(375p) Optimising Granulate Formulation through Uniaxial Powder Testing

Granulation is often employed during the production of pharmaceutical formulations for oral solid dose delivery. Due to the potency of most Active Pharmaceutical Ingredients (APIs) the quantity required per capsule or tablet is extremely small, therefore a granulation step is often required to ensure content uniformity; this is especially important when other components of the formulation have poor flow properties.

The quality of the final dried granules is dependent on both the formulation and process variables, for example, shear rate and mixing time. Inferior quality granules can reduce process efficiency and result in poor final product quality. Furthermore, as reworking the dried granulate is not possible, this may result in the loss of expensive and scarce APIs. As such optimising, the formulation and process variables is essential for efficient process performance and final product quality.

This study demonstrates the application of an Advance Uniaxial Powder Tester as a tool for the rapid evaluation of dried granulate materials produced using high shear wet granulation. It consisted of two stages, in the initial stage the water content of the wet mass was varied, increasing from 10% to 40% wt/wt whereas the second stage investigated the influence of the premix formulation on the dried granulate properties by adjusting the ratio of granulation grade lactose monohydrate to microcrystalline cellulose (MCC).

In order to prepare the granules, predetermined quantities of lactose and MCC were blended to provide 750mL of premix, the raw materials were mixed for 3 minutes using a low shear Tubula mixer to ensure a uniform mixing. The premix was then transfer to a high shear wet granulator, mixed for a further 30 seconds and then granulated for 270 seconds with water addition over the first 90 seconds of granulation. The wet mass was then screened through an 850 micron sieve before drying at 60^oC for 7 hours. Once dried the granules were sieved using a 2 mm sieve to remove large agglomerates. The granules were then evaluated using a Uniaxial Powder Tester (UPT; Freeman Technology, UK) and digital microscopy.

The results from stage 1 showed a clear correlation between the granulate properties and the water content of the wet mass, with lower uniaxial Unconfined Yield Strength (uUYS) values at higher water contents. Lower uUYS values indicate weaker interparticle bonding and improved flowability. A similar trend was also observed for compressibility with 40% water generating the least compressible granules, suggesting more efficient particle packing. Microscopic analysis of the samples showed that granules start to form at 30% water content and dominate at 40% explaining the improved flowability. Below 30% water the improvement in flowability (compared with the dry powder) may be due to a reduction in the small particle fraction and /or changes in the surface properties.

In stage 2, both the premix and dried granules were quantified with the UPT, allowing comparison of the flow properties before and after granulation, with the granulates demonstrated to be much more free-flowing. Both the premix and dried granules exhibit a similar response to increasing the lactose content, generating lower uUYS values at higher lactose contents, however the response was more pronounced for the dried granules. The compressibility results were markedly different; whilst the granules generate lower compressibility values at higher lactose contents, the premix exhibits an increase in the compressibility, demonstrating that compressibility alone is not necessarily an indicator of flowability. Again, the change in the granulate flow properties can be further rationalised by microscopic analysis. As the ratio of lactose to MCC increases, the percentage of granules also increases with a step change at 70% lactose exhibited by a significant reduction in the small particle fraction and more elongated granules. This corresponded with an observed change in the granulation behaviour with both the 70% and 85% wet masses blocking the 850 micron screen, significantly reducing yields.

Overall the results demonstrate that uniaxial testing is a quick, simple and repeatable technique for quantifying the flowability of powders and granules, enabling the influence of formulation and process changes to quantified. The results also demonstrate the granulation can result in a marked improvement in flow behaviour compared with the corresponding dry mix and that there are clear trends between water content and formulation, and flow properties of the granules.