Quality by design: Application of a segregation tester to identify the critical factors affecting the weight and content uniformity of capsules filled on the two main types of automatic filling machines.

摘要

The overall objective of this study is to use the experimental design approaches to investigate the relationship between quality uniformity and formulation parameters such as segregation tendency. The phases of this project include: (1) Optimize the experiment methodology for segregation testing following ASTM D 6940-04 standard and evaluate the segregation property of multiple formulations with varying particle ratios. (2) Investigate the effect of segregation tendency on the product quality (content, weight and drug concentration) indices in capsule filling process and the correlation of the parameters.;A segregation tester was built following the ASTM D 6940-04 standard. Formulations containing 4% aspirin with coarse and fine particle sizes, microcrystalline cellulose (AvicelRTM PH200 and PH301) and magnesium stearate were used for the correlation study. A full factorial protocol was used to select the amount of materials needed (lot size, 200 g or 400 g) and the number of segregation cycle (Ns = 1, 5). The accuracy and robustness of the testing method was evaluated by comparing the L/F ratio of the mean values when one experimental run was repeated for different times (n). The content and weight uniformity quality indices of each formulation were assessed using the coefficient of variation. The coefficient of variation was estimated for within sampling points (CVi), between sampling points (CVj) and overall sampling points (CVij). Multiple regression and principal component analysis were used to analyze the data set and build the statistical models.;Statistical analysis shows that the sample size is the critical parameter for segregation tendency testing. Segregation cycle is not statistical significant for the 400 g sample size testing. Segregation tendency measured is highly correlated to particle size ratio of drug to excipient.;The results obtained demonstrate the reliability of the test method and standardize the critical details in the testing procedures of using the segregation tester to examine segregation. Machine type was the major parameter affecting the weight variation in this study. The segregation tendency correlated with the content variation. All these information will help in designing quality into formulation and a good control or monitoring on the critical parameters will enhance the product quality.;Key words powder segregation, coefficient of variation, capsule, weight variation, content variation, drug concentration variation. Principal Component Analysis.