Crystallization method for improving morphological index and performance index of p-acetaminobenzoic acid crystal

Abstract

The invention relates to a crystallization method for improving morphological indexes and performance indexes of p-acetaminobenzoic acid crystals. The preparation method comprises the following steps: (1) adding p-acetaminobenzoic acid powder into a solvent, and dissolving and clarifying under the stirring action; (2) cooling the solution to 25-40 DEG C, and growing crystal at constant temperature; (3) continuously cooling the solution to 15-25 DEG C, reducing the cooling final temperature and the cooling temperature in the step (2) by at least 10 DEG C, and continuously stirring to grow the crystal; and (4) filtering the obtained crystal mush, and drying a filter cake to obtain the p-acetamidobenzoic acid crystal. The average aspect ratio of the crystal is 0.231-0.269, the volume average particle size is 480-650 [mu] m, and the particle size distribution variable coefficient is 60-80%. The repose angle of the crystal is less than 30 degrees, the moisture absorption amounts of the crystal are respectively 0.085 mg / g-0. 095 mg / g and 0.245 mg / g-0. 280 mg / g when the relative humidity is 20% and 95%, and the caking rate of the crystal is less than 1.2%.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical engineering pharmaceutical crystallization, and particularly relates to a crystallization method for improving the morphological indexes of p-acetaminobenzoic acid crystals, including aspect ratio, particle size and particle size distribution, and the crystal property indexes, including angle of repose, hygroscopicity and caking rate. Background Art

[0002] P-acetaminobenzoic acid, also known as 4-acetaminobenzoic acid, has the molecular formula C 9 H 9 NO 3 , and its chemical structural formula is shown in Formula (I), with the CAS registration number 556-08-1. P-acetaminobenzoic acid is an important chemical raw material. A series of compounds can be prepared after esterification. It is also a raw material for synthesizing non-barbiturate hypnotic and sedative drugs and anti-asthma drugs, and is widely used in fields such as fuels and pharmaceuticals.

[0003]

[0004] Currently, the commercially available p-acetaminobenzoic acid crystals have poor properties, poor crystal fluidity, an angle of repose of about 48°, strong crystal hygroscopicity, a moisture absorption of 0.107 mg / g at a relative humidity (RH) of 20%, and a moisture absorption of up to 0.502 mg / g at a relative humidity of 95%. Moreover, they are prone to caking, with a caking rate of 9.72%. The poor properties of the crystals are closely related to their poor morphology. The commercially available p-acetaminobenzoic acid crystals are very thin, with an aspect ratio of 0.084 - 0.169, small crystal particle size, an average volume particle size of about 200 μm, and a wide crystal particle size distribution, with a coefficient of variation greater than 100%.

[0005] The above angle of repose, moisture absorption and caking rate are the crystal property indexes. The angle of repose is defined as the angle between the cone formed by the free fall of the crystals and the horizontal plane, and is used to represent the fluidity of the crystals. Generally speaking, the smaller the angle of repose, the better the fluidity of the crystals, and when it is less than 30°, it has good fluidity. Here, the crystal moisture absorption refers to the amount of water adsorbed by the crystals at a certain relative humidity, which can reflect the ease of caking to a certain extent. The greater the crystal moisture absorption, the stronger the hygroscopicity, and the easier it is to cake. The caking rate calculation formula is as follows,

[0006]

[0007] where m 1 is the mass of the undersize sample before the humidity cycling method experiment, and m 2is the mass of the oversize sample after the experiment. The aspect ratio, particle size, and coefficient of variation of the above crystals are morphological indices of the crystals. Here, the aspect ratio is defined as the ratio of the crystal height to one-fourth of the perimeter of the bottom surface, where the bottom surface refers to the crystal face with the largest area percentage in the total surface area, and the crystal height refers to the distance between the two bottom surfaces. The smaller the aspect ratio, the thinner the crystal. The calculation formula for the coefficient of variation is as follows,

[0008]

[0009] where D 16 、D 50 and D 84 successively represent the particle size values corresponding to the cumulative volume percentages of 16%, 50%, and 84% in the particle size - cumulative volume fraction curve. The smaller the coefficient of variation, the narrower the particle size distribution range and the more concentrated the particle size distribution.

[0010] Good crystal morphological indices and performance indices can significantly improve the application effect of crystal products. Crystals with a large aspect ratio have good structural stability and high mechanical strength, and are easy to maintain a complete shape and exhibit a good appearance. Large - particle - size crystals are not prone to physical adsorption and have high product purity. Crystal products with a narrow particle size distribution and a small coefficient of variation can achieve higher tablet pressing density and better particle uniformity, improving product quality consistency. Reducing the angle of repose can improve the fluidity of the crystals, reduce the risk of material jamming and blockage during production, and enhance production efficiency. Reducing the moisture absorption of the crystals can prevent dissolution or even decomposition that may occur in a humid environment, ensuring product quality. At the same time, reducing the caking rate can reduce the agglomeration phenomenon of crystals during storage and transportation, avoiding material waste and production interruption caused by caking. Generally speaking, optimizing crystal morphological indices and performance indices can not only improve product quality and its physical and chemical properties, but also bring higher production efficiency and lower production costs, with significant economic value and practicality.

[0011] Current literature on p - acetamidobenzoic acid mostly focuses on synthetic process research and functional development, and there is a severe lack of research on crystal morphology. The literature "Synthesis Research of 4 - Acetamidobenzoic Acid" (Henan Chemical Industry, 2013, 30: 25 - 26) studied the synthetic process of p - acetamidobenzoic acid. In the article, p - methylacetanilide, potassium permanganate, and magnesium sulfate heptahydrate were reacted in water to form p - acetamidobenzoate. Hydrochloric acid was added to the reaction filtrate to adjust the pH to crystallize p - acetamidobenzoic acid, which was then centrifuged, filtered, washed, dried, and then recrystallized with ethanol to obtain p - acetamidobenzoic acid crystal products. However, the method of using ethanol as a solvent for recrystallization has drawbacks, and the prepared crystals perform poorly in terms of morphology and properties, which is not conducive to subsequent packaging, storage, transportation, use, and processing.

[0012] Patent CN106631858A discloses a method for synthesizing p-acetamidobenzoic acid. This method uses p-aminobenzoic acid as the raw material and acetic anhydride as the acylating agent, and reacts in a formic acid solution to synthesize p-acetamidobenzoic acid. The reaction solution is subjected to vacuum distillation, potassium chloride is added, and after cooling, p-acetamidobenzoic acid crystals are precipitated. Then, recrystallization is carried out in an ether solvent to obtain p-acetamidobenzoic acid crystal products. This method adopts a crystallization method combining evaporation, salting out, and cooling, with many crystallization steps, a long process, and high energy consumption for vacuum distillation. Ether is extremely volatile and requires strict exhaust gas treatment, posing a certain pollution risk to the environment. The boiling point of ether is 34.6°C, and its low boiling point makes recovery and separation difficult, increasing energy consumption and operation complexity. Moreover, ether is flammable and has an explosion risk, with low production safety.

[0013] Patent CN110845352A discloses a method for synthesizing p-acetamidobenzoic acid. This method dissolves p-aminobenzoic acid in glacial acetic acid, uses acetic anhydride as the acylating agent, and reacts at 80-90°C to synthesize p-acetamidobenzoic acid. Then, the reaction solution is cooled to 18-30°C to precipitate p-acetamidobenzoic acid crystals. The glacial acetic acid used in this method has strong irritation, is dangerous to operate as a solvent, and the temperature difference from the reaction temperature of 80-90°C to 18-30°C for crystallization is large, resulting in high energy consumption. Under the condition of a large temperature difference, if the cooling rate is low, the preparation process takes a long time; if a high cooling rate is adopted, the obtained p-acetamidobenzoic acid crystals are in the shape of long and thin needles, with poor crystal morphology and smaller particle size. The crystal products prepared by this method have poor morphological and performance indicators, which is not conducive to the subsequent processing and application of the products.

[0014] As a widely used organic synthesis intermediate, the currently disclosed crystallization method of p-acetaminobenzoic acid crystals has high energy consumption and high risk of the solvents used. The morphological and performance indicators of the commercially available p-acetaminobenzoic acid crystals are poor, manifested as follows: the crystals are flaky, the aspect ratio is between 0.084 and 0.169, the crystal particle size is small, the volume average particle size is about 200 μm, the crystal particle size distribution is wide, and the coefficient of variation is greater than 100%; the crystal fluidity is poor, the angle of repose is greater than 40°, the hygroscopicity is strong, the moisture absorption amount is 0.107 mg / g at a relative humidity of 20%, and the moisture absorption amount can reach 0.502 mg / g at a relative humidity of 95%, and it is extremely easy to agglomerate, and the agglomeration rate exceeds 9%. The poor crystal morphology and performance seriously affect the subsequent packaging, storage, transportation, use and processing of the product, as well as the efficiency of downstream reaction synthesis and the product quality. Therefore, it is necessary to develop a crystallization method of p-acetaminobenzoic acid. The p-acetaminobenzoic acid crystals prepared by this method are large and thick, have uniform particle size, good fluidity, are not easy to absorb moisture, and have strong anti-agglomeration ability, and have excellent crystal morphological and performance indicators, specifically: large aspect ratio, large particle size, small coefficient of variation, small angle of repose, small moisture absorption amount, low agglomeration rate, and the method has low energy consumption and low operation risk to solve the existing problems. Summary of the Invention

[0015] The crystal morphology largely determines the crystal properties. Crystals with a large aspect ratio have a smaller specific surface area, which helps to reduce the friction between crystals during flow, lower the aggregation probability, improve the fluidity, and avoid caking. Thicker crystals usually have a higher packing density, which enables them to better fill the space during flow, reduce voids and flow resistance, are not prone to packing densification, and lower the possibility of caking. At the same time, due to their uniform shape and structure, when the crystals are stressed, they can better disperse and evenly distribute the stress, reduce local compression or tension, and thus maintain the integrity of the morphology during flow. On the contrary, compared with crystals with the same volume and a large aspect ratio, crystals with a small aspect ratio have a larger specific surface area, which increases the contact area between each other and the contact surface with air, and are prone to adhesion due to static electricity or moisture absorption, affecting the overall fluidity and leading to caking. At the same time, their mechanical strength is poor, and they will deform or break due to stress concentration, cannot withstand physical pressure and wear, and are difficult to maintain their original shape during flow processes such as transportation and post-treatment, and are easily broken into fine crystals. The particle size of the crystals is directly related to the fluidity, and the fluidity will decrease with the decrease of the particle size because as the particle size decreases, the ratio of the frictional force between crystals to the gravity increases at a quadratic function rate. In addition, large-particle-size crystals have a small specific surface area, are not prone to physical adsorption and adhesion, have a smooth surface, high purity, and good fluidity. On the contrary, small-particle-size crystals have a large surface energy, are prone to adsorb impurities to reduce the purity and agglomerate, and the permeability of the formed filter cake is poor, resulting in low filtration efficiency and washing efficiency. When the coefficient of variation of the crystal particle size distribution is large, crystals of different sizes coexist, and small crystals are easily adsorbed on the surface of large crystals, resulting in coalescence, reduced fluidity, inconvenience for packaging and use, and also affecting the appearance and sales volume.

[0016] Currently, the poor morphological indexes of p-acetaminobenzoic acid crystals obtained by the crystallization method seriously damage the crystal properties. The crystal morphological indexes depend on the crystallization method. The purpose of the present invention is to provide a crystallization method for improving the morphological indexes and performance indexes of p-acetaminobenzoic acid crystals, and the specific technical solution is as follows:

[0017] A crystallization method for improving the morphological indexes and performance indexes of p-acetaminobenzoic acid crystals, comprising the following steps:

[0018] (1) Add p-acetaminobenzoic acid powder to a solvent and dissolve it to clarity at 40-60°C with stirring;

[0019] (2) Cool the obtained solution to 25-40°C and keep it at a constant temperature for crystal cultivation for a period of time;

[0020] (3) Continue to cool the solution to 15-25°C, and the cooling end temperature is at least 10°C lower than the cooling temperature in step (2), and continue to stir and cultivate crystals for a period of time;

[0021] (4) Filter the obtained crystal slurry, and dry the filter cake under normal pressure to obtain p-acetaminobenzoic acid crystals.

[0022] The solvent in the step (1) is a methanol-water mixed solvent, wherein the molar fraction of methanol is 0.5 to 0.9.

[0023] The mass ratio of p-acetaminobenzoic acid to the mixed solvent in the step (1) is 1:18 to 25.

[0024] The cooling rate in the step (2) is 0.05 to 0.5 °C / min.

[0025] The crystal cultivation time in the step (2) is 5 to 15 min.

[0026] The cooling rate in the step (3) is 0.1 to 1.0 °C / min.

[0027] The crystal cultivation time in the step (3) is 30 to 60 min.

[0028] The drying temperature in the step (4) is 45 to 60 °C.

[0029] The method of the present invention significantly improves the morphological index and performance index of the p-acetaminobenzoic acid crystal product. The crystal obtained by the method of the present invention has a complete morphology, is in the shape of a thick plate, the average aspect ratio is between 0.231 and 0.269, the volume average particle size increases to 480 μm to 650 μm, the coefficient of variation of the particle size distribution decreases to 60% to 80%, the distribution is concentrated, and the particle size is uniform. The angle of repose of the crystal decreases to below 30°, and the fluidity is significantly improved. The moisture absorption of the p-acetaminobenzoic acid crystal prepared by the method of the present invention is significantly decreased at relative humidities of 20% and 95%, and is between 0.085 mg / g and 0.095 mg / g and between 0.245 mg / g and 0.280 mg / g respectively. The crystal caking rate is reduced to below 1.2%, and the crystal has good moisture and caking resistance performance. The excellent morphological index and performance index of the product obtained by the method of the present invention greatly reduce the blockage risk during the production process, improve the production efficiency, and are beneficial to crystal filtration, washing, drying, storage, transportation and use.

[0030] The solution supersaturation and chemical environment directly affect crystal morphology, particle size, and particle size distribution. If the concentration of p-acetamidobenzoic acid in the solution is low or the cooling rate is small, it will result in low supersaturation. In this case, the crystals do not have sufficient growth driving force, and the particle size will be relatively small. Moreover, too small a cooling rate will prolong the crystallization unit operation time, reduce production efficiency, and increase unnecessary time costs. If the concentration of p-acetamidobenzoic acid is too high or the cooling rate is too large, it will also generate high supersaturation, leading to a relatively large crystal nucleation rate or even burst nucleation, a large number of crystal nuclei, and a small crystal particle size. Small-sized crystals are prone to agglomeration, resulting in uneven particle sizes and a wide distribution range. Moreover, agglomeration will inevitably entrap the solution, reducing the purity of the crystal product. Additionally, too high or too low supersaturation will cause a significant difference in the growth rates of fast and slow-growing crystal faces, thereby reducing the aspect ratio of the crystals. Patent CN110845352A uses glacial acetic acid as the crystallization solvent. The solubility of p-acetamidobenzoic acid in glacial acetic acid is relatively small, and the mole fraction solubility ranges from 4.036×10 -3 to 11.148×10 -3 in the temperature range of 20-60°C. On the one hand, the low concentration of p-acetamidobenzoic acid in the solution is not conducive to crystal growth. On the other hand, it is very easy to form a solution with high supersaturation during cooling, leading to rapid nucleation and the formation of needle-like fine crystals. The literature "Study on the Synthesis of 4-Acetamidobenzoic Acid" (Henan Chemical Industry, 2013, 30: 25-26) uses ethanol as the crystallization solvent. The hydroxyl group of ethanol is prone to form an OH C2H5OH …O hydrogen bond with the amide group O on the {001} crystal plane of p-acetamidobenzoic acid crystals. This may be a main reason for the limited growth of crystals along the

[001] direction and the flaky shape of the crystals.

[0031] During the cooling crystallization process, the initial solution concentration, cooling rate, and solvent composition are the key operating variables for controlling the supersaturation of the crystallization process. The present invention screens out suitable initial solution concentrations, cooling rates, and solvent compositions through experiments, enabling the crystallization process to be controlled at an appropriate supersaturation level. The present invention adopts a variable-speed cooling strategy to control the supersaturation during the initial nucleation stage and the subsequent crystal growth stage of crystallization, reducing the nucleation rate and promoting crystal growth.

[0032] The present invention introduces water to form a crystal growth environment of a methanol-water binary solvent. The interaction between water and the alcohol hydroxyl group competes with the interaction between the alcohol hydroxyl group and the amide group on the {001} crystal plane, thereby being able to alleviate the growth inhibition of the alcohol hydroxyl group on the {001} crystal plane to a certain extent and increasing the growth rate of the crystals along the

[001] direction. Additionally, the applicant measured the solubility of p-acetamidobenzoic acid in the methanol-water binary solvent. When the mole fraction of methanol is 0.5-0.9 and the temperature ranges from 10-50°C, the mole fraction solubility range of p-acetamidobenzoic acid expands to 1.687×10 -3 to 14.043×10-3 By adjusting the ratio of methanol to water, an appropriate concentration and supersaturation can be obtained, suppressing burst nucleation and promoting crystal growth, thereby obtaining large-sized crystals with a large aspect ratio.

[0033] The basal plane {001} of the p-acetaminobenzoic acid crystal is a slow-growing crystal plane that grows by relying on van der Waals interactions. The side planes include {101} and {010}, which are fast-growing crystal planes dominated by N-H…O and C-H…O hydrogen bonds for molecular packing. Molecular simulation shows that in a single methanol solvent, the hydroxyl group of methanol forms an O-H CH3OH …O hydrogen bond with the amide O of p-acetaminobenzoic acid on the {001} crystal plane, and the bond length The bond angle is 171°, close to 180°. Due to the significantly stronger hydrogen bond interaction than the van der Waals interaction, the presence of methanol greatly hinders the growth of the {001} crystal plane, making the area of the {001} crystal plane the largest in the actual morphology. In water, the hydroxyl group of water forms an O-H H2O …O hydrogen bond with the amide O of p-acetaminobenzoic acid on the {001} crystal plane, and the bond angle of 158° is significantly less than 180°. The bent hydrogen bond angle will lead to a weakening of the hydrogen bond interaction. Therefore, compared with methanol, water hinders the growth of the {001} crystal plane to a lesser extent. In the methanol-water mixed solvent, when the mole fraction of methanol is small, the alcohol hydroxyl group forms an O-H CH3OH …N hydrogen bond with the N of the amide group of p-acetaminobenzoic acid on the {001} crystal plane, and the hydroxyl group of water forms an O-H H2O …O hydrogen bond with the O of the amide group of p-acetaminobenzoic acid on the {001} crystal plane. At this time, the bond length of O-H CH3OH …N The bond angle is significantly less than 180°, the bond length of O-H H2O …O is shorter, the bond angle is larger, and the O-H H2O …O hydrogen bond strength is greater than the O-H CH3OH …N hydrogen bond. Water molecules are the main factors hindering the growth of the {001} crystal plane. As the mole fraction of methanol increases, in addition to the O-H CH3OH …N hydrogen bond, an O-H CH3OH …O hydrogen bond is also formed, and the O-H H2O …O hydrogen bond between the hydroxyl group of water and p-acetaminobenzoic acid disappears. Water molecules mainly combine with methanol molecules. Therefore, by controlling the mole fraction of methanol in the methanol-water binary solvent, the growth inhibition effect of the solvent on the {001} crystal plane can be effectively reduced, increasing the growth rate of the crystal plane along the

[001] direction and making the aspect ratio of the crystal increase.

[0034] A method for preparing p-acetamidobenzoic acid crystals according to the present invention has significantly better morphological indexes for the obtained p-acetamidobenzoic acid crystals than those of the prior art products. The applicant of the present invention carried out recrystallization experiments of p-acetamidobenzoic acid in ethanol by the method in the literature "Study on the Synthesis of 4-Acetamidobenzoic Acid" (Henan Chemical Industry, 2013, 30: 25-26). The angle of repose of the obtained crystals was 43°, as shown in Table 1. The moisture absorption amounts in environments with relative humidity of 20% and 95% were 0.122 mg / g and 0.580 mg / g respectively, and the caking rate was as high as 11.25%. The crystals were flaky, with an aspect ratio of 0.072 - 0.170, the volume average particle size was less than 250 μm, and the coefficient of variation of the particle size distribution was greater than 150%. The applicant carried out cooling crystallization experiments using glacial acetic acid disclosed in Patent CN110845352A as a solvent. The obtained p-acetamidobenzoic acid crystals had poor fluidity, the angle of repose was greater than 50°, and the caking rate reached 25.11%. The poor performance was directly related to their poor morphology. The obtained p-acetamidobenzoic acid crystals were slender needle-shaped, with a diameter-to-length ratio lower than 0.060, almost one-dimensional growth, and the volume average particle size was about 120 μm. Commercially available p-acetamidobenzoic acid crystals are as attached Figure 1 shown. The crystals were in fragment form, with an average aspect ratio of 0.131. The particle size distribution of the crystals is as attached Figure 2 shown. The crystal particle size was small, the volume average particle size was 201 μm, the crystal particle size distribution was wide, the coefficient of variation was 101%, and the particle size was very uneven. In contrast, the photograph of the p-acetamidobenzoic acid crystal sample prepared by the method of the present invention is as attached Figure 3 shown. The crystals were square thick plate-shaped, with a complete morphology, an average aspect ratio of 0.269. The crystals were significantly thicker than the commercially available products, and the crystal morphology was significantly improved. The particle size distribution of the crystals is as attached Figure 4 shown. Its volume average particle size increased to 647 μm, the coefficient of variation decreased to 62%, the particle size distribution was concentrated, and the particle size was uniform. The improvement of the morphological indexes will inevitably bring about the improvement of the performance indexes. The commercially available product had poor fluidity and an angle of repose of 48°. As shown in Table 1, under the condition of relative humidity of 20% - 95% RH, the moisture absorption amount of the commercially available product could reach 0.107 - 0.502 mg / g. The appearance of the commercially available product is as attached Figure 5 shown, with serious caking phenomenon. The angle of repose of the p-acetamidobenzoic acid crystals prepared by the method of the present invention was 28°, indicating that the flow performance was significantly improved. As shown in Table 1, under the same test conditions, the moisture absorption amount of the p-acetamidobenzoic acid crystals prepared by the method of the present invention was only 0.085 mg / g - 0.245 mg / g, greatly reducing the possibility of caking. The appearance of the crystals is as attached Figure 6As shown, the crystals are dispersed as single crystals without caking. The caking rates of commercially available paracetamol benzoic acid crystals and the products prepared by the method of the present invention were measured by the humidity cycle method. The caking rate of the commercially available product was as high as 9.72%, but the caking rate of the crystals prepared by the method of the present invention was only 0.32%, and the anti-caking performance was significantly improved. Compared with the products of the prior art, the paracetamol benzoic acid crystals prepared by the method of the present invention have a large aspect ratio, a complete morphology, large particle size, concentrated distribution, good crystal fluidity, are not easy to absorb moisture, and have good anti-caking performance.

[0035] Table 1 Moisture absorption of paracetamol benzoic acid crystal products prepared by the prior art and the method of the present invention Unit: mg / g

[0036]

[0037] The present invention provides a crystal preparation method for improving the morphological and performance indexes of paracetamol benzoic acid crystals. By controlling the key operating variables in the cooling crystallization process, including the molar fraction of methanol in the methanol-water mixed solvent, the initial solution concentration, i.e., the mass ratio of paracetamol benzoic acid to the mixed solvent, and the cooling rate, crystal products with excellent morphological and performance indexes are obtained, solving the problems of the paracetamol benzoic acid crystals prepared by the prior art being fragile, having small particle size, uneven particle size, poor fluidity, easy moisture absorption and caking. Patent CN106631858A uses flammable and low-boiling ether solvent for recrystallization, which has great potential safety hazards in the production operation process, and the recovery and separation process is relatively difficult, greatly increasing the energy consumption and the complexity of the process operation. The literature "Study on the Synthesis of 4-Acetamidobenzoic Acid" (Henan Chemical Industry, 2013, 30: 25-26) uses ethanol for crystallization, and the solution chemical environment is not conducive to the growth of crystals along the

[001] direction. Patent CN110845352A cools and crystallizes in glacial acetic acid. The rate of change of the molar fraction solubility of paracetamol benzoic acid in glacial acetic acid with temperature is 0.063×10 -3 / ℃~0.192×10 -3 / ℃. To ensure the yield and production capacity, it is necessary to cool from 80-90℃ to 18-30℃, and the temperature difference is 50-72℃, with a large temperature difference and high energy consumption. In contrast, the paracetamol benzoic acid crystal preparation method provided by the present invention uses a methanol-water binary solvent. The solution chemical environment is conducive to the growth of the {001} crystal plane; and the rate of change of the molar fraction solubility in the methanol-water binary solvent is 0.164×10 -3 / ℃~0.356×10 -3 / ℃. After dissolving and clearing at 40-60℃, it is cooled to 15-25℃, and the temperature difference is only 15-45℃, with less energy consumption; moreover, the method is simple and easy to operate, the solvent price is 2-3 thousand yuan / ton, the production cost is relatively low, and it is more economical and environmentally friendly. Therefore, the present invention has good application value. Brief Description of the Drawings

[0038] Figure 1 : Crystal morphology diagram of commercially available p - acetaminobenzoic acid.

[0039] Figure 2 : Crystal size distribution diagram of commercially available p - acetaminobenzoic acid.

[0040] Figure 3 : Crystal morphology diagram of p - acetaminobenzoic acid prepared by the method of the present invention.

[0041] Figure 4 : Crystal size distribution diagram of p - acetaminobenzoic acid prepared by the method of the present invention.

[0042] Figure 5 : Appearance of commercially available p - acetaminobenzoic acid crystals.

[0043] Figure 6 : Appearance of p - acetaminobenzoic acid crystals prepared by the method of the present invention. Detailed Description of the Invention

[0044] The above - mentioned content of the present invention will be further described in detail below through specific embodiments in the form of examples. However, it should not be understood that the scope of the above - mentioned subject matter of the present invention is limited to the following examples. All technologies implemented based on the above - mentioned content of the present invention belong to the scope of the present invention.

[0045] Example 1:

[0046] (1) Mix 27.4 g of methanol and 15.4 g of water to prepare a methanol - water mixed solvent with a methanol mole fraction of 0.5. Add 2.38 g of p - acetaminobenzoic acid powder to the solvent and dissolve it to clarity at 60°C with stirring. The mass ratio of p - acetaminobenzoic acid to the solvent in the solution is 1:18;

[0047] (2) Cool the obtained solution at a cooling rate of 0.5°C / min to 40°C and then keep it at a constant temperature for crystal cultivation for 5 min;

[0048] (3) Continue to cool the solution at a cooling rate of 1.0°C / min to 20°C and continue stirring for crystal cultivation for 30 min;

[0049] (4) Filter the obtained crystal slurry and dry the filter cake at 60°C under normal pressure to obtain p - acetaminobenzoic acid crystals.

[0050] Example 2:

[0051] (1) Mix 27.4 g of methanol and 15.4 g of water to prepare a methanol-water mixed solvent with a methanol mole fraction of 0.5. Add 1.71 g of p-acetamidobenzoic acid powder to the solvent and dissolve it clearly under stirring at 50 °C. The mass ratio of p-acetamidobenzoic acid to the solvent in the solution is 1:25;

[0052] (2) Cool the obtained solution at a cooling rate of 0.1 °C / min to 35 °C and then keep it at a constant temperature for crystal cultivation for 10 min;

[0053] (3) Continue to cool the solution at a cooling rate of 0.2 °C / min to 25 °C and continue stirring for crystal cultivation for 40 min;

[0054] (4) Filter the obtained crystal slurry and dry the filter cake at 45 °C under normal pressure to obtain p-acetamidobenzoic acid crystals.

[0055] Example 3:

[0056] (1) Mix 33.2 g of methanol and 8.0 g of water to prepare a methanol-water mixed solvent with a methanol mole fraction of 0.7. Add 2.29 g of p-acetamidobenzoic acid powder to the solvent and dissolve it clearly under stirring at 48 °C. The mass ratio of p-acetamidobenzoic acid to the solvent in the solution is 1:18;

[0057] (2) Cool the obtained solution at a cooling rate of 0.3 °C / min to 30 °C and then keep it at a constant temperature for crystal cultivation for 15 min;

[0058] (3) Continue to cool the solution at a cooling rate of 0.2 °C / min to 20 °C and continue stirring for crystal cultivation for 30 min;

[0059] (4) Filter the obtained crystal slurry and dry the filter cake at 50 °C under normal pressure to obtain p-acetamidobenzoic acid crystals.

[0060] Example 4:

[0061] (1) Mix 33.2 g of methanol and 8.0 g of water to prepare a methanol-water mixed solvent with a methanol mole fraction of 0.7. Add 1.65 g of p-acetamidobenzoic acid powder to the solvent and dissolve it clearly under stirring at 40 °C. The mass ratio of p-acetamidobenzoic acid to the solvent in the solution is 1:25;

[0062] (2) Cool the obtained solution at a cooling rate of 0.05 °C / min to 25 °C and then keep it at a constant temperature for crystal cultivation for 15 min;

[0063] (3) Continue to cool the solution at a cooling rate of 0.1 °C / min to 15 °C and continue stirring for crystal cultivation for 60 min;

[0064] (4) Filter the obtained crystal slurry and dry the filter cake at 60 °C under normal pressure to obtain p-acetamidobenzoic acid crystals.

[0065] Example 5:

[0066] (1) Mix 37.7 g of methanol and 2.4 g of water to prepare a methanol-water mixed solvent with a methanol mole fraction of 0.9. Add 2.23 g of p-acetamidobenzoic acid powder to the solvent and dissolve it completely at 40 °C with stirring. The mass ratio of p-acetamidobenzoic acid to the solvent in the solution is 1:18;

[0067] (2) Cool the obtained solution at a cooling rate of 0.3 °C / min to 28 °C and then keep it at a constant temperature for crystal cultivation for 15 min;

[0068] (3) Continue to cool the solution at a cooling rate of 0.7 °C / min to 15 °C and continue stirring for crystal cultivation for 40 min;

[0069] (4) Filter the obtained crystal slurry and dry the filter cake at 60 °C under normal pressure to obtain p-acetamidobenzoic acid crystals.

[0070] Example 6:

[0071] (1) Mix 37.7 g of methanol and 2.4 g of water to prepare a methanol-water mixed solvent with a methanol mole fraction of 0.9. Add 1.60 g of p-acetamidobenzoic acid powder to the solvent and dissolve it completely at 40 °C with stirring. The mass ratio of p-acetamidobenzoic acid to the solvent in the solution is 1:25;

[0072] (2) Cool the obtained solution at a cooling rate of 0.05 °C / min to 25 °C and then keep it at a constant temperature for crystal cultivation for 10 min;

[0073] (3) Continue to cool the solution at a cooling rate of 0.1 °C / min to 15 °C and continue stirring for crystal cultivation for 40 min;

[0074] (4) Filter the obtained crystal slurry and dry the filter cake at 60 °C under normal pressure to obtain p-acetamidobenzoic acid crystals.

[0075] Example 7:

[0076] (1) Mix 30.5 g of methanol and 11.4 g of water to prepare a methanol-water mixed solvent with a methanol mole fraction of 0.6. Add 1.85 g of p-acetamidobenzoic acid powder to the solvent and dissolve it completely at 45 °C with stirring. The mass ratio of p-acetamidobenzoic acid to the solvent in the solution is 1:23;

[0077] (2) Cool the obtained solution at a cooling rate of 0.3 °C / min to 32 °C and then keep it at a constant temperature for crystal cultivation for 5 min;

[0078] (3) Continue to cool the solution at a cooling rate of 0.5 °C / min to 20 °C and continue stirring for crystal cultivation for 50 min;

[0079] (4) Filter the obtained crystal slurry, and dry the filter cake at 60 °C under normal pressure to obtain p-acetamidobenzoic acid crystals.

[0080] The average aspect ratio, volume average particle size, coefficient of variation of particle size distribution, angle of repose, moisture absorption amount, and caking rate of the above-mentioned p-acetamidobenzoic acid crystal product were measured, as shown in Table 2 for details.

[0081] For the preparation method of a p-acetamidobenzoic acid crystal described in the present invention, the morphological indexes of the obtained p-acetamidobenzoic acid crystals are significantly better than those of the prior art products. The applicant of the present invention carried out recrystallization experiments of p-acetamidobenzoic acid in ethanol by the method in the literature "Study on the Synthesis of 4-Acetamidobenzoic Acid" (Henan Chemical Industry, 2013, 30: 25-26). The angle of repose of the obtained crystals was 43°, as shown in Table 2. The moisture absorption amounts in environments with relative humidity of 20% and 95% were 0.122 mg / g and 0.580 mg / g respectively, and the caking rate was as high as 11.25%. The crystals were flaky, with an aspect ratio of 0.072 - 0.170, the volume average particle size was less than 250 μm, and the coefficient of variation of particle size distribution was greater than 150%. The applicant carried out cooling crystallization experiments using glacial acetic acid disclosed in Patent CN110845352A as a solvent. The obtained p-acetamidobenzoic acid crystals had poor fluidity, the angle of repose was greater than 50°, and the caking rate reached 25.11%. The poor performance was directly related to its poor morphology. The obtained p-acetamidobenzoic acid crystals were slender needle-like, with an aspect ratio of less than 0.060, almost one-dimensional growth, and the volume average particle size was about 120 μm.

[0082] Table 2 Morphological indexes and performance indexes of p-acetamidobenzoic acid crystal products

[0083]

[0084] According to the results in Table 2, the morphological indexes of the p-acetamidobenzoic acid product crystals prepared by the method of the present invention, including aspect ratio, volume average particle size, and coefficient of variation of particle size distribution, and the performance indexes, including angle of repose, moisture absorption amount, and caking rate, are significantly better than those of the commercially available p-acetamidobenzoic acid products.

[0085] The above shows and describes the preferred embodiments of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What is described in the above embodiments and the specification only illustrates the principle of the present invention. Without departing from the spirit and scope of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of the present invention claimed.

Claims

1. A crystallization method for improving the crystal morphology and performance of acetaminobenzoic acid, characterized in that: The following steps are involved: (1) adding acetaminobenzoic acid powder into a solvent and dissolving it at 40-60° C. under stirring; (2) cooling the obtained solution to 25-40° C. and then growing crystals at a constant temperature; (3) cooling the solution to 15-25° C., the cooling end temperature being at least 10° C. lower than the cooling temperature in step (2), and continuing to stir and grow the crystal; (4) filtering the obtained crystal slurry, and drying the filter cake under normal pressure to obtain 4-acetaminobenzoic acid crystals.

2. The crystallization method for improving the crystal morphology index and performance index of acetaminobenzoic acid as claimed in claim 1, characterized in that: The solvent in step (1) is a methanol-water mixed solvent, wherein the molar fraction of methanol is 0.5 to 0.

9.

3. The crystallization method for improving the crystal morphology index and performance index of acetaminobenzoic acid as claimed in claim 1, characterized in that: The mass ratio of acetaminobenzoic acid to the mixed solvent in step (1) is 1:18-25.

4. The crystallization method for improving the crystal morphology index and performance index of acetaminobenzoic acid as claimed in claim 1, characterized in that: The cooling rate in step (2) is 0.05-0.5°C / min.

5. The crystallization method for improving the morphological index and performance index of acetaminobenzoic acid crystals according to claim 1, characterized in that: The crystal growing time in step (2) is 5 to 15 minutes.

6. The crystallization method for improving the morphological index and performance index of acetaminobenzoic acid crystals according to claim 1, characterized in that: The cooling rate in step (3) is 0.1-1.0°C / min.

7. The crystallization method for improving the morphological index and performance index of acetaminobenzoic acid crystals according to claim 1, characterized in that: The crystal growing time in step (3) is 30 to 60 minutes.

8. The crystallization method for improving the morphological index and performance index of acetaminobenzoic acid crystals according to claim 1, characterized in that: The drying temperature in step (4) is 45-60°C.

9. The acetaminobenzoic acid crystals prepared by the crystallization method for improving the morphological indexes and performance indexes of acetaminobenzoic acid crystals according to claim 1, characterized in that: Among the morphological indicators, the crystal morphology is complete and thick plate-like, the average aspect ratio is between 0.231 and 0.269, the volume average particle size increases to 480μm to 650μm, the coefficient of variation of the particle size distribution decreases to 60% to 80%, the distribution is concentrated, and the particle size is uniform.

10. The acetaminobenzoic acid crystals prepared by the crystallization method for improving the morphological indexes and performance indexes of acetaminobenzoic acid crystals according to claim 1, characterized in that: Among the performance indicators, the crystal repose angle is reduced to below 30°, the moisture absorption of acetaminobenzoic acid crystals at relative humidity of 20% and 95% are between 0.085 mg / g and 0.095 mg / g and 0.245 mg / g and 0.280 mg / g respectively, and the crystal agglomeration rate is reduced to below 1.2%.

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