Thermodynamic Research On The Dissolution Process Of Quinolones

Quinolones are a kind of synthetic antibiotics with good antimicrobial activity against gram-positive and gram-negative bacteria.According to the time,structure and antimicrobial spectrum of the drug,the drug has been used for three generations.Antofloxacin as a new type of fluoroquinolones,compared with other fluoroquinolones,its use is convenient,and it has good elimination of half-life,low cardiac toxicity and phototoxicity,with fewer side effects.However,fluoroquinolones are mostly amphoteric compounds,and their poor solubility limits their application in industry and clinical medicine.In order to expand the applicability of drugs,it is of great practical significance to prepare salt compounds to improve their solubility.At present,the clinical application of Antofloxacin is Antofloxacin hydrochloride.In industry,Antofloxacin hydrochloride is synthesized mainly by amino levoxycarboxylic acid,N-methylpiperazine and pyridine,followed by hydrochloric acid acidification.The final step is to purify the product by crystallization process.Solvent crystallization is based on the analysis of solubility data.Nowadays,the preparation of other salts of Antofloxacin and the solubility data in different solvents are relatively insufficient.In this paper,the solid-liquid equilibrium of several salts of Antofloxacin in pure and mixed solvents is studied,which provides basic data for the industrial separation and clinical application of Antofloxacin salt.1.Antofloxacin hydrochloride was used as raw material to prepare free base of Antofloxacin,and then Antofloxacin Sulfate and Antofloxacin Succinate were prepared.Their properties were qualitatively analyzed by IR and XRD.The solubility data of Antofloxacin hydrochloride,Antofloxacin sulfate and Antofloxacin succinate in six solvents were determined by isothermal dissolution equilibrium method in the temperature range from 273.15 K to 318.15 K,respectively.The solubility of three Antofloxacin salts increased with the increase of temperature.At the same temperature,the order of solubility of Antofloxacin hydrochloride was(methanol,DMF)> n-butanol > ethanol > n-propanol > acetonitrile,and the order of solubility of Antofloxacin sulfate in the six solvents was DMF > methanol > ethanol > acetonitrile > n-propanol > n-butanol.For Antofloxacin succinate,the order of solubility from high to low is DMF > methanol > n-butanol > n-propanol > ethanol > acetonitrile.The solubility data of Antofloxacin hydrochloride,Antofloxacin sulfate and Antofloxacin succinate in the same solvent were systematically compared in order to screen suitable solvents for pharmaceutical production and application.The experimental data were correlated by Modified Apelblat equation and ?h model.The maximum values of RMSD and RAD were 3.3×10-5 and 4.06% respectively.Generally speaking,the correlation model of Apelblat equation is better.2.The solvation effect was discussed and the thermodynamic properties of the dissolution of Antofloxacin hydrochloride,Antofloxacin sulfate and Antofloxacin succinate in pure solvents were calculated.3.The solubility data of Antofloxacin hydrochloride in two mixed solvents(water + ethanol)and(ethanol + acetonitrile)at 273.15K-318.15 K were determined by isothermal dissolution equilibrium method.The solubility of solute increases with the increase of temperature in the range of determination temperature.In(water + ethanol)system,the solubility of Antofloxacin hydrochloride decreases with the increase of ethanol content.The cosolvency appears in the system of ethanol and acetonitrile.When w(acetonitrile)= 0.4,the solubility value reaches the maximum and is larger than that in both solvents.Jouyban-Acre model and Van't Hoff-Acree model were used to correlate the solubility data of Antofloxacin hydrochloride in two mixed solvents.The maximum average relative deviation(RAD)and root mean square deviation(RMSD)of Antofloxacin hydrochloride were less than 4.68% and 4.3×10-5 respectively.The calculated deviation showed that both models could well correlate Antofloxacin hydrochloride solubility data in mixed solvents.The thermodynamic properties of solutes in two mixed solvents were also been investigated.4.In this paper,choline chloride + urea eutectic solvents were prepared,and the solubility of Antofloxacin hydrochloride in water + eutectic solvents system was determined.The data were correlated by Modified Apelblat equation,and the thermodynamic properties of Antofloxacin hydrochloride in eutectic system were calculated.