JPH0676868B2 - Freeze drying method and freeze dryer - 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 a freeze-drying method in which sublimation water vapor is condensed and collected in a trap provided in a vacuum chamber and is dried while supplying heat of sublimation from a shelf, and an improvement of a freeze-dryer of a freeze-drying apparatus.

(Prior Art) Usually, the freeze-drying means of the above-described form has a refrigerant in a pipe line provided inside a drying chamber A formed so as to maintain a predetermined vacuum degree, as shown in FIG. Further, a tray a, which is capable of adjusting the temperature of the shelf surface by circulating a heat medium, is installed, and a steam condensing device b having a steam condensing surface capable of keeping the drying cabinet A at a low temperature is stored. In trap room B,
It is configured to communicate with each other through a valve mechanism, and to connect a vacuum exhaust system to a vacuum inlet provided in the trap chamber B.

When trying to freeze-dry the object to be dried, the door of the drying cabinet A is opened, the material to be dried is placed on the upper surface of the shelf a, and the material to be dried is frozen by cooling the shelf a. At this time, the temperature of the tray a is controlled within a range where the freezing of the material to be dried is maintained while controlling the inside of the trap chamber B and the drying chamber A to a predetermined degree of vacuum by opening the valve mechanism and operating the vacuum exhaust system. The sublimation heat is controlled to be supplied, and the sublimation steam is condensed and collected in the steam condensing device b so that freeze-drying can be performed. During the freeze-drying process, the tray a in the drying cabinet A is Although the temperature and the vacuum pressure in the drying cabinet A are controlled, 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 temperature distribution accuracy of the shelf surface of the shelf a is improved to, for example, within ± 1 ° C. Even if the pressure control accuracy is improved, there is a problem that the freezing conditions and the drying conditions of the materials to be dried arranged in parallel on the shelf a ... 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 a 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 the total number of vials V .. As a result of performing an experiment for measuring the amount of sublimation, as shown in FIG. 2, the amount of sublimation of the vials V located at the peripheral portion of the tray a is located at the central portion of the tray a. The result is several times that of the existing vials V ... (In FIG. 2, the lower edge of the shelf a is the front side of the drying cabinet A, and the vials V ...
The sublimation amount is shown as in the column described above in FIG. 2).

By the way, freeze-drying is often used for the drying of pharmaceuticals, and in that case, because the subtle physical properties of the pharmaceutical ingredients, such as biological constituents, are unstable and change easily, the medicinal properties and potency after drying are Inhomogeneity of the freezing and drying process is a significant obstacle to ensuring uniformity.

The present invention has been made in order to solve this problem, in which freeze-drying of a material to be dried placed in parallel on the upper surface of a horizontal plate that is shelf-installed in the drying chamber of the freeze-drying device It is an object of the present invention to provide a new means in which the temperature conditions of the material to be dried located in the central part of the plate and the material to be dried located in the peripheral part of the tray are made substantially equal to each other so as to be uniformly 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, in the prior art, it has been already known that there is significant unevenness in the temperature distribution and the drying progress distribution of the material to be dried arranged on the tray a of the drying cabinet A, for example, the chemical solution injection vial group. The inventor has found that the cause thereof is the influence of the temperature of the wall surface (including the inner surface of the front door) of the drying cabinet A that mainly surrounds the shelves, together with the degree thereof.

Therefore, the means for solving this is, of course, how economically and without impairing various functions that the freeze-drying device should have, the wall of the drying cabinet A enclosing the trays or an enclosure provided separately. Controls or controls the temperature of the wall surface of the member (hereinafter referred to as the surface surrounding the shelf).

As to what temperature the temperature of the surface surrounding the shelf should be controlled, the vials in the outer peripheral portion forming the outer circumference of the vial group as the material to be dried on the shelf a and the drying cabinet surrounding the vial are formed. If heat is prevented from entering and leaving the wall surface, the temperature condition between the vial located on the outer peripheral portion of the shelf a and the vial located on the central portion of the shelf a surrounded by the vials having the same temperature on all sides. Are almost complete. That is, the standard is to change the temperature of the surface surrounding the shelf a during the drying process in accordance with the fluctuation of the temperature of the vial located in the center of the shelf a.

Depending on the amount of the margin surface that is separated from the vial group at the end of the upper surface of the shelf a, the relationship between the effective interval of the shelf and the height of the vial, and other geometric conditions, The accuracy of the vial and the temperature of the surface surrounding the shelf a may not be completely matched, but may be corrected slightly up and down to improve the accuracy, and by trial and error, there is no correction. The inventor has found that the equalizing effect can be obtained.

Due to the principle of freeze-drying, the temperature of the vial at the center of the shelf, which is the reference value for temperature control of the surface surrounding the shelf a, must be
It is lower than the temperature of the tray a and higher than the temperature of the steam condensing device b that condenses and collects sublimation steam.

Further, heat input and output between the surface surrounding the shelf a and the vial group on the shelf a is concentrated in some of the vials located in the outer periphery of the shelf a. In addition, it affects the progress of drying 2-3 times. However, in a device of a normal size, the total amount of heat transfer between the surface surrounding the plate a and the vial group is larger than the total amount of heat transfer between the plate a and the vial group. Is much smaller than a fraction of the former.

Based on the above findings, the inventor has realized a much more economical economy without preparing an independent temperature control system having an independent refrigerating apparatus and an independent heating apparatus for controlling the temperature of the surface surrounding the shelf. As an effective means, a part of the circulating fluid of the existing heat transfer fluid circulation system for tray temperature control is branched through a control valve, and one of the circulating fluid of the existing heat transfer fluid circulation system for the steam condenser is used. The parts are branched via a control valve, and the circulating fluid of both of them forms a temperature control circulation system for the surface surrounding the shelf, and the surface surrounding the shelf is adjusted by adjusting the flow rate ratio of both. We have also developed a means by which the temperature of can be adjusted to any temperature between the shelf temperature and the condenser temperature.

When the types of heat medium used for both systems are equal,
The branched flows from both circulation systems may be mixed, and even if the types are different or the same type, when it is desired to make the pressure relationship of each circulation system of the tray system and the steam condenser system more independent, The temperature of the surface surrounding the plate may be adjusted while the branched flows from both circulation systems exchange heat with their respective flow paths.

Further, the respective branched streams from the tray system and the steam condensing system, which are used for controlling the temperature of the surface surrounding the tray, may be joined again to the respective systems. In this case, the inflow and outflow of heat to each circulation system caused by the confluence is
It needs to be replenished within each circulatory system, but as mentioned above,
The amount of heat required to control the temperature of the surface surrounding the shelf is
The amount of heat used to control the temperature of each system itself is smaller, and the fluctuation of the target material temperature during the freeze-drying process is sufficiently gentle compared to the load fluctuations in the shelf temperature control system and the condenser system. The method does not give irrational disturbance to both circulation systems.

One of the concrete means of the present invention is that the wall surface of the drying cabinet A (including the inner surface of the front door if necessary) itself has a jacket structure, and the above-mentioned branched flow is circulated inside the jacket structure. In this case, nothing is added to the inside of the drying cabinet A, which is advantageous for cleaning and inspecting it. On the other hand, although the jacket whose temperature is to be adjusted is heat-insulated on the outside, it is directly The temperature is high, the heat capacity is large, and the pre-freezing period and sublimation period of the material to be dried on the shelf a, that is, the refrigeration load for keeping the jacket at minus several tens of degrees is large.

Another one of the concrete means of the present invention is an upright partition wall-like circulation in which a heat transfer medium can be circulated inside along a wall surface (including an inner wall surface of a front door if necessary) of the drying cabinet A. It is to provide a plate.

In this case, the influence of the outside temperature is 10 to 20 between the circulation plate and the wall surface of the drying cabinet A, in addition to the heat insulating construction of the drying cabinet A wall.
Since it is relieved by the gap of mm, the heat load for controlling the temperature of the circulation plate can be reduced. On the other hand, since a circulation plate is added inside the drying cabinet A, the burden of cleaning and inspection increases. However, since the horizontal racks a are already provided inside, it is not unreasonable to increase the load by adding a circulation plate that is easier to clean, and either one can be selected according to the purpose. .

If we discuss only the degree of achievement of equalization of temperature conditions, not only the both ends of the shelf but also the front end and the rear end of the shelf,
It goes without saying that it is desirable to suppress the influence of the wall surface of the drying cabinet A. However, at least one end of the shelf is required for the construction of piping (often flexible piping) for the heat transfer fluid that circulates in the shelf, and a peephole or the like may be desired for the front door. is there.

Under such circumstances, it is often rational to limit the countermeasures to both side edges of the shelves or to the wall surface to which either the rear edge or the front edge is added. The vials are usually arranged as shown in FIG. 3, and the vials that are most strongly affected are those with a small number of adjacent vials (2 to 3), so the effect is large even if the measures are taken on both sides.

Therefore, in the present invention, the countermeasure point can be selected in consideration of other functions and costs.

(Example) Next, an example of the embodiment will be described with reference to the structure explanatory diagrams of FIGS. 4 and 5 and the heat medium fluid piping explanatory diagram of FIG.
In any of the structure explanatory diagram and the piping explanatory diagram,
Structures which are known in the freeze-drying device and which are not necessary for the description of the invention are omitted.

FIG. 4 is a front view of the drying cabinet A (where the front door is open), in which 1 is the main body of the drying cabinet A, and a is a temperature-adjustable horizontal shelf inside the main body 1. Na shelf C
Indicates a circulation plate for circulating a heat transfer fluid.

In the illustrated example, the shelves a ... are shelved in 8 shelves including the highest temperature guarantee shelves, and the substantial shelves a on which the material to be dried is placed are 7. These upper shelves a (temperature-guaranteed shelves) are fixedly supported at the lower end of the lifting rod 20 of the upper ram 2 which is operated by hydraulic pressure or air pressure, and the shelves of the second and lower shelves are ... The steps a are slidably supported by slings 21 provided on the upper shelves, and the lifting ram 20 is lifted to the end of the lifting process by the operation of the upper ram 2.
As shown in FIGS. 4 and 5, each of the shelves a ... Is hung at an equal interval and is suspended.
By lowering 20 to the end on the lowering process side, each of the shelves a ... Is superposed and folded in a stacked state. Further, each shelf a is provided with an inlet / outlet (not shown) of a heat transfer fluid circulated therein, and the inlet / outlet is
Entry / exit manifolds 3 and 3 and flexible pipes 30 and 30 arranged in the rear part of the drying cabinet A (in FIG. 4, only the top shelf a and the second shelf a from the bottom are illustrated. Are connected).

Further, the main body 1 of the drying cabinet A is attached to the machine wall 1a on the rear surface side of the main body 1.
A vacuum piping port 13 is provided for communicating with the trap chamber B that stores the steam condensing device b (FIG. 6). The vacuum piping port 13 is provided on the ceiling wall or one side wall of the main body 1 of the drying cabinet A in some cases.

The circulation plate C which circulates the heat transfer fluid inside is placed on the inner surfaces of the left and right side walls 1b and 1b of the main body 1 and in the main body 1 in the drying chamber A of the conventional freeze-drying apparatus configured as described above. It is provided as an upright partition wall at an intermediate portion between the left and right side ends of the above-mentioned shelf a. The circulation plates C and C are fixedly supported on the inner surfaces of the ceiling walls (and / or) left and right side walls 1b and 1b of the main body 1 of the drying cabinet A, and
The pipes 40 connected to the inlet / outlet of the circulating heat medium that circulates inside thereof are drawn out of the main body 1 through the rear wall 1a or the side wall 1b of the main body 1.

The circulation plate C may be provided between the inner surface of the front door 1c of the main body 1 of the drying cabinet A and the front end of the shelves a ... In this case, the circulation plate C is fixedly supported on the inner surface of the front door 1c so as to be opened and closed together with the front door 1c (FIG. 4), or is supported so as to be opened and closed separately in a double door shape. Then, the flexible pipe connected to the inlet / outlet of the heat medium fluid circulated therein is disposed on the rotating shaft side of the front door 1c, and the main body 1
The side wall 1b may be penetrated and pulled out to the outside.

In the embodiment shown in FIGS. 4 and 5, the circulation plate C along the inner surface of the rear wall 1a of the main body 1 of the drying cabinet A does not exist, but of course it is provided inside the left and right side walls 1b and 1b of the main body 1. Like the circulation plate C, it can be added to the inside of this rear wall 1a as well. However, in this case, it is necessary to move the vacuum piping port 13 to the ceiling wall of the main body 1 or increase the distance between the circulation plate C and the rear wall 1a of the main body 1 to secure the water vapor flow path. is there.

FIG. 6 shows an example of a circulation system of the heat transfer fluid circulated in the circulation plates C provided inside the wall surface of the main body 1 of the drying cabinet A as described above. In the drawing, the drying chamber A and the trap chamber B are shown by double broken lines, and only the circulation path of the heat transfer fluid is shown. In addition, in this embodiment, the steam condensing unit b is configured as a heat exchange plate for the refrigerant and the heat transfer fluid, and also serves as a cooler for the tray. In the figure, a
Is a shelf provided in the drying cabinet A, P1 is a circulation pump for the shelf, P2
Is a circulation pump for traps, V1, V2, V3, V4 are automatic valves,
C indicates a circulation plate, and H indicates a heater.

Next, the freeze-drying apparatus described above will be described in the order of freeze-drying operations.

After arranging the material to be dried, for example, the vial group containing the chemical solution on the shelf a, open the automatic valve V1 provided in the circulation path, close the automatic valve V2, stop the circulation pump P2, and operate the circulation pump P1. As a result, the heat transfer fluid circulates through the flow paths of thick solid lines and thick broken lines, and the trays a ... Are cooled by the steam condenser / deck cooler b. As a result, the drug solution in the vials arranged on the shelves a ... is frozen. At this time, in the conventional device, the shelf a ...
Since the wall surface of the drying chamber A surrounding the vial is not cooled, the vials located on the outer peripheral part of the shelf a are cooled shallowly. However, in the above-described means of the present invention, the automatic valve V3 is automatically opened in this process, or is opened manually, so that the circulation plates C are formed (the inside of the front door 1c and the rear wall if necessary). When the circulation plate C is provided inside the 1a as well, the heat medium fluid circulates in the circulation plate C, and the temperature condition of the material to be dried located on the outer peripheral portion on the tray a is located on the central portion on the tray a. Equalize the temperature conditions of the material to be dried.

Then, after the evacuation is completed, the circulation path for the heat transfer fluid is divided into a tray system and a steam condenser system. That is, the automatic valve V1 is closed, the automatic valve V2 is opened, and both of the circulation pumps P1 and P2 are in operation.

Normally, the temperature of the trays a ... Is kept at about +20 to -10 ° C, and the temperature of the steam condenser b is kept at about -50 to -65 ° C. Since the temperature of the chemical liquid as the material to be dried is always kept between the two temperatures, the temperature of the circulation plate C can be adjusted to be approximately equal to the temperature of the chemical liquid by opening / closing the automatic valves V3 and V4. By adjusting the temperature of the circulation plate C, the sublimation rates of the chemicals in the vials arranged in parallel on the shelf a are equalized. When sublimation progressed and the frozen part in the chemical solution began to disappear, the chemical solution temperature gradually approached the temperature of the shelf a, the shelf temperature (temperature of the shelf a) was raised to +20 to + 50 ° C, and the water content disappeared. The temperature of the drug is almost equal to the shelf temperature at the end of drying. Circulating plate C according to the temperature change of this medicine
The temperature of the drug is corrected almost equally to the temperature of the drug. The temperature of the circulation plate C may depend on a program determined in advance by experiment, or the temperature of the drug in the vial located in the central portion of the tray a among the vials arranged on the tray a is measured. Alternatively, the control may be performed on an additional value basis based on the temperature signal.

The means of the present invention configured as described above operates as follows.

In the conventional device, it was difficult to prove the uniform quality because the drugs having different temperature covering history were mixed in the common lot in the pre-freezing and drying. However, according to the means of the present invention, even if the temperature history in the common lot cannot be completely equalized, the circulation plate C is provided inside the front door 1c and the rear wall 1a of the drying cabinet A. Left and right side walls without provision
Even when the circulation plate C is provided only on the inside of 1b and 1b, to (a) vial (two adjacent vials) and (b) vial (three adjacent vials) shown in the vial array diagram of FIG. (C) vials (the number of adjacent vials is 4) are those that are most strongly affected by the wall surface.
According to the experiment, the influence of the temperature of the wall surface surrounding the shelf a is stronger as the number of adjacent vials is smaller, so that the uniformity is equal to the left and right side walls 1b.
・ It is remarkable only with the circulation plates C provided on the inside of 1b. If the circulation plates C are added to the inside of the front door 1c and the inside of the rear wall 1a, it will not be caused by the influence of the temperature of the wall surface. Equality is suppressed to the point where it cannot be observed.

Even if it is proved that the non-uniformity in the conventional apparatus does not cause the non-uniformity in quality, the means of the present invention can provide a shorter drying time.

As is well known, as a common non-rare example, the material to be dried in the vial located on the outer periphery of the vials juxtaposed on the upper surface of the shelf a is shelved by additional heat input from the wall surface surrounding the shelf a. Sublimation is completed within 1/2 to 1/3 hours of the time required for drying the material to be dried in the vial located at the center of the stage a. In other words, since the material to be dried in the vial that receives additional heat input from the wall surface surrounding the shelf a is controlled to a low temperature so that the material does not melt due to excessive heat input, The heat input to the vial at the central part of the shelf a is excessively suppressed, and as a result, it takes 2-3 times longer than the time required for freeze-drying without thawing. However, according to the means of the present invention, this unevenness is at least 1.5.
Since it can be doubled or less, the temperature of the shelf a can be kept higher, the required time can be reduced to 0.5 to 0.7 times, and within the same period, 2 to 1.4 times.
Since it can be operated twice, the required shelf area can be reduced to 50-70%. If the number of effective shelves is 10, 5 to 7
Because of the number of stages, it is possible to absorb the cost of two circulation plates on each side or an additional cost of one or two.

As described above, according to the present invention, when the material to be dried that has been frozen is placed in parallel on the racks a ... The temperature of the circulation plate C or the circulation jacket is circulated by circulating a heat medium fluid through the circulation plate C disposed between the shelf a and the wall surface of the drying cabinet A or the circulation jacket provided on the wall of the drying cabinet A. Is controlled to a temperature substantially equal to the temperature of the material to be dried located in the central portion of the shelf a among the materials to be dried to be mounted on the shelf a, and the material to be dried to be mounted on the shelf a is controlled. Since the temperature conditions of the material to be dried located in the peripheral part of the shelf are closer to the temperature conditions of the material to be dried located in the central part of the shelf, freeze-drying is performed. Freeze drying of the materials to be dried placed in parallel on the upper surface of the horizontal tray The temperature conditions of the material to be dried located in the central part and the material to be dried located in the peripheral part of the tray are made to be almost the same, and it is carried out evenly. By mixing the materials to be dried with different temperature histories, it becomes possible to solve the problem that it was difficult to prove uniform quality.

[Brief description of drawings]

FIG. 1 is an explanatory view of a conventional means, FIGS. 2 and 3 are explanatory views of the operation of the conventional means, FIG. 4 is a front view of an apparatus of an embodiment of the present invention, and FIG. 5 is a vertical side view of the same. FIG. 6 is an explanatory diagram of a circulation system path for the heat transfer fluid as above. Explanation of drawing symbols A ... Drying chamber, B ... Trap chamber C ... Circulation plate, H ... Heater P1 ... Circulation pump, P2 ... Circulation pump V1 and V4 ... Automatic valve, a ... Shelf b ...... Steam condensing unit, 1 main unit 1a, rear machine wall, 1b, left and right side walls, 1c front door, 2 upper ram, 20 lifting rod, 21 hanging device, 3 Entry / exit manifold, 30 …… Flexible piping 40 …… Piping

Claims (5)

[Claims] 1. A horizontal temperature-adjustable shelf a for freezing a material to be dried and placing it in a drying cabinet A of a freeze-drying apparatus.
The sublimation heat is supplied from the shelf a while the inside of the drying cabinet A is kept at a predetermined vacuum degree, and the steam that sublimes is placed on the drying cabinet A.
In the freeze-drying method in which the water is condensed and collected in the steam condensing device b provided in the trap chamber B communicating with the drying chamber A and is placed between the tray a in the drying chamber A and the wall surface of the drying chamber A. The heat transfer fluid is circulated through the circulation plate C or the circulation jacket provided on the wall surface of the drying cabinet A, and the circulation plate C
Alternatively, the temperature of the circulation jacket is controlled to be substantially equal to the temperature of the material to be dried located in the central portion of the shelf a among the materials to be dried to be placed on the shelf a, and then placed on the shelf a. Among the materials to be dried, the freeze-drying method is characterized in that the temperature condition of the material to be dried located at the peripheral portion of the shelf is brought close to the temperature condition of the material to be dried located at the central portion of the shelf. 2. A drying cabinet A capable of maintaining a predetermined degree of vacuum,
A horizontal shelf a capable of temperature control is erected, and a circulation plate C is provided in the shape of an upright partition wall between the left and right ends of the shelf a and the left and right wall surfaces of the drying cabinet A. Inside the circulation plate C, a part of the heat transfer fluid circulated in the tray a and a part of the heat transfer fluid circulated in the steam condenser b can be circulated, and into the circulation plate C. Of the freeze-drying apparatus, in which the temperature of the circulation plate C can be adjusted by controlling the flow rate of both or one of the heat transfer fluids. 3. An upright partition wall-shaped circulation plate C supported by the front door is provided between the inside of the front door of the drying cabinet A and the front end of the shelf a, and inside the circulation plate C, A part of the heat transfer fluid circulated in the tray a and a part of the heat transfer fluid circulated in the steam condenser b can be circulated, and the circulation plate is controlled by controlling the flow rate of both or one of the heat transfer fluids. The drying cabinet of the freeze-drying device according to claim 1, wherein the temperature of C can be adjusted. 4. Between the back wall surface of the drying cabinet A and the rear end of the shelf a,
A partition wall-shaped circulation plate C is provided, and the circulation plate C
It is possible to circulate a part of the heat transfer medium fluid circulated in the tray a and a part of the heat transfer medium fluid circulated in the steam condensing device b, and to control the flow rate of both or one of the heat transfer fluids. The drying cabinet of the freeze-drying apparatus according to claims 1 and 2, wherein the temperature of the circulation plate C can be adjusted by the above. 5. A drying cabinet A capable of maintaining a predetermined degree of vacuum,
A horizontal shelf a capable of controlling the temperature is provided on a shelf, a steam condensing device b capable of maintaining a low temperature is provided in a trap chamber B communicating with the drying cabinet A, and the trap chamber B is vacuum-exhausted. In the freeze-drying device in which the system is in communication, at least the left and right wall surfaces of the drying cabinet A are formed into a jacket through which the heat transfer fluid circulates, and within the jacket, one of the heat transfer fluid circulated in the tray a is circulated. Part and a part of the heat transfer fluid circulated in the steam condensing device b can be circulated, and the temperature of the wall surface can be adjusted by controlling the flow rate of one or both of the heat transfer fluids.