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Background Adequate powder flow is a prerequisite for successful tablet manufacture in pharmaceutical industry.Poor powder flow can lead to large variations in tablet weight, poor content uniformity, and inconsistent tablet properties including mechanical strength, disintegration time, and even dissolution rate.Coating fine powders with silica nanoparticles using a dry comilling process has been shown to be an effective way to enhance flowability of cohesive microcrystalline cellulose.Earlier work on nanocoating by comilling mainly examined effects of nano particles loading and number of comilling cycles on powder flowability of pure powders.However, other factors such as type of screen used (mesh size), impeller speed, and impeller type can also potentially influence the efficiency of the nanocoating process.Objective A systematic examination of comilling parameters on nanocoating will be useful to the successful implementation of this strategy in the industry.Applicability of this technique to less cohesive formulated pharmaceutical powder was investigated in this work using a representative powder blend containing ibuprofen.Methods In this work, we have chosen an ibuprofen blend to represent common tablet formulations with marginal flowability.Using this model powder, we have systematically investigated effects of pertinent comilling parameters on flowability.Impact of nanocoating on powder tabletability is also investigated.Using a shear cell, we systematically studied effects of process parameters, including the total number of comilling cycles, silica loading level, type of screen (mesh size), impeller speed, and impeller type, on the efficiency of the nanocoating process.Impact of silica coating on powder tabletability was also assessed using a compaction simulator.Results Results confirm that coating with silica nano particles significantly improves flowability of the formulated ibuprofen blend.At both 0.1% and 0.5% silica loading levels, silica coated ibuprofen blends lead to improved flow properties as shown by the higher flow factor (Figure 1 a).Flow enhancement by 0.1% silica is less than that by 0.5% silica.The data suggest that even 0.1% silica coating is adequate for transforming the poorly flowing ibuprofen blend into a powder with suitable flowability for a high speed tableting process.As shown in Figure 1b, flowability is always better for blends containing 0.5% silica than that of 0.1% silica loading.For the same silica loading, flowability is improved with repeated milling.Figure 1.(a).Effect of nanocoating on flow factor of the ibuprofen blend at silica loading levels of 0.1% and 0.5% (five comilling cycles).The broken line indicates the flow factor of Avicel PH102.(b).Variation of flow factor of ibuprofen blends with total number of comilling cycles with 0.1% and 0.5% silica loading levels.All were run at 3 kPa pre-shear normal stress.Error bars represent the standard deviation of the measurements (n =3).Effects on flow enhancement by other process variables, including comilling speed, type of impeller, sieve opening size and type, are weak.At a given major principal stress (σn), a lower unconfined yield strength (fc) indicates easier initiation of powder flow.While other parameters were kept the same, a lower comilling speed (2200 rpm) is slightly more efficient than a higher comilling speed (3500 rpm) in improving powder flow (Figure 2a).Pair-wise Students t-tests of the unconfined yield strength values show that p values are 0.711, 0.022, 0.238, and 0.476 for 1, 3, 6, and 9 kPa pre-shear normal stresses, respectively.The different designs of the impellers lead to different powder-impeller interactions during comilling.Type II (more compression action) is more effective than type I in flow enhancement (Figure 2b).The pair-wise p values of 0.176, 0.017, 0.185, and 0.527 for 1, 3, 6, and 9 kPa pre-shear normal stresses, respectively.For effect of sieve opening size (0.018″ and 0.039″ diameter) (Figure 2c), the pair-wise p values are 0.870, 0.259, 0.193, and 0.302 for 1, 3, 6, and 9 kPa pre-shear normal stresses, respectively.When different types of screens (smooth round holes vs.grater oval opening) were used (Figure 2d), the p values are 0.222, 0.019, 0.381, and 0.793 for 1, 3, 6, and 9 kPa pre-shear normal stresses, respectively.Flow functions obtained at 45% and 23% RHs are similar.The p values at 1, 3, 6, and 9 kPa pre-shear normal stresses are 0.639, 0.607, 0.298, and 0.061, respectively.It suggests any effect due to varying RH during measurement is negligible within this RH range (Figure 2e), which is consistent with the low hygroscopicity of the major component, ibuprofen.Figure 2.Effect of (a) comilling speed, (b) impeller design, (c) sieve opening size (0.018″ vs.0.039″ diameters, round opening, smooth sieve surface), (d) sieve type (smooth sieve (round holes with 0.018″ diameter) vs.grater hole with 0.040″ short axis), and (e) humidity on flow functions of uncoated ibuprofen blend.Error bars represent the standard deviation of the measurements (n =3).Another important observation is that silica coated ibuprofen blend exhibits improved tabletability, which shows the potential of the nanocoating strategy in simultaneously improving.powder flowability and tabletability.Tabletability of the ibuprofen blend was poor.Maximum tensile strength attained is below the desired 2 MPa tensile strength for a tablet (Figure 3).However, blends coated with 0.1% and 0.5% silica both exhibited much improved tabletability (Figure 3).Figure 3.Tabletability of uncoated and coated ibuprofen blend.The broken line indicates the desired tablet tensile strength, 2MPa, for pharmaceutical tablets.Conclusions Results show that surface coating with nano sized silica can significantly improve powder flow properties of a formulated ibuprofen blend.Such nano coating can be realized by comilling and the two most prominent factors that lead to flowability improvement are repeated comilling cycles and higher silica loading.Coating process only weakly depends on milling speed, type of impeller, RH during shear cell measurement, and sieve opening size and shape within the ranges investigated.Surface coating with silica nanoparticles significantly also improves powder flow properties tabletability of the ibuprofen blend.The overall results suggest that the surface nanocoating strategy may be an effective approach for solving problems related to powder flow and compaction in pharmaceutical tablet formulation and manufacturing.