to the tanks 91 and 92 of the lyophilizate, the line L10 to the lyophilization equipment 3, the line L11 to the energy unit 11 for the transferring of energy to the lyophilization equipment 3, and the line L12 to the stirring tank 15 of the mixture to be lyophilized.
  • controlling and operative unit comprises an electronic processor (not shown), such as a personal computer, equipped with hardware and software suitable to receive electrical signals from the sensors of said devices and members and to convert them into values. These values are representative of the operational status of each member or device, or are indicative of the inner conditions of said devices or instruments.
  • the processor is equipped with a memory in which baseline values can be present for the operative parameters which are intrinsic of each equipment or device and preset on the basis of the kind of substance which must be lyophilized.
  • Such values are continuously compared to the values continuously sensed by the above-mentioned sensors and, in the case that some deviation should be reported compared to the baseline values, the processor intervenes, by sending control signals to the equipment or device, in order to bring the operative values back within the baseline ones.
  • a mixture of at least one substance of interest and at least one vehicle substance is prepared and put into the container 15, where it is kept under stirring by the stirrer 14.
  • the mixture is continuously transferred to the inlet 20 of the nebulization and freezing equipment 2 simply by gravity, or by means of a pump (not shown), the flow of which is controlled by the above-mentioned controlling and operative unit.
  • the mixture passes through the nebulizer 20, which transforms the liquid mixture into minute droplets.
  • the droplets fall inside the container 2 towards the outlet 21, and are concomitantly countercurrently run over by the cooling fluid which has been put into by a pump (not shown) which draws in the tank 13.
  • the gate 51 is opened to make the particles fall into the first compartment 50 of the chamber 5, then it is immediately closed again. At this point, some amount of vacuum is generated, which is not too high in order not to create a sudden pressure differential, which could damage the molecular structure of the substance of interest. Subsequently, the next gate 53 is opened downstream said first gate, to make the particles pass into a further compartment 50 in which, once said further lid has been closed again, a higher degree of vacuum is generated. Further steps, which are identical to the one just described, can be provided in the downstream compartments until reaching a vacuum extent which is similar to the one which is present in the lyophilization equipment 3.
  • the flow of nebulized particles and the opening of the vacuum chamber lids are synchronically controlled and operated by the operative and control unit, so as to ensure an essentially continuous flow of particles. Furthermore, the flow rate of the nebulization flow, the freezing temperature, the freezing fluid flow of the vacuum degree in each compartment of the vacuum chamber are always controlled and operated by said controlling and operative unit.
  • the opening and closing of the gates 51, 52, and 53, of the vacuum chamber 5 must be operated so that the compartments 50 are mutually insulated when the vacuum has to be applied.
  • the compartments are subjected to increasing vacuum degrees from the equipment 2 to the equipment 3, where there is a high vacuum. Therefore, the control and operational unit operates the activation of the pump, to generate the device 12 vacuum inside a particular sector of the vacuum chamber and concomitantly generate increasing vacuum degrees in the different compartments.
  • the collecting means can be such as to collect the particles and continuously release them (funnel) or at regular intervals (rotative valves) to the deposition member 7 in a continuous manner inside the lyophilization equipment 3.
  • the particles are essentially continuously deposited inside the lyophilization equipment 3 so as to fall onto the support 32.
  • the frozen particles are subjected to a vacuum heating to induce the vehicle substance sublimation.
  • the powering unit 11 supplies energy to the particles in the form of thermal energy and/or electromagnetic energy in preset amounts, on the basis of the type of product which is desired, and operated by the operative and control unit.
  • the vacuum unit 12 generates an extent of vacuum, also preestablished and controlled, again by the operative and control unit.
  • the particles sublimate that is, the lyophilizate of the substance of interest
  • the discharge device 8 discharges the lyophilizate alternatively in the tanks 91 and 92 kept at the same degree of vacuum as the lyophilization equipment 3.
  • the system in accordance with the invention advantageously allows producing a substance which is lyophilized in an essentially continuous manner.
  • the system allows implementing the method previously described, thanks to which not only the drawbacks present in the prior art systems are avoided, but, above all, the production time is drastically reduced and the end product quality is drastically improved.

Landscapes

  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Mechanical Engineering (AREA)
  • General Engineering & Computer Science (AREA)
  • Drying Of Solid Materials (AREA)
  • Medicinal Preparation (AREA)
EP07425840A 2007-12-31 2007-12-31 Gefriertrocknungsverfahren sowie System dafür Ceased EP2101131A1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP07425840A EP2101131A1 (de) 2007-12-31 2007-12-31 Gefriertrocknungsverfahren sowie System dafür

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP07425840A EP2101131A1 (de) 2007-12-31 2007-12-31 Gefriertrocknungsverfahren sowie System dafür

Publications (1)

Publication Number Publication Date
EP2101131A1 true EP2101131A1 (de) 2009-09-16

Family

ID=39496023

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07425840A Ceased EP2101131A1 (de) 2007-12-31 2007-12-31 Gefriertrocknungsverfahren sowie System dafür

Country Status (1)

Country Link
EP (1) EP2101131A1 (de)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2578974A1 (de) * 2011-10-05 2013-04-10 Sanofi Pasteur Sa Verfahrenslinie zur Herstellung von gefriergetrockneten Partikeln
US20170219283A1 (en) * 2014-07-21 2017-08-03 Sanofi Pasteur Sa Liquid feeding device for the generation of droplets
JP2017163913A (ja) * 2016-03-16 2017-09-21 大陽日酸株式会社 粒状凍結装置
US10465985B2 (en) 2015-06-01 2019-11-05 Ima Life North America Inc. Bulk freeze drying using spray freezing and agitated drying with dielectric heating
WO2021235459A1 (ja) * 2020-05-18 2021-11-25 株式会社エムアイアイ 真空凍結乾燥装置及び真空凍結乾燥方法
WO2023224103A1 (ja) * 2022-05-19 2023-11-23 株式会社神鋼環境ソリューション 粒子製造装置および凍結粒子の製造方法

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB952920A (en) * 1961-11-10 1964-03-18 Vickers Armstrong Ltd Improvements in or relating to plant for freeze drying foodstuffs
FR1356477A (fr) * 1962-03-01 1964-03-27 Procédé pour l'absorption et l'élimination continues de vapeur d'eau ou d'autres solvants par vaporisation ou sublimation à basse température sous vide
GB1027176A (en) * 1961-11-13 1966-04-27 Hupp Corp Improvements in or relating to freeze drying
US3300868A (en) * 1964-04-24 1967-01-31 Anderwert Fritz Process for drying heat-sensitive materials as well as drying apparatus for the performance of the aforementioned process
US3313032A (en) * 1966-07-28 1967-04-11 George J Malecki Freeze-drying process and apparatus
US3362835A (en) * 1964-01-15 1968-01-09 Fmc Corp Spray freeze drying system
US3431655A (en) * 1966-06-17 1969-03-11 Struthers Scient & Intern Corp Freeze drying
US3574951A (en) * 1968-04-25 1971-04-13 Leybold Heraeus Verwaltung Apparatus for continuously freeze-drying granulates
US3616542A (en) * 1969-02-24 1971-11-02 Earl L Rader Apparatus and processes for producing freeze dried products
US3621587A (en) * 1970-08-06 1971-11-23 Smitherm Industries Freeze drying apparatus
US4033048A (en) * 1976-01-12 1977-07-05 Clayton Van Ike Freeze drying apparatus
US4608764A (en) * 1984-05-19 1986-09-02 Glatt Maschinen-Und Apparatebau Ag Process of drying a particulate material and apparatus for implementing the process
US5208998A (en) * 1991-02-25 1993-05-11 Oyler Jr James R Liquid substances freeze-drying systems and methods
US5230162A (en) * 1992-06-26 1993-07-27 Oyler Jr James R Systems and methods for the deliquification of liquid-containing substances by flash sublimation
US5707636A (en) 1994-08-03 1998-01-13 Saitec S.R.L. Apparatus and method for preparing solid forms with controlled release of the active ingredient
DE102004005660A1 (de) * 2004-02-04 2005-08-25 Rheinische Friedrich-Wilhelms-Universität Bonn Verfahren und Vorrichtung zur Herstellung eines lyophilisierten pharmazeutischen Materials
WO2005105253A1 (en) * 2004-05-01 2005-11-10 Agresearch Limited Drying process and apparatus

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB952920A (en) * 1961-11-10 1964-03-18 Vickers Armstrong Ltd Improvements in or relating to plant for freeze drying foodstuffs
GB1027176A (en) * 1961-11-13 1966-04-27 Hupp Corp Improvements in or relating to freeze drying
FR1356477A (fr) * 1962-03-01 1964-03-27 Procédé pour l'absorption et l'élimination continues de vapeur d'eau ou d'autres solvants par vaporisation ou sublimation à basse température sous vide
US3362835A (en) * 1964-01-15 1968-01-09 Fmc Corp Spray freeze drying system
US3300868A (en) * 1964-04-24 1967-01-31 Anderwert Fritz Process for drying heat-sensitive materials as well as drying apparatus for the performance of the aforementioned process
US3431655A (en) * 1966-06-17 1969-03-11 Struthers Scient & Intern Corp Freeze drying
US3313032A (en) * 1966-07-28 1967-04-11 George J Malecki Freeze-drying process and apparatus
US3574951A (en) * 1968-04-25 1971-04-13 Leybold Heraeus Verwaltung Apparatus for continuously freeze-drying granulates
US3616542A (en) * 1969-02-24 1971-11-02 Earl L Rader Apparatus and processes for producing freeze dried products
US3621587A (en) * 1970-08-06 1971-11-23 Smitherm Industries Freeze drying apparatus
US4033048A (en) * 1976-01-12 1977-07-05 Clayton Van Ike Freeze drying apparatus
US4608764A (en) * 1984-05-19 1986-09-02 Glatt Maschinen-Und Apparatebau Ag Process of drying a particulate material and apparatus for implementing the process
US5208998A (en) * 1991-02-25 1993-05-11 Oyler Jr James R Liquid substances freeze-drying systems and methods
US5230162A (en) * 1992-06-26 1993-07-27 Oyler Jr James R Systems and methods for the deliquification of liquid-containing substances by flash sublimation
US5707636A (en) 1994-08-03 1998-01-13 Saitec S.R.L. Apparatus and method for preparing solid forms with controlled release of the active ingredient
DE102004005660A1 (de) * 2004-02-04 2005-08-25 Rheinische Friedrich-Wilhelms-Universität Bonn Verfahren und Vorrichtung zur Herstellung eines lyophilisierten pharmazeutischen Materials
WO2005105253A1 (en) * 2004-05-01 2005-11-10 Agresearch Limited Drying process and apparatus

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA027602B1 (ru) * 2011-10-05 2017-08-31 Санофи Пастер Са Технологическая линия для производства лиофилизированных частиц
AU2012320854B2 (en) * 2011-10-05 2015-02-19 Sanofi Pasteur Sa Process line for the production of freeze-dried particles
WO2013050162A1 (en) * 2011-10-05 2013-04-11 Sanofi Pasteur Sa Process line for the production of freeze-dried particles
CN103917841A (zh) * 2011-10-05 2014-07-09 赛诺菲巴斯德有限公司 用于生产冷冻干燥颗粒的处理线
CN103917842A (zh) * 2011-10-05 2014-07-09 赛诺菲巴斯德有限公司 用于生产冷冻干燥颗粒的处理线
JP2014530061A (ja) * 2011-10-05 2014-11-17 サノフィ パスツール ソシエテ アノニム 凍結乾燥粒子製造用プロセスライン
JP2014530685A (ja) * 2011-10-05 2014-11-20 サノフィ パスツール ソシエテ アノニム 凍結乾燥粒子の製造用工程ライン
US9920989B2 (en) 2011-10-05 2018-03-20 Sanofi Pasteur Sa Process line for the production of freeze-dried particles
CN103917841B (zh) * 2011-10-05 2015-07-08 赛诺菲巴斯德有限公司 用于生产冷冻干燥颗粒的处理线
CN103917842B (zh) * 2011-10-05 2015-08-05 赛诺菲巴斯德有限公司 用于生产冷冻干燥颗粒的处理线
EP3211355A1 (de) 2011-10-05 2017-08-30 Sanofi Pasteur SA Prozesslinie und verfahren zur herstellung von gefriergetrockneten partikeln
EA027630B1 (ru) * 2011-10-05 2017-08-31 Санофи Пастер Са Технологическая линия для производства лиофилизированных частиц
WO2013050156A1 (en) * 2011-10-05 2013-04-11 Sanofi Pasteur S A Process line for the production of freeze-dried particles
EP2578974A1 (de) * 2011-10-05 2013-04-10 Sanofi Pasteur Sa Verfahrenslinie zur Herstellung von gefriergetrockneten Partikeln
US10006706B2 (en) 2011-10-05 2018-06-26 Sanofi Pasteur Sa Process line for the production of freeze-dried particles
CN107073350B (zh) * 2014-07-21 2019-11-15 赛诺菲巴斯德股份公司 用于产生液滴的液体给送装置
US10533800B2 (en) * 2014-07-21 2020-01-14 Sanofi Pasteur Sa Liquid feeding device for the generation of droplets
US11499777B2 (en) 2014-07-21 2022-11-15 Sanofi Pasteur Sa Liquid feeding device for the generation of droplets
CN107073350A (zh) * 2014-07-21 2017-08-18 赛诺菲巴斯德股份公司 用于产生液滴的液体给送装置
US20170219283A1 (en) * 2014-07-21 2017-08-03 Sanofi Pasteur Sa Liquid feeding device for the generation of droplets
US10465985B2 (en) 2015-06-01 2019-11-05 Ima Life North America Inc. Bulk freeze drying using spray freezing and agitated drying with dielectric heating
JP2017163913A (ja) * 2016-03-16 2017-09-21 大陽日酸株式会社 粒状凍結装置
US11644236B2 (en) 2020-05-18 2023-05-09 Mii, Ltd. Vacuum freeze-drying apparatus and vacuum freeze-drying method
WO2021235459A1 (ja) * 2020-05-18 2021-11-25 株式会社エムアイアイ 真空凍結乾燥装置及び真空凍結乾燥方法
JPWO2021235459A1 (de) * 2020-05-18 2021-11-25
JP7218484B2 (ja) 2020-05-18 2023-02-07 株式会社エムアイアイ 真空凍結乾燥装置及び真空凍結乾燥方法
JP2023171213A (ja) * 2022-05-19 2023-12-01 株式会社神鋼環境ソリューション 粒子製造装置および凍結粒子の製造方法
WO2023224103A1 (ja) * 2022-05-19 2023-11-23 株式会社神鋼環境ソリューション 粒子製造装置および凍結粒子の製造方法

Similar Documents

Publication Publication Date Title
EP2101131A1 (de) Gefriertrocknungsverfahren sowie System dafür
US4608764A (en) Process of drying a particulate material and apparatus for implementing the process
US9788566B2 (en) Process for drying and powderizing functional foods, nutraceuticals, and natural health ingredients
AU2018312095B2 (en) Ultrahigh efficiency spray drying apparatus and process
US9945611B2 (en) Bulk freeze drying using spray freezing and agitated drying
US6584782B2 (en) Method for producing particulate goods
JPH05168906A (ja) 流動床コンディショニング装置
JP2007535652A (ja) 乾燥工程及び装置
JP2004232883A (ja) 噴霧式真空凍結乾燥装置
US10625281B2 (en) Ultrahigh efficiency spray drying apparatus and process
JP7038435B2 (ja) 噴霧凍結造粒乾燥粉体製造装置及び噴霧凍結造粒乾燥粉体製造システム
EP3661617B1 (de) Vorrichtung und verfahren zur sprühtrocknung mit extrem hoher effizienz
EP3303958A1 (de) Massegefriertrocknung unter verwendung von sprühvereisung und rührtrocknung mit dielektrischer erwärmung
EP2260717B1 (de) Verfahren und Vorrichtung zur Beschichtungsbereitstellung
US5694777A (en) Process and device for pellet-freezing poorable and flowable materials
CN2861908Y (zh) 真空带式干燥机组
US20010043848A1 (en) Apparatus and process for the quasi-continuous treatment of particulate materials
US3052557A (en) Method and apparatus for freezing liquid food products
RU2241178C2 (ru) Способ и система для охлаждения и изменения состояния жидкой смеси
CN113015879A (zh) 用于散装冷冻干燥系统的冷冻干燥室
US5275484A (en) Apparatus for continuously processing liquids and/or solids including mixing, drying or reacting
WO2018139419A1 (ja) 微粒子製造装置および微粒子製造方法
WO2019103731A1 (en) Spray freeze drying on a substrate
CN204739850U (zh) 一种连续式真空喷雾冷冻干燥设备
JP2018118240A (ja) 微粒子製造装置および微粒子製造方法

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 20091010