EP0317411A1 - Freeze-drying apparatus having means constituting an active thermal screen in between the freeze-drying shelves - Google Patents
Freeze-drying apparatus having means constituting an active thermal screen in between the freeze-drying shelves Download PDFInfo
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- EP0317411A1 EP0317411A1 EP88402845A EP88402845A EP0317411A1 EP 0317411 A1 EP0317411 A1 EP 0317411A1 EP 88402845 A EP88402845 A EP 88402845A EP 88402845 A EP88402845 A EP 88402845A EP 0317411 A1 EP0317411 A1 EP 0317411A1
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- Prior art keywords
- lyophilization
- shelves
- heating
- freeze
- cooling
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- 238000004108 freeze drying Methods 0.000 title claims abstract description 91
- 238000010438 heat treatment Methods 0.000 claims abstract description 44
- 238000001816 cooling Methods 0.000 claims abstract description 32
- 238000007710 freezing Methods 0.000 claims description 20
- 230000008014 freezing Effects 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 15
- 239000013529 heat transfer fluid Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000000859 sublimation Methods 0.000 claims description 9
- 230000008022 sublimation Effects 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000005057 refrigeration Methods 0.000 claims description 3
- 239000002826 coolant Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 description 22
- 239000000126 substance Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000010257 thawing Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000005496 eutectics Effects 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229920005372 Plexiglas® Polymers 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 229920006328 Styrofoam Polymers 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000000512 collagen gel Substances 0.000 description 1
- 239000004020 conductor Substances 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 239000011810 insulating material Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
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- 238000009877 rendering Methods 0.000 description 1
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- 238000003860 storage Methods 0.000 description 1
- 239000008261 styrofoam Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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
Definitions
- the present invention relates to a freeze-drying method and apparatus comprising means forming an active heat shield between the freeze-drying shelves.
- Lyophilization is a drying technique involving freezing and then sublimation of the water contained in the frozen product.
- a freeze-drying cycle has three stages: - freezing, an operation during which the product to be dried is brought to a total solidification temperature or eutectic temperature, - Sublimation during which water passes directly from the solid state to the vapor state and will be trapped in the solid state on a cold wall.
- the partial vapor pressure above the product must be less than the vapor pressure of the ice at the same temperature.
- This phase is intended to remove traces of water remaining in the product. For this, it will be necessary to have the lowest possible partial pressure and the highest possible product temperature lower than that of its denaturation.
- Lyophilization can be achieved by two types of apparatus: the first consists of balloons located in the atmosphere and connected to the vacuum enclosure containing the trap. In this system, the substance is previously frozen in the flask placed to do this in a freezer. In this system, the calories necessary for sublimation are provided by the atmosphere.
- the second type of device consists of shelves on which the product to be lyophilized is placed. The product can be pre-frozen or frozen in situ on the shelves. When the freezing is finished, the lyophilization is carried out on the same shelves which will be heated so as to provide the product with the calories necessary for the sublimation of the water.
- the first phenomenon comes from the imprisonment of a certain quantity of liquid between an envelope of ice forming on the bottom, the walls of the tray containing the substance as well as on the surface of the product.
- the frigories on the bottom and the walls are brought by conduction from the shelf of the freeze dryer while on the surface of the product, they are brought mainly by radiation from the upper shelf.
- an increase in volume occurs and the liquid passes through the frozen wall of the surface and forms a mound which freezes ( Figure 1).
- the second phenomenon that is to say the formation of a crust on the surface of the product is caused by thawing due to radiant heating of the freeze dryer shelf located just above the freeze drying tray, and the absence of sufficient thermal conduction inside the product.
- This thawing leads to the liquefaction of the water in the product which no longer sublimates but then evaporates. This results in the formation of a more compact crust on the surface of the product which makes the lyophilized material heterogeneous.
- this crust is relatively waterproof. It can in certain cases contribute to lengthening the freeze-drying time by slowing down the exchanges between the gas and the deeper layers of frozen product.
- US Patent 4,501,719 relates to a lyophilization device comprising a particular plate 14 provided with housings 12 in which the solutions 16 to be lyophilized are arranged.
- a lyophilization device comprising a particular plate 14 provided with housings 12 in which the solutions 16 to be lyophilized are arranged.
- lines 62 to 68 and in column 4, lines 50 to 58 mention is made of the use of an insulating plate 43 placed above the plate 14 containing the lyophilized solutions placed in the housings or wells. 12 (see Figure 3).
- This insulating plate 43 is made of Styrofoam with an intermediate plexiglass sheet 44. It is preferably wrapped in a aluminum foil to increase its insulation properties (column 4, lines 50 to 53).
- the present invention therefore aims to solve the new technical problem consisting in the supply of a solution making it possible to obtain, by lyophilization, lyophilized products which are homogeneous, or with greatly improved homogeneity, compared to the products obtained by the lyophilization processes and apparatus previously known.
- the main object of the present invention is also to solve the new technical problem consisting in providing a method and an apparatus for lyophilizing various viscous products or solutions, very difficult to lyophilize, making it possible to obtain very homogeneous products. and plans.
- the main object of the present invention is also to solve the new technical problem consisting in the supply of a method and an apparatus for lyophilization of various products or solutions, in particular viscous solutions, even when placed in great thickness, leading to homogeneous freeze-dried products.
- the present invention also aims to solve the new technical problem consisting in the supply of a method and an apparatus for lyophilization of various products or solutions, in particular viscous solutions, which can be arranged in great thickness, resulting in homogeneous products, of an extremely simple design, of a low manufacturing cost, usable on an industrial scale.
- the present invention provides a process for lyophilization of various products or solutions, in particular viscous solutions, which can be arranged in great thickness, comprising the placement of products or solutions to be lyophilized, which can be contained in open containers.
- said shelves comprising cooling means and associated heating means, preferably incorporated, firstly comprising a step of freezing products or solutions to freeze-drying, and then a freeze-drying step proper with sublimation of the water contained in the frozen product, characterized in that provision is made between said freeze-drying shelves, means forming an active thermal screen comprising heating and / or cooling means allowing to slow down the heat exchanges between the surface of the product and said means cooling or heating associated with the shelves, thereby obtaining substantially homogeneous lyophilized products.
- the heating means of the active screen means are put into operation during the freezing step.
- the cooling means of the above-mentioned active screen means are put into operation during the lyophilization proper.
- the heating and / or cooling means of the active screen means take the form of heating resistors.
- these heating and / or cooling means are constituted by the production of screen forming means in the form of hollow plates in which a heat transfer fluid is circulated.
- a second aspect of the present invention also relates to an apparatus for freeze-drying various products or solutions, in particular viscous solutions, which can be arranged in great thickness, comprising freeze-drying shelves placed inside a freeze-drying enclosure, on which it is possible to put products or solutions to be lyophilized, which may be contained in open containers, as well as associated cooling and / or heating means, preferably made incorporated, into said shelves, characterized in that means forming an active heat shield are disposed between said lyophilization shelves, comprising heating and / or cooling means, thereby making it possible to slow down the heat exchanges between the surface of the product to be lyophilized and the heating and / or cooling elements associated with the shelves.
- these means forming an active screen can be produced in the form of plates, advantageously of a shape adapted to the lyophilization shelves, and can be fixed under said shelves, that is to say opposite to the products. freeze-drying resting on said shelf.
- these plates constituting the means forming an active screen contain heating resistors.
- these plates contain, embedded in the mass, elements capable of heating during freezing and of cooling during the lyophilization proper (step of sublimation of water).
- the plates constituting the active screen means are hollow and are provided to allow the circulation of a heat transfer fluid inside said plates.
- the device is characterized in that the calories or the heat-transfer fluid circulating inside the plates forming the screen come from the heating and cooling system of the freeze-drying trays, the calories used being those supplied by the refrigeration unit during the cooling of the freezing operation while during the freeze-drying period, on the contrary, the frigories are sent to the plates forming an active screen and the calories in lyophilization trays.
- the lyophilization device according to the invention, it is characterized in that the calories of the heat transfer fluid circulating inside the plates forming an active screen come from an autonomous, internal heating system or external to the freeze dryer.
- the lyophilization device represented by the general reference number 1 conventionally comprises shelves 2, on which are placed various products or solutions to be lyophilized 4, possibly contained in open containers 6.
- These shelves 2 are usually equipped with heating and cooling means, making it possible to carry out the freezing step, then the step of sublimation of the water contained in the frozen product.
- the shelves 2 are made hollow and a heat transfer product is circulated inside them brought either to the temperature necessary for freezing the products, or to the temperature necessary for the sublimation of the water.
- a crust forms on the surface of the product caused by thawing due to radiation heating of the freeze dryer shelf located just above the freeze drying tray on which the product rests, and the absence of sufficient thermal conduction inside the product.
- a more compact crust forms on the surface of the product, which makes the lyophilized product heterogeneous.
- FIG 2 there is shown a lyophilization apparatus according to the invention referenced 10, which also includes lyophilization shelves 12, which may be identical to those of the lyophilization apparatus shown in Figure 1, as described below -above.
- this lyophilization device 10 comprises means forming an active thermal screen 14, arranged between the shelves 12, as is clearly understandable from FIG. 2.
- these means forming an active screen can take the form of plates.
- the plates constituting the means forming an active screen comprise heating means and / or cooling means.
- These heating means can be formed by simple heating resistors.
- the heating and / or cooling means of the screen forming means 14 can be constituted by a heat transfer fluid circulating in the plates which are then made hollow.
- This device operates according to the method previously described; thus, heating is carried out inside the screen means during freezing. This advantageously slows down the heat exchange between the surface of the product and the cooling elements of the lyophilization device, contained in the shelves, during the freezing step.
- the means forming an active screen cool down during the lyophilization stage proper, which is controlled so that the temperature of the frozen product rises gradually.
- the heating means of the active screen means 14, constituted by heating resistors, with a power of 225W / m2 are supplied with a voltage of 220V.
- the power supply is stopped and freeze-drying is started.
- a vacuum of 0.3 mb is created in the enclosure of the freeze dryer and the shelves are heated so that the temperature of the frozen product is maintained at -25 ° C.
- This last phase lasts approximately 16 hours.
- secondary desiccation during which the vacuum is lowered to 10 ⁇ 2mb and the product temperature raised to 40 ° C. This operation takes approximately 3 hours.
- the first results are also to be compared with those obtained by the same freeze dryer equipped with passive screen means made only of an insulating material.
- the invention is particularly advantageous on the one hand, in the case of lyophilization of viscous solutions inside which the heat exchanges by convection are very difficult, and on the other hand, in the case of lyophilization of large thicknesses which prevent rapid heat exchanges between the face of the product in contact with the freeze dryer shelf and the surface.
- the material constituting the plates is a thermally conductive material, advantageously a metal, for example anodized aluminum or a steel. stainless.
- the lyophilization device it is characterized in that the calories or the heat transfer fluid circulating inside the plates forming an active screen come from the system for heating and cooling the plates freeze-drying, the calories used being those supplied by a refrigeration unit during the cooling of the freezing operation, while during the freeze-drying period, on the contrary, the frigories are sent to the plates forming an active screen and the calories to the trays lyophilization.
- the lyophilization device according to the invention, it is characterized in that the calories of the heat-transfer fluid circulating inside the plates forming an active screen come from an autonomous heating system, internal or external to the freeze dryer.
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- 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)
- Freezing, Cooling And Drying Of Foods (AREA)
Abstract
Description
La présente invention concerne un procédé et un appareil de lyophilisation comportant des moyens formant écran thermique actif entre les étagères de lyophilisation.The present invention relates to a freeze-drying method and apparatus comprising means forming an active heat shield between the freeze-drying shelves.
La lyophilisation est une technique de séchage faisant appel à la congélation et ensuite à la sublimation de l'eau contenue dans le produit congelé.Lyophilization is a drying technique involving freezing and then sublimation of the water contained in the frozen product.
Ce procédé, bien qu'onéreux, se développe de plus en plus car il permet le séchage de nombreuses substances sand altérer leurs propriétés. Les principales applications sont les suivantes :
- conservation de produits fragiles d'origine biologique,
- conservation et stockage de produits alimentaires, ces produits pouvant ensuite être très facilement une structure très aérée dont la surface de contact avec le solvant sera très importante,
- solution de problème de conditionnement dans le cas où l'on désire introduire des quantités très faibles de substances solides dans des flacons. Dans ce cas, la solution de la substance est introduite dans le récipient et ensuite lyophilisée, une dilution adéquate permettant une pesée très aisée de la solution,
- solution de problème de gallénique en conduisant à la mise en forme solide de certaines substances qui trouveront une application directe dans cette présentation.This process, although expensive, is developing more and more because it allows the drying of many substances without altering their properties. The main applications are:
- conservation of fragile biological products,
- conservation and storage of food products, these products can then very easily be a very ventilated structure whose contact surface with the solvent will be very large,
- solution of packaging problem in the case where it is desired to introduce very small quantities of solid substances in bottles. In this case, the solution of the substance is introduced into the container and then lyophilized, an adequate dilution allowing a very easy weighing of the solution,
- solution of gallenic problem by leading to the solid shaping of certain substances which will find a direct application in this presentation.
Un cycle de lyophilisation comporte trois étapes :
- la congélation, opération au cours de laquelle le produit à sécher est amené à une température de solidification totale ou température eutectique,
- la sublimation au cours de laquelle l'eau passe directement de l'état solide à l'état de vapeur et va être piégée à l'état solide sur une paroi froide. Au cours de cette opération, la pression partielle de vapeur au-dessus du produit devra être inférieure à la pression de vapeur de la glace à la même température. La température du produit restant inférieure à la température eutectique,
- la dessication secondaire. Cette phase est destinée à élminer les traces d'eau subsistant dans le produit. Pour cela, il sera nécessaire d'avoir la pression partielle la plus faible possible et la température du produit la plus élevée possible inférieure à celle de sa dénaturation.A freeze-drying cycle has three stages:
- freezing, an operation during which the product to be dried is brought to a total solidification temperature or eutectic temperature,
- Sublimation during which water passes directly from the solid state to the vapor state and will be trapped in the solid state on a cold wall. During this operation, the partial vapor pressure above the product must be less than the vapor pressure of the ice at the same temperature. The temperature of the product remaining below the eutectic temperature,
- secondary desiccation. This phase is intended to remove traces of water remaining in the product. For this, it will be necessary to have the lowest possible partial pressure and the highest possible product temperature lower than that of its denaturation.
De ce qui précède, il ressort que la forme du produit est figée lors du processus de congélation et qu'elle restera inchangée jusqu'à la fin de la lyophilisation. De plus, il est absolument indispensable que la température du produit reste inférieure à la température eutectique.From the above, it appears that the shape of the product is frozen during the freezing process and that it will remain unchanged until the end of freeze-drying. In addition, it is absolutely essential that the temperature of the product remains below the eutectic temperature.
La lyophilisation peut être réalisée par deux types d'appareillage : le premier consiste dans des ballons se trouvant dans l'atmosphère et reliés à l'enceinte sous vide renfermant le piége. Dans ce système, la substance est préalablement congelée dans le ballon placé pour ce faire dans un congélateur. Dans ce système, les calories nécessaires à la sublimation sont apportées par l'atmosphère. Le deuxième type d'appareil consiste en des étagères sur lesquelles est placé le produit à lyophiliser. Le produit peut être précongelé ou congelé in situ sur les étagères. Lorsque la congélation est terminée, la lyophilisation est réalisée sur les mêmes étagères qui vont être chauffées de façon à apporter au produit les calories nécessaires à la sublimation de l'eau.Lyophilization can be achieved by two types of apparatus: the first consists of balloons located in the atmosphere and connected to the vacuum enclosure containing the trap. In this system, the substance is previously frozen in the flask placed to do this in a freezer. In this system, the calories necessary for sublimation are provided by the atmosphere. The second type of device consists of shelves on which the product to be lyophilized is placed. The product can be pre-frozen or frozen in situ on the shelves. When the freezing is finished, the lyophilization is carried out on the same shelves which will be heated so as to provide the product with the calories necessary for the sublimation of the water.
Ce dernier type d'appareil est maintenant le seul utilisé sur le plan industriel. Dans ce cas, la congélation "in situ" peut soulever de sérieuses difficultés lorsque le produit est visqueux et que de ce fait les échanges calorifiques se font difficilement. Dans ce cas, deux phénomènes peuvent se produire : d'une part, au cours de la congélation, l'apparition d'un monticule se produit, et d'autre part, au cours de la lyophilisation, la formation à la surface d'une pellicule plus compacte que le reste du produit. Ceci entraîne l'obtention d'un matériau hétérogène, défaut rendant inutilisable le produit lorsque la lyophilisation est utilisée comme moyen de mise en forme. Ces phénomènes se produiront d'autant plus nettement que l'épaisseur à lyophiliser sera plus grande.The latter type of device is now the only one used industrially. In this case, freezing "in situ" can raise serious difficulties when the product is viscous and that therefore the heat exchange is difficult. In this case, two phenomena can occur: on the one hand, during freezing, the appearance of a mound occurs, and on the other hand, during lyophilization, the formation on the surface of a more compact film than the rest of the product. This results in a heterogeneous material being obtained, a defect rendering the product unusable when freeze-drying is used. as a form of fitness. These phenomena will occur all the more clearly the greater the thickness to be freeze-dried.
Le premier phénomène provient de l'emprisonnement d'une certaine quantité de liquide entre une enveloppe de glace se formant sur le fond, les parois du plateau contenant la substance ainsi qu'à la surface du produit. Les frigories sur le fond et les parois sont apportées par conduction à partir de l'étagère du lyophilisateur tandis qu'à la surface du produit, elles sont apportées essentiellement par rayonnement à partir de l'étagère supérieure . Lorsque le liquide emprisonné commence à se congeler, une augmentation de volume se produit et le liquide passe à travers la paroi congelée de la surface et forme un monticule qui se congèle (figure 1).The first phenomenon comes from the imprisonment of a certain quantity of liquid between an envelope of ice forming on the bottom, the walls of the tray containing the substance as well as on the surface of the product. The frigories on the bottom and the walls are brought by conduction from the shelf of the freeze dryer while on the surface of the product, they are brought mainly by radiation from the upper shelf. When the trapped liquid begins to freeze, an increase in volume occurs and the liquid passes through the frozen wall of the surface and forms a mound which freezes (Figure 1).
Le deuxième phénomène, c'est-à-dire la formation d'une croûte à la surface du produit est provoquée par une décongélation due à un chauffage par rayonnement de l'étagère du lyophilisateur située juste au-dessus du plateau de lyophilisation, et à l'absence d'une conduction thermique suffisante à l'intérieur du produit. Cette décongélation entraîne la liquéfaction de l'eau du produit qui ne se sublime plus mais alors s'évapore. Ceci a pour résultat la formation d'une croûte plus compacte à la surface du produit qui rend le matériau lyophilisé hétérogène.The second phenomenon, that is to say the formation of a crust on the surface of the product is caused by thawing due to radiant heating of the freeze dryer shelf located just above the freeze drying tray, and the absence of sufficient thermal conduction inside the product. This thawing leads to the liquefaction of the water in the product which no longer sublimates but then evaporates. This results in the formation of a more compact crust on the surface of the product which makes the lyophilized material heterogeneous.
De plus, cette croûte est relativement imperméable. Elle peut dans certains cas contribuer à allonger le temps de lyophilisation en ralentissant les échanges entre le gaz et les couches plus profondes de produit congelé.In addition, this crust is relatively waterproof. It can in certain cases contribute to lengthening the freeze-drying time by slowing down the exchanges between the gas and the deeper layers of frozen product.
Le brevet US 4 501 719 est relatif à un appareil de lyophilisation comprenant une plaque particulière 14 pourvue de logements 12 dans lesquels sont disposées les solutions 16 à lyophiliser. A la colonne 2, lignes 62 à 68 et à la colonne 4, lignes 50 à 58, il est cité l'emploi d'une plaque isolante 43 disposée au-dessus de la plaque 14 contenant les solutions lyophilisées disposées dans les logements ou puits 12 (voir figure 3). Cette plaque isolante 43 est réalisée en Styrofoam avec une feuille en plexiglas intermédiaire 44. Elle est de préférence enveloppée dans une feuille d'aluminium pour augmenter ses propriétés d'isolation (colonne 4, lignes 50 à 53).US Patent 4,501,719 relates to a lyophilization device comprising a
Ainsi, selon ce document, on prévoit l'emploi d'un écran thermique passif. Cependant, il est apparu dans la pratique qu'un tel écran thermique passif ne résoud pas les problèmes techniques énoncés précédemment et présente donc les mêmes inconvénients. En outre, l'emploi d'écran thermique passif ne permet pas d'obtenir des produits homogènes et plans dans le cas de solutions visqueuses, notamment lorsqu'elles sont disposées en grande épaisseur.Thus, according to this document, provision is made for the use of a passive heat shield. However, it has appeared in practice that such a passive heat shield does not solve the technical problems stated above and therefore has the same drawbacks. In addition, the use of passive heat shield does not make it possible to obtain homogeneous and flat products in the case of viscous solutions, in particular when they are arranged in great thickness.
La présente invention a donc pour but de résoudre le nouveau problème technique consistant en la fourniture d'une solution permettant d'obtenir par lyophilisation des produits lyophilisés homogènes, ou à homogénéité grandement améliorée, par rapport aux produits obtenus par les procédés et appareillages de lyophilisation antérieurement connus.The present invention therefore aims to solve the new technical problem consisting in the supply of a solution making it possible to obtain, by lyophilization, lyophilized products which are homogeneous, or with greatly improved homogeneity, compared to the products obtained by the lyophilization processes and apparatus previously known.
La présente invention a encore pour but principal de résoudre le nouveau problème technique consistant en la fourniture d'un procédé et d'un appareil de lyophilisation de produits ou de solutions diverses visqueux, très difficiles à lyophiliser, permettant d'obtenir des produits très homogènes et plans.The main object of the present invention is also to solve the new technical problem consisting in providing a method and an apparatus for lyophilizing various viscous products or solutions, very difficult to lyophilize, making it possible to obtain very homogeneous products. and plans.
La présente invention a encore pour but principal de résoudre le nouveau problème technique consistant en la fourniture d'un procédé et d'un appareil de lyophilisation de produits ou de solutions diverses, notamment des solutions visqueuses, même disposés en grande épaisseur, aboutissant à des produits lyophilisés homogènes.The main object of the present invention is also to solve the new technical problem consisting in the supply of a method and an apparatus for lyophilization of various products or solutions, in particular viscous solutions, even when placed in great thickness, leading to homogeneous freeze-dried products.
La présente invention a encore pour but de résoudre le nouveau problème technique consistant en la fourniture d'un procédé et d'un appareil de lyophilisation de produits ou de solutions diverses, notamment des solutions visqueuses, pouvant être disposés en grande épaisseur, aboutissant à des produits homogènes, d'une conception extrêmement simple, d'un faible coût de fabrication, utilisables à l'échelle industrielle.The present invention also aims to solve the new technical problem consisting in the supply of a method and an apparatus for lyophilization of various products or solutions, in particular viscous solutions, which can be arranged in great thickness, resulting in homogeneous products, of an extremely simple design, of a low manufacturing cost, usable on an industrial scale.
Tous ces nouveaux problèmes techniques sont résolus pour la première fois par la présente invention d'une manière simple, utilisable à l'échelle industrielle.All these new technical problems are solved for the first time by the present invention in a simple manner, usable on an industrial scale.
Selon un premier aspect, la présente invention fournit un procédé de lyophilisation de produits ou solutions diverses, notamment des solutions visqueuses, pouvant être disposés en grande épaisseur, comprenant la mise en place de produits ou solutions à lyophiliser, pouvant être contenus dans des récipients ouverts, sur des étagères de lyophilisation disposées à l'intérieur d'une enceinte de lyophilisation, lesdites étagères comprenant des moyens de refroidissement et des moyens de chauffage associés, de préférence incorporés, comprenant tout d'abord une étape de congélation de produits ou solutions à lyophiliser, et ensuite une étape de lyophilisation proprement dite avec sublimation de l'eau contenue dans le produit congelé, caractérisé en ce qu'on prévoit entre lesdites étagères de lyophilisation, des moyens formant écran thermique actif comprennant des moyens chauffants et/ou refroidissants permettant de ralentir les échanges thermiques entre la surface du produit et lesdits moyens de refroidissement ou de chauffage associés aux étagères, en obtenant ainsi des produits lyophilisés sensiblement homogènes.According to a first aspect, the present invention provides a process for lyophilization of various products or solutions, in particular viscous solutions, which can be arranged in great thickness, comprising the placement of products or solutions to be lyophilized, which can be contained in open containers. , on lyophilization shelves arranged inside a lyophilization enclosure, said shelves comprising cooling means and associated heating means, preferably incorporated, firstly comprising a step of freezing products or solutions to freeze-drying, and then a freeze-drying step proper with sublimation of the water contained in the frozen product, characterized in that provision is made between said freeze-drying shelves, means forming an active thermal screen comprising heating and / or cooling means allowing to slow down the heat exchanges between the surface of the product and said means cooling or heating associated with the shelves, thereby obtaining substantially homogeneous lyophilized products.
Selon une variante de réalisation particulière, les moyens chauffants des moyens formant écran actif sont mis en fonctionnement pendant l'étape de congélation.According to a particular variant embodiment, the heating means of the active screen means are put into operation during the freezing step.
Selon une autre variante de réalisation particulière, les moyens refroidissants des moyens formant écran actif précités sont mis en fonctionnement pendant la lyophilisation proprement dite.According to another particular variant embodiment, the cooling means of the above-mentioned active screen means are put into operation during the lyophilization proper.
Selon encore une autre variante de réalisation particulière, les moyens chauffants et/ou refroidissants des moyens formant écran actif prennent la forme de résistances chauffantes.According to yet another particular variant embodiment, the heating and / or cooling means of the active screen means take the form of heating resistors.
Selon un autre mode de réalisation particulier, ces moyens chauffants et/ou refroidissants sont constitués par la réalisation des moyens formant écran sous forme de plaques creuses dans lesquelles on fait circuler un fluide caloporteur.According to another particular embodiment, these heating and / or cooling means are constituted by the production of screen forming means in the form of hollow plates in which a heat transfer fluid is circulated.
Un deuxième aspect de la présente invention concerne aussi un appareil de lyophilisation de produits ou solutions diverses, notamment des solutions visqueuses, pouvant être disposés en grande épaisseur, comprenant des étagères de lyophilisation disposées à l'intérieur d'une enceinte de lyophilisation, sur lesquelles on peut mettre des produits ou solutions à lyophiliser, pouvant être contenus dans des récipients ouverts, ainsi que des moyens de refroidissement et/ou de chauffage associés, de préférence réalisés incorporés, auxdites étagères, caractérisé en ce que des moyens formant écran thermique actif sont disposés entre lesdites étagères de lyophilisation, comprenant des moyens chauffants et/ou refroidissants, en permettant ainsi de ralentir les échanges thermiques entre la surface du produit à lyophiliser et les éléments chauffants et/ou refroidissants associés aux étagères.A second aspect of the present invention also relates to an apparatus for freeze-drying various products or solutions, in particular viscous solutions, which can be arranged in great thickness, comprising freeze-drying shelves placed inside a freeze-drying enclosure, on which it is possible to put products or solutions to be lyophilized, which may be contained in open containers, as well as associated cooling and / or heating means, preferably made incorporated, into said shelves, characterized in that means forming an active heat shield are disposed between said lyophilization shelves, comprising heating and / or cooling means, thereby making it possible to slow down the heat exchanges between the surface of the product to be lyophilized and the heating and / or cooling elements associated with the shelves.
Selon une variante de réalisation particulière, ces moyens formant écran actif peuvent être réalisés sous forme de plaques, avantageusement de forme adaptée aux étagères de lyophilisation, et peuvent être fixés sous lesdites étagères, c'est-à-dire à l'opposé des produits à lyophiliser reposant sur ladite étagère.According to a particular variant embodiment, these means forming an active screen can be produced in the form of plates, advantageously of a shape adapted to the lyophilization shelves, and can be fixed under said shelves, that is to say opposite to the products. freeze-drying resting on said shelf.
Selon un mode de réalisation particulier, ces plaques constituant les moyens formant écran actif renferment des résistances chauffantes.According to a particular embodiment, these plates constituting the means forming an active screen contain heating resistors.
Selon un autre mode de réalisation particulier, ces plaques contiennent, noyées dans la masse, des éléments susceptibles de chauffer lors de la congélation et de refroidir lors de la lyophilisation proprement dite (étape de sublimation de l'eau).According to another particular embodiment, these plates contain, embedded in the mass, elements capable of heating during freezing and of cooling during the lyophilization proper (step of sublimation of water).
Selon encore un autre mode de réalisation, les plaques constituant les moyens formant écran actif sont creuses et sont prévues pour permettre la circulation d'un fluide caloporteur à l'intérieur desdites plaques.According to yet another embodiment, the plates constituting the active screen means are hollow and are provided to allow the circulation of a heat transfer fluid inside said plates.
Selon encore un autre mode de réalisation de l'appareil selon l'invention, celui-ci est caractérisé en ce que les calories ou le fluide caloporteur circulant à l'intérieur des plaques formant écran proviennent du système de réchauffement et de refroi dissement des plateaux de lyophilisation, les calories utilisées étant celles fournies par le groupe frigorifique lors du refroidissement de l'opération de congélation tandis que pendant la période de lyophilisation, au contraire, les frigories sont envoyées dans les plaques formant écran actif et les calories dans les plateaux de lyophilisation.According to yet another embodiment of the device according to the invention, it is characterized in that the calories or the heat-transfer fluid circulating inside the plates forming the screen come from the heating and cooling system of the freeze-drying trays, the calories used being those supplied by the refrigeration unit during the cooling of the freezing operation while during the freeze-drying period, on the contrary, the frigories are sent to the plates forming an active screen and the calories in lyophilization trays.
Selon une autre variante de réalisation de l'appareil de lyophilisation selon l'invention, celui-ci est caractérisé en ce que les calories du fluide caloporteur circulant à l'intérieur des plaques formant écran actif proviennent d'un système de chauffage autonome, interne ou externe au lyophilisateur.According to another alternative embodiment of the lyophilization device according to the invention, it is characterized in that the calories of the heat transfer fluid circulating inside the plates forming an active screen come from an autonomous, internal heating system or external to the freeze dryer.
Grâce au procédé et à l'appareil selon l'invention, on obtient des produits lyophilisés de caractéristique(s) homogène(s), comme ceci sera démontré ci-après dans l'exemple indiqué en référence aux dessins annexés.Thanks to the process and the apparatus according to the invention, freeze-dried products of homogeneous characteristic (s) are obtained, as will be demonstrated below in the example indicated with reference to the accompanying drawings.
Cet exemple est donné simplement à titre d'illustration et ne saurait en aucune façon limiter la portée de la présente invention.This example is given simply by way of illustration and cannot in any way limit the scope of the present invention.
Dans les dessins :
- la figure 1 est une vue en coupe partielle de l'appareil de lyophilisation selon l'invention représentant deux étagères successives de l'appareil de lyophilisation, selon l'art antérieur,
- la figure 2 représente, en perspective, en coupe partielle, plusieurs étagères de l'appareil de lyophilisation équipé de moyens formant écran, selon l'invention.
- FIG. 1 is a partial section view of the freeze-drying device according to the invention showing two successive shelves of the freeze-drying device, according to the prior art,
- 2 shows, in perspective, in partial section, several shelves of the lyophilization device equipped with screen means, according to the invention.
En référence à la figure 1, l'appareil de lyophilisation représenté par la numéro de référence général 1 comprend de manière classique des étagères 2, sur lesquelles sont disposés des produits ou solutions diverses à lyophiliser 4, éventuellement contenus dans des récipients ouverts 6.With reference to FIG. 1, the lyophilization device represented by the
Ces étagères 2 sont habituellement équipées de moyens de chauffage et de refroidissement, permettant de réaliser l'étape de congélation, puis l'étape de sublimation de l'eau contenue dans le produit congelé.These shelves 2 are usually equipped with heating and cooling means, making it possible to carry out the freezing step, then the step of sublimation of the water contained in the frozen product.
En pratique, les étagères 2 sont réalisées creuses et on fait circuler à l'intérieur de celles-ci un produit caloporteur porté soit à la température nécessaire pour la congélation des produits, soit à la température nécessaire à la sublimation de l'eau.In practice, the shelves 2 are made hollow and a heat transfer product is circulated inside them brought either to the temperature necessary for freezing the products, or to the temperature necessary for the sublimation of the water.
Avec un tel appareil de lyophilisation, selon l'art antérieur, lorsque le liquide emprisonné dans le produit 4 commence à se congeler, du liquide passe à travers la paroi congelée de la surface en formant un monticule 8 au-dessus de l'ouverture 7 du récipient 6 dans lequel est obtenu le produit 4, qui se congèle au-dessus de cette ouverture 7, comme clairement visible à la figure 1.With such a lyophilization device, according to the prior art, when the liquid trapped in the product 4 begins to freeze, liquid passes through the frozen wall of the surface, forming a
Egalement, il se forme une croute à la surface du produit provoquée par une décongélation due à un chauffage par rayonnement de l'étagère du lyophilisateur situé juste au-dessus du plateau de lyophilisation sur lequel repose le produit, et à l'absence d'une conduction thermique suffisante à l'intérieur du produit.Also, a crust forms on the surface of the product caused by thawing due to radiation heating of the freeze dryer shelf located just above the freeze drying tray on which the product rests, and the absence of sufficient thermal conduction inside the product.
Cette décongélation entraîne la liquéfaction du produit qui ne se sublime plus mais alors s'évapore.This thawing results in the liquefaction of the product which no longer sublimates but then evaporates.
Il se forme alors une croute plus compacte à la surface du produit qui rend le produit lyophilisé hétérogèneA more compact crust forms on the surface of the product, which makes the lyophilized product heterogeneous.
Ce défaut majeur des appareils de lyophilisation antérieurs est résolu par l'appareil de lyophilisation selon l'invention représenté à la figure 2.This major defect in prior lyophilization devices is resolved by the lyophilization device according to the invention shown in FIG. 2.
A la figure 2, on a représenté un appareil de lyophilisation selon l'invention reférencé 10, qui comporte également des étagères de lyophilisation 12, qui peuvent être identiques à celles de l'appareil de lyophilisation réprésenté à la figure 1, tel que décrit ci-dessus.In Figure 2, there is shown a lyophilization apparatus according to the invention referenced 10, which also includes
Cependant, selon l'invention, cet appareil 10 de lyophilisation comprend des moyens formant écran thermique actif 14, disposés entre les étagères 12, comme cela est clairement compréhensible à partir de la figure 2.However, according to the invention, this
En pratique, il est plus aisé de fixer ces moyens formant écran actif 14 sous les étagères 12.In practice, it is easier to fix these means forming an
Ces moyens formant écran actif 14 peuvent être conformés aux dimensions des étagères 12.These means forming an
Ainsi, selon une variante de réalisation particulière, ces moyens formant écran actif peuvent prendre la forme de plaques.Thus, according to a particular embodiment, these means forming an active screen can take the form of plates.
Selon une première réalisation, les plaques constituant les moyens formant écran actif comprennent des moyens chauffants et/ou des moyens refroidissants.According to a first embodiment, the plates constituting the means forming an active screen comprise heating means and / or cooling means.
Ces moyens chauffants peuvent être formés par de simples résistances chauffantes.These heating means can be formed by simple heating resistors.
Les moyens chauffants et/ou refroidissants des moyens formant écran 14 peuvent être constitués par un fluide caloporteur circulant dans les plaques qui sont alors réalisées creuses.The heating and / or cooling means of the
Cet appareil fonctionne selon le procédé précédemment décrit ; ainsi, on effectue un chauffage à l'intérieur du moyen formant écran pendant la congélation. Ceci permet de ralentir avantageusement l'échange thermique entre la surface du produit et les éléments refroidissants de l'appareil de lyophilisation, contenus dans les étagères, pendant l'étape de congélation.This device operates according to the method previously described; thus, heating is carried out inside the screen means during freezing. This advantageously slows down the heat exchange between the surface of the product and the cooling elements of the lyophilization device, contained in the shelves, during the freezing step.
Selon un mode de réalisation avantageux, les moyens formant écran actif réalisent un refroidissement pendant l'étape de lyophilisation proprement dite, qui est contrôlé de façon que la température du produit congelé s'élève de manière graduelle.According to an advantageous embodiment, the means forming an active screen cool down during the lyophilization stage proper, which is controlled so that the temperature of the frozen product rises gradually.
On donne ci-après un exemple de réalisation pratique de l'invention mettant en ouvre le procédé de réalisation selon l'invention précédemment décrite.An exemplary practical embodiment of the invention is given below, implementing the production method according to the invention described above.
Préparation d'un tampon de collagène à visée hémostatique pour la chirurgie.Preparation of a collagen buffer for hemostatic purposes for surgery.
Dans les plateaux est versé du gel de collagène contenant 0,7 % de protéine. L'épaisseur de gel étant de l2mm. La congélation est réalisée à 60°C pendant 3 heures. Pendant ce laps de temps, les moyens chauffants des moyens formant écran actif 14, constitués par des résistances chauffantes, d'une puissance de 225W/m² sont alimentés sous une tension de 220V. A la fin de cette phase, l'alimentation électrique est stoppée et la lyophilisation est mise en route. Pour cela un vide de 0,3 mb est réalisé dans l'enceinte du lyophilisateur et les étagères sont chauffées de telle façon que la température du produit congelé se maintienne à -25°C. Cette dernière phase dure environ 16 heures. Ensuite intervient la dessication secondaire au cours de laquelle le vide est abaissé jusqu'à 10⁻²mb et la température du produit portée à 40°C. Cette opération prend à peu près 3 heures.In the trays is poured collagen gel containing 0.7% protein. The thickness of the gel is 12 mm. Freezing is carried out at 60 ° C for 3 hours. During this period of time, the heating means of the active screen means 14, constituted by heating resistors, with a power of 225W / m² are supplied with a voltage of 220V. At the end of this phase, the power supply is stopped and freeze-drying is started. For this, a vacuum of 0.3 mb is created in the enclosure of the freeze dryer and the shelves are heated so that the temperature of the frozen product is maintained at -25 ° C. This last phase lasts approximately 16 hours. Then comes secondary desiccation during which the vacuum is lowered to 10⁻²mb and the product temperature raised to 40 ° C. This operation takes approximately 3 hours.
Afin de déterminer la relative homogénéité du matériau obtenu, à l'aide d'une scie tournante, deux couches de 2mm d'épaisseur sont refendues : l'une à partir du côté du biomatériau qui était tourné vers l'étagère supérieure lors de la lyophilisation, et l'autre à partir du côté en contact avec le plateau placé sur l'étagère de refroidissement et de chauffage. Ces deux couches ont été pesées pour cinq lyophilisations différentes.
Ces résultats sont à comparer avec ceux obtenus par le même lyophilisateur non équipé des moyens écran actif faisant l'objet de l'invention :
Les premiers résultats sont également à comparer à ceux obtenus par le même lyophilisateur équipé de moyens écrans passifs constitués seulement d'un matériau isolant.The first results are also to be compared with those obtained by the same freeze dryer equipped with passive screen means made only of an insulating material.
Les résultats consignés dans le tableau suivant ont été obtenus avec des écrans passifs constitués de mousse formophénolique à pores fermés d'une épaisseur de 2 cm, distance maximum disponible entre les plateaux de lyophilisation.
Il ressort immédiatement des trois tableaux précédents que la différence de poids relative des deux couches externes du produit lyophilisé est beaucoup plus faible dans le cas de l'utilisation des moyens écrans (14) de l'invention que dans le cas d'une lyophilisation classique ou d'une lyophilisation avec des moyens écrans passifs.It immediately emerges from the three preceding tables that the difference in relative weight of the two external layers of the lyophilized product is much smaller in the case of the use of the screen means (14) of the invention than in the case of conventional lyophilization or freeze-drying with passive screen means.
L'invention est particulièrement intéressante d'une part, dans le cas de lyophilisation de solutions visqueuses à l'intérieur desquelles les échanges thermiques par convection sont très difficiles, et d'autre part, dans le cas de lyophilisation de grandes épaisseurs qui empêchent des échanges thermiques rapides entre la face du produit en contact avec l'étagère du lyophilisateur et la surface.The invention is particularly advantageous on the one hand, in the case of lyophilization of viscous solutions inside which the heat exchanges by convection are very difficult, and on the other hand, in the case of lyophilization of large thicknesses which prevent rapid heat exchanges between the face of the product in contact with the freeze dryer shelf and the surface.
Dans le cas où l'écran est formé par des plaques contenant des résistances chauffantes, ou dans lesquelles passe un fluide caloporteur, le matériau constituant les plaques est un matériau thermiquement conducteur, avantageusement un métal, par exemple de l'aluminium anodisé ou un acier inoxydable.In the case where the screen is formed by plates containing heating resistors, or in which a heat transfer fluid passes, the material constituting the plates is a thermally conductive material, advantageously a metal, for example anodized aluminum or a steel. stainless.
Selon une variante de réalisation de l'appareil de lyophilisation selon l'invention, celui-ci est caractérisé en ce que les calories ou le fluide caloporteur circulant à l'intérieur des plaques formant écran actif proviennent du système de réchauffement et de refroidissement des plateaux de lyophilisation, les calories utilisées étant celles fournies par un groupe frigorifique lors du refroidissement de l'opération de congélation, tandis que pendant la période de lyophilisation, au contraire, les frigories sont envoyées dans les plaques formant écran actif et les calories dans les plateaux de lyophilisation.According to an alternative embodiment of the lyophilization device according to the invention, it is characterized in that the calories or the heat transfer fluid circulating inside the plates forming an active screen come from the system for heating and cooling the plates freeze-drying, the calories used being those supplied by a refrigeration unit during the cooling of the freezing operation, while during the freeze-drying period, on the contrary, the frigories are sent to the plates forming an active screen and the calories to the trays lyophilization.
Selon encore une autre variante de réalisation de l'appareil de lyophilisation selon l'invention, celui-ci est caractérisé en ce que les calories du fluide caloporteur circulant à l'intérieur des plaques formant écran actif proviennent d'un système de chauffage autonome, interne ou externe au lyophilisateur.According to yet another alternative embodiment of the lyophilization device according to the invention, it is characterized in that the calories of the heat-transfer fluid circulating inside the plates forming an active screen come from an autonomous heating system, internal or external to the freeze dryer.
Claims (12)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT88402845T ATE79461T1 (en) | 1987-11-17 | 1988-11-14 | FREEZE-DRYING DEVICE WITH MEANS OF FORMING AN ACTIVE THERMAL SHIELD BETWEEN THE FREEZE-DRYING SHELVES. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8715880A FR2623277B1 (en) | 1987-11-17 | 1987-11-17 | LYOPHILIZATION METHOD AND APPARATUS COMPRISING THERMAL SHIELDING MEANS BETWEEN LYOPHILIZATION SHELVES |
| FR8715880 | 1987-11-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0317411A1 true EP0317411A1 (en) | 1989-05-24 |
| EP0317411B1 EP0317411B1 (en) | 1992-08-12 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP88402845A Expired - Lifetime EP0317411B1 (en) | 1987-11-17 | 1988-11-14 | Freeze-drying apparatus having means constituting an active thermal screen in between the freeze-drying shelves |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US4953299A (en) |
| EP (1) | EP0317411B1 (en) |
| JP (1) | JP2545592B2 (en) |
| AT (1) | ATE79461T1 (en) |
| CA (1) | CA1320428C (en) |
| DE (2) | DE317411T1 (en) |
| ES (1) | ES2010175T3 (en) |
| FR (1) | FR2623277B1 (en) |
| GR (1) | GR3005923T3 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999027315A1 (en) * | 1997-11-19 | 1999-06-03 | Ingo Heschel | Method for producing porous structures |
| WO2007066132A1 (en) * | 2005-12-09 | 2007-06-14 | Oxford Biosensors Limited | Freeze drying of target substances |
| EP2450033A1 (en) * | 2009-12-30 | 2012-05-09 | Baxter International Inc. | Thermal shielding to optimize lyophilization process for pre-filled syringes or vials |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5519946A (en) * | 1992-03-12 | 1996-05-28 | The Boc Group, Inc. | Freeze dryer shelf |
| DE4421421C2 (en) * | 1993-12-24 | 1996-08-29 | Daimler Benz Aerospace Airbus | Drying process for components made of fiber-reinforced plastics |
| US6454787B1 (en) | 1998-12-11 | 2002-09-24 | C. R. Bard, Inc. | Collagen hemostatic foam |
| US6361551B1 (en) | 1998-12-11 | 2002-03-26 | C. R. Bard, Inc. | Collagen hemostatic fibers |
| US6434913B1 (en) | 2000-09-15 | 2002-08-20 | Thomas Hatch | Single-use syringe |
| US7347004B1 (en) | 2005-01-13 | 2008-03-25 | Lyophilization Services Of New England, Inc. | Freeze drying apparatus and method |
| WO2009006891A1 (en) * | 2007-07-10 | 2009-01-15 | Niro A/S | Method for freeze-drying a product and freeze-drying apparatus for carrying out the method |
| DE102009008970A1 (en) * | 2008-12-04 | 2010-06-10 | Walter Wiedenmannott | Freeze dryer and method for operating a freeze dryer |
| GB2482166A (en) * | 2010-07-22 | 2012-01-25 | Tissue Science Lablratories Ltd | Manufacture of collagenous material from use in therapy from collagen particles |
| US8966782B2 (en) | 2010-09-28 | 2015-03-03 | Baxter International Inc. | Optimization of nucleation and crystallization for lyophilization using gap freezing |
| CA2811428A1 (en) | 2010-09-28 | 2012-04-26 | Baxter International Inc. | Optimization of nucleation and crystallization for lyophilization using gap freezing |
| EP3171109B1 (en) * | 2012-03-28 | 2018-11-14 | Baxter International Inc | Optimization of nucleation and crystallization for lyophilization using gap freezing |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3118742A (en) * | 1958-08-22 | 1964-01-21 | Nat Res Dev | Vacuum food press drier |
| US3135589A (en) * | 1961-09-29 | 1964-06-02 | Pennsalt Chemicals Corp | Drying apparatus |
| FR2284842A1 (en) * | 1974-09-11 | 1976-04-09 | Nestle Sa | IMPROVEMENT PROVIDES LYOPHILIZATION OF SOLID, LIQUID OR PASTE PRODUCTS |
| US4501719A (en) * | 1981-05-04 | 1985-02-26 | Marquest Medical Products, Inc. | Tray apparatus for freeze-drying biologicals having a predetermined unit dosage |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2602825A (en) * | 1948-01-24 | 1952-07-08 | Stokes Machine Co | Sublimation process and apparatus |
| JPS6015867B2 (en) * | 1980-07-04 | 1985-04-22 | 日本真空技術株式会社 | Vacuum freeze drying equipment |
| JPS5935242B2 (en) * | 1981-10-29 | 1984-08-28 | 山之内製薬株式会社 | freeze dryer shelf |
-
1987
- 1987-11-17 FR FR8715880A patent/FR2623277B1/en not_active Expired - Lifetime
-
1988
- 1988-11-14 DE DE198888402845T patent/DE317411T1/en active Pending
- 1988-11-14 DE DE8888402845T patent/DE3873695T2/en not_active Expired - Fee Related
- 1988-11-14 AT AT88402845T patent/ATE79461T1/en not_active IP Right Cessation
- 1988-11-14 EP EP88402845A patent/EP0317411B1/en not_active Expired - Lifetime
- 1988-11-14 ES ES198888402845T patent/ES2010175T3/en not_active Expired - Lifetime
- 1988-11-16 US US07/272,483 patent/US4953299A/en not_active Expired - Fee Related
- 1988-11-16 JP JP63287883A patent/JP2545592B2/en not_active Expired - Lifetime
- 1988-11-16 CA CA000583244A patent/CA1320428C/en not_active Expired - Fee Related
-
1992
- 1992-10-08 GR GR920402243T patent/GR3005923T3/el unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3118742A (en) * | 1958-08-22 | 1964-01-21 | Nat Res Dev | Vacuum food press drier |
| US3135589A (en) * | 1961-09-29 | 1964-06-02 | Pennsalt Chemicals Corp | Drying apparatus |
| FR2284842A1 (en) * | 1974-09-11 | 1976-04-09 | Nestle Sa | IMPROVEMENT PROVIDES LYOPHILIZATION OF SOLID, LIQUID OR PASTE PRODUCTS |
| US4501719A (en) * | 1981-05-04 | 1985-02-26 | Marquest Medical Products, Inc. | Tray apparatus for freeze-drying biologicals having a predetermined unit dosage |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999027315A1 (en) * | 1997-11-19 | 1999-06-03 | Ingo Heschel | Method for producing porous structures |
| US6447701B1 (en) | 1997-11-19 | 2002-09-10 | Ingo Heschel | Method for producing porous structures |
| WO2007066132A1 (en) * | 2005-12-09 | 2007-06-14 | Oxford Biosensors Limited | Freeze drying of target substances |
| EP2450033A1 (en) * | 2009-12-30 | 2012-05-09 | Baxter International Inc. | Thermal shielding to optimize lyophilization process for pre-filled syringes or vials |
| US8371039B2 (en) | 2009-12-30 | 2013-02-12 | Baxter International Inc. | Thermal shielding to optimize lyophilization process for pre-filled syringes or vials |
| US8544183B2 (en) | 2009-12-30 | 2013-10-01 | Baxter International Inc. | Thermal shielding to optimize lyophilization process for pre-filled syringes or vials |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2010175T3 (en) | 1993-04-01 |
| US4953299A (en) | 1990-09-04 |
| ATE79461T1 (en) | 1992-08-15 |
| FR2623277A1 (en) | 1989-05-19 |
| DE3873695D1 (en) | 1992-09-17 |
| DE317411T1 (en) | 1989-11-16 |
| EP0317411B1 (en) | 1992-08-12 |
| JPH02110281A (en) | 1990-04-23 |
| FR2623277B1 (en) | 1990-04-27 |
| CA1320428C (en) | 1993-07-20 |
| DE3873695T2 (en) | 1993-01-21 |
| ES2010175A4 (en) | 1989-11-01 |
| JP2545592B2 (en) | 1996-10-23 |
| GR3005923T3 (en) | 1993-06-07 |
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