JPS6338097B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a dissolution test device for measuring the degree of dissolution of solid preparations such as tablets and capsules into various solvents.

As is well known, dissolution tests for various solvents are extremely important as a means of quality evaluation of solid preparations. In this dissolution test, a solid preparation is immersed in a solvent and the elution amount of the active ingredient is measured using a spectrophotometer.The elution of the active ingredient can be determined by graphing the changes in the elution amount of the active ingredient over time. It is possible to understand the behavior, that is, the dissolution rate. Such dissolution test methods are stipulated in the 10th edition of the Japanese Pharmacopoeia Dissolution Test Methods. i.e. this 10th
According to the revised Japanese Pharmacopoeia, solid preparations such as tablets and capsules are placed in various solvents at 37°C, a portion of the solvent solution is collected over time, and the absorbance or fluorescence is measured using a spectrophotometer. Measure the light intensity and measure the degree of dissolution of the solid preparation. Then, for each sample collection, the same amount of eluate was collected in advance at 37°C ±
It is supposed to add a solvent (test solution) heated to 0.5°C.

By the way, as for the dissolution test method mentioned above,
A continuous circulation flow is used to guide the solvent solution from the test container containing the solid preparation and the solvent solution to the measurement cell containing the liquid to be measured in the spectrophotometer, and then continuously returns the solvent solution from the measurement cell to the test container. The so-called flow method, in which a liquid is allowed to flow and measurements are taken at intervals, and the other is the flow method, in which a predetermined amount of solvent solution is collected from a test container into an external test tube, and then transferred to a measurement cell, such as a spectrophotometer, for measurement. , and the non-flow method (hereinafter referred to as the fractionation method in this specification), which repeats a series of steps of replenishing the test container with another test liquid after collection. The latter fraction method is attracting attention because of the relationship.

As shown in FIG. 1, the conventionally proposed testing apparatus for this fraction method basically sucks the solvent liquid 2 through a suction nozzle 3 that is immersed in the solvent liquid 2 in a test container 1. This is discharged into an external test tube 7 through a conduit 4 and a suction pump 5 through a discharge nozzle 6, and the solvent solution in this test tube 7 is transferred to a measurement cell of a spectrophotometer for measurement. Aspirate replenishment solvent solution from
There is one in which a replenishment solvent solution is injected into the test container 1 through a replenishment suction nozzle 9, a replenishment line 10, and a replenishment pump 11. However, this type of device has the following problems. In other words, when measuring by suctioning fine particles of a non-eluting substance such as a substance for immobilizing a solid preparation when collecting a solvent solution from the test container 1, the particles may cause turbidity in the liquid. Normally, a filter 12 is attached to the tip of the suction nozzle 3 to prevent such solid particles from being sucked in because measurement errors occur, but in the proposed device, sampling (suction collection) is performed several times. If you do that filter 1
2 becomes clogged, making it difficult for the solvent to flow.
There is a problem that the amount of sample becomes inaccurate, and the effort required to replace the filter cannot be ignored. And usually also 1 part of the solvent solution from the test container 1
It is necessary to replenish the same amount of replenishment solvent every time the sample is collected, but in the proposed device, there are differences in characteristics between the pump 5 for suction sampling and the replenishment pump 11, and the conduit for suction sampling. 4 and supply pipe 10
The amount of suction collected and the amount of replenishment often differ due to differences in the effects of the tube wall and other factors, which may lead to inaccurate measurements.

The main object of the present invention is to provide a fraction-type dissolution test device that can effectively solve the above problems.

That is, the dissolution test device of the present invention basically aspirates the solvent solution in the test container and discharges it into an external test tube for measurement, while also replenishing the solvent solution in the reserve container into the test container. The main purpose of this project is to improve the means for transferring the solvent liquid to prevent the clogging of the filter as described above, as well as to eliminate the error between the amount of suction and the amount of replenishment due to the characteristics of the pump and the influence of the pipe wall. This is the purpose. A second object of the present invention is to provide a dissolution test device capable of performing not only fraction measurement but also flow measurement (which is different from the conventional flow method).

Specifically, in the dissolution test apparatus of the first invention, the solvent liquid transfer means includes a main suction nozzle immersed in the solvent liquid in the test container, and a discharge nozzle for discharging the solvent liquid into the test tube. , a main pipe connecting the main suction nozzle and the discharge nozzle, and a pump that can operate in both forward and reverse directions and is provided in the middle of the main pipe.
a replenishment suction nozzle that is immersed in the replenishment solvent solution in the reserve container, a replenishment pipe line that is continuous with the replenishment suction nozzle, and a pump that is disposed between the pump in the main pipe line and the discharge nozzle and that is in the main pipe line. The present invention is characterized in that it is configured to include a flow path switching device that selectively switches the side flow path to the discharge nozzle side flow path of the main pipe line and the supply pipe line. According to such a device, by switching the flow path switching device and reversing the operating direction of the pump, the solvent solution can be directed to the same nozzle (suction nozzle) in opposite directions during the solvent solution suction collection process and the replenishment process. This prevents clogging of the filter at the tip of the suction nozzle, and by using the same pump and sharing most of the flow path in the suction sampling process and the replenishment process, the pump It is possible to reduce the influence of differences in characteristics and differences in tube walls of the flow path.

Further, in the dissolution test apparatus of the second invention, the solvent liquid transfer means includes a main suction nozzle and a circulation discharge nozzle that are immersed in the solvent liquid in the test container, and a discharge nozzle for discharging the solvent liquid into the external test tube. A main conduit connecting the nozzle, a replenishment suction nozzle immersed in the replenishment solvent solution in the preliminary container, the main suction nozzle and the discharge nozzle, and a forward and reverse bidirectional operation provided in the middle of the main conduit. a flow path switching device provided between the pump and the discharge nozzle in the main pipeline, a circulation pipeline communicating between the circulation discharge nozzle and the flow path switching device, and the replenishment suction nozzle. and a supply pipe communicating between the flow path switching device and the flow path switching device, and the flow path switching device connects the flow path on the pump side of the main pipe to the flow path on the discharge nozzle side of the main pipe. It is configured to be able to switch between three states: a connected state, a state in which the flow path on the pump side of the main pipe is connected to the supply pipe, and a state in which the flow path on the pump side of the main pipe is connected to the circulation pipe. It is characterized by the fact that With this configuration, as in the first invention, it is possible to prevent clogging of the filter, eliminate the effects of differences in pump characteristics and pipe walls, and also to prevent the filter from clogging. Before (sampling), the solvent solution can be circulated through the flow path to remove the influence of the liquid remaining in the flow path during the previous sampling, thereby reducing measurement errors. If a part of the sample is made removable, measurements based on the flow method can be performed by directly guiding the sample from that part to the flow cell of the spectrophotometer.

The elution test apparatus of the present invention will be explained in more detail below with reference to FIG. 2 and subsequent figures.

FIG. 2 shows the principle structure of a main body portion 20 of a dissolution test device according to an embodiment of the present invention.
A test container constant temperature bath 21 is provided inside this device main body portion 20.
A test container 22 for accommodating a specimen (solid preparation) 26 to be measured for dissolution and a solvent solution 27 is inserted into the inside of the test container 22 from above. A stirring spindle 23 serving as stirring means is inserted into the test container 22 from above, and the stirring spindle 23 is configured to be rotated by a motor _M1 . Note that the stirring spindle 23 and the motor _M1 are supported so as to be movable up and down by a lifting support mechanism 24, which will be described later. Further, a reserve container 25 for accommodating a replenishing solvent solution 27' is disposed inside the main body portion 20.
The solvent liquid 27' in the preliminary container 25 and the constant temperature liquid 28 in the test container constant temperature bath 21 are maintained at a constant temperature by a temperature regulator (not shown). Magnetic stirrers 29 are provided at the bottom of the preliminary container 25 and the bottom of the test container constant temperature bath 21 to equalize the internal liquid temperature, and these stirrers 29 are operated by motors such as _M3 . Rotary drive mechanism 3 consisting of
It is configured to be rotated by 0.

Further, a main suction nozzle 31 and a circulation discharge nozzle 32 are inserted into the test container 22 from above, and a filter 33 is inserted at the tip of the main suction nozzle 31.
is removably attached. On the other hand, a discharge nozzle 34 extends outside the device main body portion 20, and this discharge nozzle 34 and the main suction nozzle 31
are connected by a main pipe 35, and the main pipe 3
A pump 36 that can be driven in both forward and reverse directions is disposed in the middle of the pump 5. Between the discharge nozzle 34 and the pump 36 in the main conduit 35, a first switching valve 37A and a second switching valve 37B are provided as a flow path switching device 37 in that order from the discharge nozzle 34 side. On the other hand, the circulation discharge nozzle 32 is connected to the first switching valve 37A via a circulation line 38, and a portion 38A of the circulation line 38 is drawn out to the outside of the main body portion 20, as will be described later. It is configured to be detachable so that the part can be replaced when measuring using the flow method. Further, a replenishment suction nozzle 39 is inserted into the reserve container 25 from above, and this replenishment suction nozzle 39 is connected to the replenishment pipe line 4.
0 to the second switching valve 37B. Here, the first switching valve 37A is configured to selectively switch the flow path on the pump 36 side of the main line 35 to either the flow path on the discharge nozzle 34 side of the main line 35 or the circulation line 38. and also the second
The switching valve 37B is configured to selectively switch the flow path on the pump 36 side of the main pipe line 35 to either the flow path on the discharge nozzle 34 side of the main pipe line 35 or the supply pipe line 40. . Therefore, as a whole of the flow path switching device 37, the flow path on the pump 36 side of the main pipe line 35 is connected to the discharge nozzle 34 of the main pipe line 35.
It is configured so that it can be selectively switched to any of the above three states: a state where it is connected to the flow path on the side of There is.

The main suction nozzle 31 and the circulation discharge nozzle 32 are provided with a nozzle elevating device 41 for elevating them (however, in the illustrated example, the main pipe line 35
and the circulation line 38). This nozzle lifting device 41 is driven by a pulse motor _M2 , and is configured to be able to be lowered to a preset or selected position using a numeric keypad, digital switch, or the like. Further, the discharge nozzle 34 is connected to the device main body portion 2.
On the outside of 0, there is a position for discharging the solvent liquid into a test tube 42 for storing the solvent liquid as a measurement sample, and a position for discharging the solvent liquid into a waste liquid container 43 before collecting the solvent liquid as described later. The discharge nozzle is configured to be switched between positions by a discharge nozzle movement switching means 44. Furthermore, between the preliminary container 25 and the test container 22, in addition to the above-mentioned respective pipelines, there is an initial injection conduit for injecting the solvent solution from the preliminary container 25 into the test container 22 at the beginning of the measurement. 45 and a pump 46 are provided. Further, an electric control section 47 is attached to the device main body section 20 to control the operation of each section thereof.

FIG. 3 shows an example of the appearance of the device main body portion 20 as described above. However, Fig. 3 shows an example in which three test containers 22, 22', and 22'' are arranged in parallel so that dissolution tests can be performed on three types (or three) of specimens (solid preparations) at the same time. .
In this case, the piping system is connected to each test vessel 22, 22',
22'', but the drive mechanism of each switching valve and pump is usually common, and as shown in the figure, each stirring spindle 23, 23',
23'' so as to be able to rise and fall is also common, a nozzle lifting device 41 is also common, and a spare container 25 (not visible in FIG. 3) is also common.

FIG. 4 conceptually shows an example of the coupling relationship between the above-mentioned triple device main body portion 20 and other portions when performing a fraction type measurement. In FIG. 4, three test containers 22, 2
The three discharge nozzles 34, 34', 34'' drawn out from the main body portion 20 having the discharge nozzles 2', 22'' are supported by a discharge nozzle switching means 44. This discharge nozzle switching and moving means 44 moves the discharge nozzles 34, 34', 34'' to the upper position of the waste liquid container 43 and to the test tube rack 49 in the automatic sampler 48.
This is for switching between positions where the solvent solution can be injected into the test tubes 42 housed in the test tubes 42.... In the illustrated example, the automatic sampler 48 has only one test tube rack 49 disposed therein to simplify the drawing, but in reality it accommodates a large number of test tube racks 49. The rack 49 is sequentially moved by an external electric signal, and new test tubes 42 are successively introduced into the discharge nozzles 34, 3.
It is preferable that the test tubes 42 are placed at a position to receive the solvent liquid from the automatic sampler 4' and 34'', and the test tubes 42 that have received the solvent liquid are sequentially brought to the collection position described below. The sampling nozzle 51 of the automatic sample sampling device 50 is inserted into the sample liquid, and the sample liquid (solvent liquid) is sucked and collected.The sample liquid is injected into the cell of the spectrophotometer 52, and the absorbance or fluorescence intensity is measured. The measurement results are recorded and displayed on the recording/displaying device 53.The specific configurations of the automatic sampler 48, automatic sample collecting device 50, spectrophotometer 52, and recording/displaying device 53 described above are the same as known ones. It is sufficient to have a configuration, and the details thereof will be omitted.

Next, the operation of measuring by the fraction method using the apparatus of the above embodiment will be explained with reference to the time chart of FIG. 5 and FIGS. 6A to 6D. The operation of the main body part 20 of the apparatus is exactly the same whether it is a single type (when there is one test container) or a triple type. Explain by quoting.

First, when a power switch (not shown) is turned on, rotation of the stirrer 29 is started, and a temperature regulator (not shown) is activated to control the temperatures of the preliminary container 25 and the test container thermostatic chamber 21 to a constant temperature. Then, when a measurement start switch (not shown) is activated, the stirring motor _M1 is activated, the rotation of the spindle 23 is started, and at the same time, a timer (not shown) that measures the total measurement time is activated. Then, a sampling command signal Ps is given at a sampling interval set in advance on the numeric keypad, digital switch, or selection switch. Note that in the initial state, the main suction nozzle 31 and the circulation discharge nozzle 32 are in the raised position. Also, the first switching valve 3
7A is in a state where the flow path on the side of the pump 36 is connected to the side of the circulation pipe 38, and the second switching valve 37B
is in a state where the flow path on the side of the pump 36 is connected to the side of the discharge nozzle 34, and furthermore, the discharge nozzle switching movement means 44 connects the flow path on the side of the pump 36 to the side of the discharge nozzle 34, 34', 3.
4'' is positioned above the waste liquid container 43.

If the first sampling command signal Ps is given at the preset sampling interval as described above,
The pulse motor M ₂ of the nozzle lifting device 41 rotates, and the main suction nozzle 31 and the circulating discharge nozzle 32
, the pulse motor M ₂ rotates by the number of pulses corresponding to the preset lowering position for these nozzles, and when the nozzles 31 and 32 reach the set positions, the pulse motor M ₂ stops rotating. That is, the tips of the nozzles 31 and 32 are immersed in the solvent solution 27 in the test container 22 to a predetermined depth.

Then, as shown in period A in FIG.
operates in the forward direction, that is, in the direction of suctioning the solvent liquid 27 from the main suction nozzle 31, and sucks up the solvent liquid 27 into the main pipe line 35, as shown in FIG. 6A. This solvent liquid is transferred from the second switching valve 37B to the first switching valve 37A.
through the circulation pipe 38 and the circulation discharge nozzle 3
2 and returned to the test container 22. This circulation process period A can be set in advance by a program.

Simultaneously with the end of the above-mentioned circulation process period A, the operation of the pump 36 is stopped, and in conjunction with this, the first switching valve 37A is switched to the discharge nozzle 34 side. After this switching is completed, the pump 36 operates in the forward direction again as shown in period B in FIG. 5, and the solvent liquid 27 is sucked up from the main suction nozzle 31 as shown in FIG. 6B.
This solvent liquid is transferred to the second switching valve 37B and the first switching valve 37.
A, the solvent is discharged from the discharge nozzle 34, but since the discharge nozzle 34 is located on the side of the waste liquid container 43 at this time, the solvent liquid is discarded without being subjected to spectroscopic analysis. When such a waste process period B has elapsed, the operation of the pump 36 is stopped and at the same time a discharge nozzle switching movement command pulse P _M is outputted, whereby the discharge nozzle switching movement means 44 is operated and the discharge nozzle 34 is is moved from the position of the waste liquid container 43 to the position of the test tube 42 and inserted into the test tube 42. Such a discharge nozzle switching period is indicated by period C in FIG. 5.

Then, as shown in period D in FIG.
operates again in the normal rotation direction, sucks up the solvent liquid 27 from the main suction nozzle 36 as shown in FIG. 6C, and transfers this solvent liquid to the second switching valve 37B, the first switching valve 37A,
It is injected into the test tube 42 through the discharge nozzle 34.
That is, sampling is performed. Then, when the pump 36 rotates for a time corresponding to a predetermined injection amount, the pump 36 stops, and the sampling period D ends.

After sampling is completed as described above,
The discharge nozzle switching movement command pulse P _M ' is outputted again, thereby operating the discharge nozzle switching movement means 44, and the discharge nozzle 34 returns from the position of the test tube 42 to the position of the waste liquid container 43. Thereafter, a measurement operation command signal P _A is output as shown in the bottom row of FIG. This measurement operation command signal first moves the test tube rack 49 in the automatic sampler 48, and the test tube 42 into which the solvent solution 27 has been injected reaches the collection position.When a position sensor (not shown) detects this, the collection nozzle 51 is inserted into the test tube 42 by the automatic sampling device 50, and the solvent solution in the test tube is sucked into the measurement cell in the spectrophotometer 52, and the absorbance or fluorescence intensity is measured by the spectrophotometer 52. and its value is recorded and displayed. When the measurement is completed, the automatic sampling device 50 pulls up the sampling nozzle 51 from the test tube 42 .

On the other hand, when the sampling period D ends, the first switching valve 37A returns to the circulation pipe 38 side, and the second switching valve 37B returns to the pump 36 side.
The side flow path is switched to the state where it is connected to the supply pipe line 40 side. When the switching of the second switching valve 37B is completed, the pump 36 starts operating in the opposite direction as shown in period E in FIG. The replenishment solvent liquid 27' is sucked up through the replenishment pipe 40, the second
The solvent solution is supplied into the test container 22 from the suction nozzle 31 via the switching valve 37 and the main pipe 35. This replenishment period E may be the total time of the above-mentioned disposal process period B and sampling period D.

When the above-mentioned replenishment period E ends, the second switching valve 37B switches and returns to the original state at the same time, and the pulse motor _M2 of the nozzle lifting device 41 returns to rotation, and the main suction nozzle 31 and circulation discharge nozzle 32
returns to rise.

After this, if the sampling command signal P _S is applied again, the same operation as described above is repeated. Note that the time required for the measurement operation by the spectrophotometer is usually sufficiently shorter than the sampling interval, and therefore the measurement operation is sufficiently completed before the next sampling command signal is given.

As described above, measurements are performed many times at preset sampling intervals, and when the preset total measurement time has elapsed, the entire operation is terminated by a signal from the timer. Furthermore, the pump 46
is for initially filling the test container 22 with the solvent 27 from the preliminary container 25, and is normally not operated during the measurement period.

Among the above-mentioned processes, in the circulation process (period A), the previously sampled solvent solution adheres to the pipe wall, especially the pipe wall between the main suction nozzle 31 and the first switching valve 37A in the main pipe line 35. This is to remove any remaining effects. In other words, the solvent solution with a low elution concentration usually remains attached to the tube wall due to the previous sampling, so if you sample it as is, there is a risk that the concentration will be thinner than the actual concentration, but once the solvent solution is circulated. By doing so, the effect can be significantly reduced. In addition, if only this circulation process is used, there is a possibility that the previous solvent solution may still remain between the first switching valve 37A and the discharge nozzle 34, and in order to remove the influence, the next discharge process (period B) is performed. Then, the affected solvent solution is discarded, and sampling (period D) is performed for the first time. On the other hand, when the solvent liquid 27 in the test container 22 is sucked up by the main suction nozzle 31 in each process of circulation, discharge, and sampling, the filter 33 at the tip of the main suction nozzle 31 is clogged as described above. However, in the replenishment process (period E), by flowing the replenishment solvent solution 27' in the preliminary container 25 backwards into the main suction nozzle 31, the filter 3
It is possible to eliminate or reduce the clogging caused in step 3. Therefore, the filter 33 is less likely to be clogged, and as a result, it is possible to prevent a reduction in the amount of sample to be collected and an increase in measurement errors, and to extend the service life of the filter 33, thereby reducing the effort required to replace it. Can be done.

In addition, in the case of a triple system as shown in FIG. 3 or FIG. 4, different solvent solutions are simultaneously injected into three test tubes during the sampling process, and in this case, the may be sequentially moved one test tube at a time and suctioned sequentially by the automatic sampling device 50, and sequentially measured by one spectrophotometer 52, or alternatively, three spectrophotometers 52 may be prepared. Then, three types of solvent solutions may be measured simultaneously. In addition, measurements using a spectrophotometer may be performed using only one wavelength, but in order to more accurately measure the degree of dissolution of the main drug in the sample (solid preparation), it is necessary to use the wavelength corresponding to the main drug. , and a different wavelength for blank value measurement. In this case, simultaneous measurement using two wavelengths may be performed, or sequential measurement (two-wavelength switching measurement) may be performed. When carrying out two-wavelength measurement in this manner, the elution amount may be determined from the difference or ratio of the absorbance or fluorescence intensity at each wavelength.

By the way, the sampling interval mentioned above may be a fixed interval from the start to the end of the test, but it is preferable to divide the period from the start to the end into several periods and set a different sampling interval for each period. . In other words, the dissolution rate of a solid drug is generally large in the early to middle stages, but tends to decrease considerably in the late stages, and when the dissolution rate becomes low, the sampling interval should be shortened as the dissolution rate increases. There's no need. Therefore, it is desirable to divide the entire measurement period as described above and set an optimal sampling interval for each period according to the elution rate for that period. Specifically, for example, the measurement period may be divided into three, and the sampling frequency or sampling interval for each period may be set using a switch or numeric keypad on the operation board, and this may be configured to be written in the RAM section of the electrical control unit. . In this case, not only the number of sampling times or the interval, but also
It is desirable that the configuration be such that the length of the divided period can also be set. Of course, if the configuration is such that both the sampling interval and the number of sampling times for each period are set, the length of each period will also be automatically set. Furthermore, the number of periods to be divided may not be fixed, and the structure may be such that the period can be divided into any number of periods.

The apparatus of the above-mentioned embodiments can be used not only for fraction-type measurements but also for flow-type measurements. In this case, as shown in FIGS. 8A and 8B, the removable portion 38 of the circulation pipe 38
A is removed, and the pipe line 5 extending from both ends of the measurement flow cell 54 of the spectrophotometer 52' is inserted into that part.
Connect 5 and 55'. Further, the first switching valve 37A maintains a state in which the flow path on the pump 36 side is connected to the circulation pipe 38 side, and the second switching valve 37B connects the flow path on the pump 36 side to the first switching valve 37A. remain connected to the side. That is, the flow path switching device 3
7 as a whole, the flow path on the side of the pump 36 is connected to the side of the circulation pipe 38, and no switching operation is performed during measurement. In this case, the main suction nozzle 31
A filter 33' is not only attached to the tip of the circulation discharge nozzle 32, but also a filter 33' is attached to the tip of the circulation discharge nozzle 32.

The measurement operation according to the flow method in the above-mentioned state is shown in the flowchart of Fig. 7 and Fig. 8A,
This will be explained with reference to B. First, as in the case of the above-mentioned fraction method, the power switch is turned on to start rotating the stirrer 29, thereby controlling the temperature. Then, a measurement start switch (not shown) is activated to operate the stirring motor _M1 , and at the same time as the stirring spindle 23 starts rotating, the timer starts operating. When a sampling command signal P _S generated at preset intervals is given, the pulse motor M ₂ of the nozzle lifting device 41 rotates.
The main suction nozzle 31 and the circulation discharge nozzle 32 descend to a preset position. The pump 36 then rotates in the opposite direction as shown in FIG. through the main suction nozzle 31 and back into the test vessel 22 . Such a circulation process G
After this has been carried out for a preset period of time, the operating direction of the pump 36 is reversed and operates in the forward direction, whereby the solvent liquid 27 in the test container 22 is sucked out from the main suction nozzle 31 as shown in FIG. 8B. The sample is then raised through the flow cell 54 in the spectrophotometer 52' and back into the test vessel 22 via the circulation exhaust nozzle 32. After such a sampling process H is performed for a preset time, the pump 36 is stopped, and at the same time, the suction nozzle 31 and the circulating discharge nozzle 32 return to the upward position. Note that in this state, the solvent liquid flows into the flow cell 54.
stays inside. After the sampling step is completed, a measurement command signal P _A ' is output, which causes the spectrophotometer 52' to operate and measure the absorbance or fluorescence intensity of the solvent solution in the flow cell 54.

After that, when the next sampling signal P _S is applied, the same operation as described above is repeated. In this way, measurements are performed many times at preset sampling intervals, and when the preset total measurement time has elapsed, the entire operation is terminated by a signal from the timer. The pump 46 operates only initially to fill the test container 22 from the preliminary container 25 with the solvent liquid 27, and is not operated during the measurement period.

As mentioned above, flow measurement using the device of the present invention differs slightly from conventional flow methods in that it uses a method in which the solvent solution is not allowed to flow into the flow cell 54 and is stopped during measurement, that is, an intermittent flow method. This is a measurement method called , and the solvent solution is flowed in the opposite direction before each sampling (circulation process). By flowing the solvent solution in the opposite direction before sampling in this way, clogging of the filter 33 at the tip of the suction nozzle 31 is prevented, and during sampling, the filter 33' at the tip of the circulating discharge nozzle 32 is prevented from clogging. Clogging is prevented. Furthermore, by stopping the flow of the solvent during measurement as described above, it is possible to reduce measurement errors due to the influence of pulsating flow or the like resulting from the characteristics of the pump.
In other words, in the conventional flow method, a flowing solvent solution is measured, so if the flow rate changes due to the characteristics of the pump, the absorbance and fluorescence intensity will differ even at the same concentration, resulting in large measurement errors. The above-mentioned problem does not occur in the intermittent flow method using the above device.

In the case of the above-mentioned intermittent flow method, as in the case of the fraction method, it is of course possible to adopt a two-wavelength switching method or a two-wavelength simultaneous measurement method. Of course, it can also be measured by

9 to 12 show a specific example of the elevating support mechanism 24 for movably supporting the stirring spindle 23 and motor _M1 shown in FIG. 2.

In FIG. 9, a hollow cylindrical column exterior body 56 is vertically fixed at a position lateral to the motor M ₁ and the spindle 23;
The frame body 57 accommodating M ₁ includes the pillar exterior body 5
6 is formed, and a hollow cylindrical lifting pipe 58 that hangs vertically downward is fixed to the lower surface of the extending part 57A. is inserted into the column exterior body 56 from above. On the other hand, the pillar exterior body 56
An annular bearing member 59 that surrounds the lifting pipe 58 and is rubbed against it is provided on the inner surface of the upper end, and an annular bearing member 59 made of an elastic material such as rubber is provided on the lower inner peripheral side of the bearing member 59. An annular friction member 60 is attached. Between the bearing member 59 and the fixed support member 61 at the lower end of the column exterior body 56, a plurality of, for example four, round guide rods 62 are vertically arranged and fixed from above and below with screws 63 and 64. It is set up. These guide rods 62 are arranged at equal intervals around the lifting pipe 58, and four semicircular notches are formed at the lower end of the lifting pipe 58 corresponding to each guide rod 62 from the outer circumferential side. Part 65
A horizontal plate-shaped guide receiving member 66 is fixed. On the other hand, a guide pipe 67 extending vertically upward from the fixed support member 61 is inserted inside the lifting pipe 58, and between the outer peripheral surface of the guide pipe 67 and the inner peripheral surface of the lifting pipe 58, A compression type coil spring 68 is provided to urge the lifting pipe 58 upward. Note that a screw hole 59A is formed in a predetermined position of the bearing member 59, and the screw hole 59A penetrates in the horizontal direction. They are screwed together.

In the lift support mechanism 24 as described above, the lift pipe 58 continuous with the frame 57 housing the motor M ₁ has its outer peripheral surface in sliding contact with the bearing member 59 and the friction member 60 and the cut of the guide receiving member 66 at the lower end. The recessed portion 65 can be moved up and down while in contact with the guide rod 62, and is always urged upward by a spring 68. Here, the frame 57 that accommodates the motor M ₁ and has the spindle 23 attached is relatively heavy, and the center of gravity of the frame 57 is located at a position relative to the motor.
It is close to the axial position of M ₁ and the spindle 23, and therefore its center of gravity is considerably distant from the central axial position of the lifting pipe 58 in the horizontal direction. Therefore, due to the gravity of the frame 57, the lifting pipe 58 tends to fall or bend toward the side where the spindle 23 is located, using the contact point between the guide receiving member 66 and the guide rod 62 as a fulcrum, and a part of its outer peripheral surface is pressed against the friction member 60, and due to the frictional force with this friction member 60, the lifting pipe 58 is stopped and held at an arbitrary position without descending (that is, without descending even if the auxiliary fixing knob 69 is loosened). will be done. Of course, the elastic force of the spring 68 also contributes to preventing the elevating pipe 58 from descending. On the other hand, when the frame body 57 is held by hand and the motor _M1 side is raised, the frictional force between the friction member 60 and the lifting pipe 58 is released to some extent, so that it is possible to raise and lower it as desired. In the end, if you raise and lower the frame 57 by raising the motor _M1 side by hand, and then release your hand at the desired position, the frame 5
It is stopped and held at that position by the frictional force caused by the gravity of the motor _M1 of No. 7, etc. Therefore, when it is necessary to remove the spindle 23 from the test container 22 in order to clean or replace the test container 22, the frame 57 can be easily raised and lowered and the raised and lowered position can be maintained. Of course, by operating the auxiliary fixing knob 69 and pressing the tip of the screw portion 69A against the outer peripheral surface of the lifting pipe 58, the position of the lifting pipe 58 can be fixed, and thus the frame 5 can be fixed.
The position of 7 can also be fixed. Furthermore, the guide receiving member 66 also serves as a stopper at the lowered position.

The embodiment shown in FIG. 2 described above corresponds to the second invention of the present application, and the circulation pipe 38 and the first switching valve 37 are
If A is removed, it becomes an embodiment of the first invention. That is, in this case, the flow path switching device 37 is configured with only the second switching valve 37B, in other words, the flow path on the pump 36 side of the main line 35 is connected to the supply line 40 side, and the flow path on the side of the discharge nozzle 34 is connected. The configuration is such that the state is selectively switched to either the state where the state is connected to the flow path. In this way, the measurement operation of the fraction method in the case of the first invention in which the circulation pipe 38 is omitted is the same as the operation in the case of the second invention described above, except that the circulation step A is omitted.
Other operations are exactly the same. In this case as well, in the case of the second invention, the effect of the solvent solution remaining on the tube wall during the previous sampling can be minimized by the discharge process B, and clogging can be prevented by the replenishment process E. is the same as However, if the circulation pipe 38 is omitted, unlike the case of the first invention, it cannot be used as is for intermittent flow measurement.

Furthermore, in the above embodiment, the stirring spindle 2
3, the solvent solution in the test container 22 is stirred, but in some cases, the basket containing the solid preparation (sample) may be rotated in the solvent solution in the test container 22. Of course.

As is clear from the above description, according to the dissolution test device of the first invention, a pump that can be operated in both forward and reverse directions is used as the solvent liquid transfer means to collect and aspirate the solvent liquid from the test container (sampling). The same pump is used in the process of replenishing the solvent solution into the test container (replenishment process), and most of the flow paths in the sampling process and replenishment process are common. There is little risk of differences between the sampling amount and the replenishment amount of the solvent solution due to differences in pump characteristics during the replenishment process or differences in the influence of the pipe wall of the flow path, etc., and therefore elution is accurate and stable. Tests can be conducted. Further, according to the dissolution test device of the first invention, since the solvent solution can flow in the opposite direction in the replenishment process to the main suction nozzle for sucking the solvent solution from the test container, the dissolution test device is installed at the tip of the main suction nozzle. Therefore, it is possible to prevent or reduce the occurrence of clogging of the filter, which reduces the amount of sample collected due to the clogging of the filter, and prevents the measurement error from increasing. It can be reduced.

Further, according to the elution test device of the second invention, in addition to obtaining the same effects as the first invention, the solvent solution can be circulated through the channel before the sampling process (in the embodiment, before the discharge process). Therefore, sampling before sampling removes the influence of the liquid remaining in the flow path, resulting in more accurate measurements. In addition, in the case of the second invention, if a part of the circulation pipe is configured to be detachable, intermittent flow measurement is also possible by directly connecting that part to the measurement cell of the spectrophotometer. become.

[Brief explanation of the drawing]

FIG. 1 is a schematic diagram showing the principle of an example of a conventional fractionation type dissolution test device, FIG. 2 is a schematic diagram showing the main body of a dissolution test device according to an embodiment of the present invention, and FIG. FIG. 4 is a perspective view showing an example of the external appearance of the main body of the dissolution test device of the present invention; FIG. 4 is a schematic diagram showing an example of the coupling relationship between the main body of the dissolution test device of the present invention and other parts; FIG. 2 is a time chart showing the operation of each part when performing a fractional measurement using the apparatus of the embodiment shown in FIG. A schematic diagram showing the situation step by step, FIG. 7 is a time chart showing the operation of each part when performing intermittent flow measurement using the apparatus of the embodiment shown in FIG. 2, and FIGS. 8A and B are FIG. 9 is a schematic diagram showing step by step the state of the main body of the device corresponding to the time chart in FIG. 7. FIG. A vertical cross-sectional view showing an example, FIG. 10 is an enlarged cross-sectional view taken along the line XX in FIG. 9, FIG. 11 is an enlarged cross-sectional view taken along the XI-XI line in FIG. 9, and FIG. and the 11th
FIG. 2 is a sectional view taken along line XII-XII in the figure. 22... Test container, 23... Stirring spindle (stirring means), 24... Lifting support mechanism, 25... Reserve container,
26... Specimen (solid preparation), 27... Solvent solution, 27'...
Replenishment solvent liquid, 31... Main suction nozzle, 32... Circulation discharge nozzle, 33, 33'... Filter, 34... Discharge nozzle, 35... Main pipe line, 36... Pump, 37...
Flow path switching device, 38... Circulation pipe line, 38A... Detachable portion, 39... Supply suction nozzle, 40... Supply pipe line, 41... Nozzle lifting means, 42... Test tube.

Claims (1)

[Scope of Claims] 1. A test container containing a sample and a solvent solution, a preliminary container containing a replenishing solvent solution, a stirring means for stirring the solvent solution in the test container, and a solvent solution in the test container. and a solvent liquid transfer means for sucking and discharging it into an external test tube and replenishing the solvent liquid in the preliminary container into the test container,
In the dissolution test device that measures the degree of elution of a substance from the specimen by measuring the absorbance or fluorescence intensity of the solvent solution discharged into the test tube, the solvent solution transfer means is immersed in the solvent solution in the test container. a main suction nozzle for discharging the solvent solution into the test tube, a main conduit connecting the main suction nozzle and the discharge nozzle, and a forward and reverse bidirectional operation provided in the middle of the main conduit. a replenishment suction nozzle immersed in the replenishment solvent liquid in the reserve container, a replenishment line continuous with the replenishment suction nozzle, and a supply line disposed between the pump and the discharge nozzle in the main line. and a flow path switching device that selectively switches the flow path on the pump side of the main pipe to either the flow path on the discharge nozzle side of the main pipe or the supply pipe. Dissolution test equipment. 2. The elution test device according to claim 1, wherein a filter is removably provided at the tip of the main suction nozzle. 3. The elution test device according to claim 1, wherein the main suction nozzle is configured to be movable up and down. 4. A test container containing a sample and a solvent solution, a preliminary container containing a replenishment solvent solution, a stirring means for stirring the solvent solution in the test container, and a device for sucking and stirring the solvent solution in the test container. a solvent liquid transfer means for discharging into an external test tube and replenishing the solvent liquid in the preliminary container into the test container,
In the dissolution test device that measures the degree of elution of a substance from the specimen by measuring the absorbance or fluorescence intensity of the solvent solution discharged into the test tube, the solvent solution transfer means is immersed in the solvent solution in the test container. a main suction nozzle and a circulation discharge nozzle, a discharge nozzle for discharging the solvent solution into the external test tube, a replenishment suction nozzle immersed in the replenishment solvent solution in the preliminary container, and a main suction nozzle. A main pipe line connecting the discharge nozzle, a pump provided in the middle of the main pipe line and capable of operating in both forward and reverse directions, and a flow path switching device provided between the pump and the discharge nozzle in the main pipe line; The structure includes a circulation pipe that communicates between the circulation discharge nozzle and the flow path switching device, and a replenishment pipe that communicates between the replenishment suction nozzle and the flow path switching device, and The channel switching device connects the channel on the pump side of the main channel to the channel on the discharge nozzle side of the main channel, connects the channel on the pump side of the main channel to the supply channel, and connects the channel on the pump side of the main channel to the supply channel. 1. An elution test device characterized in that it is configured to be able to switch between three states: a state in which a flow path on the pump side of the pump is connected to a circulation pipe. 5. The dissolution test device according to claim 4, wherein the main suction nozzle and the circulation discharge nozzle are configured to be movable up and down. 6. The elution test device according to claim 4, wherein a filter is removably attached to the tip of the main suction nozzle. 7. The elution test device according to claim 4, wherein a part of the circulation pipe is configured to be detachable. 8. The elution test device according to claim 7, wherein filters are removably attached to the tips of the main suction nozzle and the circulation discharge nozzle, respectively.