Mannitol-coated hydroxypropyl methylcellulose as an alternative directly compressible controlled release excipient.

One of the most common forms of controlled release technology for oral drug delivery comprises an active ingredient dispersed in a hydrophilic matrix forming polymer such as hydroxypropyl methylcellulose (HPMC), which is tableted via direct compression. However, HPMC may pose problems in direct compression due to its poor flowability. Hence, mannitol syrup was spray-coated over fluidized HPMC particles to produce co-processed HPMC-mannitol at ratios of 20:80, 50:50, and 70:30. Particles of pure HPMC, co-processed HPMC-mannitol, and their respective physical mixtures were evaluated for powder flowability, compression profiles, and controlled release performance. It was found that co-processed HPMC-mannitol consisted of particles with improved flow compared to pure HPMC particles. Sufficiently strong tablets of >2 MPa could be produced at moderate to high compression forces of 150-200 MPa. The dissolution profile could be tuned to obtain desired release profiles by altering HPMC-mannitol ratios. Co-processed HPMC-mannitol offers an interesting addition to the formulator's toolbox in the design of controlled release formulations for direct compression.

The Effects of Feed Frame Parameters and Turret Speed on Mini-Tablet Compression.

Die filling is a critical process step during tablet production as it defines the tablet weight. Achieving die fill consistency during production of mini-tablets, tablets with diameters ≤6 mm, is considerably more challenging. Although die filling in rotary presses had been studied in relation to the feed paddle design, paddle speed, and turret speed, it is unclear how these process variables could impact mini-tablet production and product properties. In this study, 1.8 and 3 mm mini-tablets were prepared using a rotary press with multiple-tip tooling using different process configurations. Mini-tablet weight variation within and across compaction cycles were determined using data from compression roller displacement and mini-tablet weight. Higher die fill densities were achieved with a flat feed wheel paddle and high paddle speed. This was attributed to better granule fluidization in the feed frame, which also increased the intercycle weight variation and reduced tensile strength. The turret speed did not impact mini-tablet properties significantly. Granule overlubrication in the feed frame potentially reduced mini-tablet tensile strength during compaction. The number of paddle passes in the die fill region was correlated to mini-tablet die fill performance. Findings from this study could provide better insights into the relationship between process variables and mini-tablet product quality.

Influence of spray nozzle aperture during high shear wet granulation on granule properties and its compression attributes.

The distribution of granulating liquid is known to affect the high shear wet granulation process but the impact of the spray nozzle attributes is still unclear. While homogenous liquid distribution can be achieved by using a spray nozzle, the effect of different nozzle aperture sizes on granule properties is not well understood. In this study, nozzles of different aperture sizes were used to introduce the granulating liquid in high shear wet granulation using different process parameters. Design of experiment approach was utilised to assess effect of process parameters on granule properties. Granules produced with different spray nozzles were evaluated for binder distribution inhomogeneity, size, shape, flowability and compression attributes such as tabletability and yield pressure. Coarser granules with better flow properties were produced using the smaller aperture size nozzle. On the other hand, granules had better tabletability and lower yield pressure when larger aperture size nozzle was used. Furthermore, size of granules produced by using larger aperture size nozzle was more affected by changes in the process variables which could be influenced by the differences in granulating liquid feed rate and spray droplet size. Although the granules aspect ratios were comparable across the nozzle aperture sizes, granules produced from smaller aperture size nozzle appeared to be rounder. Regardless of the nozzle aperture sizes, homogenous binder distribution was achieved. The findings from this study could be a useful guide to the selection of the appropriate nozzle aperture size in wet granulation.

Investigation on the impact of powder arching in small die filling.

The flow of particulate materials is critical during processes such as mixing, compression and packing. Non-cohesive arching, a feature characteristic of coarse and free-flowing particles, has been studied extensively for silos and hoppers. However, the arching of powders during die fill has received much less attention. In this study, die fill performance of coarse and free-flowing nonpareils was evaluated using a specially designed die filling device in order to investigate the impact of non-cohesive arching during die fill under gravity flow. Through evaluating die fill performance, the arching phenomenon during dynamic conditions of die fill could be captured. Nonpareils with large particle size increased the likelihood of arching and caused poorer die fill performance for narrow orifices. In contrast, die fill in large orifices was generally better with larger particles due to reduced inter-particulate friction. Both particle size and size distribution influenced non-cohesive arching during die fill. Forced feeding did not appear to affect die fill performance and non-cohesive arching. A critical particle size range beyond which die fill performance would decrease, particularly for the narrow orifices, was identified. Findings from this study provided a better insight into non-cohesive arching during die fill.

Understanding effects of process parameters and forced feeding on die filling.

Die filling is a critical step during pharmaceutical tablet production and is still not well understood due to the rather complex interplay between particle attributes, die orifice diameter and fill energetics. While shoe-die filling models have been used to simulate die filling conditions, they typically lack the sophistication of the actual production-scale, feeder-based die filling conditions. The relationship between tableting process parameters and filling into die orifices of different diameters by powders of different flowabilities requires critical examination and understanding. In this study, a special die filling contraption was designed and custom-made to simulate the effects of gravity, suction and feeder paddle assistance as present in modern rotary tablet presses. Die fill performance was studied using powders with different flow properties. Suction impact was greatest on die fill, in particular, for small orifice diameters and less permeable powders. Effect of paddle velocity on die fill was greater for compressible powders and larger orifice diameters. In comparison to suction and paddle velocity, forced feeding did not significantly affect die fill performance. Relationship between process parameters and die fill performance was found to be highly dependent on the material and orifice diameter.

Comparative evaluation of powder flow parameters with reference to particle size and shape.

Powder flow is critical to the success of various pharmaceutical processes such as tableting and capsule filling. Despite a plethora of flow characterisation techniques and parameters available, powder flow still remains to be a not well understood subject. Inter-relationships between the various powder flow parameters in particular have not been well established. Furthermore, while it is known that particle size and shape are important determinants of powder flow, their relative impact on individual flow parameter is unclear. In this study, granules were evaluated for their flow properties using various characterisation methods. Through multivariate analysis, flow parameters were classified based on the underlying physical granule property. Angle of repose, Hausner ratio, shear cell parameters and avalanche flow were found to be affected primarily by powder cohesion, which was in turn determined by the smallest granule size fraction. On the other hand, powder compressibility and inter-particulate friction were the main factors underlying basic flow energy. Angle of internal friction was primarily affected by particle roundness and did not appear to describe powder bulk flow properties. This study showed that while the various flow characterisation techniques were different in terms of their applications, there were common physical attributes that governed the measurements.

Understanding die fill variation during mini-tablet production.

Reproducibility of die fill during tablet production is critical to ensure consistent tablet drug content and mechanical attributes. In the production of mini-tablets, tablets smaller than 6mm, achievement of uniform die fill is much more challenging. Powder flow is often associated with die fill accuracy but this relationship has not been well characterised especially for mini-tablets. In this study, flow properties of different types of granules were characterised. Mini-tablets of 1.8 and 3mm diameters were prepared from the granules using a rotary press with multiple-tip compression tooling. A methodology was established to evaluate mini-tablet die fill variation within and across compaction cycles using data from compression roller displacement and mini-tablet weight. Both sizes of mini-tablets showed similar extents of inter-cycle weight variation that could be associated with granules' inter-particulate friction. However, smaller mini-tablets had higher intra-cycle weight variation due to their narrower die orifices. Multivariate and univariate analyses suggested that gravity fill influenced intra-cycle weight variation of 3mm mini-tablets while suction fill was associated with that of 1.8mm mini-tablets. Possible differences in die fill mechanisms between the mini-tablet sizes were identified and this provided a better insight into die fill variations during the production of mini-tablets.