Fluidized Bed Precision Granulation™ - Methodology

Precision Granulation™ Process

The formulations used in the PG studies and the physical properties of the lactose powder mix and acetaminophen powder mix are listed in Tables 1, 2 and 3.

PG process conditions used are as shown in Table 4. Process flow of PG, tableting and characterization of the lactose and acetaminophen batches are depicted in Figures 2 and 3.

Table 4: Process conditions for granulation in a Precision Granulation™ System
a) For Lactose powder mix Equipment MP 2/3, Aeromatic-Fielder Batch size 5 kg Amount of granulating liquid 1.67 kg (15% povidone solution) Column diameter 150 mm Insert diameter 60 mm Air cap area/opening Full/standard Inlet air volume flow rate 275 m3/h Inlet air temperature 60, 85° C Spray rate 70-120 g/min (for 60° C batches) 140-160 g/min (for 85° C batches)		b) For Acetaminophen powder mix Equipment MP 2/3 with MP-1 kit, Aeromatic-Fielder Batch size 2 kg Amount of granulating liquid 0.67 kg (15% povidone solution) Column diameter 75 mm Insert diameter 24 mm Air cap area/opening "1/2"; 2.28 mm Inlet air volume flow rate 110 m3/h Inlet air temperature 90, 95, 100° C Relative humidity in product chamber during granulation 33.8, 60.2, 88.8%

Figure 2 : Flow chart of PG, tableting and characterization of Lactose batches
	Lactose powder mix
		Granulation in Precision Granulation™ (MP 2/3, Aeromatic -Fielder)
	Lactose granules
LOD after liquid addition (IR 100, Denver Instruments) Size analysis by sieving (Sonic sifter, ATM) . Mass median diameter, D50% . Span [ (D25% -D75%) / D50% ] Poured bulk and tapped densities (JEL) on <2 mm size fraction		Milling (197S, Quadro Comil) through 94R screen at 1500 rpm
	Milled Lactose granules
		Blending Milled Lactose granules (<1 mm size fraction) with 1% Magnesium stearate
Poured bulk and tapped densities (JEL) on <1 mm size fraction		Tableting Rotary tablet press (R190-FT, Courtoy ) with 7 mm flat-faced, bevelled edged punch and die sets
	Lactose tablets
Weight variation Hardness (PTB 300, Pharmatest) Friability (Electrolab)

Figure 3 : Flow chart of PG, tableting and characterization of Acetaminophen batches
	Acetaminophen powder mix
		Granulation in Precision Granulation™ (MP-1 kit in MP2/3, Aeromatic-Fielder)
	Acetaminophen granules
LOD after liquid addition (IR 100, Denver Instruments) Size analysis by sieving (Sonic sifter, ATM) . Mass median diameter, D50% . Span [ (D25% -D75%) / D50% ] Poured bulk and tapped densities (JEL) on <2 mm size fraction		Sieving (RX-24, Tyler) through 1 mm aperture size sieve
	<1 mm size fraction Acetaminophen granules
		Blending <1 mm size fraction Acetaminophen granules with 1% Magnesium stearate 97% <1 mm size fraction Acetaminophen granules with 0.5% Magnesium stearate and 2.5% Crospovidone XL (ISP)
Poured bulk and tapped densities (JEL) on <1 mm size fraction		Tableting Rotary tablet press (Betapress, Manesty) with 9.5 mm concave punch and die sets
	Acetaminophen tablets
Weight variation Disintegration time (DT2, Sotax) Hardness (PTB 300, Pharmatest ) Friability (Electrolab)

Real Time Process Determination™

Process parameters such as inlet process air volume flow rate, inlet air temperature, product bed temperature, outlet air temperature and spray rate of granulating liquid are captured and monitored using Real Time Process Determination™. Relative humidity in the product chamber can be calculated from these process parameters using a thermodynamic model based on the conservation of mass and enthalpy (Figure 4)

Figure 4 : Thermodynamic model for RTPD

Real Time Process Determination

Figure 5: Walter diagram and deviation meter screens in RTPD

The display screens depicting data generated by RTPD are illustrated in Figure 5. Figure 6 shows an example of the dynamic specific humidity diagram for a PG trial run.

Figure 6: Dynamic specific humidity diagram for a PG trial run

Detailed article about Real Time Process Determination published in Pharmaceutical Engineering Magazine - March/April 2007 issue (Vol. 27, number 2)