Preparation method of tilmicosin phosphate_Industrial additives

Background and overview^[1]

Tilmicosin phosphate, also called tilmicosin phosphate, is a chemical semi-synthetic macrolide antibiotic. It is a new drug specially used for animals. It has a wide antibacterial spectrum and is effective against Gram-negative bacteria and Gram-positive bacteria. It has a strong inhibitory effect on bacteria, and it also has a strong inhibitory effect on a variety of mycoplasmas and spirochetes. Clinically, it is mainly used for respiratory diseases caused by Actinomyces pleuropneumoniae, Pasteurella hemolytica, Pasteurella multocida and livestock and poultry bodies.

Preparation^[1-2]

Report 1,

Dissolve tilmicosin solid in acetone at a mass:volume ratio of 1:5, mix thoroughly, heat to the reflux temperature of acetone, dissolve tilmicosin, and filter. Add a 37% phosphoric acid aqueous solution to the filtrate, stir thoroughly for 1 hour, then cool the solution to room temperature, and slowly add butyl acetate dropwise while stirring. The amount of butyl acetate added dropwise is 4 times the volume of acetone. A large amount of crystals precipitate, keep stirring for 1 hour until the crystallization is complete, and then centrifuge. The solid is washed twice with cold butyl acetate and dried to obtain tilmicosin phosphate solid. Yield: 97%, purity, 99.1%.

Report 2,

First, clean and dry the 1000-liter reactor. Add 200 liters of chloroform and 100 kg of tylosin phosphate, stir and dissolve. Add 12 kg of 3,5-dimethylpiperidine, and add 6 kg of anhydrous formic acid dropwise while maintaining stirring. After dripping the formic acid, raise the temperature and reflux and dehydrate for 1 hour (about 0.5 hours to remove the water), then quickly cool down to 40°C, add 200 liters of water, add hydrochloric acid to adjust the pH to 1.4-1.5 (precision test paper) and raise the temperature to 42-45°C , stir and react for 60 minutes, adjust PH3 with 15% liquid caustic soda, stir for 20 minutes, and let stand for 30 minutes for phase separation; beat the chloroform phase into the reaction kettle, add 100 liters of water to adjust PH3, stir for 20 minutes, and let stand for 30 minutes for phase separation; chloroform phase Pour it into the reaction kettle, add 50 liters of water to adjust PH3, stir for 20 minutes and let it stand for 30 minutes to separate the phases. Then collect the water phase into the reaction kettle, vacuum distill out the dissolved chloroform, add 1 kg of activated carbon, and press-filter into the crystallization kettle, maintaining 40 ℃, add 10 grams of OP-10, maintain the temperature at 40°C, add 15% liquid caustic soda dropwise until cloudy, stir for 20 minutes to crystallize, continue to add dropwise for 1-2 hours to pH 11, stir for 2 hours, centrifuge, filter, add water and rinse Wash until the washing water is less than PH10. Discharge the material, return the centrifuged material to the dissolving kettle, add 50 kg of water and 15 kg of 85% phosphoric acid, mix evenly, and then spray-dry to obtain 92.5 kg of tilmicosin phosphate, with a content of 89.5% (if the product will be discharged) The material is dispersed into a drying pan and dried at 65°C to obtain tilmicosin base).

Preparations^[3-4]

Report 1. Preparation of enteric-coated granules

1. Preparation of prime particles

1) The mass percentage of raw materials for preparative granules is as follows: tilmicosin phosphate 5%, microcrystalline cellulose 55%, sodium carboxymethyl starch 5%, starch 30%, sodium lauryl sulfate 1% and Hydroxypropyl methylcellulose 4%, after sieving each of the above components through a 100-mesh sieve, weigh each component with a particle size of 100 mesh according to the mass percentage of the raw material for preparing the granules;

2) Mix each component, add enough water, stir evenly to prepare a soft material, and granulate the soft material using a double spherical extruder with a 0.6mm diameter orifice plate. Spheronize the industrial additives in a spheronizing machine with a rotation speed of r/min for 10 minutes. After the spheronization, take out the wet pellets and dry them. The dried pellets are sieved, and the particles with a particle size of 30 mesh are taken to obtain the prime particles.

2. Preparation of coating solution

1) According to the mass percentage of the outer coating raw materials, weigh 78.9% of the solid content, which is 30% No. Ⅰ acrylic resin latex, 7.9% triethyl citrate and 13.2% talc;

2) Add talc powder to the purified water. The total mass of the No. 1 acrylic resin latex with a solid content of 30%, triethyl citrate and talc powder is 61.3% of the mass of the purified water. Then add Triethyl citrate, stir evenly and pass through a colloid mill to obtain a lyosol. Add the lyosol to the No. 1 acrylic resin latex liquid with a solid content of 30%. Stir evenly and pass through a 60-mesh sieve to obtain a coating liquid.

3. Coating of vegetarian granules

1) Place the prime particles in the fluidized bed, control the inlet air temperature of the fluidized bed to 55°C, the fluidized bed fan frequency to 30HZ, and the peristaltic pump speed to 200r/min. When the inlet air temperature is 55°C Start spraying the coating liquid to coat the plain granules. After the coating is completed, continue fluidization and drying. After drying, sieve, and take the granules with a particle size of 60 mesh to obtain tilmicosin phosphate enteric-coated granules

After coating the tilmicosin phosphate enteric-coated granules, the mass percentages of the plain particles and the outer coating are: 70% of the plain particles and 30% of the outer coating.

Report 2. Preparation of effervescent granules

Tilmicosin phosphate 10kg, tartaric acid 19kg, anhydrous sodium bicarbonate 14kg, sucrose 4kg, lactose 51kg, polyethylene glycol 6000 2kg. Various raw materials and auxiliary materials are crushed through a crusher and passed through an 80-mesh sieve. Dry anhydrous sodium carbonate and tartaric acid at 80°C. After drying, the moisture content is 0.08% and 0.06% respectively. Start the three-dimensional mixer and mix tilmicosin phosphate, tartaric acid, anhydrous sodium bicarbonate, sucrose, lactose, and polyethylene glycol 6000 for 10 minutes. Start the boiling dryer equipment, set the heat source temperature to 80°C, and the product temperature (granulation temperature) to 55°C. Then start the automatic drying system, control the vacuum degree at 100mbar, and add purified water at the same time. The amount of water added does not exceed the capacity specified by the equipment. . Add the mixed materials into the boiling dryer and start granulating.The time is 10min and the moisture is 0.18%. Collect the effervescent granules that pass through a 30 mesh sieve and weigh 98.5kg. The yield is 98.5%.