Method for preparing niflufenamic acid crystal form through melt crystallization

Abstract

The invention discloses a method for preparing a niflufenamic acid crystal form through melt crystallization, and relates to a preparation method of a medicine crystal form. The crystal form A prepared by the invention has characteristic peaks at 9.8 + / -0.2 degrees, 12.6 + / -0.2 degrees, 16.7 + / -0.2 degrees, 23.4 + / -0.2 degrees and 25.6 + / -0.2 degrees according to X-ray powder diffraction 2 theta. The crystal form A is good in thermal stability, the quality is basically kept stable below 200 DEG C, and the crystal form A can stably exist for more than four weeks under the condition of 40 DEG C / 75% RH; meanwhile, the hygroscopicity is low, the transportation and long-term storage of the product are facilitated, the solubility is good, the solubility in an ethanol solution at 25 DEG C for 24 hours can reach about 0.013455 mg / mL, and the absorption of the medicine in a human body can be promoted. The crystal form of niflufenamic acid (NFA) is a non-steroidal anti-inflammatory drug and has pharmacological activities of resisting inflammation, easing pain and relieving fever.

Description

Technical Field

[0001] This invention relates to a method for preparing anti-inflammatory drug crystals, specifically a method for preparing niflumethicone crystals by melt crystallization. Background Technology

[0002] Niflufenicol (NFA) is a commonly used nonsteroidal anti-inflammatory drug (NSAID) that exerts its anti-inflammatory, analgesic, and antipyretic effects by inhibiting the activity of cyclooxygenase (COX) and reducing prostaglandin synthesis. It is suitable for the clinical treatment of various inflammations and pains, including rheumatoid arthritis, osteoarthritis, soft tissue injuries, and postoperative pain. However, current niflufenicol formulations used clinically suffer from problems such as poor solubility, low bioavailability, and poor stability. These issues result in slow dissolution rates, delayed drug efficacy, and are difficult to manufacture, process, and store under stringent conditions, making it difficult to meet the clinical demand for efficient and convenient medication.

[0003] The solid crystal form of a drug is a key factor affecting its physicochemical properties and clinical application. Different crystal forms of the same drug have significant differences in solubility, dissolution rate, stability, and flowability, which directly affect the quality control of drug formulations, the feasibility of production processes, and the final clinical efficacy.

[0004] A search of domestic and international patents and literature revealed that niflufenicol exists in two crystal forms, but only one of these forms has had its crystal structure resolved; this is the commercially available form. However, this crystal form has low solubility, which affects the absorption and bioavailability of the drug in the human body, thus limiting its industrial production and clinical application. Summary of the Invention

[0005] The purpose of this invention is to provide a novel melt crystallization method for preparing niflufenic acid crystals. This method yields a new crystal form of niflufenic acid with high solubility and good stability. The preparation process is simple, easy to control, and leaves no solvent residue, making it suitable for industrial production and pharmaceutical development. This provides a new and high-quality option for the research and development and production of niflufenic acid drug formulations, and is of great significance to the clinical application and industrial development of this drug.

[0006] The objective of this invention is achieved through the following technical solution: A method for preparing niflumethicone crystals by melt crystallization, characterized in that the method employs a melt method and includes the following steps: (1) Add NFA raw material to the melting reaction equipment, control the heating rate to 5-10℃ / min, heat to 210℃ and melt at a constant temperature for 5min to fully melt the raw material; (2) After melting, control the cooling rate to 2-3℃ / min and slowly cool down to 17℃ to recrystallize the melt and obtain a white crystalline solid, which is the crystalline form of niflufenic acid (NFA).

[0007] The method for preparing niflumethicone crystal form by melt crystallization, wherein the prepared niflumethicone (NFA) crystal form has characteristic peaks in the X-ray powder diffraction pattern represented by 2θ at 9.8±0.2, 12.6±0.2, 16.7±0.2, 23.4±0.2, and 25.6±0.2 degrees.

[0008] The method for preparing niflufenic acid crystal form by melt crystallization, wherein the prepared niflufenic acid (NFA) crystal form has a characteristic endothermic peak at 204±2℃ in its DSC spectrum, corresponding to the melting process of the crystal form.

[0009] The method for preparing niflufenic acid crystal form by melt crystallization, wherein the prepared niflufenic acid (NFA) crystal form crystals show that their quality remains stable below 200℃ according to TGA spectra.

[0010] The significant features and effects of this invention are: 1. The crystal form prepared by the melt method of this invention possesses excellent physicochemical properties and process adaptability, overcoming the technical defects of existing niflufenic acid crystal forms. Niflufenic acid (NFA) crystal form is a nonsteroidal anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic pharmacological activities.

[0011] 2. The niflufenic acid crystal form A obtained by this invention exhibits excellent solubility. Experimental results show that its solubility in ethanol at a constant temperature of 25°C for 24 hours is 60.4014 mg / mL, which is higher than the solubility of the original crystal form under the same conditions (47.1620 mg / mL). This high solubility of the crystal form can effectively improve the dissolution and absorption efficiency of the drug in the human body, enhance bioavailability, and shorten the time for drug efficacy to take effect, laying the foundation for the full realization of clinical efficacy. This is of great significance for the development of niflufenic acid drug formulations.

[0012] 3. The nyflufenicol crystal form A product obtained by this invention has a significantly different structure from the original crystal form (NFA raw material), making it easy to distinguish. XRD analysis was performed on nyflufenicol crystal form A and the original crystal form, and the specific spectra are shown in Figure 4. The results show that the characteristic peak positions, intensities, and peak shapes of crystal form A and the original crystal form are significantly different, indicating that they are different crystal forms. Furthermore, crystal form A exhibits good stability under normal processing and storage temperatures, meeting the requirements for drug production and long-term storage. Attached Figure Description

[0013] Figure 1X-ray diffraction pattern of niflumethicone (NFA) crystal form A of this invention; Figure 2 Thermogravimetric analysis (TGA) diagram of niflufenic acid (NFA) crystal form A of this invention; Figure 3 Differential scanning calorimetry (DSC) curve of niflufenic acid (NFA) crystal form A of the present invention; Figure 4 Comparison of X-ray diffraction patterns of niflumethicone (NFA) crystal form A and the original crystal form (NFA raw material) in this invention. Detailed Implementation

[0014] The present invention will now be described in detail with reference to the embodiments shown in the accompanying drawings.

[0015] The chemical name and chemical structural formula of niflufenic acid (NFA); Chemical name: 2-[(3-trifluoromethyl)phenyl]aminobenzoic acid; Chemical structural formula:

[0016] Molecular formula: C 14 H 10 F3NO2 Molecular weight: 281.23 The X-ray powder diffraction pattern of the niflufenic acid (NFA) crystal prepared by this invention is shown in the appendix. Figure 1 Characteristic peaks, expressed as diffraction angle 2θ, are observed at 9.8±0.2, 12.6±0.2, 16.7±0.2, 23.4±0.2, and 25.6±0.2 degrees. These peaks are significantly different from the niflumethicone crystal forms reported in the prior art, indicating that this is a novel niflumethicone crystal form.

[0017] Thermogravimetric analysis (TGA) of the nyflufenic acid (NFA) crystal form prepared in this invention is shown in the appendix. Figure 2 The mass remains basically stable below about 200℃ with no significant weight loss, indicating that the crystal form has good thermal stability under normal processing and storage temperatures; significant weight loss begins to occur above about 200℃, corresponding to the thermal decomposition process of the sample.

[0018] The differential scanning calorimetry (DSC) chromatogram of niflufenic acid (NFA) prepared according to this invention is shown in the appendix. Figure 3 A single, sharp endothermic peak appears at 204±2℃, corresponding to the melting process of this crystal form. There is no obvious melting-to-crystal phenomenon, and the thermal behavior characteristics further confirm the uniqueness of this crystal form.

[0019] The nyflufenic acid (NFA) crystal form prepared by this invention is hereby abbreviated as crystal form A.

[0020] The nyflumecium crystalline form A crystal of this invention is prepared by a melt method, which is simple and easy to control, requires no complex solvent system, and has no risk of solvent residue. It is suitable for industrial-scale production. The specific steps are as follows: Take niflufenic acid (NFA) raw material and place it in a melting reaction device. Control the heating rate to 5-10℃ / min and heat to 210℃ for constant temperature melting for 5 min to allow the raw material to fully melt and complete the initial crystal transformation. After melting, control the cooling rate to 2-3℃ / min and slowly cool to room temperature to allow the melt to recrystallize and obtain a white crystalline solid, which is the niflufenic acid crystal form A.

[0021] The following is a specific implementation example of the melting method for NFA crystal form A.

[0022] Experimental instruments and testing conditions: General characterization instruments and testing conditions: X-ray powder diffractometer (XRPD) was Rigaku D / max-2500; Method: Cu target Ka, voltage 40KV, current 100mA, test angle 2-40°, step size 8, exposure time 0.2S, light tube slit width 1mm, detector slit width 2.7mm.

[0023] Thermogravimetric analyzer (TGA): Mettler Toledo TGA / DSC1; Method: The heating rate was 10℃ / min, and the flow rate of the protective gas nitrogen was 50ml / min.

[0024] Differential Calorimeter (DSC): Mettler Toledo DSC1 / 500 Method: The heating rate was 10℃ / min, and the flow rate of the protective gas nitrogen was 50ml / min.

[0025] Solubility determination: The shake-flask method was used, referring to the General Chapter 0631 of Part IV of the Chinese Pharmacopoeia 2020 Edition. The solvent was ethanol, the temperature was 25℃, the shaking rate was 100 r / min, and the shaking time was 5 min. The drug concentration in the dissolution solution was determined by high performance liquid chromatography (HPLC). Example 1

[0026] Take 5.0g of niflufenic acid (NFA) raw material (chemical name: 2-[(3-trifluoromethyl)phenyl]aminobenzoic acid, molecular formula C 14 H 10F3NO2 was placed in a molten reactor equipped with mechanical stirring. The heating rate was set to 5℃ / min, and the temperature was gradually increased to 35℃ and kept constant for 5 min. During this period, the mixture was continuously stirred at a low speed of 100 r / min to ensure that the raw material was fully melted and the initial crystal form transformation was completed. After melting, the cooling rate was set to 2℃ / min and the mixture was slowly cooled to room temperature. The melt recrystallized naturally to obtain a white needle-like solid, which is niflufenic acid crystal form A.

[0027] The obtained product was tested using the aforementioned general characterization instruments: the powder X-ray diffraction pattern, expressed as a diffraction angle 2θ, showed characteristic peaks at 9.8°, 12.6°, 16.7°, 23.4°, and 25.6°, which were completely consistent with the standard pattern of crystal form A in Figure 1; the TGA pattern showed no significant weight loss below 200°C (weight loss rate <0.5%), and significant weight loss began above 200°C, corresponding to the thermal decomposition process, consistent with Figure 2; the DSC pattern showed a single sharp endothermic peak at 204°C, corresponding to the melting process of crystal form A, consistent with Figure 3, confirming that the obtained product was the niflumethicone crystal form A. The crystal has high crystallinity. As determined by the shake-flask method described above, its solubility in ethanol at 35℃ for 5 min is 75.4049 mg / mL, which is significantly higher than the solubility of the original crystal form under the same conditions (59.1077 mg / mL). The high solubility of the crystal form can effectively improve the dissolution and absorption efficiency of the drug in the human body. Example 2

[0028] Take 5.0g of niflufenic acid (NFA) raw material and place it in a melting reactor equipped with mechanical stirring. Set the heating rate to 8℃ / min, gradually raise the temperature to 25℃ and hold it at a constant temperature for 5 min. During this period, stir continuously at a low speed of 100 r / min to ensure that the raw material is fully melted and completes the initial crystal transformation. After melting, set the cooling rate to 2.5℃ / min and slowly cool it to room temperature. The melt recrystallizes naturally to obtain a white needle-like solid, which is niflufenic acid crystal form A.

[0029] The obtained product was tested using the aforementioned general characterization instruments. The powder X-ray diffraction pattern was consistent with Figure 1, and the TGA and DSC patterns were consistent with Figures 2 and 3, respectively, confirming that the obtained product was the NFA crystal form A. This crystal has high crystallinity. The solubility in ethanol at 25℃ / 5 min, determined by the aforementioned shake-flask method, was 60.4014 mg / mL, significantly higher than the solubility of the original crystal form under the same conditions (47.1620 mg / mL). XRD comparison with the original crystal form (NFA raw material) showed a significant difference in crystal form. Example 3

[0030] Take 5.0g of Nefromycin (NFA) raw material and place it in a melting reactor equipped with mechanical stirring. Set the heating rate to 10℃ / min and gradually heat it to 45℃ and keep it at a constant temperature for 5 min. During this period, stir continuously at a low speed of 100 r / min to ensure that the raw material is fully melted and completes the initial crystal transformation. After melting, set the cooling rate to 3℃ / min and slowly cool it to room temperature. The melt recrystallizes naturally to obtain a white needle-like solid, which is Nefromycin crystal form A.

[0031] The obtained product was tested using the aforementioned general characterization instruments. The powder X-ray diffraction pattern was consistent with Figure 1, and the TGA and DSC patterns were consistent with Figures 2 and 3, respectively, confirming that the obtained product was the NFA crystal form A. This crystal has high crystallinity. The solubility in ethanol at 45℃ / 5 min, determined by the aforementioned shake-flask method, was 97.1992 mg / mL, significantly higher than the solubility of the original crystal form under the same conditions (76.6310 mg / mL). XRD comparison with the original crystal form (NFA raw material) showed a significant difference in crystal form. Example 4

[0032] 500.0 g of niflufenic acid (NFA) raw material was placed in an industrial-grade jacketed heating melting reactor. The heating rate was set to 5 °C / min, and the temperature was gradually increased to 30 °C using jacket steam and held at this temperature for 5 min. During this period, the mixture was continuously stirred at a low speed of 80 r / min to ensure complete melting and initial crystal transformation. After melting, the mixture was slowly cooled using jacket cooling water at a rate of 2 °C / min. After cooling to room temperature, the melt naturally recrystallized to obtain a white needle-like solid, which is niflufenic acid crystal form A. The obtained product was analyzed using the aforementioned general characterization instruments, and the powder X-ray diffraction pattern was consistent with... Figure 1 Consistent, the TGA and DSC spectra are respectively consistent with Figure 2 , Figure 3 Consistent with the above results, the obtained product is confirmed to be the NFA crystal form A. This crystal exhibits high crystallinity and good batch-to-batch uniformity. The solubility in ethanol at 30℃ / 5 min, determined by the shake-flask method described above, is 65.2214 mg / mL, significantly higher than the solubility of the original crystal form under the same conditions (50.9904 mg / mL). XRD comparison with the original crystal form (NFA raw material) shows a significant difference in crystal form, with no solvent residue, making it suitable for large-scale industrial production. Example 5

[0033] Take 500.0g of NFA raw material and place it in an industrial-grade jacketed heating melting reactor. Set the heating rate to 10℃ / min and gradually heat it to 55℃ using jacket steam. Maintain the temperature for 5 min and stir continuously at a low speed of 80 r / min to ensure that the raw material is fully melted and completes the initial crystal transformation. After melting, slowly cool it down using jacket cooling water at a cooling rate of 3℃ / min. After cooling to room temperature, the melt naturally recrystallizes to obtain a white needle-like solid, which is NFA crystal form A.

[0034] The obtained product was tested using the aforementioned general characterization instruments. The powder X-ray diffraction pattern was consistent with Figure 1, and the TGA and DSC patterns were consistent with Figures 2 and 3, respectively, confirming that the obtained product was the NFA crystal form A. This crystal has high crystallinity and good batch-to-batch uniformity. The solubility in ethanol at 55℃ / 5 min, determined by the aforementioned shake-flask method, was 112.5638 mg / mL, significantly higher than the solubility of the original crystal form under the same conditions (89.1176 mg / mL). XRD comparison with the original crystal form (NFA raw material) showed a significant difference in crystal form, with no solvent residue, making it suitable for large-scale industrial production.

Claims

1. A method for preparing niflumethicone crystal form by melt crystallization, characterized in that, The method described uses a melt-process preparation. Includes the following processes: (1) Add NFA raw material to the melting reaction equipment, control the heating rate to 5-10℃ / min, heat to 210℃ and melt at a constant temperature for 5min to fully melt the raw material; (2) After melting, control the cooling rate to 2-3℃ / min and slowly cool down to 17℃ to recrystallize the melt and obtain a white crystalline solid, which is the crystalline form of niflufenic acid (NFA).

2. The method for preparing niflumethicone crystal form by melt crystallization according to claim 1, characterized in that, The prepared niflumica (NFA) crystal has characteristic peaks at 9.8±0.2, 12.6±0.2, 16.7±0.2, 23.4±0.2, and 25.6±0.2 degrees in its X-ray powder diffraction pattern (denoted by 2θ).

3. The method for preparing niflumethicone crystal form by melt crystallization according to claim 1, characterized in that, The prepared niflufenic acid (NFA) crystal has a characteristic endothermic peak at 204±2℃ in its DSC spectrum, which corresponds to the melting process of this crystal form.

4. The method for preparing niflumethicone crystal form by melt crystallization according to claim 1, characterized in that, The prepared niflufenic acid (NFA) crystals showed stable quality at temperatures below 200°C according to TGA spectra.

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