Identifying fluid-bed parameters affecting product variability

Recent statistical/graphical methodology identifies the importance of bringing the mean to target while maintaining a low variance. Fluid-bed literature abounds in optimization strategies while overlooking product variability. In the present study, active factors (location effects) related to fluid-bed granulation of lactose with povidone (PVP) were identified using normal probability plotting and basing the slope on the calculated critical pseudo standard error value. An unreplicated fractional factorial design was employed. Residual-Fit spread plots indicated adequate empirical models through least squares. Dispersion analysis using computed residuals and resulting variances indicated spray rate binder state, and certain interactions effecting particle size variability. Additional runs confirmed the feasibility of the approach in maximizing crushing strength and minimizing particle size variability. Various factor effects could be attributed to the solubility of lactose during granulation. Variability due to spray rate was ascribed to the high inlet temperature and the surface area of the fluid-bed charge exposed to the binder solution. Rapid binder film formation promoted intragranular bonds and enhanced compactibility. Using simple empirical modeling and data visualization approaches, factors influencing product characteristics and variability were identified. The applicability of this approach in robust process development is discussed.