Preparation method and impurity control process of medicinal grade phosphorus supplement

Abstract

The application discloses a preparation method of a pharmaceutical-grade disodium hydrogen phosphate, and belongs to the technical field of chemical raw medicine preparation. In the application, anhydrous sodium carbonate is used as an alkali source to react with phosphoric acid, no stirring device is arranged in the reaction process or only a basic rotating speed is used to maintain homogeneity of the system, and solid-liquid disturbance mixing is realized by using carbon dioxide gas generated in the reaction to escape; meanwhile, three-stage pH stepwise precise regulation and control are adopted to regulate and control the reaction process. The method can effectively avoid the generation of trisodium phosphate impurities caused by local over-alkalization, the content of trisodium phosphate in the finished product is less than or equal to 0.05%, the pH difference between batches of products is less than or equal to 0.1, the main content of anhydrous substance is 99.3% to 99.8%, and all indexes meet the pharmaceutical standards in the Chinese Pharmacopoeia. The energy consumption of concentration and evaporation in the process is 18% to 22% lower than that in the traditional sodium hydroxide method, the anhydrous sodium carbonate is not a dangerous chemical product, and the storage and transportation and compliance management costs are effectively reduced. The application has the advantages of simple process, strong stability and suitability for industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of chemical raw material and pharmaceutical excipient preparation technology, specifically relating to a method for preparing pharmaceutical-grade disodium hydrogen phosphate with low impurities, excellent batch-to-batch consistency, and low energy consumption. Background Technology

[0002] Disodium hydrogen phosphate (Na2HPO4) is a widely used pharmaceutical excipient and chemical raw material, commonly used as a pH adjuster and buffer in various injectable and oral formulations. With the pharmaceutical industry's increasing demands for excipient quality, more stringent requirements have been placed on the purity, impurity limits, and batch-to-batch consistency of pharmaceutical-grade disodium hydrogen phosphate.

[0003] Currently, the mainstream process for preparing disodium hydrogen phosphate in industry is the neutralization reaction of phosphoric acid and sodium hydroxide, with the reaction equation being: H3PO4 + 2NaOH → Na2HPO4 + 2H2O. Although this process is mature, it has many unavoidable defects: (1) Sodium hydroxide is a strong alkali, which can easily cause local over-alkaliness in the system when feeding, generating mixed salts such as trisodium phosphate (Na3PO4), reducing the purity of the product; (2) The pH of the strong alkali neutralization system changes drastically, and the reaction endpoint is difficult to control precisely, resulting in large batch-to-batch differences in the finished product, which cannot meet the stringent requirements for uniformity of pharmaceutical-grade products; (3) The neutralization reaction generates a large amount of water (2 moles of water are generated per mole of phosphoric acid), and the subsequent concentration process has high evaporation energy consumption; (4) Sodium hydroxide is a hazardous chemical, and strict hazardous chemical management regulations must be implemented in the storage, transportation, and on-site use stages, resulting in high operating and compliance costs for enterprises.

[0004] To overcome the aforementioned shortcomings, existing technologies also disclose processes for preparing disodium hydrogen phosphate using sodium carbonate as the alkali source. For example, Chinese invention patent CN101659405A discloses a method for preparing food-grade disodium hydrogen phosphate, using sodium carbonate as the alkali source, controlling the pH at 8.32~8.37, and the temperature at 40~60℃, resulting in a product that meets food-grade standards. However, this process is only applicable to ordinary industrial or food-grade products and does not systematically optimize the process for the purity, impurities, and batch-to-batch stability of pharmaceutical-grade products; its pH control is relatively broad, failing to address the impurity generation problem caused by pH fluctuations during the reaction; and it does not study or control the impact of carbon dioxide escape during the reaction on system mixing and crystallization yield. Existing technologies for preparing disodium hydrogen phosphate using sodium carbonate as the alkali source generally suffer from problems such as limited pH control methods, insufficient impurity control, and poor batch-to-batch stability, making them difficult to directly use for pharmaceutical-grade product production.

[0005] Therefore, developing a method for preparing disodium hydrogen phosphate that is compatible with pharmaceutical standards, has low impurity content, good batch-to-batch consistency, and lower production energy consumption and management costs has become an urgent need in this field. Summary of the Invention

[0006] This invention addresses the shortcomings of existing technologies by providing a method for preparing pharmaceutical-grade disodium hydrogen phosphate. This method uses anhydrous sodium carbonate as the alkali source and employs a three-stage pH segmentation and precise control strategy. Combined with the in-situ disturbance of the system achieved through the escape of carbon dioxide gas during the reaction process, it effectively suppresses the formation of impurity salts such as trisodium phosphate, significantly improves the consistency of pH and main content between batches of the product, and simultaneously reduces production energy consumption and hazardous chemical compliance management costs. The product fully complies with the pharmaceutical standards of the Chinese Pharmacopoeia.

Claims

1. A method for preparing pharmaceutical-grade disodium hydrogen phosphate, characterized in that, Sodium hydrogen phosphate was prepared by reacting anhydrous sodium carbonate as an alkali source with phosphoric acid. No stirring device was set during the reaction, or only the basic rotation speed was used to maintain the homogeneity of the system. The carbon dioxide generated in the reaction was used to disturb and mix the materials. A three-stage pH segmented control strategy was used to regulate the reaction process throughout the entire reaction.

2. The method for preparing pharmaceutical-grade disodium hydrogen phosphate according to claim 1, characterized in that, The three-stage pH segmentation control specifically refers to: In the first stage, the pH of the system was increased from 3.0 to 8.5 by rapidly adding anhydrous sodium carbonate; In the second stage, the pH of the system was increased from 8.5 to 9.

0. The rate of increase of anhydrous sodium carbonate was reduced and the pH increase rate was controlled to be ≤0.2pH / min. In the third stage, the pH of the system was increased from 9.0 to 9.4, and anhydrous sodium carbonate was added in small amounts until the reaction endpoint was reached.

3. The method for preparing pharmaceutical-grade disodium hydrogen phosphate according to claim 1, characterized in that, The temperature was controlled at 30-40℃ throughout the reaction process.

4. The method for preparing pharmaceutical-grade disodium hydrogen phosphate according to claim 1, characterized in that, The anhydrous sodium carbonate is added to the reaction system either as a solid batch feed or as a continuous powder feed.

5. The method for preparing pharmaceutical-grade disodium hydrogen phosphate according to claim 1, characterized in that, The criteria for determining the reaction endpoint are: the pH of the system is stable at 9.0 to 9.4, and the pH change within 10 min is ≤0.

05.

6. The method for preparing pharmaceutical-grade disodium hydrogen phosphate according to claim 1, characterized in that, After the reaction is complete, the reaction solution is successively decolorized by activated carbon, filtered through a 0.22μm precision filter, concentrated, cooled and crystallized, centrifuged and dried to obtain the finished product, disodium hydrogen phosphate.

7. The method for preparing pharmaceutical-grade disodium hydrogen phosphate according to claim 1, characterized in that, Phosphoric acid is prepared into an aqueous solution with a mass concentration of 15% to 25% before participating in the reaction.

8. The method for preparing pharmaceutical-grade disodium hydrogen phosphate according to claim 1, characterized in that, The obtained disodium hydrogen phosphate product has a trisodium phosphate impurity content of ≤0.05%, an inter-batch pH difference of ≤0.1, and an anhydrous content of 99.3% to 99.8%.