JP6099622B2 - Drying state monitoring device and drying state monitoring method of material to be dried applied to freeze dryer - Google Patents

Description

  The present invention relates to an apparatus for monitoring a dry state of a material to be dried, which is applied to a freeze dryer that is a product obtained by drying a material to be dried, which is a raw material solution for foods and pharmaceuticals, to a predetermined moisture content by lyophilization. The present invention relates to a dry state monitoring method.

  For freeze-drying of pharmaceuticals, etc., containers such as trays and vials filled with materials to be dried are loaded into the drying chamber of a freeze dryer automatically controlled by a control panel, and the materials to be dried in each container are predetermined. It is performed by drying until the water content becomes. In general, the freeze-drying process of a material to be dried using this type of freeze-dryer is a pre-freezing process in which the liquid material to be dried is frozen, and water is removed from the material to be dried that has become icy due to the pre-freezing. A primary drying step to make a dry solid, and a small amount of antifreeze water contained in the material to be dried that has become a dry solid after the primary drying step is removed, and the material to be dried is dried to a predetermined moisture content. It consists of a next drying step.

  The applicant of the present application does not directly measure the sublimation surface temperature of the material to be dried by using a temperature sensor, but instead subtracts the average sublimation of a plurality of materials to be dried filled in a plurality of containers from the measured values of other parameters. A surface temperature, an average bottom part temperature, and a sublimation rate were obtained by calculation, and based on this, an apparatus and a method for monitoring the dry state of the material to be dried during the primary drying process were proposed (for example, see Patent Document 1). According to the technique described in Patent Document 1, since the temperature sensor is not inserted into the material to be dried, various inconveniences caused by the use of the temperature sensor, for example, (1) all of the charging in the drying chamber The average sublimation surface temperature of the material to be dried cannot be determined. (2) Since bacteria are likely to be mixed into the material to be dried, it cannot be applied to sterile preparations. (3) The material to be dried is automatically installed in the drying cabinet. It is possible to solve the problem that it cannot be applied to a freeze dryer equipped with an automatic loading device. Further, the apparatus and method previously proposed by the applicant of the present application, in the primary drying step of the material to be dried, drives the vacuum degree adjusting means to change the direction of temporarily increasing the degree of vacuum in the drying cabinet, and at least From the measurement data including the degree of vacuum in the drying chamber and the degree of vacuum in the cold trap before and after the change, the average sublimation surface temperature, average bottom part temperature, and sublimation rate of the material to be dried in the primary drying step are calculated. As a result, when the measurement data is collected, the degree of vacuum in the drying chamber is shifted to a direction higher than the vacuum control value, and the sublimation surface temperature is lowered. Thus, unlike the conventional MTM (Manometric Temperature Measurement) method, The risk of the dried material collapsing during lyophilization can be completely eliminated.

WO2012 / 108470A1 brochure

  However, the invention described in Patent Document 1 changes the degree of vacuum in the drying chamber temporarily in calculating the average sublimation surface temperature, average bottom part temperature, and sublimation speed of the material to be dried in the primary drying step. Therefore, there is a problem that it takes a long time to calculate the average sublimation surface temperature, the average bottom part temperature and the sublimation speed once, and the dry state of the material to be dried cannot be closely monitored.

  The invention described in Patent Document 1 relates to an apparatus and method that can monitor the drying state of the material to be dried in the primary drying process, and does not consider the secondary drying process. As described above, since the freeze-drying process of the material to be dried includes a primary drying process and a secondary drying process, in order to more accurately monitor the drying state of the material to be dried, the primary drying process and the secondary drying process are performed. It is desired that the drying state of the material to be dried in the process can be continuously monitored. Of course, also in this case, it is required not to use a temperature sensor and to completely eliminate the danger of the material to be dried collapsing.

  Furthermore, in the invention described in Patent Document 1, in calculating the average bottom part temperature in the primary drying step, the average bottom part temperature is calculated by using all the heat input to the material to be dried including the container as the sublimation latent heat of the material to be dried. ing. However, as shown in FIG. 19, during the shelf temperature raising period performed at the beginning of the primary drying process, the product temperature of the material to be dried including the container rises and falls, so that only the sublimation latent heat of the material to be dried is obtained. If the sensible heat of the material to be dried including the container is not taken into consideration, the average bottom part temperature in the primary drying process cannot be accurately calculated. Similarly, since the shelf temperature is raised even in the initial stage of the secondary drying process, if the average bottom part temperature is calculated without considering the sensible heat of the material to be dried including the container, the average in the secondary drying process is calculated. The bottom part temperature cannot be calculated accurately. Therefore, it is required to calculate the average bottom part temperature in consideration of the sensible heat of the material to be dried including the container in both the primary drying process and the secondary drying process.

  The present invention has been made in order to meet such a demand, and its purpose is to completely prevent the collapse of the material to be dried, and the average sublimation surface temperature of the material to be dried in the primary and secondary drying steps. Another object of the present invention is to provide a dry state monitoring apparatus and dry state monitoring method for a freeze dryer that can accurately calculate the average bottom part temperature and the sublimation rate (dehumidification rate) in a short span.

In order to solve such a problem, the present invention relates to a drying state monitoring device for a material to be dried applied to a freeze dryer, a drying cabinet (DC) for charging the material to be dried, and the drying cabinet (DC). ) A cold trap (CT) for condensing and collecting water vapor generated from the material to be dried charged in the inside, a main pipe (a) communicating the drying chamber (DC) and the cold trap (CT), A main valve (MV) for opening and closing the main pipe (a), a vacuum degree adjusting means for adjusting a vacuum degree in the drying chamber (DC), an absolute pressure in the drying chamber (DC), and the cold trap (CT) Vacuum detecting means for detecting the absolute pressure in the inside, and shelf temperature detecting means for detecting the temperature of the shelf (B) on which the container into which the material to be dried is dispensed is placed, which is installed in the drying cabinet (DC) And the drying chamber (DC), the cold trap (CT And a freeze dryer equipped with a control device (PLC) for automatically controlling the operation of the vacuum degree adjusting means, the control device (PLC) includes the dryer (DC), the cold trap (CT), and the A control program for controlling the drive of the vacuum degree adjusting means to execute the primary drying step and the secondary drying step of the material to be dried, a required calculation program and a formula, and a time interval for executing the calculation program; Data on the heat capacity of the material to be dried including the container and constant data including the wall temperature of the drying cabinet (DC) in the primary drying step and the wall temperature of the drying cabinet (DC) in the secondary drying step are stored. In the primary drying step, the degree of vacuum (Pdc) in the drying cabinet (DC) is changed without any operation of the vacuum degree adjusting means, and the control is performed. For each time interval stored in the apparatus (PLC), the control apparatus (PLC) includes the measurement data of the vacuum detection means and the shelf temperature detection means, and the wall temperature of the drying cabinet (DC) in the primary drying step. From the constant data and the calculation formula stored in the controller (PLC), the sublimation speed (Qm) of the material to be dried, the sublimation latent heat of the material to be dried and the sensible heat of the material to be dried including the container are calculated. The average bottom part temperature (Tb) and the average sublimation surface temperature (Ts) taken into consideration are obtained in this order, and each calculation data is recorded in the recording means (e). In the secondary drying step, the drying cabinet (DC The degree of vacuum (Pdc) in () is changed without any manipulation of the vacuum degree adjusting means, and the vacuum detecting means and the shelf are changed at each time interval stored in the control device (PLC). Temperature detection From the measurement data of the means and the constant data of the controller (PLC) including the wall temperature of the drying cabinet (DC) in the secondary drying step and the calculation formula stored in the controller (PLC) An average bottom part temperature (Tb) and an average product temperature (Tm) in consideration of the material dehumidification rate (Qm ′), the sublimation latent heat of the material to be dried and the sensible heat of the material to be dried including the container are obtained in this order. These calculation data are recorded in the recording means (e).

  In the dry state monitoring method of the above configuration, the primary drying step may be performed by using a freeze dryer having a damper type opening degree controller (C) in the main pipe (a) as the vacuum degree adjusting means. In the secondary drying step, the controller (PLC) adjusts the opening of the opening controller (C), and sets the opening angle of the opening controller (C) to the drying chamber (DC). ) To change following the change in the degree of vacuum (Pdc).

  Further, in the dry state monitoring method having the above-described configuration, the vacuum control circuit (f) with a leak control valve (LV) is used as the vacuum degree adjusting means in the drying cabinet (DC), the cold trap (CT), and the vacuum control circuit (f). In the primary drying step and the secondary drying step, the control means (PLC) drives the leak control valve (LV) using a freeze dryer provided in any of the vacuum systems including the main pipe (a). The degree of vacuum (Pdc) in the drying cabinet (DC) is controlled to a set value or the leak control valve (LV) is closed, and thereafter the degree of vacuum (Pdc) in the drying cabinet (DC) is increased. It is characterized by leaving it to.

On the other hand, with respect to the dry state monitoring device, a drying chamber (DC) in which the material to be dried is charged, and a cold trap that condenses and collects water vapor generated from the material to be dried charged in the drying chamber (DC) ( CT), a main pipe (a) communicating with the drying cabinet (DC) and the cold trap (CT), a main valve (MV) for opening and closing the main pipe (a), and the inside of the drying cabinet (DC) The vacuum degree adjusting means for adjusting the degree of vacuum, the vacuum detecting means for detecting the absolute pressure in the drying chamber (DC) and the absolute pressure in the cold trap (CT), and the drying chamber (DC). The shelf temperature detecting means for detecting the temperature of the shelf (B) on which the container into which the material to be dried is placed is placed, the drying chamber (DC), the cold trap (CT), and the vacuum degree adjusting means. Equipped with a control device (PLC) that automatically controls operation The controller (PLC) controls the driving of the drying cabinet (DC), the cold trap (CT), and the vacuum degree adjusting means, and executes the primary drying process and the secondary drying process of the material to be dried. Control program, required calculation program and formula, time interval for executing the calculation program, data on heat capacity of the material to be dried including the container, and wall temperature of the drying chamber (DC) in the primary drying step And constant data including the wall temperature of the drying cabinet (DC) in the secondary drying step is stored, and in the primary drying step, the degree of vacuum (Pdc) in the drying cabinet (DC) is adjusted to the degree of vacuum. The operation is performed without changing the means, and at each time interval stored in the control device (PLC), the vacuum detection means and the shelf temperature detection means Sublimation of the material to be dried from constant data and constant data of the controller (PLC) including the wall temperature of the drying cabinet (DC) in the primary drying step and the calculation formula stored in the controller (PLC) The average bottom part temperature (Tb) and the average sublimation surface temperature (Ts) in consideration of the speed (Qm), the sublimation latent heat of the material to be dried and the sensible heat of the material to be dried including the container are obtained in this order, Each calculation data is recorded in the recording means (e), and in the secondary drying step, the degree of vacuum (Pdc) in the drying cabinet (DC) is changed depending on the course without operating the degree of vacuum adjusting means. The control including the measurement data of the vacuum detection means and the shelf temperature detection means and the wall temperature of the drying cabinet (DC) in the secondary drying step for each time interval stored in the control device (PLC) apparatus From the constant data of (PLC) and the calculation formula stored in the controller (PLC), the dehumidification rate (Qm ′) of the material to be dried, the sublimation latent heat of the material to be dried, and the object to be dried including the container An average bottom part temperature (Tb) and an average part temperature (Tm) in consideration of the sensible heat of the dry material are obtained in this order, and each calculation data is recorded in the recording means (e).

  Further, the present invention provides the dry state monitoring device having the above-mentioned configuration, wherein the main opening (C) includes a damper type opening degree controller (C) as the vacuum degree adjusting means, and the primary drying step and the secondary drying step. The controller (PLC) adjusts the opening of the opening controller (C), and determines the opening angle of the opening controller (C) according to the degree of vacuum in the dryer (DC) ( Pdc) is changed in accordance with the change of Pdc).

In the dry state monitoring apparatus having the above-described configuration, the vacuum control circuit (f) with a leak control valve (LV) is used as the vacuum degree adjusting means, the drying chamber (DC), the cold trap (CT). And in any of the vacuum systems including the main pipe (a), in the primary drying step and the secondary drying step, the control means (PLC) drives the leak control valve (LV) to drive the drying cabinet. The degree of vacuum (Pdc) in (DC) is controlled to a set value, or the leak control valve (LV) is closed , and thereafter, the degree of vacuum (Pdc) in the drying chamber (DC) is left to the future. Features.

  According to the present invention, in the primary drying process and the secondary drying process, the sublimation speed of the material to be dried (dehumidification speed in the secondary drying process) is changed in a state where the degree of vacuum in the drying chamber is changed. The average bottom part temperature and the average sublimation surface temperature are calculated in this order, so that the degree of vacuum in the drying chamber is forcibly changed, and each calculated value is obtained from the change in parameters before and after the change. Therefore, it is not necessary to wait for the next calculation until the degree of vacuum in the drying chamber which has been changed is settled, and a necessary calculated value can be obtained at an arbitrary time interval set in the arithmetic unit. In addition, data related to the heat capacity of the material to be dried including the container is stored in the control device (PLC), and the sublimation latent heat of the material to be dried and the container are included when calculating the average bottom part temperature in the primary drying process and the secondary drying process. Since the sensible heat of the material to be dried is taken into account, an accurate average bottom part temperature can be calculated as compared with the case where the calculation considering only the latent heat is performed. Furthermore, since the wall temperature of the drying cabinet (DC) in the primary drying step and the wall temperature of the drying cabinet (DC) in the secondary drying step are stored in the control device (PLC), the average bottom in the primary drying step and the secondary drying step In calculating the product temperature, it becomes possible to apply an appropriate wall temperature of the drying cabinet (DC), and from this point, an accurate average bottom part temperature can be calculated. Therefore, the dry state of the material to be dried can be monitored finely and accurately, and the collapse of the material to be dried can be completely prevented.

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 flowchart of channel opening degree vacuum control. It is a flowchart which shows the process sequence from the data input of the monitoring method which concerns on 1st Embodiment to the completion | finish of a primary drying process. It is a flowchart which shows the process sequence of the secondary drying process following the primary drying process of the monitoring method which concerns on 1st Embodiment. It is a graph showing the relationship between the opening angle θ of the opening controller C and the main pipe resistance R (θ). A graph showing the comparison of the calculated values of the average sublimation surface temperature and average bottom part temperature with the actual measured product temperature when the aqueous lactose solution was freeze-dried by the method of the present invention using a freeze-dryer with a channel opening vacuum control method It is. It is a graph which expands and shows the initial stage of the primary drying process in FIG. A graph showing a comparison of the calculated value of the average sublimation surface temperature and average bottom part temperature with the measured product temperature when the lactose aqueous solution is freeze-dried by a conventional method using a freeze-dryer with a channel opening vacuum control method. is there. It is a graph which expands and shows the initial stage of the primary drying process in FIG. It is a block diagram of the freeze-dryer of the leak type vacuum control system to which the monitoring apparatus and monitoring method which concern on 2nd Embodiment are applied. It is a flowchart of leak type vacuum control. It is a flowchart which shows the process sequence from the data input of the monitoring method which concerns on 2nd Embodiment to the completion | finish of a primary drying process. It is a flowchart which shows the process sequence of the secondary drying process following the primary drying process of the monitoring method which concerns on 2nd Embodiment. It is a graph showing the relationship between the steam flow resistance coefficient Cr of the main pipe flow path, and the sublimation speed Qm. It is a graph which compares the calculated value of the average sublimation surface temperature and the average bottom part temperature, and measured product temperature when the sucrose aqueous solution is freeze-dried by the method of the present invention using a leak valve type freeze-dryer. It is a graph which expands and shows the initial stage of the primary drying process in FIG. It is a graph which compares the calculated value of average sublimation surface temperature and average bottom part temperature, and measured product temperature when the sucrose aqueous solution is freeze-dried by a conventional method using a freeze valve type freeze dryer. It is a graph which expands and shows the initial stage of the primary drying process in FIG. It is a graph which shows the change of the shelf temperature in the primary drying process and the secondary drying process, and the change of product temperature.

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

[First Embodiment]
The dry state monitoring method and the dry state monitoring device according to the first embodiment are provided with a damper type opening as a vacuum degree adjusting means for adjusting the degree of vacuum in the dry compartment in the main pipe connecting the dry compartment and the cold trap. The present invention is applied to a freeze-dryer of a flow path opening vacuum control system provided with a degree adjuster.

<Configuration of freeze dryer>
That is, as shown in FIGS. 1 and 2, the freeze dryer M1 according to the first embodiment is generated from the drying chamber DC in which the material to be dried is charged and the material to be dried charged in the drying chamber DC. Connected to the cold trap CT for condensing and collecting the water vapor to be trapped by the trap coil ct, the main pipe a communicating with the drying chamber DC and the cold trap CT, the inlet valve V attached to the cold trap CT, and the inlet valve V The vacuum pump P is provided. One to a plurality of shelf boards B are installed in the drying cabinet DC, and a plurality of containers E into which materials to be dried are dispensed are placed on the shelf boards B. As the container E, a vital, a tray, etc. are used according to the kind of material to be dried. The shelf board B is provided with a temperature sensor (shelf temperature detection means) S for detecting the temperature (shelf temperature) of the shelf board B. Further, the drying cabinet DC and the cold trap CT are provided with a vacuum gauge (vacuum detection means) b for detecting the absolute pressure in the drying cabinet DC and the absolute pressure in the cold trap CT. Instead of the configuration in which the vacuum gauge b is individually provided in each of the drying cabinet DC and the cold trap CT, a differential pressure vacuum gauge that detects the differential pressure between the absolute pressure in the drying cabinet DC and the absolute pressure in the cold trap CT is provided. It can also be set as the structure provided. The main pipe a is provided with a main valve MV that switches it to a fully open state or a fully closed state, and a damper-type opening degree adjuster C that adjusts the opening degree of the main pipe a. The opening adjuster C is provided with an angle sensor g such as a rotary encoder for detecting the opening angle θ. Note that the opening angle θ of the opening controller C refers to the rotation angle of the opening controller C from the fully open state (0 °).

  In FIG. 1, the symbol CR indicates a control panel provided in the freeze dryer M1. The freeze dryer M1 is automatically controlled by the control panel CR, and freeze-drys the material to be dried. As shown in FIG. 1, the control panel CR is composed of a sequencer PLC and a recorder (recording means) e. The sequencer PLC controls the driving of the drying cabinet DC, the cold trap CT, and the opening degree adjuster C. The control program for performing the preliminary drying process, the primary drying process and the secondary drying process of the material to be dried, the necessary calculation program, the relational expression and the constant data, and the time interval when the calculation program is repeatedly executed are preset. Remembered. Instead of the configuration in which the freeze dryer M1 includes the control panel CR, a configuration is adopted in which a personal computer storing a required control program, calculation program, relational expression, constant data, and time interval is connected to the freeze dryer M1. You can also.

  3 and 4 show an example of a calculation program stored in the sequencer PLC. Freeze drying of the material to be dried charged in the drying cabinet DC is performed through the steps of preliminary freezing, primary drying and secondary drying. The sublimation speed Qm of the material to be dried in the primary drying step, the average bottom part temperature Calculation of Tb and average sublimation surface temperature Ts, and calculation of dehumidification rate Qm ′, average bottom part temperature Tb, and average product temperature Ts ′ of the material to be dried in the secondary drying step are the procedures described in FIGS. Done in Each calculated data is sequentially recorded in the recorder e. The operator of the freeze dryer can monitor the dry state of the material to be dried by checking the record data of the recorder e.

  When the material to be dried is freeze-dried, constant data shown in step S1 is input to the sequencer PLC before starting the control program. As constant data, the inner diameter D (mm) of the main pipe a, the outer diameter d (mm) of the opening controller C, the thickness t (mm) of the opening controller C, the outside of the vial into which the material to be dried is dispensed. Diameter d1 (mm), vial thickness t1 (mm), number of vials N1 charged in the drying chamber DC, amount of drug dispensed into vials V1 (mL / 1), dispensed into vials The solid content s (%) of the drug, the specific gravity e (Kg / L) of the drug dispensed in the vial, the weight Wv (g) of the vial, the weight Wc (g) of the rubber stopper that seals the opening of the vial, The width W (mm) of the tray frame T placed on the shelf B installed in the drying cabinet DC, the length L (mm) of the tray frame T, the number N2 of the tray frames T, A gap δ that exists between the bottom surface and the top surface of the shelf B on which this is placed is input. These can be obtained from the specifications of the freeze dryer and the work plan.

  The constant data includes the thermal conductivity λ of the frozen layer formed on the material to be dried in the vial by preliminary freezing, the radiation heat transfer coefficient Kr of the heat radiated from the wall surface of the drying cabinet DC to the vial, and at the time of primary drying Of the opening degree controller C obtained by the water load with the main valve MV fully opened, the wall temperature Tw1 of the drying cabinet DC, the wall temperature Tw2 of the drying cabinet DC at the time of secondary drying, the initial freezing temperature Tbi at the start of primary drying, Sublimation from the steam flow resistance obtained with a water load with the opening angle θ and the main pipe resistance (resistance acting on water vapor flowing through the main pipe a) R (θ) constant values a and b and the main valve MV fully opened. Constant values j and k of the formula for calculating the speed Qm are also input to the sequencer PLC. These are obtained by prior experiments. How to obtain the constant values a and b and how to obtain the constant values j and k will be described later.

  Next, in step S2, a time interval N (min) for executing the calculation program is input to the sequencer PLC. As in the invention described in Patent Document 1, the degree of vacuum in the drying cabinet DC is changed in a direction to temporarily increase, and the degree of vacuum (drying chamber vacuum degree) Pdc and cold trap in the drying cabinet DC before and after the change. When the average sublimation surface temperature Ts, average bottom part temperature Tb and sublimation rate Qm of the material to be dried in the primary drying period are calculated from the measurement data including the degree of vacuum (cold trap vacuum) Pct in the CT, Until the condition is settled, the next drying chamber vacuum degree Pdc and cold trap vacuum degree Pct cannot be measured, so the average sublimation surface temperature Ts, the average bottom part temperature Tb, and the sublimation speed Qm are calculated at intervals of about 30 minutes at most. It can only be done. On the other hand, the present invention calculates the average sublimation surface temperature Ts, the average bottom part temperature Tb, and the sublimation speed Qm of the material to be dried without changing the degree of vacuum in the drying chamber DC temporarily. Therefore, any time interval N can be set as long as the time interval exceeds the time required for one calculation. For this reason, according to the present invention, it becomes possible to calculate the average sublimation surface temperature Ts, the average bottom part temperature Tb, and the sublimation speed Qm of the material to be dried at intervals of several minutes, for example, at intervals of 1 minute. Compared to the case of the described invention, the dry state of the material to be dried can be monitored more closely.

Next, the process proceeds to step S3. From the constant data input to the sequencer PLC in step S1, the bottom area Av of the vial, the surface area At of the tray frame T, the effective heat transfer area Ae from the tray frame B to the vial, and The sublimation area As of the material to be dried is obtained by calculation.
The bottom area Av of the vial is obtained by the following formula (1).
Av = 0.000001 × π / 4 × d1 ² × N1 (1)
The surface area At of the tray frame B is obtained by the following formula (2).
At = 0.000001 × W × L × N2 (2)
The effective heat transfer area Ae is obtained by the following equation (3).
Ae = 2 / [(1 / Av) + (1 / At)] (3)
The sublimation area As is obtained by the following formula (4).
As = 0.000001 × π / 4 × (d1-2 × t1) ² × N1 (4)

Next, the process proceeds to step S4, and the dehydration amount W from the vial and the initial frozen layer thickness L0 of the material to be dried are obtained by calculation from the constant data input to the sequencer PLC in step S1.
The dewatering amount W is obtained by the following equation (5).
W = 0.001 × N1 × V1 × e × 0.01 × (100−s) (5)
The initial frozen layer thickness L0 is obtained by the following equation (6).
L0 = 0.001 × N1 × V1 / (0.917 × As) (6)
The initial average bottom part temperature Tb0 is the initial freezing temperature Tbi at the start of primary drying, as shown in the following equation (7).
Tb0 = Tbi (7)
The sublimation amount M0 at the start of primary drying is set to 0 (M0 = 0).

  After the input of the constant data is completed, the control program is started and the preliminary freezing, primary drying and secondary drying steps are executed in this order. First, for a few minutes immediately after the preliminary freezing process is completed and the primary drying process is started, that is, the sublimation of frost on the shelf B in the drying cabinet DC is finished, and the drying cabinet vacuum degree Pdc becomes the vacuum control value. As shown in step S5, the process waits without performing the calculation process from step S6 onward until it is controlled and stabilized. This makes it possible to accurately calculate the average sublimation surface temperature Ts, the average bottom part temperature Tb, and the sublimation speed Qm described below.

  After the elapse of the standby time, as shown in step S6, every time the time interval N set in the sequencer PLC elapses, in the initial several seconds, the vacuum gauge b is turned multiple times (in this embodiment, The drying chamber vacuum degrees Pdc1 to Pdc5 and the cold trap vacuum degrees Pct1 to Pct5 are fetched five times, the opening angle θ is fetched from the angle sensor g, and the shelf temperature Th is fetched from the temperature sensor S.

Next, the process proceeds to step S7. From the constant data D, d, t input to the sequencer PLC in step S1 and the opening angle θ taken from the angle sensor g in step S5, the following equation (7) To calculate the channel cross-sectional area A (cm ² ) of the main pipe a.
A = 0.01 × (π / 4 × D ² −d × t × cos θ−π / 4 × d ² × sin θ)] (8)

Next, the process proceeds to step S8. From the constant data a and b input to the sequencer PLC in step S1 and the flow path cross-sectional area A obtained in step S7, the main pipe resistance R ( θ) is calculated.
R (θ) = [a + (b / A) ² ] ^0.5 + b / A (9)

  The derivation of equation (9) and the determination of the constants a and b are performed by a water load test. Below, the derivation | leading-out method of Formula (9) and the calculation method of the constant values a and b are demonstrated.

  The water load test is performed by inserting a tray filled with water into the drying chamber DC, starting the freeze dryer M1, and sequentially executing a predetermined freeze drying process according to a control signal from the sequencer PLC. . In this example, in the primary drying step after pre-freezing the water in the tray to −45 ° C., the shelf temperature Th is set to −20 ° C., and the drying cabinet vacuum degree Pdc is 4 Pa, 6.7 Pa, 10 Pa, While changing to 13.3 Pa, 20 Pa, 30 Pa, 40 Pa, and 60 Pa, each was held for 3 hours, and a total of 8 water load tests were performed. In each water load test, the opening angle θ of the opening controller C, the shelf temperature Th, the ice temperature Tb at the bottom of the tray, the drying cabinet vacuum Pdc, and the cold trap vacuum Pct are measured and recorded.

  Next, the ice sublimation speed Qm (Kg / h) is determined by measuring the sublimation amount or calculating the heat input, and the relationship between the opening angle θ of the opening controller C and the main pipe resistance R (θ) is obtained. Table 1 shows the relationship between the opening angle θ of the opening controller C and the main pipe resistance R (θ) obtained by calculation, and the main pipe resistance R ( θ). FIG. 5 is a graph showing the relationship between the opening angle θ of the opening controller C created based on the data in Table 1 and the main pipe resistance R (θ). As is apparent from Table 1 and FIG. 5, the main pipe resistance R (θ) obtained by calculation and the main pipe resistance R (θ) obtained by measurement are in good agreement.

From the data in Table 1 (FIG. 5), a relational expression between the opening angle θ of the opening controller C and the main pipe resistance R (θ) can be derived. Further, if the opening angle θ of the opening adjuster C is obtained, the flow passage cross-sectional area A of the main pipe a can be calculated from the equation (8), so the opening angle θ of the opening adjuster C and the main pipe resistance R ( The relational expression with θ) can be converted into a relational expression between the flow passage cross sectional area A of the main pipe a and the main pipe resistance R (θ) shown in Expression (9). Further, the constants a and b in the equation (9) can be determined from the data in Table 1 (FIG. 5). The following formula (10) was derived from the water load test example described above.
R (θ) = [3408.65+ (2223.7 / A) ² ] ^0.5 + 2223.7 / A (10)
From this equation (10), a = 3408.65 and b = 2223.7 are obtained.
Thus, by storing the constants a and b obtained in the prior water load test in the sequencer PLC, the main pipe resistance R (θ) can be calculated in step S8.

Next, the process proceeds to step S9, and the average drying chamber vacuum degree Pdc, the sublimation speed Qm (Kg / hr) of the material to be dried, and the sublimation amount M are calculated.
The average drying chamber vacuum degree Pdc is obtained by the following equation (11).
Pdc = (Pdc1 + Pdc2 + Pdc3 + Pdc4 + Pdc5) / 5 (11)
The sublimation speed Qm of the material to be dried is obtained by the following formula (12).
Qm = 3.6 × Pdc / R (12)
Further, the sublimation amount M of the material to be dried is obtained by the following formula (13).
M = M0 + Qm × N / 60 (13)
However, M0 is the amount of sublimation from the start of drying to N minutes ago.
Thus, when the sublimation speed Qm of the material to be dried is calculated using the average drying chamber vacuum degree Pdc obtained by the equation (11), even when the drying chamber vacuum degree taken in from the vacuum gauge b fluctuates. Since the influence can be mitigated, the sublimation speed Qm of the material to be dried can be calculated more accurately than in the case of using the instantaneous drying chamber vacuum taken from the vacuum gauge b.

Next, the process proceeds to step S10, the heat transfer coefficient K from the shelf B to the bottom of the vial E by gas conduction, the heat capacity C of the entire material to be dried including the vial, rubber stopper, ice and filling, and the material to be dried An average bottom part temperature Tb and an average sublimation surface temperature Ts of the material are calculated.
The heat transfer coefficient K (Kcal / hm ² ° C) is calculated by the following formula (14).
K = 14.5 / (δ + 2.12 × 29 × 0.13332 / Pdc) (14)
However, δ is a gap at the bottom of the container, the unit is mm, and is input to the sequencer PLC as constant data in step S1. Pdc is the pressure in the drying cabinet DC, and is measured with the vacuum gauge b.

The heat capacity C is the number of vials N1, the vial weight Wv, the rubber stopper weight Wc, the drug dispensing amount V1, the drug solid content s, the drug specific gravity e, and the formula (5) input to the sequencer PLC in step S1. From the calculated dehydration amount W and the sublimation amount M calculated by the equation (13), it is obtained by the following equation (15).
C = 0.001 × N1 × (0.22 × Wv + 0.33 × Wc + 0.33 × V1 × 0.01 × s × e) + 0.5 × (WM)
... (15)

The average bottom part temperature Tb is calculated in consideration of the sublimation latent heat of the material to be dried and the sensible heat of the material to be dried including the container E. For this reason, in the present invention, when calculating the average bottom part temperature Tb, first, the average product temperature Tm of the material to be dried in the primary drying step is obtained using the heat transfer equation shown in the following equation (16).
C × dTm / dt = Qh + Qr−Qm × ΔHs (16)
However, in Formula (16), C is the heat capacity of the material to be dried including the container, Tm is the average product temperature from the bottom of the material to be dried to the sublimation surface, and Qh is from the shelf B by gas transmission to the bottom of the container E. The amount of heat input, Qr is the amount of radiant heat input from the wall of the drying cabinet DC to all containers, Qm is the sublimation speed, and ΔHs is the sublimation latent heat.

The amount of heat input Qh from the shelf B due to gas conduction to the bottom of the container E is calculated by the following equation (17).
Qh = Ae × K × (Th−Tm) (17)
However, Ae is an effective heat transfer area (m ² ), K is a heat transfer coefficient from the shelf B by gas conduction to the bottom of the container E, Th is a shelf temperature (° C.), and Tm is an average product temperature (° C.). .

Further, the width incident heat quantity Qr from the drying cabinet wall to the container E is obtained from the following equation (18).
Qr = 5.67 × ε × Ar × [(Tw1 / 100) ⁴ − (Tm / 100) ⁴ ] (18)
In the equation, ε is a radiation coefficient, Ar is an area (m ² ) that receives radiant heat , Tw1 is a drying cabinet wall temperature during primary drying, and Tm is an average product temperature. The area Ar that receives radiant heat can be approximated by an effective heat transfer area Ae.

Then, the width incident heat quantity Qr from the drying chamber wall to all containers can be approximately calculated by the following equation (19).
Qr = Ar * Kr * (Tw1-Tm) (19)
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.

Therefore, when Expression (17) and Expression (19) are substituted into the heat transfer equation of Expression (16), the following Expression (20) is established.
C × dTm / dt = Ae × K × (Th−Tm) + Ar × Kr × (Tw1-Tm) −Qm × ΔHs (20)
However, sublimation latent heat ΔHs = 680 kcal / Kg = 2850 KJ / Kg.

The average bottom part temperature Tb is the heat transfer coefficient K calculated by the equation (14), the sublimation speed Qm of the material to be dried calculated by the equation (12), and the shelf temperature Th measured by the temperature sensor S. From the radiation heat transfer coefficient Kr input to the sequencer PLC in step S1, the drying warehouse wall temperature Tw1 during primary drying, and the effective heat transfer area Ae, the following equation (21) can be used.
Tb = K × Ae × Th + Kr × Ar × Tw1 + C × 60 × Tb0 / N-Qm × 680 / (K × Ae + Kr × Ar + C × 60 / N)
... (21)

Therefore, the average sublimation surface temperature Ts of the material to be dried is the average bottom part temperature Tb calculated by the equation (21), the sublimation speed Qm of the material to be dried calculated by the equation (12), and the equation (4). ), The sublimation area As calculated in Formula (5), the dehydration amount W calculated in Formula (5), the initial frozen layer thickness L0 calculated in Formula (6), and the formula (13). From the sublimation amount M, it can be calculated by the following equation (22).
Ts = Tb-Qm × 680 / (As × λ) × 0.001 × L0 × (1-M / W) (22)

  Thereafter, the process proceeds to step S11, and the calculated average sublimation surface temperature Ts (° C.), sublimation speed Qm (Kg / hr) and average bottom part temperature Tb (° C.) are recorded in the recorder e. The procedure from the procedure S6 to the procedure S11 described above is repeated for every time interval N set in the procedure S2 until the primary drying process is completed. The operator of the freeze dryer can grasp the drying state of the material to be dried in the primary drying process in time series by monitoring the data recorded in the recorder e.

  After the completion of the primary drying process, the process proceeds to the secondary drying process. Even after the transition to the secondary drying step, as shown in the step S12, for a time interval N set in the sequencer PLC in the step S2, a plurality of times (in this embodiment, five times) from the vacuum gauge b. The drying chamber vacuum degrees Pdc1 to Pdc5 and the cold trap vacuum degrees Pct1 to Pct5 are taken in, the opening angle θ is taken in from the angle sensor g, and the shelf temperature Th is taken in from the temperature sensor S.

Next, the process proceeds to step S13, and from the constant data D, d, t input to the sequencer PLC in step S1 and the opening angle θ taken from the angle sensor g in step S12, the following equation (23) Thus, the channel cross-sectional area A (m ² ) of the main pipe a is calculated.
A = 0.000001 × [π / 4 × D ² -d × t × cos θ-π / 4 × d ² × sin θ] (23)

Next, the procedure proceeds to step S14, and the drying chamber is obtained from the drying chamber vacuum degrees Pdc1 to Pdc5 and the cold trap vacuum degrees Pct1 to Pct5 taken from the vacuum gauge b in step S12 by the following formulas (24) and (25). An average value Pdc of the vacuum degree and an average value Pct of the cold trap vacuum degree are calculated.
Pdc = (Pdc1 + Pdc2 + Pdc3 + Pdc4 + Pdc5) / 5 (24)
Pct = (Pct1 + Pct2 + Pct3 + Pct4 + Pct5) / 5 (25)

In step S14, the constant data j and k input to the sequencer PLC in step S1, the average value Pdc of the drying chamber vacuum degree and the average value of the cold trap vacuum degree obtained by the equations (24) and (25). A dehumidifying rate Qm ′ (Kg / hr) of the material to be dried is calculated from Pct and the flow path cross-sectional area A calculated in step S13 by the following equation (26).
Qm ′ = j × A × (Pdc ² −Pct ² ) ^k (26)
The constant data j and k are constant values of a calculation formula from the steam flow resistance coefficient of the main channel to the sublimation speed, and are obtained by measuring the actual dry amount in a water load experiment.
Further, in the expression (26), when Pdc <Pct, Qm ′ = 0 is set.

  Next, the process proceeds to step S15, the heat transfer coefficient K from the shelf board B to the bottom of the vial E by gas conduction, the heat capacity C of the entire material to be dried including the vial, the rubber stopper and the filling, and the material to be dried Constant values a1, a2, and a3 of the formula for obtaining the average product temperature, the average bottom part temperature Tb of the material to be dried, and the average sublimation surface temperature Ts are calculated in this order.

The heat transfer coefficient K (W / m ² ° C) in the secondary drying period can be calculated by the following equation (27).
K = 14.5 / (δ + 2.12 × 29 × 0.13332 / Pdc) +1.1 (27)
However, (delta) is the clearance (mm) of a container bottom part, and is input into sequencer PLC as constant data by procedure S1. Pdc is the average value of the degree of vacuum in the drying cabinet calculated using the equation (24).

The heat capacity C is calculated by the following formula (28) from the number of vials N1, the vial weight Wv, the rubber stopper weight Wc, the drug dispensing amount V1, the drug solid content s, and the drug specific gravity e input to the sequencer PLC in step S1. Calculated by
C = 0.001 x N1 x (0.22 x Wv + 0.33 x Wc + 0.33 x V1 x 0.01 x s x e) (28)

Moreover, the average product temperature Tm of the material to be dried in the secondary drying step can be obtained from the heat transfer equation shown in the following equation (29).
C × dTm / dt = Qh + Qr−Qm ′ × ΔHs ′ (29)
However, in Formula (29), C is the heat capacity of the material to be dried, Tm is the average product temperature from the bottom of the material to be dried to the sublimation surface, Qh is the amount of heat input from the shelf B to the bottom of the container E by gas conduction, Qr is the width incident heat quantity from the drying cabinet wall to all containers, Qm ′ is the dehumidification rate, and ΔHs ′ is the latent heat of evaporation.

As described in the column of the primary drying step, the amount of heat input Qh from the shelf B to the bottom of the container E by gas conduction is calculated by the following equation (30).
Qh = Ae × K × (Th−Tm) (30)
However, Ae is an effective heat transfer area (m ² ), K is a heat transfer coefficient from the shelf B by gas conduction to the bottom of the container E, Th is a shelf temperature (° C.), and Tm is an average product temperature (° C.). .

Further, the width incident heat quantity Qr from the drying chamber wall to the container E is obtained from the following equation (31).
Qr = 5.67 × ε × Ar × [(Tw2 / 100) ⁴ − (Tm / 100) ⁴ ] (31)
In the equation, ε is a radiation coefficient, Ar is an area (m ² ) that receives radiant heat , Tw2 is a drying cabinet wall temperature during secondary drying, and Tm is an average product temperature. The area Ar that receives radiant heat can be approximated by an effective heat transfer area Ae.

Then, the width incident heat quantity Qr from the drying chamber wall to all containers can be approximately calculated by the following equation (32).
Qr = Ar * Kr * (Tw2-Tm) (32)
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.

Therefore, when Expression (30) and Expression (32) are substituted into the heat transfer equation of Expression (29), the following Expression (33) is established.
C × dTm / dt = Ae × K × (Th-Tm) + Ar × Kr × (Tw2-Tm) −Qm´ × ΔHs´
... (33)
However, ΔHs is latent heat of vaporization, and ΔHs = 2850 KJ / Kg.

Therefore, the average product temperature Tm of the material to be dried in the secondary drying step can be calculated by the following equation (34).
C × (Tm-Tm0) / Δt = Ae × K × (Th-Tm) + Ar × Kr × (Tw2-Tm) -Qm´ × ΔHs ′
Tm = (Tm0 + a1 × Th + a2 × Tw2-a3) / (1 + a1 + a2)
However, a1 = K × Ae × N / (60 × C),
a2 = Kr × Ae × N / (60 × C),
a3 = Qm ′ × 680 × N / (60 × C) (34)
Therefore, the average product temperature Tm of the material to be dried in the secondary drying step is calculated from the dehumidification rate Qm ′ of the material to be dried obtained by the equation (26) and a1, a2, and a3 obtained by the equation (34). can do.

  Since Tm = Tb at the end of the secondary drying step, the average bottom part temperature Tb of the material to be dried is obtained from the equation (34).

  Thereafter, the process proceeds to step S16, and the calculated average sublimation surface temperature Ts (° C.), dehumidification rate Qm ′ (Kg / hr), and average bottom part temperature Tb (° C.) are recorded on the recorder e. The procedure from the procedure S12 to the procedure S16 described above is repeated at every time interval N set in the procedure S2 until the secondary drying process is completed. The operator of the freeze dryer can grasp the drying state of the material to be dried in the secondary drying step in time series by monitoring the recorded data in the recorder e.

6 and 7, using the freeze-dryer M1 of the channel opening vacuum control method, when calculating the average bottom part temperature Tb in the above-described method of the present invention, that is, the primary drying step and the secondary drying step, A method of considering the sensible heat and latent heat of the material to be dried including the container E, applying a drying chamber wall temperature peculiar to each process, and obtaining an average value Pdc of the drying chamber vacuum degree when calculating the sublimation speed Qm. (This method is referred to as “the method of the present invention” in this specification) and the measured value and calculation of the product temperature when a 10% aqueous solution of lactose (Lactose, molecular formula: C ₁₂ H ₂₂ O ₁₁ ) is lyophilized. Shown in comparison with values. FIG. 6 is a diagram showing changes in the measured and calculated values of the product temperature from the preliminary freezing process through the primary drying process to the initial stage of the secondary drying process, and FIG. 7 is an enlarged view of the initial stage of the primary drying process. It is a figure shown.

8 and 9, the average bottom part temperature Ts in the primary drying step and the secondary drying step is different from the method of the present invention described above by using the freeze-dryer M1 of the flow path opening vacuum control system. In the calculation, only the latent heat is considered without considering the sensible heat of the material to be dried including the container E, the constant drying cabinet wall temperature is applied without applying the drying cabinet wall temperature specific to each process, and In calculating the sublimation speed Qm, the average value Pdc of the drying chamber vacuum is not calculated, but a method of using the drying chamber vacuum that is instantaneously taken in from the vacuum detection means at a predetermined timing (this method is referred to in this specification as in) as "conventional method", lactose (lactose, molecular formula:. shown by comparing the measured value of the material temperature in the case of a 10% aqueous solution of lyophilized C _{12 H} 22 _{O 11)} and the calculated values. FIG. 8 is a diagram showing changes in the measured and calculated values of the product temperature from the preliminary freezing process through the primary drying process to the initial stage of the secondary drying process, and FIG. 9 expands the initial stage of the primary drying process. It is a figure shown.

  In any of the experimental examples, 660 vials into which the material to be dried was dispensed were loaded into the drying cabinet DC, and the material to be dried was freeze-dried according to the procedure stored in the sequencer PLC. Of the 660 vials loaded in the drying cabinet DC, one vial loaded in the center of the shelf B and one other vial loaded near the wall of the drying cabinet DC. For the vial and another one of the vials inserted between them, the temperature sensor is inserted, and the product temperature of the material to be dried dispensed in the vial (product temperature 1, product temperature 2). The product temperature 3) was measured. In the primary drying of the material to be dried, the solution is pre-frozen at −45 ° C. for 2 hours, and then the shelf temperature Th is set to −20 ° C. and the opening angle θ of the opening controller C is adjusted to adjust the drying chamber DC. The vacuum degree Pdc inside was controlled by controlling to 6.7 Pa. In secondary drying, the shelf temperature was raised from −20 ° C. to 30 ° C. in one hour, and the degree of vacuum Pdc in the drying cabinet DC was changed accordingly, and the opening degree controller C was rotated in the fully open direction. . 6 and FIG. 7 at an interval of 1 minute, and in the experiment examples of FIG. 8 and FIG. 9 at an interval of 5 minutes, the degree of vacuum Pdc in the dryer DC, the degree of vacuum Pct in the cold trap CT, and the opening angle θ The shelf temperature Th was detected, and the sublimation speed Qm (dehumidification speed Qm ′), the average bottom part temperature Tb, and the average sublimation surface temperature Ts were calculated. And each detected value and each calculated value were recorded on the recorder e, and the graph shown in FIGS. 6-9 was obtained.

  As shown in FIGS. 8 and 9, the average sublimation surface temperature Ts of the material to be dried calculated by the conventional method approximates the product temperature 1, the product temperature 2, and the product temperature 3 detected by the temperature sensor. However, in the conventional method, since the sensible heat of the material to be dried including the container E is not taken into consideration, as shown in more detail in FIG. 9, during the shelf temperature raising period performed in the initial stage of the primary drying process. The average bottom part temperature calculated in the above tends to be higher than the actually measured part temperature. For this reason, as shown in FIG. 8, since the average bottom part temperature calculated in the primary drying step reaches the shelf temperature earlier than the actually measured part temperature, the average bottom part temperature can follow the temperature change of the material to be dried. In the latter stage of the primary drying process, the calculated average bottom part temperature tends to deviate from the actually measured part temperature. In the conventional method, since the sensible heat of the material to be dried is not taken into consideration, the measurement value fluctuates when detecting the degree of vacuum Pdc in the drying cabinet DC, the opening angle θ of the opening controller C, and the shelf temperature Th. If even a little occurs, the calculated sublimation speed Qm is blurred. For this reason, as shown in FIG. 8, the calculated sublimation surface temperature Ts fluctuates unnaturally. Note that the same tendency is observed in the secondary drying step.

  On the other hand, in the method of the present invention, when calculating the average bottom part temperature Tb in the primary drying step and the secondary drying step, the sensible heat and latent heat of the material to be dried including the container E are taken into account, which is apparent from FIG. Thus, the average bottom part temperature calculated in the initial stage of the primary drying process does not tend to be higher than the actually measured part temperature. In addition, since the average bottom part temperature calculated in the primary drying process does not reach the shelf temperature earlier than the actually measured product temperature, as is clear from the comparison between FIG. 6 and FIG. The difference between the exhibition temperature and the measured product temperature is small. Since the method of the present invention considers the sensible heat of the material to be dried, the calculated sublimation surface temperature Ts smoothly changes even if the calculated sublimation speed Qm fluctuates as shown in FIG. . Further, in the method of the present invention, when calculating the sublimation speed Qm, the average value Pdc of a plurality of drying chamber vacuum degrees detected over a few seconds is applied, and thus the fluctuation of the calculated sublimation speed Qm is small. Furthermore, since the drying warehouse wall temperature Tw1 at the time of primary drying is applied to the calculation of the average bottom part temperature Tb in the primary drying step, the difference between the calculated product temperature and the actually measured product temperature can be reduced. In addition, the method of the present invention calculates the average sublimation surface temperature Ts, the average bottom part temperature Tb, and the sublimation speed Qm of the material to be dried in the primary drying step at intervals of 1 minute. Can be increased. Note that the same tendency is observed in the secondary drying step.

  Thus, according to the method of the present invention, the calculated sublimation surface temperature Ts of the material to be dried can be made to coincide well with the product temperature 1, the product temperature 2, and the product temperature 3 detected by the temperature sensor. By monitoring the sublimation surface temperature Ts, the sublimation surface temperature in the primary drying step and the secondary drying step is applied to the material to be dried dispensed into all the vials charged in the drying chamber DC of the freeze dryer M1. Can be monitored without contact. Moreover, the collapse of the material to be dried in the primary drying step and the secondary drying step can be completely prevented.

[Second Embodiment]
The calculation method and the calculation device according to the second embodiment are applied to a lyophilizer of a leak type vacuum control system provided with a leak valve as a vacuum degree adjusting means for adjusting the degree of vacuum in the drying box. Is.

<Configuration of freeze dryer>
That is, as shown in FIGS. 10 and 11, the freeze dryer M2 according to the second embodiment is generated from the drying chamber DC in which the material to be dried is charged and the material to be dried charged in the drying chamber DC. A cold trap CT that condenses and collects steam to be trapped by a trap coil ct, a main pipe a that communicates the dryer DC with the cold trap CT, a main valve MV that opens and closes the main pipe a, and a leak control connected to the dryer DC Vacuum control circuit f with valve LV, inlet valve V attached to cold trap CT, vacuum pump P connected to inlet valve V, absolute pressure in dryer DC and absolute in cold trap CT It is mainly comprised from the vacuum gauge b which detects a pressure, and control apparatus CR which controls automatically operation | movement of each part of the apparatus mentioned above. The control panel CR is composed of a sequencer PLC and a recorder (recording means) e. The sequencer PLC controls the driving of the drying chamber DC, the cold trap CT and the vacuum control circuit f to reserve the material to be dried. A control program for executing the drying process, the primary drying process, and the secondary drying process is stored in advance. Since others are the same as those of the freeze dryer M1 according to the first embodiment, the corresponding parts are denoted by the same reference numerals and description thereof is omitted.

  12 and 13 show an example of a calculation program stored in the sequencer PLC. The freeze-drying of the non-drying material charged in the drying cabinet DC is performed through the steps of preliminary freezing, primary drying and secondary drying. The sublimation speed Qm of the material to be dried in the primary drying process, the average bottom part temperature Calculation of Tb and average sublimation surface temperature Ts, and calculation of dehumidifying speed Qm ′ and average bottom part temperature Tb of the material to be dried in the secondary drying step are performed according to the procedures shown in FIGS. Each calculated data is sequentially recorded in the recorder e. The operator of the freeze dryer can monitor the drying state of the material to be dried at any time by checking the record data of the recorder e.

  When the material to be dried is freeze-dried, constant data is input to the sequencer PLC in step S21 prior to starting the control program. As constant data, the inner diameter D (mm) of the main tube a, the length L1 (mm) of the main tube a, the outer diameter d1 (mm) of the vial into which the material to be dried is dispensed, the wall thickness t1 (mm) of the vial, Number of vials N1 charged in the drying chamber DC, amount of drug dispensed into vials V1 (mL / 1), solid content s (%) of drug dispensed into vials, dispensed into vials Specific gravity e (Kg / L) of the material to be dried, weight Wv (g) of the vial, weight Wc (g) of the rubber stopper that seals the opening of the vial, width dimension W (mm) of the tray frame T on which the vial is placed ), The length dimension L (mm) of the tray frame T, the number N2 of the tray frames T, and the gap δ existing between the bottom surface of the vial and the top surface of the shelf B on which the vial is placed. These can be obtained from the specifications of the freeze dryer and the work plan.

  The constant data includes the thermal conductivity λ of the frozen layer formed on the material to be dried in the vial by preliminary freezing, the radiation heat transfer coefficient Kr of the heat radiated from the wall surface of the drying cabinet DC to the vial, and at the time of primary drying The wall temperature Tw1 of the drying cabinet DC, the wall temperature Tw2 of the drying cabinet DC at the time of secondary drying, the initial freezing temperature Tbi at the start of primary drying, the steam flow in the main channel obtained by fully opening the main valve MV and water load Constant values j and k of the calculation formula from the resistance coefficient Cr to the sublimation speed Qm are also input to the sequencer PLC. These are obtained by prior experiments. How to obtain the constant values j and k will be described later.

  Next, in step S22, a time interval N (min) for executing the calculation program is input to the sequencer PLC. As described in the first embodiment, as in the invention described in Patent Document 1, the degree of vacuum in the drying chamber DC before and after the change is changed by temporarily increasing the degree of vacuum in the drying chamber DC. When the average sublimation surface temperature Ts, average bottom part temperature Tb, and sublimation rate Qm of the material to be dried in the primary drying period are calculated from the measurement data including the vacuum degree Pct in the Pdc and the cold trap CT, the degree of vacuum in the drying chamber DC is calculated. Since the next measurement of the degree of vacuum Pdc, Pct or the like cannot be performed until the temperature settles, the average sublimation surface temperature Ts, the average bottom part temperature Tb, and the sublimation speed Qm can be calculated only at intervals of about 30 minutes. On the other hand, the present invention calculates the average sublimation surface temperature Ts, the average bottom part temperature Tb, and the sublimation speed Qm of the material to be dried without changing the degree of vacuum in the drying chamber DC temporarily. Therefore, an arbitrary time can be set as the calculation time interval N as long as the time interval exceeds the time required for one calculation. For this reason, according to the present invention, it becomes possible to calculate the average sublimation surface temperature Ts, the average bottom part temperature Tb, and the sublimation speed Qm of the material to be dried at intervals of several minutes, for example, at intervals of 1 minute. Finer monitoring of the drying state of the material to be dried is possible than in the case of the described invention.

Next, the process proceeds to step S23, and from the constant data D, d1, N1, W, N, N2, t1 input to the sequencer PLC in step S21, the main pipe channel cross-sectional area A, the bottom area Av of the vial, The total area At of the tray frame T, the effective heat transfer area Ae from the shelf B to the vial, and the sublimation area As of the material to be dried are obtained by calculation.
The main pipe channel cross-sectional area A is obtained by the following equation (35).
A = π / 4 × (0.001 × D) ² (35)
The bottom area Av of the vial, the total area At of the tray frame B, the effective heat transfer area Ae, and the sublimation area As are obtained by the above formulas (1) to (4), respectively.

  Next, the process proceeds to step S24, and the dehydration amount W of the material to be dried is calculated using the constant data N1, V1, e, and s input to the sequencer PLC in step S21, and is input to the sequencer PLC in step S21. The initial frozen layer thickness L0 of the material to be dried is calculated using the constant data N1, V1 and the sublimation area As obtained in step S23. The dewatering amount W and the initial frozen layer thickness L0 are obtained by the above equations (5) and (6), respectively. The initial average bottom part temperature Tb0 is the initial freezing temperature Tbi at the start of primary drying, and the sublimation amount M0 at the start of primary drying is 0.

  After the input of the constant data is completed, the control program is started and the preliminary freezing, primary drying and secondary drying steps are executed in this order. First, for a few minutes immediately after the preliminary freezing process is completed and the primary drying process is started, that is, the sublimation of frost on the shelf B in the drying cabinet DC is finished, and the drying cabinet vacuum degree Pdc becomes the vacuum control value. As shown in step S25, the process waits without performing the calculation process after step S26 for the time until it is controlled and stabilized. This makes it possible to accurately calculate the average sublimation surface temperature Ts, the average bottom part temperature Tb, and the sublimation speed Qm described below.

  After the elapse of the standby time, as shown in step S6, every time the time interval N set in the sequencer PLC elapses, in the initial several seconds, the vacuum gauge b is turned multiple times (in this embodiment, The drying chamber vacuum degrees Pdc1 to Pdc5 and the cold trap vacuum degrees Pct1 to Pct5 and the shelf temperature Th from the temperature sensor S are captured for five times.

Next, the procedure proceeds to step S27, and the drying chamber is obtained from the drying chamber vacuum degrees Pdc1 to Pdc5 and the cold trap vacuum degrees Pct1 to Pct5 taken from the vacuum gauge b in the procedure S26 by the following equations (36) and (37). An average value Pdc of the vacuum degree and an average value Pct of the cold trap vacuum degree are calculated.
Pdc = (Pdc1 + Pdc2 + Pdc3 + Pdc4 + Pdc5) / 5 (36)
Pct = (Pct1 + Pct2 + Pct3 + Pct4 + Pct5) / 5 (37)

In step S27, the sublimation speed Qm is also calculated. The sublimation speed Qm can be calculated from the average value Pdc of the drying chamber vacuum degree and the average value Pct of the cold trap vacuum degree. That is, the water vapor sublimated from the sublimation surface of the material to be dried flows from the drying chamber DC into the cold trap CT through the main pipe a, and is condensed and collected by the trap coil Ct. In the case of leak type vacuum control, the flow of water vapor in the main pipe a becomes a viscous flow, and therefore the sublimation speed Qm from the material to be dried can be calculated by the following equation (38).
Qm = 3.6 × (Pdc−Pct) /R=3.6×ΔP/R (38)
However, in Formula (38), (DELTA) P is a differential pressure | voltage between drying cabinet vacuum Pdc and cold trap vacuum Pct, and R is main pipe resistance.

The differential pressure ΔP is expressed by the following formula (39) from the calculation formula of the pipe pressure drop of the viscous flow.
ΔP = Cr / 2 × ρ × u ² = Cr / 2 × ρ × [Qm / (3600 × A × ρ)] ² (39)
Where Cr is the steam flow resistance coefficient of the main channel, ρ is the ideal gas equation of state ρ = P × M / (R × T) (P is the pressure of the gas, M is the molecular weight of the gas, R Is a gas constant, T is a gas temperature), and A is a channel area of the main pipe a.

Substituting into equation (39) the ideal gas state equation ρ = P × M / (R × T), molecular weight M = 18, gas constant R = 8314, gas temperature T = 288, ΔP = Pdc−Pct, and sublimation When converted into the equation of velocity Qm, the following equation (40) is obtained.
Qm = A × [(Pdc ² −Pct ² ) / (8314 × 288 / (18 × 36002) × Cr)] ^0.5
= A × [(Pdc ² −Pct ² ) / (0.0103 × Cr)] ^0.5 (40)
According to this method, since it is not necessary to equip an expensive measuring instrument other than a vacuum gauge, the sublimation speed Qm can be calculated easily and at low cost.

  The water vapor flow resistance coefficient Cr of the equation (39) is obtained by a water load test. The water load test is performed by controlling the operation of the freeze dryer M2 by the control device CR and executing a predetermined drying process in a state where a tray filled with water is loaded in the drying cabinet DC. In this example, the shelf temperature Th is set to −20 ° C. and the degree of vacuum Pdc in the drying cabinet DC is set to 6.7 Pa in the primary drying step after the water in the tray is frozen to −45 ° C. Hold for 3 hours. Further, the shelf temperature Th was set to −10 ° C., and the degree of vacuum Pdc in the drying cabinet DC was sequentially controlled to 6.7 Pa, 13.3 Pa, and 20 Pa, and held for 3 hours, respectively. Further, the shelf temperature Th was set to 5 ° C., and the degree of vacuum Pdc in the drying cabinet DC was controlled to 6.7 Pa and 13.3 Pa, and held for 3 hours. Further, the shelf temperature Th was set to 20 ° C., and the degree of vacuum Pdc in the drying cabinet DC was controlled to 6.7 Pa and 13.3 Pa, and held for 3 hours, respectively. While carrying out the water load test under the above nine conditions, the shelf temperature Th, the tray bottom component temperature Tb, the drying cabinet vacuum Pdc, and the cold trap vacuum Pct were measured and recorded. Furthermore, from these measurement results, the ice sublimation rate Qm (Kg / h) and the steam flow resistance coefficient Cr of the main pipe flow path were determined. Table 4 shows the shelf temperature Th, the vacuum degree Pdc of the drying cabinet DC, the vacuum degree Pct of the cold trap CT, the sublimation speed Qm, and the water vapor flow resistance coefficient Cr obtained in the water load test.

FIG. 14 is a graph showing the relationship between the steam flow resistance coefficient Cr and the sublimation rate Qm of the main pipe flow path created based on the data in Table 2. From the data in Table 2 (FIG. 14), a relational expression between the steam flow resistance coefficient Cr of the main pipe channel and the sublimation speed Qm can be derived. The following equation (41) was derived from the water load test described above.
Cr = 4.065 / Qm ^0.8 (41)
When the relational expression (41) between the steam flow resistance coefficient Cr and the sublimation speed Qm of the main pipe channel is substituted into the above expression (40), the following calculation expression (42) of the sublimation speed Qm is derived.
Qm = 0.9 × A × (Pdc ² −Pct ² ) ^0.875 (42)
From this equation (42), j = 0 and k = 0.875 are obtained.
In this way, by storing the constants j and k obtained in the prior water load test in the sequencer PLC, the main channel cross-sectional area A calculated in step S23 and the drying chamber vacuum degree calculated in step S27. The sublimation rate Qm can be easily calculated from the average value of Pdc and the average value of the cold trap vacuum.

  Next, the process proceeds to step S28, and the sublimation amount M is calculated. The sublimation amount M of the material to be dried is obtained by the above equation (13).

  Next, the process proceeds to step S29, the heat transfer coefficient K from the shelf B to the bottom of the vial E by gas conduction, the heat capacity C of the entire material to be dried including the vial, rubber stopper, ice and filling, and the material to be dried An average bottom part temperature Tb and an average sublimation surface temperature Ts of the material are calculated. The heat transfer coefficient K is obtained by the above equation (14), and the heat capacity C of the entire material to be dried is obtained by the above equation (15). When calculating the average bottom part temperature Tb and the average sublimation surface temperature Ts, as in the first embodiment, the sensible heat of the material to be dried including the container E is taken into consideration, and the average product temperature Tm of the material to be dried in the primary drying process. Is obtained from the heat transfer equation shown in the above equation (16). Therefore, the average bottom part temperature Tb is obtained by the above equation (21), and the average sublimation surface temperature Ts is obtained by the above equation (22).

  Thereafter, the process proceeds to step S30, and the calculated average sublimation surface temperature Ts (° C.), sublimation speed Qm (Kg / hr), and average bottom part temperature Tb (° C.) are recorded on the recorder e. The procedure from the procedure S26 to the procedure S30 described above is repeated for every time interval N set in the procedure S22 until the primary drying process is completed. The operator of the freeze dryer can grasp the drying state of the material to be dried in the primary drying process in time series by monitoring the data recorded in the recorder e.

  After the completion of the primary drying process, the process proceeds to the secondary drying process. Even after the transition to the secondary drying step, as shown in the step S31, it takes a plurality of times (in this embodiment, five times) from the vacuum gauge b at every time interval N set in the sequencer PLC in step S22. The drying chamber vacuum degrees Pdc1 to Pdc5 and the cold trap vacuum degrees Pct1 to Pct5 are taken in, and the shelf temperature Th from the temperature sensor S is taken in.

  Next, the process proceeds to step S32, the constant data j and k input to the sequencer PLC in step S21, the average value Pdc of the drying chamber vacuum degree and the cold trap vacuum degree obtained by the equations (36) and (37). The dehumidifying rate Qm ′ (Kg / hr) of the material to be dried is calculated by the above equation (26) from the average value Pct of the above and the flow path cross-sectional area A calculated in step S23.

Next, the process proceeds to step S33, and the heat transfer coefficient K, the heat capacity C, the constants a1, a2, and a3, the average bottom component temperature Tb, and the average product temperature Tm are calculated. The heat transfer coefficient K is obtained by the above equation (27), the heat capacity C is obtained by the above equation (28), the constants a1, a2, and a3 are obtained by the above equation (34), and the average bottom part temperature Tb Is obtained by the above equation (34), and the average product temperature Tm is obtained by Tm = Tb.

Thereafter, the process proceeds to step S34, and the calculated average product temperature Tm (° C.), sublimation rate Qm (Kg / hr), and average bottom part temperature Tb (° C.) are recorded in the recorder e. The procedure from step S31 to step S34 described above is repeated for every time interval N set in step S22 until the secondary drying step is completed. The operator of the freeze dryer can grasp the drying state of the material to be dried in the secondary drying step in time series by monitoring the recorded data in the recorder e.

15 and 16, the container E is included in the calculation of the average bottom part temperature Tb in the above-described method of the present invention, that is, the primary drying step and the secondary drying step, using the leak valve type freeze dryer M2. Considering the sensible heat and latent heat of the material to be dried, applying the drying cabinet wall temperature specific to each process, and calculating the average value Pdc of the drying cabinet vacuum when calculating the sublimation speed Qm (this method In this specification, it is referred to as “the method of the present invention”), and the measured value and the calculated value of the sucrose (Sucrose, molecular formula: C ₁₂ H ₂₂ O ₁₁ ) in the case of freeze-drying are compared Show. FIG. 15 is a diagram showing changes in measured values and calculated values of the product temperature from the pre-freezing step through the primary drying step to the initial stage of the secondary drying step, and FIG. 16 is an enlarged view of the initial stage of the primary drying step. It is a figure shown.

17 and 18, when the average bottom part temperature Tb in the primary drying process and the secondary drying process is calculated using the leak valve type freeze dryer M1, unlike the method of the present invention described above, Considering only latent heat without considering sensible heat of the material to be dried including E, applying a constant drying chamber wall temperature without applying a drying chamber wall temperature specific to each process, and sublimation rate Qm When calculating the value, the average value Pdc of the drying chamber vacuum is not calculated, but a method using the drying chamber vacuum that is instantaneously taken in from the vacuum detection means at a predetermined timing (this method is referred to as “conventional method” in this specification). The measured value and the calculated value of the product temperature when a 10% aqueous solution of sucrose (Sucrose, molecular formula: C ₁₂ H ₂₂ O ₁₁ ) is freeze-dried are compared and shown. FIG. 17 is a diagram showing changes in measured values and calculated values of the product temperature from the pre-freezing process through the primary drying process to the initial stage of the secondary drying process, and FIG. 18 is an enlarged view of the initial stage of the primary drying process. It is a figure shown.

  In any of the experimental examples, 660 vials into which the material to be dried was dispensed were loaded into the drying cabinet DC, and the material to be dried was freeze-dried according to the procedure stored in the sequencer PLC. Of the 660 vials loaded in the drying cabinet DC, one vial loaded in the center of the shelf B and one other vial loaded near the wall of the drying cabinet DC. For the vial and another one of the vials inserted between them, the temperature sensor is inserted, and the product temperature of the material to be dried dispensed in the vial (product temperature 1, product temperature 2). The product temperature 3) was measured. The primary drying of the material to be dried includes pre-freezing the solution at −45 ° C. for 2 hours, setting the shelf temperature Th to −20 ° C., and setting the variable leak valve and the leak control valve LV provided in the vacuum control circuit f. It was performed by controlling the degree of vacuum Pdc in the drying cabinet DC to 6.7 Pa by introducing external air into the freeze dryer M2 via the via. In secondary drying, the shelf temperature is raised from -20 ° C to 30 ° C in 1 hour, the degree of vacuum Pdc in the drying cabinet DC is controlled from 6.7 Pa to 1 Pa in 1 hour, and then the vacuum changes according to the course. I let you. 15 and FIG. 16, the degree of vacuum Pdc in the drying chamber DC, the degree of vacuum Pct in the cold trap CT, and the shelf temperature Th are set at intervals of 1 minute in the experimental example of FIGS. Then, the sublimation speed Qm (dehumidification speed Qm ′), the average bottom part temperature Tb, and the average sublimation surface temperature Ts were calculated. And each detected value and each calculated value were recorded on the recorder e, and the graph shown in FIGS. 15-18 was obtained.

  As is clear from the comparison between FIG. 15 and FIG. 17 and the comparison between FIG. 16 and FIG. 18, the freeze-dryer M1 of the channel opening vacuum control system is used even when the freeze-dryer M2 of the leak valve system is used. The same effect is observed as if

  That is, as shown in FIGS. 17 and 18, the average sublimation surface temperature Ts of the material to be dried calculated by the conventional method approximates the product temperature 1, the product temperature 2, and the product temperature 3 detected by the temperature sensor. However, in the conventional method, since the sensible heat of the material to be dried including the container E is not taken into consideration, as is apparent from FIG. 18, it is calculated during the shelf temperature raising period performed at the initial stage of the primary drying process. The average bottom part temperature tends to be higher than the actually measured part temperature. For this reason, as shown in FIG. 17, since the average bottom part temperature calculated in the primary drying step reaches the shelf temperature earlier than the actually measured part temperature, the average bottom part temperature can follow the temperature change of the material to be dried. In the latter stage of the primary drying process, the calculated average bottom part temperature tends to deviate from the actually measured part temperature. Further, in the conventional method, since the sensible heat of the material to be dried is not taken into consideration, if the measurement value fluctuates at the time of detecting the vacuum degree Pdc, the cold trap vacuum degree Pct and the shelf temperature Th in the drying chamber DC, The calculated sublimation speed Qm is blurred. For this reason, as shown in FIG. 17, the calculated sublimation surface temperature Ts fluctuates unnaturally. Note that the same tendency is observed in the secondary drying step.

  In contrast, in the method of the present invention, when calculating the average bottom part temperature Tb in the primary drying step and the secondary drying step, the sensible heat and latent heat of the material to be dried including the container E are taken into account. Thus, the average bottom part temperature calculated in the initial stage of the primary drying process does not tend to be higher than the actually measured part temperature. Further, since the average bottom part temperature calculated in the primary drying process does not reach the shelf temperature earlier than the actually measured product temperature, as is clear from the comparison between FIG. 15 and FIG. The difference between the exhibition temperature and the measured product temperature is small. Since the method of the present invention takes into consideration the sensible heat of the material to be dried, as shown in FIG. 15, the calculated sublimation surface temperature Ts smoothly changes even when the calculated sublimation speed Qm is fluctuated. . Further, in the method of the present invention, when calculating the sublimation speed Qm, the average value Pdc of a plurality of drying chamber vacuum degrees and the average value Pct of the cold trap vacuum degree detected over a few seconds are applied, so the calculated sublimation speed Qm The blur is getting smaller. Furthermore, since the drying warehouse wall temperature Tw1 at the time of primary drying is applied to the calculation of the average bottom part temperature Tb in the primary drying step, the difference between the calculated product temperature and the actually measured product temperature can be reduced. In addition, the method of the present invention calculates the average sublimation surface temperature Ts, the average bottom part temperature Tb, and the sublimation speed Qm of the material to be dried in the primary drying step at intervals of 1 minute. Can be increased. Note that the same tendency is observed in the secondary drying step.

  Thus, according to the method of the present invention, the calculated sublimation surface temperature Ts of the material to be dried can be made to coincide well with the product temperature 1, the product temperature 2, and the product temperature 3 detected by the temperature sensor. By monitoring the sublimation surface temperature Ts, the sublimation surface temperature in the primary drying process and the secondary drying process is applied to the material to be dried dispensed into all the vials charged in the drying chamber DC of the freeze dryer M2. Can be monitored without contact. Moreover, the collapse of the material to be dried in the primary drying step and the secondary drying step can be completely prevented.

  The present invention can be used for a freeze dryer used for freeze drying of foods, medicines and the like.

B Shelf plate T Tray frame C Opening controller CT Cold trap CR Control panel DC Dryer E Container M1, M2 Freeze dryer MV Main valve P Vacuum pump PLC Sequencer S Temperature sensor V Inlet valve a Main pipe b Vacuum gauge ct Trap Coil (plate)
e Recorder f Vacuum control circuit g Angle sensor

Claims (6)

A drying chamber (DC) for charging the material to be dried, a cold trap (CT) for condensing and collecting water vapor generated from the material to be dried charged in the drying chamber (DC), and the drying chamber (DC) ) And the cold trap (CT), a main pipe (a), a main valve (MV) for opening and closing the main pipe (a), and a vacuum degree adjusting means for adjusting the degree of vacuum in the drying chamber (DC) And a vacuum detection means for detecting the absolute pressure in the drying cabinet (DC) and the absolute pressure in the cold trap (CT), and installed in the drying cabinet (DC) to dispense the material to be dried. A shelf temperature detecting means for detecting the temperature of the shelf (B) on which the container is placed, and a controller (PLC) for automatically controlling the operation of the drying chamber (DC), the cold trap (CT) and the vacuum degree adjusting means. )
The controller (PLC) controls the driving of the drying cabinet (DC), the cold trap (CT), and the vacuum degree adjusting means, and executes the primary drying process and the secondary drying process of the material to be dried. Control program, required calculation program and formula, time interval for executing the calculation program, data on heat capacity of the material to be dried including the container, and wall temperature of the drying chamber (DC) in the primary drying step And constant data including the wall temperature of the drying cabinet (DC) in the secondary drying step,
In the primary drying step, the degree of vacuum (Pdc) in the drying cabinet (DC) is changed without any operation of the vacuum degree adjusting means, and the time stored in the control device (PLC) is changed. For each interval, the measurement data of the vacuum detection means and the shelf temperature detection means and the constant data of the control device (PLC) including the wall temperature of the drying cabinet (DC) in the primary drying step and the control device (PLC) From the stored calculation formula, the sublimation rate (Qm) of the material to be dried, the sublimation latent heat of the material to be dried and the average bottom part temperature (Tb) considering the sensible heat of the material to be dried including the container, The average sublimation surface temperature (Ts) is obtained in this order, and each of these calculation data is recorded in the recording means (e),
In the secondary drying step, the degree of vacuum (Pdc) in the drying cabinet (DC) is changed without depending on the degree of vacuum adjusting means, and stored in the controller (PLC). Constant data of the controller (PLC) including the measurement data of the vacuum detecting means and the shelf temperature detecting means and the wall temperature of the drying cabinet (DC) in the secondary drying step and the control device (PLC) for each time interval The average bottom part temperature in consideration of the dehumidification rate (Qm ′) of the material to be dried, the sublimation latent heat of the material to be dried and the sensible heat of the material to be dried including the container (Tb) and average product temperature (Tm) are obtained in this order, and each calculation data is recorded in the recording means (e), and the drying state of the material to be dried applied to the freeze dryer is characterized. Method.   A freeze-type dryer equipped with a damper-type opening degree controller (C) in the main pipe (a) as the vacuum degree adjusting means, and in the primary drying step and the secondary drying step, the control device (PLC) Adjusts the opening of the opening controller (C), and adjusts the opening angle of the opening controller (C) following the change in the degree of vacuum (Pdc) in the drying chamber (DC). The method for monitoring a dry state of a material to be dried applied to the freeze dryer according to claim 1, wherein the dry state is changed.   A vacuum control circuit (f) with a leak control valve (LV) is provided as any one of the vacuum systems including the drying cabinet (DC), the cold trap (CT), and the main pipe (a) as the vacuum degree adjusting means. In the primary drying process and the secondary drying process using a freeze dryer, the control device (PLC) drives the leak control valve (LV) and the degree of vacuum (Pdc) in the drying cabinet (DC). 2 is controlled to a set value, or the leak control valve (LV) is closed, and thereafter, the degree of vacuum (Pdc) in the drying chamber (DC) is left to the event. A method for monitoring a dry state of a material to be dried applied to a freeze dryer. A drying chamber (DC) for charging the material to be dried, a cold trap (CT) for condensing and collecting water vapor generated from the material to be dried charged in the drying chamber (DC), and the drying chamber (DC) ) And the cold trap (CT), a main pipe (a), a main valve (MV) for opening and closing the main pipe (a), and a vacuum degree adjusting means for adjusting the degree of vacuum in the drying chamber (DC) And a vacuum detection means for detecting the absolute pressure in the drying cabinet (DC) and the absolute pressure in the cold trap (CT), and installed in the drying cabinet (DC) to dispense the material to be dried. A shelf temperature detecting means for detecting the temperature of the shelf (B) on which the container is placed, and a controller (PLC) for automatically controlling the operation of the drying chamber (DC), the cold trap (CT) and the vacuum degree adjusting means. )
The controller (PLC) controls the driving of the drying cabinet (DC), the cold trap (CT), and the vacuum degree adjusting means, and executes the primary drying process and the secondary drying process of the material to be dried. Control program, required calculation program and formula, time interval for executing the calculation program, data on heat capacity of the material to be dried including the container, and wall temperature of the drying chamber (DC) in the primary drying step And constant data including the wall temperature of the drying cabinet (DC) in the secondary drying step,
In the primary drying step, the degree of vacuum (Pdc) in the drying cabinet (DC) is changed without any operation of the vacuum degree adjusting means, and the time stored in the control device (PLC) is changed. For each interval, the measurement data of the vacuum detection means and the shelf temperature detection means and the constant data of the control device (PLC) including the wall temperature of the drying cabinet (DC) in the primary drying step and the control device (PLC) From the stored calculation formula, the sublimation rate (Qm) of the material to be dried, the sublimation latent heat of the material to be dried and the average bottom part temperature (Tb) considering the sensible heat of the material to be dried including the container, The average sublimation surface temperature (Ts) is obtained in this order, and each of these calculation data is recorded in the recording means (e),
In the secondary drying step, the degree of vacuum (Pdc) in the drying cabinet (DC) is changed without depending on the degree of vacuum adjusting means, and stored in the controller (PLC). Constant data of the controller (PLC) including the measurement data of the vacuum detecting means and the shelf temperature detecting means and the wall temperature of the drying cabinet (DC) in the secondary drying step and the control device (PLC) for each time interval The average bottom part temperature in consideration of the dehumidification rate (Qm ′) of the material to be dried, the sublimation latent heat of the material to be dried and the sensible heat of the material to be dried including the container (Tb) and average product temperature (Tm) are obtained in this order, and each calculation data is recorded in the recording means (e), and the drying state of the material to be dried applied to the freeze dryer is characterized. apparatus.   A damper-type opening degree controller (C) is provided in the main pipe (a) as the vacuum degree adjusting means, and the controller (PLC) controls the opening degree adjustment in the primary drying step and the secondary drying step. The opening degree of the container (C) is adjusted, and the opening angle of the opening degree controller (C) is changed following the change in the degree of vacuum (Pdc) in the drying chamber (DC). The dry condition monitoring apparatus applied to the freeze dryer according to claim 4. As the vacuum degree adjusting means, a vacuum control circuit (f) with a leak control valve (LV) is connected to any one of the vacuum systems including the drying chamber (DC), the cold trap (CT), and the main pipe (a). In the primary drying step and the secondary drying step, the control means (PLC) drives the leak control valve (LV) to set the degree of vacuum (Pdc) in the drying cabinet (DC) to a set value. The freeze-drying machine according to claim 4, wherein the control is performed or the leak control valve (LV) is closed , and thereafter, the degree of vacuum (Pdc) in the drying cabinet (DC) is left to random. Applied dry condition monitoring device.