NL1022668C2 - Stirred freeze drying. - Google Patents

Abstract

Method and device for freeze drying solutions and liquid containing solid substances, in which a vessel (1) is applied having a downwardly conical shape with inside a rotating mixing member (3) that moves with a small inter-space along the wall (2) of the vessel. With the new method in an advantageous manner free flowing products are obtained. Even new homogenous mixtures of a molecular scale of two or more substances are obtained, which are excellently usable in the industry of new materials.

Description

Short description: Stirred freeze drying

Description 5

The invention relates to a method and an apparatus for drying solutions and liquid-containing solids, wherein a vessel with a downwardly conical shape 1 with a mixer 3 circulating along the wall 2 thereof is used, said mixer 3 having low space around said wall 2, said vessel 1 is provided with a jacket 4 and connected to a vacuum system 5.

From US-A-4,245,399 a device is known for drying products of different types, which may be particulate materials with different moisture contents, comprising substances thoroughly wetted with, for example, organic solvents and possibly of a tacky nature, with substantially the above characteristics.

With reference to the term essentially, it is to be understood that this means that the above-mentioned vessel 1 is a cylindrical vessel with a downwardly conical end, wherein a mixing member 3 circulating along the entire inner wall 2 with a small gap is provided.

The clearance or clearance is at most 5 mm (see column 2, lines 26-30). The provision of the mixing member 30 3 circulating with a small gap in order to effectively prevent caking of the material to be freeze-dried i / .2 § 6 I on the inner wall of the vessel 1.

The drying device known from US-A-4,245,399 is provided with a supply of a drying gas and, in view of the consideration of sticky substances in particular, was not seen as a device for freeze-drying relatively large loads of I products.

Freeze drying or lyophilization, on the other hand, is sublimation of a solvent which is crystallized at low temperature. The solvent is hereby sublimated directly from the solid state in the vapor phase. With freeze-drying a product can be obtained with good shelf life and what will remain unchanged after re-combining with the solvent. In other words, through the freeze-drying process, the material to be dried is frozen in its original structure I and the solvent is removed from this structure I without changing this structure. In the case of, for example, an organic cell, the external cell wall will retain its original shape with lyophilization, while with thermal drying the cell will gradually shrink and the original structure cannot be fully obtained after rewetting. Another important aspect of freeze drying is the low drying temperature, so there is no thermal load on the material to be dried.

I Conventional freeze dryers are of the "trays-in-cabinet" type I in cupboard. The freeze dryer is in that case a stationary chamber with a number of fixed plates (or plates) covered with the frozen substrate.

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A heating circuit is provided under the trays or plates for supplying the sublimation energy. After closing the room, the system is evacuated and the sublimation process begins.

A major disadvantage of this type of freeze dryer is clod formation when the material is dried on a large scale. Despite the optimum structure of the individual product particles, the material on the trays or plates will usually form a piece of hard-caked material. Often the product must be crushed after freeze drying, which can lead to damage to the product structure.

Another disadvantage is the relatively low heat transfer rate due to the resting state of the material.

Surprisingly, it has now been found that by using a vessel with a downwardly conical shape a mixing member 3, which is provided with a mixing member 3 circulating with little space between it, the drawbacks of the usual freeze-drying process can be avoided.

With a so-called "stirred freeze dryer" according to the invention, operated at low temperature and low pressure, it appeared to be possible to obtain a lump-free and free-flowing product.

Stirred freeze dryers also have the advantage of a better heat transfer rate, due to the continuous mixing of the product to be dried, which shortens the drying process.

Finally, the use of a stirred freeze dryer often leads to a simplification of the freezing step, i). 1 r ·.

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H since it can be carried out in the same device as that of the drying step. After all, no separate freezer is now required. In conventional devices, the material to be freeze-dried is often frozen in separate freezers and subsequently introduced into separate vacuum drying devices.

Very often said conical vessel will form part H of a conical mixer 6, because of the good technical results obtained with conical mixers.

It is noted that cylindrical vessels provided with a conical end with a mixing member circulating along the inner wall thereof at a small space between them are also applicable and can be used because of the advantage of saving space.

In connection with good mixing, however, a certain dimension ratio of the cylindrical part and the conical part must be taken into account in that case. It is also noted that a mixing vessel 1 of a so-called "classical" conical mixer in the vicinity of the lid often comprises a short cylindrical portion, in connection with space for auxiliary equipment such as drive motors and material supplies. Reference is further made, for example, to JP-2001263942 (5 pages), in which a conical mixer is described with a cylindrical part connected to the conical end, see the I figures on pages 1 and 4.

The term conical mixer is also understood to be a so-called double-conical mixer, although the construction thereof is more complicated.

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According to a variant of the new freeze-drying method, a charge to be dried is frozen in the vessel 1 by direct cooling.

A suitable method of direct cooling is to introduce liquid nitrogen or solid carbonic acid into the vessel 1 and to mix with the charge to be dried.

Of course, cooling for freezing the charge in the vessel 1 can also take place by indirect cooling via the wall 2 of the vessel by introducing a suitable cooling medium into the jacket 4. A low temperature cooling medium is used as the cooling medium.

It has been found experimentally that it is advantageous to freeze the charge to be dried at a freezing rate of 0.1 - 10 ° C / min. Of course, the freezing takes place with stirring or moving of the mixer 3, the freezing speed being controlled by dosing direct coolant or controlling flow rate and / or temperature of the low temperature coolant.

After freezing the charge to be dried, the temperature thereof is 0 - -60 ° C. The temperature of the frozen charge to be freeze-dried depends on the solvent to be sublimated and the nature of the charge to be freeze-dried.

Preferably, the temperature of the charge to be dried after freezing is -55 - -15 ° C.

A suitable vacuum for sublimating the solvent is a vacuum running from 5 mbar - 0.01 mbar (preferably <0.1 mbar). Of course, all this is I Ü .c. L afhankelijk 6 H depends on the solvent to be sublimated and the H nature of the charge to be dried.

When used with a technically used conical mixer, for a 50 liter load, a two-stage or five-stage vacuum pump system 5 has been found to be particularly suitable in connection with H process control.

It is of course possible to freeze-dry solutions such as solutions of proteins and / or other pharmaceutical products to use a so-called dry single vacuum pump without a condenser, as described in US-A-5948144 or the corresponding WO99 / 18402.

The use of such a vacuum system is dependent on the solvent vapor to be sublimated.

It is further noted that in column 4 lines I 14-16 of USA-A-5948144 it is stated "Lyophilized cakes looked as good or better than those produced with an I cold trap condenser in opertion". Thus, with the previously known method for freeze-drying solutions, no free-flowing product, but a cake is obtained. US-A-5948144 relates to a freeze dryer of the "trays-on-cabinet" type mentioned in the introduction I.

With regard to the required small gap between the wall 2 of the conical vessel 1 and the mixer 3 scraping off the wall, it is noted that it is preferably between 0.5 and 15 mm.

More preferably, the gap between wall 2 and mixer 3 is between 1 and 10 mm.

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Without limitation to a specific type of wall-scraper mixing member 3, preferred mixing members are a centrally driven ribbon-shaped element, a centrally driven blade element or an orbital screw element provided with a swinging arm.

Because freeze drying is a slow process, typical drying times 10-100 hours for a 50 liter load, only a slight mixing action during the freeze drying step is necessary. The above-mentioned mixing members are now extremely suitable for this purpose. Slight mixing action during freeze-drying prevents excessive heat input and a product of excellent quality is surprisingly obtained.

The use of a particular type of element used as a mixing device 15 depends on the required application, which in turn depends on the material to be dried and the freezing method used.

When using a wall scraper mixer, it is of paramount importance that the member or element 3, during its movement, strokes the entire area where the product to be obtained is in contact with the wall 2.

Since low vacuum leakage rates are essential for maintaining a high vacuum level, according to a preferred embodiment the mixer 3 is coupled to its drive 6 via a magnetic coupling 16.

Another preferred solution is that only a drive 6 is used for the mixer 3 with only a rotating seal relative to the vessel 1.

* 022668 H In the case where relatively low temperatures are used, according to a preferred embodiment, the drive unit 6 is constructed such that it has bearings 7 outside the vessel 1.

5 This is to prevent the lubricants in the bearings 7 from freezing, resulting in operational failures.

H According to a preferred embodiment of the new H method, the conical vessel 1 is connected to an H condenser 8, as known from the aforementioned US-A-4245399, see figure 1, reference number 48 and column 3 lines 58 and 59.

Since a lot of water must be removed therefrom during lyophilization of solutions and the like, this condenser 8 has a gap between 15 cooling housings 9 of at least 3-4 cm for operating conditions up to a maximum ice layer of approximately 1 cm on the cooling housings 9.

In connection with the large amount of solvent to be sublimated (water vapor), a double condenser 8 is used according to a preferred embodiment, one of which is in operation during freeze-drying and the other is thawed.

According to a preferred embodiment, a filter 10 with a large filter surface is used between the condenser 8 and the vessel 1, to prevent contamination of the condenser 8 by dust from the product to be dried during freeze-drying. The filter must then have a large filter surface in order to keep the pressure drop across it low.

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At high vacuum levels, however, it is preferable to avoid even this pressure drop and to connect the condenser 8 directly to the vessel 1.

According to another preferred embodiment, when connecting the condenser 8 directly to the vessel 1, the condenser is placed next to the vessel 1.

It is also possible to provide the filter 8 with a heat exchanger 16.

The invention is explained below with nine figures, in which the same reference numerals are used for parts with the same functions.

It is noted that not all of the aforementioned aspects of the invention have been explained in the accompanying figures, inter alia not explained is the direct freezing by means of liquid nitrogen or solid carbonic acid and the use of a dual condenser.

In the figures: FIG. 1 a general system overview of the stirred freeze-drying according to the invention; FIG. 2 a construction in which the condenser is mounted directly above the drying vessel; FIG. 3 a construction in which the condenser is mounted next to the drying vessel;

FIG. 4 a construction in which the filter is present between drying vessel and condenser;

FIG. 5 a construction in which a centrally driven ribbon-shaped mixer is used in the drying vessel; '' · '· O j 3 H Fig. 6 a construction in which a central H-driven vane element is used in the drying vessel; H FIG. 7 a construction in which an orbital screw element provided with a swinging arm is used in the drying vessel;

FIG. 8 is a construction in which the drive unit and the bearings are located outside and at a distance from the drying vessel; FIG. 9 shows a construction in which there is a magnetic coupling between the drive of the mixer outside the drying vessel and the mixer itself inside the drying vessel.

Description of the figures

In the general system diagram shown in FIG.

1 represent 1,2,3 and 4 respectively for the vessel 1, the inner wall 2 thereof, the mixer 3 and the jacket 4 of the vessel 1.

Above the vessel 1 there is a condenser 8 which is connected to a two-stage vacuum system 5, which comprises two vacuum pumps 13 and 14. The vessel jacket 4 is connected to both a cooling unit 11 and a heating unit 12.

The freeze-drying method is controlled with a pressure and temperature control unit 15, which is indicated by P and T.

In the control diagram the drive 6 of the mixer 4 is shown with Μ, M or 6 not included in the circuit of the control unit 15. Not including the drive M or 6 in this circuit is because slow and good mixing of the charge in the vessel 1 is such that incorporation of the mixing motor power 5 into the circuit is superfluous.

This nevertheless leads to an exceptionally good product and a simplification of the required control circuit.

FIG. 2 is a representation of a structure 10 in which the condenser 8 is located directly on the vessel 1.

FIG. 3 is an illustration of a construction in which the condenser 8 is located next to it to prevent the material 1 from being spilled over.

FIG. 4 is a representation of a construction in which a filter 10 provided with a heat exchanger 16 is placed between the vessel 1 and the condenser 8. The heat exchanger 16 serves to prevent condensation of vapor by heating, as a result of which the filter 10 could otherwise to hide.

FIG. 5 is a depiction of a construction in which a centrally driven ribbon-shaped mixer 3a is located within the vessel.

FIG. 6 and 7 are illustrations of constructions, wherein a centrally driven vane mixing element 3b and an orbital screw mixing element provided with a swinging arm 3c are present within the vessel 1, respectively.

FIG. 8 is a representation of a structure 30 in which the bearings 7 of the drive unit 6 for the mixing element 3 are located outside the vessel 1.

H As stated earlier, the bearings 7 are located outside the vessel 1 in connection with the prevention of freezing H of the lubricants therein.

FIG. 9 is an illustration of a construction 5 wherein the drive 6 is coupled to the mixing element 3 by means of a magnetic coupling 16. As stated earlier, this construction is used to minimize vacuum leakage losses. After all, the wall 2 of the vessel 1 is in this case not cut through by a bore for an axis.

Naturally, modifications of the structures illustrated with figures are possible within the scope of the appended claims.

With regard to applications of the new method for freeze-drying, it can be stated that the H main application lies in the field of the pharmaceutical industry. About 30% of all antibiotics, 90% of the macromolecules and 50% of the electrolytes are produced using lyophilization.

Other products that are typically prepared with lyophilization are proteins, hormones, vaccines, bacteria, yeasts, blood serum, liposomes and transplantation materials such as collagen sponge.

I The decisive factor to apply freeze-drying to all these products I is the maintenance of structure I and the low temperature load.

In the food industry, the second important application area of freeze-drying lies.

Maintaining taste, improved shelf life and ready-made features are important issues. Vegetables, potatoes, fruit, juices, coffee, eggs and rice are typically freeze-dried materials.

A third important area of application for the large-scale application of freeze-drying is the area of new materials. In particular, one can think of metal oxides, ceramics, special composite materials and nanomaterials. Application of freeze drying with these materials has special advantages. During the freezing and drying process, the particles suspended in a liquid or solvent remain separated from each other, so that hard agglomerates that are caked together are not obtained. It is even possible to obtain homogeneous mixtures at a molecular scale through lyophilization. This is an important completely new development in which new mixtures of two or more substances are obtained on a molecular scale.

The new homogeneous mixtures of two or more substances on a molecular scale are particularly well applicable in the industry of new materials.

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Claims (33)

Method according to claim 1, characterized in that said conical vessel (1) forms part of an I conical mixer (6). Method according to claim 1 or 2, characterized in that a charge to be dried is frozen in said conical vessel (1) by direct cooling. 4. A method according to claim 3, characterized in that liquid nitrogen or solid carbonic acid is introduced into said conical vessel (1) and mixed with the charge to be dried. 5. A method according to any one of the preceding claims, characterized in that the load to be cooled is frozen at a freezing speed of 0.1 - 10 ° C / min. Method according to claim 5, characterized in that the temperature of the charge to be dried in the vessel (1) after freezing is 0 - -60 ° C. 5 Method according to claim 6, characterized in that the temperature of the charge to be dried after freezing is -55 - -15 ° C. Method according to one of the preceding claims, characterized in that during the vacuum drying the vacuum is from 5 mbar - 0.01 mbar (preferably <0.1 mbar). Method according to claim 8, characterized in that a two or multi-stage vacuum pump system (5) is used to maintain the vacuum. Method according to any of the preceding claims, characterized in that in the conical vessel (1) a wall (2) scraping mixer (3) is used with a small gap between wall (2) and mixer (3), which 0.5 - 15 mm. 25 A method according to claim 10, characterized in that the space between wall (2) and mixer (3) is 1 - 10 mm. Method according to one of the preceding claims, characterized in that a centrally driven H ribbon-shaped element, a centrally driven vane element or an orbital screw element provided with a swinging arm is used as the "H H mixing element (3). Method according to any of the preceding claims, characterized in that the mixer (3) is coupled to its drive (6) via a magnetic coupling (16). 14. Method according to any of claims 1-12, characterized in that only one drive (6) is used for the mixer (3) with only a rotating seal relative to the vessel (1). Method according to any of the preceding claims, characterized in that the drive I (6) has bearings (7) outside the vessel (1). I 20 16. Method according to any of the preceding claims, wherein said conical vessel (1) is connected to a condenser (8), characterized in that the condenser (8) has a space between at least 3 cooling housings (9) of at least 3 -4 cm, for I operating conditions up to a maximum ice layer I of approximately 1 cm on the cold stores (9). A method according to claim 16, characterized in that a double condenser (8) is used. I 1 0 / Ί β o o Method according to any of the preceding claims, characterized in that a filter (10) with a large filter surface is used between condenser (8) and the vessel (1). 5 A method according to claim 16, characterized in that the condenser (8) is directly connected to the vessel (1). Method according to claim 16 or 19, characterized in that the condenser (8) is placed next to the vessel (1). Device for carrying out the method according to any of claims 1-20, comprising a vessel with a downwardly conical shape (1), with a mixer (3) circulating along the wall (2) thereof, said mixer (3) ) circulates along the wall (2) thereof with a small gap, said vessel (1) is provided with a jacket (4) and connected to a vacuum system (5), characterized in that said conical vessel (1) is arranged for freeze-drying solutions and liquid-containing solids. 25 Device according to claim 21, characterized in that said conical vessel (1) forms part of a conical mixer. An apparatus according to claim 21 or 22, characterized in that the apparatus further comprises an H H cooling unit (11) and a heating unit (12) H of the casing (4) and one behind the vessel (1) placed condenser (8), the condenser (8) H being connected to a two-stage vacuum pump system 5 (5) comprising two vacuum pumps (13) and (14) and a pressure and temperature control unit (15) in the vessel (1) ). Device according to one of claims 21 to 23, characterized in that the condenser (8) is placed above the H vessel (1). 25. Device as claimed in any of the claims 21-23, characterized in that the condenser (8) is placed next to the vessel (1). Device according to claim 24 or 25, characterized in that a filter (10) is placed between the vessel (1) and condenser (8). I 20 Device according to claim 26, characterized in that the filter (10) is provided with a heat exchanger (16). Device according to any of claims 21-27, characterized in that a centrally driven ribbon-shaped mixer (3a) is present in the vessel (1). Device according to any of claims 21-27, characterized in that a centrally driven vane mixer (3b) is present in the vessel (1). Device according to any of claims 21-27, characterized in that an orbital screw element or mixer provided with a swing arm (3c) is present in the vessel (1). Device according to any of claims 21-30, characterized in that the drive unit (6) and the associated bearings (7) are located outside the vessel (1). Device according to any of claims 21-30, characterized in that the mixer (3) is coupled to its drive (6) by means of a magnetic coupling (16). Device according to any of claims 21 to 32, characterized in that the condenser (8) is two-fold. 34. Homogeneous molecular-scale mixtures of two or more substances obtained by freeze-drying with the process according to any of claims 1-20. 1022668