Granulation Endpoint

Kay, D. Record, P.C. Automatic wet granulation endpoint control system. Manuf. Chem. Aerosol News 1978, 9, 45 6. 

The use of power consumption to monitor and attempt to identify the granulation endpoint continues to be very popular however, newer techniques such as on-line probes using NIR spectroscopic techniques can also offer much assistance to the pharmaceutical formulator. The power consumption curve can be divided into five distinct regions or phases which also correspond to the amount of granulating liquid added (Fig. 10) (117,118). 

Impeller shaft power intensity (kW/kg) has been used both as a rheological tool to characterize formulation deformability and as a control technique to judge granulation endpoint, primarily due to its relationship to granule deformation [see Kristensen et al., Acta. Pharm. Sci., 25, 187 (1988), and Holm et al.. Powder Technol., 43, 225 (1985)]. Swept volume ratio is a preliminary estimate of ejq)ected... 

Moisture assessment Drying endpoint target (moisture test) Granule size Sieve analysis... 

V fet granulation Moisture Performed at-line Drying endpoint solid fraction range Tools available for online ... 

Impeller tip speed corresponds to the shear rate and has been used as a scale-up parameter in fluid mixing. For processing of lactose granulations in Gral mixers, however, it was shown by Horsthuis et al. that the same tip speed did not result in the same endpoint [in terms of particle size distribution (PSD)]. These findings were contradicted by other studies with Fielder mixers indicating that for a constant tip speed, successful scale-up is possible when liquid volume is proportional to the batch size and wet massing time is related to the ratio of impeller speeds. ° ... 

Power consumption of the mixer motor for endpoint determination and scale-up is widely used (Leuenberger and subsequent work, HoW and subsequent work, Landin et al. Faure et and many others because the measurement is economical, does not require extensive mixer modifications, and is well correlated with the granule growth. 

Chirkot, T. Scale-up and endpoint issues of pharmaceutical wet granulation in a V-type low shear granulator. Drug Dev. Ind. Pharm. 2002, 28 (7), 871-888. 

Whether the application is drying a slurry, powder or granulation, the ultimate goal is achievement of some solvent level appropriate for transfer of the dried material to a subsequent process step. Thus, a method of endpoint determination is crucial to the economic success of the drying step as well as to the endowment of the proper physical characteristics on the dried material. For example, over-drying may result in unwanted static charge or reduced particle size due abradement of particles. 

Recent research attempting to improve on these techniques includes efforts with measurement of acoustic emissions (152-154). This approach utilizes placement of piezoelectric sensors at multiple locations, and has the advantages of being non-invasive, does not contact the product, and is relatively inexpensive. The authors showed that the optimum endpoints occurred near the start of a plateau region, however they also noted that data from trials in a PMA-10 model did not give profiles that corre.sponded to changes in the granulation process. 

Laicher A, Profitlich T, Schwitzer K. Ahlert D. Modified signal analysis system for endpoint control during granulation. Eur J Pharm Sci 1997 5(1) 7-14. 

Hartung T, Coecke S, Bal-Price AK (2009) Gene expression as a sensitive endpoint to evaluate cell differentiation and maturation of the developing central nervous system in primary cultures of rat cerebellar granule cells (CGCs) exposed to pesticides. Toxicol Appl Pharmacol 235 268-286... 

Prake P, Greenhalgh D, Grierson SM, Hempenstall JM, Rudd DR. Process control and endpoint determination of a fluid bed granulation by application of near infra-red spectroscopy. Inti J Pharm 1997 51 75 -80. 

Alden et al. extended the method by estimating the equilibrium relative humidity based on the wet-bulb temperature (TJ, the partial pressure of water at the solid s temperature, and the saturated vapor pressure of water at 7 [46]. Thus, the moisture content of a given material can be inferred from the estimated temperature difference (AT) and the equilibrium relative humidity. This method has been successfully implemented to control the endpoint in batch fluid-bed dryer for aqueous and aqueous-alcohol granules. An pirical method was used to determine the desired AT value by frequent sampling of the dried material and moisture content determination. The realtime AT was estimated using a computer program based on the temperature measurements this value was then compared with the desired value and used as the drying-endpoint indicator. 

Figure 9 SIMCA prediction output during high-shear granulation. The SIMCA distance reduces as the batch approaches its endpoint.

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