JP5859495B2 - Method for monitoring freeze-dried state of material to be dried applied to freeze dryer and freeze-dried state monitoring device thereof - Google Patents

Description

  The present invention is a freeze-dried state monitoring method for monitoring a freeze-dried state of a material to be dried, which is applied to a freeze-dryer that is a product obtained by drying a raw material solution such as food or medicine to a predetermined moisture content by freeze-drying, and its The present invention relates to a freeze-dried state monitoring device.

  For freeze-drying of pharmaceuticals, etc., a large number of trays and vials filled with the material to be dried are placed in the freeze-dryer drying chamber, and the material to be dried in each container is dried to a predetermined moisture content. Is done.

  The freeze-drying process of the material to be dried using this type of freeze-dryer is generally included in a pre-freezing process in which the material to be dried is freeze-solidified until the material to be dried becomes a dry solid, and in the ice-like material to be dried. The primary drying process to remove the water content and the trace of non-freezing water contained in the material to be dried that has become a dry solid after the primary drying process is removed, and the material to be dried is dried to a predetermined moisture content. It consists of a secondary drying process.

  Here, in order to satisfactorily freeze-dry the material to be dried with a freeze dryer, the freeze-drying status of the material to be dried is accurately grasped in any of the preliminary freezing step, the primary drying step, and the secondary drying step. There is a need to.

  Therefore, conventionally, temperature sensors are inserted at several points of the material to be dried charged in the drying chamber, and the sublimation surface temperature of the material to be dried is detected to grasp the freeze-drying state.

  However, the method of inserting a temperature sensor into the material to be dried merely grasps the freeze-drying status of several materials to be dried, and the freeze-drying status of the entire material to be dried cannot be ascertained. Because it is inserted directly into the dry material, bacteria are likely to be mixed into the dry material and cannot be applied to aseptic preparations. In addition, due to the wiring of the temperature sensor inserted into the dry material, the dry material is automatically placed in the drying cabinet. There was a problem that it could not be used for a lyophilizer of the loading type.

  In view of such problems, the applicant has proposed a method for detecting the absolute pressure in the drying cabinet and in the cold trap and calculating the freeze-drying status of the material to be dried from this detected pressure (Patent Document 1). . That is, according to the present invention, during the primary drying process, the pressure in the drying chamber is temporarily increased by controlling the vacuum degree adjusting means disposed in the main pipe connecting the drying chamber and the cold trap, and drying before and after the pressure change is performed. This is a method for calculating the freeze-dried state of the material to be dried from the degree of vacuum in the chamber and the degree of vacuum in the cold trap.

  In addition, in the method for calculating the dry state of the material to be dried, the applicant applied for a patent separately, in the secondary drying process, the degree of vacuum in the drying chamber was changed by changing the degree of vacuum in the drying chamber. And a method for calculating the freeze-dried state of the material to be dried from the degree of vacuum in the cold trap and the temperature of the shelf board.

WO2012 / 108470A1 brochure

  However, the invention described in Patent Document 1 monitors the drying state of the material to be dried during the primary drying process, and the invention according to the latter patent application states the drying status of the material to be dried during the secondary drying process. In both cases, the preliminary freezing process is not considered at all. That is, the freeze-drying process of the material to be dried includes a preliminary freezing process, a primary drying process, and a secondary drying process, and thus is not a method or apparatus that can monitor the freeze-drying status throughout each process.

  Although the object of the present invention is using a temperature sensor in view of the above-mentioned conventional problems, it is also suitable for aseptic preparations as a material to be dried, and can also be applied to an automatic loading type freeze dryer, The freeze-drying state monitoring method for the material to be dried and its freeze-drying state, which can accurately determine the freeze-drying status in all the preliminary freezing step, primary drying step and secondary drying step, and can reliably avoid the collapse of the material to be dried. It is to provide a monitoring device.

  In order to solve the above-mentioned problems, the freeze-dried state monitoring method according to the present invention includes a drying chamber for charging a material to be dried placed on a shelf board, and a main valve that communicates with the drying chamber. A main pipe through which water vapor generated from the material to be dried passes, a cold trap that condenses and collects water vapor that flows into the main pipe from the main pipe, a vacuum detection means that detects the pressure in the drying chamber, and a vacuum detection means Vacuum degree adjusting means for adjusting the degree of vacuum in the drying chamber based on the detected pressure, a heat medium circulation pipe for circulating the heat medium to the shelf, and a cooling means for cooling the heat medium in the heat medium circulation pipe A heating means for heating the heat medium in the heat medium circulation pipe, a heat medium valve for controlling circulation of the heat medium in the heat medium circulation pipe, and a heat medium temperature on the inlet side of the shelf The first temperature sensor and the temperature of the heat medium on the outlet side of the shelf are detected. A pre-freezing step for freezing the material to be dried in the drying chamber, and water vapor generated from the material to be dried following the pre-freezing step. A freeze-dryer that freeze-drys the material to be dried by sequentially performing a primary drying step for collecting and collecting, and a secondary drying step for removing a small amount of non-freezing water contained in the material to be dried following the primary drying step. The freeze-dried state monitoring method to be applied, wherein the control means includes a detection program of each temperature sensor, a required calculation program for calculating an average product temperature of the material to be dried in the preliminary freezing step, and a required relational expression. Storing a required calculation program for calculating an average product temperature, an average sublimation temperature and an average sublimation speed of the material to be dried in the primary drying step, and a required relational expression; A required calculation program for calculating an average product temperature and an average dehumidifying rate of the material to be dried and a required relational expression are stored, and in the preliminary freezing step, the detected temperature of the first temperature sensor and the detected temperature of the second temperature sensor Is calculated by a calculation program, and then the average product temperature of the material to be dried in the preliminary freezing process is calculated from the calculated temperature difference and the relational expression. In the primary drying process, the first temperature sensor is detected. The temperature difference between the temperature and the temperature detected by the second temperature sensor is calculated by a calculation program, and then the average product temperature, average sublimation temperature and average sublimation of the material to be dried in the primary drying step are calculated from the calculated temperature difference and the relational expression. The speed is calculated, and in the secondary drying step, the temperature difference between the detected temperature of the first temperature sensor and the detected temperature of the second temperature sensor is calculated by a calculation program, and then the calculated temperature difference and The average product temperature and average dehumidification rate of the material to be dried in the secondary drying step are calculated from the degree of vacuum in the drying chamber and the relational expression.

  According to the invention of claim 1, in any of the preliminary freezing step, the primary drying step and the secondary drying step, the temperature of the heat medium temperature on the inlet side of the shelf and the temperature of the heat medium on the outlet side of the shelf. Based on the difference, the average product temperature in the preliminary freezing process, the average product temperature in the primary drying process, the average sublimation temperature and the average sublimation speed, the average sublimation temperature and the average sublimation speed in the secondary drying process can be calculated, and Data that accurately reflects the lyophilization status of the entire material to be dried is acquired, and an appropriate lyophilized state can be maintained.

  The freeze-dried state monitoring method according to a second aspect of the present invention is the method according to the first aspect, wherein, as the relational expression, the control means heats the unloaded shelf board without the material to be dried once by a heater. Then, the relationship between the shelf temperature rise rate, the temperature difference between the entrance and exit of the shelf board and the shelf temperature when the main valve is fully opened and the heater is stopped and the heat medium valve is closed is stored. .

  According to a third aspect of the present invention, the freeze-dried state monitoring method according to the first and second aspects of the invention is characterized in that, in the primary drying step, the degree of vacuum in the drying chamber is controlled to a set value by the degree of vacuum adjustment means and the heating After the shelf temperature is controlled to a set value by opening and closing the heater and the heat medium valve, the heat medium valve is closed for a short time and the heater is stopped, and then the calculation process of the primary drying step is performed in advance. It is performed every time interval.

  According to the invention of claim 3, the material to be dried is primarily dried by controlling the degree of vacuum and the shelf temperature in the drying chamber to set values, while the heater is stopped for a short time during the primary drying step. And the heat medium valve is closed. Thereby, since the supply of the heated heat medium to the shelf is stopped, in this time zone, the sublimation heat that sublimates the ice in the material to be dried is transmitted to the shelf and the heat medium in the shelf, Along with this, the shelf board temperature is lowered and the temperature of the heat medium on the outlet side of the shelf board is lowered. Thereby, since the sublimation heat for sublimating the ice can be accurately obtained, not only the average product temperature but also the average sublimation temperature and the average sublimation speed can be accurately calculated.

  According to a fourth aspect of the present invention, the freeze-dried state monitoring method according to any of the first, second, and third aspects of the present invention uses, as the vacuum degree adjusting means, an opening degree controller that adjusts an opening degree in the main pipe, and After the operation of the degree adjuster in the fully open direction, the calculation process of the secondary drying step is performed at predetermined time intervals.

  According to the invention of claim 4, the degree of vacuum in the drying chamber in the secondary drying process changes depending on the situation by fully opening the opening controller, and the drying state of the material to be dried is predetermined in this state. Judge by time interval. Thereby, the drying condition in a secondary drying process can be judged accurately.

  According to a fifth aspect of the present invention, the freeze-dried state monitoring method according to any one of the first, second, and third aspects of the present invention uses an opening degree adjuster that adjusts the opening degree in the main pipe as the vacuum degree adjusting means. The means is characterized in that after the opening degree controller is driven and controlled, the degree of vacuum in the drying chamber is controlled to a set value, and then the calculation process of the secondary drying step is performed at predetermined time intervals. Thus, you may transfer to a secondary drying process, after controlling the vacuum degree in a drying chamber to a setting value.

  The freeze-dried state monitoring method according to the inventions of claims 6 and 7 uses a vacuum control line provided with a leak control valve as the vacuum degree adjusting means. As in the invention of claim 6, the leak control valve is After the closing operation, the calculation process of the secondary drying process may be performed at predetermined time intervals, and the degree of vacuum in the drying chamber is controlled to a set value as in the invention of claim 7. You may make it implement the calculation process of a secondary drying process for every predetermined time interval later.

  The data calculated in the preliminary freezing step, the primary drying step, and the secondary drying step may be recorded in a recording means (claim 8). Thereby, the operator can confirm the various data of each process via a recording means.

  The inventions of claims 9 to 16 are freeze-dried state monitoring devices corresponding to the freeze-dried state monitoring method according to claims 1 to 8. In addition, you may install a 1st temperature sensor and a 2nd temperature sensor in the exterior of a drying cabinet (Claim 17).

  According to the present invention, the lyophilized state of the entire material to be dried charged in the drying cabinet, that is, the average product temperature in the preliminary freezing step, the average product temperature and the average sublimation surface temperature and the average sublimation rate in the primary drying period, Since the average product temperature and average dehumidification rate in the secondary drying period can be accurately calculated, it is possible to consistently monitor the freeze-dried state of the material to be dried from the start to the end of the freeze-drying process. it can. Therefore, the collapse of the material to be dried can be reliably avoided, and the productivity of the product related to the material to be dried can be increased.

It is a lineblock diagram of a freeze-dryer of a channel opening vacuum control system to which a monitoring device and a monitoring method concerning a 1st embodiment are applied. It is a block diagram which shows the control circuit of the freeze dryer which concerns on 1st Embodiment. It is a flowchart which shows all the processes of the freeze dryer based on 1st Embodiment. It is a flowchart which shows the calculation process at the time of the preliminary freezing process of the freeze dryer which concerns on 1st Embodiment. It is a block diagram which shows the heat-medium flow at the time of the preliminary freezing process of the freeze dryer which concerns on 1st Embodiment, and a refrigerant | coolant flow. It is sectional drawing which shows the drying warehouse where the vial was inserted into the freeze dryer which concerns on 1st Embodiment. It is a graph which shows the shelf temperature average at the time of the preliminary freezing process in which the vial was inserted into the freeze dryer which concerns on 1st Embodiment, the product temperature 1, 2, 3, and calculated temperature. It is a graph which shows the shelf temperature at the time of the preliminary freezing process in which the vial was inserted into the freeze dryer which concerns on 1st Embodiment, item temperature 1,2,3, and calculated temperature. It is a 1st flowchart which shows an example of the calculation process at the time of the primary drying process of the freeze dryer which concerns on 1st Embodiment. It is a 2nd flowchart which shows an example of the calculation process at the time of the primary drying process of the freeze dryer which concerns on 1st Embodiment. It is a block diagram which shows the air flow at the time of the primary drying process of the freeze dryer which concerns on 1st Embodiment, a heat-medium flow, and a refrigerant | coolant flow. In the freeze dryer which concerns on 1st Embodiment, it is a graph which shows the shelf temperature at the time of a primary drying process, the product temperature 1-3, the calculated sublimation speed, and the calculated temperature by the opening / closing control of a heat-medium valve. In the freeze dryer which concerns on 1st Embodiment, it is a graph which shows the shelf temperature at the time of a primary drying process by the PID control of a heat-medium valve, the goods temperature 1-3, the calculated sublimation speed, and the calculated temperature. It is a flowchart which shows an example of the calculation process at the time of the secondary drying process of the freeze dryer which concerns on 1st Embodiment. It is a block diagram which shows the heat-medium flow and refrigerant | coolant flow at the time of the secondary drying process of the freeze dryer which concerns on 1st Embodiment. It is a flowchart which shows the other of the calculation process at the time of the secondary drying process of the freeze dryer which concerns on 1st Embodiment. It is a flowchart which shows the further another example of the calculation process at the time of the secondary drying process of the freeze dryer which concerns on 1st Embodiment. It is a partial omission block diagram of the freeze-dryer of the vacuum control line system with a leak control valve to which the monitoring apparatus and monitoring method which concern on 2nd Embodiment are applied.

  Hereinafter, a dry state monitoring device and a dry state monitoring method according to the present invention will be described for each embodiment with reference to the drawings.

[First Embodiment]
The dry state monitoring apparatus and the dry state monitoring method according to the first embodiment are shown in FIGS. 1 to 17, and are for adjusting the degree of vacuum in the drying chamber in the main pipe that connects the drying chamber and the cold trap. The present invention is applied to a freeze-dryer of a flow path opening vacuum control system provided with an opening controller (damper).

<Configuration of freeze dryer>
As shown in FIG. 1, a freeze dryer W1 according to the first embodiment includes a drying cabinet 1 that freeze-drys a material to be dried S, and a main pipe 2 that communicates with the drying chamber 1 and passes water vapor generated from the material to be dried S. And a cold trap 3 that communicates with the main pipe 2 and condenses and collects water vapor flowing from the main pipe 2.

  Here, the plurality of materials to be dried S charged in the drying cabinet 1 are placed on a shelf plate 4 arranged in a plurality of upper and lower stages, and as shown in FIG. 6, a container (vial bottle) 5 is in a state of being housed. Further, a vacuum gauge (vacuum detection means) 6 is installed in the drying chamber 1 to detect the absolute pressure in the drying chamber 1.

The main pipe 2 has a main valve 2a that controls opening and closing of the gas flow. Further, on the upstream side of the main valve 2a established the open degree adjustor 2b of the damper system, the open degree adjustor 2 b by opening control, so as to control the degree of vacuum in the drying chamber 1 Yes. Specifically, when the degree of vacuum in the drying chamber 1 reaches the set upper limit value, the opening degree of the opening degree controller 2b increases, and conversely, the degree of vacuum in the drying chamber 1 becomes the lower limit value. In some cases, the opening degree of the opening degree regulator 2b becomes small.

  The cold trap 3 is connected to the vacuum pump 8 through the inlet valve 7. When the inlet valve 7 is opened and the vacuum pump 8 is driven, the gas in the drying chamber 1 is sucked through the main pipe 2 and the cold trap 3. The inside of the drying chamber 1 including the main pipe 2 and the cold trap 3 can be evacuated. In addition, a trap coil 3a is disposed in the cold trap 3, and heat is exchanged with a heat medium circulation pipe 9 and a cooling device 10 to be described later by the trap coil 3a to condense and collect water vapor flowing into the cold trap 3. It has become.

  In the drying cabinet 1 and the cold trap 3 configured as described above, as shown in FIG. 1, the heat medium circulates by the heat medium circulation line 9 and the heat medium circulation line by the cooling device (cooling means) 10. 9 heat medium is cooled.

  Specifically, the heat medium circulation pipe line 9 includes an outlet of each shelf plate 4, a first heat medium valve 11 a, a trap coil 3 a, a first circulation pump 12 a, a heater (heating means) 13, and each shelf plate 4. It has a pipeline that is sequentially connected to the inlet. The heat medium circulation pipe 9 has a first bypass pipe 14a, one end of the first bypass pipe 14a is connected between the outlet of each shelf plate 4 and the first heat medium valve 11a, and the other end Is connected between the trap coil 3a and the first circulation pump 12a, and a second heat medium valve 11b is installed in the pipe. Further, the heat medium circulation pipe 9 has a second bypass pipe 14b connected in parallel with the first bypass pipe 14a, and one end of the second bypass pipe 14b is located between the first heat medium 11a and the trap coil 3a. The other end is connected between the trap coil 3a and the first circulation pump 12a, and the second circulation pump 12b is installed in the pipeline. Furthermore, a first temperature sensor 15a and a second temperature sensor 15a are provided on the inlet side and the outlet side of each shelf plate 4 in the heat medium circulation conduit 9, and the first temperature sensor 15a provides an inlet side for each shelf plate 4. The heat medium temperature is detected, and the outlet side heat medium temperature of each shelf board 4 is detected by the second temperature sensor 15b.

  On the other hand, the cooling device 10 is connected to the compressor 10a, the condenser 10b, the expansion valve 10c, and the trap coil 3a in order to circulate the refrigerant, and the water cooling condenser 10b, the water pump 10d, and the cooling tower 10e are connected in order to perform water cooling. It has a structure that cools the refrigerant.

  With such a heat medium circulation line 9 and the cooling device 10, heat is exchanged between the heat medium in the heat medium circulation line 9 and the refrigerant in the cooling device 10 by the trap coil 3 a, and each shelf plate in the dryer 1. While 4 is cooled, water vapor is condensed and collected in the cold trap 3. Further, the heat medium in the heat medium circulation line 9 can be heated by energizing the heater 13 to heat each shelf plate 4.

<Configuration of freeze-dried state monitoring method and freeze-dried state monitoring device>
In the lyophilizer W1 configured as described above, the lyophilized state monitoring method and the lyophilized state monitoring device applied to the lyophilizer W1 are configured as follows.

  As shown in FIG. 2, the freeze-dried state monitoring method and the freeze-dried state monitoring apparatus use a control panel 16 as a control means, and the control panel 16 is equipped with a sequencer 16a and a recorder 16b.

  The sequencer 16a is based on output signals from the operation switch 17, the vacuum gauge 6, the first and second temperature sensors 15a and 15b, the opening controller 2b, the heater 13, the first and second circulation pumps 12a and 12b, The first and second heat medium valves 11a and 11b, the inlet valve 7, the vacuum pump 8, and the cooling device 10 are driven and controlled.

  The sequencer 16a stores detection data of the first and second temperature sensors 15a and 15b, a required calculation program for calculating the average product temperature of the material to be dried S in the preliminary freezing step, and a required relational expression.

  In the primary drying process, the sequencer 16a, as a relational expression, once cools the unloaded shelf board 4 without the material to be dried S and heats it with the heater 13, and then fully opens the main valve 2a and the heater 13 And the relationship between the shelf temperature rise rate when the first heat medium valve 11a is closed and the temperature difference between the heat medium entering and exiting the shelf board and the shelf temperature is stored, and the average product temperature of the material S to be dried, A required calculation program for calculating the average sublimation temperature and average sublimation speed and a required relational expression are stored.

  Further, the sequencer 16a stores a required calculation program for calculating the average product temperature and average dehumidification rate of the material to be dried S in the secondary drying step and a required relational expression.

<Overall control of freeze-drying operation>
Hereinafter, with regard to drive control by the sequencer 16a, first, overall control of the freeze-drying operation will be described with reference to FIG.

  As shown in FIG. 3, when the operation switch 17 of the freeze-drying apparatus W1 is turned on (S1), a preliminary freezing process is started to freeze the material to be dried S in the drying cabinet 1 (S2). When this preliminary freezing step is completed (S3), the process proceeds to the primary drying step, and water vapor generated from the material to be dried S is condensed and collected (S4). When the primary drying process is completed (S5), the process proceeds to the secondary drying process to remove a small amount of non-freezing water contained in the material to be dried S (S6). When this secondary drying process is completed (S7), the entire freeze-drying process is completed.

  Hereinafter, calculation processing such as average product temperature calculation in each step will be described in order of the preliminary freezing step, the primary drying step, and the secondary drying step.

<Calculation method of average product temperature Tm in preliminary freezing step>
The step of calculating the average product temperature Tm in the preliminary freezing step will be described in detail below.

  First, the heat transfer equation of the material to be dried is expressed by the following equation.

C × dTm / dt = Qh + QL
However, in this equation, C is the heat capacity of the material to be dried S, Tm is the average product temperature, Qh is the amount of heat transferred from each shelf 4 to the material to be dried S via the bottom of the container, and QL is due to convection in the drying chamber. This is the amount of heat transfer to all containers 5.

  First, the heat transfer amount Qh from each shelf plate 4 to the material to be dried S via the container bottom is calculated by the following equation.

Qh = Ae × K × (Th−Tm)
Where Ae is the effective heat transfer area (m ² ), K is the overall heat transfer coefficient from each shelf 4 to the material to be dried S via the bottom of the container, Th is the shelf temperature (° C.), and Tm is the average product temperature. (° C).

The effective heat transfer area Ae can be calculated by Ae = 2 / (1 / Av + 1 / At),
In the formula for calculating the effective heat transfer area Ae, Av is the container bottom area (m ² ), and At is the tray frame area (m ² ).

The container bottom area Av can be calculated by Av = π / 4 × n1 × d ² (where n1 is the number of vials and d is the vial diameter), and the tray frame area At is At = n2 × W × L (where n2 Is the number of frames; W is the width of the frame, and L is the length of the frame).

  The overall heat transfer coefficient K from the shelf board 4 to the material to be dried via the container bottom can be calculated by K = 1 / (1 / K1 + 1 / K2).

The heat transfer coefficient K1 (W / m ² ° C) from the shelf board 4 to the container bottom by air gas conduction is
K1 = λg / δ1.

λg is the thermal conductivity of air, λg = 0.205 W / m ² ° C., δ1 is the gap at the bottom of the container, and the unit is m. When δ1 = 0.3 mm, K1 = 80 W / m ² ° C.

The heat transfer coefficient K2 (W / m ² ° C) from the bottom of the container to the material S to be dried is
The material to be dried S is a liquid that has not been frozen yet, and K2 = λ / (δ2 / 4).

λ is the thermal conductivity of the liquid material to be dried, λ = 0.465 W / m ² ° C., δ2 is the thickness of the liquid material to be dried in the container, and the unit is m. When δ2 = 10 mm, K2 = 186 W / m ² ° C.

  The material to be dried S is in a frozen solid state, and K2 = λi / (δ3 / 2).

λi is the thermal conductivity of the frozen solid material to be dried, λi = 2.2 W / m ² ° C., δ3 is the thickness of the frozen solid material to be dried in the container 5, and the unit is m. When δ3 = 10.9 mm, K2 = 404 W / m ² ° C.

  On the other hand, the heat transfer amount QL to all the containers 5 by convection in the drying cabinet is obtained from the following equation.

QL = Ae × Kc × (Tw−Tm)
However, Tw in a formula is a drying warehouse wall temperature, Tm is an average product temperature, Kc is a natural convection heat transfer coefficient in a drying warehouse.

  When the formula for calculating the heat transfer amount is included in the heat transfer equation, the following equation is established.

C × dTm / dt = Ae × K × (Th−Tm) + Ae × Kc × (Tw−Tm)
The average product temperature of the material to be dried S during preliminary freezing can be calculated by the following equation.

C × (Tm−Tm0) / Δt
= Ae * K * (Th-Tm) + Ae * Kc * (Tw-Tm)
Tm = (Tm0 + a1 × Th + a2 × Tw) / (1 + a1 + a2)
a1 = K × Ae × Δt / C
a2 = Kc × Ae × Δt / C
Th = (Th1 + Th2)
However, C is the heat capacity of the material S to be dried.

Therefore, if the inlet temperature (Th1) and outlet temperature (Th2) of the shelf board 4 are measured during preliminary freezing, the average product temperature Tm of the material to be dried S can be calculated from the above formula.
<Calculation method of heat capacity C of material to be dried in preliminary freezing step>
When entering the preliminary freezing step, the shelf temperature 4 is cooled to the preset temperature for preliminary freezing. Thereby, the water | moisture content in to-be-dried material S cools, freezes and solidifies, and product temperature also falls. The heat capacity C of the material to be dried S includes the heat capacity Ct of the tray, the heat capacity Cv of the vial and the rubber stopper, the heat capacity Cs of the chemicals, and the heat capacity Cw of the moisture.

  (1) The heat capacity Ct of the tray is calculated by Ct = csus × Wt. csus is the specific heat of stainless steel. Wt is the tray weight, the extraction tray is the weight of the frame, and the bottomed tray is the weight including the bottom.

  (2) The heat capacity Cv of the vial and the rubber stopper is calculated by Cv = cv × Wv + cc × Wc. cv is the specific heat of the vial, Wv is the weight of the vial, cc is the specific heat of the rubber stopper, and Wv is the weight of the rubber stopper.

  (3) The heat capacity Cs of the medicinal component is calculated by Cs = cs × Ws. cs is the specific heat of the chemical, and Ws is the chemical weight.

(4) The heat capacity Cw of water is calculated by Cw = cw × Ww. cw is the specific heat of water, and Ww is the weight of water.
However, the calculation of the specific heat cw of water is divided into three: cooling of water, freezing and solidification of water, and cooling of ice.

i) During water cooling (Tm> 0 ° C.), Cw1 = cw1 × Ww
Specific heat of water cw1 = 4.186 kJ / kg ° C.
ii) When water frozen and solidified (Tf <Tm <= 0 ° C.)
Cw2 = [(cw1 + cw3) / 2 + Δh / Tf] × Ww
Specific heat of ice cw = 2.09 kJ / kg ° C., heat of solidification of water Δh = 334.9 kJ / kg, Tf is the freezing point of the material S to be dried.

iii) When the ice temperature falls (Tm <Tf), Cw3 = cw3 × Ww
(5) Accordingly, the heat capacity C of the material to be dried S is C = Ct + Cv + Cs + Cw.

<Control flow chart of pre-freezing step and heat medium / refrigerant / air flow>
The calculation process of the preliminary freezing step in the first embodiment is as described above, and this preliminary freezing step will be described below with reference to the control flowchart of FIG. 4 and the heat medium / refrigerant and air flow of FIG.

  In the calculation process in the preliminary freezing step, when the preliminary freezing step is started, the first heat medium valve 11a is opened, the second heat medium valve 11b is closed, and the main valve 2a is further closed (S11). . Moreover, the 1st circulation pump 12a is driven and the cooling device 10 is driven (S12). As a result, as shown in FIG. 5, the refrigerant of the cooling device 10 circulates from the compressor 10a → the condenser 10b → the expansion valve 10c → the trap coil 3a → the compressor 10a as shown by the one-dot chain line arrow, while the refrigeration device 10 As shown by the solid line arrows, the heat medium circulates in order of water pump 10d → cooling tower 10e → water cooling condenser 10b → water pump 10d. On the other hand, as indicated by solid arrows, the heat medium in the heat medium circulation pipe 9 is each shelf plate 4 → first heat medium valve 11a → trap coil 3a → first circulation pump 12a → heater 13 (stopped state) → each Sequentially circulates with the shelf 4.

  The material to be dried S charged in the drying chamber 1 shown in FIG. 5 is cooled by the refrigerant / heat medium flow in the cooling device 10 and the heat medium circulation pipe 9 as described above.

  When the average product temperature Tm of the material to be dried S is obtained in this preliminary freezing step, the inlet side heat medium temperature (inlet temperature) of the shelf board 4 is measured by the first temperature sensor 15a, and the shelf temperature is changed to the second temperature sensor 15b. The outlet side heat medium temperature (outlet temperature) of the plate 4 is measured (S13). Subsequently, a temperature difference (Th1-Th2) between the inlet temperature and the outlet temperature is calculated, and the average product temperature of the material to be dried S is calculated from the calculated temperature difference and the relational expression (S14). The contents of step S14 are exactly the contents of <calculation method of average product temperature Tm in the preliminary freezing step> and <calculation method of heat capacity C of the material to be dried in the preliminary freezing step>. Subsequently, the calculated average product temperature is recorded in the recorder 16b (S15). Steps 13 to 15 are continued until the completion of the preliminary process (S16).

<Calculation result of average product temperature Tm in preliminary freezing process and its evaluation>
Below, when the freeze-dryer W1 of the channel opening vacuum control method is used, the average average product temperature Tm of the material to be dried S in the preliminary freezing step, which is obtained by performing a drying test using an actual load. The calculation result of is shown.

<When the container is a vial>
The lyophilizer W1 is a 10% aqueous solution of a mixture of mannitol (Mannitol, molecular formula: C ₆ H ₁₄ O ₆ ) and sucrose (Sucrose, molecular formula: C ₁₂ H ₂₂ O ₁₁ ), which is a material to be dried, in a drying cabinet DC. 220 vials / tray × 8 = 1760 bottles were dispensed, and controlled by the control panel CR to start a predetermined preliminary freezing step. In order to verify the suitability of the calculation method and the calculation apparatus according to the present invention, a product temperature sensor is inserted into the three vials inserted in the center of the shelf, and the dispensed material is dispensed into the vials. The product temperature (product temperature 1, product temperature 2, product temperature 3) of the mixture of the dried material mannitol and sucrose was measured. The solution is frozen at −45 ° C. for 2 hours, and the inlet temperature Th1 and the outlet temperature Th2 of the shelf are measured and recorded at intervals of 10 s. The calculation software stored in the sequencer 16a is used to calculate the material to be dried. The average product temperature Tm was calculated. FIG. 7 shows the calculation result.

  FIG. 7 is a graph of the average product temperature Tm of the material to be dried S in the preliminary freezing step calculated under the above conditions. As is apparent from this figure, the calculated average product temperature Tm of the material to be dried S is well with the type of the material to be dried S (product temperature 1, product temperature 2, product temperature 3) detected by the product temperature sensor. Match. Thereby, it was possible to verify the appropriateness of the calculation method and the calculation apparatus according to the present invention. The data shown in FIG. 7 is recorded on a recorder 16 b provided on the control panel 16. The operator of the freeze dryer W1 can know the preliminary frozen state of the material to be dried filled in the vial container by monitoring the data of the average product temperature Tm recorded in the recorder 16b.

<When the container is a tray>
The freeze dryer W1 is loaded with 8 × 8 trays in which 1350 ml of a 10% aqueous solution of mannitol (Mannitol, molecular formula: C ₆ H ₁₄ O ₆ ), which is a material to be dried S, is dispensed into the drying chamber 1, Controlled by the control panel 16, a predetermined preliminary freezing process is started. In order to verify the suitability of the calculation method and the calculation apparatus according to the present invention, a product temperature sensor is inserted into the three trays, and the product temperature (product temperature) of the material mannitol to be dried dispensed in the trays. 1, product temperature 2 and product temperature 3) were measured. The solution is frozen at −45 ° C. for 2 hours, and the inlet temperature (Th1) and the outlet temperature (Th2) of the shelf are measured and recorded at intervals of 10 s. Using the calculation software stored in the sequencer PLC, The average product temperature Tm of the material to be dried S was calculated. FIG. 8 shows the calculation result.

  FIG. 8 is a graph of the average product temperature Tm of the material to be dried S in the preliminary freezing step calculated under the above conditions. As is apparent from this figure, even in the tray container, the calculated average product temperature Tm of the material to be dried S is the product temperature of the material to be dried (product temperature 1, product temperature 2, product temperature) detected by the product temperature sensor. It is in good agreement with 3). Thereby, it was possible to verify the appropriateness of the calculation method and the calculation apparatus according to the present invention. The data shown in FIG. 8 is recorded on a recorder 16 b provided on the control panel 16. The operator of the freeze dryer W1 can know the preliminary frozen state of the material to be dried S filled in the tray container by monitoring the data of the average product temperature Tm recorded in the recorder 16b.

<Calculation method of sublimation speed Qm in primary drying period>
Next, the primary drying process performed following the preliminary freezing process will be described with reference to FIGS.

  In the invention described in Patent Document 1 listed in the background art, the sublimation speed Qm in the primary drying period is a vacuum in the drying chamber 1 measured by a vacuum gauge attached to the drying chamber 1 and the cold trap 3 of the freeze dryer W1. And the degree of vacuum in the cold trap 3 were calculated.

  On the other hand, in the present invention, a large number of containers such as trays and vials filled with the material to be dried S are placed in the drying chamber 1 via the shelf plate 4, and the material to be dried S in each container is predetermined. Sublimation heat Qh for sublimating the ice in the material to be dried S in each container during the primary drying period is supplied from a heat medium circulating in the shelf board 4 and is sublimated. Qh is the product of the sublimation speed Qm (kg / hr) and the sublimation latent heat Δhs (680 Kcal / kg), and is proportional to the sublimation speed Qm. Further, the sublimation heat Qh is transmitted from the heat medium circulating in the shelf 4, and the shelf The outlet temperature Th2 of the heat medium circulating in the plate 4 is lower than the inlet temperature Th1 of the shelf plate 4. If the inlet temperature Th1 and outlet temperature Th2 of the shelf board 4 are accurately measured, the sublimation speed Qm in the primary drying period can be calculated.

  According to this method, since it is not necessary to equip an expensive measuring instrument other than the thermometer for measuring the heat medium temperature, the sublimation speed Qm can be calculated easily and at low cost.

  Hereinafter, the calculation method of the sublimation speed Qm in the above-described primary drying step of the present invention will be described in detail below.

  After completion of the preliminary freezing process, the vacuum exhausting process starts, exhausts to a predetermined drying chamber vacuum degree, enters the primary drying process, heats the shelf board 4 with the set shelf temperature program, The degree of vacuum is set to a control value by the opening degree controller 2b, and freeze drying of the material to be dried S is started. The water vapor sublimated from the material to be dried flows from the drying chamber 1 through the main pipe 2 into the cold trap 3 and is condensed and collected by the trap coil 3a.

  The amount of heat supplied from the heat medium circulating in the shelf board 4 at the stage of raising the shelf temperature in the initial stage of the primary drying process is the temperature rise of the shelf board 4, the temperature rise of the frozen body in the material to be dried S, and the ice sublimation. It is complicated to calculate the heating rate Qm from the difference between the inlet temperature Th1 and the outlet temperature Th2 of the shelf board. In a simple calculation, the surface temperature of the frozen body in the material S to be dried is Ti, the equilibrium vapor temperature of the drying chamber vacuum degree, Ti is the bottom part temperature of the frozen body, and the sublimation speed Qm can be calculated by the following equation. .

Qm = A × λi / δi × (Tm−Ti) / Δhs
Where A is the heat transfer area of the frozen solid material to be dried S, and λi is the thermal conductivity of the frozen solid material to be dried S. δi is the thickness of the frozen solid material S to be dried in the container, and the unit is m. Tm is the average product temperature, and Ti is the equilibrium vapor temperature of the drying chamber vacuum degree Pdc.

  When the average product temperature Tm is lower than the equilibrium vapor temperature Ti at the beginning of the primary drying process (Tm <Ti), the sublimation rate Qm = 0.

  In a period in which the shelf temperature 4 is controlled to a constant temperature during the primary drying process, the first heat medium valve 11a that controls the shelf temperature (or PID control) and the heater 13 that heats the shelf temperature are turned on / off. The shelf temperature is controlled to a set value by turning OFF. During this period, the heat consumed for raising the temperature of the frozen body in the material to be dried S is negligible, and the amount of heat supplied from the heat medium circulating in the shelf board 4 depends on the temperature change of the shelf board 4 and the ice sublimation. Is consumed. The first heat medium valve 1 is closed (or PID controlled) in a short time at a constant time interval (for example, 30 min), the heater 13 is turned off, and the inlet temperature Th1 and outlet temperature Th2 of the shelf 4 are measured. Then, the sublimation heat Qh for sublimating the ice in the material to be dried S is calculated from the shelf plate temperature change rate dTh / dt and the shelf entry / exit temperature difference Th2-Th1, and the sublimation rate Qm can also be calculated.

  While the first heat medium valve 11a is closed (or PID controlled) and the heater 13 is turned off, the sublimation heat Qh that sublimates the ice in the material to be dried S in each container is the shelf plate 4 and the shelf plate 4. It is transmitted to the heat medium circulating inside, and the shelf board temperature is lowered, and the outlet temperature Th2 of the shelf board is lowered. The temperature drop rate of the shelf board 4 is dTh / dt, the temperature difference between entering and leaving the shelf is ΔTh = Th2−Th1, and the sublimation rate Qm is calculated by the following equation.

Qm = − [Csus × (dTh / dt−dTh ′ / dt)
+ Q × ρl × cp × (ΔTh−ΔTh ′)] / Δhs
Where Csus is the heat capacity of the shelf board 4, q is the flow rate of the heat medium circulating in the shelf board 4, ρl is the density of the heat medium, and cp is the specific heat of the heat medium.

  dTh / dt is the rate at which the shelf temperature rises when the first heat medium valve 11a is closed and the heater 13 is turned off when the shelf temperature is controlled to a constant temperature when there is no load, and ΔTh ′ Shelf entry / exit temperature difference Th2′−Th1 ′ (including measurement errors of the first and second temperature sensors 15a and 15b).

  When the first heat medium valve 11a is PID-controlled, dTh / dt−dTh ′ / dt = 0, and the sublimation speed Qm is calculated by the following equation.

Qm = −q × ρl × cp × (ΔTh−ΔTh ′)] / Δhs
The flow rate q of the heat medium circulating in the shelf board 4 is calculated by measuring the inlet temperature Th1 and the outlet temperature Th2 of the shelf board 4 when the shelf board 4 is heated after the shelf board 4 is once cooled without load. Is required. When the shelf temperature is controlled when there is no load, if the first heat medium valve 11a is closed and the heater 13 is turned off, the shelf plate temperature rise rate dTh ′ / dt and the shelf entry / exit temperature difference ΔTh ′ can be obtained. As described above, the measurement data of the inlet temperature Th1 and the outlet temperature Th2 of the shelf board 4 by closing the first heat medium valve 11a at a constant time interval in the primary drying period and turning off the heater 13 in a short time. Can be used to determine the heating rate Qm.
<Calculation method of average bottom part temperature Tm and average sublimation surface temperature Ts in the primary drying step>
The average product temperature Tm and average sublimation surface temperature of the entire material to be dried S in the primary drying step can be calculated from the following equations.

  First, the heat transfer equation of the material to be dried S is expressed by the following equation at the stage of shelf temperature increase in the initial stage of primary drying.

C × dTm / dt = Qh−Qm × ΔHs
In this equation, C is the heat capacity of the material S to be dried, Tm is the average product temperature, Qh is the amount of heat input from the shelf 4 to the bottom of the container by gas conduction, Qm is the sublimation rate, and ΔHs is the sublimation latent heat.

  The amount of heat input Qh from the shelf to the container bottom due to gas conduction is calculated by the following equation.

Qh = Ae × K × (Th−Tm)
However, Ae is an effective heat transfer area (m ² ), K is a heat transfer coefficient from the shelf 4 to the bottom of the container by gas conduction, Th = (Th1 + Th2) / 2 is a shelf temperature (° C.), and Tm is a bottom part temperature ( ° C).

The effective heat transfer area Ae can be calculated by Ae = 2 / (1 / Av + 1 / At),
The heat transfer coefficient K (W / m ² ° C) from the shelf board to the container bottom by gas conduction is
K = 16.86 / (δ + 2.12 × 29 × 0.133 / Pdc).

In the formula for calculating the effective heat transfer area Ae, Av is the container bottom area (m ² ), and At is the tray frame area (m ² ).

The container bottom area Av can be calculated by Av = π / 4 × n1 × d ² (where n1 is the number of vials and d is the vial diameter), and the tray frame area At is At = n2 × W × L (where n2 Is the number of frames; W is the width of the frame, and L is the length of the frame).

  Moreover, in the calculation formula of the heat transfer coefficient K from the shelf board 4 to the container bottom by gas conduction, δ is a gap at the container bottom and the unit is mm.

When the formula for calculating the heat input is included in the heat transfer equation, the following formula is established.
C x dTm / dt
= Ae × K × (Th−Tm) −Qm × Δhs
However, Δhs is sublimation latent heat, and Δhs = 2850 KJ / Kg.

Qm = A × λi / δi × (Tm−Ti) / Δhs
When Tm <Ti, Qm = 0.

  The average product temperature of the material to be dried S can be calculated by the following equation during the shelf temperature increase period in the initial stage of primary drying.

C × (Tm−Tm0) / Δt = Ae × K × (Th−Tm)
−A × λi / δi × (Tm-Ti)
Tm = (Tm0 + a1 × Th + a2 × Ti) / (1 + a1 + a2)
a1 = K × Ae × Δt / C
a2 = A × λi / δi × Δt / C
When the average bottom part temperature Tm is lower than the equilibrium vapor temperature Ti (Tm <Ti), Qm = 0,
Tm = (Tm0 + a1 × Th) / (1 + a1)
In the shelf temperature control in the primary drying period, the heat transfer equation of the material S to be dried is expressed by the following equation.

Qh + Qr = Qm × Δhs
The amount of radiation heat input Qr from the wall 1a of the drying cabinet 1 to all the containers is obtained from the following equation.

Qr = 5.67 × ε × Ae × [(Tw / 100) ⁴ − (Tm / 100) ⁴ ]
In the equation, ε is a radiation coefficient, Tw is a drying cabinet wall temperature (K), and Tm is an average bottom part temperature (K).

  Moreover, the amount of radiation heat input Qr from the wall 1a of the drying cabinet 1 to all containers can be approximately calculated by the following equation.

Qr = Ae × Kr × (Tw−Tm)
However, Kr are equivalent heat transfer coefficient due to radiation heat input, Kr = 0.7W / m ² ℃ in tester can be approximated as Kr = 0.2W / m ² ℃ production machine.

  When the formula for calculating the heat input is included in the heat transfer equation, the following formula is established.

Ae × K × (Th−Ts) + Ae × Kr × (Tw−Tm) −Qm × Δhs
The average bottom part temperature of the material to be dried S can be calculated by the following formula:
Tm = (K × Th + K × Tw−Qm × Δhs / Ae) / (1 + K + Kr)
The average sublimation surface temperature Ts of the material to be dried S can be calculated from the heat conduction equation in the frozen layer δi of the material to be dried S.

  The heat conduction equation is expressed by the following equation.

A × λi / δi × (Tm−Ts) = Qm × Δhs
The average sublimation surface temperature is calculated by the following formula.

Ts = Tm−Qm × Δhs × δi / (A × λi)
Therefore, if the sublimation speed Qm is measured in the primary drying period, the average bottom part temperature Tm and the average sublimation surface temperature Ts of the entire material to be dried S can be calculated from the above formula.

  Specifically, with the material to be dried S charged in the drying chamber 1, the freeze dryer W1 is operated, the shelf temperature is set to Th, and the degree of vacuum in the drying chamber 1 is adjusted to an opening degree. The control value is set at 2b and freeze-drying of the material to be dried S is started. After the start of freeze-drying, first, a primary drying process is started, and moisture contained in the ice-like material to be dried S is removed by sublimation.

When entering the primary drying step, water vapor sublimated from the material to be dried S condenses and collects in the cold trap 3 from the drying chamber 1 through the main pipe 2, and the opening controller 2 b rotates to vacuum in the drying chamber 1. Control the degree to the set value. At this time, the sequencer 16a closes the first heat medium valve 11a (or PID control) at a constant time interval (for example, 30 min interval) in a short time (for example, 120 s), turns off the heater 13, and opens the shelf board. The inlet temperature Th1 and outlet temperature Th2 of 4 and the degree of vacuum in the drying chamber 1 are taken in and recorded in the recorder 16b. Further, the sequencer 16a calculates the overall average bottom part temperature Tm, average sublimation surface temperature Ts, and sublimation speed Qm of the material to be dried S in the primary drying step according to the calculation program stored in the sequencer 16a in the following procedure.
(1) The shelf plate 4 is temporarily cooled with no load (the state where the material to be dried S is not placed on the shelf plate 4), and then the shelf plate 4 is heated at the inlet temperature Th1 and the outlet when the shelf plate 4 is heated. The temperature Th2 is measured, and the calculated flow rate is taken in as the flow rate q of the heat medium circulating in the shelf board 4.
(2) Results of shelf temperature rise rate dTh ′ / dt and shelf entry / exit temperature difference ΔTh ′ measured when each shelf temperature is controlled at no load, the first heat medium valve 11a is closed, and the heater 13 is turned off. From this, dTh ′ / dt and ΔTh ′ are calculated.
(3) The first heat medium valve 11a is closed (or PID controlled) in a short time, the heater 13 is turned off, and the temperature drop rate dTh of the shelf is determined from the recorded data of the inlet temperature Th1 and the outlet temperature Th2 of the shelf 4. / Dt and shelf entry / exit temperature difference ΔTh.
(4) The sublimation speed Qm is calculated by the following formula: Qm = − [Csus × (dTh / dt−dTh ′ / dt) + q × ρ1 × cp × (ΔTh−ΔTh ′)] / Δhs.
(5) The average bottom part temperature Tm of the material to be dried S is calculated by the following formula: Tm = (K × Th + Kr × Tw−Qm × Δhs / Ae) / (1 + K + Kr).
(6) The average sublimation surface temperature Ts of the material to be dried S is calculated by the calculation formula of Ts = Tm−Qm × Δhs × δi / (A × λi).

<How to obtain the flow rate q of the heat medium circulating in the shelf board 4 in the primary drying step>
When calculating the average bottom part temperature Tm, average sublimation surface temperature Ts, and sublimation speed Qm of the material S to be dried in the primary drying step, it is necessary to measure the flow rate q of the heat medium circulating in the shelf 4 in advance. . The measuring method is that the shelf is cooled to −50 ° C. with no load, vacuumed and heated to 30 ° C., and the inlet temperature Th′1 and outlet temperature Th′2 of the shelf when the shelf is heated are measured. From the data, the temperature rise rate dTh ′ / dt of the shelf 4 and the temperature difference ΔTh ′ entering and exiting the shelf are calculated, and the shelf from the heat medium circulating in the shelf 4 by the heat capacity of the shelf 4 and the temperature rise rate dTh ′ / dt is calculated. The heat flow rate to the plate 4 is calculated, and the flow rate q of the heat medium is measured from the heat flow rate and the temperature difference ΔTh ′ entering and leaving the shelf.

  The heat transfer equation of the shelf board 4 when the shelf is heated without load is represented by the following equation.

C1 × dTh ′ / dt = q × ρ × Cp × (Th′2-Th′1) + QL
In this equation, C1 is the heat capacity of the shelf board 4, ρ is the density of the heat medium, Cp is the specific heat of the heat medium, heat input from the shelf board 4 to the container bottom by gas conduction, and QL is the shelf from the drying cabinet wall 1a. This is the amount of heat transferred to the plate 4.

  QL can be calculated by the following equation.

QL = a × 2 × A × (Tw−Th)
a is the heat transfer coefficient from the drying cabinet wall 1a to the shelf surface in a vacuum, A is the shelf area, and Tw is the temperature of the drying cabinet wall 1a.

With the above formula, the flow rate q of the heat medium circulating in the shelf board 4 is obtained.
q = (C1 × dTh ′ / dt−QL) / (ρ × Cp × (Th′2-Th′1))
<Specific method for determining the flow rate q of the heat medium in the primary drying step>
Hereinafter, a specific method for obtaining the flow rate q of the heat medium circulating in the shelf board 4 will be described.

  First, in a no-load test, the flow rate q of the heat medium circulating in the shelf board 4 is obtained. The no-load test is performed by controlling the lyophilizer W1 in the same procedure as the lyophilization of the normal material to be dried S without charging the material to be dried S in the drying chamber 1. As an example, the shelf board 4 is cooled to −50 ° C. during the preliminary freezing step, a vacuum is drawn, and the shelf temperature Th is raised to 30 ° C. At that time, the inlet temperature Th'1 and the outlet temperature Th'2 of the shelf plate 4 were measured and recorded in the recorder 16b.

Here, the shelf effective area of the freeze dryer W1 is 2.3 m ² , the first circulation pump 12a is 2.2 Kw, 30 Hz, the heat capacity C1 of the shelf board 4 = 180 kJ / ° C., and the density of the heat medium ρ = 960 kg / m. ^{3. When} the specific heat Cp of the heat medium is 1.67 kJ / kg ° C., the flow rate q of the heat medium circulating in the shelf board 4 from the inlet temperature Th′1 and the outlet temperature Th′2 of the raised shelf board 4 The results obtained are shown in Table 1. The flow rate q of the heat medium was measured to be about 100 L / min.

＜無負荷で第１熱媒体弁１１ａを閉じ、加熱器１３をＯＦＦした時のｄＴｈ’／ｄｔとΔＴｈ’の求め方＞
棚板の入口温度Ｔｈ１と出口温度Ｔｈ２の測定から一次乾燥における被乾燥材料Ｓの平均底部品温Ｔｍ、平均昇華面温度Ｔｓ及び昇華速度Ｑｍの算出をするために、棚出入り温度を測定する。その際、第１熱媒体弁１１ａと閉じないと、コールドトラップ３側の低い温度の熱媒が棚系の高い温度の熱媒と混合し、棚板４の入口温度Ｔｈ１と出口温度Ｔｈ２も変動するし、また、加熱器１３をＯＦＦしないと、棚板４の入口温度Ｔｈ１と出口温度Ｔｈ２も変化し、平均底部品温Ｔｍと昇華速度Ｑｍを算出できない。そのため、一定の時間間隔で、一時的に第１熱媒体弁１１ａを約２ｍｉｎ間閉じ、加熱器１３もＯＦＦする必要がある。

<How to obtain dTh ′ / dt and ΔTh ′ when the first heat medium valve 11a is closed without load and the heater 13 is turned off>
In order to calculate the average bottom part temperature Tm, the average sublimation surface temperature Ts, and the sublimation speed Qm of the material S to be dried in the primary drying from the measurement of the inlet temperature Th1 and the outlet temperature Th2 of the shelf board, the entry / exit temperature is measured. At that time, if the first heat medium valve 11a is not closed, the low temperature heat medium on the cold trap 3 side mixes with the high temperature heat medium in the shelf system, and the inlet temperature Th1 and the outlet temperature Th2 of the shelf plate 4 also fluctuate. If the heater 13 is not turned off, the inlet temperature Th1 and the outlet temperature Th2 of the shelf board 4 also change, and the average bottom part temperature Tm and the sublimation speed Qm cannot be calculated. For this reason, it is necessary to temporarily close the first heat medium valve 11a for about 2 minutes and turn off the heater 13 at regular time intervals.

  Further, in order to calculate the sublimation rate Qm, when the constant shelf temperature at the time of no load is controlled in advance, the rate of increase of the shelf plate temperature dTh ′ when the first heat medium valve 11a is closed and the heater 13 is turned off. / Dt and the temperature difference ΔTh ′ entering and leaving the shelf must be measured.

  Below, when the constant shelf temperature at the time of no load is controlled, the rise rate dTh ′ / dt of the shelf plate temperature and the shelf entry / exit temperature difference ΔTh ′ when the first heat medium valve 11a is closed and the heater 13 is turned off are Specific examples for measurement are shown below.

  The no-load test is performed by controlling the lyophilizer W1 in the same procedure as the lyophilization of the normal material to be dried S. As an example, the shelf is cooled to −40 ° C. during preliminary freezing, a vacuum is drawn, and the shelf temperature Th is changed to −30 ° C., −25 ° C., −20 ° C., −15 ° C., −10 ° C., −5 ° C. , 0 ° C., 10 ° C., 20 ° C., 30 ° C., the first heat medium valve 11a is closed for 2 minutes, the heater 13 is turned OFF for 2 minutes, and the inlet temperature Th′1 and outlet of the shelf 4 at that time The temperature Th′2 was measured and recorded in the recorder 16b. From the recorded data, the shelf temperature rise rate dTh ′ / dt and the shelf entry / exit temperature difference ΔT ′ were measured.

In this embodiment, the shelf effective area of the freeze dryer W1 is 2.3 m ² , the first circulation pump 12a is 2.2 Kw, 30 Hz, and the circulation flow rate q of the heat medium is about 100 L / min. When the temperature is controlled, the first heat medium valve 11a is closed, the heater 13 is turned off, and the inlet temperature Th1 and outlet temperature Th2 of the shelf plate 4 are recorded at a recording speed of 10 s during that time, and recorded between 80 s and 120 s. The average temperature of the shelf temperature increase rate dTh ′ / dt and the shelf entry / exit temperature difference ΔT ′ was calculated from the data, and the results are shown in Table 2.

第１熱媒体弁１１ａを閉とし、加熱器１３をＯＦＦとして、この無負荷時の棚温上昇速度ｄＴｈ’／ｄｔと棚出入温度差ΔＴ’の測定結果により、負荷時の一次乾燥工程における被乾燥材料Ｓの昇華速度Ｑｍと平均底部品温Ｔｍを算出する時、負荷時の棚温の変化率ｄＴｈ／ｄｔと無負荷時の棚温上昇速度ｄＴｈ’／ｄｔとの差で計算するので、乾燥庫壁１ａから輻射入熱による昇華速度の分を含め、表２の結果から、棚温が低く制御されると、ｄＴｈ’／ｄｔが大きくなり、乾燥庫壁１ａから輻射入熱が多くなる。また、負荷時の棚出入り温度差ΔＴと無負荷時の棚出入り温度差ΔＴ’との差（ΔＴ−ΔＴ’）で計算されるため、第１及び第２温度センサ１５ａ，１５ｂの棚出入り温度に誤差があっても、引き算でこの影響を無くすことができる。

The first heat medium valve 11a is closed, the heater 13 is turned OFF, and the measurement result of the shelf temperature rise rate dTh ′ / dt and the shelf entry / exit temperature difference ΔT ′ at the time of no load is used in the primary drying process at the time of load. When calculating the sublimation speed Qm of the drying material S and the average bottom part temperature Tm, the calculation is based on the difference between the shelf temperature change rate dTh / dt during loading and the shelf temperature rising speed dTh ′ / dt during no loading. From the results shown in Table 2, including the amount of sublimation speed due to radiation heat input from the drying cabinet wall 1a, when the shelf temperature is controlled to be low, dTh '/ dt increases, and radiation input heat increases from the drying cabinet wall 1a. . Moreover, since it is calculated by the difference (ΔT−ΔT ′) between the shelf entry / exit temperature difference ΔT ′ during load and the shelf entry temperature difference ΔT ′ during no load, the entry / exit temperatures of the first and second temperature sensors 15a, 15b are calculated. Even if there is an error, the effect can be eliminated by subtraction.

  Next, when the material to be dried S is freeze-dried according to the freeze-drying program, the first heat medium valve 11a is closed in a short time (or PID control) at a constant time interval, the heater 13 is turned off, If the inlet temperature Th1 and outlet temperature Th2 of the shelf 4 and the degree of vacuum in the drying cabinet 1 are measured and recorded, the shelf temperature rise rate dTh ′ / dt and the shelf entry / exit temperature difference obtained by the above-described no-load measurement. From the relationship between ΔT ′ and the shelf control temperature, the overall average bottom part temperature Tm and the average sublimation rate Qm in the primary drying process can be monitored without measuring the product temperature of the individual containers.

<Control flow chart of primary drying process and heat medium / refrigerant / air flow>
The calculation process of the primary drying process in the first embodiment is as described above, and this primary drying process will be described below with reference to the control flowcharts of FIGS. 9 and 10 and the heat medium / refrigerant and air flow of FIG. .

  As shown in FIG. 9, after completion of the preliminary freezing process, the evacuation process starts. In this evacuation process, the main valve 2a and the inlet valve 7 are opened, and the vacuum pump 8 is driven to suck air in the main pipe 2 including the drying chamber 1 and the cold trap 3 (S21). Thereby, it continues until the vacuum degree of the drying chamber detected by the vacuum gauge 6 becomes a set value (S22) (refer to the white arrow in FIG. 11).

  After this evacuation process is completed, the process proceeds to the primary drying process. In the primary drying step, the first and second heat medium valves 11a and 11b are controlled to open and close, and the first and second circulation pumps 12a and 12b, the heater 13, the opening degree adjuster 2b, and the cooling device 10 are driven and controlled. (S23).

  Thereby, in the drying process, the cooling device 10 is driven in the same manner as the preliminary freezing process described above. As shown by the solid line arrow in FIG. 11, the heat medium circulation pipe 9 divides the heat medium into the outlet of the shelf plate 4 → the second heat medium valve 11 b → the first circulation pump 12 a → the heater (operation drive) → the shelf plate 4. The cycle of the drying chamber 1 that circulates sequentially with the inlet, the cycle of the cold trap 3 that circulates sequentially with the second circulation pump 12b → the trap coil 3a → the second circulation pump 12b, and the drying chamber as shown by the broken line arrows in FIG. 1 and the cold trap 3 circulate the heat medium. The selection of each cycle and ON / OFF of the heater 13 are driven and controlled by the shelf temperature program of the sequencer 16a, and the shelf plate 4 is set to a set value. On the other hand, the degree of vacuum in the drying chamber 1 is controlled to the control value by controlling the degree of opening of the opening controller 2b (S25). Thereby, the shelf 4 in the drying chamber 1 is heated, freeze drying of the material to be dried S is started, and water vapor sublimated from the material to be dried S flows from the drying chamber 1 into the cold trap 3 through the main pipe 2. Condensed and collected by the trap coil 3a.

  In the middle of the drying process of the material to be dried S, the process proceeds to a process of stopping the supply of the heat medium to the shelf board 4 (heat medium supply stop process) as shown in FIG. In this heat medium supply stop process, it is determined whether or not the calculation processing operation is the first (first time) after the transition to the primary drying process (S31), and when it is the first time, the heater 13 is stopped. Then, the first heat medium valve 11a is closed (S32). On the other hand, if it is determined in step S31 that it is not the first time, it is determined whether or not 30 minutes have passed since the previous process (S33). If 30 minutes have passed, the heater 13 is stopped in step S32. And the first heat medium valve 11a is closed. Subsequently, it is determined whether or not a short time (2 minutes) has elapsed for the stop and close times (S34). When 2 minutes have elapsed, the process proceeds to a sublimation rate calculation process.

  In this calculation step, the inlet temperature Th1 and the outlet temperature Th2 of the shelf board 4 are measured, and the sublimation speed, the average bottom part temperature, and the average sublimation surface temperature are calculated from the above-described calculation program and relational expressions (S35). These calculated data are recorded in the recorder 16b (S36). Such a calculation process is performed until the primary drying process is completed (S37).

  As is apparent from the control flowchart of the primary drying process described above, in the primary drying process, the average bottom part temperature and the like are calculated every predetermined time interval (30 minutes), and when calculating, in a short time. Then, the heater 13 is stopped and the first heat medium valve 11a is closed, and then the process proceeds to the calculation step. Thus, when calculating the average bottom part temperature, the low temperature heat medium on the cold trap 3 side does not flow into the shelf plate 4 side, and the heating medium flows into the shelf plate 4 side with the heater 13. Therefore, the average bottom part temperature or the like can be accurately calculated.

<Calculation result and evaluation of average bottom part temperature Tm and sublimation speed Qm in primary drying process>
Below, when the freeze-dryer W1 of the flow path opening vacuum control system is used, the average bottom part of the entire material to be dried S in the primary drying period, which is obtained by performing a freeze-drying test using an actual load The calculation result of temperature Tm and sublimation speed Qm is shown.

<When opening and closing the first heat medium valve 11a>
The lyophilizer W1 contains 10% of the mixture of mannitol (Mannitol, molecular formula; C ₆ H ₁₄ O ₆ ) and sucrose (Sucrose, molecular formula; C ₁₂ H ₂₂ O ₁₁ ) as the material to be dried S in the drying chamber 1. 200 vials / tray × 8 = 1760 vials into which 3 mL of aqueous solution was dispensed were charged and controlled by the control panel 16 to start a predetermined drying process. In order to verify the suitability of the calculation method and the calculation apparatus according to the present invention, a product temperature sensor is inserted into the three vials inserted in the center of the shelf, and the dispensed material is dispensed into the vials. The product temperature (product temperature 1, product temperature 2, product temperature 3) of the dried material S was measured. The solution is frozen at −45 ° C. for 2 hours, and the shelf temperature Th is raised to 0 ° C. in 1 hr at the time of primary drying, and is set to 0 ° C., and the opening angle θ of the opening controller 2b is adjusted to the drying cabinet. The degree of vacuum in 1 was controlled to 10.0 Pa, and the material to be dried S was freeze-dried. In the primary drying period, the first heat medium valve 11a is closed for 120s at intervals of 30 minutes, the heater 13 is also turned off for 120s, and the inlet temperature Th1 and outlet temperature Th2 of the shelf 4 and the degree of vacuum in the drying chamber 1 are set. The average bottom part temperature Tm and the average sublimation rate Qm of the material to be dried S were calculated using the calculation software that was measured and recorded and stored in the sequencer 16a. FIG. 12 shows the calculation result.

  FIG. 12 is based on the opening / closing control of the freeze-dryer W1 and the first heat medium valve 11a of the flow path opening vacuum control method, and the average bottom part temperature Tm and the sublimation speed Qm of the material to be dried S calculated under the above conditions are shown. It is a graph to show. As is apparent from this figure, the calculated average bottom part temperature Tm of the material to be dried S is the product temperature of the material to be dried S detected by the product temperature sensor (product temperature 1, product temperature 2, product temperature 3). And agrees well. Thereby, it was possible to verify the appropriateness of the calculation method and the calculation apparatus according to the present invention. The data shown in FIG. 12 is recorded on a recorder 16 b provided on the control panel 16. The operator of the freeze dryer W1 can know the primary drying state of the material to be dried S by monitoring the data of the average bottom part temperature Tm and the data of the sublimation speed Qm recorded in the recorder 16b.

<When PID control is performed on the first heat medium valve 11a>
The lyophilizer W1 contains 10% of the mixture of mannitol (Mannitol, molecular formula; C ₆ H ₁₄ O ₆ ) and sucrose (Sucrose, molecular formula; C ₁₂ H ₂₂ O ₁₁ ) as the material to be dried S in the drying chamber 1. 1760 vials into which 3 mL of aqueous solution has been dispensed are charged and controlled by the control panel 16 to start a predetermined drying process. In order to verify the suitability of the calculation method and the calculation apparatus according to the present invention, a product temperature sensor is inserted into the three vials inserted in the center of the shelf, and the dispensed material is dispensed into the vials. The product temperature (product temperature 1, product temperature 2, product temperature 3) of the dried material S was measured. The solution is frozen at −45 ° C. for 2 hours, the shelf temperature Th is set to −10 ° C. during the primary drying, and the degree of vacuum in the drying chamber 1 is adjusted by adjusting the opening angle θ of the opening controller 2b. The material to be dried S was lyophilized by controlling to 7 Pa. The first heat medium valve 11a is PID control (Proportional Integral Derivative Controller), and the heater 13 is turned off for 120 seconds at intervals of 30 minutes in the primary drying period, the inlet temperature Th1 and the outlet temperature Th2 of the shelf board 4, and the drying chamber The degree of vacuum in 1 was measured and recorded, and the average bottom part temperature Tm and the average sublimation rate Qm of the material to be dried S were calculated using calculation software stored in the sequencer 16a. FIG. 13 shows the calculation result.

  FIG. 13 is based on the PID control of the flow path opening vacuum control type freeze dryer W1 and the first heat medium valve 11a. The average bottom part temperature Tm and the sublimation speed Qm of the material to be dried S calculated under the above conditions are shown in FIG. It is a graph. As is apparent from this figure, the calculated average bottom part temperature Tm of the material to be dried S is the product temperature of the material to be dried S detected by the product temperature sensor (product temperature 1, product temperature 2, product temperature 3). And agrees well. Thereby, it was possible to verify the appropriateness of the calculation method and the calculation apparatus according to the present invention. The data shown in FIG. 13 is recorded in a recorder 16b provided in the control panel 16. The operator of the freeze dryer W1 can know the primary drying state of the material to be dried S by monitoring the data of the average bottom part temperature Tm and the data of the sublimation speed Qm recorded in the recorder 16b.

The shelf area of this freeze dryer W1 is 2.3 m ² and there are 16 trays with 4 shelves. In the above two experimental examples, 220 vials / tray × 8 sheets = 1760 are loaded. In addition, the charge is halved, and the flow rate q of the shelf-type heat medium circulation pump is about 100 L / min, which is 2.5 times the normal 40 L / min. An error occurs when the sublimation temperature Qm is calculated below 0.2 ° C. If a normal shelf system heat medium circulation pump flow rate of 40 L / min and 220 vials / tray × 16 sheets = 3520 bottles are loaded in all shelves, the temperature difference ΔT between loading and unloading during loading increases, and the sublimation speed Qm Therefore, the calculated value of the average bottom part temperature Tm is more approximate to the product temperature of the material to be dried S detected by the product temperature sensor.

  After the completion of the primary drying step, a secondary drying step is entered, and a small amount of antifreeze water contained in the material to be dried S that has become a dry solid through the primary drying step is removed, so that the material to be dried S has a predetermined content. Dry until moisture content.

<Calculation method of average product temperature Tm in secondary drying process>
The average product temperature Tm of the entire material to be dried S in the secondary drying period can be calculated from the following equation.

  First, the heat transfer equation of the dried product is expressed by the following equation.

C × dTm / dt = Qh + Qr−Qm × ΔHs
In this equation, C is the heat capacity of the material to be dried S, Tm is the average product temperature, Qh is the heat input from the shelf 4 to the bottom of the container by gas conduction, and Qr is the radiation input heat from the drying cabinet wall to all containers. , Qm is the dehumidification rate, and ΔHs is the latent heat of evaporation.

  First, the amount of heat input Qh from the shelf due to gas conduction to the bottom of the container is calculated by the following equation.

Qh = Ae × K × (Th−Tm)
However, Ae is an effective heat transfer area (m ² ), K is a heat transfer coefficient from the shelf board 4 to the bottom of the container by gas conduction, Th is a shelf temperature (° C.), and Tb is a bottom part temperature (° C.).

The effective heat transfer area Ae can be calculated by Ae = 2 / (1 / Av + 1 / At),
The heat transfer coefficient K (W / m ² ° C) from the shelf board 4 to the container bottom by gas conduction is
K = 16.86 / (δ + 2.12 × 29 × 0.133 / Pdc).

In the formula for calculating the effective heat transfer area Ae, Av is the container bottom area (m ² ), and At is the tray frame area (m ² ).

The container bottom area Av can be calculated by Av = π / 4 × n1 × d ² (where n1 is the number of vials and d is the vial diameter), and the tray frame area At is At = n2 × W × L (where n2 Is the number of frames; W is the width of the frame, and L is the length of the frame).

  Moreover, in the calculation formula of the heat transfer coefficient K from the shelf board 4 to the container bottom by gas conduction, δ is a gap at the container bottom and the unit is mm.

  On the other hand, the radiant heat input Qr from the drying chamber wall 1a to all the containers 5 is obtained from the following equation.

Qr = 5.67 × ε × Ae × [(Tw / 100) ⁴ − (Tm / 100) ⁴ ]
In the equation, ε is a radiation coefficient, Tw is a drying cabinet wall temperature (K), and Tm is an average product temperature (K).

  Moreover, the amount of radiation heat input Qr from the drying chamber wall 1a to all the containers 5 can be approximately calculated by the following equation.

Qr = Ae × Kr × (Tw−Tm)
However, Kr are equivalent heat transfer coefficient due to radiation heat input, Kr = 0.7W / m ² ℃ in tester can be approximated as Kr = 0.2W / m ² ℃ production machine.

  When the formula for calculating the heat input is included in the heat transfer equation, the following formula is established.

C x dTm / dt
= Ae * K * (Th-Tm) + Ae * Kr * (Tw-Tm) -Qm * [Delta] Hs
However, ΔHs is latent heat of vaporization, and ΔHs = 2850 KJ / Kg.

  The average product temperature of the material to be dried S in the secondary drying period can be calculated by the following equation.

C × (Tm−Tm0) / Δt
= Ae * K * (Th-Tm) + Ae * Kr * (Tw-Tm) -Qm * [Delta] Hs
Tm = (Tm0 + a1 × Th + a2 × Tw−a3) / (1 + a1 + a2)
a1 = K × Ae × Δt / C
a2 = Kr × Ar × Δt / C
a3 = Qm × ΔHs × Δt / C
However, C is the heat capacity of the material S to be dried.

  Therefore, the average product temperature Tm of the entire material to be dried S can be calculated by measuring the dehumidification rate Qm in the secondary drying period from the above formula.

<Calculation method of heat capacity C of material to be dried S in secondary drying step>
When entering the secondary drying step, the shelf temperature is raised to the set temperature for secondary drying. Thereby, the antifreeze water of the material S to be dried is dehumidified, and the product temperature is also increased. The heat capacity C of the material to be dried S includes the heat capacity Ct of the tray, the heat capacity Cv of the vial and the rubber stopper, the heat capacity Cs of the medicine, and the heat capacity Cw of the antifreeze water.

  (1) The heat capacity Ct of the tray is calculated by Ct = csus × Wt. csus is the specific heat of stainless steel. Wt is the tray weight, and is the total value of the extraction tray and the bottomed tray.

  (2) The heat capacity Cv of the vial and the rubber stopper is calculated by Cv = cv × Wv + cc × Wc. cv is the specific heat of the vial, Wv is the weight of the vial, cc is the specific heat of the rubber stopper, and Wv is the weight of the rubber stopper.

  (3) The heat capacity Cs of the medicinal component is calculated by Cs = cs × Ws. cs is the specific heat of the drug, and Ws is the weight of the drug.

  (4) The heat capacity Cw of the antifreeze water is calculated by Cw = cw × Ww. cw is the specific heat of the antifreeze water, and Ww is the weight of the antifreeze water.

  (5) Therefore, the heat capacity of the material to be dried S is C = Ct + Cv + Cs + Cw.

<Secondary drying process control flowchart and heat medium / refrigerant / air flow>
The calculation process of the secondary drying process in the first embodiment is as described above, and this secondary drying process will be described below with reference to the control flowchart of FIG. 14 and the heat medium / refrigerant and air flow of FIG.

  When the primary drying process ends and the process proceeds to the secondary drying process, the degree of vacuum in the drying cabinet 1 is changed depending on the situation. Here, the flow of the heat medium and the refrigerant flows as shown in FIG. That is, while the cooling device 10 flows in the same manner as in the primary drying process, the heat medium is passed through the outlet of the shelf plate 4 → the second heat medium valve 11b → the first circulation pump in the heat medium circulation line 9 as indicated by the solid line arrow. 12a → heater (driving drive) → cycle of the drying chamber 1 that circulates sequentially with the inlet of the shelf 4 and cycle of the cold trap 3 that circulates sequentially with the second circulation pump 12b → the trap coil 3a → the second circulation pump 12b. Circulated. As a result, the shelf board 4 is heated, and the water vapor sublimated from the material to be dried S flows from the drying chamber 1 through the main pipe 2 into the cold trap 3, and a trace amount of non-removable material that cannot be removed from the material to be dried S in the primary drying process. Frozen water is removed.

  In such a secondary drying process, the calculation process of the average bottom part temperature and the dehumidification rate is carried out. Whether or not this calculation process is the first (first time) after shifting to the secondary drying process. If it is determined (S41) and it is the first time, the degree of vacuum in the drying chamber 1 is measured by the vacuum gauge 6, and the inlet temperature Th1 and the outlet temperature of the shelf board 4 are measured by the first and second temperature sensors 15a and 15b. Th2 is measured (S42). On the other hand, if the calculation process is the second or later, it is determined whether 30 minutes have passed since the previous calculation process (S43), and 30 minutes have passed since the previous calculation process. If so, the process proceeds to step S42, and the degree of vacuum and temperature are measured. Thereafter, as described above, the average bottom part temperature and the dehumidifying rate are calculated from the degree of vacuum, the temperature difference between the measured temperatures, the relational expression, and the like (S44). The calculated data is recorded in the recorder 16b (S45). Such a calculation process is continued until the secondary drying process is completed (S46).

  In the control flowchart of the secondary drying process described above, the average bottom part temperature and the dehumidification rate are calculated every predetermined time interval (30 minutes).

  FIG. 16 is a control flowchart showing another example of the calculation process of the secondary drying process. The same steps as those in the control process of FIG. 15 are denoted by the same reference numerals, and the description thereof is omitted.

  The difference between this calculation process and the calculation process of FIG. 15 is that the vacuum degree of the drying chamber 1 is maintained at the control value as a condition for shifting to step S41 in this calculation process ( S51). That is, when the secondary drying process is stably performed, the average bottom part temperature and the dehumidification rate are calculated.

  FIG. 17 is a control flowchart showing still another example of the calculation process of the secondary drying process. The same steps as those in the control process of FIG. 15 are denoted by the same reference numerals, and the description thereof is omitted.

  The difference between the main calculation process and the calculation process of FIG. 15 is that the opening degree controller 2b is fully opened as a condition for shifting to step S41 in the main calculation process (S61).

[Second Embodiment]
FIG. 18 shows a dry state monitoring apparatus and a dry state monitoring method according to the second embodiment.

  The second embodiment differs from the first embodiment only in the following points. That is, in the first embodiment, the damper type opening degree controller 2b is used as the vacuum degree adjusting means for adjusting the degree of vacuum in the drying chamber 1, but in the second embodiment, the drying chamber 1 is replaced with this. A connected vacuum control line 20 is used. In the second embodiment, the same parts as those in the first embodiment are denoted by the same reference numerals, and the description thereof is omitted.

  The vacuum control line 20 is a line in which a leak control valve 21 and a variable leak valve 22 are connected in series from the drying chamber 1 to the outside. When the degree of vacuum in the drying chamber 1 reaches the upper limit value of the set value, the opening degree of the leak control valve 21 increases, and conversely, when the degree of vacuum in the drying chamber 1 reaches the lower limit value, the leakage control valve. The opening degree of 21 becomes small.

  As described above, since the vacuum control line 20 is not functionally different from the opening degree controller 2b, the second embodiment can obtain the same result as the first embodiment. That is, it goes without saying that the average product temperature in the preliminary freezing step, the average product temperature and average sublimation surface temperature in the primary drying period, the average product temperature in the secondary drying period, and the average dehumidification rate can be accurately determined by calculation.

  In the second embodiment, the vacuum control line 20 is connected to the drying chamber 1, but may be provided in the main pipe 2 or connected to the cold trap 3 as long as it is connected to the vacuum system. You may do it.

  W1 ... freeze dryer, 1 ... drying cabinet, 2 ... main pipe, 2a ... main valve, 2b ... opening controller, 3 ... cold trap, 4 ... shelf board, 5 ... container, 6 ... vacuum gauge, 7 ... inlet Valves, 8 ... Vacuum pump, 9 ... Heat medium circulation line, 10 ... Cooling device, 11a, 11b ... First and second heat medium valves, 13 ... Heater, 15a, 15b ... First and second temperature sensors, 20 ... Vacuum control line, S ... Material to be dried.

Claims (17)

A drying chamber for charging the material to be dried placed on the shelf, a main pipe communicating with the drying chamber and having a main valve for passing water vapor generated from the material to be dried, and steam flowing into the main pipe from the main pipe. A cold trap for condensing and collecting; a vacuum pump for sucking and discharging the air in the drying cabinet; a vacuum detection means for detecting the pressure in the drying cabinet; and the drying cabinet based on the detected pressure of the vacuum detection means A degree-of-vacuum adjustment means for adjusting the degree of vacuum inside, a heat medium circulation pipe having a circulation pump for circulating a heat medium on the shelf, a cooling means for cooling the heat medium in the heat medium circulation pipe, first temperature detecting a heater for heating the heat medium of the heat medium circulation conduit, and a heat medium valve for controlling the circulation of the heat medium of the heat medium circulation line, the inlet side of the heat medium temperature of the shelves Detect the temperature of the heat medium on the outlet side of the sensor and the shelf And second temperature sensor, sensing the pressure of said vacuum sensing means, based on the detected temperature of the first temperature sensor and the second temperature sensor, a vacuum pump, circulation pump, the cooling means, and control means for controlling the heater and the heat medium valve Prepared,
A preliminary freezing step for freezing the material to be dried in the drying chamber, a primary drying step for condensing and collecting water vapor generated from the material to be dried following the preliminary freezing step, and a material to be dried following the primary drying step. A lyophilization state monitoring method applied to a lyophilizer for performing lyophilization of a material to be dried by sequentially performing a secondary drying process for removing a small amount of antifreeze contained therein,
The control means stores the detection data of each temperature sensor, a required calculation program for calculating an average product temperature of the material to be dried in the preliminary freezing step, and a necessary relational expression, and also the material to be dried in the primary drying step. A required calculation program for calculating the average product temperature, average sublimation temperature and average sublimation rate of the material and a required relational expression are stored, and further, the average product temperature and average dehumidification rate of the material to be dried in the secondary drying step are stored. Store the required calculation program to calculate and the required relational expression,
In the preliminary freezing step, a temperature difference between the detected temperature of the first temperature sensor and the detected temperature of the second temperature sensor is calculated by a calculation program, and subsequently, the drying target in the preliminary freezing step is calculated from the calculated temperature difference and the relational expression. Calculate the average product temperature of the material,
In the primary drying step, a temperature difference between the temperature detected by the first temperature sensor and the temperature detected by the second temperature sensor is calculated by a calculation program, and then the object to be dried in the primary drying step is calculated from the calculated temperature difference and the relational expression. Calculate the average product temperature, average sublimation temperature and average sublimation speed of the material,
In the secondary drying step, a temperature difference between the detected temperature of the first temperature sensor and the detected temperature of the second temperature sensor is calculated by a calculation program, and subsequently, the calculated temperature difference and the degree of vacuum in the drying chamber, The freeze-dried state monitoring method, wherein the average product temperature and average dehumidification rate of the material to be dried in the secondary drying step are calculated from the relational expression. As the relational expression, the control means once cools an unloaded shelf board with no material to be dried and then heats it with a heater, then fully opens the main valve and stops the heater to close the heat medium valve. 2. The freeze-dried state monitoring method according to claim 1, wherein a relational expression of a shelf temperature rise rate when the temperature is set, a temperature difference between the heat medium entering and exiting the shelf board, and the shelf temperature is stored. In the primary drying step, the vacuum degree in the drying chamber is controlled to a set value by the vacuum degree adjusting means, and the shelf temperature is controlled to the set value by opening and closing the heater and the heat medium valve, and then for a short time. The freeze-dried state according to claim 1 or 2, wherein the heating medium valve is closed and the heater is stopped, and then the calculation process of the primary drying step is performed at predetermined time intervals. Monitoring method. As the vacuum degree adjusting means, using an opening controller for adjusting the opening in the main pipe,
4. The calculation process of the secondary drying step is performed at predetermined time intervals after the opening controller is started to operate in the fully open direction. 5. Lyophilized state monitoring method. As the vacuum degree adjusting means, using an opening controller for adjusting the opening in the main pipe,
The control means drives the opening controller to control the degree of vacuum in the drying chamber to a set value, and then performs the calculation process of the secondary drying step at predetermined time intervals. The freeze-dried state monitoring method according to any one of claims 1 to 3. As the vacuum degree adjusting means, a vacuum control line provided with any one of the vacuum system including the drying cabinet, the cold trap or the main pipe, and having a leak control valve,
The said control means implements the calculation process of the said secondary drying process for every predetermined time interval, after closing the said leak control valve. The Claim 1 thru | or 3 characterized by the above-mentioned. Lyophilized state monitoring method. As the vacuum degree adjusting means, a vacuum control line provided with any one of the vacuum system including the drying cabinet, the cold trap or the main pipe, and having a leak control valve,
The control means performs the calculation process of the secondary drying step at predetermined time intervals after driving the leak control valve to control the degree of vacuum in the drying chamber to a set value. The freeze-dried state monitoring method according to any one of claims 1 to 3. The freeze-dried state monitoring method according to any one of claims 1 to 7, wherein data calculated in the preliminary freezing step, the primary drying step, and the secondary drying step is recorded in a recording unit. . A drying chamber for charging the material to be dried placed on the shelf, a main pipe communicating with the drying chamber and having a main valve for passing water vapor generated from the material to be dried, and steam flowing into the main pipe from the main pipe. A cold trap for condensing and collecting; a vacuum pump for sucking and discharging the air in the drying cabinet; a vacuum detection means for detecting the pressure in the drying cabinet; and the drying cabinet based on the detected pressure of the vacuum detection means A degree-of-vacuum adjustment means for adjusting the degree of vacuum inside, a heat medium circulation pipe having a circulation pump for circulating a heat medium on the shelf, a cooling means for cooling the heat medium in the heat medium circulation pipe, first temperature detecting a heater for heating the heat medium of the heat medium circulation conduit, and a heat medium valve for controlling the circulation of the heat medium of the heat medium circulation line, the inlet side of the heat medium temperature of the shelves Detect the temperature of the heat medium on the outlet side of the sensor and the shelf And second temperature sensor, sensing the pressure of said vacuum sensing means, based on the detected temperature of the first temperature sensor and the second temperature sensor, a vacuum pump, circulation pump, the cooling means, and control means for controlling the heater and the heat medium valve Prepared,
A preliminary freezing step for freezing the material to be dried in the drying chamber, a primary drying step for condensing and collecting water vapor generated from the material to be dried following the preliminary freezing step, and a material to be dried following the primary drying step. A lyophilization state monitoring device applied to a lyophilizer for performing lyophilization of a material to be dried by sequentially performing a secondary drying process for removing a trace amount of antifreeze contained therein,
The control means stores the detection data of each temperature sensor, a required calculation program for calculating an average product temperature of the material to be dried in the preliminary freezing step, and a necessary relational expression, and also the material to be dried in the primary drying step. A required calculation program for calculating the average product temperature, average sublimation temperature and average sublimation rate of the material and a required relational expression are stored, and further, the average product temperature and average dehumidification rate of the material to be dried in the secondary drying step are stored. Stores the required calculation program to calculate and the required relational expression,
The control means includes
In the preliminary freezing step, a temperature difference between the detected temperature of the first temperature sensor and the detected temperature of the second temperature sensor is calculated by a calculation program, and subsequently, the drying target in the preliminary freezing step is calculated from the calculated temperature difference and the relational expression. A calculation means for calculating an average product temperature of the material;
In the primary drying step, a temperature difference between the temperature detected by the first temperature sensor and the temperature detected by the second temperature sensor is calculated by a calculation program, and then the object to be dried in the primary drying step is calculated from the calculated temperature difference and the relational expression. A calculation means for calculating the average product temperature, average sublimation temperature and average sublimation speed of the material;
In the secondary drying step, a temperature difference between the detected temperature of the first temperature sensor and the detected temperature of the second temperature sensor is calculated by a calculation program, and subsequently, the calculated temperature difference and the degree of vacuum in the drying chamber, A freeze-drying state monitoring apparatus, comprising: a calculating unit that calculates an average product temperature and an average dehumidification rate of the material to be dried in the secondary drying step from the relational expression. As the relational expression, the control means once cools an unloaded shelf board with no material to be dried and then heats it with a heater, then fully opens the main valve and stops the heater to close the heat medium valve. The freeze-dried state monitoring apparatus according to claim 9, wherein a relational expression of a shelf temperature rise speed when the temperature is changed, a temperature difference between the heat medium entering and exiting the shelf board, and the shelf temperature is stored. The control means, in the primary drying step, after controlling the degree of vacuum in the drying chamber to a set value by the degree of vacuum adjustment means and controlling the shelf temperature to a set value by opening and closing the heater and the heat medium valve, The heat-processing valve is closed for a short time, the heater is stopped, and thereafter, calculation processing means for performing the calculation processing of the primary drying step at predetermined time intervals is provided. The freeze-dried state monitoring apparatus according to claim 9 or claim 10. As the vacuum degree adjusting means, using an opening controller for adjusting the opening in the main pipe,
The calculation processing means for performing the calculation process of the secondary drying step at predetermined time intervals after starting the movement of the main valve in the fully open direction. The freeze-dried state monitoring device according to item. As the vacuum degree adjusting means, using an opening controller for adjusting the opening in the main pipe,
The control means includes calculation processing means for performing the calculation process of the secondary drying step at predetermined time intervals after controlling the degree of vacuum in the drying chamber to a set value by drivingly controlling the opening degree controller. The freeze-dried state monitoring device according to any one of claims 9 to 11, wherein As the vacuum degree adjusting means, a vacuum control line provided with any one of the vacuum system including the drying cabinet, the cold trap or the main pipe, and having a leak control valve,
The control means includes calculation processing means for performing calculation processing of the secondary drying step at predetermined time intervals after closing the leak control valve. The freeze-dried state monitoring device according to claim 1. As the vacuum degree adjusting means, a vacuum control line provided with any one of the vacuum system including the drying cabinet, the cold trap or the main pipe, and having a leak control valve,
The control means includes calculation processing means for performing the calculation process of the secondary drying process at predetermined time intervals after controlling the degree of vacuum in the drying chamber to a set value by drivingly controlling the leak control valve. The freeze-dried state monitoring device according to any one of claims 9 to 11, characterized in that: The freeze-dried state monitoring according to any one of claims 9 to 15, further comprising recording means for recording data calculated in the preliminary freezing step, the primary drying step, and the secondary drying step. apparatus. The freeze-dried state monitoring device according to any one of claims 9 to 16, wherein the first temperature sensor and the second temperature sensor are installed outside a drying cabinet.

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