Results and Discussion

Process Monitoring and Control by RTPD

End-Point Determination for Drying

Figure 7: Plot of product humidity vs. end-point relative humidity in product chamber

RTPD can be used to determine the end-point for drying in a PG run. For end-point determination, it assumes a relationship between the relative humidity in the product chamber at the end of the run (end-point), and the humidity of the product. The product humidities (as measured by LOD) of several PG batches were plotted against the corresponding end-point relative humidities as calculated by RTPD (Figure 7). From the plot, 25-30% relative humidity in product chamber (corresponding to about 1.5-2.8% product humidity) can be used as a reference point for determining the end-point for drying during the PG lactose trials.

Comparison of 6 Repeat PG Lactose Batches

Six PG lactose trials were carried out using the same equipment setup, batch size, amount of granulating liquid and setpoint process conditions (inlet air temperature 85° C, and spray rates 140-160 g/min). The end-points of the PG trial runs were determined using 25-30% relative humidity in product chamber as a reference point, giving granule batches with LOD values, size and density properties as shown in Table 5.

Precision Granulation™ of Lactose

Influence of Inlet Air Temperature

From Figure 8a, mean granule size decreased with an increase in inlet air temperature (0.453 mm (avg.) at 60¡C and 0.315 mm (avg.) at 85°C). Lactose granules formed at lower inlet air temperature also generally had higher proportions of >1 mm size fraction. The poured bulk density, tapped density, Hausner ratio and Carr index values of the milled <1 mm size fractions for use in tableting were 0.5-0.6 g/mL, 0.6-0.8 g/mL, 1.2-1.3 and 15-23%, respectively (Figure 8b).

Figure 8a: Size and size distribution data of the Lactose granule batches

Figure 8b: Poured bulk and tapped densities, Hausner ratio and Carr index values of the Lactose granule batches

Tablet Compression of Lactose Granules

Tableting of the lactose granules with 1% Magnesium stearate gave tablet batches with group mean hardness and weight of 64 (± 26) N and 134 (± 2) mg, respectively. Tablet friability values of the various lactose batches were <1% and weight variation ranged between 0.8-3.1% (Figure 9).

Figure 9: Weight variation, hardness and friability of tablets prepared from Lactose granules and 1% Magnesium stearate

Precision Granulation™ of Acetaminophen

Investigation on Influence of Inlet Air Temperature and Relative Humidity Using RTPD

Acetaminophen has been described as a cohesive powder that tends to agglomerate quickly during granulation to give large aggregates [3]. Difficulties in granulating acetaminophen for producing tablets with good quality have also been reported. In the following investigation, acetaminophen was used as a model drug for investigating PG for preparing granules for tableting.

Acetaminophen was granulated at inlet air temperatures of 80, 90, 95 and 100°C and relative humidities of 33.8, 60.2 and 88.8% during PG in the product chamber. The wetting gradient and amount of water transferred to product for the various PG acetaminophen trial runs were obtained using RTPD and plotted out in Figure 10. Figure 11 shows the amount of water transferred to product as a function of the elapsed process time.

Figure 10: Wetting gradient and amount of water transferred to product for the various PG Acetaminophen trial runs

Figure 11: Plot of the amount of water transferred to product as a function of the elapsed process time

In the 3D plot of wetting gradient, amount of water transferred to product and inlet air temperature, the envelope defines the volume where process conditions are favorable for PG of acetaminophen for producing granules suitable for tableting.

Figure 12: 3D plot of wetting gradient, amount of water transferred to product and inlet air temperature for the various PG Acetaminophen trial runs