Device for monitoring drug diffusion across interface in real time and detection method thereof

Abstract

The present application relates to experimental equipment technical field, disclose a kind of real-time monitoring drug interfacial diffusion device and its detection method, by the two same frequency same direction stirring device of independent design, in diffusion cell it constructs an ideal mass transfer model, phase concentration is uniform, interfacial stability is stable, make the concentration change of drug in phase only reflect the interfacial diffusion process of drug.And by real-time monitoring the absorbance change in phase obtains the concentration change information of drug, to obtain the interfacial diffusion rate of drug per unit area in real time accurately.The present application includes a kind of real-time monitoring drug interfacial diffusion method and device, can accurately reflect the dynamic process of molecular diffusion at liquid-liquid interface, thereby has extensive application value.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of experimental equipment, and particularly relates to a device for real-time monitoring of drug interfacial diffusion and a detection method thereof. BACKGROUND

[0002] The diffusion and mass transfer of substances between fluids are very common in the fields of medicine, chemical industry and the like. According to the composition of the diffusion system, the diffusion and mass transfer can be roughly divided into internal mass transfer of fluid, binary fluid diffusion and mass transfer of multi-component fluid. For fluid diffusion, the diffusion process of substances in fluid is described by Fick's law [1] and Maxwell-Stefan diffusion model [2] . These theories are first established for a unary ideal gas, and then are extended to binary or multi-component gas, and the state of matter is changed from gas to liquid or even fluid-structure coupling. However, the diffusion process of substances in binary or multi-component fluid includes the mutual collision between the same molecules and different molecules, and the mass transfer mechanism is more complex, so there is no perfect and systematic theory to describe the mass transfer in liquid phase.

[0003] The flow state of fluid can be laminar flow, transition flow and turbulent flow [3] according to the size of Reynolds number. When the flow rate increases or other conditions change, the fluid will gradually change from laminar flow with layered flow to turbulent flow with irregular flow. The motion of fluid in turbulent flow has randomness, including transverse flow and reverse motion relative to the total motion of fluid, and the transfer rate of momentum, heat and mass caused by such random motion is several orders of magnitude higher than that in laminar flow. Therefore, the formation of turbulent flow by high-speed stirring can accelerate the mass transfer of substances and improve the diffusion rate in fluid.

[0004] The ultraviolet-visible spectrophotometry is a method for quantitative analysis of a measured substance by measuring the absorbance of the measured substance at a specific wavelength. According to the Lambert-Beer law [4] , the absorbance is proportional to the concentration of the measured substance and the thickness of the absorption layer. Therefore, by continuously measuring the absorbance of a sample cell with a certain thickness, the change of the concentration of the measured substance with time can be obtained.

[0005] Drug interfacial diffusion process as a binary fluid diffusion, has extremely important significance in the field of preparation research, industrial production, not only as an important aspect of interface theory research, but also has a great influence on the prescription development and production process of preparation. For example, in the preparation of microspheres by the most commonly used O / W emulsion method, the interfacial diffusion of drug in the emulsion droplet to the external water phase is an important factor affecting the encapsulation efficiency and drug loading of microspheres. If the diffusion amount of drug at the interface is monitored, the diffusion information of drug in the emulsion process of microsphere preparation can be obtained. However, the kinetics of drug interfacial diffusion and mass transfer law are not clear and lack of accurate characterization means. SUMMARY

[0006] The technical problem to be solved by the present application is to provide a method for real-time monitoring of drug interfacial diffusion, which can accurately obtain the change of drug interfacial diffusion rate with time.

[0007] The technical problem to be solved by the present application is to provide a method for real-time monitoring of drug interfacial diffusion, which can accurately obtain the change of drug interfacial diffusion rate with time.

[0008] In order to solve the above technical problems, the technical scheme adopted by the present application is as follows:

[0009] A device for real-time monitoring of drug interfacial diffusion, characterized by comprising a diffusion cell, a bearing, a bearing seat, a transmission rod, a first magnet, a second magnet, a first magnetic stirring sleeve, a second magnetic stirring sleeve, a magnetic stirring sleeve cover, a magnetic stirrer, a light source, a monochromator and a photodetector; a second assembly composed of the magnetic stirring sleeve cover, the magnet and the magnetic stirring sleeve is arranged at the bottom of the diffusion cell; a first assembly composed of the bearing, the bearing seat, the transmission rod, the magnet and the magnetic stirring sleeve is arranged on the second assembly;

[0010] The bearing seat is provided with a bearing in the assembly, the upper end of the transmission rod is inserted into the bearing to drive the inner ring of the bearing to rotate in the bearing seat, the first magnetic stirring sleeve is tightly matched with the lower end of the transmission rod, and the first magnetic stirring sleeve drives the transmission rod to rotate coaxially; the first magnet is arranged in the clamping groove of the first magnetic stirring sleeve and is fixed; the second magnet is arranged in the clamping groove of the second magnetic stirring sleeve and is fixed, the lower part of the second magnetic stirring sleeve is located at the bottom of the diffusion cell, the magnetic stirring sleeve cover is arranged at the upper end of the second magnetic stirring sleeve and is tightly matched with the second magnetic stirring sleeve, and the two magnetic stirring sleeves rotate in the same direction and at the same frequency; the outside of the diffusion cell is transparent; the light source and the monochromator form monochromatic light which transmits through the diffusion cell and is detected by the photodetector to change the absorbance.

[0011] The magnetic stirring sleeve has a plurality of external shapes which can be replaced to provide different flow fields for mixing, and the external shape of the magnetic stirring sleeve includes but is not limited to one or a combination of a cylindrical body, an olive type, a straight cylinder with a section, a straight cylinder type, a cross shape and an eight-tooth type.

[0012] The material of the bearing seat, the transmission rod and the magnetic stirring assembly includes, but is not limited to, a combination of one or more of alumina, zirconia, titania, silicon nitride, boron carbide, polytetrafluoroethylene and silicon dioxide.

[0013] The material of the diffusion cell includes, but is not limited to, a combination of one or more of silicon dioxide and polydimethylsiloxane.

[0014] The device for real-time monitoring of drug interfacial diffusion, wherein the light source includes a combination of one or more of a tungsten lamp, a hydrogen lamp and a xenon lamp, the monochromator is a device for decomposing continuous light spectrum emitted by the light source into monochromatic light, and the photodetector includes a combination of one or more of a selenium photocell, a phototube, a photomultiplier tube and a photodiode array detector.

[0015] A method for real-time monitoring of drug interfacial diffusion, comprising the following steps:

[0016] 1) Sample addition: place the assembly composed of the magnetic stirring sleeve cover, the second magnet and the second magnetic stirring sleeve in the bottom of the diffusion cell, slowly add two mixed dispersion systems according to the density, and cover the assembly composed of the bearing, the bearing seat, the transmission rod, the first magnet and the first magnetic stirring sleeve on the diffusion cell;

[0017] 2) Start the magnetic stirrer and real-time monitor the absorbance of the liquid in the diffusion cell;

[0018] 3) Establish a standard curve of the target drug molecule at the monitoring wavelength, convert the change of absorbance with time into the change of concentration with time, and obtain the change of drug interfacial diffusion rate per unit area with time by formula ①;

[0019] Wherein formula ① is:

[0020]

[0021] Wherein, ν is the drug interfacial diffusion rate per unit area, C is the concentration of the dispersed phase in the mixed dispersion system, and S is the cross-sectional area of the diffusion cell (1).

[0022] The method for real-time monitoring of drug interfacial diffusion, wherein the two mixed dispersion systems in step 1) are a combination of one or more of molecular dispersion system, colloidal dispersion system and coarse dispersion system; the mixed dispersion system includes dispersed phase and dispersant; and the dispersants in the two mixed dispersion systems are two liquids that are partially miscible or completely immiscible.

[0023] The dispersed phase size in the molecular dispersion system is below 1 nm; the dispersed phase size in the colloidal dispersion system is between 1 nm and 1000 nm; and the dispersed phase size in the coarse dispersion system is above 1000 nm.

[0024] The working principle of the present application is as follows:

[0025] The present application provides a method for real-time monitoring of drug diffusion across an interface and a device for realizing the method.

[0026] The present application builds an ideal mass transfer model with uniform phase concentration and stable interface between phases in a diffusion cell through high-speed stirring in the two-phase fluid by using two self-designed same-frequency and same-direction stirring devices. The uniform phase concentration eliminates the measurement error caused by the mass transfer of the drug in the fluid, and the stable interface between phases makes the interfacial diffusion area of the drug stable, so that the change of the drug concentration in the phase only reflects the interfacial diffusion process of the drug. The concentration change information of the drug is obtained by continuously monitoring the absorbance change in the phase, and the real-time and accurate interfacial diffusion rate of the drug is obtained. The present application includes a method for real-time monitoring of drug diffusion across an interface and a device, which can accurately reflect the kinetic process of molecular diffusion at the liquid-liquid interface, and thus has wide application value in the fields of medicine, chemical industry and the like. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 FIG. 1 is a schematic diagram of a device for real-time monitoring of drug diffusion across an interface;

[0028] Figure 2 FIG. 2 is a schematic diagram of an assembly, wherein Figure 2 a is an upper and lower isometric drawing of a first assembly (12); Figure 2 b is an upper and lower isometric drawing of a second assembly (13); Figure 2 c is a split drawing of the first assembly (12) and the second assembly (13);

[0029] Figure 3 FIG. 3 is a sectional view of the assembly, wherein Figure 3 a is a left sectional view of the first assembly (12); Figure 3 b is a front sectional view of the first assembly (12); Figure 3 c is a left sectional view of the second assembly (13); Figure 3 d is a front sectional view of the second assembly (13);

[0030] wherein Figures 1-3The components include: a central diffusion cell (1), a bearing (2), a bearing housing (3), a transmission rod (4), a first magnet (5a), a second magnet (5b), a first magnetic stirring kit (6a), a second magnetic stirring kit (6b), a magnetic stirring kit cover (7), a magnetic stirrer (8), a light source (9), a monochromator (10), a photodetector (11), a first assembly (12), and a second assembly (13).

[0031] Figure 4 This is a graph showing the actual rotational speeds of the two magnetic stirring kits under the conditions of Example 1;

[0032] Figure 5 This is a graph showing the change in the concentration of isoniazid in the aqueous phase over time under the conditions of Example 2.

[0033] Figure 6 This is a graph showing the change in the concentration of methylprednisolone in the aqueous phase over time under the conditions described in Example 3.

[0034] Figure 7 This is a graph showing the change in the interfacial diffusion rate per unit area of ​​methylprednisolone over time under the conditions of Example 3. Detailed Implementation

[0035] The specific embodiments of the present invention will be described in further detail below with reference to the accompanying drawings and examples. The following examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[0036] Example 1

[0037] A device for real-time monitoring of drug cross-interface diffusion, characterized in that it comprises a diffusion pool 1, a bearing 2, a bearing seat 3, a transmission rod 4, a first magnet 5a, a second magnet 5b, a first magnetic stirring kit 6a, a second magnetic stirring kit 6b, a magnetic stirring kit cover 7, a magnetic stirrer 8, a light source 9, a monochromator 10, and a photodetector 11; a second assembly 13, composed of the magnetic stirring kit cover 7, the second magnet 5b, and the second magnetic stirring kit 6b, is disposed at the bottom of the diffusion pool 1; a first assembly 12, composed of the bearing 2, the bearing seat 3, the transmission rod 4, the first magnet 5a, and the first magnetic stirring kit 6a, is disposed on the second assembly 13;

[0038] Wherein the bearing 2 is arranged in the bearing seat 3 in the first assembly body 12, the upper end of the transmission rod 4 is inserted into the bearing 2 to drive the bearing 2 to rotate in the bearing seat 3, the first magnetic stirring sleeve 6a is tightly matched with the lower end of the transmission rod 4, and the first magnetic stirring sleeve 6a drives the transmission rod 4 to rotate coaxially; the first magnet 5a is arranged in the clamping groove of the first magnetic stirring sleeve 6a and is fixed; wherein the second magnet 5b is arranged in the clamping groove of the second magnetic stirring sleeve 6b in the second assembly body 13, the lower part of the second magnetic stirring sleeve 6b is located at the bottom of the diffusion cell 1, the magnetic stirring sleeve cover 7 is arranged at the upper end of the second magnetic stirring sleeve 6b, and the two magnetic stirring sleeves (6a and 6b) rotate in the same direction and at the same frequency; the outside of the diffusion cell 1 is transparent; the monochromatic light formed by the light source 9 and the monochromator 10 transmits through the diffusion cell 1, and the absorbance change is detected by the photodetector 11.

[0039] The second assembly body 13 composed of the magnetic stirring sleeve cover 7, the second magnet 5b and the second magnetic stirring sleeve 6b is placed at the bottom of the diffusion cell 1, 1800 μL of water and 500 μL of ethyl acetate are slowly added into the diffusion cell 1 in sequence, and the first assembly body 12 composed of the bearing 2, the bearing seat 3, the transmission rod 4, the first magnet 5a and the first magnetic stirring sleeve 6a is arranged on the diffusion cell 1. Figure 4 ) is recorded by using a high-speed camera (n=3, 1080p / 50fps) for 1 min.

[0040] Example 2

[0041] The second assembly body 13 composed of the magnetic stirring sleeve cover 7, the second magnet 5b and the second magnetic stirring sleeve 6b is placed at the bottom of the diffusion cell 1, 1800 μL of water and 500 μL of ethyl acetate are slowly added into the diffusion cell 1 in sequence, and the first assembly body 12 composed of the bearing 2, the bearing seat 3, the transmission rod 4, the first magnet 5a and the first magnetic stirring sleeve 6a is arranged on the diffusion cell 1. The detection wavelength is set to be 288 nm, the monitoring time is set to be 6 min, and the monitoring frequency is set to be 0.2 times / s. The magnetic stirrer 8 is started, the rotating speed is set to be 0, 400 rpm, 600 rpm, 800 rpm, 1000 rpm and 1200 rpm in sequence, the absorbance change of the drug in the water phase is recorded by the photodetector 11 (n=3, SD<0.01), and the concentration of isoniazid in the water phase with the change of time under different rotating speeds is obtained. Figure 5), it can be seen that the stirring speed of the device at 600-1200 rpm keeps the drug always in a similar interfacial diffusion process, so it can be known that stirring accelerates the internal mass transfer of the fluid, and the concentration difference on both sides of the interface is maintained stable.

[0042] Example 3

[0043] This example is used to investigate the effect of stirring to accelerate the internal mass transfer of the fluid. The second assembly 13 composed of the magnetic stirring kit cover 7, the second magnet 5b and the second magnetic stirring kit 6b is placed on the bottom of the diffusion cell 1, 1800 μL of water and 500 μL of methylprednisolone ethyl acetate solution (100 μg / mL) are slowly added into the diffusion cell 1 in turn, and the first assembly 12 composed of the bearing 2, the bearing seat 3, the transmission rod 4, the first magnet 5a and the first magnetic stirring kit 6a is arranged on the diffusion cell 1. The detection wavelength is set to 278 nm, the monitoring time is 30 min, and the monitoring frequency is 0.2 times / s. The magnetic stirrer 8 is started, the rotating speed is set to 1000 rpm, and the photoelectric detector 11 records the absorbance change of the drug in the water phase (n=3, SD<0.1). The concentration change of methylprednisolone in the water phase with time ( Figure 6 ) is obtained, and the interfacial diffusion rate of methylprednisolone per unit area with time ( Figure 7 ) is calculated.

[0044] References

[0045] [1]Thorstenson D C,Pollock D W.Gas transport in unsaturated porousmedia:The adequacy of Fick's law[J].Reviews of Geophysics,1989,27(1):61-78.

[0046] [2]Krishna R,Wesselingh J A.The Maxwell-Stefan approach to mass transfer[J].Chemical engineering science,1997,52(6):861-911.

[0047] [3]Rott N.Note on the history of the Reynolds number[J].Annual review of fluid mechanics,1990,22(1):1-12.

[0048] [4] Weismüller J A, Chanady A. Quantitative multicomponent analysis of complex mixtures by means of Full Spectrum quantitation and principal component analysis [J]. TrAC Trends in Analytical Chemistry, 1992, 11(3): 86-90.

Claims

1. A device for real-time monitoring of drug diffusion across interfaces, characterized in that, It includes a diffusion cell, bearings, bearing housings, transmission rods, a first magnet, a second magnet, a first magnetic stirring kit, a second magnetic stirring kit, a magnetic stirring kit cover, a magnetic stirrer, a light source, a monochromator, and a photodetector; A second assembly consisting of a magnetic stirring kit cover, a second magnet, and a second magnetic stirring kit is disposed at the bottom of the diffusion tank; a first assembly consisting of a bearing, a bearing housing, a transmission rod, a first magnet, and a first magnetic stirring kit is disposed on the second assembly; The first assembly contains a bearing housing with a bearing. The upper end of a transmission rod is inserted into the bearing, causing the inner ring of the bearing to rotate within the bearing housing. A first magnetic stirring assembly is tightly fitted with the lower end of the transmission rod, and the first magnetic stirring assembly drives the transmission rod to rotate coaxially. A first magnet is located and fixed in a slot of the first magnetic stirring assembly. A second magnet is located and fixed in a slot of the second magnetic stirring assembly. The lower part of the second magnetic stirring assembly is located at the bottom of the diffusion cell. A magnetic stirring assembly covers the upper part of the second magnetic stirring assembly and tightly fits it. The two magnetic stirring assemblies rotate and stir in the same direction and at the same frequency. The outside of the diffusion cell is transparent. Monochromatic light generated by the light source and monochromator passes through the diffusion cell, and the change in absorbance is detected by a photodetector.

2. The device for real-time monitoring of drug cross-interface diffusion as described in claim 1, characterized in that, The external shape of the magnetic stirring kit includes any one of the following: cylindrical, olive-shaped, straight, cross-shaped, and eight-toothed.

3. The device for real-time monitoring of drug cross-interface diffusion as described in claim 1, characterized in that, The light source includes one or more combinations of tungsten filament lamps, hydrogen lamps, and xenon lamps; the monochromator is a device that decomposes the continuous spectrum emitted by the light source into monochromatic light; and the photodetector includes one or more combinations of selenium photovoltaic cells, phototubes, photomultiplier tubes, and photodiode array detectors.

4. A method for real-time monitoring of drug diffusion across interfaces, characterized in that, The apparatus as described in claim 1 includes the following steps: 1) Sample addition: Place the second assembly at the bottom of the diffusion cell, slowly add the two mixed dispersion systems according to their density, and cover the diffusion cell with the first assembly; 2) Start the magnetic stirrer and monitor the absorbance of the liquid in the diffusion tank in real time; 3) Establish a standard curve for the target drug molecule at the monitoring wavelength, convert the change in absorbance over time into the change in concentration over time, and obtain the change in the drug diffusion rate per unit area across the interface over time using formula ①. Formula ① is: Where v is the drug diffusion rate per unit area across the interface, C is the concentration of the dispersed phase in the mixed dispersion system, and S is the cross-sectional area of ​​the diffusion cell (1).

5. The method for real-time monitoring of drug cross-interface diffusion as described in claim 4, characterized in that, In step 1), the two mixed dispersion systems are one or more combinations of molecular dispersion systems, colloidal dispersion systems, and coarse dispersion systems; the mixed dispersion system includes a dispersed phase and a dispersant; the dispersant in the two mixed dispersion systems is two liquids that are partially miscible or completely immiscible.

6. The method for real-time monitoring of drug cross-interfacial diffusion as described in claim 5, characterized in that, The dispersed particles in the molecular dispersion system are smaller than 1 nm; the dispersed particles in the colloidal dispersion system are between 1 nm and 1000 nm; and the dispersed particles in the coarse dispersion system are larger than 1000 nm.

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