A Design of Experiments for Tablet Compression - Pharmaceutical Technology

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A Design of Experiments for Tablet Compression
The author prepared and analyzed a detailed design of experiments for the manufacture of a simple tablet formulation. The aim was to test whether tablet hardness and weight could be controlled during the compression process by adjusting certain machine parameters.

Pharmaceutical Technology
Volume 35, Issue 9

Optimization study and discussion of response

Table VI: Analysis of variance for augmented central composite design model according to tablet weight.
Once the initial screening study and the augmented CCD study were concluded, sufficient data had been generated to support an optimization study. The optimization process provides an opportunity to set the two responses, hardness and weight, to desirable outcomes and allow Design-Expert software to produce recommended experiments that should yield tablets with the desired criteria. Optimization is the ultimate goal of any experimental-design process. In this case, a target hardness of 7 kP and a weight of 190 mg were selected. The upper and lower factor limits from the augmented CCD study were used during the optimization process, and eight experiments were performed.

Table VII: Optimization study results.
The results of this study were mixed. Two runs were acceptable, but the other six produced undesirable hardness. The results of the optimization experiments are shown in Table VII. For added benefit, output responses from the tablet press were recorded for precompression force and main compression force in kN. Although it would have been preferable to have several more factor setpoint combinations to produce the desired tablet characteristics, several hypotheses can explain why the other experiments did not produce the desired tablet.

Figure 7: 3D response plot for optimization run 7.
The predicted response 3D plot shows how optimization run 7 responded at the given factor setpoints shown in Table VII. In Figure 7, a small window is evident on the concentric rings in the x axis. The window shows that a limited range of error is permissible to maintain the desired hardness and weight values. The area in red on the 3D contour represents the most desirable response. Further studies could be performed in the small red region with the intent of clearly defining the acceptable factor tolerances when moving a product into a manufacturing environment.

High turret speeds can cause tablet weight to decrease, especially if the feed-frame paddles are turning slowly. This effect occurs when insufficient powder is placed into the tablet-punch die in the brief amount of time that it is under the feed frame. It is also possible that at such high radial velocities, high centrifugal forces push the powder fill out of the die.

When precompression or main compression forces were high, tablet defects were observed in the form of lamination. Lamination likely occurs when the tablet is compressed too quickly, causing the tablet to separate in layers. This defect was often associated with high turret speeds. Lamination may also result from inadequate removal of the entrapped air in the die cavity during the precompression step. A tablet that has begun to laminate may provide false readings on the hardness tester. Lamination was more prevalent when main compression forces were less than precompression forces.

Experienced formulation scientists and production operators understand the complexities of tablet-press operation, and this knowledge can help them to prepare targeted experimental designs that would produce optimization responses with great flexibility in the processing specification setpoints. As the processing specification setpoint error gets larger, the likelihood that the batch will be rejected for undesirable responses decreases. The larger the allowable variation from the processing setpoint, the greater the chance of producing an acceptable tablet.


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