JPS5842954A - Continuous measuring apparatus of concentration of solution - Google Patents

Abstract

PURPOSE:To perform an elution test of tablets and capsuled medicines, etc. automatically and continuously, by sending plural concentation measuring cells arranged in a line to an arrangement direction intermittently and providing a transporting mechanism for circulating a solution between an inspection body dissolution vessel corresponding to each cell and each cell. CONSTITUTION:Plural concentration measuring cells (e.g. six cells A, B-F) 45 arranged in a line are sent to an arrangement direction intermittently by a specific plate cam 52 rotating the cells 45 in the arrow mark direction and detecting dissolution vessels (A, B-F) 42 in a thermostat 41 are sent to the cells 45 through a tube 47 by a pump 44 at a measuring position M and then, consructed to measure the elution quantity of tablets, etc. in the vessel 42 by using a spectrophotometer 51. When the measurements of all cells are finished, a cell moving stand 50 is returned to the original position and the measurements are performed repeatedly in a prescribed period. Movement of the cells 45, an operation of the pump, the measurement and calculation and display of measured results, etc. are carried out automatically by using a computer.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a continuous solution concentration measuring device, for example, a device for measuring a change in dissolution rate in a dissolution test of a solid pharmaceutical preparation.

Dissolution testing of solid preparations such as tablets, granules, and capsules is becoming increasingly important as a means of evaluating the quality of preparations. In this dissolution test, a solid drug is dissolved in a solution and the elution amount of the active ingredient is measured using a spectrophotometer.The elution behavior of the active ingredient can be determined by graphing the changes in the elution amount of the active ingredient over time. In other words, it is possible to grasp the elution rate. Furthermore, the content of the active ingredient in the formulation can be tested by measuring the elution amount of the active ingredient.

The present invention is a device that measures temporal changes in the concentration of a predetermined component in a solution, such as a dissolution test device, and is capable of continuously measuring the concentration of a large number of samples at once without requiring a large space. The purpose is to provide a device that can do this.

Another object of the present invention is to provide an apparatus that can automatically calculate the ratio of the measured concentration to the standard concentration of the standard solution and record the change.

Hereinafter, examples in which the present invention is applied to a dissolution test device will be described in detail with reference to the drawings.

In this example, dissolution tests for six samples are performed simultaneously.

In Figures 1 and 2, there are 6
Dissolution containers (42) are provided.These containers (
42 or the solid preparations (specimen) dissolved and measured in these containers are distinguished using the symbols (g) ~. Each container (421) is equipped with a stirrer (43), and the solid preparation is dissolved while being stirred in the container (42). , is sent to the corresponding measuring cell (a) by the pump (through the filter (4!1) and the supply tube (4η),
From the measuring cell it is returned to each container 1a through an evacuation tube (machine).

A bubble remover (4j5) is provided on the side of the pump (supply tube 147). This bubble remover (ω) is composed of a vertically arranged large diameter tube. Bubbles generated by stirring the solution in 14z accumulate at the top of this vertical tube, so the measurement cell (45
This prevents air bubbles from entering the solution supplied to 1. If the tube (4η) is made of a flexible material,
When the amount of bubbles in the vertical tube becomes large, the bubbles can be returned to the container (41) through the tube (47), the measuring cell and the tube (bar) by turning the vertical tube upside down. Although the passage of air bubbles is temporary,
There is almost no negative effect on measurements.

There are also 6 measuring cells (4 cells) corresponding to 6 samples, and they are arranged in a straight line on the moving table ω. It is supported so that it can move freely in the direction.

The longitudinal direction of the moving table ω coincides with the arrangement direction of the measurement cells. A push rod □□□ is fixed to one end of the moving table and extends outward, and the tip of the push rod □□□ is in contact with the cam surface on the circumferential surface of the plate cam ω.

The plate cam t521 is intermittently driven to rotate around the cam t521 by a drive device (55), which will be described later. plate cam 6
The cam surface on the circumferential surface of 21 is formed so that the distance from the center 0) increases sequentially, and furthermore, the distance from the center 0) is
There is a continuous sharp return from the point (P2) to the point of minimum distance.

As the plate cam eel rotates, the push rod □□□ is pushed by the cam surface, so that each measurement cell (a is on the side) to (F) is sent to the measurement position (goods) in order. Each measurement cell (45) positioned at a measurement position (good)
It is stopped for a certain period of time for measurement.

The movable stage ring is always urged in the direction of the plate cam @ by a spring (path shown), and after the measurement cell (451) reaches the measurement position, the tip of the push rod reaches the point ( Pl)～
At (P2), it returns to its original position.

Then, as the plate cam ω continues to rotate, the movable table ω is transferred again, and the positioning of each measurement cell (451) to the measurement position (goods) is repeated.

The spectrophotometer 61) measures the absorbance of the solution in the cell (451) positioned at the measurement position.The measurement wavelength of the spectrophotometer (51) varies depending on the active drug to be tested. Appropriate selection will be made.

A protrusion (to) is provided at the point (Pl) of the plate cam (5B). Also, six limit switches are installed at required locations on the circular motion locus of the point (Pl) of the plate cam @. is arranged. When each measurement cell on the moving table ω is positioned at the measurement position by the rotation of the plate cam mark, the protrusion (
) hits the lever of the corresponding limit 1, 1 switch (goods), and each position is detected.

The limit switch can also be operated by a lever or the like that is provided coaxially with the plate cam ω and rotates together with the plate cam . In this case, the limit fist switch is placed on the trajectory of the tip of the lever or the like.

FIG. 3 shows the electrical configuration of the dissolution test device.

The drive device ω is composed of a motor for rotating the plate cam @ and a timer relay that controls this motor, and receives position detection signals from each limit switch. The plate cam @ rotates as the motor rotates, and when a detection signal is output from one of the limit switches, the motor stops rotating. Then, a certain period of time is measured by a timer. After a certain period of time has elapsed, the motor rotates again and the plate cam @ rotates. When the detection signal force is output from the next limit switch, the motor stops for a certain period of time and this operation is repeated. ) Since measurements are taken on the cell (451) positioned at
1), and the absorbance output of the spectrophotometer (51) is sent to the recorder (5η).

The pen of the recorder 1571 is moved up and down by a solenoid (support). The solenoid haze is driven by a control signal from the drive bag @ω. While the motor of the drive device ω is driven and the plate cam @ is rotating, the pen is held in the raised position and no recording is performed. When the plate cam ■ is stopped and measurement is being performed, the pen is lowered. At this time,
Since the absorbance output from the spectrophotometer 61) is input to the recorder 67), the pen is positioned based on the value of this input signal, and the absorbance is recorded. Since the absorbance measurement is carried out sequentially for each measurement cell (a) positioned at the measurement position, the absorbance of each sample is time-divided on the recording paper of the recorder, as shown in Figure 4. recorded.

In FIGS. 3 and 4, only graphs for three samples are shown for simplicity.

Figure 5 shows the motor and pump (441
The figure shows an example in which a central processing unit (CPU) processes the control such as the above and the calculation of the dissolution rate of the main drug based on the absorbance output of the spectrophotometer (51).

It is preferable to use a microprocessor as the CPU. The CPU Kasumi has its execution block; ROM 1661. RAM (67) that stores various data
, a register to temporarily store the measured and calculated absorbance @
It is equipped with a timer for measuring haze and print setting time. The timer book may be an external timer, a counter that counts the clock of the CPU, or a specific area of the RAM may be used as a timer. The position detection signal of the limit switch is input to the CPU-. The drive motor for the plate cam (and the pump 144) is controlled by the control circuit based on instructions from the CPU. Test result data such as the dissolution rate calculated by the CPU based on the output of the spectrophotometer Sll are printed by the printer and represented in a graph by the x-y recorder (Corporation). The operation panel σl) is mainly used to set various setting values, and its details are shown in FIG.

The operating panel σl) is provided with various setting devices, push buttons/switches, and indicators. With this dissolution test device, four types of measurement time (30
, 60, 90 and 180 minutes). No matter which measurement time is set, the number of samplings for measurement is a constant value (for example, 120 times).
is fixed. Therefore, for example, the measurement time is 3
If set to 0 minutes, the sampling interval will be 15 seconds, and if set to 60 minutes, the sampling interval will be 30 seconds. The results measured at this sampling time interval are represented as a graph by an X-Y recorder, as will be described later. It is also possible to perform measurement at a time unrelated to the sampling time and print it out using the printer (731). This is the print setting time, and
It is arbitrarily set within the measurement time range by the setting device. The maximum number of times of printing is predetermined (for example, 32 times), and any number of times of printing within this range can be set by a setting device. The number of specimens to be measured simultaneously is set by the setting device. In this example, for convenience, the maximum number of specimens is set to three.

There are four types of modes set by the mode setter σω. Mode 1 is for setting printing time, mode 2 is for cell blank absorbance measurement, mode 3 is for standard solution absorbance measurement, and mode 4 is for dissolution test measurement. . The cell blank absorbance is the absorbance obtained when a solution in which no main drug is eluted is passed through the cell, and serves as the starting point of measurement (elution rate 0%). The standard solution absorbance is the absorbance when a specified amount of the main drug is dissolved in the solid preparation that is the specimen (dissolution rate 100%). The absorbance measured for each measurement is displayed on the display by Digital. Others ° on the operation panel σ1)
, the start button for each operation (811, the print command button for pudding (reverse), the reset button (83), the start button for the X-Y recorder (A), the drive start button for the pump+441 (I) and a power switch.

FIG. 7 shows the contents of RAMvI. RAM@ has an area (Ml) that stores the input number of prints and print setting time, an area (M2) that stores the set sampling interval (measurement time), and an area (M2) that stores the cell blank absorbance and standard solution absorbance. Elijah (M
3) and (M4), and areas (M5) to (Ml) for storing, for each sample, the elution wheel calculated based on the measurement results for each sampling time.

FIG. 8 shows the procedure for executing the elution test by the CPU 165). First, check whether the start button g31) has been pressed (steps f, tl), and if it has been pressed, check which mode is set using the mode setting device (to) (steps (2) to (5)) . When mode 1 is set, the operator sets the number of prints (for example, 7 times) using the setting device, presses the start button (81), and then uses the setting device σ to set the first printing setting time (for example, 7 times). 5 minutes) and press the print button. Therefore, if the start button (81) is pressed (step (1)) and mode l is set (step (2)), the number of prints is stored in the RAM.
(Please remember this step in Elijah (Ml) (not shown))
When the print button is pressed (step (6)), the set print setting time is stored in the area (Ml) (step (7)), and the printer a3 prints (step (8)). FIG. 9 shows a sheet of paper (■) printed by the printer (2). By step (8), the top J
O1005J is printed. Then, check whether the time setting has been completed the number of times set on the setting device (
Step +91), if not completed, step (
Return to 6). Next, the operator sets the second printing setting time (10 minutes) using the setting device σ9 and presses the print button (step (6)). Remember step (7)), “0
201.0" is printed (step (8)). In this way, the printing setting time is set sequentially, and when the setting is completed a predetermined number of times (step (9)), the process returns to step tl.

Next, the operator sets mode 2 and presses the pump drive start button to drive the pump, which is already in the container (421).
The solution contained in the cell (the main drug is not eluted) is circulated through each cell.

When the start button Ill is pressed (step (1)), if mode 2 is selected (step f3+), cell blank absorbance measurement is executed (step io1).
). First, drive the motor to position the cell (G) at the measurement position (T) and read the output of the spectrophotometer 61).
It is stored in the storage location corresponding to the prisoner in the storage area (M3) of RAM-. Next, position the cell area [F]) at the measurement position and read the output of the spectrophotometer 61).
Similarly, the cell blank absorbance of the cell (C) is read and stored in the area (M3). Then, these cell blank absorbances are printed by a printer (step (II+')> (see FIG. 9), and the process returns to step (1).

After measuring the cell blank absorbance, the operator places a pre-prepared standard solution (a solution in which a specified amount of the main drug has been eluted) into each container (42), sets it to mode 3, and drives the pump. Press the start button (841) and start the pump (4
4) to circulate the standard solution in each container (421) to each cell 4. When the standard solution is sufficiently circulated, the operator presses the start button (step I+), so mode 3 is set. If so (step +41), move on to the standard solution absorbance measurement (step (12+). First, position the cell (a) in (A) at the measurement position (good), and move the spectrophotometer 5.
Read the absorbance output of 1) into the register (681).Then, read out the cell blank absorbance of (G) from the area (M3), calculate the difference with the measured absorbance of the register, and calculate the result of this calculation (standard solution absorbance). ) is stored in the memory location of the prisoner of Elijah (, M4).Similarly, for the [F]) mouth cell, calculate the difference between the measured absorbance and the cell blank absorbance stored in Elijah (M3). And Elijah (M4)
to be memorized. After completing the above process, print the standard solution absorbance using the printer (2) (+31)
(See Figure 9), return to step (+l).As can be seen from the above calculation process, the absorbance of this standard solution is
Since the value is corrected by the blank absorbance, the value is almost the same in all cells as shown in FIG. 9.

The operator usually sets the measurement time using a setting device after setting the print setting time. The CPU +651 reads the set measurement time and stores it in the storage area (M
2) Store the sampling interval (measurement time) (this step, the path shown).

When the processing in modes 1 to 3 is completed, the operator sets mode 4, fills the container with a predetermined amount of solution, and puts in the solid preparation to be tested. Then, stirrer (43) and pump (
441. The solution in the container (421) is in the cell (4
When the time required to reach step 5) has elapsed, press the start button (81). If the start button (81) is pressed (step +1) and mode 4 is set (step (6)), check whether the printing time settings in steps (6) to (9) have been completed (step ( I4)), check whether there are any errors in the settings (step (15)'), and if necessary, check whether the measurement of each absorbance in mode 2゜3 has been completed to make sure there are no errors in the confirmation. If the printer (to) rMODE 4 GOJ
(step (161)), and proceed to measurement at start (step (1st edition)).If the printing time setting has not been completed or there is an error in the setting, print an error (step (161)). (1η) Return to step (1).

In the measurement at the start, first, the cell (4) (451) is positioned at the measurement position, the output of the spectrophotometer (51) is read into the register (68), and the cell (451) in the area (M3) is read.
The absorbance is calculated by calculating the difference between the blank absorbance and the standard solution absorbance.

Calculate the elution rate by determining the ratio. 03) (C
) Calculate the calculated absorbance and elution rate in the same way for each cell, and print these using printer G for each w to (C) (step (19)) (see Figure 9). Store in (M5) to (M7). After this, check whether the initial print setting time (5 minutes in this example) has elapsed by the output of the timer (step -).
, if the sampling time (measurement time is 3) has not elapsed.
If it is 0 minutes, check whether 15 seconds have elapsed (step Q1). The sampling time may be measured by a timer σe, by counting the black vines of the CPUt651, or by using an appropriate area of the RAM- as a timer. If the sampling time has elapsed, read the output of the spectrophotometer (51) every cell (49 in Calculated absorbance is obtained by subtracting the cell blank absorbance (Eliya (M3)) from the measured absorbance, and the elution rate is calculated by dividing the calculated absorbance by the standard solution absorbance (Eliya (M4)) and multiplying by 100. @), Elijah (M
5) ~ (M7), remember each hometown (step @).

Then, check whether the measurement for all sample points (120 in this example) has been completed (step @) 1
．． If not finished, return to Gf step diarrhea. ct (step 120)) when the print setting time has been reached, and as in step @(8), each sample (g) to (C
), the calculated absorbance and elution rate are calculated based on the measured absorbance (step (231)), and these are printed together with the print setting time (step (product)) (Fig. 9). ).Then, check whether the processing has been completed for all print setting times (step (251), and if it has not been completed, return to step -.
Repeat the process from ~ ■, and repeat the process from step (2) to # every time the print setting time C24) is reached, and when the process is completed for all print setting times (step (2)), step ( ) and move to '1・l.

When the processing is completed for all sampling points (step c!s), print [EN DJ] (step (
311).

The operator then presses the start button ship (step C
(11) Read the data of the specimen specified by this button (2) from the area (M5) (M6) or (M7) and draw a graph of the elution rate using the x-Y-recorder (Step ■) . Then, if the reset button is pressed all the way (step ■), all processing ends. FIG. 10 shows a graph showing the temporal change in elution rate drawn by an X-Y recorder.

In the above example, the control of positioning to the measuring cell (a/me measurement i position (goods) is not illustrated, but this control is performed when the position detection signal from the limit switch (goods) is input. A method that stops driving the motor and starts counting a certain period of time, and then, when the certain period of time has elapsed, drives the motor again until a detection signal is output from the next limit switch. This can be easily achieved by

In addition, in the above embodiment, the calculated absorbance and elution rate are printed for each sample (2) to (C) at each print setting time, but as shown in FIG. )
It is also possible to print separately for each of (C) to (C).

In this example, the cell blank value and the standard value are measured and stored, and the absorbance of the dissolved solution of the main drug in the formulation is measured at predetermined intervals. Subtract the stored cell blank value from this measured value, divide this subtraction result by the standard value to automatically determine the elution rate, and print out the calculated elution rate using a printer or print it on an X-Y recorder. Since the graphs are drawn using , a series of test processes can be performed quickly with simple operations.

Needless to say, the present invention can be applied to dissolution tests for soft capsules, etc., and to measurement of changes in concentration of other solutions.

As described above, in the present invention, a plurality of measurement cells are arranged in a line on a movable table, a concentration measuring device is provided at a position overlooking a desired location on the movable table, and the movable table is intermittently sent.
The measurement cells on the movable table are sequentially transferred to the measurement position and positioned.

Since the measurement cells are arranged in a straight line, the arrangement space only needs to be as long as the length of the arrangement of measurement cells, and is therefore extremely small. Therefore, it is possible to measure a large number of specimens at once.

[Brief explanation of the drawing]

Fig. 1 is a block diagram showing the overall arrangement of the dissolution test device, Fig. 2 is a block diagram showing the solution flow path, Fig. 3 is a block diagram showing the electrical configuration of the dissolution test device, and Fig. 4 is a block diagram showing the electrical configuration of the dissolution test device. A diagram showing a graph drawn by a recorder, FIG. 5 is a block diagram showing an example of controlling the dissolution test device by a CPU, FIG. 6 is a front view of the operation panel, and FIG. 7 is a diagram showing the contents of the RAM.
FIG. 8 is a flow chart showing the procedure for performing a dissolution test;
Figure 9 is a diagram showing the content printed by the printer,
FIG. 0 is a diagram showing a graph drawn by the X-Y recorder, and FIG. 11 is a diagram showing another example of the content printed by the printer. 13... Container for sample dissolution, +441 @Φ・Pump,
Sir...Measuring cell, -...Moving table, (51)...
Spectrophotometer, @...Plate cam, (Foundation)...Limit...
Switch, ω...Driver, @@...Recorder, -
...-Motor, t[i51 ”” CP TJ SFl
mmm printer. Figure 7 RAM67

Claims (1)

[Claims] +11 - A movable moving table that supports a plurality of measuring cells arranged in a row, the moving table is intermittently sent in the direction in which the measuring cells are arranged, and the moving table is moved after all the measuring cells have been transferred. A drive device that returns the table to its original position and repeats the transfer operation at a predetermined period, and is placed at a desired location on the movement path of the measurement cell, and measures the concentration of the solution in each measurement cell in synchronization with the intermittent feeding of the movement table. A continuous solution concentration measuring device comprising: a concentration measuring device for measuring; and a recording device for recording data regarding the measured concentration for each measurement cell. (2) A device for measuring temporal changes in the dissolution rate of specific components contained in a sample, which includes multiple containers for dissolving the sample, and a measurement cell that corresponds to each dissolution container. The concentration measuring device is provided with a feeding mechanism that circulates the solution, and the concentration measuring device measures the concentration of a specific component eluted in the solution in the measurement cell. Continuous measurement device. (3) A storage device for storing the blank value measured by the concentration measuring device and the standard concentration of the standard solution, and for each measurement cell, subtracting the blank value from the measured value, dividing the result of this subtraction by the standard concentration, A continuous solution concentration measuring device according to claim 11.1, comprising: an arithmetic device for calculating a ratio to a standard concentration; and a recording device for recording the calculated ratio.