JP4911377B2 - Judgment method and apparatus for determining completion of drying of material to be dried - Google Patents

Description

  In the present invention, a raw material solution of food / pharmaceutical is filled in a container such as a vial, charged into a drying chamber of a vacuum drying apparatus by a batch system, and dried to a predetermined moisture content by freeze drying to obtain a product. The present invention relates to a drying completion determination method for an object to be dried for determining that a material to be dried has a predetermined moisture content and has reached a drying end point to be taken out as a product from a drying cabinet in a vacuum drying means.

  Judgment that the material to be dried in the drying chamber has finished drying when the material to be dried is placed in the drying cabinet of the freeze vacuum drying apparatus and the material to be dried is dried to a predetermined moisture content by vacuum drying. As a means, firstly, a thermocouple is inserted into the material to be dried charged in the drying chamber, and the container filled with the material to be dried in the drying chamber is placed from the start of drying. Display and record the product temperature of the material to be dried, as well as the shelf temperature of the shelf and the degree of vacuum in the drying cabinet, and dry when the product temperature approaches the shelf temperature and there is no temperature difference. There is a means for determining the end point.

  This means that the detected product temperature is the temperature of the part where the thermocouple inserted as the product temperature sensor is inserted, and the entire product temperature of the material to be dried in the drying cabinet is not reflected. There is a problem in that reproducibility is difficult because the location where the thermocouple is installed is not the same every time.

  Second, display and record the degree of vacuum change accompanying the load reduction during the drying process in the drying cabinet, read the trend, or display the temperature change of the cold trap that collects the generated water vapor -There is a means to determine the end of drying by recording and reading the trend. Although this means reflects the increase and decrease in the amount of water vapor generated in the entire material to be dried and reflects the dry state of the entire material to be dried, there is a problem that it is difficult to quantify.

  Thirdly, as a generally popular means, as shown in FIG. 1, the freeze vacuum drying apparatus W has a drying chamber DC in which a material to be dried is charged, and a material to be dried in the drying chamber DC. And the cold trap CT that condenses and collects the water vapor generated from the gas, and communicates with each other via the duct a, and the main valve MV is provided in the duct a. Next, the main valve MV is closed for a certain period of time, and the change in the degree of vacuum during this period is measured. From the change, the amount of gas generated in the drying chamber DC is measured and the dry state of the material to be dried is determined from the amount of gas generated Means.

  This means that when the material to be dried is charged into the drying cabinet DC and the freeze vacuum drying apparatus is activated to start the drying process, the drying cabinet is empty before charging the material to be dried into the drying cabinet DC. In this state, the amount of air leakage (Qair) with respect to the inside of the drying chamber is measured, and the drying state of the object to be dried during the drying process is determined by the change in the degree of vacuum in the chamber and the change in the amount of gas generation measured thereby. From this, it is necessary to subtract this external air leakage amount (Qair) from the measured value of the degree of vacuum in the cabinet. However, there is a possibility that the amount of air leakage may change. When this is performed, there is a problem that an estimated value is obtained and an error occurs in the measured amount of generated water vapor (Qwater). Moreover, the gauge b which measures the vacuum degree in a drying chamber must use the meter which measures absolute pressure. The instrument that detects the change in the thermal conductivity of the gas due to the degree of vacuum by the electrical resistance of the hot wire, such as the Pirani vacuum gauge, differs in the actual vacuum level depending on the gas composition (air / water vapor) in the chamber with respect to the reading value. come. Therefore, the error is further increased in the relative vacuum gauge.

  4thly, the moisture sensor which measures the moisture content in the gaseous-phase in a warehouse is installed in the drying warehouse of a freeze vacuum drying apparatus, and the drying which dries the to-be-dried material in a drying warehouse As shown in FIG. 2, there is a means for measuring and storing the moisture content of the internal gas phase inside the chamber, thereby determining the end of drying.

  This measure reflects the degree of dryness of the entire material to be dried in the measured value, but the disadvantage is that the measuring instrument is expensive and the moisture sensor of the measuring instrument cannot be sterilized by steam. It cannot be used with the corresponding freeze-drying equipment.

Incidentally, FIG. 3 shows a measurement example of a trap of a normal refrigerant direct expansion system. In this example, the degree of vacuum varies greatly due to the fluctuation of the cold trap temperature. In this state, a large error is generated in the leakage amount measurement.
Japanese Patent No. 3644845

  The problem to be solved in the present invention is that when a material to be dried is charged into a drying cabinet of a freeze vacuum drying apparatus and dried by a batch method, the material to be dried has a predetermined moisture value. It can be accurately determined based on the measured value by the measuring device that detects the degree of vacuum or water vapor pressure in the warehouse, etc., in the technical field of pharmaceutical manufacturing, The purpose of the present invention is to provide a judgment means capable of satisfying reproducibility and equivalence between product batches as required in the initial design as validation of the manufacturing method based on the Pharmaceutical Affairs Law.

  The means of the present invention for solving the above-mentioned problems is that the main valve provided in the duct communicating between the drying chamber and the cold trap shown as the third conventional means is closed, and the vacuum in the drying chamber is closed. This is an improved means for measuring the degree of change, measuring the amount of gas generated in the chamber from the measured value, and determining the drying end point based on the measured amount. That is, when the conventional means measures the drying state from the amount of gas generated in the drying chamber DC, the main valve MV is in the state where the drying chamber DC is empty before the material to be dried is charged in the drying chamber DC. Is closed, and the change in the degree of vacuum in the drying cabinet DC is measured for a certain period of time, the amount of external air leakage (Qair) is measured, this is set as the leakage amount, and the material to be dried is loaded in the drying cabinet DC. When the water vapor generation amount (Qwater) is measured from the change in the degree of vacuum in the system from the drying cabinet DC to the cold trap CT during the actual drying process performed by opening the main valve MV, The amount of water vapor generation (Qwater) is obtained by subtracting the leakage amount (Qair) as an estimated value, and the dry state is determined based on the amount of water vapor generation.

  On the other hand, in the means of the present invention, before the main valve MV is closed and the change in the degree of vacuum in the drying chamber DC is measured, the main valve MV is opened and the inlet valve V is closed. The change in the degree of vacuum over a certain period of time was measured, thereby measuring the amount of air leakage [Qair (DC + CT)] in the system during this period, and then the main valve MV was closed with the inlet valve V closed. The change in the degree of vacuum in the drying chamber DC system and the cold trap CT system over a certain period of time is measured separately, whereby the air leakage amount [Qair (CT)] of the cold trap CT system alone, the air and water vapor in the drying chamber DC system The amount of leakage [Qt (DC)] of the drying cabinet DC system is calculated, the amount of air leakage [Qair (DC)] of the drying cabinet DC is calculated, and the amount of leakage [Qt (DC)] of this drying cabinet DC is calculated. Reduce air leakage [Qair (DC)] A means that so as to accurately calculate the water vapor generation amount in the drying cabinet DC [Qwater (DC)] by calculation to.

More specifically, as shown in FIG. 4, the drying cabinet DC and the cold trap CT are separated from each other, and communicate with each other through a duct a equipped with the main valve MV. The trap CT is equipped with a suction valve V that communicates with the vacuum pump P, and a freeze vacuum drying apparatus W having a vacuum gauge b attached to the drying chamber DC and the cold trap CT, respectively, is dried in the drying chamber DC. When the material is charged and the freeze vacuum drying apparatus W is operated to dry, before the main valve MV is closed and the change in the degree of vacuum in the drying chamber DC is measured, the main valve MV is first opened. Then, the inlet valve V exhausted from the cold trap CT to the vacuum pump P is closed. In this state, since the water vapor generated from the material to be dried in the drying cabinet DC is iced on the cold trap CT, there is a water vapor partial pressure corresponding to the temperature of the cold trap CT. Since the air flowing in from the outside does not condense at the temperature of the trap body ct of the cold trap CT (usually −50 to −70 ° C. by a two-stage compression refrigerator), the partial pressure of air enters the system between the drying chamber DC and the cold trap CT. Appears and changes in the degree of vacuum. The amount of leakage between the drying chamber DC and the cold trap CT when the volume of the drying chamber DC is V (DC), the volume of the cold trap CT system is V (CT), and the change in the degree of vacuum during a certain time (T) is ΔP. Is calculated as the air leakage amount [Qair (DC + CT)] as follows.
(1) Qair (DC + CT) = V (DC + CT) · ΔP / T (m3 · Pa / sec)
Subsequently, the main valve MV is also closed while the inlet valve V is closed. And the vacuum degree change of the drying chamber DC and cold trap CT for a fixed time (T ') is measured. Thereby, first, the air leakage amount [Qair (CT)] of only the cold trap system is measured.
(2) Qair (CT) = V (CT) · ΔPct / T ′ (m3 · Pa / sec)
ΔPct is the amount of change in the vacuum degree of the cold trap system. Next, the air leak amount [Qair (DC)] of the drying cabinet system is calculated by (1)-(2).
(3) Qair (DC) = Qair (DC + CT) −Qair (CT)
Next, the amount of air and water vapor leakage (Qt (DC)) in the drying cabinet system is Qt (DC) = V (DC) · ΔPdc / T ′
Measured by
Next, only the water vapor amount [Qwater (DC)] can be accurately measured by subtracting the equation (3) from the leakage amount “Qt (DC)] of the drying cabinet DC system.
Qwater (DC) = Qt (DC) −Qair (DC)

  These leaks measured by a change in the degree of vacuum between the drying chamber DC and the cold trap CT measured by the vacuum gauge b, a change in the degree of vacuum in the drying chamber DC system, and a change in the degree of vacuum in the cold trap CT system. Amount [Qair (DC + CT)], [Qair (CT)], [Qair (DC)] and the amount of leakage of air and water vapor [Qt (DC)] measured from the amount of leakage, and water vapor The quantity [Qwater (DC)] is sequentially calculated in an electronic device (sequencer) that is installed in the control panel c and performs a control operation, and the result is displayed on the display unit provided in or near the control panel c. The When the amount of water vapor generated that is measured and displayed is the amount that is the dryness of the moisture value that is acceptable as the quality of the product, the end of drying is determined by the display on the display unit or the generation of a signal It is a means of becoming, and this is what is raised.

  Further, according to the means of the present invention, since the measured amount of water vapor is captured as the flow rate of water vapor generated from the entire material to be dried in the drying cabinet DC, the product quality is verified in the production process as process validation before the production starts. In the trial production stage, a correlation diagram between the water vapor flow rate and the average value obtained by measuring the moisture content of each product can be determined. FIG. 6 is a correlation diagram, which is a graph in which the correlation between the average value of the moisture content of the dried product and the amount of water vapor is approximated as a linear function with high accuracy. Thus, by using this graph, it is possible to set a numerical value of the amount of water vapor generation that matches the average moisture content, so that the amount of water vapor generation for determining the end of drying of a dried product having a desired moisture value is to use this graph. It can be easily obtained. For this reason, a determination means for setting a water vapor generation amount for determining the end of drying using this correlation diagram is also proposed.

  In the means of the present invention, the amount of external air leakage is measured as an actual value, so the measurement of the amount of water vapor generated as the end point of drying is more accurate than the conventional method in which this amount of external air leakage was introduced as an estimated value. It will be a thing.

  In addition, if the correlation between the average value of moisture content of dried products and the amount of water vapor is graphed, it is a graph that can be approximated very accurately as a linear function, so this graph sets the amount of water vapor generated that matches the average water content. By doing so, it is always possible to define a product of a certain quality in-line and online.

  Next, examples will be described in detail.

  FIG. 4 is a schematic development view of the freeze vacuum drying apparatus W used in the implementation of the means of the present invention. DC is a drying cabinet, CT is a cold trap, a is a duct for connecting and connecting them, and MV is installed in the duct a. Main valve, b is a vacuum gauge attached to the drying chamber DC and the cold trap CT, V is an inlet valve attached to the cold trap CT, P is a vacuum pump connected to the inlet valve V, ct is a cold trap CT The trap coil, c is a control panel, and d is a sequencer incorporated in the control panel c.

The freeze vacuum drying apparatus W is loaded with a material to be dried in the drying cabinet DC and controlled by the controller of the control panel c to start a predetermined drying process. FIG. 5 shows this measurement example. The temperature inside the cold trap CT is controlled to −64 ° C. by the surface temperature of the cold trap body ct. The equilibrium water vapor pressure at that temperature corresponds to 0.617 Pa. First, the inlet valve V is closed, and the change in the degree of vacuum between the drying chamber DC and the cold trap CT is measured. Both the drying chamber DC vacuum gauge b and the cold trap CT vacuum gauge b rose from 1090 min 0.8 Pa to 1 Pa in 1125 min. The amount of air leakage [Qair (DC + CT)] between the drying chamber DC and the cold trap CT when the DC volume of the drying cabinet is 5 m3 and the cold trap CT volume is 1 m3 is Qair (DC + CT) = 5 × (1-0.8) / (35 × 60) = 4.76 × 10 ⁻⁴ m ³ · Pa / sec
The inlet valve V is opened and the degree of vacuum is restored to the original one. This time, the main valve MV and the inlet valve V are closed. During this time, the cold trap CT vacuum gauge b has hardly changed. Therefore, Qair (CT) = 0
Qair (DC) = Qair (DC + CT) −Qair (CT) = 4.76 × 10 ⁻⁴ m ³ · Pa / sec.
The drying chamber DC vacuum gauge b changes from 0.8 Pa to 0.88 Pa for 4 minutes.
Qt (DC) = 4 × (0.88−0.8) / (4 × 60) = 1.33 × 10 ⁻³ m ³ · Pa / sec
Therefore, the water vapor generation amount [Qwater (DC)] is Qwater (DC) = Qt (DC) −Qair (DC) = (13.3-4.76) 10 ⁻⁴ m ³ · Pa / sec = 3.1 m ³ · Pa / h can be obtained.
Therefore, the drying end point can be accurately determined from the water vapor generation amount [Qwater (DC)].
This means that since the cold trap CT is controlled at a constant temperature, the degree of vacuum does not move, so the amount of air leakage can be accurately measured. Accurately measured.

It is a general | schematic expanded view of the freeze vacuum drying apparatus used for the conventional method which judges the completion | finish of drying from the water vapor generation amount in a drying cabinet. It is a chart of the measurement example of the conventional method which measures a moisture value with a moisture sensor and judges the end of drying. It is a chart of the example of a measurement by a refrigerant direct expansion system trap. It is a general | schematic expanded view of the freeze vacuum drying apparatus used for this invention means. It is a chart of the measurement example in the Example of this invention means. In this invention means, it is a correlation diagram of the water vapor generation amount which arises in a drying cabinet, and the average value of the moisture content which the dry product measured.

Explanation of symbols

  CT ... Cold trap, DC ... Dryer, MV ... Main valve, V ... Inlet valve, W ... Freeze vacuum dryer, a ... Duct, b ... Vacuum gauge, c ... Control panel, ct ... Trap coil (plate), d ... Sequencer, e ... Correlation diagram.

Claims (3)

  The drying chamber DC in which the material to be dried is charged and freeze-vacuum dried is separated from the cold trap CT that freezes and collects water vapor generated from the material to be dried in the drying chamber DC. A freeze vacuum drying apparatus connected through a duct a equipped with a valve MV is used. The drying chamber DC and the cold trap CT are each equipped with a vacuum gauge b capable of measuring absolute pressure, and the cold trap CT. Is equipped with a suction valve V, and the freeze-drying apparatus W in which the material to be dried is charged into the drying cabinet DC and the freeze-drying process is started, the main valve MV is opened, and the suction valve V is closed. Measure the change in the degree of vacuum over a certain period of time from the drying cabinet DC to the cold trap CT, and measure the amount of air leakage [Qair (DC + CT)] from the drying cabinet DC to the cold trap CT. Then, with the inlet valve V closed and the main valve MV closed, the changes in the degree of vacuum in the drying chamber DC system and the cold trap CT system for a certain period of time are measured, whereby the air in the cold trap CT system is measured. The amount of leakage [Qair (CT)] and the amount of air and water vapor leakage [Qt (DC)] of the drying cabinet DC system are measured, and the amount of air leakage [Qair (DC + CT) between the drying cabinet DC and the cold trap CT ] Is subtracted from the air leak amount [Qair (CT)] of the cold trap CT system, and the air leak amount [Qair (DC)] of the dryer DC system is calculated, thereby generating the water vapor generation amount [Qwater (DC) in the dryer DC )] And determining the end point of drying based on the amount of water vapor generated [Qwater (DC)]. A method for determining the end of drying of a material to be dried during freeze-drying.   A freezing vacuum drying apparatus W is loaded with a material to be dried and dried in a freeze chamber DC, and a cold trap CT for collecting and collecting water vapor generated from the material to be dried in the drying chamber DC. And a control panel incorporating a duct a equipped with a main valve MV for communicating between the dryer DC and the cold trap CT, and a control means capable of controlling the temperature of the trap coil (ct) of the cold trap CT within a certain value. c, a vacuum gauge b capable of measuring the absolute pressure respectively provided in the dryer DC and the cold trap CT, and a suction valve V provided in the cold trap CT, and the control panel c includes the vacuum By the meter b, the change in the degree of vacuum for a certain time between the drying chamber DC and the cold trap CT measured, the change in the degree of vacuum for a certain time in the drying chamber DC system, and the cold trap C The amount of air leakage [Qair (DC + CT)] from the drying chamber DC to the cold trap CT, the air leakage amount [Qair (CT)] of the cold trap system, and the drying chamber DC system Air leakage amount [Qair (DC)] and the leakage amount [Qt (DC)] of air and water vapor in the drying cabinet DC are measured, and the water vapor generation amount [Qwater (DC) in the drying cabinet DC is measured therefrom. )] For calculating the completion of drying of the material to be dried in the drying cabinet in the freeze-drying apparatus incorporating the sequencer d.   A freezing vacuum drying apparatus W is loaded with a material to be dried and dried in a freeze chamber DC, and a cold trap CT for collecting and collecting water vapor generated from the material to be dried in the drying chamber DC. And a control panel incorporating a duct a equipped with a main valve MV for communicating between the dryer DC and the cold trap CT, and a control means capable of controlling the temperature of the trap coil (ct) of the cold trap CT within a certain value. c, a vacuum gauge b capable of measuring the absolute pressure respectively provided in the dryer DC and the cold trap CT, and a suction valve V provided in the cold trap CT, and the control panel c includes the vacuum According to the meter b, the change in the degree of vacuum for a certain period of time from the drying chamber DC to the cold trap CT, the variation in the degree of vacuum for a certain period of time in the drying chamber DC system, and the cold tra The amount of air leakage [Qair (DC + CT)] from the drying chamber DC to the cold trap CT, the amount of air leakage [Qair (CT)] of the cold trap system, and the drying chamber DC The amount of air leakage [Qair (DC)] of the system and the amount of leakage [Qt (DC)] of the air and water vapor in the drying cabinet DC are measured, and the water vapor generation amount [Q water ( DC)] is calculated, and a correlation diagram e prepared from the water vapor flow rate and the average value obtained by measuring the moisture content of each product in the trial production stage in which the product quality is verified in the manufacturing process. Is a device for determining the completion of drying of the material to be dried in the drying cabinet of the freeze vacuum drying apparatus.