Category: Formulation and Quality
Purpose: In solid dosage formulations, glidants are added to the blends with the intention of improving their flow. The goal of this work was to carry out a systematic evaluation of flow improvement promoted by glidants (1), to compare compendial methodologies with different powder rheometer tests (2) and finally to compare the flowability results collected from the different methodologies with the final tablets physical attributes (3).
Methods: Four excipients with different particle sizes were selected for this study, namely lactose monohydrate, such as Tablettose 100 (T100; d50 > 150 µm) and Granulac 200 (G200; d50 < 80 µm) and microcrystalline cellulose, such as Vivapur®200 (V200; d50 > 150 µm) and Vivapur® 101(V101; d50 < 80 µm). Each excipient was blended in a TURBULA® mixer with two different glidants: SYLOID®244FP silica(SY) and Cab-O-Sil M-5P (Cb) and/or one lubricant, magnesium stearate (MgSt). Two different amounts of Cb were added to the blends (Table 1). Tablets (250mg) were only produced with the blends containing MgSt. For ternary blends, individual excipients were firstly mixed with Cb (10min) and then with MgSt (5min). Intrinsic flowability (IF) and angle of repose (AoR) were measured for all the individual materials and blends. Blends were also characterized by different tests in a FT4 powder rheometer, which included bulk (Compressibility), dynamic (Stability and variable flow rate, SVFR) and shear (Shear Cell) characterization of the blends. The tablet’s weight variability was compared with flow characteristics of the blends.
Results: Figure 1a shows how the AoR and IF of the individual excipients are impacted by the addition of Cb, Sy and MgSt, separately (binary blends). Results showed that 1% of Cb had a higher ability of reducing the AoR of the blends than Sy. 0.5% of Cb showed to be enough to significantly reduce the AoR of smaller particle size excipients. MgSt, on the other hand, displayed the lowest influence on the flow improvement, especially in smaller particle size materials. Regardless of the additive, the reduction of AoR was aligned with the reduction of the orifice diameter in which the blends can freely flow (IF). Compressibility and Shear cell tests results showed to be aligned with the AoR in terms of the ranking order for the flow improvement promoted by the different glidants and lubricant (Figure 1, b and c). However, in the SVFR test, blends containing MgSt displayed the greatest decrease of the Specific energy (SE) to values below 5, indicating low interlocking and friction between particles and, therefore, good flow . These results could not be linearly compared with compendial AoR (Figure 1,d).
For samples containing 2 additives (ternary blends), the AoR showed to be about the mean of the values obtained with 1% of Cb and 1% of MgSt (Figure 2a). SE values also showed to be higher in ternary blends (Figure 2b) then in blends containing just MgSt. This indicates that the lubricant effect on the interlocking and friction reduction is lower if Cb is primary mixed with the excipients. Powder’s stability (SI) enables powder stability prediction: values close to 1.0 indicate that the resistance of the powder to flow, whilst it is in motion, is the same during all the test. However, binary blends containing MgSt showed low SI (< 0.85) indicating that MgSt continues to be mixed during the test, i.e, this additive did not reach a homogeneous level during the blending step. However, when MgSt was added after Cb, SI values closed to unity were observed, indicating that an uniform mixing of this additive was achieved during blending. This is probably related with ability of Cb to decrease the adhesion force between similar MgSt particles enhancing blend homogeneity . Therefore, SI and SE results showed to be suitable parameters to understand not only how these additives are able to reduce interparticle friction, but also they give an insight about how these additives may be distributed within the blend with impact on blend’s homogeneity. The weight variation of the tablets containing MgSt showed the highest correlation with compressibility index obtained in the compressibility test in FT4 rheometer (r=0.96,Figure 2c) and in the AoR test (r=0.93,Figure 2c).
Conclusion: Cb and Sy showed to improve the flow of all of the tested materials. SI and SE results showed that the presence of glidants within the blend increase the blending efficacy of MgSt. Apart from dynamic test, all the other rheometer tests showed results that were comparable with the more conventional AoR test. Compressibility and AoR tests showed the highest correlation with the tablets weigh uniformity. As it is critical for tablet production, the conclusions of this study highlight the importance of considering the interaction that glidants and lubricants may have on flowability.
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