CN-122005468-A - Preparation method of probenecid sodium freeze-dried powder

Abstract

The invention relates to a preparation method for salt formation freeze-drying of probenecid, which is characterized in that probenecid and a salt forming agent are reacted in injection water to form salt, a pH regulator is added to regulate the pH value, absolute ethyl alcohol is added, activated carbon is used for adsorption decoloration, filtration and freeze-drying are carried out to obtain a product, wherein the salt forming agent and the pH regulator are combined into sodium hydroxide and sodium carbonate in a certain proportion, namely the probenecid is sodium hydroxide/sodium carbonate=1:1:0.01 mol ratio, a solvent is injection water containing 3% -5% of ethanol, the freeze-drying is carried out in an annealing mode for prefreezing, the temperature is raised, small ice crystals are melted, and the prefreezing is completed. The probenecid freeze-dried powder has the advantages of good appearance, stable salt forming rate, controllable pH and improved re-dissolution time, improves the freeze-drying process efficiency of the product, and ensures the controllable quality of the product. The process is simple and is suitable for industrial production.

Inventors

• Hong Meixian
• ZHU HOULIANG
• JIANG YUSHENG
• WANG XI
• WU XIAOHUI

Assignees

• 安徽康正康元药业有限公司

Dates

Publication Date

20260512

Application Date

20260327

Claims (2)

1. 1. The preparation method for probenecid salifying freeze-drying comprises a salifying agent and pH regulator combination, a mixed solvent and a freeze-drying annealing process, and is characterized in that the salifying agent and the pH regulator combination are sodium hydroxide and sodium carbonate, the solvent is water for injection containing 3% -5% of ethanol, the material ratio of freeze-drying powder is probenecid, the molar ratio of sodium hydroxide to sodium carbonate=1:1:0.01, and the preparation method of the freeze-drying powder injection is as follows: 1) Weighing probenecid equivalent sodium hydroxide in a reaction bottle, adding 5 times of volume of water for injection, heating to 40-50 ℃, and stirring until the solution is clear; 2) Weighing probenecid, adding into the sodium hydroxide solution, and stirring until the pH value is not changed; 3) Adding 10% sodium carbonate solution prepared from 0.01 equivalent sodium carbonate into the feed liquid slowly and gradually, heating and stirring to dissolve completely, wherein the pH value of the solution is 8.0-9.0; 4) Adding absolute ethyl alcohol with the injection water dosage of 3% -5% after the reaction is finished, adding active carbon for adsorption and decolorization, cooling to room temperature, adopting a 0.45um filter element to filter and remove active carbon once, then adopting a 0.22um filter element to filter for the second time, loading the feed liquid into a tray, and freeze-drying.
2. 2. The preparation method for probenecid salifying freeze-drying according to claim 1, wherein the freeze-drying process of the freeze-dried powder injection is as follows: 1) Subpackaging the filtered probenecid sodium feed liquid into each sterilized freeze-drying plate by using a quantitative container, respectively placing the whole thickness of the liquid into each freeze-drying plate layer by about 1.2-1.8cm, placing a temperature probe into the freeze-drying plate filled with the probenecid sodium solution, closing a freeze-drying machine door, and opening a freeze-drying program; 2) The pre-freezing stage, namely, the temperature is reduced to-40 ℃ within 20 minutes, and the time lasts for 1h to 2.5h; 3) The annealing operation is that the temperature is raised to-5 ℃ within 0.5h, the temperature is continued to be reduced to-40 ℃ for 1h to 1.5h, and the temperature is maintained for 2h to 3h; 4) Sublimation drying, namely after prefreezing the bundles, starting vacuum and reaching 0.15-0.25mbar, slowly heating the plate layer to 25 ℃, and performing vacuum drying for 11-15 hours to enable most of free water to be pumped out in vacuum; 5) Resolving and drying, namely after sublimation and drying are finished, slowly raising the temperature of the plate layer to 45 ℃ and keeping for 5-7 h to fully volatilize bound water; 6) And (3) collecting materials, namely releasing vacuum in a freeze dryer after freeze drying of the samples is finished, collecting raw materials in a freeze drying tray, and sampling and detecting.

Description

Preparation method of probenecid sodium freeze-dried powder Technical Field The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of probenecid sodium freeze-dried powder. Background Probenecid is white crystalline powder, is an auxiliary drug for anti-gout drugs and antibiotic treatment, and sodium salt (probenecid sodium) is white crystalline powder, has no odor and slightly bitter taste, and is extremely easy to dissolve in water. The probenecid (sodium) can obviously optimize the pharmacokinetics characteristics of various beta-lactam antibiotics, and has clinical application with compound preparations consisting of antibiotics such as ampicillin, and the like, and the combined use of the probenecid (sodium) and the antibiotics can greatly reduce the dosage of the antibiotics, reduce the incidence of adverse reactions, promote the treatment compliance and reduce the selection of drug-resistant bacteria, thereby having important clinical value and positive social significance. In order to prepare a compound preparation of probenecid sodium and beta-lactam antibiotics, sterile probenecid sodium bulk drugs for injection need to be developed. The preparation method is generally freeze-drying and solvent crystallization. Clarity, pH and salt formation rate of a medicine are all the time quality key indexes, and particularly the salt formation rate is a very key quality attribute of the medicine, and influences the solubility, pH value, color of a solution and the like of the medicine. The patent literature [1] reports that the evaluation and extraction of the pharmaceutical in 2023 state prove that the salt formation rate of 238 batch injection ceftizoxime sodium is distributed at 0.95-1.03 (the theoretical value of the salt formation rate is 1.0), the salt formation rate is over-wide in distribution range (the salt formation rate of 238 batch injection ceftizoxime sodium is shown as figure 1), and the salt formation is unstable. The existing freeze-drying technology has a plurality of defects that firstly, the freeze-drying pH regulator is used for sodium hydroxide, hydrochloric acid, carbonate, phosphate and other reagents, and the strong acid and strong alkali reagents have strong acid and alkali, so that the pH exceeds the control limit and is unstable due to trace amount of the strong acid and alkali reagents. Weak acid and weak base are weak in acid and alkali, so that when the weak acid and weak base are used as a pH regulator, the product is easy to disqualified in clarity or large in consumption, so that the fluctuation of the salt forming rate of the product is large, and excessive salt forming agent is brought into the product. In addition, the freezing point of the tertiary butanol is far higher than that of water, the tertiary butanol is easy to crystallize firstly in the pre-freezing process, so that solute is unevenly distributed, and particularly products added with auxiliary materials are easy to have poor uniformity. Tertiary butanol belongs to three solvents in ICH Q3C, but is slow to metabolize in the human body, has a high risk of long-term accumulation, and is potentially genotoxic. The traditional pure water is used as a freeze-drying solvent to be indissolvable and hydrophobic substance, and has long drying period, low production efficiency and high energy consumption. In addition, pure water is poor in volatilization in the freeze-drying process, and the product is easy to form blocks or be closely arranged, so that the product is long in redissolution time. Therefore, optimizing the probenecid freeze-dried powder process becomes a key for solving the pain point in the prior art. Disclosure of Invention The invention aims to provide a preparation process of probenecid freeze-dried powder, which optimizes the probenecid salifying freeze-drying process, realizes the purposes of good appearance property, stable salifying rate, controllable pH and improved re-dissolution time of the probenecid freeze-dried powder, improves the efficiency of the product freeze-drying process, and ensures controllable product quality. The invention has simple process and is suitable for industrial production. The invention discloses a preparation method for salt formation freeze-drying of probenecid, which comprises the steps of salifying agent and pH regulator combination, mixed solvent and freeze-drying and annealing, and is characterized in that probenecid reacts with salifying agent in injection water to form salt, pH regulator is added to regulate pH value, absolute ethyl alcohol is added, activated carbon is used for adsorption decoloration, filtration and freeze-drying to obtain the product, wherein the salifying agent and pH regulator combination is sodium hydroxide and sodium carbonate in a certain proportion, the solvent is injection water containing 3% -5% of ethanol, the freeze-drying is prefreezing in an annealing mode, small ice