S-(-)-bisoprolol fumarate crystal and a continuous production method thereof

Abstract

The application discloses a continuous preparation method of S-(-)-fumarate bisoprolol crystals, which comprises the following steps: pumping S-(-)-fumarate bisoprolol solution into a micro-channel reactor in a continuous flow mode, and cooling to form a suspension containing fine crystal nuclei; continuously pumping the suspension into a first continuous crystallizer, and performing crystal nucleus growth in an ultrasonic field to obtain crystal slurry; continuously feeding the crystal slurry into a second continuous crystallizer, and performing crystal growing; and filtering, washing, drying, and thus obtaining S-(-)-fumarate bisoprolol crystals. With the synergistic effect of precise temperature control of the micro-channel reactor and the ultrasonic assisted crystallizer, the I crystal product with narrow particle size distribution and significantly reduced hygroscopicity is prepared.

Description

Technical Field

[0001] This invention belongs to the field of drug crystallization technology, specifically relating to an S-(-)-fumaric acid bisoprolol crystal and its continuous preparation method. Background Technology

[0002] Bisoprolol fumarate, developed in 1985 by Merck in Germany, is a β1-receptor blocker that dilates blood vessels and lowers blood pressure, making it a commonly used antihypertensive drug in clinical practice. Its chemical name is 1-[4-[[2-(1-methylethoxy)ethoxy]methyl]phenoxy]-3-[(1-methylethyl)amino]-2-propanol fumarate, and its structural formula is shown below: , It possesses a chiral center and exists as two enantiomers, R and S. Currently, this drug is used in its racemic form for clinical use, pharmacological studies, and toxicological research. Studies have shown that S-(-)-bisoprolol has an 80-fold greater blocking effect on β-receptors than its R-(+)-enantiomer (see the paper "Polymorphic forms of bisoprolol fumarate", Journal of Thermal Analysis and Calorimetry, 2018).

[0003] Bisoprolol fumarate is a white, odorless powder that is highly soluble in water, readily soluble in ethanol, slightly soluble in acetone, and insoluble in ether. Due to its high water solubility, the crystallization process directly affects the particle size distribution, morphology, and hygroscopic properties of the crystals, thereby influencing the drug's dissolution rate and bioavailability.

[0004] Existing bisoprolol fumarate crystallization technologies primarily focus on crystal form control and improving moisture absorption resistance. CN106349090B, by dissolving bisoprolol fumarate in isopropanol and controlling the temperature for crystallization, prepared a crystal form (I) with better solubility, stability, and lower hygroscopicity compared to the original drug. However, under RH 80% conditions, the weight gain due to moisture absorption was only 1%~1.5% after 24 hours, indicating a need for further reduction in hygroscopicity. CN118221534A employs pressure crystallization technology, dissolving at 35~55℃ and then pressurizing to 80~200 MPa for crystallization. The resulting product has a chemical purity >99.9% and hygroscopicity far lower than conventional products (0.5%~0.6% weight gain due to moisture absorption after 10 days under RH 80%). However, this method involves high pressure and demanding process conditions. CN118221533A produces large-particle, elongated cubic crystals with a D90 of 300-500 μm by heating and dissolving the crystals, rapidly cooling them to 35-45℃, adding seed crystals, and combining this with ultrasonic treatment. These crystals have good fluidity and effectively reduce the dissolution rate, making them suitable as sustained-release agents. However, they rely on the addition of external seed crystals.

[0005] Microchannel continuous crystallization is a chemical reaction technology based on the special structure of microchannels. Its core lies in crystallization operations within micrometer-scale channels (typically with characteristic dimensions ranging from tens to hundreds of micrometers). Utilizing the extremely high specific surface area of ​​these channels, heat and mass transfer processes are greatly enhanced, overcoming the kinetic limitations of traditional crystallizers and achieving millisecond-level ideal mixing and isothermal changes. This technology enables continuous crystal preparation, yielding crystal products with narrow particle size distributions and significantly reduced hygroscopicity.

[0006] There are currently no publicly reported methods for preparing S-(-)-fumarate bisoprolol I crystal form using a combination of continuous flow microchannels and continuous ultrasonic crystallizers. Summary of the Invention

[0007] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0008] In view of the problems existing in the above and / or prior art, the present invention is proposed.

[0009] One objective of this invention is to provide an S-(-)-fibranoic acid bisoprolol crystal, which, with the aid of precise temperature control in a microchannel reactor and the synergistic effect of an ultrasonic-assisted crystallizer, produces an I-type product with a narrow particle size distribution and significantly reduced hygroscopicity.

[0010] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a continuous preparation method for S-(-)-fumaric acid bisoprolol crystals, comprising, The S-(-)-fumaric acid bisoprolol solution was pumped into a microchannel reactor in a continuous flow manner and cooled to form a suspension containing fine crystal nuclei. The suspension is continuously pumped into a first continuous crystallizer, where crystal nuclei grow in an ultrasonic field to obtain a crystal slurry; The crystal slurry is continuously fed into a second continuous crystallizer for crystal growth; After filtration, washing, and drying, S-(-)-bioprolol fumarate crystals are obtained.

[0011] In this paper, the term "microchannel reactor" refers to a microreactor whose internal structure is mainly composed of micron-sized channels.

[0012] As a preferred embodiment of the continuous preparation method of S-(-)-fibranoic acid bisoprolol crystals of the present invention, wherein: the S-(-)-fibranoic acid bisoprolol solution is prepared by dissolving S-(-)-fibranoic acid bisoprolol in an organic solvent and maintaining the solution temperature at 45~60℃ until complete dissolution; The organic solvent is selected from one or two of ethyl acetate, isopropanol, n-propanol, ethanol, and methanol, preferably isopropanol, and the mass-to-volume ratio of the organic solvent to S-(-)-bioprolol fumarate is 2~4 mL:1g.

[0013] As a preferred embodiment of the continuous preparation method of S-(-)-fibranoic acid bisoprolol crystals of the present invention, the microchannel reactor is composed of several microchannel modules, the volume of the microchannel module is 5~60 mL, the inner diameter of the channel of the microchannel module is 500~800 μm, and the feed flow rate is 1~10 mL / min.

[0014] In a preferred embodiment of the continuous preparation method of S-(-)-fibranoic acid bisoprolol crystals of the present invention, the step of cooling to form a suspension containing fine crystal nuclei is to cool to 25-30°C at a cooling rate of 10-15°C / min.

[0015] As a preferred embodiment of the continuous preparation method of S-(-)-fibranoic acid bisoprolol crystals of the present invention, the S-(-)-fibranoic acid bisoprolol solution is pumped into a first microchannel module for cooling to 35~40°C, continuously introduced into a second microchannel module for cooling to 30~35°C, and then introduced into a third microchannel module for cooling to 25~30°C, so that the system enters a supersaturated state and forms fine crystal nuclei, and a suspension containing fine crystal nuclei is obtained by discharging the material.

[0016] As a preferred embodiment of the continuous preparation method of S-(-)-fibranoic acid bisoprolol crystals of the present invention, the crystal nucleus growth is carried out in an ultrasonic field with an ultrasonic frequency of 10~30 kHz, an ultrasonic power of 100~300 W, a stirring speed of 50~200 r / min, and the crystal nucleus growth is carried out in the ultrasonic field at 25~30 ℃ for a residence time of 15~35 min.

[0017] As a preferred embodiment of the continuous preparation method of S-(-)-fibranoic acid bisoprolol crystals of the present invention, the crystal growth process involves rapidly cooling to 15~20 ℃ and growing crystals for 2~6 h; wherein the rapid cooling rate is 0.5~2 ℃ / min and the stirring speed is 50~100 r / min.

[0018] As a preferred embodiment of the continuous preparation method of S-(-)-fibranoic acid bisoprolol crystals of the present invention, wherein: the washing solvent is selected from one or two of ethyl acetate, isopropanol, n-propanol, ethanol, and methanol, preferably isopropanol; The drying process is vacuum drying at a temperature of 50 ℃ for 4-6 hours. The washing solvent used for the filter cake after negative pressure filtration is the same as the organic solvent used to dissolve S-(-)-fibrinolytic acid bisoprolol.

[0019] Another object of the present invention is to provide an S-(-)-fibranoic acid bisoprolol crystal, wherein the XRD pattern of the crystal, when subjected to Cu-Kα radiation for X-ray powder analysis, exhibits characteristic diffraction peaks at 2θ angles of 5.523°, 10.852°, 13.418°, 16.259°, 19.843°, 20.938°, 21.793°, 22.293°, 23.949°, 24.232°, 25.773°, 27.242°, and 28.784°.

[0020] As a preferred embodiment of the S-(-)-bioprolol fumarate crystal of the present invention, the crystal further possesses the following characteristics: (i) The DSC spectrum of the crystal has a characteristic melting endothermic peak at 102.68 °C; (ii) The weight gain after 24 hours of humidification under RH 80% conditions is ≤0.45%.

[0021] Compared with the prior art, the present invention has the following beneficial effects: This invention achieves continuous preparation of S-(-)-fumaric acid bisoprolol crystals by combining a microchannel reactor with a continuous crystallizer, which is suitable for large-scale industrial production.

[0022] This invention confines the nucleation process to a microchannel reactor, achieving uniform nucleation through millisecond-level rapid cooling; and transfers the crystal growth process to a continuous crystallizer, where it is carried out under mild conditions, resulting in a product with an extremely narrow particle size distribution.

[0023] This invention introduces an ultrasonic field into a continuous crystallizer, utilizing the cavitation effect of ultrasound to promote secondary nucleation and crystal growth, thus obtaining a stable product without the need for external seed crystals.

[0024] The I-type product prepared by this invention has a significantly lower weight gain after 24 hours of moisture induction under RH 80% conditions compared to existing batch process products, which is beneficial for improving the storage stability of the formulation. Attached Figure Description

[0025] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein: Figure 1 This is a schematic diagram of the apparatus used in the continuous preparation method of the present invention.

[0026] Figure 2 The X-ray powder diffraction (XRD) pattern of the S-(-)-fumaric acid bisoprolol I crystal form obtained in Example 1 of this invention.

[0027] Figure 3 The differential scanning calorimetry (DSC) curve of the S-(-)-fumaric acid bisoprolol I crystal form obtained in Example 1 of this invention.

[0028] Figure 4 The Fourier transform infrared (FTIR) spectrum of the S-(-)-fumaric acid bisoprolol I crystal form obtained in Example 1 of this invention. Detailed Implementation

[0029] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0030] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0031] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0032] Unless otherwise specified, all raw materials used in the examples are commercially available.

[0033] The microchannel reactor used in this embodiment is a Corning LFR-3FM microchannel reactor with an inner diameter of 500 μm, a single plate holding capacity of 27 mL, and the plate material is high borosilicate glass. The connecting pipeline is made of polytetrafluoroethylene. The feeding unit has two feed pumps with a flow rate range of 0.1~10 mL / min and a flow rate accuracy of ±0.3%; the maximum pressure is 1.8 MPa, and the upper limit of the shut-off pressure can be set to 1.8 MPa. The reaction unit consists of several microchannel modules, featuring a modular design that allows for disassembly and assembly as needed. This facilitates module maintenance and adjustments based on the synthesis process requirements, offering high flexibility. The microchannel reactor typically uses three or more microchannel modules, which can be selected by those skilled in the art based on the required mass / heat transfer efficiency and residence time. Each microchannel module has a volume of 27 mL and is made of high borosilicate glass. The normal operating temperature range is -20℃ to 200℃, expandable to -40℃ to 200℃. Temperature control is achieved using a heat exchanger. The reactor system pressure is ≤18 bar; the applicable fluid flow rate range is 1 mL / min to 10 mL / min. The liquid-to-liquid specific surface area range within the modules is 1,000 to 10,000 m². -1 Overall mass transfer coefficient Kla: 1.9~41 s -1 The gas-liquid specific surface area range in the module is 160~1,300 m². -1 Overall mass transfer coefficient Kla: 0.2~3 s -1 .

[0034] The reaction temperature in the microchannel reactor can be precisely controlled by a heat exchanger. The reactants enter the reactor through a sample introduction device, which may include, but is not limited to, methods such as pumping, extrusion, permeation, or jetting. In some embodiments, the reactants are pumped by plunger pumps and fed into the microchannel reactor through a feed frame for reaction.

[0035] The first and second continuous crystallizers used in this embodiment have the same structure, only the internal working volume is different. The continuous crystallizer adopts the high-pressure ultrasonic stirring reactor of Shanghai Laibei Scientific Instrument Co., Ltd. The reactor is equipped with a jacket, which can be circulated with water to control the temperature. The temperature control range is 0-100 ℃, the stirring speed range is 0-1000 rpm, and the ultrasonic parameters range is 0-50 kHz and 0-1000 W.

[0036] like Figure 1 As shown, the continuous processing device includes a microchannel reactor 100, a first continuous crystallizer 200 and a second continuous crystallizer 300. The microchannel reactor 100 includes a first microchannel module 101, a second microchannel module 102, a third microchannel module 103, a heat exchanger (not shown in the figure), and a feed pump 104.

[0037] The feed pump 104 pumps the raw drug solution into the microchannel reactor 100 in a continuous flow manner. The microchannels nucleate and form a suspension containing fine crystal nuclei. The peristaltic pump 201 continuously pumps the suspension into the first continuous crystallizer 200, where crystal nuclei grow in an ultrasonic field. The peristaltic pump 301 continuously feeds the resulting crystal slurry into the second continuous crystallizer 300 for crystal growth. Finally, the target crystal is obtained after post-processing such as filtration, washing, and drying.

[0038] Example 1

[0039] This embodiment provides a method for the continuous preparation of S-(-)-fumaric acid bisoprolol I crystal form, specifically including the following steps: Take 20 g of S-(-)-bioprolol fumarate raw material, add 50 mL of isopropanol (liquid-to-solid ratio 2.5 mL / g), heat to 45℃, stir for 60 min until completely dissolved, remove mechanical impurities by hot filtration, obtain filtrate, and keep warm at 45℃ for later use. Pump the above filtrate continuously into microchannel reactor 100 at a flow rate of 3 mL / min through feed pump 104 (vibrating high-pressure constant flow pump). Microchannel reactor 100 consists of three heart-shaped microchannel modules connected in series (total channel volume 27 mL), with a residence time of 9 min. The material flows sequentially through three temperature zones at a cooling rate of 10℃ / min. It is cooled to 35℃ in the first microchannel module 101, then continuously enters the second microchannel module 102 for cooling to 30℃, and finally enters the third microchannel module 103 for cooling to 25℃. The outlet temperature is stabilized at 25℃, and a suspension containing fine crystal nuclei is obtained as the discharged material. The suspension was continuously pumped into the first continuous crystallizer 200 (working volume 45 mL) using a peristaltic pump 201 at a flow rate of 3 mL / min. The stirring speed was set to 160 r / min, the ultrasonic frequency to 20 kHz, and the ultrasonic power to 200 W. The first continuous crystallizer 200 was jacketed and circulated with water to maintain a temperature of 25℃, with a residence time of 15 min. The crystal slurry was continuously pumped from the first continuous crystallizer 200 into the second continuous crystallizer 300 (working volume 450 mL) using a peristaltic pump 301, and cooled to 15℃ at a rate of 0.5℃ / min. The stirring speed was set to 80 r / min, and the residence time to 2.5 h. After being filtered under negative pressure, the filter cake was washed twice with isopropanol and dried under vacuum at 50℃ for 6 h to obtain a white crystalline powder.

[0040] The crystal prepared in Example 1 is of crystal form I. X-ray powder analysis using Cu-Kα radiation revealed characteristic diffraction peaks in its XRD pattern at 2θ angles of 5.523°, 10.852°, 13.418°, 16.259°, 19.843°, 20.938°, 21.793°, 22.293°, 23.949°, 24.232°, 25.773°, 27.242°, and 28.784° (see...). Figure 2 Its DSC spectrum shows a characteristic melting endothermic peak at 102.68℃ (see...). Figure 3 Infrared spectrum (see) Figure 4 ) and the Spectrum Collection of the Chinese Pharmacopoeia 859 Figure 1 To.

[0041] Example 2

[0042] Compared to Example 1, the dissolution temperature of S-(-)-fibranoic acid bisoprolol in isopropanol was changed to 55°C. It then entered the first microchannel module 101 for cooling to 45°C, continuously entered the second microchannel module 102 for cooling to 35°C, and then entered the third microchannel module 103 for cooling to 25°C. The outlet temperature was stabilized at 25°C, while all other parameters remained consistent. A white crystalline powder was obtained.

[0043] Example 3

[0044] Compared to Example 1, an isopropanol solution of S-(-)-bioprolol fumarate was continuously pumped into a microchannel reactor at a flow rate of 5 mL / min using a vibratory high-pressure constant flow pump, with a residence time of 5.4 min in the microchannel module. All other parameters remained the same, resulting in a white crystalline powder.

[0045] Example 4

[0046] Compared to Example 1, the suspension containing fine crystal nuclei obtained from the third microchannel module 103 was continuously pumped into the first continuous crystallizer by a peristaltic pump at a flow rate of 1.8 mL / min and a residence time of 25 min. All other parameters remained the same. A white crystalline powder was obtained.

[0047] Example 5

[0048] Compared to Example 1, the suspension containing fine crystal nuclei obtained from the third microchannel module 103 was continuously pumped into the first continuous crystallizer by a peristaltic pump at a flow rate of 1.29 mL / min and a residence time of 35 min. All other parameters remained the same. A white crystalline powder was obtained.

[0049] Example 6

[0050] Compared to Example 1, the ultrasonic frequency was 20 kHz and the ultrasonic power was 100 W. All other parameters remained the same. A white crystalline powder was obtained.

[0051] Example 7

[0052] Compared to Example 1, the ultrasonic frequency was 20 kHz and the ultrasonic power was 300 W. All other parameters remained the same. A white crystalline powder was obtained.

[0053] Example 8

[0054] Compared to Example 1, the ultrasonic frequency was 30 kHz and the ultrasonic power was 200 W. All other parameters remained the same. A white crystalline powder was obtained.

[0055] Comparative Example 1

[0056] The preparation method was carried out according to Example 1 of the patent specification in CN106349090B. 20 g of bisoprolol fumarate raw material was added to 60 mL of isopropanol, heated and dissolved at 55°C, and after hot filtration, the temperature was slowly reduced to 15-20°C under stirring at 120 r / min for 4 h to crystallize. After filtration, the powder was vacuum dried at 55°C for 5.5 h to obtain a white crystalline powder.

[0057] Comparative Example 2

[0058] The difference between this comparative example and Example 1 is that no ultrasonic treatment is applied in the first continuous crystallizer, while all other process parameters remain unchanged. The steps are as follows: Take 20 g of S-(-)-bioprolol fumarate raw material, add 50 mL of isopropanol (liquid-to-solid ratio 2.5 mL / g), heat to 45℃, stir for 60 min until completely dissolved, remove mechanical impurities by hot filtration, and keep the filtrate at 45℃ for later use. Pump the filtrate continuously into a microchannel reactor at a flow rate of 3 mL / min using a vibratory high-pressure constant flow pump. The microchannel reactor consists of three heart-shaped microchannel modules connected in series (total channel volume 27 mL). The material flows sequentially through the three temperature zones at a cooling rate of 10℃ / min. It is cooled to 35℃ in the first microchannel module 101, then continuously cooled to 30℃ in the second microchannel module 102, and finally cooled to 25℃ in the third microchannel module 103. The outlet temperature is stabilized at 25℃, and a suspension containing fine crystal nuclei is obtained as the discharged material. The suspension was continuously fed into the first continuous crystallizer (working volume 45 mL), with a stirring speed of 160 r / min, a temperature controlled at 25℃, and a residence time of 15 min. The crystal slurry was continuously fed from the first continuous crystallizer into the second continuous crystallizer (working volume 450 mL), cooled to 15℃ at a rate of 0.5℃ / min, with a stirring speed of 80 r / min and a residence time of 2.5 h. After being filtered under negative pressure, the filter cake was washed twice with isopropanol and dried under vacuum at 50℃ for 6 h to obtain a white crystalline powder.

[0059] Comparative Example 3

[0060] The difference between this comparative example and Example 1 is that in the first continuous crystallizer (working volume 45 mL), the ultrasonic frequency was 50 kHz and the ultrasonic power was 800 W. All other parameters remained the same. A white crystalline powder was obtained.

[0061] Comparative Example 4

[0062] Compared to Example 1, an isopropanol solution of S-(-)-bioprolol fumarate was continuously pumped into a microchannel reactor at a flow rate of 9 mL / min using a vibratory high-pressure constant flow pump, with a residence time of 3 min in the microchannel module. All other parameters remained the same, resulting in a white crystalline powder.

[0063] The comparison results of the crystallization parameters and performance indicators of bisoprolol fumarate obtained from the above examples and comparative examples are shown in Table 1.

[0064] Table 1

[0065] Among them, hygroscopicity Weight gain after 24 hours of humidification under RH 80% conditions; hygroscopicity The weight gain was determined by 120 hours of humidification under RH 80% conditions.

[0066] In Table 1, the yield is calculated as: Crystallization yield = Actual crystal mass obtained / Theoretical crystal mass obtained.

[0067] The purity in Table 1 was determined by high-performance liquid chromatography (HPLC). A Waters e2695 HPLC system was used, with octadecylsilane-bonded silica gel as the stationary phase. The mobile phase A was phosphate buffer (3.45 g ammonium dihydrogen phosphate, 900 mL water, pH adjusted to 2.5 with phosphate, and water added to a final volume of 1000 mL). The mobile phase B was phosphate buffer-acetonitrile (20:80, V / V). Gradient elution was used. The column temperature was 30℃, the flow rate was 1.0 mL / min, the detection wavelength was 225 nm, and the injection volume was 10 μL. The gradient is shown in Table 2. Table 2

[0068] The test methods for D90, D50, and D10 in Table 1 refer to the laser diffraction method in the Chinese Pharmacopoeia (General Chapter 0982). A laser particle size analyzer is used, the dispersion pressure is 0.2~0.4 MPa, the injection speed is 50~80%, and the light shading rate is 0.5%~5%. Each sample is measured 3 times, and the average value is taken. The values ​​of D10, D50, and D90 are reported.

[0069] The hygroscopicity test method in Table 1 is as follows: The examples and comparative examples are placed in clean weighing bottles and laid flat with the bottles open. The moisture absorption and weight gain are examined under the conditions of 25℃±1℃ and RH80%±2% for 24 hours and 120 hours.

[0070] As can be seen from the data in Table 1: Example 1 (ultrasound 200 W) showed a weight gain of only 0.20% after 24 hours and 0.30% after 120 hours under RH 80% conditions; while Comparative Example 1 (intermittent crystallization without ultrasound) showed gains of 0.65% and 1.35% respectively, and Comparative Example 2 (continuous crystallization without ultrasound) showed gains of 0.40% and 0.80% respectively. This indicates that the ultrasonic process of the present invention can reduce hygroscopicity by approximately 50% to 70%, and the advantages are more pronounced over long-term storage.

[0071] In Example 1, the D90 was 230.2 μm, the D50 was 193.9 μm, and the D10 was 131.2 μm. The calculated Span = (D90-D10) / D50 ≈ 0.51, indicating an extremely narrow particle size distribution. In Comparative Example 1, the D90 was only 113.6 μm, the D10 was only 20.2 μm, and the Span ≈ 1.46, showing a wider distribution and more fine powder. In Example 5 (residence time 35 min), the D90 reached 320.5 μm, and the Span ≈ 0.47, demonstrating that adjusting the residence time can yield larger and more uniform crystals, which is beneficial for formulation flowability.

[0072] Comparing Example 1 (200 W, 15 min), Example 6 (100 W, 15 min), Example 7 (300 W, 15 min), and Example 4 (200 W, 25 min) and Example 5 (200 W, 35 min): products with low hygroscopicity were obtained in the power range of 100~300 W. The hygroscopicity increased slightly at 300 W (0.23% / 0.50%), but was still within the excellent range. Extending the residence time to 35 min yielded the largest particle size (D90 320.5 μm) and the lowest hygroscopicity (0.15% / 0.20%), indicating a wide process window and strong controllability.

[0073] Examples 1-8 all achieved yields ≥89.3% and purity ≥99.80%, with the best reaching 99.92%, comparable to the 93.6% yield of Comparative Example 1. However, the production cycle was shortened from several hours of intermittent production to about 1-2 hours of continuous production, and no external seed crystals were required, making the operation simple.

[0074] Comparative Example 5

[0075] The difference from Example 1 is that the S-(-)-fumaric acid bisoprolol isopropanol solution was pumped into the first microchannel module 101 at 45°C and directly cooled to 25°C. The temperature in the second microchannel module 102 and the third microchannel module 103 was maintained at 25°C. It was found that the pressure drop in the third microchannel module 103 increased significantly and the flow rate gradually decreased. After maintenance, it was found that the heart-shaped channel of the microchannel module was blocked.

[0076] This invention enables continuous production and improves crystallization efficiency. By combining a microchannel reactor with a continuous crystallizer, the continuous preparation of S-(-)-fumaric acid bisoprolol crystals is achieved, making it suitable for large-scale industrial production.

[0077] The present invention separates the nucleation and growth spaces, resulting in precise and controllable particle size distribution. The nucleation process is confined to a microchannel reactor, achieving uniform nucleation through millisecond-level rapid cooling; the crystal growth process is transferred to a continuous crystallizer, carried out under mild conditions, resulting in a product with an extremely narrow particle size distribution.

[0078] This invention employs ultrasound-assisted synergistic effects to promote crystal nucleation. An ultrasonic field is introduced into the continuous crystallizer, utilizing the cavitation effect of ultrasound to promote secondary nucleation and crystal growth, thus obtaining a stable product without the need for external seed crystals.

[0079] This invention reduces the hygroscopicity of the product and improves formulation stability. The I-crystal product prepared by this invention exhibits significantly lower hygroscopic weight gain after 24 hours at RH 80% compared to products produced using existing batch processes, which is beneficial for improving the storage stability of the formulation.

[0080] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A continuous preparation method for S-(-)-fibranoic acid bisoprolol crystals, characterized in that: include, S-(-)-Biprolol fumarate was dissolved in an organic solvent, and the solution temperature was maintained at 45~60℃ until complete dissolution was obtained to obtain an S-(-)-Biprolol fumarate solution; S-(-)-Fumaric acid bisoprolol solution was pumped into a microchannel reactor in a continuous flow manner. The microchannel reactor consisted of several microchannel modules with a volume of 5-60 mL and an inner diameter of 500-800 μm. The feed flow rate was 1-5 mL / min, and the solution was cooled to 25-30 °C at a cooling rate of 10-15 °C / min to form a suspension containing fine crystal nuclei. The suspension is continuously pumped into a first continuous crystallizer, where crystal nuclei are grown in an ultrasonic field. The ultrasonic frequency is 10-30 kHz, the ultrasonic power is 100-300 W, the stirring speed is 50-200 r / min, and the crystal nuclei are grown at 25-30 ℃ in the ultrasonic field for a residence time of 15-35 min to obtain a crystal slurry. The crystal slurry is continuously fed into a second continuous crystallizer and rapidly cooled to 15-20°C at a rate of 0.5-2°C / min for 2-6 hours to grow crystals. After filtration, washing, and drying, S-(-)-bioprolol fumarate crystals are obtained.

2. The continuous preparation method of S-(-)-fibranoic acid bisoprolol crystals as described in claim 1, characterized in that: The organic solvent is selected from one or two of ethyl acetate, isopropanol, n-propanol, ethanol, and methanol, and the mass-to-volume ratio of the organic solvent to S-(-)-bisolol fumarate is 2~4 mL : 1g.

3. The continuous preparation method of S-(-)-fibranoic acid bisoprolol crystals as described in claim 1, characterized in that: During the crystal growth process, the stirring speed is 50~100 r / min.

4. The continuous preparation method of S-(-)-fibranoic acid bisoprolol crystals as described in any one of claims 1 to 3, characterized in that: The washing solvent is selected from one or two of ethyl acetate, isopropanol, n-propanol, ethanol, and methanol. The drying process is performed under vacuum at a temperature of 50 °C for 4–6 h.

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