A particle size control method for ultrasonic-assisted gamma-aminobutyric acid crystallization

Abstract

The application provides a particle size control method for ultrasonic-assisted gamma-aminobutyric acid crystallization. After impurity removal and decolorization of a gamma-aminobutyric acid feed liquid, the feed liquid is concentrated to a near-saturated state through heating and stirring, then ultrasonic-assisted crystallization is performed, cooling and temperature reduction are performed, aging is performed, and crude crystals are obtained through suction filtration, and finally, the target crystals are obtained through washing and drying. The method is a synergistic process of raw material liquid pretreatment, evaporation concentration-ultrasonic-cooling coupled crystallization, aging and post-treatment, uses ultrasonic cavitation effect to reduce nucleation potential barrier, and combines supersaturation precision control and gradient cooling strategies to realize crystal particle size refinement, obvious narrowing of particle size distribution and effective inhibition of agglomeration, so that the median particle size of the crystals can be controlled to be less than or equal to 200 microns, the particle size distribution span is less than or equal to 1.5, the agglomeration phenomenon is significantly inhibited, the crystal form remains stable, the crystal habit is complete and smooth, the crystal product quality and process efficiency are significantly improved, and the method has important industrial application value.

Description

Technical Field

[0001] This invention relates to the field of amino acid crystallization technology, and in particular to a method for controlling the particle size of ultrasound-assisted γ-aminobutyric acid crystallization. Background Technology

[0002] Gamma-aminobutyric acid (GABA) is a naturally occurring non-protein amino acid. As a major inhibitory neurotransmitter in the mammalian central nervous system, it exhibits clear physiological activities in areas such as nerve sedation, anti-anxiety effects, and cardiovascular function regulation, and is therefore widely used in pharmaceuticals and functional foods. In pharmaceutical formulations, the crystal quality of GABA (e.g., particle size distribution, crystal integrity) directly affects the dissolution rate, bioavailability, and subsequent processing properties of the formulation (LMBelca, M. Krajnc. The use of ultrasound in the crystallization process of an active pharmaceutical ingredient, Ultrason. Sonochem. 58 (2019) 104642; L. d. LS Castillo-Peinado, MD Luque deCastro. The role of ultrasound in pharmaceutical production: sonocrystallization, J. Pharm. Pharmacol. 68 (2016) 1249–1267; PH Zhao, BS Liu, CX Xie, QJ Li, X. Du, H. Sun. Crystallization of citicoline sodium by anti-solvent assisted with ultrasound, J. Cryst. Growth. 593 (2022) 126738). Smaller crystal particle size can provide a larger specific surface area, thereby accelerating the dissolution rate of the drug and improving the absorption efficiency of the human body; while a narrower single-peak distribution can ensure the consistency of drug dissolution and the uniformity of tablet compression. Therefore, as a key step in the separation and purification of γ-aminobutyric acid, the optimization of the crystallization process is crucial for improving product quality.

[0003] However, there is a strong hydrogen bond network in the γ-aminobutyric acid molecule (mainly formed by the interaction between the amino group and the carboxyl group), which leads to the formation of lamellar aggregates and serious agglomeration in the traditional crystallization process, resulting in a generally large median particle size (Dv50) and a wide particle size distribution span. The agglomeration phenomenon leads to particle adhesion and stacking, which seriously restricts the subsequent preparation process (such as dissolution, mixing, and tabletting) and the exertion of drug efficacy.

[0004] Currently, the crystallization of γ-aminobutyric acid mainly relies on traditional processes, which have obvious limitations. In the solvent-out crystallization, mutual-solvent anti-solvent is added to the GABA solution to reduce the solubility by changing the solvent composition, but the fluctuation of the solvent composition easily leads to uneven crystal morphology, and a large amount of anti-solvent is consumed. In the evaporation crystallization, the removal of the solvent is relied on to increase the concentration, which has high energy consumption and the crystal particle size is difficult to accurately control. In the cooling crystallization, the temperature gradient is used to induce crystallization, and the uneven cooling rate easily induces secondary nucleation, further increasing the discreteness of the particle size distribution (increasing the DS value) and the degree of agglomeration.

[0005] To solve the above problems, ultrasonic technology has been gradually applied in the field of crystal regulation. Through cavitation effect (local high temperature and high pressure generated by bubble collapse), acoustic streaming effect (strengthening mass transfer), and interface energy regulation, the ultrasonic technology can reduce the solid-liquid interfacial tension, promote uniform nucleation, and destroy the hydrogen bond connection between particles to inhibit agglomeration. The technology has been proven to effectively refine the particle size and narrow the distribution in the crystallization of compounds such as sodium choline phosphate. However, there are still key bottlenecks in the ultrasonic-assisted crystallization of GABA: the response mechanism of the strong hydrogen bond network between GABA molecules to ultrasonic cavitation effect is not clear, making it difficult to establish a targeted regulation model; the timing of ultrasonic intervention (such as the metastable zone trigger node), the energy input mode (such as power and action time), and the synergistic optimization of evaporation-cooling process lack systematic research. Therefore, the existing technology cannot simultaneously achieve the multi-objective synergistic regulation of particle size refinement (Dv50<200 μm), distribution narrowing (DS<1.5), agglomeration inhibition, and crystal form stability of γ-aminobutyric acid, limiting its application in high-end preparations.

[0006] Therefore, it is of great significance to develop an ultrasonic-assisted process that can accurately regulate the particle size of GABA, especially achieve the breakthroughs in distribution narrowing and agglomeration inhibition, and maintain the stability of the crystal form, to break through the bottlenecks of the existing technology and promote the development of amino acid drug crystallization technology. SUMMARY

[0007] The technical problem to be solved by the present application is to provide a particle size regulation method for ultrasonic-assisted γ-aminobutyric acid crystallization.

[0008] The technical solution adopted by the present application is:

[0009] An ultrasonic-assisted gamma-aminobutyric acid (GABA) crystallization particle size control method, after impurity removal and decolorization of the gamma-aminobutyric acid-containing feed liquid, heating, stirring and concentration to a near-saturation state, then ultrasonic-assisted crystallization, cooling, aging, and filtration to obtain crude crystals, and finally washing and drying to obtain the target crystals, the specific steps are as follows:

[0010] (1) Impurity removal and decolorization: impurity removal and decolorization of the gamma-aminobutyric acid-containing feed liquid, filtration to collect the filtrate as the solution to be concentrated;

[0011] (2) Heating and concentration: placing the filtrate in a crystallizer for heating and stirring and concentration, and concentrating to a near-saturation state;

[0012] (3) Ultrasonic-assisted crystallization: when the filtrate is concentrated to a near-saturation state, ultrasonic-assisted crystallization is started, and heating and stirring and evaporation are continued until the crystal precipitation rate reaches 50% (based on the volume of the saturated filtrate), then the evaporation is stopped, and the temperature is immediately lowered at a rate of 0.4-0.6 ℃ / min to 20-25 ℃, the ultrasonic and stirring effects are stopped, and the aging is continued for 60-120 min to obtain a crystal mother liquor;

[0013] (4) Washing and drying: filtering the crystal mother liquor to obtain crude crystals, washing the crystals, and drying to obtain gamma-aminobutyric acid crystals.

[0014] Preferably, in the above ultrasonic-assisted gamma-aminobutyric acid crystallization particle size control method, the heating and concentration conditions in step (2) and the heating and stirring and evaporation conditions in step (3) are: temperature 60-75 ℃, vacuum degree 0.07-0.09 MPa, and stirring speed 250-450 r / min.

[0015] Preferably, in the above ultrasonic-assisted gamma-aminobutyric acid crystallization particle size control method, the heating and concentration conditions / heating and stirring and evaporation conditions are: temperature 65-70 ℃, vacuum degree 0.08 MPa, and stirring speed 300 r / min.

[0016] Preferably, in the above ultrasonic-assisted gamma-aminobutyric acid crystallization particle size control method, the cooling rate is 0.5 ℃ / min.

[0017] Preferably, in the above ultrasonic-assisted gamma-aminobutyric acid crystallization particle size control method, the aging time of the crystals after the cooling in step (3) is 90 min.

[0018] Preferably, in the above ultrasonic-assisted gamma-aminobutyric acid crystallization particle size control method, the ultrasonic-assisted crystallization conditions in step (3) are: ultrasonic power density 20-30 W / L (lower power can avoid excessive crushing of the crystals, and cooperatively inhibit agglomeration and maintain narrow distribution), ultrasonic probe inserted to a depth of 1 / 3-1 / 2 of the liquid level in the crystallizer (based on the effective volume of the crystallizer), and intermittent ultrasonic mode is used.

[0019] Preferably, the particle size control method for ultrasonic-assisted γ-aminobutyric acid crystallization has the ultrasonic power density of 24.4 W / L.

[0020] Preferably, the particle size control method for ultrasonic-assisted γ-aminobutyric acid crystallization has the intermittent ultrasonic mode of 2-4 s of ultrasonic and 8-16 s of pause (to avoid excessive particle breakage and agglomeration caused by continuous ultrasonic).

[0021] Preferably, the particle size control method for ultrasonic-assisted γ-aminobutyric acid crystallization has the ultrasonic probe inserted into the liquid surface of the crystallizer to a depth of 1 / 3 (based on the effective volume of the crystallizer), and has the intermittent ultrasonic mode of 3 s of ultrasonic and 12 s of pause.

[0022] The beneficial effects of the present application are as follows:

[0023] The particle size control method for ultrasonic-assisted γ-aminobutyric acid crystallization realizes the refinement of GABA crystal particle size, the significant narrowing of particle size distribution, and the effective inhibition of agglomeration, while ensuring the stability of crystal form, the integrity of crystal habit, and the smoothness of crystal surface, by the synergistic process of raw material liquid pretreatment, evaporation concentration-ultrasonic-cooling coupled crystallization, aging and post-treatment, the use of ultrasonic cavitation effect to reduce the nucleation barrier, and the combination of supersaturation precision control and gradient cooling strategy. The present application significantly improves the quality of crystal product and the process efficiency, and has important industrial application value. Specifically, the present application has the following advantages:

[0024] (1) The present application realizes the synergistic breakthrough of particle size refinement, distribution narrowing and agglomeration inhibition. In the traditional process, the particle size Dv50 is greater than 500 μm, the distribution span (DS) is greater than 2.0 (wide bimodal distribution), and the agglomeration is serious (particles are adhered and stacked). The present application controls the median particle size (Dv50) of GABA crystal to be less than or equal to 200 μm, significantly narrows the particle size distribution span (DS) to less than or equal to 1.5 (narrow unimodal distribution), effectively breaks the hydrogen bond adhesion, and inhibits agglomeration, thereby realizing the synergistic optimization of “particle size refinement+distribution narrowing+agglomeration inhibition”, and solving the core problems of uneven drug dissolution and poor flowability from the root;

[0025] (2) The process efficiency and controllability are significantly improved. The key parameters such as ultrasonic power and cooling rate can be quantitatively controlled, thereby providing a popular paradigm for similar amino acid crystallization processes.

[0026] (3) The stability of crystal form and functional groups is ensured. X-ray diffraction (XRD) and infrared spectrum analysis confirm that the crystal form does not change before and after ultrasonic treatment. The scanning electron microscope (SEM) results show that the crystal morphology is complete and the surface is smooth. The particle dispersion is significantly improved after agglomeration inhibition, thereby ensuring the product quality consistency and meeting the needs of high-end preparation development. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 Figure is a structural schematic diagram of the ultrasonic-assisted GABA crystallization experimental device,

[0028] In the figure, 1-ultrasonic generator, 2-light intensity recorder, 3-photoelectric transformer, 4-magnetic stirring controller, 5-laser generator, 6-laser power supply, 7-high-low temperature circulating thermostat, 8-ultrasonic probe, 9-thermometer, 10-magnetic rotor, 11-jacketed crystallizer;

[0029] Figure 2 Figure is a graph of the effect of stirring speed on particle size distribution;

[0030] Figure 3 Figure is a graph of the effect of cooling rate on particle size distribution;

[0031] Figure 4 Figure is a graph of the effect of ultrasonic power density on crystal habit, wherein a. 19.4 W / L, b. 30.9 W / L, c. 40.5 W / L, d. 51.6 W / L, e. 82.4 W / L;

[0032] Figure 5 Figure is a graph of the effect of aging time on crystal habit, wherein a. 30 min, b. 60 min, c. 90 min, d. 120 min;

[0033] Figure 6 Figure is a graph of the comparison of GABA particle size distribution before and after optimization;

[0034] Figure 7 Figure is an XRD graph of GABA crystals before and after optimization;

[0035] Figure 8 Figure is an infrared spectrum of GABA before and after optimization;

[0036] Figure 9 Figure is a SEM image of GABA before and after optimization, wherein (a) is before optimization, and (b) is after optimization. DETAILED DESCRIPTION

[0037] In order for those skilled in the art to better understand the technical solutions of the present application, the technical solutions of the present application will be further described in detail below in combination with the accompanying drawings and specific embodiments.

[0038] Unless otherwise specified, the raw materials in the examples of the present application are purchased through commercial channels and directly used without any special treatment.

[0039] Unless otherwise specified, the analysis methods in the examples all use the conventional settings of instruments or equipment and conventional analysis methods.

[0040] Example 1

[0041] Ultrasonic-assisted GABA crystallization experimental device

[0042] The GABA crystallization experimental device provided by the application comprises an ultrasonic generator 1, a light intensity recorder 2, a photoelectric transformer 3, a magnetic stirring controller 4, a laser generator 5, a laser power supply 6, a high-low temperature circulating temperature controller 7, an ultrasonic probe 8, a thermometer 9, a magnetic rotor 10 and a jacketed crystallizer 11. Figure 1 The experimental device takes the jacketed crystallizer 11 (a core reaction container, which carries GABA liquid and performs concentration, crystallization and other reactions) as the center, the magnetic rotor 10 is arranged at the bottom of the jacketed crystallizer 11, the magnetic stirring controller 4 is arranged horizontally below the jacketed crystallizer 11, the magnetic stirring controller 4 is arranged directly below the magnetic rotor 10, and the magnetic stirring controller 4 is arranged in the liquid in the jacketed crystallizer 11 during work. The magnetic stirring controller 4 drives the rotor to rotate through a magnetic field. The thermometer 9 and the ultrasonic probe 8 are commonly suspended in the jacketed crystallizer 11, one end of the thermometer 9 is inserted into the liquid in the jacketed crystallizer 11, and the other end is exposed for temperature measurement. One end of the ultrasonic probe 8 is inserted into the crystalline slurry in the jacketed crystallizer 11 to a depth of 1 / 3-1 / 2 of the liquid surface, and the other end is connected to the ultrasonic generator 1 located on the side of the jacketed crystallizer 11 through a wire. The high-low temperature circulating temperature controller 7 is arranged on the side or below the jacketed crystallizer 11, and is connected to the jacket around the outer periphery of the jacketed crystallizer 11 through a pipeline to realize circulation of the temperature control medium. The laser generator 5 and the light intensity recorder 2 are respectively arranged horizontally and symmetrically on the two sides of the jacketed crystallizer 11. The laser emission port of the laser generator 5 is aligned in height with the recorder receiving port of the light intensity recorder 2. The laser generator 5 is electrically connected to the laser power supply 6, and the light intensity recorder 2 is electrically connected to the photoelectric transformer 3, so as to form a complete particle size monitoring path for particle size monitoring.

[0043] Example 2

[0044] Influence of stirring speed on crystallization of γ-aminobutyric acid

[0045] The filtrate after impurity removal and decolorization is transferred into the jacketed crystallizer, and is concentrated to near saturation at 70℃, 0.08MPa and an arbitrary stirring speed. Ultrasonic-assisted crystallization is started immediately in the intermittent mode of 24.4W / L power and “ultrasonic 3s pause 12s”, the stirring speed of the magnetic stirrer is adjusted as a variable, and the evaporation is stopped until the crystallization rate reaches 50% (calculated based on the volume of the saturated filtrate). Then, the temperature is cooled to 25℃ at a gradient of 0.5℃ / min, the ultrasonic is paused and the solution is aged for 90min. Then, the crystalline slurry is separated by vacuum filtration, the crystals are washed with 95% ethanol, and the crystals are vacuum dried at 60℃ and 0.08MPa for 3-5h until the weight is constant. Finally, the particle size, distribution and crystal morphology of the dried crystals are characterized by a laser particle size analyzer and a scanning electron microscope, so as to obtain the crystallization results under different stirring speeds.

[0046] The influence of stirring speed on particle size distribution was studied under the conditions of evaporation temperature 70℃, ultrasonic power 24.4W / L, ultrasonic 3s pause 12s, cooling rate 0.5℃ / min, and aging time 90min. Table 1 and Figure 2 The particle size and distribution of the crystals under different stirring speeds are shown.

[0047] The experimental results of different stirring speeds are shown in Table 1. As can be seen from Table 1, with the increase of stirring speed, the Dv50 of the crystals showed a decreasing trend, and the surface area average particle size D[3,2] and volume average particle size D[4,3] also decreased. When the stirring speed exceeded 300r / min, this trend weakened. DS also showed a decreasing trend with the increase of stirring speed, but when the stirring speed increased to 500r / min, DS increased significantly. From the above, Figure 2 It can be seen that when the stirring speed is 100r / min, the particle size distribution is wide and the crystal particle size is relatively large. This is because low stirring speed is not sufficient for mass transfer, resulting in a mismatch between nucleation and growth rate, and finally the particle size is uneven. When the stirring speed is 500r / min, the strong shear causes the crystal to break, the particle size distribution appears obvious bimodal, and the particle size distribution becomes wide. Finally, 300r / min was selected as the subsequent process condition.

[0048] Table 1 Experimental results of different stirring speeds

[0049]

[0050] Example 3

[0051] On the basis of Example 2, the influence of cooling rate on the crystallization of γ-aminobutyric acid was explored

[0052] Under the conditions of stirring speed 300r / min, ultrasonic power 24.4W / L; ultrasonic 3s pause 12s; aging time 90min, the influence of cooling rate on particle size distribution was studied. Table 2 and Figure 3 The particle size and distribution of the crystals under different cooling rates are shown.

[0053] The experimental results of different cooling rates are shown in Table 2. As can be seen from Table 2 and Figure 3 It can be seen that with the increase of cooling rate, the Dv50 of the product crystals showed a decreasing trend, and the DS showed an increasing trend, and the particle size distribution became wide. This is because when the cooling rate increases, the nucleation rate is much faster than the crystal growth, and a large number of crystal nuclei compete for growth resources, limiting the growth of single crystals (Dv50 decreases); at the same time, the nucleation asynchrony and solute diffusion are not uniform, which amplifies the size difference of the crystals, resulting in a wide particle size distribution (DS increases), which is essentially a reflection of the competition between nucleation and growth kinetics. Considering comprehensively, 0.5℃ / min was selected as the condition for subsequent experimental research.

[0054] Table 2 Experimental results of different cooling rates

[0055]

[0056] Example 4

[0057] Influence of ultrasonic interval time on γ-aminobutyric acid crystallization was explored on the basis of Example 3

[0058] In order to avoid local overheating caused by continuous ultrasonic, interval ultrasonic mode was adopted. Ultrasonic working time and pause time were set, and ultrasonic pause can avoid local overheating, balance crystal breaking and growth, and also can improve the utilization rate of cavitation effect and optimize the crystallization effect.

[0059] Under the conditions of cooling rate 0.5℃ / min, stirring speed 300r / min, ultrasonic power 24.4W / L, and aging time 90min, the influence of 5 kinds of ultrasonic interval and no ultrasonic on particle size distribution and crystal integrity was investigated, and Table 3 shows the particle size distribution and integrity of the product under different ultrasonic interval times.

[0060] The experimental results of different ultrasonic time intervals are shown in Table 3. As can be seen from Table 3, the crystal particle size decreases with the increase of ultrasonic working time, but after the ultrasonic interval is 4s, the Dv50 decreases no longer significantly, and with the prolongation of ultrasonic working time, the crystal appears to be broken, which shows that the ultrasonic working time is too long, which will lead to the breaking of the crystal and the production of fine fragments, so that the particle size distribution becomes wide. When the time interval is in the range of ultrasonic 2-4s pause 8-16s, the Dv50, DS and crystal integrity are considered to be ideal, therefore, the range is determined as the best ultrasonic interval.

[0061] Table 3 Experimental results of different ultrasonic interval times

[0062]

[0063] Example 5

[0064] Influence of ultrasonic power density was explored on the basis of Example 4

[0065] Under the conditions of ultrasonic 3s pause 12s, stirring speed 300r / min, cooling rate 0.5℃ / min, and aging time 90min, the influence of 5 kinds of ultrasonic power density (19.4W / L, 30.9W / L, 40.5W / L, 51.6W / L, 82.4W / L) on the product crystal was studied. Lower power was not designed, because too low power cavitation effect is weak, which cannot effectively disperse the agglomerates and promote uniform nucleation, and the existing 19.4W / L is close to the lower limit of function, and further reduction will lead to the failure to inhibit agglomeration and the widening of particle size distribution, which is contrary to the process goal. The influence of different ultrasonic power densities on crystal habit is shown in Table 4. Figure 4As shown in the figure, when the ultrasonic power density is 19.4 W / L, the crystal morphology is complete and the surface is smooth; when the ultrasonic power density is 30.9 W / L, the crystal is smooth and defect-free and there is no obvious agglomeration; when the ultrasonic power density reaches 40.5 W / L, small crystal grains are obviously attached to the surface of the crystal; when the ultrasonic power density increases to 51.6 W / L, the edge of the crystal is broken and the number of small crystal grains on the surface increases; and when the ultrasonic power density reaches 82.4 W / L, the crystal is severely broken and is accompanied by a large amount of fine crystal agglomeration.

[0066] With the increase of ultrasonic power density, the crystal is more severely broken. When the ultrasonic power density exceeds 30.9 W / L, small crystal grains are obviously attached to the surface of the crystal. In combination, 20-30 W / L is selected as the condition for subsequent process research.

[0067] Example 6

[0068] Influence of aging time on the crystal habit is studied based on Example 5

[0069] Under the conditions of ultrasonic power 24.4 W / L, ultrasonic 3 s and pause 12 s, stirring speed 300 r / min, and cooling rate 0.5 ℃ / min, the influence of different aging times on the crystal habit is studied, and the results are shown in the figure. Figure 5 As shown in the figure, the crystal surface is not smooth and small crystals are attached at 30 min; the number of small crystals decreases and the surface is still rough at 60 min; the crystal is smooth and complete and there is no obvious small crystal at 90 min; and there is no significant difference between 90 min and 120 min, and the number of small crystals does not increase. Because there is a balance between dissolution and growth in the crystallizer, with the increase of aging time, part of the small crystals are dissolved and the crystal growth is more complete. As can be seen from the figure, the crystal habit changes little after 90 min, the number of small crystals is small, and the crystal surface is smooth. In combination, 90 min of aging time is selected.

[0070] Example 7

[0071] A particle size control method for ultrasonic-assisted γ-aminobutyric acid (GABA) crystallization, the specific steps are as follows:

[0072] 1. Filtration for removing impurities and decolorization: decolorize the GABA-containing solution, and collect the filtrate as a solution to be concentrated.

[0073] 2. Concentration: evaporate and stir the filtrate in a crystallizer to concentrate, the heating temperature is 70 ℃, the vacuum degree is 0.08 MPa, and the stirring speed is 300 r / min, and the concentration is carried out to a near-saturated state.

[0074] 3. Ultrasonic-assisted crystallization: when the filtrate is concentrated to near saturation, the stirring speed is 300 r / min, and the ultrasonic assistance is turned on. The ultrasonic probe is inserted into the crystal slurry to a depth of 1 / 3 of the liquid surface, and the ultrasonic power is 24.4 W / L. Ultrasonic for 3 s, pause for 12 s, and evaporate and crystallize under the conditions of a temperature of 70 °C and a vacuum degree of 0.08 MPa until the crystal precipitation rate reaches 50% (based on the volume of saturated filtrate). After stopping evaporation, cool to 25 °C at a rate of 0.5 °C / min, stop ultrasonic and stirring, and age the crystals for 90 min.

[0075] 4. Washing and drying of crystals: filter the crystal mother liquor to obtain wet crystals, wash the crystals, dry, and obtain GABA crystals. The obtained crystal particle size distribution span DS is 1.422, the median particle size Dv50 is 196.3 μm, there is no agglomeration phenomenon, and the crystals are complete and smooth in surface.

[0076] Example 8

[0077] The GABA crystals obtained after optimization of the ultrasonic-assisted process (Example 7) were characterized together with the crystals obtained without ultrasonic assistance (before optimization) (the method of obtaining crystals without ultrasonic assistance is referred to in patent CN120081754A). The obtained GABA crystals were analyzed by scanning electron microscopy (SEM), particle size analyzer, X-ray diffraction (XRD), and infrared spectroscopy (IR).

[0078] (1) Particle size analysis

[0079] The particle sizes of the GABA crystals before and after optimization were measured, and the particle size data before and after optimization are compared in Table 4.

[0080] As shown in Table 4 and Figure 6 , before optimization: wide bimodal distribution (Dv50 = 587.8 μm, DS = 2.283); after optimization: narrow unimodal distribution (Dv50 = 196.3 μm, DS = 1.422); the particle size refinement amplitude is more than 66%, and the distribution narrowing amplitude is more than 35%.

[0081] Table 4 Comparison of particle size data before and after optimization

[0082]

[0083] (2) X-ray powder diffraction (XRD) and infrared spectroscopy (IR) analysis

[0084] As shown in Figure 7 , Figure 8 , the XRD characteristic peak positions before and after ultrasonic optimization are consistent, and the IR absorption peaks are identical, confirming that the ultrasonic treatment only regulates the particle size, distribution, and agglomeration state of the crystals, and does not change the crystal form and chemical structure.

[0085] (3) Scanning electron microscope (SEM) analysis

[0086] The morphology of GABA crystals before and after optimization was observed by SEM, and the results are shown in Table 1. Figure 9 Before optimization: the crystals were broken, irregular in shape (serious agglomeration, and the particles were adhered to each other); after optimization: the crystal shape was smooth and complete, and the particles were dispersed (the agglomeration phenomenon was significantly inhibited, and the narrow distribution was intuitively reflected).

[0087] The above-described embodiments are merely preferred embodiments of the present application and are not intended to limit the scope of the present application. Various modifications and improvements to the technical solutions of the present application made by those of ordinary skill in the art without departing from the design spirit of the present application shall fall within the scope of the present application.

Claims

1. A particle size control method for ultrasonic-assisted gamma-aminobutyric acid crystallization, after impurity removal and decolorization of a gamma-aminobutyric acid-containing feed liquid, the feed liquid is heated and stirred to concentrate to a near-saturated state, then ultrasonic-assisted crystallization is performed, cooling and temperature reduction, aging, and filtration to obtain coarse crystals, and finally washing and drying to obtain target crystals, the specific steps are as follows: (1) Impurity removal and decolorization: impurity removal and decolorization of a gamma-aminobutyric acid-containing feed liquid, filtration to collect the filtrate as a solution to be concentrated; (2) Heating and concentration: the filtrate is placed in a crystallizer, heated and stirred at a temperature of 60-75℃, a vacuum degree of 0.07-0.09 MPa, and a stirring speed of 250-450 r / min, and concentrated to a near-saturated state; (3) Ultrasonic-assisted crystallization: after the filtrate is concentrated to a near-saturated state, ultrasonic-assisted crystallization is started, the ultrasonic-assisted crystallization conditions are: ultrasonic power density of 20-30 W / L, ultrasonic probe inserted into the crystalline slurry liquid surface to a depth of 1 / 3-1 / 2, intermittent ultrasonic mode, the intermittent ultrasonic mode is 2-4 s of ultrasonic and 8-16 s of pause; continue heating and stirring evaporation at a temperature of 60-75℃, a vacuum degree of 0.07-0.09 MPa, and a stirring speed of 250-450 r / min until the crystallization rate reaches 50%, then stop evaporation, immediately cool to 20-25℃ at a cooling rate gradient of 0.4-0.6℃ / min, stop ultrasonic and stirring, continue aging for 60-120 min to obtain a crystal mother liquor; (4) Washing and drying: filtration of the crystal mother liquor to obtain coarse crystals, washing of the crystals, drying to obtain gamma-aminobutyric acid crystals, the median particle size of the gamma-aminobutyric acid crystals is controlled to ≤200 μm, and the particle size distribution span is narrowed to ≤1.

5. The heating and concentration conditions and the heating and stirring evaporation conditions are: a temperature of 65-70℃, a vacuum degree of 0.08 MPa, and a stirring speed of 300 r / min. The cooling rate is 0.5℃ / min. The aging time of the crystals after the temperature reduction in step (3) is 90 min. The ultrasonic power density is 24.4 W / L.

2. The method of claim 1, wherein the method is characterized by: The ultrasonic probe is inserted into the crystalline slurry liquid surface to a depth of 1 / 3, and the intermittent ultrasonic mode is 3 s of ultrasonic and 12 s of pause.

3. The method of claim 1, wherein the method is characterized by: ​ 4. The method of claim 1, wherein the method is characterized by: ​ 5. The method of claim 1, wherein the method is characterized by: ​ 6. The method of claim 1, wherein the method is characterized by: ​

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