A flowsheet model for the development of a continuous process for pharmaceutical tablets: An industrial perspective

Abstract

A dynamic model of a continuous direct compression process for pharmaceutical tablets is presented. The objective is to assess the impact of the variability from the feeder system on the concentration of drug in the powder in the feed frame of a tablet press. The model is based on principles of dispersed flow from the reaction engineering field. An estimability analysis was performed to understand the impact of the available measurements on the estimated parameters and suggest better ways to approach the parametrization. Predictions are successfully contrasted with experimental data. The model is used to produce residence time distributions at different process conditions and a graphical representation of the allowable range of disturbances in the feeders that can be mitigated by the process. The model was used in support of the method development for an online near infrared sensor. V C 2017 American Institute of Chemical Engineers AIChE J, 64: 511-525, 2018

Estimation of mass‐based composition in powder mixtures using Extended Iterative Optimization Technology (EIOT)

“…First, we defined six independent and mostly nonoverlapping peaks; intended to represent the pure spectra of six species (A to F), spectra for species D and E have a strong overlap (Figure a). Using a flowsheet model of a continuous direct compression system, a simulation was performed to generate the concentration curves (Figure b) obtained, when the material feeders are switched off one by one, compensating the mass flow into the system with the feed rate of the major filler excipient. Excipient B has the lowest nominal mass fraction in the blend, while excipient C has the largest.…”

“…As can be seen in the magnified insert in the figure, both PLS models had difficulty accurately predicting the API concentration from the placebo spectra. In comparison, EIOT was able to accurately predict the API concentration in placebo spectra This accuracy is attributed to the effect of the constraint in Eq.. Having a predicted concentration that follows the expected behavior of a mass fraction (nonnegative between 0 and 1) allows the straightforward use of such predictions to estimate the parameters from a deterministic model of the system …”

“…The various materials are continuously fed at the top of the unit and moved downward by gravity through a mixing unit and into the tablet press. Mixing in the system occurs by forced convection as well as by dispersion as the material moves from top to bottom and is not limited to occur exclusively in the mixing unit but throughout the length of transit . The last free volume where mixing occurs is the feed‐frame of the tablet press; the mixing of the powders is incomplete before this point.…”

Superstructure-based process synthesis and economic assessment under uncertainty for solid drug product manufacturing

“…Several authors have covered the entire manufacturing process. Flowsheet models have been developed to predict dynamics for processes based on direct compression [16], dry granulation [17], and wet granulation [18]. Singh et al developed a control strategy for dry granulation and implemented it into a process-wide flowsheet based on firstprinciples models [19].…”

Dynamic Flowsheet Model Development and Sensitivity Analysis of a Continuous Pharmaceutical Tablet Manufacturing Process Using the Wet Granulation Route

“…Previous work on the development of flowsheet models are restricted to direct compaction [3][4][5][6] and dry granulation routes [7,8] for continuous solid oral dosage manufacturing. Park et al [7] created a flowsheet model of continuous dry granulation and applied it for optimization.…”