Results and Discussion (continued) & Conclusions

Tablet Compression of Acetaminophen Granules

The inlet air temperature and relative humidity conditions during PG for 4 example batches of acetaminophen granules to be used for tableting are shown in Table 6.

The size and density characteristics of the acetaminophen granule batches are given in Figure 13.

Figure 13: Size and size distribution, poured bulk and tapped densities, Hausner ratio and Carr index values of the acetaminophen granule batches

Using Formulation Containing Acetaminophen Granules + 1% Magnesium Stearate

Weight variation, friability, hardness and disintegration characteristics of Acetaminophen:1% Magnesium stearate tablets are shown in Figure 14.

Figure 14 : Characteristics of tablets prepared from Acetaminophen granules and 1% Magnesium stearate

In summary

Tablets compressed at 1000 lb compression force had some chipping on the edges and were generally less hard and more friable compared to those tableted at 3000 lb. Tablets compressed at 3000 lb had acceptable weight variation, hardness and friability values but generally did not disintegrate quickly. For tablets compressed at 6000 lb, capping was observed and the tablets did not disintegrate completely even after 30 minutes of disintegration testing. A tablet sample complies with the British Pharmacopoeial disintegration test for uncoated tablets if all six tablets tested disintegrate within 15 minutes [5].

Using Formulation Containing 97% Acetaminophen Granules + 0.5% Magnesium Stearate + 2.5% Crospovidone XL

In this formulation, Crospovidone XL was added as an extra-granular disintegrant. The characteristics of the tablets formed are given in Figure 15.

Figure 15 : Characteristics of tablets prepared from 97% Acetaminophen granules, 0.5% Magnesium stearate and 2.5% Crospovidone XL

In summary

Disintegration times for tablets compressed at 3000 and 4500 lb were markedly improved by the addition of Crospovidone XL in the tableting formulation. Tablets compressed at 1500 and 3000 lb had acceptable weight variation, hardness (tablet hardness increased when compression force was increased from 1500 to 3000 lb), disintegration time and friability. However, with further increase in compression force to 4500 lb, tablets formed showed capping.

Conclusions

Real Time Process Determination™

With Real Time Process Determination™, the formulator is able to monitor and control the Precision Granulation™ process. The program calculates the current relative humidity in the product chamber based on feedback from the measured process parameters, giving an insight into the current status of the granulation process and into the interplay between process parameters during granulation. It can also calculate for adjustments that need to be made to the various controllable process parameters in order to move the Precision Granulation™ process from its current conditions to the desired/target conditions. In addition, Real Time Process Determination™ can collect measured process values and compute derived (normally hidden) process values for the formulator to correlate with granule and/or tablet properties.

Precision Granulation™

Precision Granulation™ can give good quality granules for tableting. Compared to traditional top spray fluidized bed granulation, higher inlet air temperatures can be employed in Precision Granulation™. Use of high inlet air temperature increases the drying potential, allowing for greater success in granulation at higher humidity conditions. With higher inlet air temperatures, mean granule size and the proportion of oversize particles also tend to decrease, narrowing size distribution.

Tablet Compression of Precision Granulation™ Acetaminophen Granules

Tablets with acceptable weight variation, hardness and friability can be prepared from acetaminophen granules produced by Precision Granulation™. Although capping was observed in tablets compressed at the high end of the range of investigated compression forces, tablets compressed at 3000 lb did not show capping. An extra-granular disintegrant can be added to the tablet formulation to improve disintegration and to ensure that tablets formed are in compliance with the pharmacopoeial disintegration test for uncoated tablets [5].

Analysis of Collected and Derived Process Values

Real Time Process Determination™ aids the formulator in identifying critical process conditions that influence the granulation process. This study revealed that Real Time Process Determination™ is capable of determining the end-point for drying by correlating process chamber relative humidity with product humidity determined by Loss on Drying (LOD). By using Real Time Process Determination™ in exploring Precision Granulation™ of acetaminophen for tableting, each investigated inlet air temperature was found to have a sharply limited range of wetting gradients and amounts of water transferred to the product during the granulation process for producing granules suitable for tableting. From the process data collected and derived by Real Time Process Determination™, it is possible to uncover the existing envelope where process conditions are favorable for granulating acetaminophen for tablet compression.

References

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