Micro-flow field preparation method of dasatinib nanocrystal

Abstract

The invention discloses a micro-flow field preparation method of dasatinib nanocrystals. The method comprises the following steps: dissolving dasatinib in an organic solvent to serve as a solvent phase A; dissolving a surfactant in deionized water to serve as an anti-solvent phase B, simultaneously pumping the solvent phase A and the anti-solvent phase B into a micro-flow field device for full reaction, collecting dasatinib crystal dispersion liquid at an outlet, centrifuging to remove supernate, taking bottom precipitate, and performing vacuum drying to obtain the solid nanocrystal. According to the present invention, the micro-flow field device is adopted, the mixing process of the solvent and the anti-solvent is enhanced, the surfactant is adopted as the dispersant, the transport efficiency and the supersaturation degree of the drug molecules are regulated and controlled, the efficient preparation of the dasatinib nanocrystal is achieved, the operation is simple, the reaction speed is fast, and the safety is high.

Description

Technical Field

[0001] The invention belongs to the field of microchemical engineering, and particularly relates to a microflow field preparation method of dasatinib nanocrystals. Background Art

[0002] Dasatinib is a drug used to treat Philadelphia chromosome-positive chronic myeloid leukemia that is resistant or intolerant to imatinib mesylate. As a second-generation tyrosine kinase inhibitor, its efficacy is 325 times that of the first-generation tyrosine kinase inhibitor imatinib. It has a strong efficacy in treating chronic myeloid leukemia, and can also increase the efficacy of chemotherapy for core binding factor-positive polar myeloid leukemia. It also has a strong active inhibitory effect on various tumor cells such as ovarian cancer and breast cancer.

[0003] Studies have shown that the bioavailability of dasatinib in mammals is only 14-34%. Incomplete absorption and high first-pass effect are the main reasons limiting the bioavailability of dasatinib. If we want to improve the absorption effect of dasatinib and reduce the chance of treatment failure caused by individual differences, diet and medication, we first need to improve the water solubility of dasatinib. Summary of the invention

[0004] Purpose of the invention: In order to solve the problems of low solubility and low utilization rate of existing dasatinib, the present invention provides a microfluidic field preparation method of dasatinib nanocrystals, which is efficient, safe, environmentally friendly and can effectively reduce energy loss during the reaction process.

[0005] Using microfluidic technology, nanocrystallization experiments can be conveniently carried out under conditions of free interface diffusion and nanovolume. Higher supersaturation can be produced in microfluidic devices than traditional crystallization, and crystal nucleation can be strictly controlled and manipulated to obtain single crystals with ideal size and shape, greatly improving the solubility and stability of drugs.

[0006] In order to solve the above technical problems, the present invention discloses a microfluidic field preparation method of dasatinib nanocrystals, comprising the following steps:

[0007] (1) dissolving dasatinib in an organic solvent as solvent phase A;

[0008] (2) dissolving the surfactant in deionized water as anti-solvent phase B;

[0009] (3) The solvent phase A of step (1) and the anti-solvent phase B of step (2) are simultaneously pumped into a microfluidic reactor for sufficient reaction, and the dasatinib crystal dispersion is collected at the outlet, centrifuged and the supernatant is discarded, and the bottom precipitate is taken and vacuum dried to obtain solid nanocrystals;

[0010] Specifically, in step (1), the organic solvent is selected from any one of dimethyl sulfoxide, N,N-dimethylacetamide and N,N-dimethylformamide, preferably N,N-dimethylformamide.

[0011] Specifically, in step (1), the concentration of dasatinib in the organic solvent is 15 to 45 mg / mL, preferably 45 mg / mL.

[0012] Specifically, in step (2), the surfactant is selected from any one of sodium dodecylbenzene sulfonate, hexadecyltrimethylammonium bromide, and dodecyl dimethyl betaine, or a mixture of two or more thereof, preferably a mixture of sodium dodecylbenzene sulfonate and dodecyl dimethyl betaine, and more preferably a combination of the two in a mass ratio of 1:1; in the anti-solvent phase solution B, the mass concentration of the surfactant is 0.5% to 2.5%.

[0013] Specifically, in step (3), the pumping rate of solvent phase A is 0.1 to 2 mL / min, preferably 2 mL / min; the pumping rate of anti-solvent phase solution B is 2 to 40 mL / min, preferably 2 mL / min.

[0014] Preferably, in step (3), the microfluidic device comprises a microfluidic mixer, the microfluidic mixer has a channel diameter of 8 to 12 mm, a channel length of 60 to 100 mm, and a reaction time of 0.15 to 7.5 min.

[0015] At least one baffle is arranged in the pipeline of the microfluidic field reactor. The baffle has a diameter of 8 to 12 mm and is in complete contact with the inner wall of the pipeline. The baffle is arranged perpendicular to the length direction of the pipeline and is provided with a circular hole.

[0016] Preferably, each baffle surface is provided with a first circular hole, a second circular hole and a third circular hole, the radius of the first circular hole is 1 to 1.5 mm, and the radius of the second circular hole and the third circular hole are both 0.6 to 0.9 mm; the three circular holes are distributed on the baffle in an isosceles triangle with the center of the first circular hole as the vertex, wherein the distance from the center point of the baffle to the center of the first circular hole is 1.25 mm, and the distance from the center point of the baffle to the center of the first circular hole and the center of the second circular hole are both 0.6 mm.

[0017] Preferably, in step (3), the centrifugal speed is controlled at 8000-10000 r / min, and the centrifugal time is controlled at 5-10 min.

[0018] In a preferred embodiment, the solvent phase A and the anti-solvent phase B are pumped into the micromixer at a flow rate ratio of 1:20, the anti-solvent phase flow rate is 40 mL / min, the concentration of dasatinib in the organic solvent is 45 mg / mL, and the surfactant is a mixture of sodium dodecylbenzene sulfonate and dodecyl dimethyl betaine in a mass ratio of 1:1. Under this condition, crystals with small particle size can be prepared.

[0019] Preferably, in step (3), the applicable fluid physical parameters are: pressure of 0.8-4 MPa; temperature of 10-80° C., Reynolds number of 1-2000; and the thermal conductivity of the material used in the microfluidic reactor is 0.1-0.6 W / m·k.

[0020] Beneficial effects: Compared with the prior art, this application has the following advantages:

[0021] (1) The present invention adopts micro-reaction technology to regulate the transport efficiency and supersaturation of dasatinib drug molecules to achieve the preparation of dasatinib nanocrystals, which has simple operation, fast reaction speed and high safety;

[0022] (2) The microfluidic reactor used in the present invention has three circular baffles arranged in an isosceles triangle, which is conducive to the rapid passage of small-sized crystals from the small holes on the top and the passage of large-sized crystals from the large holes on the bottom. On the one hand, it can alleviate the agglomeration of nanocrystals and on the other hand, it can avoid the problem of particles blocking the microfluidic field.

[0023] (3) The present invention uses a microfluidic device to explore the molecular transport process of dasatinib in a solvent-antisolvent, and examines the effects of flow ratio, flow rate, API concentration, surfactant, etc. on particle size, providing a new idea for the preparation of dasatinib nanocrystals using microfluidic technology. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is a graph showing the particle size distribution and average particle size of the dasatinib nanocrystals prepared in Examples 1 to 5;

[0025] Figure 2 is a graph showing the particle size distribution and average particle size of the dasatinib nanocrystals prepared in Examples 5 to 8;

[0026] Figure 3 is a graph showing the particle size distribution and average particle size of the dasatinib nanocrystals prepared in Examples 5, 9, and 10;

[0027] Figure 4 is a graph showing the particle size distribution and average particle size of the dasatinib nanocrystals prepared in Examples 11 to 15;

[0028] Figure 5 This is a scanning electron micrograph of commercialized dasatinib and dasatinib crystals prepared using microfluidics;

[0029] Figure 6 This is a schematic diagram of the structure of the microfluidic field reactor of this application. DETAILED DESCRIPTION

[0030] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0031] like Figure 5 As shown, the microfluidic reactor of the present application includes two injection pumps, a U-shaped mixer and a collecting device, wherein the U-shaped mixer includes a U-shaped end inlet and a reaction pipe, the pipe diameter D is 8mm, and the mixing channel distance L is 60mm, wherein 8 circular hole baffles are arranged periodically in the pipe, the circular hole baffle is arranged perpendicular to the length direction of the pipe, and the surface of the circular hole baffle is provided with circular holes. Each circular hole baffle surface is provided with a first circular hole, a second circular hole and a third circular hole, the radius of the first circular hole is 1mm, and the radius of the second circular hole and the third circular hole are both 0.6mm; the three circular holes are distributed in an isosceles triangle with the center of the first circular hole as the vertex on the circular hole baffle, wherein the distance from the center of the circular hole baffle to the center of the first circular hole is 1.25mm, and the distance from the center of the circular hole baffle to the center of the first circular hole and the center of the second circular hole is 0.6mm.

[0032] Embodiment 1:

[0033] Weigh 0.35g of dasatinib and dissolve it in 10mL of N,N-dimethylformamide to obtain a solvent phase A with a concentration range of 35mg / mL; then weigh 2.04g of a surfactant sodium dodecylbenzene sulfonate (SDBS) and dissolve it in 100mL of deionized water to obtain an anti-solvent phase B with a surfactant concentration of 2wt%. At 25°C, start the syringe pump to pump the two-phase solution into the micro-reactor according to the flow rate ratio of the solvent phase to the anti-solvent phase A:B=1:20 (the flow rate of the solvent phase is 0.25mL / min, and the flow rate of the anti-solvent phase is 5mL / min), and collect the dasatinib crystal dispersion at the outlet. Take the above dispersion and centrifuge it at a speed of 10,000r / min for 5 minutes, discard the supernatant, take the bottom precipitate, and vacuum dry it for 12 hours to obtain solid nanocrystals.

[0034] Embodiment 2:

[0035] Weigh 0.35g of dasatinib and dissolve it in 10mL of N,N-dimethylformamide to obtain a solvent phase A with a concentration range of 35mg / mL; then weigh 2.04g of a surfactant sodium dodecylbenzene sulfonate (SDBS) and dissolve it in 100mL of deionized water to obtain an anti-solvent phase B with a surfactant concentration of 2wt%. At 25°C, start the syringe pump to pump the two-phase solution into the micro-reactor according to the flow rate ratio of the solvent phase to the anti-solvent phase A:B=1:20 (the flow rate of the solvent phase is 0.5mL / min, and the flow rate of the anti-solvent phase is 10mL / min), and collect the dasatinib crystal dispersion at the outlet. Take the above dispersion and centrifuge it at a speed of 10,000r / min for 5 minutes, discard the supernatant, take the bottom precipitate, and vacuum dry it for 12 hours to obtain solid nanocrystals.

[0036] Embodiment 3:

[0037] 0.35 g of dasatinib was weighed and dissolved in 10 mL of N,N-dimethylformamide to obtain a solvent phase A with a concentration range of 35 mg / mL; 2.04 g of a surfactant sodium dodecylbenzene sulfonate (SDBS) was weighed and dissolved in 100 mL of deionized water to obtain an anti-solvent phase B with a surfactant concentration of 2 wt%. At 25°C, the injection pump was started to pump the two-phase solution into the micro-reactor according to the flow rate ratio of the solvent phase to the anti-solvent phase A:B=1:20 (the flow rate of the solvent phase was 1.5 mL / min, and the flow rate of the anti-solvent phase was 30 mL / min), and the dasatinib crystal dispersion was collected at the outlet. The above dispersion was centrifuged at a speed of 10,000 r / min for 5 minutes, the supernatant was discarded, the bottom precipitate was taken, and solid nanocrystals were obtained after vacuum drying for 12 hours.

[0038] Example 4

[0039] Weigh 0.35g of dasatinib and dissolve it in 10mL of N,N-dimethylformamide to obtain a solvent phase A with a concentration range of 35mg / mL; then weigh 2.04g of a surfactant sodium dodecylbenzene sulfonate (SDBS) and dissolve it in 100mL of deionized water to obtain an anti-solvent phase B with a surfactant concentration of 2wt%. At 25°C, start the syringe pump to pump the two-phase solution into the micro-reactor according to the flow rate ratio of the solvent phase to the anti-solvent phase A:B=1:20 (the flow rate of the solvent phase is 2mL / min, and the flow rate of the anti-solvent phase is 40mL / min), and collect the dasatinib crystal dispersion at the outlet. Take the above dispersion and centrifuge it at a speed of 10,000r / min for 5 minutes, discard the supernatant, take the bottom precipitate, and vacuum dry it for 12 hours to obtain solid nanocrystals.

[0040] Embodiment 5:

[0041] Weigh 0.35g of dasatinib and dissolve it in 10mL of N,N-dimethylformamide to obtain a solvent phase A with a concentration range of 35mg / mL; then weigh 2.04g of a surfactant sodium dodecylbenzene sulfonate (SDBS) and dissolve it in 100mL of deionized water to obtain an anti-solvent phase B with a surfactant concentration of 2wt%. At 25°C, start the syringe pump to pump the two-phase solution into the micro-reactor according to the flow rate ratio of the solvent phase to the anti-solvent phase A:B=1:20 (the flow rate of the solvent phase is 1mL / min, and the flow rate of the anti-solvent phase is 20mL / min), and collect the dasatinib crystal dispersion at the outlet. Take the above dispersion and centrifuge it at a speed of 10,000r / min for 5 minutes, discard the supernatant, take the bottom precipitate, and vacuum dry it for 12 hours to obtain solid nanocrystals.

[0042] Embodiment 6:

[0043] 0.35 g of dasatinib was weighed and dissolved in 10 mL of N,N-dimethylformamide to obtain a solvent phase A with a concentration range of 35 mg / mL; 2.04 g of a surfactant sodium dodecylbenzene sulfonate (SDBS) was weighed and dissolved in 100 mL of deionized water to obtain an anti-solvent phase B with a surfactant concentration of 2 wt%. At 25°C, the injection pump was started to pump the two-phase solution into the micro-reactor according to the flow rate ratio of the solvent phase to the anti-solvent phase A:B=1:10 (the flow rate of the solvent phase was 1.91 mL / min, and the flow rate of the anti-solvent phase was 19.1 mL / min), and the dasatinib crystal dispersion was collected at the outlet. The above dispersion was centrifuged at a speed of 10,000 r / min for 5 minutes, the supernatant was discarded, the bottom precipitate was taken, and solid nanocrystals were obtained after vacuum drying for 12 hours.

[0044] Embodiment 7:

[0045] Take 0.35g of dasatinib and dissolve it in 10mL of N,N-dimethylformamide to obtain a solvent phase A with a concentration range of 35mg / mL; then weigh 2.04g of the surfactant sodium dodecylbenzene sulfonate (SDBS) and dissolve it in 100mL of deionized water to obtain an anti-solvent phase B with a surfactant concentration of 2wt%. At 25°C, start the syringe pump to pump the two-phase solution into the micro-reactor according to the flow rate ratio of the solvent phase to the anti-solvent phase A:B=1:5 (the flow rate of the solvent phase is 3.5mL / min, and the flow rate of the anti-solvent phase is 17.5mL / min), and collect the dasatinib crystal dispersion at the outlet. Take the above dispersion and centrifuge it at a speed of 10,000r / min for 5 minutes, discard the supernatant, take the bottom precipitate, and obtain solid nanocrystals after vacuum drying for 12 hours.

[0046] Embodiment 8:

[0047] Take 0.35g of dasatinib and dissolve it in 10mL of N,N-dimethylformamide to obtain a solvent phase A with a concentration range of 35mg / mL; then weigh 2.04g of the surfactant sodium dodecylbenzene sulfonate (SDBS) and dissolve it in 100mL of deionized water to obtain an anti-solvent phase B with a surfactant concentration of 2wt%. At 25°C, start the syringe pump to pump the two-phase solution into the micro-reactor according to the flow rate ratio of the solvent phase to the anti-solvent phase A:B=1:2 (the solvent phase flow rate is 7mL / min, and the anti-solvent phase flow rate is 14mL / min), and collect the dasatinib crystal dispersion at the outlet. Take the above dispersion and centrifuge it at a speed of 10,000r / min for 5 minutes, discard the supernatant, take the bottom precipitate, and obtain solid nanocrystals after vacuum drying for 12 hours.

[0048] Embodiment 9:

[0049] Take 0.25g of dasatinib and dissolve it in 10mL of N,N-dimethylformamide to obtain a solvent phase A with a concentration range of 25mg / mL; then weigh 2.04g of the surfactant sodium dodecylbenzene sulfonate (SDBS) and dissolve it in 100mL of deionized water to obtain an anti-solvent phase B with a surfactant concentration of 2wt%. At 25°C, start the syringe pump to pump the two-phase solution into the micro-reactor according to the flow rate ratio of the solvent phase to the anti-solvent phase A:B=1:20 (the flow rate of the solvent phase is 1mL / min, and the flow rate of the anti-solvent phase is 20mL / min), and collect the dasatinib crystal dispersion at the outlet. Take the above dispersion and centrifuge it at a speed of 10,000r / min for 5 minutes, discard the supernatant, take the bottom precipitate, and obtain solid nanocrystals after vacuum drying for 12 hours.

[0050] Embodiment 10:

[0051] Take 0.45g of dasatinib and dissolve it in 10mL of N,N-dimethylformamide to obtain a solvent phase A with a concentration range of 45mg / mL; then weigh 2.04g of the surfactant sodium dodecylbenzene sulfonate (SDBS) and dissolve it in 100mL of deionized water to obtain an anti-solvent phase B with a surfactant concentration of 2wt%. At 25°C, start the syringe pump to pump the two-phase solution into the micro-reactor according to the flow rate ratio of the solvent phase to the anti-solvent phase A:B=1:20 (the flow rate of the solvent phase is 1mL / min, and the flow rate of the anti-solvent phase is 20mL / min), and collect the dasatinib crystal dispersion at the outlet. Take the above dispersion and centrifuge it at a speed of 10,000r / min for 5 minutes, discard the supernatant, take the bottom precipitate, and obtain solid nanocrystals after vacuum drying for 12 hours.

[0052] Embodiment 11:

[0053] Weigh 0.35g of dasatinib and dissolve it in 10mL of N,N-dimethylformamide to obtain a solvent phase A with a concentration range of 35mg / mL; then weigh 2.04g of surfactant hexadecyltrimethylammonium bromide (CTAB) and dissolve it in 100mL of deionized water to obtain an anti-solvent phase B with a surfactant concentration of 2wt%. At 25°C, start the syringe pump to pump the two-phase solution into the micro-reactor according to the flow rate ratio of the solvent phase to the anti-solvent phase A:B=1:20 (the flow rate of the solvent phase is 1mL / min, and the flow rate of the anti-solvent phase is 20mL / min), and collect the dasatinib crystal dispersion at the outlet. Take the above dispersion and centrifuge it at a speed of 10,000r / min for 5 minutes, discard the supernatant, take the bottom precipitate, and vacuum dry it for 12 hours to obtain solid nanocrystals.

[0054] Embodiment 12:

[0055] 0.35 g of dasatinib was weighed and dissolved in 10 mL of N,N-dimethylformamide to obtain a solvent phase A with a concentration range of 35 mg / mL; 2.04 g of surfactant dodecyl dimethyl betaine (BS-12) was weighed and dissolved in 100 mL of deionized water to obtain an anti-solvent phase B with a surfactant concentration of 2 wt%. At 25°C, the injection pump was started to pump the two-phase solution into the micro-reactor according to the flow rate ratio of the solvent phase to the anti-solvent phase A:B=1:20 (the flow rate of the solvent phase was 1 mL / min, and the flow rate of the anti-solvent phase was 20 mL / min), and the dasatinib crystal dispersion was collected at the outlet. The above dispersion was centrifuged at a speed of 10,000 r / min for 5 minutes, the supernatant was discarded, the bottom precipitate was taken, and solid nanocrystals were obtained after vacuum drying for 12 hours.

[0056] Embodiment 13:

[0057] Weigh 0.35g of dasatinib and dissolve it in 10mL of N,N-dimethylformamide to obtain a solvent phase A with a concentration range of 35mg / mL; then weigh 1.02g of surfactant sodium dodecylbenzene sulfonate and 1.02g of hexadecyltrimethylammonium bromide (SDBS / CTAB=1:1, mass ratio), respectively, and dissolve both in 100mL of deionized water to obtain an anti-solvent phase B with a surfactant concentration of 2wt%. At 25°C, start the syringe pump to pump the two-phase solution into the micro-reactor according to the flow rate ratio of the solvent phase to the anti-solvent phase A:B=1:20 (solvent phase flow rate is 1mL / min, anti-solvent phase flow rate is 20mL / min), and collect the dasatinib crystal dispersion at the outlet. Take the above dispersion and centrifuge it at a speed of 10,000r / min for 5 minutes, discard the supernatant, take the bottom precipitate, and vacuum dry it for 12 hours to obtain solid nanocrystals.

[0058] Embodiment 14:

[0059] Weigh 0.35g of dasatinib and dissolve it in 10mL of N,N-dimethylformamide to obtain a solvent phase A with a concentration range of 35mg / mL; then weigh 1.02g of surfactant sodium dodecylbenzene sulfonate and 1.02g of dodecyl dimethyl betaine (SDBS / BS-12=1:1, mass ratio), respectively, and dissolve both in 100mL of deionized water to obtain an anti-solvent phase B with a surfactant concentration of 2wt%. At 25°C, start the syringe pump to pump the two-phase solution into the micro-reactor according to the flow rate ratio of the solvent phase to the anti-solvent phase A:B=1:20 (solvent phase flow rate is 1mL / min, anti-solvent phase flow rate is 20mL / min), and collect the dasatinib crystal dispersion at the outlet. Take the above dispersion and centrifuge it at a speed of 10,000r / min for 5 minutes, discard the supernatant, take the bottom precipitate, and vacuum dry it for 12 hours to obtain solid nanocrystals.

[0060] Embodiment 15:

[0061] Weigh 0.35g of dasatinib and dissolve it in 10mL of N,N-dimethylformamide to obtain a solvent phase A with a concentration range of 35mg / mL; then weigh 1.02g of surfactant dodecyl dimethyl betaine and 1.02g of hexadecyl trimethyl ammonium bromide (BS-12 / CTAB=1:1, mass ratio), respectively, and dissolve both in 100mL of deionized water to obtain an anti-solvent phase B with a surfactant concentration of 2wt%. At 25°C, start the syringe pump to pump the two-phase solution into the micro-reactor according to the flow rate ratio of the solvent phase to the anti-solvent phase A:B=1:20 (solvent phase flow rate is 1mL / min, anti-solvent phase flow rate is 20mL / min), and collect the dasatinib crystal dispersion at the outlet. Take the above dispersion and centrifuge it at a speed of 10,000r / min for 5 minutes, discard the supernatant, take the bottom precipitate, and obtain solid nanocrystals after vacuum drying for 12 hours.

[0062] Figure 1 The particle size distribution and average particle size of the dasatinib nanocrystals prepared in Examples 1 to 5 show that when the total flow rate (the sum of the flow rates of the solvent phase and the anti-solvent phase) increases from 5.25 mL / min to 31.5 mL / min, the main dispersion area of ​​the nanocrystals gradually moves from 712 to 1718 nm to 342 to 712 nm, and the average particle size d of the dasatinib nanocrystals is avgThe diameter of dasatinib nanocrystals also decreased from 1110nm to 505nm. When the total flow rate was further increased to 42mL / min, the dispersion area of ​​dasatinib nanocrystals was mainly concentrated in the range of 59 to 142nm. The results showed that when the flow rate ratio remained unchanged, the larger the flow rate, the smaller the particle size of dasatinib nanocrystals, and the smaller the distribution range.

[0063] Figure 2 The particle size distribution and average particle size of the dasatinib nanocrystals prepared in Examples 5 to 8 show that when the flow rate ratio is 1:2, the main distribution range of the nanocrystal particle size is 955 to 1718 nm, and at this time, the average particle size d avg =1288nm; when the flow rate ratio is 1:20, the main distribution range of the nanocrystal particle size is 396~825nm. Dasatinib has the largest average particle size d when the flow rate ratio is 1:2 avg =1288nm, and has the smallest average particle size d when the flow rate ratio is 1:20 avg =549nm. The results show that when the total flow rate of the solvent phase and the anti-solvent phase is the same, as the flow rate ratio of the solvent phase to the anti-solvent phase continues to decrease, the particle size of the generated nanocrystals also continues to decrease, and the distribution range also tends to decrease.

[0064] Figure 3 The particle size distribution and average particle size of the dasatinib nanocrystals prepared in Examples 5, 8, and 9 can be seen: as the original drug concentration gradually increases from 25 mg / mL to 45 mg / mL, the main distribution area of ​​the nanocrystals gradually changes from 615 to 2048 nm to 79 to 190 nm, and the average particle size of the nanocrystals decreases from 1099 nm to 217 nm. When the drug concentration reaches 45 mg / mL, most of the nanocrystal particle size distribution becomes narrower, between the small particle size of 79 to 190 nm, but at this time a bimodal distribution appears, with about 12% of the nanocrystals distributed in the 490 to 1990 nm interval. The results show that as the original drug concentration gradually increases, the nanocrystal particle size continues to decrease, but there is a tendency to agglomerate to form a large particle size distribution.

[0065] Figure 4 The particle size distribution and average particle size of the dasatinib nanocrystals prepared in Examples 11 to 15 show that:

[0066] Among single surfactants, the nanocrystals generated by CTAB and BS-12 are mainly distributed in the range of 531-1990 nm, with average particle sizes of 1021 nm and 998 nm, respectively, while the nanocrystals generated by SDBS are mainly distributed in the range of 396-955 nm, with an average particle size of d avg=549nm, indicating that among the single surfactants, SDBS is more suitable for preparing DAS nanocrystals with small particle size and narrow distribution. In the binary mixed surfactants, the nanocrystals generated by CTAB / SDBS have a particle size distribution range of 712 to 2669nm, with an average particle size of d avg =1255nm, the particle size distribution of DAS nanocrystals prepared by CTAB / BS-12 is mainly between 122 and 342nm, and the average particle size d avg =489nm, the nanocrystal particle size prepared by SDBS / BS-12 is mainly distributed in the range of 122 to 342nm, and the average particle size d avg =386nm. The results show that the binary mixed surfactant SDBS / BS-12 has the best effect, and the binary mixed surfactant has a smaller PDI value than a single surfactant.

[0067] Figure 5 (a) and (b) are scanning electron microscope images of commercialized dasatinib and dasatinib crystals prepared by microfluidics, respectively. It can be seen that the commercialized dasatinib crystal solid presents an irregular plate shape, stacked on top of each other, while the dasatinib nanocrystals prepared by microfluidics present an irregular flake shape in morphology. The latter has a larger specific surface area, which is more conducive to drug delivery and human absorption.

[0068] The present invention provides a preparation idea and method of dasatinib nanocrystals. There are many methods and ways to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the protection scope of the present invention. All components not specified in this embodiment can be implemented by existing technologies.

Claims

1. A microfluidic field preparation method of dasatinib nanocrystals, characterized in that: The steps include: (1) dissolving dasatinib in an organic solvent as solvent phase A; (2) dissolving the surfactant in deionized water as antisolvent phase B; (3) The solvent phase A of step (1) and the anti-solvent phase B of step (2) are simultaneously pumped into a microfluidic reactor for full reaction, the dasatinib crystal dispersion is collected at the outlet, the supernatant is discarded by centrifugation, the bottom precipitate is taken, and solid nanocrystals are obtained after vacuum drying; The flow rate ratio of the solvent phase A and the anti-solvent phase B pumped into the micromixer is 1:1~1:20; the pumping speed of the solvent phase A is 0.1~2mL / min, and the pumping speed of the anti-solvent phase B is 2~40mL / min.

2. The microfluidic field preparation method according to claim 1, characterized in that: The organic solvent in step (1) includes any one of dimethyl sulfoxide, N,N-dimethylacetamide and N,N-dimethylformamide or a mixture of several of them.

3. The microfluidic field preparation method according to claim 1, characterized in that: In step (1), the concentration of dasatinib in the organic solvent is 15-45 mg / mL.

4. The microfluidic field preparation method according to claim 1, characterized in that: In step (2), the surfactant is any one of sodium dodecylbenzene sulfonate, hexadecyltrimethylammonium bromide, and dodecyldimethylbetaine, or a mixture of two or more thereof; and in the anti-solvent phase B, the surfactant mass concentration is 0.5% to 2.5%.

5. The microfluidic field preparation method according to claim 1, characterized in that: In step (3), the microfluidic device includes a microfluidic mixer, wherein the channel diameter of the microfluidic mixer is 8-12 mm, the channel length is 60-100 mm, and the reaction time is 0.15-7.5 min.

6. The microfluidic field preparation method according to claim 5, characterized in that: At least one baffle is arranged in the pipeline of the microfluidic field reactor. The baffle has a diameter of 8-12 mm and is in complete contact with the inner wall of the pipeline. The baffle is arranged perpendicular to the length direction of the pipeline and is provided with a circular hole.

7. The microfluidic field preparation method according to claim 6, characterized in that: A first circular hole, a second circular hole and a third circular hole are arranged on the surface of each baffle plate, wherein the radius of the first circular hole is 1-1.5 mm, and the radius of the second circular hole and the third circular hole are both 0.6-0.9 mm; the three circular holes are distributed in an isosceles triangle on the baffle plate with the center of the first circular hole as the vertex, wherein the distance from the center point of the baffle plate to the center of the first circular hole is 1.25 mm, and the distance from the center point of the baffle plate to the center of the first circular hole and the center of the second circular hole are both 0.6 mm.

8. The microfluidic field preparation method according to claim 1, characterized in that: In step (3), the centrifugal speed is controlled at 8000-10000 r / min, and the centrifugal time is 5-10 min.

9. The microfluidic field preparation method according to claim 1, characterized in that: The flow rate ratio of solvent phase A and anti-solvent phase B pumped into the micromixer was 1:20, the flow rate of the anti-solvent phase was 40 mL / min, the concentration of dasatinib in the organic solvent was 45 mg / mL, and the surfactant was a mixture of sodium dodecylbenzene sulfonate and dodecyl dimethyl betaine in a mass ratio of 1:

1.

10. The microfluidic field preparation method according to claim 1, characterized in that: The pressure of the reaction fluid is 0.8~4MPa; the temperature is 10~80℃, and the Reynolds number is 1~2000; the thermal conductivity of the material used in the microfluidic reactor is 0.1~0.6W / m·k.

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