An integrated Quality-by-Design (QbD) approach for pharmaceutical powder blending unit operation: Process monitoring, endpoint determination, and concentration quantification Conference Paper uri icon


  • The objective of this study was to develop an integrated QbD approach using process monitoring to determine the blending end-point and constituent concentrations of final blending mixture. A mixture design was created to include 26 powder formulations consisting of ibuprofen as the model drug and three excipient components (HPMC, MCC, and Eudragit L100-55). The mixer was stopped at various time points to enable NIR scan of the powder mixture and sampling for UV assay. Moving block standard deviation was applied to the NIR spectra for trend analysis and blending end-point determination. To quantify the concentrations of well-blended powder mixture, two types of multivariate calibration models (PLS and PCR) were constructed and validated. The first model was constructed to correlate the UV spectral data with the targeted concentrations of a binary mixture of ibuprofen and Eudragit L 100-55. This model was then used to predict the concentrations of ibuprofen and eudragit L100-55 in the final well-blended powders. The second model was constructed to correlate the NIR spectra of well-blended 4-component powder mixture and the concentrations of blended powders. The present study showed that the time to reach blending end-point ranges from 5 to 20 minutes. The multivariate PLS and PCR models based on UV spectra has R2 value of 0.99 and could predict the concentrations of both ibuprofen and Eudragit L100-55 well. The multivariate PLS and PCR models based on NIR spectra could predict the concentrations of both ibuprofen and excipients well for the final well-blended 4-component mixtures. The discrepancy between the prediction results from the two multivariate calibration models was discussed based on the fact that NIR and UV have different scale of scrutiny.

published proceedings

  • AIChE Annual Meeting, Conference Proceedings

author list (cited authors)

  • Wu, H., Tawakkul, M., & Khan, M. A.

complete list of authors

  • Wu, H||Tawakkul, M||Khan, MA

publication date

  • December 2007