Optimization of a semi-batch tablet coating process for a continuous manufacturing line by design of experiments
The aim of the study was to optimize a tablet coating process for a continuous manufacturing line. High throughputs should be achieved while inter-tablet coating variability should be as small as possible. Drug-free cores were coated with a colored suspension. All processes were monitored in-line with Raman spectroscopy. A statistical design of experiment was performed to find optimum process parameters. Tablet loading, spray rate and drum rotation speed were studied. Image analysis was performed using a computer scanner. Tablet hue and saturation were evaluated to obtain information about the inter-tablet color variabilities and the numbers of outliers. Low variabilities could be achieved using low spray rates and high rotation speeds and they were independent from the tablet batch sizes in the studied factor space. For the prediction of the coating thickness, univariate analysis was compared to PLS-regression. Calibration models were built based on the three center points of the statistical design of experiment resulting in RMSEC of 1.07 % of sprayed suspension with R2 of 0.9989 and Q2 of 0.9987. Model prediction was possible independent from loading, spray rate and drum rotation speed. The experiment with lowest color variability was conducted with a desired throughput rate of 25 kg/h and with a RMSEP of 2.5 %.
A DoE was performed in order to optimize a coating process at the end of a CM line. Raman spectroscopy is a feasible tool for obtaining real-time information about a colored coating process. It was possible to build robust calibration models and predict process endpoints. As this method does not detect single brighter colored tablets, color homogeneity needs to be verified with another method. To analyze individual tablet colors, image analysis was conducted using a computer scanner. To obtain small coefficient of variation of hue and saturation and hence small color variability, small spray rates and high rotation speeds should be used. Nevertheless, using drum rotation speeds between 15 and 18 rpm, the spray rate has only small effect on the coefficient of variation of saturation. In the studied range between 9 and 15 kg, tablet batch size does not have a significant influence on any of the responses. This is advantageous, as a throughput rate of 25 kg/h could be achieved with loading of 15 kg, spray rate of 80 g/min and rotation speed of 18 rpm.
Verified coating processes, which lead to coatings with low inter-tablet coating variability, can be monitored in-line with Raman spectroscopy. Robust calibration models lead to low prediction errors and endpoint prediction of processes can be predicted. This is a further step towards process automatization during a continuous production process.
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