JPH02157587A - Freeze drying apparatus and freeze drying method - Google Patents

Abstract

PURPOSE:To uniformly dry the drying items that are arranged in rows on shelves, by a method wherein a horizontal drum type dryer is housed in a trap chamber and the drying items that are placed on the circumferential side are controlled to nearly the same temperature of the items placed in the middle of the shelves by a heater that s mounted on the drum wall of a trap. CONSTITUTION:Drying items are placed on shelves 'b' in a trap chamber 'e', a door 3 is shut, and the heat carrier is cooled by a trap 'd' consisting of a double tube containing the heat carrier and circulated in the shelves 'b', so that the trap 'd' and the shelves 'b' are uniformly cooled. After the drying items are frozen at a desired temperature, both the drying chamber 'a' and the trap chamber 'e' are evacuated by discharging air from an evacuating port 'f', the temperature of the shelves 'b' is controlled at a desired temperature, and freeze drying is performed in a vacuum. During this process, the sides of drum wall 1 of the drying chamber 'a' is kept at a low temperature by cooling it by the trap 'd', however, when it is too low, the heat input to vials arranged along the circumference is controlled to the same level as the heat input to vials arranged in the middle by controlling a heater 'h'.

Description

Detailed Description of the Invention (Industrial Application Field) The great invention is to place dried materials on the top surface of a temperature-adjustable horizontal shelf provided in a drying chamber that can maintain the dried material in a frozen state under vacuum. This invention relates to an improvement in a freeze-drying method and a freeze-drying apparatus in which sublimated water vapor is condensed and collected in a trap provided in a vacuum chamber and dried while supplying heat of sublimation from a shelf.

(Prior Art) As shown in FIG. 1, the freeze-drying means of the above-mentioned form usually supplies a refrigerant and a heat medium to a pipe line provided inside a drying chamber a that is sealed to maintain a vacuum. A trap d is provided with a water vapor condensation surface that can maintain the drying chamber a at a low temperature via a valve mechanism C. The trap chamber e is connected to the trap chamber e in which the trap chamber e is stored, and the vacuum exhaust system is connected to a vacuum outlet f provided in the trap chamber e. and,
When attempting to freeze-dry the material to be dried, open the door of the drying cabinet a, place the material to be dried on the upper surface of the shelf a, keep it in a frozen state by cooling the shelf, and turn on the valve mechanism C. When opened, the vacuum evacuation system is activated to control the inside of the drying chamber a to a predetermined degree of vacuum, and the temperature of the shelves is controlled within a range that keeps the material to be dried frozen, supplying sublimation heat and sublimating water vapor. is condensed and collected in trap d, thereby making it possible to perform freeze-drying.During the freeze-drying process, drying chamber a
Although the temperature of the shelves inside and the vacuum pressure inside the drying oven a are controlled, the wall temperature of the drying oven a is not controlled.

(Problems to be Solved by the Invention) In this freeze-drying means, even if the temperature distribution accuracy of the shelf surface of the shelf is improved to within ±1°C, the drying chamber a
Even if the control accuracy of the vacuum pressure inside is improved, shelf b...
There is a problem in that it is not possible to equalize the freezing conditions and drying conditions for the materials to be dried that are arranged in parallel on the shelf surface.

This unevenness of freezing and drying conditions is significant, and when using the above-mentioned freeze drying equipment,
Vial V injected with water log as material to be dried...
An experiment was conducted in which the specified freeze-drying process was performed by placing the vials V in parallel, the drying process was interrupted midway through this process, and the amount of sublimation was measured for all the vials V... placed in parallel on the shelves. As shown in Figure 2, the amount of sublimation in vial V located at the periphery of the shelf was greater than that of vial ■ located in the center of the shelf. (In Figure 2, the lower edge of the shelf is the front side of the drying oven a, and the pattern in which each vial V... is painted differently is The amount of sublimation is shown in the column above the figure).

By the way, freeze-drying is often used to dry pharmaceuticals, and in this case, the delicate physical properties of the pharmaceutical materials, such as biological components, are unstable and easily change, so it is difficult to maintain quality, such as efficacy and potency, after drying. Non-uniformity in the freezing and drying process is a significant hindrance in ensuring uniformity.

The present invention was made to solve this problem, and the materials to be dried, which are placed in parallel on the upper surface of horizontal shelves installed in a horizontal cylindrical drying chamber, can be freeze-dried evenly. The purpose is to provide new means for achieving this goal.

Therefore, the present invention was completed based on the knowledge obtained through repeated various studies and experiments for the above-mentioned purpose. In other words, we predicted that the uneven sublimation rate observed in the experiment as described above was due to the convective air in the drying chamber a, so we conducted a similar experiment by surrounding the shelves with a transparent film or other similar film. As shown in Figure 3, almost the same results were observed, and from this it was found that convective air had almost no effect, so it was predicted that it was due to radiant heat from the circumferential wall of drying chamber a. When a similar experiment was conducted by surrounding the shelves with aluminum foil, it was observed that the unevenness was improved as shown in Fig. 4.

From this, in order to control the radiant heat input from the cylindrical wall that is the circumferential wall of the drying chamber a toward the side edges of the shelf spacing of the shelves, the drying chamber a is moved into the trap chamber e in which the trap d is built. The periphery of the trunk wall of the drying chamber a is surrounded by a trap d disposed in the trap chamber e, and the drying chamber a
The temperature of the circumferential wall of the drying chamber A is lowered to a low temperature by the trap d, and the circumferential wall of the drying chamber a is heated by a heater attached to the vial V. When freeze-drying was performed by controlling the temperature so that the temperature was approximately equal to that of the vial V located in the center of the shelf, each of the parallel vials V... This is based on the fact that the unevenness in the amount of sublimation that had occurred was resolved and the drying process of all the vials V became more uniform.

For this reason, in the present invention, as a means to achieve the above-mentioned object, a horizontal cylindrical drying chamber with horizontal shelves that can be used for temperature adjustment is housed in the trap chamber, The frozen material to be dried is placed on the shelf, and the temperature of at least the left and right sides of the trunk wall of the drying chamber is controlled by a trap installed in the trap chamber and a heater attached to the trunk wall. , proposes a freeze-drying method characterized in that freeze-drying is performed by controlling the temperature to be approximately equal to the temperature of the material to be dried located in the center of the materials to be dried placed on the shelf. It is.

More specifically, conventionally, a horizontal cylindrical drying cabinet a that accommodates horizontal shelves on which materials to be dried are arranged is
As shown in the figure, a trap d provided with a water vapor condensation surface is formed separately from a trap chamber e in which it is housed, placed in a separate space, and connected via a valve mechanism C, or the above-mentioned shelf The trap d, which is provided with a water vapor condensation surface, is housed in a continuous vacuum chamber without the use of a valve mechanism C. (
Here, the term "circumferential wall" includes not only cylindrical walls but also rectangular cylindrical walls, and in the case of a rectangular shape, the side, top, and bottom surfaces are collectively referred to as the circumferential wall), and at least the horizontal cylindrical drying wall. One end wall in the front and back direction (axial direction) of the drying cabinet a (including the trunk peripheral wall and both front and rear end walls, that is, the entire drying cabinet a) is connected to a trap d, which has a water vapor condensation surface inside the trap chamber e.
At that time, a part or all of the trap d is placed in a position opposite to both left and right sides of the trunk circumferential wall of the drying oven a.

The drying oven a is provided with heaters for heating the circumferential wall of the drying oven a on the left and right sides facing the side edges of the shelves, and is located inside the trap chamber e. One of the front and rear end walls (preferably all of them, depending on the circumstances, that part) is used as a door that can be opened and closed to form a valve mechanism that communicates the drying chamber a and the trap chamber e.

In this case, when the door serving as the valve mechanism is on the front side of the drying chamber a, the opening/closing door of the trap chamber e should be provided at a position facing the front surface of the drying chamber a on the rear wall of the front side of the trap chamber e. By opening the opening/closing door of the trap chamber e and the valve mechanism door of the drying chamber a, it becomes possible to carry in and out the target material for the drying chamber a.

When freeze-drying the material to be dried, the vials filled with the material to be dried are placed in parallel on shelves in the drying chamber a, and the normal process of freeze-drying is carried out.
At that time, by means of heaters provided on both left and right sides of the trunk circumferential wall of the drying oven a, the wall temperature of both sides of the trunk circumferential wall facing the left and right edges of the shelves in the drying oven a is controlled; A temperature environment is created in which the amount of heat input to the material to be dried placed at the periphery of the top surface of the shelf is approximately the same as the amount of heat input to the material to be dried placed at the center of the top surface of the shelf. do it,
That is, the operation of the heater is controlled so that the wall temperature of the left and right sides of the trunk wall becomes approximately equal to the temperature of the material to be dried placed at the center of the upper surface of the shelf.

If freeze-drying is performed in this way, if freeze-drying is performed by placing a large number of drug solution injection vials (V) (medicine bottles for injections) in parallel on shelves, (1) Pre-freezing. In the process, vial V...
・After placing the group on the shelves, heat the shelves to -40℃ to -50℃.
℃ to freeze the chemical solution, trap d to -50℃ to -
After cooling to 65°C, the trap chamber e is evacuated and freeze-drying is performed. However, in conventional equipment, even if the trap d is cooled when placed on a tray, the drying process surrounding the tray is Although the wall surfaces on both sides of the trunk circumferential wall and the front and rear walls of the drying cabinet a are slightly cooled by the convection of air inside the drying cabinet a as the shelves cool, for example, if the shelves are 50
When it reaches ℃, it stays around -5℃. For this reason, the cooling of the group of vials V located at the outermost periphery on the shelf is hindered depending on the degree to which the adjacent vials V... are missing, and the cooling of the trap d in the trap chamber e is is drying cabinet a
does not contribute to the cooling of the walls.

However, in the means of the present invention, the horizontal cylindrical drying chamber a has at least its trunk peripheral wall and one end wall (preferably its trunk peripheral wall and both front and rear end walls) inside the trough chamber e, and is connected to the outside air. There is a space inside the trap chamber e between them, and the trap chamber e has a built-in trap d (condenser) that is cooled as much as or even more than when it is placed on a shelf. The wall surface of the vial V is quickly cooled by the contribution of the trap d, and the vials V and V.
...Does not interfere with cooling of the group.

(2) During the sublimation stage and sublimation stage of freeze-drying, the material to be dried in the vial V maintains a frozen state and receives sublimation heat from the higher temperature tray, and the sublimated water vapor is transferred to a lower temperature. Since the material is collected in trap d, the temperature of the material to be dried is naturally equal to the temperature of the shelf and trap d.
In conventional equipment, the wall surface of the drying chamber a around the shelves is in contact with the outside air, albeit through a heat insulating material, and the shelves and the material to be dried are in contact with the outside air through a vacuum. Therefore, the vials located on the outer periphery of the shelves, which are most strongly affected by the outside temperature and significantly higher than the temperature of the material to be dried, receive additional heat input from the surrounding wall of the drying chamber a. The central vial V is surrounded by vials V having the same temperature and receives a larger amount of heat than the vial V group. Therefore, conversely, the temperature of the shelf is kept low to the limit that the total amount of heat input to the vials located on the outer periphery of the top surface of the shelf does not exceed the limit of freezing and retention of the material to be dried. Therefore, the freeze-drying of the vials V located at the center of the upper surface of the shelf is delayed.

However, in the means of the present invention, most of the peripheral wall of the drying chamber a is inside the trap chamber e, and the wall surface temperature is the shelf temperature that is the temperature of the shelves, the temperature of the material to be dried, and the temperature of the trap d. Since the temperature is determined by the condenser temperature, the temperature is close to the temperature of the material to be dried, which is between the shelf temperature and the condenser temperature, and additional heat input from the peripheral wall can be controlled. Since the wall surface temperature of the peripheral wall of the drying chamber a can be adjusted using a heater, there is no need to suppress the shelf temperature to an excessively low level, and drying can be done evenly.
Drying time is also reduced.

In addition, in the freeze-drying method of the present invention, at least one of the front and rear end walls of the drying chamber a is located inside the trap chamber e and constitutes a valve mechanism that can be opened and closed. The connection with is maintained.

(3. Final drying period, in the final process of freeze-drying, the temperature of the material to be dried after sublimation gradually approaches the temperature of the tray, and when the desired moisture content is evenly reached, it should be considered as the end point. However, in the freeze-drying method of the present invention, this requirement can be approached not only by using shelves but also by controlling the wall temperature of the peripheral wall of the drying chamber a.

In addition, although it is the temperature of the circumferential wall and the front and rear end walls of the drying cabinet a that houses the shelves that disturbs the uniformity of the temperature conditions of the vial ■... group of shelves b-hi. The reason why we were able to control the wall surface temperature on both the left and right sides of the circumferential wall was because of the arrangement (Fig. 2, Fig. 3, Fig. Figure 4)
, since the protruding vials (two or three adjacent vials) that are most affected by the wall surface of the peripheral wall of drying chamber a are lined up on both sides, This is because a significant improvement has been achieved by suppressing the influence of heat input from both sides.

Needless to say, if necessary, the entire drying chamber a is housed in the trap chamber e, and the trap d is placed not only on the left and right sides of the peripheral wall of the drying chamber a, but also within the range that does not obstruct the loading and unloading of the materials to be dried. It is arranged at a position facing both end walls of the peripheral wall, and does not prevent the heater from being attached to both end walls as well.

(Example) Next, an example will be described in detail with reference to the drawings. Note that the same reference numerals in the drawings as in the previous means are used for components having the same effect.

FIG. 5 is a longitudinal sectional explanatory view of the main parts of the apparatus according to the embodiment of the present invention, and FIG. 6 is a sectional explanatory view of the same. In the figure, a is a horizontal cylindrical drying cabinet, b is a shelf that can adjust the temperature by circulating a refrigerant and a heat medium inside the drying cabinet a, and d is a horizontal shelf in the drying cabinet a. A trap (condenser), e indicates a trap chamber, l indicates a circumferential wall of the drying chamber a, and h indicates a heater provided on the circumferential wall l of the drying chamber.

The drying chamber a is arranged in the trap chamber e such that the body circumferential wall 1 and both front and rear end walls are all located inside the trap chamber e, and the front end wall has a valve mechanism that can be opened and closed. In the example shown in the figure, it is configured with a disc 2 that can be opened and closed and serves as a large door for carrying out the material to be dried onto the shelves.
The disk 2 is attached to an opening/closing door 3 provided on the rear wall of the front side of the trap chamber e by a horizontal shaft 20 so as to be horizontally movable in the front and back direction. Of course, the opening/closing door 3 of the trap chamber e and the disk 2 are each on one side! ! # It may be supported, and the point is that the disk 2 can be opened and closed in a state where the opening/closing door 3 provided on the front side of the trap chamber e is closed.

The trap chamber e is formed as a sealed chamber and is equipped with a vacuum outlet f connected to a vacuum exhaust system for maintaining the interior at a predetermined degree of vacuum. The trap d (condenser) arranged in the trap chamber e, which is formed in a size that can accommodate the entire drying chamber a, is a double pipe consisting of a refrigerant pipe and a heat medium pipe, Its heat transfer pipes are adapted to circulate through the interior of the tray. In order to avoid bending with a small curvature, the trough 2 d is formed to wrap around the outer periphery of the trunk wall 1 of the drying oven a. However, there are cases in which double pipes are not used, and only refrigerant pipes or heat medium pipes are used, and a group of parallel pipes running from the rear end (right end in Figure 5) to the front end of trap chamber e is connected with a U-shaped pipe. It may be a shape or a plate.

The heating device is an electric heater, and is provided on the outer surface side of the left and right sides of the trunk wall l of the drying oven a facing the left and right side edges of the shelf b. There is no problem even if it is provided on the entire surface.

The heat medium pipe 4 to the shelves installed in the drying oven a is connected to the drying oven a.
The heat medium is guided to the outside through the end wall on the rear side and further through the rear wall on the rear side of the trap chamber e, and the heat medium circulating in the heat medium tube is heated outside. There is. In addition, in the drawing, there is a drain for the ice melting water condensed in trap d, a vacuum gauge installation port, a thermometer lead wire, etc.
Members that do not require particular explanation are omitted.

In addition, the disk 2 serving as the entrance door of the drying chamber a can be moved close to the inner surface of the opening/closing door 3 by rotating or sliding the horizontal shaft 20 that penetrates the opening/closing door 3 of the trap chamber e and protrudes to the outside. By pulling the opening/closing door 3 toward the opening/closing door 3 and opening the opening/closing door 3 integrally with the opening/closing door 3 using, for example, a single hinge 30, the opening/closing door 3 is opened together with the opening/closing door 3.

Next, the operation of the freeze-drying apparatus configured in this way will be explained.

First, the disk 2 is opened together with the opening/closing door 3 of the trap chamber e, and the material to be dried is placed on the shelf. Next, the opening/closing door 3 is closed, and then the horizontal shaft 20 is moved manually or automatically. The actuator closes the disc 2 and starts preliminary quick-tying. In this embodiment, the heat medium cooled by the trap d, which is a double pipe with a built-in heat medium tube, circulates within the shelf, so that the trap d and the shelf are equally cooled. Even if the trap d is only a refrigerant pipe or a heat medium pipe, cooling can be performed in parallel by arranging them in stages. Therefore, although the trunk wall 1 of the drying chamber a between the trap d and the shelf is slightly later than the shelf,
Natural convection from both the front and back surfaces cools the product to a temperature close to that of the shelf.

After the material to be dried is frozen to the desired temperature,
The disk 2 at the front end of the drying chamber a is opened, and both the drying chamber a and the trap chamber e are evacuated from the vacuum outlet f, the temperature of the tray is suppressed to a desired value, and freeze-drying under vacuum proceeds. do. During this time, the side surface of the trunk wall l of the drying chamber a is exposed to the trap d.
If the temperature is too low, the temperature of the material to be dried is kept equal to that of the material to be dried by controlling the heater, and the amount of heat input into the peripherally arranged vials is transferred to the centrally arranged vials. The amount of heat input can be controlled to be equivalent to the amount of heat input.

The end point of drying can be determined by closing the disc 2 and measuring the pressure increase in the drying chamber a.

Next, FIG. 7 shows another embodiment of the present invention. This embodiment is an example in which a drying chamber a is accommodated in a trap chamber e with its front end protruding from the trap chamber e. A plate) 2 is provided on the front end surface protruding from the trap chamber e, and a valve mechanism C for opening and closing communication with the trap chamber e is provided on the rear end surface located within the trap chamber e. Other than the omission of the door 3, this embodiment is the same as the previous embodiment, and the same reference numerals are given to the same constituent members, and detailed explanation thereof will be omitted. Note that the valve mechanism C provided on the rear end surface of the drying chamber a opens on an upper hinge in the example shown in Figure 1, but it may of course open horizontally like the disc 2 in the above-mentioned embodiment. Also, in this embodiment, although not shown in the drawings, the front end sides of the drying chamber a and the trap chamber e are the same as those in the embodiment shown in FIGS. 5 and 6, and the rear end surface of the drying chamber a is There is a case where a door 2 is provided that projects outside the trap chamber e and opens and closes the loading/unloading port.

(Effect) In an apparatus with a conventional configuration, for example, when vials V are placed on shelves as shown in FIG. 8 and shelf B is cooled, the shelf temperature is -50 as shown in FIG. ℃, the drug solution in the center vial reaches -49℃, but the vials lined up on the outer periphery reach temperatures of -36℃ to -25℃ due to air flowing through part of the side of the vial. It is only cooled to 47℃, and the shelf temperature is -20℃ during the drying process under vacuum for 20 hours.
The amount of sublimation of the distilled water in the vial V after the passage of time is the 8th
As shown in the figure, in the central vial, 3.1±0
．． Although the weight was 6 g, sublimation of 5 to 8 g, which is 2 to 3 times that amount, was observed in the vial V on the outer periphery. The degree of this differs somewhat depending on various conditions, but based on the above example,
The severity of the disparity can be seen.

However, in the present invention, a horizontal cylindrical drying chamber with temperature-adjustable horizontal shelves installed inside is stored in the trap chamber, and the frozen material to be dried is placed on the shelves. , the temperature of at least the left and right sides of the trunk wall of the drying chamber is controlled by a trap disposed in the trap chamber and a heater attached to the trunk wall of the drying material placed on the shelf. Freeze-drying is carried out by controlling the temperature to be approximately equal to the temperature of the material to be dried located in the center of the drying cabinet A, so that The influence of heat input from the surrounding wall l is eliminated, and the materials to be dried, which are placed in parallel on the top surface of the horizontal shelves installed in the horizontal cylindrical drying chamber, can be freeze-dried evenly. . Furthermore, it is no longer necessary to keep the temperature of the shelves low, so the drying process time can be shortened.

Furthermore, in the freeze drying apparatus according to the present invention, at least the main part of the horizontal cylindrical drying chamber a, which conventionally existed outside the trap chamber e, is disposed inside the trap chamber e. By simply attaching it to the inner or outer surface of the circumferential wall 1 of the warehouse a, it becomes possible to greatly suppress the unevenness of the drying process that occurs in the materials to be dried that are placed in parallel on the shelves. Also,
The trap chamber e needs to be made large in order to enclose the drying chamber a, but on the other hand, the drying chamber a does not require vacuum pressure resistance.
Can absorb higher costs. In particular, in the configurations of the embodiments shown in FIGS. 5 and 6, the valve mechanism C between the drying chamber a and the trap chamber e has a structure and position that facilitates cleaning and inspection, which is advantageous in preventing contamination.

[Brief explanation of the drawing]

Fig. 1 is an explanatory diagram of the conventional means, Fig. 2, Fig. 3, and Fig. 4 are explanatory diagrams of the observation results of the amount of sublimation in the drying process of the conventional method, and Fig. 5 is a longitudinal cross-sectional view of the freeze-drying apparatus according to the present invention. FIG. 6 is a longitudinal cross-sectional rear view of the same as above. FIG. 7 is a longitudinal side view of another embodiment, and FIG. 8 is an explanatory diagram of the observation results of the temperature of the material to be dried during the drying process of the conventional means. Explanation of drawing symbols b...Shelf d...Trough, f...Vacuum opening ■...Vial 2...Disc 3...Opening/closing door 4...Heating medium tube a ...Drying chamber C...Valve mechanism e...Trap chamber h...Heater! ... Trunk wall 20 ... Horizontal shaft 30 ... Single hinge Figure I IJ'4)'b 1υ l? W +6 Figure 1';'3'4'5'6'll! ' l○ Ill'14' lb fig fig fig.

Claims (1)

[Claims] (1) A horizontal cylindrical drying chamber with temperature-adjustable horizontal shelves installed inside is stored in a trap chamber, and the material to be dried is frozen on the shelves. The temperature of at least the left and right sides of the body circumferential wall of the drying chamber is controlled by a trap installed in the trap chamber and a heater attached to the body circumferential wall. A freeze-drying method characterized by performing freeze-drying by controlling the temperature to be approximately equal to the temperature of the material to be dried located in the center of the drying material (
2) A cylindrical horizontal drying chamber a has a built-in horizontal shelf b for arranging the material to be dried and whose temperature can be adjusted, and communicates with the drying chamber a via a valve mechanism c. In a freeze-drying apparatus, a trap d having a water vapor condensation surface that can be maintained at a low temperature is built into a trap chamber e, and a vacuum exhaust system connected to the trap chamber e includes a cylindrical horizontal drying chamber a. , a part or all of the trap d provided with the water vapor condensation surface is accommodated in the trap chamber e such that its circumferential wall and at least one of the front and rear end walls are located in the trap chamber e, and the trap d provided with the water vapor condensation surface is It is arranged at a position facing the outer surface of both left and right sides of the trunk peripheral wall 1 of the drying cabinet a, and the trunk peripheral wall 1 of the drying cabinet a
A freeze-drying apparatus characterized in that a heater is provided on both the left and right sides of the drying chamber, and a valve mechanism c is provided for opening and closing one of the front and rear end walls of the drying chamber a located inside the trap chamber e. . (3) The end wall on the front end side of the drying chamber a located in the trap chamber e is formed into a front door, and the wall surface portion of the trap chamber e located in front of the front door is used to open and close the trap chamber e. Claim 2: A door is provided, and by opening the opening/closing door of the trap chamber e and the front door of the drying chamber a, it is possible to carry the material to be dried into and out of the shelf b inside the drying chamber a.
Lyophilization equipment as described.