A crystallization process for p-aminosalicylic acid

Abstract

The present invention relates to the field of pharmaceutical chemistry technology, specifically, to a crystallization process for p-aminosalicylic acid. It comprises the following steps: p-aminosalicylic acid crude product is dissolved in a solvent, disodium edetate is added synchronously to form a homogeneous solution; polyvinyl pyrrolidone and sodium lauryl sulfate are dissolved in water to form a composite micelle system, and acetone is added to form an anti-solvent phase; the anti-solvent phase is added dropwise to the homogeneous solution, and target crystal form seed is injected; the solution is subjected to solid-liquid two-phase separation; solid phase is treated to obtain wet crystals; wet crystals are processed by a vacuum belt dryer to obtain p-aminosalicylic acid crystals. In the present invention, metal-catalyzed decarboxylation is blocked by disodium edetate, free impurities are adsorbed with polyvinyl pyrrolidone-sodium lauryl sulfate micelles, and polyvinyl pyrrolidone can stabilize the target crystal lattice, and sodium lauryl sulfate can induce crystal growth, so as to stably output low residual high-purity pharmaceutical-grade p-aminosalicylic acid.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, in particular to a crystallization process of p-aminosalicylic acid. Background Art

[0002] Para-aminosalicylic acid is an anti-tuberculosis drug whose main ingredient is para-aminosalicylic acid. It inhibits the synthesis of folic acid in Mycobacterium tuberculosis, thereby preventing its growth and reproduction. Folic acid is essential for bacterial growth. By competitively inhibiting the synthesis of folic acid, para-aminosalicylic acid can effectively inhibit the activity of Mycobacterium tuberculosis.

[0003] For example, CN104402749B relates to a new crystal form of p-aminosalicylic acid and a preparation method thereof. Crystals of the new crystal form are subjected to X-ray powder diffraction, and the diffraction peak position 2θ is used as the characteristic parameter of the spectrum. The 2θ is: 7.36±0.2, 14.61±0.2, 17.01±0.2, 21.91±0.2, 29.28±0.2, in sequence; the preparation method is to mix p-aminosalicylic acid and an organic solvent, then crystallize by a temperature difference method, separate the solid and liquid, and dry the solid to obtain crystals of the new crystal form.

[0004] The above-mentioned preparation method involves a step that affects crystal purity, namely the temperature-difference crystallization step. Para-aminosalicylic acid readily decomposes and undergoes decarboxylation under heating, producing meta-aminophenol. During this temperature-difference crystallization step, the raw material (para-aminosalicylic acid) is dissolved in a selected organic solvent. To achieve sufficient solubility, this step typically requires heating. During this heating and dissolution stage, some para-aminosalicylic acid molecules inevitably undergo decarboxylation, producing meta-aminophenol, thereby reducing the purity of the final product. Summary of the Invention

[0005] The purpose of the present invention is to avoid the problem of impurities generated due to heating in the existing preparation technology of p-aminosalicylic acid, which reduces the purity of the final product.

[0006] The object of the present invention is to provide a crystallization process for p-aminosalicylic acid, which avoids the carboxylic acid reaction of p-aminosalicylic acid caused by the heating step through low-temperature purification operation, blocks the generation path of decarboxylation impurities, and thus obtains p-aminosalicylic acid with higher purity.

[0007] To achieve the above object, the present invention provides a crystallization process for p-aminosalicylic acid, comprising the following steps:

[0008] Step S1: dissolving crude p-aminosalicylic acid in a solvent at 5°C, and simultaneously adding disodium ethylenediaminetetraacetic acid to form a homogeneous solution;

[0009] Polyvinyl pyrrolidone was dissolved in pre-cooled deionized water, and sodium lauryl sulfate was added after ultrasonic dispersion to form a composite micelle system, and acetone was then added to form an anti-solvent phase;

[0010] Step S2: adding the antisolvent phase dropwise to the homogeneous solution, maintaining the system temperature ≤ 10°C and monitoring the turbidity in real time;

[0011] When the turbidity reaches 15, the target crystal seed is injected, and a step-by-step cooling program is performed, and the crystals are matured for 4 h under shear stirring at 50 rpm;

[0012] Step S3: centrifuging the solution after crystal ripening to separate the solid and liquid phases;

[0013] The obtained solid phase is sequentially subjected to surface adsorbed impurities removal treatment, organic residue cleaning treatment, and ion complex replacement treatment to obtain wet crystals;

[0014] Step S4: The wet crystals were treated in a vacuum belt dryer at 30° C. and 0.095 MPa to obtain p-aminosalicylic acid crystals.

[0015] As a further improvement of the present technical solution, in step S1, the solvent is an acetone-deionized water co-solvent system, and the volume ratio of acetone to deionized water in the system is 9:1.

[0016] As a further improvement of the present technical solution, in step S1, the mass fraction of the solute in the homogeneous solution is 8-12%.

[0017] As a further improvement of the present technical solution, in step S1, the ultrasonic dispersion treatment takes 5-15 minutes.

[0018] As a further improvement of the present technical solution, in step S1, the volume ratio of deionized water to acetone in the anti-solvent phase is 4:1.

[0019] As a further improvement of the present technical solution, in step S2, the anti-solvent phase is added dropwise to the homogeneous solution at a constant flow rate of 1-3 mL / min.

[0020] As a further improvement of the present technical solution, in step S2, the particle size of the target crystal seed during injection is 20-50 μm and is pre-wetted with 0.1% acetone.

[0021] As a further improvement of the present technical solution, in step S3, the rotation speed during centrifugal separation is 2700-3300 rpm, and the temperature is no more than 5°C.

[0022] As a further improvement of the present technical solution, in step S3, the surface adsorbed impurities removal treatment is to wash the solid phase with an aqueous solution containing 0.01% sodium dodecyl sulfate at a temperature of 5°C;

[0023] The organic residue cleaning treatment is to use an acetone solution at a temperature of 5°C on the solid phase to dissolve the residual sodium dodecyl sulfate and small molecular impurities, wherein the volume ratio of acetone to water in the acetone solution is 1:4;

[0024] The ion complex replacement treatment was performed by washing the solid with 5% sodium chloride solution at room temperature.

[0025] As a further improvement of the present technical solution, in step S4, the processing time of the vacuum belt dryer is 20-30 hours.

[0026] In the present invention, disodium ethylenediaminetetraacetic acid is used to block metal-catalyzed decarboxylation, and polyvinylpyrrolidone-sodium lauryl sulfate micelles are used to adsorb free impurities. Polyvinylpyrrolidone can stabilize the target crystal lattice, and sodium lauryl sulfate can induce crystal growth, thereby stably producing high-purity pharmaceutical-grade p-aminosalicylic acid with low residue.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] In the crystallization process of p-aminosalicylic acid, disodium ethylenediaminetetraacetic acid is introduced into the low-temperature dissolving phase to capture catalytic ions through carboxyl chelation, cutting off the degradation path of m-aminophenol produced by decarboxylation reaction, and eliminating key impurities at the source; polyvinylpyrrolidone-sodium lauryl sulfate composite micelles are used to form a dynamic molecular sieve network in the anti-solvent phase, and polyvinylpyrrolidone selectively adsorbs m-aminophenol and polar impurities through hydrogen bonds. Sodium lauryl sulfate then encapsulates small organic molecule impurities with the help of hydrophobic tail chains. The two work together to construct an "impurity retention-lattice purification" interface barrier to block impurity co-crystallization; pre-wetted crystal seeds are injected at the turbidity trigger point, and the molecules are driven to grow epitaxially along the target lattice template in a step cooling field to ensure the singleness of the crystal form, thereby producing high-purity p-aminosalicylic acid. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Flowchart of the present invention. DETAILED DESCRIPTION

[0030] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of the present invention.

[0031] See also Figure 1 As shown, the present invention aims to provide a crystallization process of p-aminosalicylic acid, comprising the following steps:

[0032] Step S1: The crude p-aminosalicylic acid (≥98%) was dissolved in a solvent (an acetone-deionized water co-solvent system with a volume ratio of acetone to deionized water of 9:1) at 5°C. Disodium ethylenediaminetetraacetic acid (100 ppm) was added simultaneously to passivate metal ions such as Fe³⁺ / Cu²⁺ through chelation, thereby blocking the heat-sensitive decarboxylation degradation pathway and forming a homogeneous solution. The mass fraction of the solute in the homogeneous solution was 8-12%.

[0033] Polyvinyl pyrrolidone (0.25 wt%) was dissolved in pre-cooled deionized water (5°C). After ultrasonic dispersion for 5-15 minutes, sodium dodecyl sulfate (0.02 wt%) was added to form a composite micelle system. Acetone was then added to form an anti-solvent phase with selective adsorption capacity for impurities. It is worth noting that the volume ratio of deionized water to acetone in the anti-solvent phase is 4:1.

[0034] Step S2: Add the antisolvent phase dropwise to the homogeneous solution at a constant flow rate of 1-3 mL / min, maintain the system temperature ≤ 10°C, and monitor the turbidity in real time.

[0035] When the turbidity reaches 15 (primary nucleation point), the target crystal seed (0.1 wt%) is injected. The target crystal seed has a particle size of 20-50 μm and is pre-wetted with 0.1% acetone. Then, a step cooling program (10°C → 5°C, cooling rate 3°C / h) is performed, and the crystal is matured for 4 h under shear stirring at 50 rpm.

[0036] Step S3: centrifuging the solution after crystal ripening to achieve solid-liquid two-phase separation, wherein the rotation speed during centrifugal separation is 2700-3300 rpm and the temperature is no more than 5°C.

[0037] The obtained solid phase is sequentially subjected to surface adsorbed impurities removal treatment, organic residue cleaning treatment, and ion complex replacement treatment to obtain wet crystals.

[0038] Specifically, the surface adsorbed impurities removal treatment is to wash the solid phase with an aqueous solution containing 0.01% sodium lauryl sulfate at a temperature of 5°C to dissociate the polyvinylpyrrolidone-impurity complex;

[0039] The organic residue cleaning treatment is to use an acetone solution at a temperature of 5°C on the solid phase to dissolve the residual sodium dodecyl sulfate and small molecular impurities, wherein the volume ratio of acetone to water in the acetone solution is 1:4;

[0040] The ion complex replacement treatment was to wash the solid with 5% sodium chloride solution at room temperature to replace the EDTA-metal chelate.

[0041] Step S4: The wet crystals are treated in a vacuum belt dryer at 30°C and 0.095 MPa for 20-30 hours, and the tail gas is deep condensed to recover acetone (recovery rate > 95%) to obtain p-aminosalicylic acid crystals.

[0042] The crystallization process of p-aminosalicylic acid provided by the present invention is further illustrated by the following specific examples.

[0043] Example 1

[0044] This embodiment provides a crystallization process for p-aminosalicylic acid, and the specific steps are as follows:

[0045] Step S1: Crude p-aminosalicylic acid (≥98%) was dissolved in a solvent (an acetone-deionized water co-solvent system with a volume ratio of acetone to deionized water of 9:1) at 5°C, and disodium ethylenediaminetetraacetate (100 ppm) was added simultaneously to form a homogeneous solution with a solute mass fraction of 8%.

[0046] Polyvinyl pyrrolidone (0.25 wt%) was dissolved in pre-cooled deionized water (5°C). After ultrasonic dispersion for 15 minutes, sodium dodecyl sulfate (0.02 wt%) was added to form a composite micelle system. Acetone was then added to form an antisolvent phase. It is worth noting that the volume ratio of deionized water to acetone in the antisolvent phase is 4:1.

[0047] Step S2: The antisolvent phase was added dropwise to the homogeneous solution at a constant flow rate of 1 mL / min, the system temperature was maintained at ≤10°C, and the turbidity was monitored in real time.

[0048] When the turbidity reached 15, the target crystal seed (0.1 wt%) was injected. The target crystal seed had a particle size of 50 μm and was pre-wetted with 0.1% acetone. Then, a step cooling program (10°C → 5°C, cooling rate 3°C / h) was performed, and the crystals were matured for 4 h under shear stirring at 50 rpm.

[0049] Step S3: centrifuging the solution after crystal ripening to achieve solid-liquid two-phase separation, wherein the rotation speed during centrifugal separation is 2700 rpm and the temperature is not greater than 5°C.

[0050] The obtained solid phase is sequentially subjected to surface adsorbed impurities removal treatment, organic residue cleaning treatment, and ion complex replacement treatment to obtain wet crystals.

[0051] Specifically, the surface adsorbed impurities removal treatment is to wash the solid phase with an aqueous solution containing 0.01% sodium dodecyl sulfate at a temperature of 5°C;

[0052] The organic residue cleaning treatment is to use an acetone solution at a temperature of 5°C on the solid phase to dissolve the residual sodium dodecyl sulfate and small molecular impurities, wherein the volume ratio of acetone to water in the acetone solution is 1:4;

[0053] The ion complex replacement treatment was performed by washing the solid with 5% sodium chloride solution at room temperature.

[0054] Step S4: The wet crystals were treated in a vacuum belt dryer at 30° C. and 0.095 MPa for 30 h to obtain p-aminosalicylic acid crystals.

[0055] Example 2

[0056] This embodiment provides a crystallization process for p-aminosalicylic acid, and the specific steps are as follows:

[0057] Step S1: Crude p-aminosalicylic acid (≥98%) was dissolved in a solvent (an acetone-deionized water co-solvent system with a volume ratio of acetone to deionized water of 9:1) at 5°C, and disodium ethylenediaminetetraacetate (100 ppm) was added simultaneously to form a homogeneous solution with a solute mass fraction of 10%.

[0058] Polyvinyl pyrrolidone (0.25 wt%) was dissolved in pre-cooled deionized water (5°C). After ultrasonic dispersion for 10 minutes, sodium dodecyl sulfate (0.02 wt%) was added to form a composite micelle system. Acetone was then added to form an antisolvent phase. It is worth noting that the volume ratio of deionized water to acetone in the antisolvent phase is 4:1.

[0059] Step S2: The antisolvent phase was added dropwise to the homogeneous solution at a constant flow rate of 2 mL / min, the system temperature was maintained at ≤10°C, and the turbidity was monitored in real time.

[0060] When the turbidity reached 15, the target crystal seed (0.1 wt%) was injected. The target crystal seed had a particle size of 35 μm and was pre-wetted with 0.1% acetone. Then, a step cooling program (10°C → 5°C, cooling rate 3°C / h) was performed, and the crystals were matured for 4 h under shear stirring at 50 rpm.

[0061] Step S3: centrifuging the solution after crystal ripening to achieve solid-liquid two-phase separation, wherein the rotation speed during centrifugal separation is 3000 rpm and the temperature is not greater than 5°C.

[0062] The obtained solid phase is sequentially subjected to surface adsorbed impurities removal treatment, organic residue cleaning treatment, and ion complex replacement treatment to obtain wet crystals.

[0063] Specifically, the surface adsorbed impurities removal treatment is to wash the solid phase with an aqueous solution containing 0.01% sodium dodecyl sulfate at a temperature of 5°C;

[0064] The organic residue cleaning treatment is to use an acetone solution at a temperature of 5°C on the solid phase to dissolve the residual sodium dodecyl sulfate and small molecular impurities, wherein the volume ratio of acetone to water in the acetone solution is 1:4;

[0065] The ion complex replacement treatment was performed by washing the solid with 5% sodium chloride solution at room temperature.

[0066] Step S4: The wet crystals were treated in a vacuum belt dryer at 30° C. and 0.095 MPa for 24 h to obtain p-aminosalicylic acid crystals.

[0067] Example 3

[0068] This embodiment provides a crystallization process for p-aminosalicylic acid, and the specific steps are as follows:

[0069] Step S1: Crude p-aminosalicylic acid (≥98%) was dissolved in a solvent (an acetone-deionized water co-solvent system with a volume ratio of acetone to deionized water of 9:1) at 5°C, and disodium ethylenediaminetetraacetate (100 ppm) was added simultaneously to form a homogeneous solution with a solute mass fraction of 12%.

[0070] Polyvinyl pyrrolidone (0.25 wt%) was dissolved in pre-cooled deionized water (5°C). After ultrasonic dispersion for 5 minutes, sodium dodecyl sulfate (0.02 wt%) was added to form a composite micelle system. Acetone was then added to form an antisolvent phase. It is worth noting that the volume ratio of deionized water to acetone in the antisolvent phase is 4:1.

[0071] Step S2: The antisolvent phase was added dropwise to the homogeneous solution at a constant flow rate of 3 mL / min, the system temperature was maintained at ≤10°C, and the turbidity was monitored in real time.

[0072] When the turbidity reached 15, the target crystal seed (0.1 wt%) was injected. The target crystal seed had a particle size of 20 μm and was pre-wetted with 0.1% acetone. Then, a step cooling program (10°C → 5°C, cooling rate 3°C / h) was performed, and the crystals were matured for 4 h under shear stirring at 50 rpm.

[0073] Step S3: centrifuging the solution after crystal ripening to achieve solid-liquid two-phase separation, wherein the rotation speed during centrifugal separation is 3300 rpm and the temperature is not greater than 5°C.

[0074] The obtained solid phase is sequentially subjected to surface adsorbed impurities removal treatment, organic residue cleaning treatment, and ion complex replacement treatment to obtain wet crystals.

[0075] Specifically, the surface adsorbed impurities removal treatment is to wash the solid phase with an aqueous solution containing 0.01% sodium dodecyl sulfate at a temperature of 5°C;

[0076] The organic residue cleaning treatment is to use an acetone solution at a temperature of 5°C on the solid phase to dissolve the residual sodium dodecyl sulfate and small molecular impurities, wherein the volume ratio of acetone to water in the acetone solution is 1:4;

[0077] The ion complex replacement treatment was performed by washing the solid with 5% sodium chloride solution at room temperature.

[0078] Step S4: The wet crystals were treated in a vacuum belt dryer at 30° C. and 0.095 MPa for 20 h to obtain p-aminosalicylic acid crystals.

[0079] According to the crystallization process provided in Examples 1-3, p-aminosalicylic acid crystals were prepared and tested for purity. Specifically, a mixed sample (≥100 g) was cut from the crystallization batch using the quartering method, vacuum dried to constant weight (30°C / 24 h), and then packaged. Then, 20 mg was accurately weighed and dissolved in 0.1% aqueous phosphoric acid-acetonitrile (85:15) to a volume of 10 mL. A gradient elution program was performed on a ZORBAX SB-C18 column (4.6 × 250 mm, 5 μm):

[0080] A 0.1% phosphoric acid aqueous solution (A)-acetonitrile (B) solution was linearly transitioned from A:B = 85:15 to A:B = 70:30 (20 min) at a flow rate of 1.0 mL / min and a column temperature of 30°C. Signals were collected at a characteristic absorption wavelength of 265 nm with a theoretical plate number ≥ 5000 (main peak of p-aminosalicylic acid). The total impurity content in the crystals was measured and recorded in Table 1.

[0081] Table 1 Total impurity content of p-aminosalicylic acid crystals prepared in Examples 1-3

[0082]

[0083] According to Table 1, the total impurity content of the p-aminosalicylic acid crystals obtained in Examples 1-3 is lower than 0.20, indicating that the crystallization process of p-aminosalicylic acid provided by the present invention can produce p-aminosalicylic acid crystals with low total impurity content, i.e., high purity.

[0084] In the present invention, disodium ethylenediaminetetraacetic acid is introduced into the low-temperature solution phase, and catalytic ions such as Fe³⁺ / Cu²⁺ are captured through carboxyl chelation, thereby cutting off the degradation path of m-aminophenol generated by decarboxylation reaction and eliminating key impurities at the source; and a dynamic molecular sieve network is formed in the anti-solvent phase through polyvinylpyrrolidone-sodium lauryl sulfate composite micelles. Polyvinylpyrrolidone selectively adsorbs m-aminophenol and polar impurities through hydrogen bonds, and then sodium lauryl sulfate encapsulates organic small molecule impurities with the help of hydrophobic tail chains. The two cooperate to construct an "impurity retention-lattice purification" interface barrier to block impurity co-crystallization; pre-wetted crystal seeds are injected at the turbidity trigger point, and the molecules are driven to grow epitaxially along the target lattice template in a step cooling field to ensure the singleness of the crystal form, thereby producing high-purity p-aminosalicylic acid.

[0085] Example 4

[0086] In the preparation process of the present invention, metal ions such as Fe³⁺ / Cu²⁺ are necessary conditions for catalyzing decarboxylation to generate the key impurity m-aminophenol. Disodium EDTA completely blocks the activity of metal ions through a five-membered ring chelate structure, blocking the degradation pathway. Furthermore, by treating the product in a low-temperature environment of 5°C, ion diffusion can be further inhibited, chelation selectivity can be improved, and residual m-aminophenol can be reduced.

[0087] In order to prove that the addition of disodium EDTA in step S1 is one of the important factors for the preparation of high-purity p-aminosalicylic acid crystals in the present invention, this example is based on the above Example 1, except that disodium EDTA is missing, or disodium EDTA is replaced by citric acid, while the rest remains unchanged. Then, p-aminosalicylic acid crystals are prepared and tested according to the detection method provided in the above example. The measured values ​​are shown in Table 2.

[0088] Table 2 Comparison of total impurity content of p-aminosalicylic acid crystals

[0089]

[0090] According to Table 2, compared with Example 1, when disodium edetate is missing in step S1, the total impurity content of the obtained para-aminosalicylic acid crystals is significantly increased, resulting in a decrease in the purity of the aminosalicylic acid crystals. In addition, when disodium edetate is replaced with citric acid in step S1, although citric acid can stabilize the carboxyl group and complex metal ions, the effect of adding citric acid is not as good as that of adding disodium edetate.

[0091] This shows that the addition of disodium EDTA in step S1 is one of the important factors for the preparation of high-purity p-aminosalicylic acid crystals in the present invention.

[0092] The above shows and describes the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely preferred examples of the present invention and are not intended to limit the present invention. Various changes and improvements may be made to the present invention without departing from the spirit and scope of the present invention. Such changes and improvements fall within the scope of the present invention. The scope of protection claimed in the present invention is defined by the appended claims and their equivalents.

Claims

1. A crystallization process for p-aminosalicylic acid, characterized in that: The following steps are involved: Step S1: dissolving crude p-aminosalicylic acid in a solvent at 5°C, and simultaneously adding disodium ethylenediaminetetraacetic acid to form a homogeneous solution; Polyvinyl pyrrolidone was dissolved in pre-cooled deionized water, and sodium lauryl sulfate was added after ultrasonic dispersion to form a composite micelle system, and acetone was then added to form an anti-solvent phase; Step S2: adding the antisolvent phase dropwise to the homogeneous solution, maintaining the system temperature ≤ 10°C and monitoring the turbidity in real time; When the turbidity reaches 15, the target crystal seed is injected, and a step-by-step cooling program is performed, and the crystals are matured for 4 h under shear stirring at 50 rpm; Step S3: centrifuging the solution after crystal ripening to separate the solid and liquid phases, with the rotation speed of the centrifugal separation being 2700-3300 rpm and the temperature being no greater than 5° C.; The obtained solid phase is sequentially subjected to surface adsorbed impurities removal treatment, organic residue cleaning treatment, and ion complex replacement treatment to obtain wet crystals; The surface adsorbed impurities were removed by washing the solid phase with an aqueous solution containing 0.01% sodium dodecyl sulfate at a temperature of 5°C; The organic residue cleaning treatment is to use an acetone solution at a temperature of 5°C on the solid phase to dissolve the residual sodium dodecyl sulfate and small molecular impurities, wherein the volume ratio of acetone to water in the acetone solution is 1:4; The ion complex replacement treatment was performed by washing the solid with 5% sodium chloride solution at room temperature; Step S4: The wet crystals were treated in a vacuum belt dryer at 30° C. and 0.095 MPa to obtain p-aminosalicylic acid crystals; The processing time of the vacuum belt dryer is 20-30 hours.

2. The crystallization process of p-aminosalicylic acid according to claim 1, wherein: In step S1, the solvent is an acetone-deionized water co-solvent system, and the volume ratio of acetone to deionized water in the system is 9:

1.

3. The crystallization process of p-aminosalicylic acid according to claim 1, characterized in that: In step S1, the mass fraction of the solute in the homogeneous solution is 8-12%.

4. The crystallization process of p-aminosalicylic acid according to claim 1, wherein: In step S1, the ultrasonic dispersion treatment takes 5-15 minutes.

5. The crystallization process of p-aminosalicylic acid according to claim 1, wherein: In step S1, the volume ratio of deionized water to acetone in the anti-solvent phase is 4:

1.

6. The crystallization process of p-aminosalicylic acid according to claim 1, characterized in that: In the step S2, the antisolvent phase is added dropwise to the homogeneous solution at a constant flow rate of 1-3 mL / min.

7. The crystallization process of p-aminosalicylic acid according to claim 1, characterized in that: In step S2, the target crystal seed has a particle size of 20-50 μm during injection and is pre-wetted with 0.1% acetone.

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