| Vancomycin is a glycopeptide antibiotic against gram-positive bacteria.Its adverse reaction has close relation to impurities.Thus,it is very important to study the lyophilization process to obtain high purity of vancomycin hydrochloride.By referring to numerous literature and combining to the production experience,one lyophilization process with high purity was developed,and the following concerns are studied:The process parameters obtained after the lab study on the reversed phase column for purification:The equilibrium agent is 0.3%～1.0%(W/V)Ammonia Chloride solution(p H3.5～4.5);Charging volume is controlled at 2%～6%,p H3.5～4.5;Reversed phase pre-washing agent is 2%～6%(V/V)Ethanol solution(p H3.5～4.5)containing0.3%～1.0%(W/V)Ammonia Chloride;Pre-washing is completed till the assay of the solution remained is not less than 93.0%;Chromatographic agent is 10%～15%(V/V)Ethanol solution(p H 3.5～4.5)containing 0.3%～1.0%(W/V)Ammonia Chloride.The critical quality items,including chromatographic purity,absorbance and water content,are controlled as monitoring points,the optimized lyophilization process is obtained:Lyophilization p H is 2.0～4.0;Concentration is 15%～25%(W/W);Thickness is8mm～12 mm.Lyophilization curve for high purity is obtained after pilot study on four batches,which is listed as below:Minsimum pre-freezing temperature is-50.0℃ and keep for 150 minutes.1st drying stage,vacuum in the lyophilizer is controlled at 0.3600 mbar,gradually raise the temperature to 20.0℃ and keep for 600 minutes.For desorption drying,vacuum is adjusted to 0.5000 mbar from 0.3600 mbar and temperature is raised to 25.0℃ from20.0℃,preserve the temperature for 340 minutes;finally vacuum drying is conducted for 210 minutes.Based on the above study,three scale-up batches were manufactured and the stability study is carried out accordingly.The study results show that there is no obvious change trend for the products manufactured with the process mentioned above,the critical quality items,including absorbance,vancomycin B and related substances are significantly better than that controlled in pharmacopoeia,which can be further concluded that the optimized lyophilization process is reasonable and reliable for vancomycin hydrochloride. |
