Continuous micro-fluidization crystallizer and preparation method of active pharmaceutical ingredient micro-nano particles

Abstract

The invention provides a continuous micro-fluidization crystallizer and a preparation method of fluticasone propionate micro-nano particles, and the preparation method comprises the following steps: (1) providing acetone, adding fluticasone propionate into acetone, and preparing an acetone solution of fluticasone propionate; (2) providing water; (3) simultaneously inputting the acetone solution of the fluticasone propionate and water into a continuous micro-fluidization crystallizer according to a ratio, separating out crystals of the fluticasone propionate in the process of mixing the acetone solution of the fluticasone propionate and the water in the continuous micro-fluidization crystallizer, and suspending the formed micro-nano particles in crystal mush; and (4) collecting crystal mush, separating and drying to obtain the fluticasone propionate micro-nano particles, wherein the particle size D90 of the fluticasone propionate micro-nano particles is 1-20 [mu] m. The preparation method of the fluticasone propionate micro-nano particles is suitable for industrial large-scale production, the product quality is stable, the operation is simple, and the requirement on equipment is low.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drug preparation production, and more specifically, relates to a device for preparing micro-nano particles of active drug ingredients and a method for preparing micro-nano particles of active drug ingredients. Background Art

[0002] With the development of drugs, people have developed a variety of drug delivery methods, including oral agents, injections, suspensions, nasal sprays, inhalers, etc. Nasal sprays and inhalers require the preparation of drugs in the form of aerosols, and the active ingredients of the drugs reach the airways or lungs through the aerosols to exert their efficacy. Studies have shown that when the aerodynamic diameter of aerosol particles is greater than 10μm, they tend to be deposited in the oropharynx; when they are 5-10μm, they tend to be deposited in the upper bronchi; when they are about 3μm, they can be deposited in the alveoli; nano-fine particles are easily exhaled out of the lungs again. Generally, the particle size of inhaled preparations is controlled between 1 and 5μm, so that the drugs are deposited in the effective parts of the lungs. Suspensions used for the eyes generally require the particle size of the active ingredients of the drugs to be smaller, for example, ≤1.5μm.

[0003] At present, the preparation of small-particle active ingredients of medicines usually adopts micronization technology such as air flow milling, wet grinding or high-pressure homogenization, supercritical fluid technology to adjust the particle size and improve the uniformity of the product. For example, the prior art CN112933047A discloses a method for preparing ultrafine powdered salmeterol and fluticasone, which micronizes salmeterol, fluticasone propionate and excipients by supercritical fluid technology to enhance drug stability, improve powder fluidity, reduce agglomeration, and more stable and efficient lung deposition rate. However, supercritical equipment belongs to ultra-high pressure equipment, with high energy consumption and large equipment footprint, which hinders large-scale industrial application. For example, the prior art CN106604720B discloses a preparation containing glycopyrronium, in which magnesium stearate and active substances are co-jet-milled to obtain mixed particles, and the mixed particles are exposed to a certain temperature and humidity to obtain the desired mixed particles. This method can avoid the agglomeration of active substances and improve the stability of inhaled powder aerosols. However, this method has extremely high operational requirements. If it is not operated properly, a local solvation process will occur, causing the micronized particles to agglomerate, thus affecting the efficacy of the powder aerosol.

[0004] In addition, the micronization process has defects in control, which may lead to chemical degradation or deterioration of the API, which will reduce the stability of the drug, more agglomeration, poor atomization, etc. Moreover, micronization often brings problems such as electrostatic agglomeration and adhesion, which reduces the fluidity of the powder and may affect the efficacy of the product. The periodic batch production method requires meticulous parameter control and relies heavily on the expertise of the operator.

[0005] Therefore, how to more conveniently prepare high-quality small-particle active pharmaceutical ingredients is a technical problem that those skilled in the art have been seeking to solve.

[0006] Fluticasone propionate is a glucocorticoid drug with strong lipophilicity. When used as an external medicine, it can be well combined with human skin tissue and glucocorticoid receptors, and has strong anti-inflammatory and anti-allergic effects. Fluticasone propionate nasal spray can be used to prevent and treat seasonal allergic rhinitis (including hay fever) and perennial allergic rhinitis, and aerosol can be used for long-term control of asthma. Therefore, it is necessary to prepare fluticasone propionate with a small particle size. For example, the prior art CN115887372A discloses a fluticasone propionate suspension for ophthalmic preparations and a preparation method thereof, in which the fluticasone propionate raw material is uniformly dispersed in a concentrated solution containing a suspending agent, and then a microjet ultra-high pressure homogenization process is used to reduce the particle size of the fluticasone propionate in the concentrated solution to ≤1.5μm, with uniform particle size and good resuspension effect. Prior art CN116370411A discloses a fluticasone propionate nasal spray and its production process. The solubility and dispersion performance of the product can be effectively improved by combining dissolution, multiple shearing and homogenization during the production process of the nasal spray. The droplet distribution of the nasal spray is uniform and delicate, and easy to absorb. The technical solutions disclosed in the above two prior arts both adopt micro-jet or multiple shearing, high-pressure homogenization and other means. The mechanical force of this method may cause chemical degradation or deterioration of the raw material drug, causing the quality risk of the raw material drug. And this method still belongs to an intermittent production method, fails to improve the production efficiency of micro-nano particles, and has problems such as high energy consumption, low efficiency, and large equipment volume. Summary of the invention

[0007] In view of the problems existing in the prior art in preparing ultrafine powdered active pharmaceutical ingredients, an object of the present invention is to provide a simple-structured continuous microfluidized crystallizer for continuously mixing a solution of an active pharmaceutical ingredient with an anti-solvent and then continuously crystallizing it to continuously prepare micro-nanoparticle-sized API crystals.

[0008] The continuous microfluidized crystallizer of the present invention comprises a T-shaped connector, a microchannel tube and a crystallization tube segment with a cylindrical chamber, the T-shaped connector comprises a main tube and a branch tube, the main tube is divided into a left main tube and a right branch tube with the axis where the branch tube is located as the center, the microchannel tube is located in the left main tube and the right branch tube, the left main tube is used to fix the microchannel tube, the right branch tube is connected to the crystallization tube segment and is in fluid communication with the branch tube, the microchannel tube is used to transport a solution of an active pharmaceutical ingredient, the branch tube is used to transport an anti-solvent, and the microchannel tube and the crystallization tube segment are aligned and positioned in an axial direction under the fixation of the T-shaped connector, so that the solution of the active pharmaceutical ingredient is introduced at the axis of the crystallization tube segment and mixed with the anti-solvent, so that the active pharmaceutical ingredient is crystallized and precipitated to form a crystal slurry.

[0009] In another preferred example, the microchannel tube passes through the left main tube and the right branch tube. In another preferred example, the microchannel tube passes through the left main tube and the right branch tube, and extends from the left end of the left main tube. In another preferred example, the depth of the microchannel tube inserted into the right branch tube is less than the length of the right branch tube.

[0010] In another preferred embodiment, the inner diameter of the right branch pipe is the same as the diameter of the cylindrical chamber of the crystallization tube segment.

[0011] On the other hand, the present invention provides a device for preparing micro-nano particles of active pharmaceutical ingredients, the device comprising a first tank, a second tank, a first pump, a second pump, a first temperature controller, a second temperature controller, the above-mentioned continuous microfluidization crystallizer and a separator, the first tank and the second tank are respectively used to store the active pharmaceutical ingredient solution and the anti-solvent, the first pump and the second pump are respectively used to transport the active pharmaceutical ingredient solution in the first tank and the anti-solvent in the second tank to the continuous microfluidization crystallizer, the first temperature controller and the second temperature controller are respectively used to adjust the temperature of the active pharmaceutical ingredient solution and the anti-solvent entering the continuous microfluidization crystallizer from the first tank and the second tank, so that they reach the target temperature before mixing, so that the active pharmaceutical ingredient crystallizes and precipitates at the target temperature to form a slurry, and the separator is connected to the continuous microfluidization crystallizer to collect and separate the slurry to obtain micro-nano particles of active pharmaceutical ingredients.

[0012] In another preferred embodiment, the separator is selected from a filter device or a centrifuge.

[0013] Another aspect of the present invention provides a method for preparing fluticasone propionate micro-nanoparticles, comprising the following steps:

[0014] (1) providing acetone, and adding fluticasone propionate to the acetone to prepare an acetone solution of fluticasone propionate;

[0015] (2) Providing water;

[0016] (3) The acetone solution of fluticasone propionate and water are simultaneously introduced into the continuous microfluidized crystallizer according to claim 1 in a proportion, and during the mixing process of the acetone solution of fluticasone propionate and water, fluticasone propionate crystals are precipitated to form a slurry.

[0017] (4) collecting the slurry, separating and drying to obtain fluticasone propionate micro-nanoparticles,

[0018] The particle size D of the fluticasone propionate micro-nano particles 90 1~20μm.

[0019] In another more preferred embodiment, the particle size D of the fluticasone propionate micro-nanoparticles is 90 In another more preferred embodiment, the particle size D of the fluticasone propionate micro-nanoparticles is 90 1~5μm.

[0020] In another preferred embodiment, the concentration of the fluticasone propionate acetone solution is 10 to 50 g / L. In another more preferred embodiment, the concentration of the fluticasone propionate acetone solution is 25 to 35 g / L. In another more preferred embodiment, the concentration of the fluticasone propionate acetone solution is 30 g / L.

[0021] In another preferred embodiment, the temperature of the acetone solution of fluticasone propionate and the water are adjusted to 0-10°C, preferably 5°C, respectively, before being transported to the continuous microfluidized crystallizer.

[0022] In another preferred embodiment, the ratio of the acetone solution of fluticasone propionate to water simultaneously fed into the continuous microfluidized crystallizer is 1:5-25, more preferably 1:5-15, and most preferably 1:8.

[0023] In another preferred embodiment, the inner diameter of the microchannel tube of the continuous microfluidized crystallizer is 0.33 mm, the inner diameter of the branch tube is 2.54 mm, the diameter of the cylindrical chamber of the crystallization tube section is 2.54 mm, and the length is 920 mm. The acetone solution of fluticasone propionate is input into the continuous microfluidized crystallizer at a flow rate of 6 to 10 ml / min, and water is input into the continuous microfluidized crystallizer at a flow rate of 6 to 100 ml / min. The residence time of the mixture of the acetone solution of fluticasone propionate and water in the crystallization tube section is 0.5 to 2.0 s.

[0024] In another more preferred example, the inner diameter of the microchannel tube of the continuous microfluidized crystallizer is 0.33 mm, the inner diameter of the branch tube is 2.54 mm, the diameter of the cylindrical chamber of the crystallization tube section is 2.54 mm, and the length is 920 mm. The acetone solution of fluticasone propionate is input into the continuous microfluidized crystallizer at a flow rate of 12.5 ml / min, and water is input into the continuous microfluidized crystallizer at a flow rate of 100 ml / min. The residence time of the mixture of the acetone solution of fluticasone propionate and water in the crystallization tube section is 1.38 s.

[0025] In another aspect, the present invention provides a method for preparing micro-nano particles of active pharmaceutical ingredients, comprising the following steps:

[0026] (1) providing a good solvent for the pharmaceutically active ingredient, and adding the pharmaceutically active ingredient to the good solvent to prepare a pharmaceutically active ingredient solution;

[0027] (2) providing an anti-solvent for the active ingredient of the drug, wherein the anti-solvent has good miscibility with the good solvent;

[0028] (3) simultaneously feeding the pharmaceutical active ingredient solution and the anti-solvent into the continuous microfluidized crystallizer according to claim 1 in a proportion, wherein during the mixing process of the pharmaceutical active ingredient solution and the anti-solvent, the pharmaceutical active ingredient crystallizes and forms a slurry;

[0029] (4) collecting the slurry, separating and drying to obtain micro-nano particles of active pharmaceutical ingredients,

[0030] The particle size distribution D of the micro-nano particles 90 1~20μm.

[0031] In another preferred embodiment, the particle size distribution D of the micro-nano particles is 90 In another more preferred embodiment, the particle size distribution D of the micro-nano particles is 90 1~5μm.

[0032] In another preferred embodiment, the pharmaceutically active ingredient is selected from fluticasone propionate, salmeterol, indacaterol, salmeterol, olodaterol, vilanterol, formoterol, ciclesonide, budesonide, tiotropium bromide, terbutaline sulfate, salbutamol sulfate, ipratropium bromide, beflomethasone, mometasone, beclomethasone propionate, fluticasone, prednisone, prednisolone, dexamethasone, or a pharmaceutically acceptable salt thereof.

[0033] In another preferred embodiment, the anti-solvent is selected from water, and the good solvent is selected from an organic solvent having good miscibility with water.

[0034] In another preferred embodiment, the organic solvent having good miscibility with water is selected from acetone, methanol, ethanol, isopropanol, ethylene glycol, furan, N,N-dimethylformamide, dimethyl sulfoxide, tert-butanol, 2-butanol, ethyl acetate, acetonitrile, 2-butanone, 3-pentanone, tetrahydrofuran, 1,4-dioxane, or a combination thereof.

[0035] In another preferred embodiment, the concentration of the pharmaceutical active ingredient solution is 10-100 g / L.

[0036] In another preferred embodiment, the temperature of the drug active ingredient solution and the anti-solvent are respectively adjusted to -10 to 30°C before being transported to the continuous microfluidized crystallizer.

[0037] In another preferred embodiment, in step (4), separation is performed by centrifugation or filtration.

[0038] In another preferred embodiment, in step (4), the solid obtained by separation is washed and then dried, for example, by washing with water for 1 to 3 times.

[0039] Compared with the prior art, the preparation method of fluticasone propionate micro-nanoparticles of the present invention has the following advantages:

[0040] 1. Fluticasone propionate is continuously crystallized using a continuous microfluidized crystallizer to obtain micro-nano particles. The continuous microfluidized crystallizer device has a simple structure, low cost, and can be flexibly expanded. It reliably realizes the process of continuously preparing micro-nano particles in one step, and has low energy consumption, high efficiency, small footprint, and is easy to scale up for production.

[0041] 2. The preparation method of fluticasone propionate micro-nanoparticles provided by the present invention is simple to operate and suitable for industrial production. The obtained product has a small particle size and concentrated distribution, a complete crystal morphology, and good powder dispersibility, and is particularly suitable for inhalation preparation raw materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1a A schematic structural diagram of the continuous microfluidized crystallizer of the present invention is shown.

[0043] Figure 1b The figure shows the regional division of the crystallization tube section of the continuous microfluidized crystallizer of the present invention, where area a represents the liquid mixture area and area b represents the crystal nucleation and growth area.

[0044] Figure 2 The schematic diagram of the structure of the device for preparing micro-nano particles of active pharmaceutical ingredients of the present invention is shown.

[0045] Figure 3 The solubility of fluticasone propionate in different solvents is shown, wherein the data are expressed as mean ± SD, n = 3.

[0046] Figure 4 In the figure, a, b and c show the solubility (ln x1) of fluticasone propionate in acetone-water solution with different mole fractions (x2) at 5, 15 and 25 °C, respectively. The curves are obtained by fitting the CNIBS / RK model.

[0047] Figure 5 A schematic diagram showing the fluid boundary definition and geometric model dimensions used for numerical simulations is shown.

[0048] Figure 6 In the figure, figure a shows the velocity streamline profile on the XOZ space coordinate axis plane; figure b shows the pressure contour profile on the XOZ space coordinate axis plane.

[0049] Figure 7 The acetone mass fraction distribution diagram on the XOZ spatial coordinate axis plane is shown.

[0050] Figure 8 In the figure, Figure a shows the residence time distribution function F(t)-t curve of the liquid in the continuous microfluidized crystallizer; Figure b shows the flow pattern in the continuous microfluidized crystallizer characterized by the E(θ)-θ curve.

[0051] Fig. 9 The mixing distance L is shown at different feed flow rates (active pharmaceutical ingredient (API) solution: antisolvent, ml / min). x The mixed exponential curve at .

[0052] Fig.10 The effect of different process parameters on D 90 influence trend.

[0053] Fig.11 In the figure, the contour maps of Figure a, Figure b, and Figure c show the 90 The concentration of the active pharmaceutical ingredient solution (C API ), the flow rate of the active pharmaceutical ingredient solution (Q API ) and antisolvent ratio (R ATS )’s interaction response surface.

[0054] Fig.12 The operating curve of the continuous crystallization process using the continuous microfluidized crystallizer of the present invention is shown.

[0055] Fig.13 The curves showing the mixing index changing with mixing time under different solvent ratios and total flow rates are shown. The scattered points represented by ●, ■ and ▲ correspond to the mixing index when the total flow rates are 50, 100 and 150 ml / min, respectively.

[0056] Fig.14The D of the product obtained by continuous crystallization in a continuous microfluidized crystallizer under selected operating conditions is shown. 90 and particle size span (Span).

[0057] Fig.15 The particle size distribution test results of the fluticasone propionate micro-nanoparticle product prepared in Example 1 of the present invention are shown.

[0058] Fig.16 The particle size distribution test results of the fluticasone propionate micro-nanoparticle product prepared in Example 2 of the present invention are shown.

[0059] Fig.17 In the figure, Figure a and Figure c respectively show polarizing microscope and scanning electron microscope photographs of the crystals prepared by the continuous microfluidizer of the present invention, and Figure b and Figure d respectively show polarizing microscope and scanning electron microscope photographs of the crystals prepared by the intermittent crystallization reactor.

[0060] Fig.18 The figure shows the comparison of the particle sizes of the crystal product prepared by the continuous microfluidized crystallizer of the present invention, the crystal product prepared by the batch crystallization reactor and the fluticasone propionate powder available on the market. DETAILED DESCRIPTION

[0061] In view of the problems existing in the prior art in preparing small-sized active pharmaceutical ingredients, the inventors of the present application have conducted in-depth research and found that by mixing a solution of an active pharmaceutical ingredient and an anti-solvent in a continuous microfluidized crystallizer, a slurry containing small-sized active pharmaceutical ingredients can be continuously prepared, and micro-nanoparticles of the active pharmaceutical ingredients, for example, 1 to 5 μm, can be obtained by separation.

[0062] In the description of the present invention, a "good solvent" is a solvent that has good solubility for the active pharmaceutical ingredient. For example, at 25°C, the amount of the active pharmaceutical ingredient dissolved in 1g of the solvent is equal to or greater than 20mg.

[0063] In the description of the present invention, "the anti-solvent and the good solvent have good miscibility" means that the good solvent dissolves well in the anti-solvent, for example, the anti-solvent and the good solvent are miscible when the volume ratio is 1:1 or greater than 1:1.

[0064] The present invention takes fluticasone propionate as an example and studies the influencing factors of preparing fluticasone propionate micro-nano particles by using a continuous microfluidized crystallizer.

[0065] In the present invention, the operation and analysis steps of the particle size distribution test (PSD) of fluticasone propionate micro-nanoparticles are as follows:

[0066] Malvern 2000 laser particle size analyzer, wet dispersion sample injector, disperser speed 1500rpm. Dispersant is 1% Tween 80 aqueous solution, ultrasonic oscillation for 3 minutes to fully disperse the sample powder in the dispersant into a suspension, and then add it into the sample injector for testing.

[0067] Solubility determination of fluticasone propionate

[0068] The solubility of fluticasone propionate in various organic solvents and acetone-water system was determined by static method. In this method, 10.0 ml of the solvent to be tested was added to multiple glass bottles, and then the glass bottles were placed in a water bath (VIVO-RT2, JULABO, Germany) to maintain the desired temperature. A magnetic stirrer was used to continuously stir at a speed of 250 rpm. After reaching the target temperature and ensuring that the temperature was constant, an excess of FP powder was added to each vial. Stirring was continued for 24 hours to achieve solid-liquid equilibrium, and then stirring was stopped to allow undissolved solids to settle. The supernatant was filtered through a 0.45 μm pore size filter membrane into a centrifuge tube (m0), and the total weight of the centrifuge tube and the saturated solution (m1) was recorded. The centrifuge tube containing the saturated solution was dried at 60°C until a constant weight was reached (m2). At a given temperature, the saturated solubility (c*) of FP in a given solvent can be calculated using the following formula (1):

[0069]

[0070] Three sets of measurements were performed simultaneously for each solvent to calculate the average and relative error. It is worth noting that when measuring the solubility at 5°C and 15°C, precautions were taken to pre-cool the syringe and filter to prevent temperature-induced crystallization or dissolution of the solute during filtration.

[0071] Fluid dynamics simulation

[0072] Before the final structural dimensions were determined, computational fluid dynamics (CFD) simulations were performed on the continuous microfluidized crystallizer of the present invention using Fluent software (ANSYS, USA). Except for the simplified processing of the threaded interface, the rest of the crystallizer geometry model was exactly the same as the experimental device. The geometry model was customized meshed using structured hexahedron / tetrahedron units, and the mesh at the nozzle was encrypted to improve the accuracy of the calculation.

[0073] The fluids were defined as incompressible water and acetone, the mold wall was defined as a stationary wall boundary, and the global temperature was set to 5 °C. The semi-implicit pressure coupled equations (SIMPLE) were used as the pressure-velocity coupling algorithm, and the high-order quadratic upwind interpolation (QUICK) was used as the density interpolation scheme. Formula (2) was used using Fluent Post software (ANSYS Inc.).

[0074]

[0075] Among them, σ max is the variance of the inlet concentration of the component before mixing, σ 2 is the concentration variance at any plane downstream of the inlet plane. Based on the derived data, the mass ratio of the components at each point in the fluid domain is obtained. i , and then calculate the average (b) and standard deviation (σ) of the concentration at each plane to obtain the mixing index MI. For the reference plane (inlet L x =0), the mixing index MI=0; for a completely mixed homogeneous system, the mixing index MI=1.

[0076] Experimental instruments

[0077] The structural schematic diagram of the continuous microfluidized crystallizer used is shown in Figure 1a As shown, the specific continuous microfluidization crystallizer shown in the figure includes a T-shaped connector 1, a microchannel tube 2 and a crystallization tube segment 3 with a cylindrical chamber, the T-shaped connector 1 includes a main tube 11 and a branch tube 12, the main tube 11 is divided into a left main tube 11-1 and a right main tube 11-2 with the axis of the branch tube 12 as the center, the microchannel tube 2 is located in the left main tube 11-1 and the right main tube 11-2, the left main tube 11-1 is used to fix the microchannel tube, the right branch tube 11-2 is connected to the crystallization tube segment 3 (for example, by threaded connection) and is in communication with the branch tube 12, the left main tube 11-1 is not in communication with the right branch tube 11-2 and the branch tube 12, and the liquid does not enter the left main tube 11-1 when in use. The microchannel tube 2 is used to transport the active pharmaceutical ingredient solution, the branch tube 12 is used to transport the anti-solvent, and the microchannel tube 2 and the crystallization tube segment 3 are aligned and positioned in an axial direction under the fixation of the T-shaped connector 1, so that the active pharmaceutical ingredient solution is introduced at the axis of the crystallization tube segment 3.

[0078] The microchannel tube 2 can penetrate the left main tube 11-1 and the right main tube 11-2, and extend from the left end of the left main tube 11-1 (such as Figure 1a As shown in FIG. 1 ). The microchannel tube 2 may also penetrate the left main tube 11-1 and the right main tube 11-2 (i.e., the length of the microchannel tube 2 is equal to that of the main tube 11). The microchannel tube 2 may also be inserted into the right main tube 11-2 to a depth less than the length of the right branch tube 11-2. In this case, the active pharmaceutical ingredient solution and water begin to mix in the right branch tube.

[0079] When in use, the anti-solvent is first transported through the branch pipe 12 to fill the right branch pipe 11-2 (the anti-solvent cannot enter the left main pipe 11-1) and the crystallization tube section 3. Then the active pharmaceutical ingredient solution passes through the microchannel tube 2, contacts, mixes and crystallizes with the anti-solvent at the axis of the crystallization tube section 3 to form a crystal slurry. After the crystal slurry is collected, separated and dried to obtain the active pharmaceutical ingredient micro-nano particles.

[0080] In the process of preparing fluticasone propionate micro-nanoparticles, the active pharmaceutical ingredient solution refers to an acetone solution of fluticasone propionate, and the anti-solvent refers to water.

[0081] See also Figure 1b , Figure 1a The cylindrical chamber of the crystallization tube section 3 of the continuous microfluidized crystallizer can be divided into a liquid mixture zone (zone a) and a crystal nucleation and growth zone (zone b). The active pharmaceutical ingredient solution and the antisolvent are mixed violently in the mixing zone, and a high supersaturation ratio is quickly formed (in this state, the crystal nucleation rate is fast, the number of nuclei is large (explosive nucleation is prone to occur), and the supersaturation is quickly consumed, so that the crystal particles grow small). Figure 1b The liquid mixture zone and the crystal nucleation and growth zone of the crystallization tube section 3 are shown only by way of example. In fact, there is no strict boundary between the two. The total residence time of the crystallizer can be controlled by adjusting the length of the crystal nucleation and growth zone.

[0082] The schematic diagram of the structure of the device for preparing micro-nano particles of active pharmaceutical ingredients is shown in Figure 2 As shown. The specific device shown in the figure includes a first tank 10a, a second tank 10b, a first pump 20a, a second pump 20b, a first temperature controller 30a, a second temperature controller 30b, a continuous microfluidization crystallizer 40 and a separator 50. The first tank 10a and the second tank 10b are used to store the active pharmaceutical ingredient solution and the anti-solvent, respectively. The first pump 20a and the second pump 20b are used to transport the active pharmaceutical ingredient solution in the first tank 10a and the anti-solvent in the second tank 10b to the continuous microfluidization crystallizer 40, respectively. The first temperature controller 30a and the second temperature controller 30b are used to adjust the temperature of the active pharmaceutical ingredient solution and the anti-solvent entering the continuous microfluidization crystallizer 40 from the first tank 10a and the second tank 10b, respectively, so that they reach the required temperature (T) before mixing, so as to crystallize at the target temperature of the active pharmaceutical ingredient. The separator 50 is connected to the continuous microfluidization crystallizer 40 to collect and separate the crystal slurry formed in the continuous microfluidization crystallizer 40 to obtain micro-nano particles of the active pharmaceutical ingredient.

[0083] In a preferred embodiment of the present invention, the first pump and the second pump may each independently be a horizontal flow pump.

[0084] In a preferred embodiment of the present invention, the first temperature controller and the second temperature controller can each independently consist of a compact heat exchanger connected to a constant temperature water bath.

[0085] In a preferred embodiment of the present invention, the separator is a filtering device or a centrifuge.

[0086] Sample processing and characterization

[0087] The crystal slurry (suspension) of fluticasone propionate was collected for 30 seconds (usually 61 seconds during the crystallization process) after three times the residence time (i.e., about 5 seconds, the residence time refers to the residence time of the mixed solution in the crystallization tube section), and then filtered with a Buchner funnel. The filter cake was divided into two parts. One part was dispersed in a 10% w / w Tween-80 aqueous solution and ultrasonicated for 3 minutes to obtain the particle size distribution (PSD). A particle size analyzer (Mastersizer 2000, Malvern, UK) equipped with a wet sample dispersion device (Hydro 2000SM small volume, Malvern, UK) was used for PSD analysis. The remaining samples were vacuum dried at 45°C for further characterization. The crystal morphology was examined using a field emission scanning electron microscope (SEM, TM 3000, HITACHI, Japan). The solid-state chemical properties of the samples were analyzed using powder X-ray diffractometer (PXRD, Ultima IV, Rigaku Corporation, Japan), thermogravimetric analysis (TGA, Q500, TA Instruments, USA), and differential scanning calorimeter (DSC, Q2000, TA Instruments, USA).

[0088] Solubility Curves and Solvent Selection

[0089] The solubility of fluticasone propionate in 24 organic solvents at 25°C was determined by static method. Figure 3 As shown in (Solubility of fluticasone propionate in different solvents (data are expressed as mean ± SD, n = 3), the solubility of fluticasone propionate in different solvents can be roughly arranged in the following order: ketones > heterocyclics > halogenated hydrocarbons > esters > alcohols > ethers > alkanes. Among them, tetrahydrofuran (THF) has the highest solubility of 151.21 mg / g, followed by acetone, which is 59.34 mg / g. However, due to the restrictions of the ICH Q3C guidelines, the use of tetrahydrofuran should be limited. Since acetone is a more suitable solvent for recrystallization, acetone was selected to prepare the active pharmaceutical ingredient solution. The solubility of fluticasone propionate in alkanes is low, all below 5 mg / g, and the solubility in water is below the detection limit. Considering the cost advantage of water and its miscibility with acetone, the acetone-water system is considered to be the best crystallization solvent combination.

[0090] Then the solubility curves of fluticasone propionate in acetone-water system at 5℃, 10℃ and 25℃ were determined. The solubility mass of fluticasone propionate in binary mixed solvents with different proportions was also determined by static method. The CNIBS / RK model is applicable to binary systems at constant temperature, and the model can be simplified to formula (3):

[0091]

[0092] Wherein, B0, B1, B2, B3 and B4 are model constants; x1 and x2 are the molar fractions of fluticasone propionate and acetone in the mixed solvent, respectively. The solubility curve of fluticasone propionate in acetone-water system was fitted using formula (3), as shown in Figure 4 shown.

[0093] The square of the correlation coefficient R, the average relative deviation (ARD) and the root mean square deviation (RMSD) were used to evaluate the fitting effect. Table 1 lists the values ​​of ARD and RMSD.

[0094] Table 1. Experimental mole fraction solubility model fitting parameters of fluticasone propionate in acetone-water system at different temperatures

[0095]

[0096] As can be seen from Table 1, the R2 values ​​of the fitting results of the CNIBS / RK model for the solubility data of fluticasone propionate at different temperatures were all greater than 0.98, and the ARD and RMSD were both within 10 -5 The order of magnitude indicates that the model can effectively fit the solubility data of fluticasone propionate in the binary solvent of acetone-water. According to the fitting results, the model parameters in Table 1 are substituted into formula (3) and transformed into formula (4), and the solubility equation of fluticasone propionate is obtained:

[0097]

[0098] Development of a Continuous Microfluidized Crystallizer Assisted by Computational Fluid Dynamics (CFD)

[0099] In order to determine the optimization parameters, a CFD model was used to simulate the crystallizer. The dimensions of the established geometric model are as follows: Figure 5 As shown in Figure 2, it is used for CFD simulation. The inner diameter of the microchannel tube for transporting the active pharmaceutical ingredient solution is d jet , the depth (length) of the microchannel tube inserted into the T-connector is L insert , and the inner diameter of the antisolvent inlet pipe (branch) is d in The diameter of the cylindrical chamber of the crystallization tube section where mixing and crystallization take place is d out , length L out Finally, crystals precipitate, grow and are discharged with the slurry.

[0100] from Figure 6 Figure a shows that the antisolvent streamlines at the T-shaped channel are divided into two streams: one stream flows to the left, then turns 180° to merge with the antisolvent stream on the right. The chaotic arrows at the turning point indicate the presence of turbulence. Turbulence is extremely unstable and random, causing uncontrollable changes in fluid mixing. Therefore, it is best to avoid the formation of turbulence. Pressure cloud diagram on the XOZ spatial coordinate axis ( Figure 6Figure b) also confirms the existence of turbulence, which is related to Figure 6 The figure a corresponds to the figure a, which shows a low pressure area. This turbulence disrupts the flow field and causes solid deposition, leading to scaling and blockage. Based on these findings, blocking measures are taken in the dead zone to prevent the formation of low pressure areas and turbulence.

[0101] In addition, the mixing process of acetone and water was simulated. Figure 7 The mass fraction distribution of acetone is shown. As can be seen from the figure, the mass fraction of acetone decreases rapidly along the flow direction on the channel axis and eventually reaches a constant value. These findings indicate that pure acetone solvent can be completely mixed within a distance of about 10 mm in the coaxial mixer, which also proves the high mixing efficiency of the continuous microfluidized crystallizer. Therefore, a high level of supersaturation can be quickly achieved during the mixing of acetone solution of fluticasone propionate and water.

[0102] It is worth noting that the injection point of acetone is located at a 90° angle of the T-shaped channel. The impact force of the antisolvent flow causes the acetone to move toward the tube wall, which is reflected in the experiment as crystallization on the tube wall. The accumulation of crystalline material can lead to scaling and channel blockage. Therefore, when optimizing the geometry of the crystallizer, the effect of the mixing point on the feed flow should be considered, and the nozzle of the coaxial mixer should be away from the antisolvent inlet flow. This arrangement ensures that the mixing is carried out in the laminar flow region, the streamlines are smoother, and it is more conducive to precise control of the crystallization process.

[0103] After optimizing the crystallizer geometry, the corresponding size parameters were determined. Acetone at a flow rate of 10 ml / min and water at a flow rate of 90 ml / min (flow rate ratio of 1:9) were added to the crystallization tube section, and the acetone concentration curve in the outlet mixed liquid was monitored, recorded as c(t), to simulate the distribution of the liquid residence time in the continuous microfluidized crystallizer.

[0104] Six different sizes of crystallization tube segments were simulated, with the diameter of the cylindrical chamber ranging from 1.27 mm to 10.06 mm, all of which are common pipe sizes available on the market. Figure 8 Figure a depicts the residence time distribution function F(t)-t curve obtained from the processing data. It can be found that when the size of the crystallization tube segment and the flow rate ratio are fixed, the smaller the crystallization tube segment inner diameter (d out ) will result in a higher feed flow rate, resulting in more intense mixing, which is reflected in a steeper curve on the F(t)-t graph. out ) is large, the flow rate is slow, the mixing is relatively incomplete, and it takes a longer time to reach the maximum outlet concentration.

[0105] The flow pattern in the crystallization tube can be characterized by the peak width of the E(θ)-θ curve, which represents the density function of the residence time distribution expressed in dimensionless time. The peak width is narrow and the variance (σ 2 ) is smaller, indicating that it is closer to the ideal plug flow, while the curve of the fully mixed flow is the widest and has the largest variance (σ 2 =1). Figure 8 As can be seen from Figure b, when d out =1.27mm, the distribution of E(θ)-θ curve is wide, which is not conducive to the consistency of crystallization. out =7.62mm and 10.16mm, the E(θ)-θ curve shows an asymmetric phenomenon, with the peak appearing earlier and the peak appearing later. In contrast, the diameter of the cylindrical chamber (d out ) are 1.91mm, 2.54mm and 5.08mm respectively, the reverse mixing phenomenon in the axial direction is reduced, the mixing in the same radial plane is more uniform, and the crystal residence time is consistent. out =2.54 mm produces the smallest variance, indicating the closest to the ideal piston flow state. Therefore, the diameter size of the cylindrical chamber of the optimized crystallization tube section can be set to 2.54 mm.

[0106] After determining the optimal dimensions, the crystallizer simulated the mixing process at different feed flow rates. Fig. 9 Shows MI-L x The curve shows the mixing index along the channel axial distance (L) under different solvent ratio conditions. x ). It is worth noting that although the feed flow ratio and total flow are different, L x = 12 mm, the MI value is always close to 1. Therefore, in this study, the mixing zone length of the continuous microfluidized crystallizer is preferably 12 mm.

[0107] For the calculation of the length of the crystal growth zone, the crystal growth rate based on the grain size (or length L) is defined as formula (5):

[0108]

[0109] Combined with the fluid flow continuity equation (6):

[0110]

[0111] Where t is the crystal growth time; Q is the total volume flow rate of the fluid flowing through the pipeline; A is the cross-sectional area of ​​the pipeline; d is the inner diameter of the pipeline; and v is the average velocity of the fluid in the pipeline. The length of the crystal growth zone can be solved by the following formula (7):

[0112]

[0113] To ensure the flexibility of operation, the flow rate is taken as the maximum flow rate of the horizontal flow pump, that is, Q = 200ml / min, and the crystal growth rate is

[0114] The lower limit of the antisolvent crystallization rate is G = 3.63 μm / s, and the target particle size is less than 5 μm. The diameter of the continuous microfluidized crystallizer is d out =2.54mm. Substituting the above values ​​into formula (7), we can calculate L out Considering that the length of the mixing zone is 12 mm, the total length of the discharge pipe is rounded to 920 mm.

[0115] Process parameter analysis

[0116] An orthogonal experiment was designed to analyze the effects of process parameters (crystallization temperature, concentration and flow rate of the active pharmaceutical ingredient solution, and antisolvent ratio (the antisolvent ratio refers to the volume ratio of the antisolvent to the active pharmaceutical ingredient solution entering the continuous microfluidized crystallizer per unit time, i.e., the flow rate ratio of the antisolvent to the active pharmaceutical ingredient solution entering the continuous microfluidized crystallizer)) on particle size. Fig.10 .

[0117] According to orthogonal experimental analysis, within the parameter range studied, the antisolvent ratio (R ATS ) for the preparation of particles D 90 The temperature and concentration of the active ingredient solution (C API ) is the second most important factor, while the flow rate of the active pharmaceutical ingredient solution (Q API ) had no statistically significant effect. However, considering productivity, the higher the flow rate, the higher the time-space yield (TSY). Therefore, maximizing the solution flow rate, considering particle size and productivity, provides the best conditions.

[0118] according to Fig.10 Analysis of temperature and D 90 Positively correlated, k i The average value of D is the smallest, which is consistent with the phenomenon that the crystal growth rate is lower at low temperatures, indicating that 5°C is the preferred crystallization condition. However, extremely low temperatures may lead to increased operating costs and the risk of water freezing. 90 The U-shaped trend indicates that there is an optimal value in the range of 15-30 mg / ml, which needs further study. ATS ) and D 90 Inversely proportional, which means that R ATS The higher the value, the smaller the particle size.

[0119] After studying the influence of various factors on particle size through orthogonal experiments, response surface analysis was also performed to find out the cross variables of process parameters.

[0120] In order to obtain a more comprehensive and accurate operating space, we conducted a three-factor interaction response surface analysis to study the effect of process parameters on particle size. The results are shown in Table 2, where each influencing factor is used as an independent variable and particle size D 90 As an evaluation index of the experiment. The particle size span (Span) is also used as a response index for process optimization. Its calculation method is shown in formula (8):

[0121]

[0122] Among them, D 10 , D 50 and D 90 It is measured based on particle size distribution data.

[0123] Table 2. Interaction effect response surface experiment and results

[0124]

[0125] The response surface was fitted using Design-Expert 8.0.6 software, and the variance analysis results of the regression model are shown in Tables 3 and 4. From the variance analysis results, it can be seen that solution concentration and RATS have a significant effect on D 90 and Span had significant and highly significant effects.

[0126] Table 3.D 90 Second-degree polynomial model ANOVA

[0127]

[0128] a "HS" means highly significant; "S" means statistically significant; "IN" means not statistically significant.

[0129] Table 4. Analysis of variance of the linear regression model of Span

[0130]

[0131] The quadratic polynomial model and linear regression model were used to describe the effect of each factor on D 90 and Span. 90 The process parameter equations for and particle size span are shown in Formula (9) and Formula (10).

[0132] D 90 =26.85-0.245A-0.297B-4.17C-1.73×10-4 AB-7.13×10 -3 AC+0.0474BC+3.46×10 -3 A 2 -5.01×10 -4 B 2 +0.204C 2 (9)

[0133] Span=2.40-6.71×10 -3 A-5.30×10 -3 B-0.0558C (10)

[0134] Among them, A is C API (mg / ml), B is Q API (ml / min), C is R ATS (v / v). The quadratic term represents the interaction effect between two factors. The smaller the coefficient, the smaller the influence of the factor on the experimental index. Fig.11 Shows a constant Q at 17.5 ml / min API Under these conditions, D 90 For solution concentration and R ATS On the other hand, the effect of solution concentration showed a parabolic trend, and the minimum particle size was observed at a concentration of about 26 mg / ml. Fig.11 Figure b shows a constant R at 5.5 ATS Under these conditions, D 90 Particle size varies with solution concentration and Q API It can be seen that the solution flow rate has no significant effect on the particle size, which indicates that a higher solution flow rate can be used within the capacity of the pump to improve production efficiency. The conclusion drawn from the response surface analysis is that the minimum D can be achieved by selecting the optimal solution concentration, increasing the solution flow rate, and increasing the antisolvent ratio. 90 particle size and highest process productivity.

[0135] The smaller the span value, the more uniform the particle size and the higher the size consistency. In the linear model, the influence of each factor shows a single trend, among which R ATS The influence coefficient is the largest. Therefore, the optimization direction of improving crystal size consistency and controlling particle size is consistent, and both can be achieved by increasing the proportion of antisolvent. Within the linear range of model fitting, the higher the solution concentration and flow rate, the more concentrated the crystal distribution of the crystal product.

[0136] The crystal size D obtained after response surface analysis 90 The regression model equation of Span is based on the crystal size D 90 Less than 5μm and the minimum span are the optimization targets, taking different R ATSSubstitute the value into the model equation and draw the running curve to obtain Fig.12 .

[0137] Fig.12 Shows D 90 =5μm when different antisolvent ratios (R ATS =7.5, 8, 8.5, 9) operating curves, the operating space above the curve corresponds to D 90 >5μm, and <5μm below. By comparison, it can be found that when the antisolvent ratio is 8 times, the operating space area is the largest, which means that in the continuous crystallization process, the operating flexibility is greater and the process is more adaptable to fluctuations in operating parameters.

[0138] Mechanism of particle size control

[0139] Factor interaction experiments showed that the antisolvent ratio had a significant effect on crystal size. To further investigate the mechanism of the mixing process of acetone and water, CFD simulations were performed on the geometry of the continuous microfluidized crystallizer. Three different solvent ratios were selected, each with three different total flow rates. Fig.13 Mixing curves for various conditions are shown to compare the mixing index at the same mixing time. The curves show that complete mixing can be achieved within 40ms at all solvent ratios. However, the solvent ratio clearly has a large impact on the mixing performance, with lower solvent ratios resulting in poorer mixing in the same amount of time.

[0140] The effect of total flow rate on mixing performance can be analyzed in two stages. In the initial stage of mixing (0-7ms), the higher the total flow rate, the better the mixing effect. However, in the subsequent stage (>7ms), its influence depends on the solvent ratio. The lower the solvent ratio, the greater the influence of total flow rate on mixing performance, while the higher the solvent ratio, the smaller the influence. In other words, the effect of solvent ratio on mixing performance is more obvious and lasting, while the effect of total flow rate is relatively small. Therefore, it is observed from the experiment that manipulating the mixing state in the mixer by adjusting the solvent ratio is a more feasible method.

[0141] Furthermore, the smaller crystal size observed at higher solvent to solution ratios can be attributed to the increase in the overall flow rate. This creates turbulence, ensuring adequate mixing and a higher concentration of antisolvent within the crystallization zone. Higher antisolvent concentrations lead to increased supersaturation levels. Analysis of the crystallization kinetics data showed that the nucleation rate at high supersaturation levels increased significantly compared to the crystal growth rate.

[0142] Stable operating performance

[0143] The present invention also evaluates the scale-up production performance and continuous stable operation performance of the continuous microfluidized crystallizer. The crystallization process temperature is 5°C, the solution concentration is 25 mg / ml, and QAPI 12.5ml / min, R ATS Set to 8 times. The monitoring time starts from the slurry leaving the crystallizer, and samples are taken every 2 minutes. The PSD and PXRD patterns of the samples are measured to evaluate the consistency of the product during continuous operation.

[0144] The online sampling and offline test was carried out for 22 minutes. The test results are shown in Fig.14 As can be seen from the figure, D 90 The Span value remains consistent throughout the long run. Although there are slight fluctuations, the D 90 The data points of Span are evenly distributed around the expected horizontal line. 90 The relative deviation is only 2.6%, and the span relative deviation is only 2.1%, indicating that the data values ​​are concentrated and the process performance is stable. The continuous microfluidized crystallizer of the present invention has excellent continuous and stable operation capabilities, and can run continuously for at least 25 minutes each time it is started, and can process a total of 2000 ml of liquid, and can continuously generate 7420 mg of fluticasone propionate micro-nanoparticles, with a yield of up to 97%, which is equivalent to about 990 doses of commercial products.

[0145] According to the above research results, using Figure 2 The continuous mixing crystallization device shown is used to prepare fluticasone propionate micro-nanoparticles.

[0146] The size parameters of the continuous microfluidization crystallizer used in Example 1 and Example 2 are as follows:

[0147] The diameter d of the microtube into which the acetone solution of fluticasone propionate is introduced jet = 0.33 mm, the depth of the microchannel tube inserted into the T-connector is L insert =20mm, and the inner diameter of the branch pipe 12 is d in = 2.54 mm, the diameter of the cylindrical chamber used for mixing acetone solution and water and crystal nucleation and growth is d out =2.54mm, length is L out =920mm.

[0148] The water mentioned in the following examples and comparative examples may be distilled water or deionized water.

[0149] Example 1 Small-scale preparation of fluticasone propionate micro-nanoparticles

[0150] Weigh 3.5g of fluticasone propionate and dissolve it in 120ml of acetone to prepare a fluticasone propionate acetone solution. Fill the first tank 10a with the fluticasone propionate acetone solution and fill the second tank 10b with water. Set the flow rate of the first pump 20a (horizontal flow pump) (20ml / min) and the flow rate of the second pump 20b (horizontal flow pump) (160ml / min). After the temperature of the first thermostat 20a and the second thermostat 20b stabilizes to 5°C, turn on the second pump 20a and pump purified water for 15 minutes to completely eliminate the bubbles in the continuous microfluidized crystallizer (in the right main pipe 11-2, the branch pipe 12 and the crystallization pipe section) and keep the system running stably. After the bubbles are removed and the flow rate and temperature are stable, the first pump 20b is turned on to allow the fluticasone propionate acetone solution and purified water to be continuously mixed and crystallized at a low temperature of 5°C. The residence time of the mixed solution in the crystallization tube section 3 of the continuous microfluidized crystallizer is 1.55s. The crystal slurry flowing out of the continuous microfluidized crystallizer is collected and immediately filtered; after vacuum drying at 45°C, 3.4g of dry product is obtained, with a total yield of 97.1%.

[0151] Example 2 Small-scale preparation of fluticasone propionate micro-nanoparticles

[0152] Weigh 3.5 g of fluticasone propionate and dissolve it in 120 ml of acetone to prepare a fluticasone propionate acetone solution. Fill the first tank 10a with the fluticasone propionate acetone solution, and fill the second tank 10b with water. Set the flow rate (8 ml / min) of the first pump 20a (horizontal flow pump) and the flow rate (100 ml / min) of the second pump 20b (horizontal flow pump). After the temperature of the first temperature controller 20a and the second temperature controller 20b to be controlled is stabilized to 5°C, the second pump 20a is turned on to pump purified water for 15 minutes to completely eliminate the bubbles in the continuous microfluidized crystallizer (in the right main pipe 11-2, the branch pipe 12 and the crystallization tube section) and keep the system running stably; after the bubbles are eliminated, the flow rate and temperature are stabilized, the first pump 20b is turned on to continuously mix and crystallize the fluticasone propionate acetone solution and purified water at a low temperature of 5°C, and the residence time of the mixed solution in the crystallization tube section 3 of the continuous microfluidized crystallizer is 2.59s. The crystal slurry flowing out of the continuous microfluidized crystallizer is collected and immediately filtered, and 3.3g of dry product is obtained after vacuum drying at 45°C, with a total yield of 94.3%.

[0153] The PSD diagram of the fluticasone propionate micro-nanoparticles prepared in Example 1 is as follows: Fig.15 As shown, the particle size D 90 The PSD of the fluticasone propionate micro-nanoparticles prepared in Example 2 is shown in FIG. Fig.16 As shown, the particle size D 90 The result is 4.736 μm, which meets the particle size requirement of the raw material for dry powder inhalation preparations (<5 μm), as shown in Table 5.

[0154] Table 5

[0155] Sample source <![CDATA[D 90 (μm)]]> Example 1 5.907 Example 2 4.736 Qualified product requirements ＜5

[0156] Conclusion: According to the PSD results measured in Example 1 and Example 2, it can be seen that the particle size distribution of the fluticasone propionate micro-nanoparticles prepared by the device and method provided by the present invention is concentrated, D 90 The size can be adjusted by the anti-solvent ratio, and the product particle size can be adjusted as needed.

[0157] Example 3 Scale-up preparation of fluticasone propionate micro-nanoparticles

[0158] Keep the size and process of the continuous microfluidized crystallizer unchanged, and extend the operation time to prepare a larger amount of fluticasone propionate micro-nanoparticles. Weigh 30.0 g of fluticasone propionate and dissolve it in 1200 ml of acetone to prepare a fluticasone propionate acetone solution. Fill the first tank 10a with the fluticasone propionate acetone solution and fill the second tank 10b with water. Set the flow rate of the first pump 20a (horizontal flow pump) (8 ml / min) and the flow rate of the second pump 20b (horizontal flow pump) (100 ml / min). After the temperature of the first thermostat 20a and the second thermostat 20b stabilizes to 5°C, the second pump 20a is turned on to pump purified water for 15 minutes to completely remove the bubbles in the continuous microfluidized crystallizer and keep the system running stably; after the bubbles are removed and the flow rate and temperature are stable, the first pump 20b is turned on to allow the fluticasone propionate acetone solution and purified water to be continuously mixed and crystallized at a low temperature of 5°C. The residence time of the mixed solution in the crystallization tube section 3 of the continuous microfluidized crystallizer is 2.59s. The crystal slurry flowing out of the continuous microfluidized crystallizer is collected and immediately filtered. After vacuum drying at 45°C, 29.3g of dry product is obtained, with a total yield of 97.7%, D 90 It is 4.689μm.

[0159] Comparative Example 1 Preparation of Fluticasone Propionate Micropowder Using an Intermittent Crystallization Reactor (Intermittent Crystallization Method)

[0160] In order to compare with the continuous crystallization process, batch crystallization was carried out using a 1000 ml batch crystallizer.

[0161] Weigh 3.0g of fluticasone propionate, add 100ml of acetone to prepare a drug active ingredient solution, and place 600ml of water as an anti-solvent in an intermittent crystallization kettle. The drug active ingredient solution is added dropwise to the intermittent crystallization kettle and mixed with water. The anti-dissolution crystallization is carried out at a low temperature of 10°C and under vigorous stirring to obtain micro-nano particles. After the crystal slurry is filtered and vacuum dried at 45°C, 2.8g of dry product is obtained, with a total yield of 93.3%.

[0162] The fluticasone propionate micro-nanoparticles prepared in Example 2 and Comparative Example 1 were imaged using a polarizing microscope and a scanning electron microscope to compare the differences in their crystal morphologies. The results are as follows: Fig.17 shown. Fig.17 Figures a and c show the morphology of the crystals of Example 2, which are mainly short plate-like crystals. These crystals appear intact and well dispersed, with very little agglomeration between particles. Most of the crystals are less than 5 μm in size and have smooth and intact surfaces. Fig.17 Figures b and d show the morphology of the crystals of Comparative Example 1, showing irregular long flakes, obvious agglomeration between the flake crystals, poor dispersibility, and overlapping and sticking of the flake crystals. Compared with the continuous microfluidized crystallizer of the present invention, the mixing effect of the intermittent crystallization kettle is poor, which may be the reason for the observed larger crystal size. In addition, the residence time of the mixed solution in the intermittent crystallization kettle is long, and the opportunities for crystal growth, contact and agglomeration are increased, resulting in relatively poor dispersibility.

[0163] The particle size distribution (PSD) of the fluticasone propionate micro-nanoparticles prepared in Example 2 and Comparative Example 1 and a commercially available fluticasone propionate powder was measured. The results are as follows: Fig.18 As shown. Fig.18 The PSD results show that the fluticasone propionate micro-nanoparticles prepared by the continuous microfluidized crystallizer of the present invention have smaller particle sizes and more concentrated distribution than the fluticasone propionate crystals prepared by the intermittent crystallization reactor and the commercially available fluticasone propionate powder. This indicates that more consistent and uniform fluticasone propionate micro-nanoparticles can be obtained by the continuous microfluidized crystallizer of the present invention.

[0164] The inventors of the present application also compared the process parameters of preparing fluticasone propionate micro-nanoparticles using the continuous microfluidized crystallizer of the present invention and using an intermittent crystallization reactor, and calculated the yield (actual product mass received divided by initial feed mass) and time-space yield (the number of products obtained per unit volume of equipment in a given time) of the products obtained by the two crystallizers when the material composition is the same. The results are summarized in Table 6.

[0165] Table 6. Comparison of the process characteristics of crystallization using a continuous microfluidizer and crystallization using a batch crystallizer

[0166]

[0167] It can be seen from Table 6 that compared with the preparation of micro-nano particles using an intermittent crystallization kettle, the continuous microfluidized crystallizer of the present invention has higher flexibility and production efficiency in the preparation of fluticasone propionate micro-nano particles. This is mainly reflected in that the continuous microfluidized crystallizer can adjust the single batch output as needed without being limited by the volume of the reactor. In terms of crystallization yield, the yield of the continuous crystallization process exceeds that of the kettle crystallizer, which shows that the continuous microfluidized crystallizer of the present invention has a higher material recovery capacity. In addition, the continuous microfluidized crystallizer of the present invention has a smaller volume and a more compact structure, which greatly improves the space utilization rate, and the significant shortening of the residence time also makes the time-space yield ten times higher than that of the traditional process. Therefore, compared with the traditional intermittent crystallization kettle, the crystallization efficiency of the continuous microfluidized crystallizer of the present invention has been greatly improved, which is in line with the development trend of rapid, lean and agile manufacturing in the pharmaceutical industry and has broad application prospects.

[0168] In addition, it should be understood that the protection content of the present invention is not limited to the above-mentioned embodiments. After reading the above-mentioned teaching content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A continuous microfluidized crystallizer, characterized in that: The continuous microfluidized crystallizer comprises a T-shaped connector, a microchannel tube and a crystallization tube section with a cylindrical chamber. The T-shaped connector includes a main pipe and a branch pipe, wherein the main pipe is divided into a left main pipe and a right branch pipe with the axis where the branch pipe is located as the center, the microchannel pipe is located in the left main pipe and the right branch pipe, the left main pipe is used to fix the microchannel pipe, and the right branch pipe is connected to the crystallization pipe segment and is in flow communication with the branch pipe. The microchannel tube is used to transport a solution of an active pharmaceutical ingredient, and the branch tube is used to transport an anti-solvent. The microchannel tube and the crystallization tube segment are aligned and positioned axially under the fixation of the T-shaped connector, so that the solution of the active pharmaceutical ingredient is introduced at the axis of the crystallization tube segment and mixed with the anti-solvent, so that the active pharmaceutical ingredient is crystallized and precipitated to form a crystal slurry.

2. A device for preparing micro-nano particles of active pharmaceutical ingredients, the device comprising a first tank, a second tank, a first pump, a second pump, a first temperature controller, a second temperature controller, the continuous microfluidization crystallizer according to claim 1, and a separator, The first tank and the second tank are used to store the active pharmaceutical ingredient solution and the anti-solvent, respectively. The first pump and the second pump are used to transport the active pharmaceutical ingredient solution in the first tank and the anti-solvent in the second tank to the continuous microfluidization crystallizer, respectively. The first temperature controller and the second temperature controller are used to adjust the temperature of the active pharmaceutical ingredient solution and the anti-solvent entering the continuous microfluidized crystallizer from the first tank and the second tank, respectively, so that they reach the target temperature before mixing, so that the active pharmaceutical ingredient is crystallized and precipitated at the target temperature to form a crystal slurry. The separator is connected to the continuous microfluidized crystallizer to collect and separate the crystal slurry to obtain micro-nano particles of active pharmaceutical ingredients.

3. A method for preparing fluticasone propionate micro-nanoparticles, characterized in that: The preparation method comprises the following steps: (1) providing acetone, and adding fluticasone propionate to the acetone to prepare an acetone solution of fluticasone propionate; (2) Providing water; (3) The acetone solution of fluticasone propionate and water are simultaneously introduced into the continuous microfluidized crystallizer according to claim 1 in a proportion, and during the mixing process of the acetone solution of fluticasone propionate and water, fluticasone propionate crystals are precipitated to form a slurry. (4) collecting the slurry, separating and drying to obtain fluticasone propionate micro-nanoparticles, The particle size D of the fluticasone propionate micro-nano particles 90 It is 1 to 20 μm, more preferably 1 to 8 μm, and most preferably 1 to 5 μm.

4. The method for preparing fluticasone propionate micro-nanoparticles according to claim 3, characterized in that: The concentration of the fluticasone propionate acetone solution is 10 to 50 g / L, more preferably 25 to 35 g / L, and / or Before being transported to the continuous microfluidized crystallizer, the temperature of the fluticasone propionate acetone solution and water are adjusted to 0-10°C, more preferably 0-5°C.

5. The method for preparing fluticasone propionate micro-nanoparticles according to claim 4, characterized in that: The volume ratio of the fluticasone propionate acetone solution to water input into the continuous microfluidized crystallizer is 1:5-25, preferably 1:5-15.

6. The method for preparing fluticasone propionate micro-nanoparticles according to claim 5, characterized in that: The inner diameter of the microchannel tube of the continuous microfluidized crystallizer is 0.33 mm, the inner diameter of the branch tube is 2.54 mm, the diameter of the cylindrical chamber of the crystallization tube section is 2.54 mm, and the length is 920 mm. The acetone solution of fluticasone propionate is input into the continuous microfluidized crystallizer at a flow rate of 5 to 25 ml / min, and water is input into the continuous microfluidized crystallizer at a flow rate of 25 to 200 ml / min. More preferably, the acetone solution of fluticasone propionate is input into the continuous microfluidized crystallizer at a flow rate of 12.5 ml / min, and water is input into the continuous microfluidized crystallizer at a flow rate of 100 ml / min. The residence time of the mixed solution of the fluticasone propionate acetone solution and water in the crystallization tube section is 0.5 to 2.0 seconds, preferably 1.38 seconds.

7. A method for preparing micro-nano particles of active pharmaceutical ingredients, characterized in that: The preparation method comprises the following steps: (1) providing a good solvent for the pharmaceutically active ingredient, and adding the pharmaceutically active ingredient into the good solvent to prepare a pharmaceutically active ingredient solution; (2) providing an anti-solvent for the active ingredient of the drug, wherein the anti-solvent has good miscibility with the good solvent; (3) simultaneously feeding the pharmaceutical active ingredient solution and the anti-solvent into the continuous microfluidized crystallizer according to claim 1 in a proportion, wherein during the mixing process of the pharmaceutical active ingredient solution and the anti-solvent, the pharmaceutical active ingredient crystallizes and forms a slurry; (4) collecting the slurry, separating and drying to obtain the micro-nanoparticles of the active pharmaceutical ingredient, The particle size distribution D of the micro-nano particles 90 It is 1 to 20 μm, more preferably 1 to 8 μm, and most preferably 1 to 5 μm.

8. The method for preparing micro-nano particles of active pharmaceutical ingredients according to claim 7, characterized in that: The pharmaceutically active ingredient is selected from fluticasone propionate, salmeterol, indacaterol, salmeterol, olodaterol, vilanterol, formoterol, ciclesonide, budesonide, tiotropium bromide, terbutaline sulfate, salbutamol sulfate, ipratropium bromide, beflomethasone, mometasone, beclomethasone propionate, fluticasone, prednisone, prednisolone, dexamethasone, or a pharmaceutically acceptable salt thereof.

9. The method for preparing micro-nano particles of active pharmaceutical ingredients according to claim 8, characterized in that: The anti-solvent is selected from water, and the good solvent is selected from an organic solvent having good miscibility with water. Preferably, the organic solvent having good miscibility with water is selected from acetone, methanol, ethanol, isopropanol, ethylene glycol, furan, N,N-dimethylformamide, dimethyl sulfoxide, tert-butanol, 2-butanol, ethyl acetate, acetonitrile, 2-butanone, 3-pentanone, tetrahydrofuran, 1,4-dioxane, or a combination thereof.

10. The method for preparing micro-nano particles of active pharmaceutical ingredients according to claim 7, characterized in that: The concentration of the active pharmaceutical ingredient solution is 10 to 100 g / L, and / or The temperatures of the active pharmaceutical ingredient solution and the anti-solvent are adjusted to -10 to 30° C. respectively before being transported to the continuous microfluidization crystallizer.

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