CN109988212B

CN109988212B - Prednisolone sodium phosphate production method

Info

Publication number: CN109988212B
Application number: CN201910322636.0A
Authority: CN
Inventors: 姬卫忠; 李合兴; 黄燕鸽; 孟栋梁; 潘严彬; 宋张胜
Original assignee: Henan Lihua Pharmaceutical Co ltd
Current assignee: Henan Lihua Pharmaceutical Co ltd
Priority date: 2019-04-22
Filing date: 2019-04-22
Publication date: 2020-11-20
Anticipated expiration: 2039-04-22
Also published as: CN109988212A

Abstract

A process for preparing prednisolone sodium phosphate includes such steps as dissolving prednisolone phosphate in the mixture of acetone and water, dropping aqueous solution of sodium hydroxide in tank, controlling temp at 10-25 deg.C, regulating pH value to 9.0-9.5, stirring, filtering, pumping acetone in diluting tank, regulating temp, adding reaction liquid, stirring to educe out a lot of crystals, laying aside for not less than 8 hr, washing with acetone, dry swinging, and drying. The method changes various solvents in the traditional process into a single solvent, solves the bottleneck of diversification of residual solvents in the bulk drugs, shortens half of the drying time, and has the advantages of less than 2.0 percent of total amount of impurities and great quality.

Description

Prednisolone sodium phosphate production method

Technical Field

The invention relates to a medicine production technology, in particular to a prednisolone sodium phosphate salifying production method, and belongs to the technical field of pharmacy.

Background

The prednisolone sodium phosphate is used as adrenocortical hormone medicine clinically. Has antiinflammatory, antiallergic and immunity inhibiting effects. Anti-inflammatory action: glucocorticoids reduce and prevent the tissue's response to inflammation, thereby reducing the manifestations of inflammation. Immunosuppressive action: prevent or inhibit a cell-mediated immune response, delay a sexual allergic response, and reduce the spread of a primary immune response. Anti-toxic and anti-shock effects: the glucocorticoid can resist the stimulation reaction of bacterial endotoxin to body, reduce cell damage and protect body. The applicant Chinese patent number 201310539987.X (a production process of prednisolone sodium phosphate) discloses a process for salifying prednisolone sodium phosphate, which is widely applied to production in the past. However, with the development of situation, the process has the following problems that methanol is adopted for dissolution, then the methanol is added into an ethanol tank, various solvents are used in the production process, so the final waste liquid in the process contains methanol and ethanol, the mixed solvent can not be recycled and reused, the mixed solution of methanol and ethanol is difficult to separate, a high-purity rectifying tower is required for separation, the investment of equipment of the high-purity rectifying tower is high, if the investment benefit of the high-purity rectifying tower is not cost-effective for enterprises for the purpose of separating the waste materials, the operation cost of the enterprises is greatly increased, but no positive contribution is made to the economic benefit, the strict environmental protection control at present does not allow the random discharge of the waste liquid at all, and the treatment of the waste liquid produced after the production by the process is a great problem for the enterprises, enterprises can only temporarily store the waste liquid by using a storage tank, but the storage tank is also a measure, and the solvent residues in the final product are diversified due to various solvents used in the process. And because the boiling point of the ethanol is 78.4 ℃, the ethanol can generate more impurities after long time in the drying process, and the content of the finally obtained impurities in the process is between 1.5 and 2.5 percent, thereby influencing the quality of steroids.

Disclosure of Invention

The invention aims to overcome the problems in the prior prednisolone sodium phosphate salt-forming production and provides a prednisolone sodium phosphate salt-forming production method.

In order to realize the purpose of the invention, the following technical scheme is adopted: a prednisolone sodium phosphate production method comprises the steps of using prednisolone phosphate as a raw material, dissolving prednisolone phosphate with a mixed solution of acetone and water, dropwise adding a sodium hydroxide water solution into a tank, controlling the temperature to be 10-25 ℃, adjusting the pH value to be 9.0-9.5, stirring, filtering after repeatedly measuring the unchanged pH value, pumping acetone into a dilution tank, adjusting the temperature, adding a reaction solution, stirring to separate out a large amount of crystals, standing for not less than 8 hours for discharging, washing the discharged material with acetone, performing dry flinging, drying after obtaining the material to obtain prednisolone sodium phosphate, and further, wherein the volume ratio of the acetone to the water in the mixed solution of the acetone and the water is 1-3: 2-6, the adopted mixed solvent is 6-10 times of the prednisolone phosphate, and further, the amount of acetone pumped into the dilution tank is 15-20 times of the prednisolone phosphate.

The invention has the positive and beneficial technical effects that: the method changes a plurality of solvents in the traditional process into a single solvent, solves the bottleneck of diversification of residual solvents in the raw material medicines, ensures the medication safety, can conveniently recycle and apply the single solvent, basically does not produce waste liquid discharge, is environment-friendly, and reduces the pressure. Because the method adopts acetone, the boiling point is 56.63 ℃ lower, the structure is simple and volatile, the difference of the boiling points is 21.77 ℃, the drying time of the X process of the patent number 201310539987 is 4-8 days, the drying time of the method is 3-4 days, the drying time is shortened by half, and the drying time has obvious advantages. In the production of the medicines, the generation of impurities has a direct function relation with the drying time, namely, the longer the drying time is, the larger the total amount of the impurities is, and the poorer the quality is, so the method has great advantages in impurity control if the drying time is short, the total amount of the impurities of the product obtained by adopting the process of the patent number 201310539987.X is 1.5-2.5%, the total amount of the impurities obtained by adopting the method is less than 2.0%, the minimum amount can reach below 1.0%, and the method has great advantages in quality.

Detailed Description

In order to more fully explain the implementation of the present invention, the implementation examples of the present invention are provided, which are merely illustrative of the present invention and do not limit the scope of the present invention.

The prednisolone phosphate is a fixed material, and is measured by g, the liquid material is measured by ml, and the ratio of the prednisolone phosphate to the prednisolone phosphate is ml: g.

example 1:

weighing 100g of prednisolone phosphate, dissolving in 8 times of mixed solvent of acetone and water, wherein the volume ratio of acetone to water in the mixed solution of acetone and water is 1: 2, adjusting the pH value to 9.5 by using a sodium hydroxide aqueous solution, controlling the temperature to be 10-15 ℃, and filtering the feed liquid. Diluting the feed liquid into acetone with a ratio of 25 times, stirring to obtain a large amount of crystals, standing for 9 hours, filtering, drying after obtaining the feed, wherein the total amount of impurities is 1.3%, and the product quality meets the standards of EP9.0 and USP 39.

Example 2:

weighing 100g of prednisolone phosphate, dissolving in 10 times of mixed solvent of acetone and water, wherein the volume ratio of acetone to water in the mixed solution of acetone and water is 3: 2, adjusting the pH value to 9.2 by using a sodium hydroxide aqueous solution, controlling the temperature to be 15-20 ℃, and filtering the feed liquid. Diluting the feed liquid into acetone with a ratio of 20 times, stirring to obtain a large amount of crystals, standing for 8.5 hours, filtering, drying after obtaining the feed, wherein the total amount of impurities is 1.5%, and the product quality meets the standards of EP9.0 and USP 39.

Example 3:

weighing 100g of prednisolone phosphate, dissolving in a mixed solvent of acetone and water of 7, wherein the volume ratio of acetone to water in the mixed solution of acetone and water is 1.5: 6, adjusting the pH value to 9.3 by using a sodium hydroxide aqueous solution, controlling the temperature to be 20-25 ℃, and filtering the feed liquid. Diluting the feed liquid into acetone with a proportion of 16 times, stirring to obtain a large amount of crystals, standing for 8 hours, filtering, drying after obtaining the feed, wherein the total amount of impurities is 1.6%, and the product quality meets the standards of EP9.0 and USP 39.

Example 4:

weighing 100g of prednisolone phosphate, dissolving in 70 times of mixed solvent of acetone and water, wherein the volume ratio of acetone to water in the mixed solution of acetone and water is 3: 5, adjusting the pH value to 9.2 by using a sodium hydroxide aqueous solution, controlling the temperature to be 20-25 ℃, and filtering the feed liquid. Diluting the feed liquid into acetone with a proportion of 16 times, stirring to obtain a large amount of crystals, standing for 8 hours, filtering, drying after obtaining the feed, wherein the total amount of impurities is 0.98%, and the product quality meets the standards of EP9.0 and USP 39.

After the embodiments of the present invention have been described in detail, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention, and it is intended that all simple modifications, equivalent changes and modifications made to the above embodiments based on the technical spirit of the present invention shall fall within the technical scope of the present invention, and the present invention shall not be limited to the embodiments illustrated in the description.

Claims

1. A method for producing prednisolone sodium phosphate takes prednisolone phosphate as a raw material, and is characterized in that: dissolving prednisolone phosphate with a mixed solution of acetone and water, dropwise adding a sodium hydroxide aqueous solution into a tank, controlling the temperature to be 10-25 ℃, adjusting the pH value to 9.0-9.5, stirring, filtering after repeatedly measuring the pH value and keeping the pH value unchanged, pumping acetone into a dilution tank, adjusting the temperature, adding a reaction solution, stirring to separate out a large amount of crystals, standing for not less than 8 hours to discharge, washing the discharged material with acetone, dry-throwing, drying after obtaining the material to obtain prednisolone sodium phosphate, wherein the volume ratio of acetone to water in the mixed solution of acetone and water is 1-3: 2-6, the adopted mixed solvent is 6-10 times of prednisolone phosphate.

2. The method for producing prednisolone sodium phosphate according to claim 1, characterized in that: the amount of acetone pumped into the dilution tank is 15-20 times of prednisolone phosphate.