(W0930-01-02) Physical Stability of an Excipient System – How to Approach This Critical Performance Parameter?

Purpose: A new excipient system including mannitol (MAN) and magnesium stearate (MST) is developed for tablet production, specifically for direct compression technology. With this product combining multiple functionalities as filler, binder and lubricant, the production process is more efficient. In batch production, the overall number of process steps is reduced as the final mixing step with MST is no longer necessary. In continuous manufacturing the feeder number can be reduced, and the dosing of MST is not anymore crucial. The flowability and dosing performance is excellent for the excipient system. However, a crucial performance aspect of such an excipient is the physical stability and with that, the segregation tendency. This aspect is addressed in this work. As there isn´t any defined procedure available to evaluate the physical stability of a raw material, different scenarios are designed. Overall, the material has been mechanically stressed. The homogeneity of the product is assessed, and the performance is finally tested in tablet production.

Methods: An excipient system containing mannitol and 3 or 5 % Magnesium stearate (“Parteck® LM low” or “high”, MilliporeSigma, Darmstadt, Germany) is used. The products (three batches each) are mechanically stressed by using a vibrating plate (150 g powder, shaking for 20 min at medium intensity, horizontal movement) and jolting volumeter (150 g powder, 20 min tapping, = 4850 x, vertical movement). MST homogeneity of samples taken at different positions is determined using elementary spectroscopy (n=3, 1g each). The product is also transported to India and back (3x 22kg packages, air/road transportation). MST Homogeneity (n=10, 1 g each) and tableting performance (Korsch EK0 DMS, Korsch AG, Berlin, Germany) are assessed. Tablet weight has been set to 500 mg, diameter 11 mm. The machine is equipped with strain gauge to capture the ejection force (Catman Software, HBM Messtechnik, Darmstadt, Germany).

Results: In Figure 1, the homogeneity results of the MST content are shown for the stressed samples compared to unstressed (expressed as average standard deviation of the analyzed samples). It is seen that the standard deviation is comparable for the unstressed versus stressed samples. Mechanical movement (vertically, horizontally) obviously does not impact the homogeneity, neither the samples with 3 % MST nor 5 %. Also, after transportation to India and back, MST is still homogeneously distributed in the product. The check of the single data further confirm that the result is independent on the position of the analyzed sample, the components do not segregate. The tableting performance of the shipped samples is assessed and summarized in Figure 2. The tableting profile demonstrates that the shipped material performs as well as before transportation. Processibility is good, seen by the low ejection forces. The disintegration time (not shown) is comparable as well.

Conclusion: Different scenarios are designed to assess the stability of an excipient systems and the risk of segregation. Mechanical stress is applied in different ways, finally a transport study is done. The results underline the stability of the excipient systems including mannitol and magnesium stearate as a lubricant. The homogeneity of the product is demonstrated in all stress tests. The performance of the combination is very robust, no impact on processibility, tablet hardness or disintegration time is seen.

Figure 1: Homogeneity results (expressed as standard deviation) of stressed samples; 3 % MST results above, 5 % MST results below.

Figure 2: Tablet hardness (above) for tablets with 3 and 5 % MST, before and after transportation. Ejection force of the process is shown below.