Optimising wet granulation using dynamic powder characterisation

Research demonstrates that specific tablet properties can be achieved using different process conditions and that dynamic powder properties correlate directly to the critical quality attributes of the final product

Wet granulation is frequently employed during the manufacture of oral solid dosage forms to convert fine and cohesive ingredients into more uniform, free-flowing granules that are optimised for downstream processing.

The overall aim is to make the process more efficient, improve the throughput and produce tablets with the required critical quality attributes. To achieve these goals, it is necessary to identify the granule characteristics that can be used to predict specific tablet properties.

During wet granulation, the constituents of the oral solid dosage form blend are combined, along with water, to form granules with a homogenous composition.

These granules then undergo further processing — drying, milling and lubrication — to produce an optimal feed material for the tablet press.

The properties of the feed can be controlled by manipulating certain processing parameters, including during granulation, which are fundamentally influenced by factors such as water content, powder feed rate and screw speed. By altering these variables, granule properties can be adjusted to ensure optimal performance.

To produce granules with specific properties, however, it is necessary to understand how critical process parameters impact the properties of the granules. Equally important is understanding the correlation between granule properties and the finished tablet. This study shows how dynamic powder testing can help to meet these objectives.

Dynamic powder testing provides a direct measure of the properties of a powder in motion, allowing powders to be characterised while being subjected to conditions that represent the actual process environment. Dynamic properties can be measured during powder consolidation, under low stress, aerated or even fluidised conditions to generate process-relevant data.

Dynamic flow

Dynamic flow properties are determined by measuring the torque and force acting on a blade as it rotates along a defined path through a powder sample. Basic Flowability Energy (BFE) is measured as the blade descends through the sample and reflects how the powder will flow under forced flow conditions, such as in an extruder or feed frame.

The study, done by Freeman Technology and GEA, determined whether the dynamic flow properties of granules could be linked to tablet hardness, a common critical quality attribute. Trials were completed using a ConsiGma 1 continuous high shear granulator and dryer, which is capable of running samples from a few hundred grammes up to 5kg or more. Characterisation of the resulting granules was done using an FT4 Powder Rheometer (Figure 1).

Figure 1: Basic schematic of the FT4 Powder Rheometer in operation. The resistance that the blade experiences as it moves through a sample quantifies the bulk flow properties of a powder

Two formulations, based on paracetamol (APAP) and dicalcium phosphate (DCP), were tested. Process parameters, including water content, powder feed rate and granulator screw speed, were varied and the BFE of the resulting wet granules was measured.

Results

Data gathered for the APAP formulation showed that increasing the water content results in a higher BFE if the screw speed is kept constant (Figure 2). Lower screw speeds also produce a higher BFE for a comparable water content. Both trends were expected: a higher water content and lower screw speeds tend to produce larger, denser and more adhesive granules that present a higher level of resistance to blade movement.

Figure 2: The BFE of granules produced for the APAP formulation rises with increasing water content and decreasing screw speed

Figure 3: The BFE of granules produced for the DCP formulation increases significantly as the feed rate is reduced

The data also indicate that a water content of 11% and a screw speed of 600 RPM produce granules with a similar BFE to those generated using a screw speed of 450 RPM and 8% water content. This demonstrates that granules with similar properties can be produced under different operating conditions.

Figure 3 shows how, at a water content of 15% and a screw speed of 600 RPM, the BFE of granules produced for the DCP formulation substantially increases as the powder feed rate is reduced.

The data also show that granules with the same BFE can be made at lower water contents by reducing the feed rate. For example, granules with a water content of 15% produced at a feed rate of 18kg/h have similar properties to granules containing 25% water made at a feed rate of 25kg/h.

As with the studies on the APAP blend, this shows how granules that are identical in terms of a specific powder property can be produced using multiple processing conditions. Table I shows the process parameters used to produce two pairs of granules with different properties. Conditions 1 and 2 generated BFE values for the wet mass of approximately 2200mJ, whereas conditions 3 and 4 resulted in BFE values of around 3200mJ.

The BFE of the granules was also measured after the subsequent drying, milling and lubrication steps. Throughout these stages, the relative BFE values remain consistently grouped, with the BFE values of 3 and 4 being consistently higher than 1 and 2.

Figure 4 plots the properties of the granules after each stage of the process. Conditions 3 and 4 show an increase in BFE following drying, owing to the granules’ large relative size, higher density and higher mechanical strength. Following milling, particle sizes are more similar, although variations in granule density, shape and stiffness explain the differences observed, which still remain following lubrication.

Figure 4: The BFE changes significantly during the manufacturing stages, but a distinct difference remains between groups

Discussion

These results show that it is possible to produce granules with specific properties using a range of process conditions, and demonstrate how BFE can be employed to develop and optimise wet granulation operations. However, can BFE then be used to predict in-press behaviour and can it be correlated with critical quality attributes?

The four batches of lubricated granules were run on a tablet press and the hardness of the resulting tablets was measured. Figure 5 shows tablet hardness data with respect to flow properties of the granules at each stage and highlights the strong correlation between BFE and tablet hardness (with particularly robust relationships for the dried and milled granules). Correlations for the wet mass and lubricated granules are also reasonable — with the poorer fit for the lubricated granules attributed to the overwhelming effect of magnesium stearate.

Figure 5: A strong correlation is found between the BFE of the granules and final tablet hardness

These data reinforce the relationship between flow properties of the granules at each stage of production and a critical quality attribute of the final tablet. Once a specific BFE has been linked to optimal tablet hardness, it can then be used to optimise a wet granulation process. If the target BFE is attained for the wet granules, the quality of the tablet, as quantified by hardness, can be assured.

Traditional batch-based processing remains dominant in pharmaceutical production, but many within the industry anticipate that continuous manufacturing will be adopted for a substantial share of products in the near future.

This research takes a substantial step towards making this a reality by demonstrating that it is possible to generate specific tablet properties using different process conditions and that dynamic powder properties correlate directly to the critical quality attributes of the final product.

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