CN107556352B

CN107556352B - Crystallization method for preparing millimeter-grade large-particle-size azithromycin

Info

Publication number: CN107556352B
Application number: CN201710791066.0A
Authority: CN
Inventors: 龚俊波; 吴送姑; 陈明洋; 侯宝红; 杜世超; 张得江; 许史杰
Original assignee: Tianjin University
Current assignee: Tianjin University
Priority date: 2017-09-05
Filing date: 2017-09-05
Publication date: 2020-07-24
Anticipated expiration: 2037-09-05
Also published as: CN107556352A

Abstract

The invention relates to a crystallization method for preparing millimeter-sized large-particle-size azithromycin, wherein an azithromycin crystallization product is a white crystal, the appearance of the product is in a rhombohedral shape with a sharp head at one end, the bulk density is better and reaches more than 0.58g/m L, the fluidity is good, the angle of repose can be less than 36 degrees, the method comprises the steps of adding a crude azithromycin product and an acetone solvent into a crystallizer with stirring, heating and dissolving, adding water to reach supersaturation, adding azithromycin seed crystals for crystal growth, dropwise adding water to enable the crystals to grow, filtering the crystals after completing the dropwise adding, and drying to obtain an azithromycin crystal product.

Description

Crystallization method for preparing millimeter-grade large-particle-size azithromycin

Technical Field

The invention belongs to the technical field of chemical engineering medicine, and particularly relates to a crystallization method for preparing millimeter-grade large-particle-size azithromycin

Background

Azithromycin (9-deoxy-9 α -aza-9 α -methyl-9 α -erythromycin A) is a third generation macrolide antibiotic with the chemical structural formula:

azithromycin kills bacteria by hindering the bacterial transpeptidation process and inhibiting the synthesis of bacterial proteins. Has strong antibacterial effect on gram-positive bacteria, partial gram-negative bacteria, chlamydia, mycoplasma and the like, and has obvious curative effect on respiratory tract infection. The azithromycin has high bioavailability, strong in-vivo antibacterial activity, strong tissue permeability, obvious curative effect, good safety and tolerance. Azithromycin is described in US4517359 and US 4474768.

The azithromycin mainly comprises tablets and injection, and the applicability of the tablets is better in consideration of medication convenience, the requirements of the tablets on the granularity, bulk density and fluidity of products are higher, the powder performances of azithromycin products are greatly influenced by refining and crystallization methods, at present, domestic and foreign reports mainly focus on purifying and refining methods of azithromycin, U.S. Pat. No. 5,000,527 reports a purifying and refining method of purifying azithromycin by using methanol, acetone and water, U.S. Pat. No. 35 reports a refining method of adsorbing, eluting, reduced pressure distillation and elution, dissolving and analyzing, CN 104429 reports purifying azithromycin by extraction and acid-base neutralization reaction, CN105001283B reports a refining method of purifying azithromycin by using acetone and water for recrystallization after crystallization of ethanol and water, CN101418026B reports a crystal form and a controllable crystallization process, the refining method of preparing azithromycin products with the granularity range of 20-180 micrometers by using solvent and water for agglomeration, evaporation or extraction and neutralization reaction is found to realize a refining process of agglomeration, the refining method of the agglomeration, the refining process of the elution or the neutralization reaction is difficult to realize an urgent development process of the bulk density of azithromycin, the product with the granularity of the azithromycin, the purity of the azithromycin is more than that the agglomeration, the bulk density of an agglomeration, the azithromycin is higher than that the azithromycin, the bulk density of an agglomeration, the azithromycin is found by an agglomeration, the azithromycin is higher than that the particle size of an agglomeration, the azithromycin is found by an agglomeration, the azithromycin, the agglomeration, the particle size of an agglomeration, the azithromycin is found by an agglomeration.

An azithromycin product obtained by industrial production at present is easily aggregated as shown in figure 1, is seriously crushed, has the particle size of 30-200 microns, is easy to cause agglomeration and coalescence phenomena due to too small particle size, can cause solvent preservation and has low purity; moreover, agglomeration and disintegration affect the flowability and bulk density of the granules, and the flowability and bulk density of the product are poor. In response to these problems, it is desirable to develop a process that results in a product having a large particle size, no agglomeration, and high flow and bulk density.

Disclosure of Invention

In order to solve the technical defects, the invention aims to provide the method for preparing the azithromycin with the large granularity, the prepared azithromycin crystal product is white crystals, the appearance of the product is in a rhombohedral shape with a sharp head at one end, the crystals are not agglomerated into single dispersed millimeter-sized large-granularity particles, the product purity can reach 99.8 percent, the crushing phenomenon is avoided, the bulk density is better and can reach more than 0.58g/m L, the fluidity is good, the angle of repose can be less than 36 degrees, the filtering and drying are very easy, and the method for dissolving and crystallizing is simple in crystallization process, high in yield and high in product purity.

A crystallization method for preparing millimeter-sized large-particle-size azithromycin is characterized in that:

heating and dissolving the azithromycin crude product by using acetone, adding water to reach supersaturation, adding seed crystals before crystal growth, then growing crystals after adding the seed crystals, continuously dripping water for dissolution, further growing the crystals into millimeter level, and filtering and drying to obtain the bright white unagglomerated millimeter level azithromycin product.

The technical scheme of the invention is as follows:

a crystallization method for preparing millimeter-sized large-particle-size azithromycin comprises the steps of adding a crude azithromycin product and an acetone solvent into a crystallizer with a stirrer, heating for dissolving, adding water to reach supersaturation, adding azithromycin crystal seeds for growing crystals, dropwise adding water to grow the crystals, filtering the crystals after the water is dropwise added, and drying to obtain an azithromycin crystal product.

The mass ratio of the azithromycin to the acetone solvent is 1: 2-5.

The heating and dissolving temperature is 30-50 ℃.

The added water is supersaturated, and the mass of the added water is 0.5-2 times of the total mass of the azithromycin.

The adding mass of the seed crystal is 0.5 to 2 percent of the total mass of the azithromycin; growing the crystal for 10-40 min.

The crystal grows by dropping water, and the mass of the dropped water is 2-6 times of the total mass of the azithromycin; the time for dripping water is 5-10 h.

The crystallization method for preparing the millimeter-sized large-particle-size azithromycin has the advantages that the main particle size of the prepared particles reaches more than 1.5 mm, the product purity is high, the particles are not agglomerated and have very good fluidity, the bulk density, the particle size and the fluidity of the particles are very important powder indexes in the drug production, the bulk density is increased, the fluidity is improved, and the storage and the transportation of the product are facilitated, so the improvement of the characteristics of the azithromycin particles is an important target in the crystallization process.

Drawings

FIG. 1 scanning electron microscope photograph of azithromycin raw material product sold in market

FIG. 2 SEM photograph of the product obtained in example 1;

FIG. 3 is a scanning electron micrograph of the product obtained in example 2;

FIG. 4 is a SEM photograph of a product obtained in example 3.

FIG. 5 is a SEM photograph of the product obtained in example 4.

Detailed description of the invention

The following will be embodied by way of example, with the following specific steps: adding a crude azithromycin product and an acetone solvent into a crystallizer with stirring, adding 1 part by mass of the crude azithromycin product, adding 2-5 parts by mass of acetone, raising the temperature to 30-50 ℃, ensuring that azithromycin solid is completely dissolved, adding 0.5-2 parts by mass of water, adding azithromycin crystals accounting for 0.5-2% of the total mass of azithromycin crystals as crystal seeds, growing crystals for 10-40 min, continuously dripping 2-6 parts by mass of water, controlling the dripping time to be 5-10 h, controlling the stirring speed to be uniform when the system can be suspended, filtering the crystals after the dripping is finished, and drying to obtain the azithromycin product. The above-mentioned aspects of the present invention will be described in further detail. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Example 1

Adding 5g of azithromycin and 10g of acetone into a crystallizer with a stirrer, heating to 50 ℃, keeping the temperature, adding 2.5g of water after the azithromycin is completely dissolved, adding azithromycin crystals accounting for 0.5 percent of the total weight of the azithromycin as seed crystals after a system is stabilized, growing the crystals at a constant temperature for 30min, slowly dropwise adding 10g of water, controlling the whole dropwise adding time to be about 5h, filtering and drying after the water is added to obtain the product, wherein an SEM photograph of the product is shown in figure 2, the particle size of a single crystal product is larger than 1.4 mm, the particle size distribution of the product is uniform, the bulk density is 0.58g/m L, the angle of repose is 37.2 degrees, and the purity of the product is 99.7 percent through liquid phase detection.

Example 2

Adding 10g of azithromycin and 50g of acetone into a crystallizer with a stirrer, keeping the temperature at 30 ℃, adding 20g of water after the azithromycin is completely dissolved, adding azithromycin crystals accounting for 2 percent of the total weight of the azithromycin as seed crystals after the system is stabilized, growing the crystals at constant temperature for 10min, slowly adding 60g of water dropwise, controlling the whole dropwise adding time to be about 10h, filtering and drying to obtain the product, wherein an SEM photograph of the product is shown in figure 3, and the SEM photograph shows that the granularity of a single crystal product is more than 1.6 millimeters, the product granularity is uniformly distributed, the bulk density is 0.59g/m L, the angle of repose is 36.5 degrees, and the product purity is 99.8 percent through liquid phase detection.

Example 3

Adding 8g of azithromycin and 32g of acetone into a crystallizer with a stirrer, keeping the temperature at 50 ℃, adding 12g of water after the azithromycin is completely dissolved, adding azithromycin crystals accounting for 1 percent of the total weight of the azithromycin as seed crystals after the system is stabilized, growing the crystals at a constant temperature for 40min, slowly adding 40g of water dropwise, controlling the whole dropwise adding time to be about 8h, filtering and drying to obtain the product, wherein an SEM photograph of the product is shown in figure 4, and the SEM photograph shows that the granularity of a single crystal product is more than 1.5 millimeters, the product granularity is uniformly distributed, the bulk density is 0.60g/m L, the angle of repose is 37.9 degrees, and the product purity is 99.8 percent through liquid phase detection.

Example 4

Adding 6g of azithromycin and 18g of acetone into a crystallizer with a stirrer, keeping the temperature at 40 ℃, adding 6g of water after the azithromycin is completely dissolved, adding azithromycin crystals accounting for 1.5 percent of the total weight of the azithromycin as seed crystals after a system is stabilized, growing the crystals at a constant temperature for 20min, slowly dropwise adding 24g of water, controlling the whole dropwise adding time to be about 9h, filtering and drying after the water is added to obtain a product, wherein the granularity of a single crystal product is more than 1.7 mm, the product granularity distribution is uniform, the bulk density is 0.58g/m L, the angle of repose is 38.0 degrees, and the purity of the product is 99.6 percent through liquid phase detection.

Example 5

Adding 4g of azithromycin and 14g of acetone into a crystallizer with a stirrer, keeping the temperature at 35 ℃, adding 6.4g of water after the azithromycin is completely dissolved, adding azithromycin crystals accounting for 0.8 percent of the total weight of the azithromycin as seed crystals after the system is stable, growing the crystals at the constant temperature for 25min, slowly dropwise adding 22g of water, controlling the whole dropwise adding time to be about 7h, and filtering and drying after the water is added to obtain the product, wherein the granularity of a single crystal product is more than 1.4 mm, the granularity distribution of the product is uniform, the bulk density is 0.57g/m L, the angle of repose is 35.80 degrees, and the purity of the product is 99.8 percent through liquid phase detection.

Example 6

Adding 10g of azithromycin and 25g of acetone into a crystallizer with a stirrer, keeping the temperature at 45 ℃, adding 8g of water after the azithromycin is completely dissolved, adding azithromycin crystals accounting for 1.2 percent of the total weight of the azithromycin as seed crystals after the system is stabilized, growing the crystals at a constant temperature for 15min, slowly dripping 35g of water, controlling the whole dripping time to be about 8h, filtering and drying after the water is added to obtain the product, wherein the granularity of a single crystal product is more than 1.5 mm, the product granularity distribution is uniform, the bulk density is 0.59g/m L, the angle of repose is 36.50 degrees, and the purity of the product is 99.6 percent through liquid phase detection.

Claims

1. A crystallization method of millimeter-grade large-particle-size azithromycin is characterized by comprising the following steps: adding a certain proportion of azithromycin crude product and an acetone solvent into a crystallizer with stirring, heating for dissolving, adding water to reach supersaturation, adding azithromycin seed crystals for growing crystals, then dropwise adding water to grow the crystals, filtering the crystals after the addition of the water is finished, and drying to obtain an azithromycin crystal product;

the mass ratio of the azithromycin to the acetone solvent is 1: 2-5; the added water is supersaturated, and the mass of the added water is 0.5-2 times of the total mass of the azithromycin; the crystal grows by dropping water, the mass of the dropped water is 2-6 times of the total mass of the azithromycin, and the time for dropping the water is 5-10 hours; the addition amount of the seed crystal is 0.5 to 2 percent of the total mass of the azithromycin.