Preparation of Riboflavin Sodium Phosphate_Industrial Additive

Background and overview^[1][2]

Riboflavin sodium phosphate molecular formula: C17H21N4O9P.Na, relative molecular mass is 478.33. Riboflavin sodium phosphate is an anti-inflammatory drug, suitable for angular stomatitis, cheilitis, glossitis, etc. caused by riboflavin deficiency. treatment of inflammation and scrotal inflammation. It can also be used for the prevention and treatment of cardiovascular disease, iron deficiency anemia, and malignant tumors of the esophageal system. It can also be used as a large amount of food nutrition fortifier. Riboflavinsodiumphosphate (riboflavin5′-phosphatesodium), the NaOH neutralization product of FMN (riboflavin5′-phosphate, riboflavin5′-phosphate), is one of the important derivatives of riboflavin. Its physiological effects are similar to Riboflavin is basically the same and is mainly used as a drug, food nutritional fortifier or feed additive to treat various VB2 deficiencies. Many studies have shown that riboflavin and its derivatives also have diuretic, anti-cancer, lowering blood lipids and improving heart function. Compared with riboflavin, the solubility of riboflavin sodium phosphate in water is greatly increased, and it is easily absorbed and utilized by the body. Clinically, it can be made into compound VB2 preparations, eye drops and injections with stable concentration, etc., which is more convenient to use. The scope of application is wider.

Riboflavin Sodium Phosphate

Apply^[3]

Riboflavin sodium phosphate is a derivative of vitamin B2. Because it has excellent water solubility, it can be made into an injection solution for subcutaneous, intramuscular or intravenous injection. This solves the problem that vitamin B2 can only be taken orally and cannot be made into injections. It has the same role as vitamin B2 and is a component of the prosthetic group of flava enzymes in the body. Flavoenase plays a hydrogen transfer role in biological oxidation and reduction and has the following physiological functions: 1. Participates in the metabolism of carbohydrates, proteins, nucleic acids and fats. Improve the body’s utilization of protein and promote growth and development. 2. Participate in cell growth and metabolism and is an essential nutrient for body tissue metabolism and repair. 3. Strengthen liver function and regulate the secretion of adrenaline. 4. Protect the function of skin hair follicles, mucosa and sebaceous glands. When lacking, it will affect the body’s biological oxidation and cause metabolic disorders. The lesions are mostly manifested as inflammation of the mouth, eyes, and external genitalia.

Preparation^[2]

The current synthesis method mainly involves phosphorylating riboflavin with phosphorus oxychloride in a mixed solvent of pyridine and acetonitrile, then hydrolyzing the reaction mixture, and then neutralizing it with sodium hydroxide to obtain riboflavin sodium phosphate. . There is also a synthesis method using γ-butyrolactone instead of pyridine. The products produced by the above synthesis method have low riboflavin sodium phosphate content and are difficult to meet the requirements of the “Chinese Pharmacopoeia”. The related substances riboflavin diphosphate content is high and the free phosphoric acid content is high; there are many impurities and the quality is not high. ; The processing volume of contaminated waste liquid is large. The main factors affecting the quality of riboflavin sodium phosphate are related substances and free phosphoric acid content. The related substances are riboflavin diphosphate and free riboflavin, of which riboflavin diphosphate is 3′,4′-riboflavin. The sum of diphosphates, 3′,5′-riboflavin diphosphate, and 4′,5′-riboflavin diphosphate; the pharmacopoeia standard content control upper limit is 6%.

Specific method:

1. Phosphorylation reaction

⑴ Add 42.55g of phosphorus oxychloride and 59g of acetonitrile into the reaction vessel in sequence, cool the temperature to 10°C, first add 14.67g of pyridine dropwise into the reaction solution, and then slowly add pyridine solution (7.3g of pyridine → 3mL of purified water ), react for 30 minutes, and control the temperature not to exceed 25°C; add 25g of vitamin B2 to perform the phosphorylation reaction. The reaction temperature is controlled at 35°C, the stirring speed is controlled at 60rpm-80rpm, and the reaction time is 30 minutes;

(2) Add 100 mg of riboflavin silicone oil cyclic phosphate seed crystals and stir for 60 minutes to crystallize; separate the riboflavin cyclic phosphate crystals.

2. Hydrolysis reaction

Prepare 43.2 ml of 18% hydrochloric acid solution, and add riboflavin cyclic phosphate crystals for hydrolysis reaction. The reaction temperature is controlled at 50°C, the stirring speed is controlled at 80rpm ~ 100rpm, and the reaction time is controlled at 3 hours;

3. Neutralization reaction

⑴ Reduce the temperature of the reaction solution to 35°C, add 6M sodium hydroxide dropwise to neutralize the reaction. After crystals appear, stop dropping and stir for 30 minutes.

⑵Continue to add 6M sodium hydroxide solution dropwise until the reaction endpoint pH is 4.5, and then continue to crystallize for 30 minutes to isolate crude riboflavin sodium phosphate.

4. Washing

⑴ Wash the crude riboflavin sodium phosphate crystals in 60% methanol solution for 1 hour, control the temperature to 25°C, adjust the pH to 8.0 with 3M sodium hydroxide solution, and separate the riboflavin sodium phosphate crystals.

⑵ Wash the riboflavin sodium phosphate crystals in 70% methanol solution for 1 hour, control the temperature to 25°C, adjust the pH to 5.75 with 3M hydrochloric acid solution, and separate the riboflavin sodium phosphate crystals.

⑶ Wash the riboflavin sodium phosphate crystals in 95% ethanol solution for 2 hours, control the temperature to 55°C, and separate the riboflavin sodium phosphate crystals.

5. Drying and crushing

⑴ Riboflavin sodium phosphate crystals are dried for 9 hours and the temperature is controlled at 55℃-60℃.

⑵Crush to 100 mesh.

Test results of key indicators of the prepared riboflavin sodium phosphate: riboflavin sodium phosphate content: 77.80%; related substances: riboflavin diphosphate: 0.76%, free riboflavin: 1.90%; free phosphoric acid: 0.062%; weight loss on drying: 4.86%. The relevant substances riboflavin diphosphate and free riboflavin are far lower than the 6% specified in the Chinese Pharmacopoeia.