CN-122010832-A - Method for preparing niflumic acid crystal form by melt crystallization

Abstract

The invention discloses a method for preparing niflumic acid crystal forms by melt crystallization, and relates to a method for preparing medicine crystal forms. The crystal form A prepared by the invention 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 shown by X-ray powder diffraction 2 theta. The crystal form A has good thermal stability, basically stable quality below 200 ℃ and stable existence for more than four weeks under the condition of 40 ℃/75% RH, and meanwhile, the crystal form A has low hygroscopicity, is favorable for the transportation and long-term storage of products, has good solubility, can reach about 0.013455mg/mL in an ethanol solution at 25 ℃ for 24 hours, and can promote the absorption of medicines in human bodies. The crystal form of niflumic acid (NFA) is a non-steroidal anti-inflammatory drug and has the pharmacological activities of anti-inflammatory, analgesic and antipyretic.

Inventors

• LI YUNSHAN
• LIU YU
• MIAO HONGYU
• ZHANG YANKE
• TANG CHEN
• HUANG SHUQI
• Zhao Diran

Assignees

• 沈阳化工大学

Dates

Publication Date

20260512

Application Date

20260319

Claims (4)

1. 1. The method for preparing the niflumic acid crystal form by melt crystallization is characterized by comprising the following steps of: (1) Adding niflumic acid (NFA) raw material into melting reaction equipment, controlling the heating rate to be 5-10 ℃ per min, heating to 210 ℃ and melting at constant temperature for 5min, so that the raw material is fully melted; (2) After the melting is finished, the cooling rate is controlled to be 2-3 ℃ per minute, and the temperature is slowly reduced to 17 ℃ to enable the melt to be recrystallized, so that white crystalline solid is obtained, namely the niflumic acid (NFA) crystal form crystal.
2. 2. The method of preparing niflumic acid crystalline form according to claim 1, characterized in that said prepared niflumic acid (NFA) crystalline form has a characteristic peak in X-ray powder diffraction pattern expressed in 2Θ at 9.8±0.2, 12.6±0.2, 16.7±0.2, 23.4±0.2, 25.6±0.2 degrees.
3. 3. The method of claim 1, wherein the crystalline form of niflumic acid (NFA) is prepared as a crystal having a DSC profile with a characteristic endothermic peak at 204 ± 2 ℃ corresponding to the melting process of the crystalline form.
4. 4. The method of claim 1, wherein the crystalline form of niflumic acid (NFA) is prepared as crystals having a TGA spectrum which shows stable quality below 200 ℃.

Description

Method for preparing niflumic acid crystal form by melt crystallization Technical Field The invention relates to a preparation method of anti-inflammatory drug crystals, in particular to a method for preparing niflumic acid crystal forms by melting crystallization. Background Niflufenamic acid (NFA) is a non-steroidal anti-inflammatory drug commonly used in clinic, and by inhibiting the activity of Cyclooxygenase (COX), the synthesis of prostaglandin is reduced, so that the niflumic acid has the effects of resisting inflammation, easing pain and relieving fever, and is suitable for the clinical treatment of various inflammations and pains such as rheumatoid arthritis, osteoarthritis, soft tissue injury, postoperative pain and the like. The existing niflumic acid crystal forms of the niflumic acid related preparations applied in the current clinic have the problems of poor solubility, low bioavailability, poor stability and the like, so that the preparation has slow dissolution rate, delayed drug effect, high production and processing difficulty, severe storage and transportation conditions and difficulty in meeting the clinical high-efficiency and convenient drug demands. The solid crystal forms of the medicines are key factors influencing the physicochemical properties and clinical application, and the same medicines with different crystal forms have obvious differences in the aspects of solubility, dissolution rate, stability, fluidity and the like, and are directly related to the quality control, the production process feasibility and the final clinical efficacy of the medicine preparation. Through domestic and foreign patent and literature search, two crystal forms exist in the prior reported niflumic acid, and only one crystal form analyzes the crystal structure and is a commercially available crystal form. However, the solubility of the crystal form is low, so that the absorption and bioavailability of the medicine in a human body are affected, and the industrial production and clinical application of the medicine are limited. Disclosure of Invention The invention aims to provide a method for preparing niflumic acid crystal forms by melt crystallization, which is a novel melt crystallization preparation method, and the obtained niflumic acid is a novel crystal form, has high solubility, good stability, simple preparation process, easy control and no solvent residue, is suitable for industrial production and medicinal development, provides a novel high-quality choice for research and development and production of niflumic acid pharmaceutical preparations, and has important significance for clinical application and industrial development of the medicines. The invention aims at realizing the following technical scheme: the method for preparing the niflumic acid crystal form by melt crystallization is characterized by comprising the following steps of: (1) Adding niflumic acid (NFA) raw material into melting reaction equipment, controlling the heating rate to be 5-10 ℃ per min, heating to 210 ℃ and melting at constant temperature for 5min, so that the raw material is fully melted; (2) After the melting is finished, the cooling rate is controlled to be 2-3 ℃ per minute, and the temperature is slowly reduced to 17 ℃ to enable the melt to be recrystallized, so that white crystalline solid is obtained, namely the niflumic acid (NFA) crystal form crystal. The method for preparing the niflumic acid crystal form by melt crystallization is characterized in that the prepared niflumic acid (NFA) crystal form 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 an X-ray powder diffraction pattern expressed by 2 theta. The melting crystallization method for preparing the niflumic acid crystal form is characterized in that the DSC spectrum of the prepared niflumic acid (NFA) crystal form shows a characteristic endothermic peak at the position of 204+/-2 ℃ and corresponds to the melting process of the crystal form. The method for preparing the niflumic acid crystal form by melt crystallization is characterized in that the prepared niflumic acid (NFA) crystal form crystal has a TGA spectrum which shows that the quality is stable below 200 ℃. The invention has the remarkable characteristics and effects that: 1. The crystal form prepared by the melting method has excellent physicochemical properties and process suitability, and solves the technical defects of the existing niflumic acid crystal form. The crystal form of niflumic acid (NFA) is a non-steroidal anti-inflammatory drug and has the pharmacological activities of anti-inflammatory, analgesic and antipyretic. 2. The niflumic acid crystal form A solid obtained by the invention has excellent solubility, and the solubility of 60.4014 mg/mL in ethanol at the constant temperature of 25 ℃ for 24 hours is determined by experiments, so that the dissolution and absorption efficiency of the medicine in a human body can be effect