JPH0635912B2 - Freeze-drying device and freeze-drying method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention mounts a dry material on a top surface of a temperature-controllable horizontal shelf provided in a drying chamber capable of holding a dry state in a vacuum. The present invention relates to an improvement of a freeze-drying method and a freeze-drying apparatus in which sublimation steam is condensed and collected in a trap provided in a vacuum chamber and dried while supplying heat of sublimation from a tray.

(Prior Art) As shown in FIG. 1, the freeze-drying means of the above-mentioned form is usually provided with a refrigerant and heat in a pipe line provided inside a drying cabinet a which is hermetically sealed so that it can be kept in a vacuum. A tray b having a steam condensing surface capable of maintaining a low temperature through a valve mechanism c is provided by arranging shelves b ... By which the temperature of the shelves can be adjusted by circulating a medium. It is configured to communicate with a trap chamber e to be stored and to communicate a vacuum exhaust system with a vacuum inlet f provided in the trap chamber e. When trying to freeze-dry the object to be dried, the door of the drying cabinet c is opened and the material to be dried is placed on the upper surface of the shelf b, and the shelf b
In the frozen state by cooling, the valve mechanism c is opened and the vacuum evacuation system is operated to control the inside of the drying cabinet a to a predetermined degree of vacuum, and the tray b is kept in a range where the freezing of the material to be dried is maintained. The temperature of the sublimation heat is controlled to supply the sublimation steam to the trap d to condense and collect it so that freeze-drying can be performed. During the freeze-drying process, the drying chamber a
The temperature of the tray b in the inside and the vacuum pressure in the drying cabinet a are controlled, but the wall surface temperature of the drying cabinet a is not controlled.

(Problems to be Solved by the Invention) In this freeze-drying means, even if the accuracy of temperature distribution on the shelf surface of the shelf b is improved to, for example, within ± 1 ° C., the vacuum in the drying chamber a is increased. Even if the pressure control accuracy is improved, there is a problem that the freezing conditions and the drying conditions of the drying target materials arranged in parallel on the shelf b ... Shelf surface cannot be equalized.

The unevenness of the freezing and drying conditions is remarkable, and the above-mentioned freeze-drying device is used, and on the upper surface of the tray b of the drying cabinet a,
The vials V into which 10 g of water has been injected as a material to be dried are placed in parallel to perform a predetermined freeze-drying process, the drying process is interrupted in the middle of this process, and all the vials V are arranged in parallel on the tray b. An experiment was conducted to measure the amount of sublimation, and as shown in FIG. 2, the amount of sublimation of the vials V located at the peripheral portion of the tray b was located at the central portion of the tray b. The result is several times that of the existing vials V ... (In FIG. 2, the lower edge of the shelf b is the front side of the drying cabinet a, and the vials V ... , The sublimation amount is shown as shown in the column above in FIG. 2).

By the way, freeze-drying is often used for the drying of pharmaceuticals, and in that case, because the delicate physical properties of the pharmaceutical ingredients, such as bio-ingredients, are unstable and subject to change, even after drying, the medicinal effect, potency, etc. Inhomogeneity of the freezing and drying process is a significant obstacle to guaranteeing sex.

The present invention has been made to solve this problem, and the freeze-drying of the material to be dried, which is placed in parallel on the upper surface of the horizontal trays that are placed in the horizontal tubular drying cabinet, is evenly dried. The aim is to provide new means of being carried out.

Therefore, the present invention has been completed based on the findings obtained by repeating various studies and experiments for the above purpose. That is, the unevenness of the sublimation rate observed in the experiment as described above was predicted to be due to the convective air in the drying cabinet a, and the same experiment was conducted by surrounding the shelf b with a transparent vinyl film. As shown in Fig. 3, almost the same results were observed. From this, it was found that the convection air had almost no effect, so it was predicted that this was due to radiant heat from the peripheral wall of the drying cabinet a. Then, when the same experiment was performed by surrounding the shelf b with an aluminum foil, the result that the unevenness was improved was observed as shown in FIG.

From this, in order to control the radiant heat input from the cylindrical wall, which is the cylinder peripheral wall of the drying cabinet a, toward the side end of the shelf interval of the shelf b, the drying cabinet a is trapped inside the trap chamber e. In the dry chamber a, the circumference of the body of the dry chamber a is surrounded by a trap d provided in a trap chamber e.
The temperature of the body peripheral wall of the above is lowered to a low temperature by the trap d, and the body peripheral wall of the drying cabinet a is heated by a heater (heater) attached thereto, and the vial V to be placed in parallel on the shelf b ... Of the vials V arranged in parallel, the temperature was controlled so as to be substantially equal to the temperature of the vials V located in the central part of the tray b, and freeze-dried.
It is based on the fact that the unevenness of the sublimation amount that has occurred in the ... Is eliminated and the drying process of all the vials V is made uniform.

Therefore, in the present invention, as a means for achieving the above-mentioned object, a horizontal cylindrical drying cabinet having a temperature-controllable horizontal shelf installed inside is stored in the trap chamber, Place the frozen material to be dried on the tray, the temperature of at least the left and right sides of the body peripheral wall of the drying cabinet, by the trap disposed in the trap chamber and the heater attached to the body peripheral wall, To provide a freeze-drying method characterized in that freeze-drying is performed by controlling the temperature to be substantially equal to the temperature of the material to be dried located in the central portion of the material to be dried placed on the tray. is there.

More specifically, conventionally, the horizontal tubular drying cabinet a that accommodates the horizontal tray b in which the material to be dried is placed is
As shown in the figure, it is formed separately from the trap chamber e in which the trap d having a steam condensing surface is housed, placed in a separate space, and is connected through the valve mechanism c, or the above-mentioned tray. Although b and the trap d having a steam condensing surface are housed in a connected vacuum chamber without a valve mechanism c, in the present invention, the drying chamber a is surrounded by its peripheral wall. (Here, the term “circumferential wall includes not only a cylindrical wall but also a rectangular tubular wall, and in the case of a prism, the side surface, the upper surface, and the bottom are collectively referred to as a circumferential wall”) and at least the horizontal tubular shape. Drying cabinet a
And one end wall in the front-back direction (axial direction) (including the case peripheral wall and both front-rear end walls, that is, the case of the entire drying cabinet a) are housed inside the trap chamber e together with the trap d having the steam condensation surface. At this time, part or all of the trap d occupies positions facing both left and right sides of the peripheral wall of the drying cabinet a.

A heater for heating the body peripheral wall is provided on the body peripheral wall of the dryer a on both left and right sides facing the side edge of the shelf b, and the dryer a positioned inside the trap chamber e is provided. One of the front and rear end walls (preferably all of them, or part thereof depending on circumstances) is used as a door that can be opened and closed to form a valve mechanism that connects 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, an opening / closing door of the trap chamber e is provided on the machine wall on the front side of the trap chamber e at a position facing the front face of the drying chamber a. Thus, by opening the opening / closing door of the trap chamber e and the door serving as the valve mechanism of the drying cabinet a, the target material for the drying cabinet a can be carried in and out.

Then, when the material to be dried is freeze-dried, the vials V filled with the material to be dried are placed in parallel on the shelf b in the drying cabinet a and the freeze-drying is performed in the normal process. The wall temperature of both sides of the body wall facing the left and right side edges of the shelf b in the dryer a is controlled by the heaters provided at both left and right sides of the body circumference wall of the dryer a. The heat input to the material to be dried arranged in the peripheral portion of the upper surface of b is performed so as to realize a temperature environment in which the amount of heat input to the material to be dried arranged in the central portion of the upper surface of the shelf b is substantially the same. . That is, the operation of the heater is controlled so that the wall temperatures of the left and right side portions of the body peripheral wall are approximately equal to the product temperature of the material to be dried placed on the central portion of the upper surface of the shelf b.

If freeze-drying is performed in this way, in the case where a large number of drug solution injection vials V (injection drug bottles) are placed in parallel on the shelf b and freeze-dried, (1) pre-freezing In the process, after arranging the vials V ... Group on the tray b, the tray b is cooled to −40 ° C. to −50 ° C. to freeze the drug solution, and the trap d is cooled to −50 ° C. to −65 ° C. After that, it is a normal operation to evacuate the trap chamber e and shift to freeze-drying. However, in the conventional apparatus, even if the tray b and the trap d are cooled, the drying chamber a surrounding the tray b is not used.
Although both the side wall surfaces and the front and rear wall surfaces of the body peripheral wall, which is the wall surface, are slightly cooled by the convection of the air in the drying cabinet a accompanying the cooling of the tray b, for example, the tray b arrives at −50 ° C. Sometimes stays around -5 ° C. For this reason, the vials V ...
The cooling is hindered depending on the degree of lacking of ... And the cooling of the trap d in the trap chamber e does not contribute to the wall surface of the drying chamber a.

However, in the means of the present invention, the horizontal cylindrical drying chamber a has at least its body peripheral wall and one end wall (preferably its body peripheral wall and both front and rear end walls) inside the trap chamber e, and is not exposed to the outside air. There is a space in the trap chamber e between
Moreover, since the trap chamber e has therein a trap d (condenser) that is cooled to the same level as or higher than the tray b, the wall surface of the drying chamber a is contributed by the trap d.
Vials V that are cooled quickly and lined up on the outer periphery of the upper surface of the shelf b
Does not interfere with the cooling of the flock.

(2) During the sublimation period and sublimation period of freeze-drying, the material to be dried in the vial V maintains the frozen state, receives sublimation heat from the tray b having a higher temperature, and sublimates the steam at a lower temperature. Since it is collected in a certain trap d, the temperature of the material to be dried is naturally between the temperature of the tray b and the temperature of the trap d. In the conventional apparatus, the wall surface of the drying cabinet a around the shelf b is in contact with the outside air even though the heat insulating material is interposed, and since the shelf b and the material to be dried are in vacuum, the outside temperature is not affected. The vials V, which are most strongly affected and are significantly higher than the temperature of the material to be dried and located on the outer periphery of the tray b, receive additional heat input from the wall surface around the drying cabinet a, and the vials having the same temperature around the periphery. More heat will be received than the group of vials V ... in the center surrounded by V ... Therefore, conversely, the temperature of the tray b must be kept low to the extent that the total heat input of the vials V located on the outer peripheral portion of the upper surface of the tray b does not exceed the limit of freezing and holding the material to be dried. Therefore, the freeze-drying of the vials V located at the center of the upper surface of the shelf b is delayed.

However, in the means of the present invention, most of the peripheral wall of the drying cabinet a is inside the trap chamber e, and the wall temperature thereof is the shelf temperature which is the temperature of the tray b, and the temperature of the material to be dried and the trap d. Since it is determined by the temperature of the condenser, which is the 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 the additional heat input from the peripheral wall can be controlled. And since the wall surface temperature of the peripheral wall of the drying cabinet a can be adjusted by the heater, it is not necessary to suppress the shelf temperature to an excessively low level, and even drying can be achieved.
The drying time is also shortened.

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

(3) In the final drying stage and the final process of freeze-drying, when the temperature of the material to be dried, which has finished sublimation, gradually approaches the temperature of the tray b, and reaches a uniform desired water content, the end point should be reached. However, in the freeze-drying method of the present invention, not only the shelf b but also the wall temperature of the peripheral wall of the drying cabinet a can be controlled to meet this requirement.

It is to be noted that, even though it is the temperatures of the peripheral wall and the front and rear end walls of the drying cabinet a that accommodates the tray b that disturb the uniformity of the temperature conditions of the vials V ... Group on the tray b, The reason why the wall temperature on both the left and right sides of the body wall is controlled is that it is due to the arrangement in freeze-drying the vial group that requires the strictest uniformity (Fig. 2, Fig. 3, Fig. 4). Since the vials in the protruding state (two adjacent vials or three vials) that are most strongly influenced by the wall surface of the peripheral wall of the drying cabinet a are lined up on both left and right sides, This is because a great improvement has been obtained by controlling the influence of heat input from both sides.

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

(Example) Next, an example will be described in detail with reference to the drawings. The same reference numerals as those used in the conventional means are used for the constituent elements having the same effect.

FIG. 5 is a longitudinal explanatory view of the main part of the apparatus of the embodiment of the means of the present invention, and FIG. 6 is a transverse explanatory view of the same. In the figure, a is a drying chamber formed in a horizontal tubular shape, b
Is a shelf which is formed so that its temperature can be adjusted by circulating a refrigerant and a heat medium inside and is horizontally laid in a drying cabinet a, d is a trap (condenser), e is a trap chamber, 1 is a drying cabinet a. And h is a heater provided on the body circumferential wall 1.

The drying chamber a is arranged in the trap chamber e such that all of the body peripheral wall 1 and both front and rear end walls are located inside the trap chamber e, and the front end wall thereof is a valve mechanism that can be opened and closed. In addition, the disc 2 is configured to be openable and closable and serves as a door for loading and unloading the material to be dried into and out of the shelf b. In the example shown,
The disk 2 is attached to an opening / closing door 3 provided on the machine wall on the front side of the trap chamber e so as to be horizontally movable in the front-rear direction by a horizontal shaft 20. Of course, the opening / closing door 3 of the trap chamber e and the disc 2 may be hinge-supported on one side. In short, when the opening / closing door 3 provided on the front side of the trap chamber e is closed, the disc 2 is opened. It should be able to open and close.

The trap chamber e is formed as a hermetically sealed chamber, and also has a vacuum inlet f that is connected to and communicates with a vacuum exhaust system for maintaining the inside at a predetermined degree of vacuum. And is formed in a size capable of accommodating the drying cabinet a.

As the trap d (condenser) arranged in the trap chamber e, a double pipe of a refrigerant pipe and a heat medium pipe is used, and the heat medium pipe circulates through the inside of the tray b. There is. The trap d is formed in a shape of winding the outer circumference of the body peripheral wall 1 of the drying chamber a in order to avoid bending with a small curvature. However, there is a case where only a refrigerant pipe or a heat medium pipe is used without using a double pipe, and a parallel pipe group extending from the rear end (right end in FIG. 5) of the trap chamber e to the front end is connected by a U-shaped pipe. The shape may be a plate or a plate.

The heater h is an electric heater and is provided on the outer surface side of the left and right side portions of the body peripheral wall 1 of the drying cabinet 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 shelf b installed in the drying cabinet a penetrates through the end wall on the rear side of the drying cabinet a and further penetrates through the machine wall on the rear side of the trap chamber e to the outside. The heating of the heating medium circulating in the heating medium pipe is performed outside. In the drawings, a drain port of ice-melting water condensed in the trap d, a mounting port of a vacuum gauge, a lead wire of a thermometer, and other members not particularly described are omitted.

Further, the disk 2 serving as the entrance door of the drying chamber a is rotated or slid on the horizontal shaft 20 penetrating the opening / closing door 3 of the trap chamber e and protruding to the outside. When the door 3 is pulled close to the door 3 and is integrated with the opening / closing door 3, the opening / closing door 3 is opened by, for example, a single hinge 30, so that the door 3 and the opening / closing door 3 are opened.

Next, the operation of the thus configured connected dryer will be described.

First, the disc 2 is opened together with the opening / closing door 3 of the trap chamber e, the material to be dried is placed on the shelf b, and then the opening / closing door 3 is closed, and then the horizontal shaft 20 is operated manually or automatically. Then, the disk 2 is closed and the pre-freezing is started. In this embodiment, since the heat medium cooled by the trap d formed of a double tube having a heat medium pipe circulates in the tray b, the trap d and the tray b are equally cooled. Even when the trap d is only a refrigerant pipe or a heat medium pipe, the tray b can be simultaneously cooled in parallel. Therefore, the body peripheral wall 1 of the drying chamber a intermediate between the trap d and the shelf b is slightly behind the shelf b,
It is cooled to near the temperature of the shelf b by natural convection from both sides.

This freezes the material to be dried to the desired temperature,
The disk 2 at the front end of the drying cabinet a is opened, the drying cabinet a and the trap chamber e are both vacuum-exhausted from the vacuum inlet f, the temperature of the tray b is suppressed to a desired value, and freeze drying under vacuum is performed. proceed. During this time, the side surface portion of the body peripheral wall 1 of the drying cabinet a can be kept low by cooling from the trap d, and if it is too low, it is kept substantially equal to the temperature of the material to be dried by controlling the heater h. The amount of heat input to the peripherally arranged vials can be controlled to be equal to the amount of heat input to the centrally arranged vials.

The end point of the 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 the drying cabinet a is housed in the trap chamber e with its front end protruding from the trap chamber e, and a door (circle) for opening and closing the loading / unloading port of the material to be dried of the drying cabinet a. A plate 2 is provided on the front end face protruding from the trap chamber e, and a valve mechanism c for opening and closing the communication with the trap chamber e is provided on the rear end face located inside the trap chamber e, and is opened and closed from the trap chamber e. Except that the door 3 is omitted, there is no difference from the above-described embodiment, and the same reference numerals are given to the components having the same effect, and detailed description thereof will be omitted. The valve mechanism c provided on the rear end surface of the drying chamber a has an upper hinge opening in the illustrated example, but of course, even if it has a horizontal opening like the disk 2 in the above-described embodiment, But no problem. Further, in this embodiment, although not shown, the drying chamber a and the front end side of the trap chamber e are the same as the examples shown in FIGS. 5 and 6, and the rear end surface of the drying chamber a is the trap chamber e. In some cases, the door 2 may be provided so as to be projected to the outside and open and close the loading / unloading port.

(Effect) In the apparatus having the conventional configuration, for example, when the vials V ... Are arranged on the shelf b as shown in FIG. 8 and the shelf b is cooled, the shelf temperature of −50 ° C. is set as shown in FIG. At this time, while the drug solution in the central vial reaches −49 ° C., the vials lined up on the outer periphery have −36 ° C. to −47 ° C. because air at −25 ° C. to −29 ° C. flows through part of the side surface. Only cooled to ℃. Further, the sublimation amount of the distilled water in the vial V after a lapse of 20 hours at a shelf temperature of -20 ° C in the drying process under vacuum is 3.1 ± 0.6 g in the vial at the center as shown in Fig. 8. However, in the outer peripheral vial V ...
Sublimation of 5 to 8 g is seen three times. The extent of this varies somewhat depending on various conditions, but the above example shows the severity of the unevenness.

However, in the present invention, a horizontal cylindrical drying cabinet having a temperature-controllable horizontal shelf provided therein is stored in the trap chamber, and the frozen material to be dried is placed on the shelf. The temperature of at least the right and left side portions of the drum peripheral wall of the drying chamber is controlled by the trap disposed in the trap chamber and the heater mounted on the drum peripheral wall, and the temperature of the material to be dried placed on the tray is Since the freeze-drying is performed by controlling the temperature to be approximately equal to the temperature of the material to be dried located in the central part of the drying chamber a, the drying chamber a for the material to be dried placed in parallel on the tray b in the drying chamber a is provided. The influence of heat input from the body peripheral wall 1 is eliminated, and the freeze-drying of the material to be dried, which is placed in parallel on the upper surface of the horizontal plate shelf that is placed in the horizontal tubular drying cabinet, is performed uniformly. . Further, it is not necessary to keep the temperature of the shelf b at a low temperature, and the drying process time can be shortened.

Further, in the freeze-drying apparatus according to the present invention, a heater h is provided except that at least a main part of the horizontal cylindrical drying chamber a existing outside the trap chamber e is disposed inside the trap chamber e.
And, by only attaching it to the inner surface or the outer surface of the body peripheral wall 1 of the drying cabinet a, it becomes possible to largely suppress the unevenness of the drying process which has occurred in the material to be dried placed in parallel on the shelf b. Also,
The trap chamber e needs to be large in size to wrap the drying chamber a, but on the other hand, the drying chamber a does not require vacuum pressure resistance.
Can absorb high cost. In particular, in the configuration of the embodiment shown in FIGS. 5 and 6, the valve mechanism c between the drying chamber a and the trap chamber e has a structure and a position for easy cleaning and inspection, which is advantageous in preventing contamination.

[Brief description of drawings]

FIG. 1 is an explanatory view of a conventional means, FIGS. 2, 3, and 4 are explanatory views of an observation result of a sublimation amount in a drying process of the conventional means, and FIG. 5 is a longitudinal side view of a freeze-drying apparatus according to the present invention. Figure,
FIG. 6 is a longitudinal rear view of the same as above, FIG. 7 is a longitudinal side view of another embodiment, and FIG. 8 is an explanatory view of the observation result of the temperature of the material to be dried in the drying process of the conventional means. Description of drawing symbols a ... Drying chamber, b ... Shelf c ... Valve mechanism, d ... Trap e ... Trap chamber, f ... Vacuum port h ... Heater, V ... Vial 1 ... Circumferential wall, 2 ... Disc 20 ... Horizontal axis, 3 ... Open / close door 30 ... Single hinge, 4 ... Heat medium tube

Claims (3)

[Claims] 1. A horizontal cylindrical drying cabinet having horizontal temperature-controllable shelves installed therein is stored in a 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 body peripheral wall of the drying chamber is controlled by the trap arranged in the trap chamber and the heater attached to the body peripheral wall. The freeze-drying method is characterized in that the freeze-drying is performed at a temperature substantially equal to the temperature of the material to be dried located in the central portion of the material to be dried placed on the tray. 2. A horizontal drying cabinet a having a temperature controllability for arranging a material to be dried is built in a cylindrical horizontal drying cabinet a and communicated with the drying cabinet a via a valve mechanism c. In a freeze-drying apparatus having a trap d having a steam condensing surface that can be kept at a low temperature in the trap chamber e and having a vacuum exhaust system connected to the trap chamber e, a cylindrical horizontal drying chamber a A trap d having a water vapor condensing surface, which is housed inside 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.
Is disposed at a position facing the outer surfaces of both left and right sides of the body peripheral wall 1 of the drying cabinet a, and heaters h are provided at left and right sides of the body peripheral wall 1 of the drying cabinet a. The freeze-drying device is characterized in that one of the front and rear end walls of the drying cabinet a located inside the trap chamber e is a valve mechanism c that can be opened and closed. 3. An end wall on the front end side of a drying cabinet a located in the trap chamber e is formed on a front door, and the wall of the trap chamber e located in front of the front door is provided with the trap chamber e. The opening / closing door is provided, and by opening and closing the opening / closing door of the trap chamber e and the front door of the drying cabinet a, it is possible to carry in and carry out the material to be dried with respect to the tray b inside the drying cabinet a. Freeze dryer.