A novel crystalline form of acrinamidin and a method for preparing the same

Abstract

The application discloses a new crystal form C of acetylamino-avermectin and a preparation method thereof. The crystal form C has characteristic diffraction peaks at 6.8+ / -0.2, 8.2+ / -0.2, 9.7+ / -0.2, 11.5+ / -0.2, 13.4+ / -0.2, 14.9+ / -0.2, 16.2+ / -0.2, 17.8+ / -0.2, 19.1+ / -0.2, 20.5+ / -0.2, 21.8+ / -0.2, 23.2+ / -0.2, 24.6+ / -0.2 and 26.4+ / -0.2 degrees in an X-ray powder diffraction pattern. The preparation method uses poly (N-vinyl pyrrolidone-co-acrylic acid) as a crystal form directing agent, and is prepared through an ultrasonic-microwave synergic crystallization process in a green solvent system composed of ethyl acetate / ethanol (a good solvent) and isopropyl alcohol / water (a poor solvent). The crystal form C has the advantages of low hygroscopicity, good stability, high purity, small solvent residue and the like, the preparation process is green and environment-friendly, simple in operation, and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drug chemical engineering crystallization technology, specifically relating to a new crystal form of acetaminophen and its preparation method. Background Technology

[0002] Eprinomectin is a macrolide antibiotic developed by Merck in 1996. It is a semi-synthetic derivative obtained by oxidation, reductive amination, and acetylation of the 4″-position of avermectin B1. Its main component is B1. 1a (≥90%) and B1b. It has extremely high anthelmintic activity against internal and external nematodes and arthropods in livestock, and due to its extremely low partition coefficient in dairy products, it is the only anthelmintic drug approved by the US FDA for use as an internal and external parasite anthelmintic in dairy cows during lactation.

[0003] Due to the instability of the amide bond in the chemical structure of acetaminophen, this product is highly susceptible to oxidation and easily degrades in water, under light, and in aerobic environments. Its high hygroscopicity and poor stability remain persistent problems. Existing purification methods mainly employ acetonitrile recrystallization, but its main drawbacks are high solvent residue, failure to meet veterinary pharmacopoeia requirements, and difficulty in formulating it into an injectable dosage form. The disclosed crystalline form A can be obtained through a dissolution-crystallization method, and the amorphous form can be prepared using a similar method. Crystalline form B can be obtained by crystallizing the amorphous form while suspending it in a mixture. However, these crystalline forms still have shortcomings in terms of hygroscopicity suppression and long-term storage stability, necessitating the development of new crystalline forms with lower hygroscopicity and higher physicochemical stability.

[0004] On the other hand, ultrasound-microwave synergistic technology has been explored in the field of inorganic material crystallization, such as the preparation of calcium sulfate hemihydrate whiskers using ultrasound-microwave synergy. However, there are few published reports on its application to the crystal form regulation of organic drug molecules—especially macrolide antibiotics. Meanwhile, polymer-assisted crystallization strategies have shown unique advantages in the anisotropic growth control of nanomaterials such as two-dimensional covalent organic frameworks (COFs). Chemically asymmetric polyvinylpyrrolidone (PVP) can selectively interact with specific crystal faces to induce directional growth; however, reports on extending this technology to the field of veterinary drug crystal form engineering are still limited. Summary of the Invention

[0005] The purpose of this invention is to provide a new crystal form C of acetaminophen and its preparation method, so as to solve the technical defects of existing crystal forms such as strong hygroscopicity, poor stability and high solvent residue.

[0006] Technical Solution: To achieve the above objectives, the present invention provides the following technical solution: An acetaminophen crystal form C exhibits characteristic diffraction peaks at 2θ values ​​of 6.8±0.2°, 8.2±0.2°, 9.7±0.2°, 11.5±0.2°, 13.4±0.2°, 14.9±0.2°, 16.2±0.2°, 17.8±0.2°, 19.1±0.2°, 20.5±0.2°, 21.8±0.2°, 23.2±0.2°, 24.6±0.2°, and 26.4±0.2°, as measured by Cu-Kα radiation.

[0007] Preferably, its differential scanning calorimetry (DSC) curve has an endothermic peak in the range of 168~172℃ under the following test conditions: heating rate of 10℃ / min, nitrogen atmosphere, aluminum crucible, and sample amount of 2~5 mg.

[0008] A method for preparing acetaminophen crystal form C, using N-vinylpyrrolidone-acrylic acid copolymer as a soluble crystal form directing agent, and completing the crystallization process in an ultrasonic-microwave synergistic crystallization system, wherein the soluble crystal form directing agent selectively induces the nucleation and growth of acetaminophen crystal form C in a homogeneous solution through intermolecular non-covalent interactions; the method includes the following steps: (1) Dissolve acetaminophen raw material in a good solvent, add N-vinylpyrrolidone-acrylic acid copolymer, stir evenly to obtain a homogeneous solution; (2) The homogeneous solution is placed in an ultrasonic-microwave synergistic reaction device, and a poor solvent is added dropwise at a rate of 0.5~5 mL / min under the simultaneous action of ultrasound and microwave and stirring. (3) After the addition is complete, continue to keep the crystals warm under the condition of simultaneous ultrasonic and microwave operation; (4) The temperature is reduced, filtered and dried to obtain acetaminophen crystal form C.

[0009] Preferably, the benign solvent in step (1) is a mixture of ethyl acetate and ethanol in a volume ratio of 6:4 to 8:2; the ratio of the acetaminophen raw material to the benign solvent is 1g:8~15mL.

[0010] Preferably, the undesirable solvent in step (2) is a homogeneous mixture of isopropanol and water, with a volume ratio of isopropanol to water of 9:1 to 7:3; the volume ratio of the good solvent to the undesirable solvent is 1:3 to 1:6; the stirring rate in step (2) is 200 to 600 rpm, and the dropping rate of the undesirable solvent is 1 to 4 mL / min.

[0011] Preferably, the N-vinylpyrrolidone-acrylic acid copolymer in step (1) has a number average molecular weight of 8,000 to 12,000 Da, the molar ratio of N-vinylpyrrolidone to acrylic acid is 3:1 to 4:1, and its amount is 0.5% to 3.0% of the mass of acetaminophen raw material; the copolymer is prepared by free radical copolymerization.

[0012] Preferably, in steps (2) and (3), the microwave power is 200~400 W, the ultrasonic frequency is 20~40 kHz, the ultrasonic power is 100~300 W, the system temperature is 40~60℃, and the crystal growth time is 30~90 minutes.

[0013] Preferably, the cooling rate in step (4) is 1~3℃ / min, the final temperature of cooling is 0~10℃, the drying temperature is 40~50℃, and the vacuum drying time is 6~12 hours.

[0014] Preferably, the crystal form directing agent is a soluble copolymer prepared by free radical copolymerization of N-vinylpyrrolidone (NVP) and acrylic acid (AA), namely poly(N-vinylpyrrolidone-co-acrylic acid), wherein the molar ratio of NVP to AA is 3:1 to 4:1 and the number average molecular weight is 8,000 to 12,000 Da; the crystal form directing agent selectively induces acetaminophen to form crystal form C through intermolecular hydrogen bonding and hydrophobic interactions during homogeneous solution crystallization.

[0015] The beneficial effects of this invention are as follows: 1. The molecular packing structure design of the novel crystal form C in this invention solves the defects of hygroscopicity and stability. Compared with the XRPD patterns of the previously disclosed crystal forms A and B, crystal form C exhibits a more regular and densely packed diffraction peak group, indicating that it has a more compact unit cell packing mode. The core function of this compact packing mode is to encapsulate the amide groups and glycoside hydroxyl groups in the acetaminophen molecule, which are prone to forming hydrogen bonds with water molecules, inside the crystal lattice, making them less likely to be exposed to the outside of the crystal face and come into contact with water molecules in the environment, thereby suppressing hygroscopicity from the root of crystal engineering. At the same time, the more compact molecular arrangement effectively reduces the oxygen diffusion channels in the crystal lattice, slows down the oxidative degradation reaction rate of amide bonds, and significantly improves the long-term storage stability of the product. Differential scanning calorimetry (DSC) analysis shows that the melting point of crystal form C is 168-172℃, and the melting endothermic peak is sharp, indicating high crystallinity and excellent thermodynamic properties.

[0016] 2. This invention provides a novel green crystallization solvent system, comprising a combination of a beneficial solvent and a detrimental solvent. The beneficial solvent is a mixture of ethyl acetate and ethanol in a volume ratio of 6:4 to 8:2; the detrimental solvent is a mixture of isopropanol and water in a volume ratio of 9:1 to 7:3. The volume ratio of the beneficial solvent to the detrimental solvent is 1:3 to 1:6. This solvent system completely avoids the use of acetonitrile (a Class 2 residual solvent with moderate toxicity), diethyl ether (which easily forms peroxides and poses an explosion risk), and chlorinated solvents in traditional processes. All solvents used are Class 3 low-toxicity solvents recommended by the ICH Q3C guidelines, significantly improving the safety of the product. Furthermore, this invention is the first to apply ultrasonic-microwave synergistic crystallization technology to the preparation of acetaminophen crystals. Acetaminophen raw material was dissolved in the aforementioned good solvent. In an ultrasonic-microwave synergistic reaction apparatus, the microwave power was controlled at 200-400W, the ultrasonic frequency at 20-40kHz, and the ultrasonic power at 100-300W. The system temperature was maintained at 40-60℃. The unsuitable solvent was added dropwise to the system at a uniform rate under the simultaneous action of ultrasound and microwave. After the addition was complete, the system was kept at the ultrasonic-microwave synergistic condition for crystal growth for 30-90 minutes. After the reaction was completed, the temperature was programmed to decrease to 0-10℃ at a rate of 1-3℃ / min. After filtration, the product was vacuum dried at 40-50℃ for 6-12 hours to obtain the purified acetaminophen crystal form C.

[0017] 3. This invention is the first to propose using poly(N-vinylpyrrolidone-co-acrylic acid) (abbreviated as P(NVP-co-AA)), a free radical copolymer of N-vinylpyrrolidone (NVP) and acrylic acid (AA), as a crystal form directing agent in the crystallization process of acetaminophen. The copolymer has a molar ratio of NVP to AA of 3:1 to 4:1 and a number-average molecular weight (Mn) of 8. The dosage is 0.00 to 12,000 Da, and the amount used is 0.5%-3.0% (w / w) of the acetaminophen raw material mass. The mechanism of action of the crystal form directing agent lies in the van der Waals affinity of the pyrrolidone five-membered ring unit in the copolymer chain for the hydrophobic region on the macrolide backbone of acetaminophen. Simultaneously, the carboxyl group (-COOH) on the copolymer chain can form complementary hydrogen bonds with the amide group and glycoside hydroxyl group in the acetaminophen molecule. Through the synergistic recognition of the hydrophobic and hydrophilic dual sites, P(NVP-co-AA) preferentially binds to process-related impurities such as 8a-oxo-impurities and incompletely acetylated B1 precursor impurities in solution, "locking" them onto the polymer chain and removing them with the mother liquor. This reduces the content of key impurities in the product to below 0.3% without adding additional purification steps. At the same time, the copolymer selectively adsorbs onto the surface of specific growth facets of crystal form C, reducing the surface energy and growth rate of those facets and inducing directional packing of molecules along the dominant facet direction, ultimately forming the close-packed structure unique to crystal form C.

[0018] 4. Synergistic effect of the green mixed solvent system (good solvent + bad solvent). The mixed good solvent of ethyl acetate and ethanol balances good solubility with a moderate boiling point. Ethyl acetate provides a moderately polar ester group solubility environment, while ethanol provides polarity supplementation with its hydroxyl groups. Together, they disrupt the disordered intermolecular aggregation state of crude acetaminophen within the crystallization temperature range of 40-60℃. In the mixed bad solvent of isopropanol and water, isopropanol, as a non-polar medium, significantly reduces the dielectric constant of the mixed system, initiating supersaturation. The presence of trace amounts of water utilizes the high affinity of the amide bonds and hydroxyl groups in the acetaminophen molecule for water molecules, forming transient water bridges that promote pre-orientation of molecules in solution and reduce nucleation activation energy. Together, they provide a controllable and gradual supersaturation driving force, ensuring a proper match between nucleation rate and growth rate, which is beneficial for the formation of highly ordered crystalline C. Furthermore, all components are Class 3 low-toxicity solvents, simultaneously addressing both safety and crystal quality issues.

[0019] 5. Synergistic effect of ultrasonic and microwave fields. Microwaves provide uniform and rapid bulk heating to the reaction system through dipole rotation and ion conduction mechanisms, effectively avoiding the local supersaturation problem caused by the temperature gradient from the container wall to the solution center in traditional heating methods, and reducing the formation of impurity crystals caused by explosive nucleation. The ultrasonic field, through the local high-temperature and high-pressure micro-regions ("hot spots") generated by acoustic cavitation and the strong microjets, promotes the mass transfer and diffusion of solute molecules, eliminates the adsorption layer on the crystal nucleus surface and the aggregation of already attached small crystallites, effectively suppressing secondary nucleation and twinning. The synergistic effect of the two fields achieves a complementary mechanism of "uniform thermal nucleation by microwaves and mass transfer promoted by ultrasonic cavitation," inducing the formation of a single crystal habit of crystal form C and improving the consistency of crystal form between batches.

[0020] 6. Chemical-physical synergy between P(NVP-co-AA) crystal form directing agent and ultrasonic-microwave physical field. The microjets generated by ultrasonic cavitation allow the P(NVP-co-AA) copolymer chains to fully extend in solution, increasing the probability of contact between functional groups on the copolymer chains and impurity molecules and crystal faces. Furthermore, the microwave thermal effect promotes dynamic and reversible hydrogen bonding between the copolymer and target molecules, preventing irreversible co-crystallization of impurities. Under the assistance of the physical field, the selective adsorption of P(NVP-co-AA) shifts from a "static" to a "dynamically regulated" mode—the copolymer continuously undergoes reversible adsorption and desorption processes on specific crystal faces, dynamically modifying the crystal surface and continuously selectively promoting molecular stacking in the preferred direction. This chemical-physical synergy significantly improves impurity separation efficiency and the selectivity of crystal facet directional growth, achieving significant crystal form control effects with an ultra-low addition amount of only 0.5%-3.0%. Attached Figure Description

[0021] Figure 1The X-ray powder diffraction (XRPD) pattern of acetaminophen crystal form C prepared according to the present invention.

[0022] Figure 2 Differential scanning calorimetry (DSC) curve of acetaminophen crystal form C prepared for this invention.

[0023] Figure 3 Thermogravimetric analysis (TGA) curve of acetaminophen crystal form C prepared in this invention.

[0024] Figure 4 Scanning electron microscope (SEM) image of acetaminophen crystal form C prepared for this invention.

[0025] Figure 5 The image shows the Fourier Transform Infrared (FT-IR) spectrum of the P(NVP-co-AA) copolymer prepared in this invention.

[0026] Figure 6 The image shows a crystallized specimen of acetaminophen crystal form C prepared according to the present invention.

[0027] Figure 7 This is a photograph of the physical crystal of acetaminophen C prepared according to the present invention. Detailed Implementation

[0028] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0029] Example 1: Synthesis of P(NVP-co-AA) crystal directing agent 11.1 g (0.10 mol) of N-vinylpyrrolidone (NVP) and 2.4 g (0.033 mol) of acrylic acid (AA, NVP:AA molar ratio ≈ 3:1) were dissolved in 50 mL of anhydrous ethanol. 0.13 g of azobisisobutyronitrile (AIBN) (1.0% of the total monomer mass) was added, and the mixture was purged with nitrogen for 30 minutes to remove oxygen. The mixture was then sealed and stirred at 70 °C for 8 hours. After cooling, the reaction solution was added dropwise to 300 mL of diethyl ether to precipitate the product. The precipitate was filtered, washed three times with diethyl ether, and dried under vacuum at 40 °C to constant weight. The resulting P(NVP-co-AA) copolymer was a white powder. Gel permeation chromatography (GPC) determined the number-average molecular weight (Mn) to be approximately 8,500 Da. The Fourier transform infrared (FT-IR) spectrum of the prepared P(NVP-co-AA) copolymer is shown in the appendix. Figure 5By adjusting the monomer feeding ratio (NVP:AA molar ratio of 4:1, 5:1, and 6:1 respectively), copolymers with different compositions can be obtained.

[0030] Example 2: Preparation of Acetaminophen Crystal Form C 10.0 g of crude acetaminophen (HPLC purity approximately 95%) was dissolved in 80 mL of a good solvent consisting of ethyl acetate and ethanol in a 7:3 volume ratio, and stirred at 40 °C until completely dissolved. 0.15 g of the P(NVP-co-AA) copolymer synthesized according to Example 1 (1.5% of the raw material mass) was added, and the mixture was stirred until homogeneous.

[0031] The above solution was transferred to an ultrasonic-microwave synergistic reaction apparatus. The microwave power was set to 300W, the ultrasonic frequency to 28kHz, and the ultrasonic power to 200W. The system temperature was controlled at 50℃ with both ultrasonic and microwave functions operating simultaneously. Using a ZD2000 automatic dropper, 320 mL of a mixture of isopropanol and water in a volume ratio of 8:2 (good solvent to bad solvent volume ratio ≈ 1:4) was added dropwise at a rate of 1 mL / min. After the addition was complete, the system was kept at this temperature for 60 minutes under ultrasonic-microwave synergistic conditions to allow crystal growth. The ultrasonic and microwave systems were then turned off, and the temperature was programmed to decrease to 5℃ at a rate of 2℃ / min. The mixture was allowed to stand for 2 hours. A photograph of the crystals of acetaminophen crystal form C is attached. Figure 6 The mixture was filtered under reduced pressure, and the filter cake was washed with a small amount of pre-cooled isopropanol. It was then vacuum dried at 45°C for 8 hours to obtain 9.1 g of white crystalline crystals, with a yield of 91.0%. A picture of the actual crystals of acetaminophen (crystal form C) is attached. Figure 7 .

[0032] The XRPD pattern of the obtained product showed characteristic diffraction peaks at 2θ of 6.8±0.2°, 8.2±0.2°, 9.7±0.2°, 11.5±0.2°, 13.4±0.2°, 14.9±0.2°, 16.2±0.2°, 17.8±0.2°, 19.1±0.2°, 20.5±0.2°, 21.8±0.2°, 23.2±0.2°, 24.6±0.2°, and 26.4±0.2°, confirming it as crystal form C. The XRPD pattern of acetaminophen crystal form C is attached. Figure 1 The scanning electron microscope (SEM) image of acetaminophen crystal form C is attached. Figure 4 HPLC analysis showed a purity ≥99.5%, with individual impurity content ≤0.2%. DSC analysis determined the melting point to be 169.5℃ (onset), with a melting range of 168.1-171.3℃ and a sharp peak shape. The differential scanning calorimetry (DSC) curve for acetaminophen crystal form C is attached. Figure 2The product's moisture absorption weight gain after 30 days at 25℃ / 75%RH was only 0.3%, significantly lower than that of crystal form B under the same conditions (approximately 1.5%), indicating that crystal form C has excellent anti-hygroscopic properties. Accelerated stability testing (40℃ / 75%RH, 6 months) showed that the content of crystal form C decreased by less than 0.5%, far superior to existing crystal forms. The thermogravimetric analysis (TGA) curve for acetaminophen crystal form C is attached. Figure 3 .

[0033] Example 3: Optimization of Ultrasonic-Microwave Parameters Using the same formulation as in Example 2, the effects of different ultrasound-microwave synergistic parameters on crystal purity and yield were investigated.

[0034]

[0035] The comparative results show that pure crystalline C could not be obtained under either microwave heating alone (ultrasound off, group 4) or conventional heating combined with ultrasound alone (microwave off, group 5). This indicates that the synergistic effect of ultrasound and microwave is necessary for the stable formation of crystalline C. Under optimized conditions (group 2), "ultrasound only + oil bath heating" and "microwave only + mechanical stirring" showed lower crystalline purity than the synergistic group, highlighting the necessity of enhancing the synergistic effect. The crystalline C product with optimal purity and yield could be obtained at a microwave power of 300W, an ultrasound frequency of 28kHz, an ultrasound power of 200W, and a temperature of 50℃.

[0036] Example 4: Effect of P(NVP-co-AA) dosage on impurity suppression effect Using the process conditions of Example 2, only the amount of P(NVP-co-AA) added was changed to investigate its effect on the content of key impurities (total 8a-oxo-impurities and avermectin B1b) in the product.

[0037]

[0038] The results showed that adding P(NVP-co-AA) effectively reduced the content of key impurities in the product. Without the addition of polymer, the total amount of key impurities in the crystalline product was 0.62%; when the addition amount reached 1.5%, the total impurities decreased to 0.15%, a reduction of over 75%, fully demonstrating the selective adsorption function of this crystal-directing agent.

[0039] Example 5: Effect of water content in solvent system on the directional growth of C crystal form Using the basic process of Example 2, the composition of the benign solvent (ethyl acetate: ethanol = 7:3) was fixed and The organic component (isopropanol) in the undesirable solvent was used to investigate its effect on the formation of crystal form C by only changing the volume ratio of water in the undesirable solvent.

[0040]

[0041] The results show that the presence of an appropriate amount of water in poorly mixed solvents plays a crucial role in obtaining pure crystalline form C. Under anhydrous conditions (isopropanol:water = 10:0), crystalline form A is dominant, while excessive water (6:4) leads to mixing of crystalline forms B and C. Pure crystalline form C can be obtained with optimal yield and purity when the isopropanol:water volume ratio is between 8:2 and 9:1. This result confirms the synergistic mechanism by which trace amounts of water promote molecular pre-orientation alignment through the formation of transient water bridges.

[0042] Example 6: Scale-up preparation and verification of crystal form C The preparation process of Example 2 was scaled up to the kilogram level: 1.0 kg of crude acetaminophen was dissolved in 8.0 L of a mixed solvent of ethyl acetate and ethanol (7:3, v / v), and 15.0 g of P(NVP-co-AA) (1.5 wt%) was added. In a 100 L ultrasonic-microwave co-crystallization vessel (ultrasonic frequency 20–40 kHz, microwave frequency 2450 MHz), with the same parameters as in Example 2, 32.0 L of a poor solvent (isopropanol:water = 8:2, v / v) was added dropwise at a uniform rate. After crystallization for 60 minutes, the temperature was lowered to 5°C, filtered, washed, and vacuum dried to obtain 919 g of purified crystal form C, with a yield of 91.9% and an HPLC purity of 99.4%. XRPD confirmed it to be pure crystal form C. The product showed a moisture gain of 0.35% after 30 days at 25°C / 75%RH. The accelerated stability test data were consistent with the laboratory small-scale test results, demonstrating that the preparation process of this invention has good industrial scale-up feasibility and batch reproducibility.

[0043] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. An acetaminophen crystal form C, characterized in that, The X-ray powder diffraction pattern obtained using Cu-Kα rays exhibits characteristic diffraction peaks at 2θ of 6.8±0.2°, 8.2±0.2°, 9.7±0.2°, 11.5±0.2°, 13.4±0.2°, 14.9±0.2°, 16.2±0.2°, 17.8±0.2°, 19.1±0.2°, 20.5±0.2°, 21.8±0.2°, 23.2±0.2°, 24.6±0.2°, and 26.4±0.2°.

2. The acetaminophen crystal form C according to claim 1, characterized in that, Its differential scanning calorimetry (DSC) curve has an endothermic peak in the range of 168~172℃ under the following test conditions: heating rate of 10℃ / min, nitrogen atmosphere, aluminum crucible, and sample amount of 2~5 mg.

3. A method for preparing acetaminophen crystal form C as described in claim 1, characterized in that, An N-vinylpyrrolidone-acrylic acid copolymer was used as a soluble crystal form directing agent to complete the crystallization process in an ultrasonic-microwave synergistic crystallization system. The soluble crystal form directing agent selectively induced the nucleation and growth of acetaminophen crystal form C in a homogeneous solution through intermolecular non-covalent interactions. The method includes the following steps: (1) Dissolve acetaminophen raw material in a good solvent, add N-vinylpyrrolidone-acrylic acid copolymer, stir evenly to obtain a homogeneous solution; (2) The homogeneous solution is placed in an ultrasonic-microwave synergistic reaction device, and a poor solvent is added dropwise at a rate of 0.5~5 mL / min under the simultaneous action of ultrasound and microwave and stirring. (3) After the addition is complete, continue to keep the crystals warm under the condition of simultaneous ultrasonic and microwave operation; (4) The temperature is reduced, filtered and dried to obtain acetaminophen crystal form C.

4. The preparation method according to claim 3, characterized in that, The benign solvent mentioned in step (1) is a mixture of ethyl acetate and ethanol in a volume ratio of 6:4 to 8:2; the ratio of the acetaminophen raw material to the benign solvent is 1g:8~15mL.

5. The preparation method according to claim 3, characterized in that, The undesirable solvent in step (2) is a homogeneous mixture of isopropanol and water, with a volume ratio of isopropanol to water of 9:1 to 7:3; the volume ratio of the good solvent to the undesirable solvent is 1:3 to 1:6; the stirring rate in step (2) is 200 to 600 rpm, and the dropping rate of the undesirable solvent is 1 to 4 mL / min.

6. The preparation method according to claim 3, characterized in that, The N-vinylpyrrolidone-acrylic acid copolymer mentioned in step (1) has a number average molecular weight of 8,000 to 12,000 Da, a molar ratio of N-vinylpyrrolidone to acrylic acid of 3:1 to 4:1, and its amount is 0.5% to 3.0% of the mass of acetaminophen raw material; the copolymer is prepared by free radical copolymerization.

7. The preparation method according to claim 3, characterized in that, In steps (2) and (3), the microwave power is 200~400 W, the ultrasonic frequency is 20~40 kHz, the ultrasonic power is 100~300 W, the system temperature is 40~60℃, and the crystal growth time is 30~90 minutes.

8. The preparation method according to claim 3, characterized in that, The cooling rate in step (4) is 1~3℃ / min, the final temperature of cooling is 0~10℃; the drying temperature is 40~50℃, and the vacuum drying time is 6~12 hours.

9. A crystal-directing agent for acetaminophen crystallization, characterized in that, The crystal form directing agent is a soluble copolymer prepared by free radical copolymerization of N-vinylpyrrolidone (NVP) and acrylic acid (AA), namely poly(N-vinylpyrrolidone-co-acrylic acid), wherein the molar ratio of NVP to AA is 3:1 to 4:1 and the number average molecular weight is 8,000 to 12,000 Da; the crystal form directing agent selectively induces acetaminophen to form crystal form C as described in claim 1 through intermolecular hydrogen bonding and hydrophobic interactions during homogeneous solution crystallization.

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