阅读说明：本技术 大晶体、高堆积密度甲芬那酸的制备方法 (Preparation method of large-crystal high-bulk-density mefenamic acid ) 是由 寇世超 孙滨 张宾 张治中 王萌 李明纲 张彤 于 2020-12-08 设计创作，主要内容包括：本发明属于医药技术领域,具体涉及一种大晶体、高堆积密度甲芬那酸的制备方法。氮气保护下,将甲芬那酸粗品加入溶剂中,经升温溶解,脱色热滤,保温养晶,梯度降温,保温析晶、过滤得到滤饼,烘干,得到大晶体、高堆积密度甲芬那酸。本发明采用乙酸、丙酮或1,4-二氧六环作为溶剂进行精制,得到的甲芬那酸晶体流动性好、晶体稳定、易于粉碎、堆积密度高、成药性更佳。本发明的制备方法,安全环保、操作简单。易于工业化生产。(The invention belongs to the technical field of medicines, and particularly relates to a preparation method of large-crystal high-bulk-density mefenamic acid. Adding the crude mefenamic acid into a solvent under the protection of nitrogen, heating to dissolve, decoloring, hot filtering, keeping warm, growing crystal, gradient cooling, keeping warm, crystallizing, filtering to obtain a filter cake, and drying to obtain the large-crystal high-bulk density mefenamic acid. The invention adopts acetic acid, acetone or 1, 4-dioxane as solvent for refining, and the obtained mefenamic acid crystal has good fluidity, stable crystal, easy pulverization, high bulk density and better pharmaceutical property. The preparation method disclosed by the invention is safe, environment-friendly and simple to operate. Is easy for industrialized production.)

1. A preparation method of large-crystal high-bulk density mefenamic acid is characterized by comprising the following steps: adding the crude mefenamic acid into a solvent, preserving heat, growing crystals, performing gradient cooling, preserving heat, crystallizing, filtering and drying to obtain large-crystal high-bulk-density mefenamic acid.

2. A process for the preparation of large crystal, high bulk density mefenamic acid as claimed in claim 1, characterized in that: the solvent is acetic acid, acetone or 1, 4-dioxane.

3. A process for the preparation of large crystal, high bulk density mefenamic acid as claimed in claim 2, characterized in that: when the solvent is acetic acid or acetone, the mass ratio of the mefenamic acid crude product to the solvent is 1: 3-20; when the solvent is 1, 4-dioxane, the mass ratio of the mefenamic acid crude product to the solvent is 1: 2-5.

4. A process for the preparation of large crystal, high bulk density mefenamic acid as claimed in claim 2, characterized in that: when the solvent is acetic acid, the temperature for heat preservation and crystal growth is 95-105 ℃; when the solvent is acetone, the temperature for heat preservation and crystal growth is 40-50 ℃; when the solvent is 1, 4-dioxane, the temperature for heat preservation and crystal growth is 85-95 ℃; the heat preservation and crystal growth time is 1-3 h.

5. A process for the preparation of large crystal, high bulk density mefenamic acid as claimed in claim 1, characterized in that: the gradient cooling rate is 10-45 ℃/h, and the temperature is reduced to 20-25 ℃.

6. A process for the preparation of large crystal, high bulk density mefenamic acid as claimed in claim 1, characterized in that: the heat preservation crystallization temperature is 20-25 ℃, and the heat preservation crystallization time is 1-3 hours.

7. A process for the preparation of large crystal, high bulk density mefenamic acid as claimed in any one of claims 1 to 6, characterized in that: adding the crude mefenamic acid into a solvent under the protection of nitrogen, heating up for dissolving, decoloring and hot filtering, preserving heat for growing crystal, performing gradient cooling, preserving heat for crystallizing, filtering and drying to obtain large-crystal high-bulk-density mefenamic acid.

8. The method of preparing large crystal, high bulk density mefenamic acid according to claim 7, characterized in that: activated carbon is adopted for decolorization, and the mass ratio of the mefenamic acid crude product to the activated carbon is 1: 0.01-0.05.

9. The method of preparing large crystal, high bulk density mefenamic acid according to claim 7, characterized in that: heating to 50-120 deg.c; the stirring speed is 5-50r/min when the heat preservation and the crystal growth are carried out.

10. The method of preparing large crystal, high bulk density mefenamic acid according to claim 7, characterized in that: the drying temperature is 60-100 ℃, and the drying time is 5-6 hours.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of large-crystal high-bulk-density mefenamic acid.

Background

Mefenamic Acid is also known as Mefenamic Acid, paracetamol, etc., and its english name is Mefenamic Acid. Mefenamic acid is an anti-inflammatory analgesic agent, and has antipyretic, analgesic and anti-inflammatory effects. The relative molecular mass is 241.3, and the structural formula is as follows:

mefenamic acid itself is an anti-inflammatory agent, and mainly plays a role in stabilizing the protein structure of cell membranes and interfering with tissue metabolic processes by inhibiting the synthesis of prostaglandins and protein-decomposing enzymes. Is clinically used for treating diseases such as rheumatic arthritis, rheumatoid arthritis, dysmenorrheal, headache, neuralgia, myalgia, other postoperative inflammatory pains and the like. In addition, mefenamic acid can also be used as a precursor for acridine antimalarials and anticancer drugs. The preparation method disclosed at present is to take o-halobenzoic acid and 2, 3-dimethylaniline as starting materials, add an acid-binding agent and a catalyst, and take toluene, xylene and DMF or DMSO as solvents to prepare the mefenamic acid product.

Chinese patent CN107602400A discloses a method for accelerating the synthesis time of mefenamic acid, which comprises the steps of taking o-chlorobenzoic acid, sodium carbonate and 2, 3-dimethylaniline as main raw materials, copper powder as a catalyst, DMF and toluene as solvents for reaction, heating, introducing mixed steam in a reaction kettle into a rectifying tower with a theta ring as a filler, and finally acidifying, cooling and filtering to obtain a crude product of mefenamic acid.

Chinese patent CN102344384A discloses a process for synthesizing mefenamic acid, 1) adding water and o-chlorobenzoic acid into a reaction kettle, mixing uniformly, and dripping sodium hydroxide solution under stirring to obtain a mixed solution; 2) adding solid sodium bicarbonate into the mixed solution obtained in the step 1), and adding copper sulfate pentahydrate, 2, 3-dimethylaniline and hexadecyl trimethyl ammonium chloride for reflux reaction; 3) after the reflux reaction in the step 2) is finished, dropwise adding hydrochloric acid, and filtering the materials to obtain a crude product; 4) washing the crude product in the step 3) with water, filtering to obtain a crude product, and drying under reduced pressure to obtain a crude product; 5) adding dimethylformamide and water into the crude product obtained in the step 4) for dissolving, adding activated carbon for reflux decoloring, filtering, cooling to room temperature for crystallization, filtering, recrystallizing again, filtering for the last time for recrystallization, leaching with water, and drying under reduced pressure to obtain a refined mefenamic acid product. The patent carries out multiple recrystallization on crude mefenamic acid, the steps are complicated, and the bulk density of the mefenamic acid is not involved.

Chinese patent CN103420863A discloses a short-flow synthesis and refining method of mefenamic acid, the refining process of which is: adding a proper amount of crude mefenamic acid into N, N-dimethylformamide serving as a solvent, heating, stirring and dissolving until the mixture is clear; adding medicinal carbon in a proper proportion, and keeping the temperature at 90 +/-5 ℃ for decoloring for 40 minutes; freezing to 0 ℃, preserving heat for crystallization, and removing a liquid phase to obtain a crystal phase, namely the mefenamic acid with the molar content and the purity higher than 99 percent. Nor does this patent relate to the bulk density of mefenamic acid.

At present, a great deal of literature and patents are available for researching the synthesis process of mefenamic acid, but the crystal form and the bulk density of the mefenamic acid are not researched. In the prior art, N-dimethylformamide, N-diethylformamide, N-dimethylacetamide, N-diethylacetamide and the like are used as refining solvents of mefenamic acid; or adding sodium hydroxide into mefenamic acid to change the mefenamic acid sodium salt, and regulating the pH value to obtain the mefenamic acid again. The research shows that the product obtained by the method has poor fluidity, uneven dispersion and poor pharmacy.

Disclosure of Invention

The invention aims to provide a preparation method of large-crystal high-bulk density mefenamic acid, and the prepared crystal has good fluidity, stable crystal, easy crushing, large bulk density and good pharmaceutical property; the preparation method is safe and environment-friendly, is simple and convenient to operate, and is easy for industrial production.

The technical scheme adopted by the invention for solving the technical problems is as follows:

the preparation method of the large-crystal high-bulk density mefenamic acid comprises the following steps: adding the crude mefenamic acid into a solvent, preserving heat, growing crystals, performing gradient cooling, preserving heat, crystallizing, filtering and drying to obtain large-crystal high-bulk-density mefenamic acid.

Wherein:

the solvent is acetic acid, acetone or 1, 4-dioxane.

When the solvent is acetic acid or acetone, the mass ratio of the mefenamic acid crude product to the solvent is 1: 3-20; when the solvent is 1, 4-dioxane, the mass ratio of the mefenamic acid crude product to the solvent is 1: 2-5.

When the solvent is acetic acid, the temperature for heat preservation and crystal growth is 95-105 ℃; when the solvent is acetone, the temperature for heat preservation and crystal growth is 40-50 ℃; when the solvent is 1, 4-dioxane, the temperature for heat preservation and crystal growth is 85-95 ℃; the heat preservation and crystal growth time is 1-3 h.

The gradient cooling rate is 10-45 ℃/h, and the temperature is reduced to 20-25 ℃.

The heat preservation crystallization temperature is 20-25 ℃, and the heat preservation crystallization time is 1-3 hours.

The preparation method of the large-crystal high-bulk density mefenamic acid comprises the following steps: adding the crude mefenamic acid into a solvent under the protection of nitrogen, heating up for dissolving, decoloring and hot filtering, preserving heat for growing crystal, performing gradient cooling, preserving heat for crystallizing, filtering and drying to obtain large-crystal high-bulk-density mefenamic acid.

Wherein:

decolorizing with activated carbon, preferably with medicinal activated carbon; the mass ratio of the crude mefenamic acid to the active carbon is 1: 0.01-0.05.

Heating to 50-120 deg.c; stirring speed is 5-50r/min during heat preservation and crystal growth, paddle stirring is adopted during stirring, shearing force is small, nucleation is weakened, and crystal growth is promoted.

The drying temperature is 60-100 ℃, and the drying time is 5-6 hours.

After the large-crystal high-bulk-density mefenamic acid obtained by the invention is further ground and crushed, a product with higher bulk density can be obtained.

The invention has the following beneficial effects:

(1) according to the invention, acetic acid, acetone or 1, 4-dioxane is used as a solvent for refining, the solvent has good solubility to mefenamic acid at high temperature, and the system can slowly reach supersaturation degree in the cooling process; in the processes of heat preservation crystal growth and heat preservation crystallization, regular crystals are formed, and no solvate is generated; the mefenamic acid refined by the three solvents has good density and stable property in the drying process, thereby obtaining the large-crystal and high-bulk density mefenamic acid product. The product mefenamic acid crystal has good fluidity, stable crystal, easy pulverization, high bulk density and better drug property.

(2) The preparation method disclosed by the invention is safe, environment-friendly and simple to operate. Is easy for industrialized production.

(3) Compared with the defects of mixed crystals and mefenamic acid with low bulk density in practical application, the mefenamic acid prepared by the invention is a flaky large crystal or a columnar large crystal, and the refining yield of the mefenamic acid and the stability of a preparation medicine thereof are improved. The refining yield of the mefenamic acid is 92-96%, the purity is more than 99.95%, and the bulk density can reach 0.88g/cm³The above.

Drawings

FIG. 1 is a topographical view of the flaky mefenamic acid crystal prepared in example 1;

FIG. 2 is a topographical view of columnar mefenamic acid crystals prepared in example 2;

FIG. 3 is a topographical view of columnar mefenamic acid crystals prepared in example 3;

fig. 4 is a morphology diagram of a common mefenamic acid crystal prepared in comparative example 1.

Detailed Description

The present invention is further described below with reference to examples.

Example 1

Adding 30g of crude mefenamic acid into 360g of acetic acid under the protection of nitrogen, and heatingDissolving at 115 ℃, adding 0.3g of medicinal activated carbon for decolorization, carrying out hot filtration, cooling, carrying out heat preservation and crystal growth at 100 ℃ for 2 hours, wherein the stirring speed in the process is 20r/min, then cooling to 25 ℃ at the speed of 15 ℃/h, carrying out heat preservation and crystal growth at the temperature for 2 hours, filtering, carrying out rinsing by using ethanol, drying the obtained solid in a normal-pressure forced air drying oven at 60 ℃ for 6 hours, and obtaining 28.5g of flaky mefenamic acid crystals, wherein the appearance graph of the flaky mefenamic acid crystals is shown in figure 1. The purification yield was 95%, the purity was 99.98%, and the bulk density was 0.814g/cm³Further pulverized to have a bulk density of 0.92g/cm³。

Example 2

Adding 30g of crude mefenamic acid into 450g of acetone under the protection of nitrogen, heating to 58 ℃ for dissolving, adding 0.3g of medicinal activated carbon for decoloring, cooling after heat filtration, keeping the temperature at 47 ℃ for growing crystals for 2 hours, wherein the stirring speed in the process is 20r/min, then cooling to 20 ℃ at the speed of 10 ℃/h, keeping the temperature for crystallizing for 2 hours, filtering, rinsing with ethanol, drying the obtained solid in a normal-pressure forced air drying oven at 80 ℃ for 5 hours, and obtaining 27.8g of columnar mefenamic acid crystals, wherein the appearance graph of the columnar mefenamic acid crystals is shown in figure 2. The purification yield was 93%, the purity was 99.97%, and the bulk density was 0.75g/cm³Further pulverized to have a bulk density of 0.9g/cm³。

Example 3

Adding 100g of crude mefenamic acid into 250g of 1, 4-dioxane under the protection of nitrogen, heating to 105 ℃ for dissolution, adding 1g of medicinal activated carbon for decolorization, cooling after heat filtration, keeping the temperature at 93 ℃ for crystal growth for 2 hours, wherein the stirring speed in the process is 20r/min, then cooling to 20 ℃ at the speed of 15 ℃/h, keeping the temperature for crystal growth for 2 hours, filtering, rinsing with ethanol, and drying the obtained solid in a normal-pressure forced air drying oven at 80 ℃ for 6 hours to obtain 94g of columnar mefenamic acid crystals, wherein the appearance graph of the columnar mefenamic acid crystals is shown in figure 3. The purification yield was 94%, the purity was 99.97%, and the bulk density was 0.7g/cm³Further pulverized to have a bulk density of 0.88g/cm³。

Comparative example 1

Under the protection of nitrogen, 100g of crude mefenamic acid is added into 100g N, N-Dimethylformamide (DMF) solvent, the temperature is raised to 110 ℃ for dissolution, and 1g of medicinal activity is addedDecolorizing with carbon, cooling after hot filtering, keeping the temperature at 95 ℃ for crystal growth for 2 hours, stirring at 20r/min, cooling to 20 ℃ at 15 ℃/h, keeping the temperature for crystal growth for 2 hours, filtering, leaching, drying the obtained solid for 6 hours at 80 ℃ in a reduced-pressure drying oven to obtain 89g of mixed crystal mefenamic acid product, wherein the appearance diagram is shown in figure 4. The purification yield was 89%, the purity was 99.94%, and the bulk density was 0.58g/cm³Further pulverized to have a bulk density of 0.75g/cm³。

Comparative example 2

Under the protection of nitrogen, 100g of crude mefenamic acid is added into 100g N, N-Dimethylacetamide (DMAC) solvent, the temperature is increased to 110 ℃ for dissolution, 1g of medicinal activated carbon is added for decolorization, the temperature is reduced after heat filtration, the temperature is kept at 95 ℃ for crystal growth for 2 hours, the stirring speed in the process is 20r/min, then the temperature is reduced to 20 ℃ at the speed of 15 ℃/h, the temperature is kept for crystal growth for 2 hours, filtration and leaching are carried out, and the obtained solid is dried in a reduced-pressure drying oven at 80 ℃ for 6 hours to obtain 88g of mixed crystal mefenamic acid product. The purification yield was 88%, the purity was 99.93%, and the bulk density was 0.57g/cm³Further pulverized to have a bulk density of 0.73g/cm³。

As can be seen from fig. 1 to 4, the mefenamic acid crystals obtained in example 1 are plate crystals, the mefenamic acid crystals obtained in examples 2 and 3 are columnar crystals, and the mefenamic acid product obtained in comparative example 1 is amorphous. Mefenamic acid in the form of flakes or columns has significantly better flowability than the amorphous form.

The stability of the mefenamic acid products obtained in examples 1-3 and comparative examples 1-2 was tested by High Performance Liquid Chromatography (HPLC) and the data are shown in table 1.

TABLE 1 stability data table for mefenamic acid products obtained in examples 1-3 and comparative examples 1-2

As can be seen from the data in table 1, the purity of example 1, example 2 and example 3 varied by only 0.02% over 90 days, whereas the purity of comparative example 1 and comparative example 2 varied by 0.04% over 90 days. Therefore, the purity of the mefenamic acid product obtained by the invention has small change in the same time, and the smaller the change in the purity, the more stable the properties of the mefenamic acid crystal are.