(255c) Comparison of Granule Properties Obtained in Two Different Twin-Screw Granulators at the Same Shear Rate

Introduction: In recent years, the pharmaceutical industry has considered moving from the historical production method in batch to continuous manufacturing. The latter is a faster and more efficient production process and FDA has encouraged the pharmaceutical industry to implement it in order to improve product quality and reduce hold times. Among different technologies for producing oral solid dosage forms, wet granulation is a well-known technique for processing materials with poor flow properties and/or with limited tabletability properties. Wet granulation (WG) is a commonly used size enlargement process to obtain granules by starting from particulate drugs and excipients and using a liquid as ligand. Granules obtained possess improved flow properties compared to raw materials. Usually, twin-screw extruders are used for continuous wet granulation. As different extruders, with varied dimensions and process capabilities are available, direct comparison among granulators cannot be made without considering further adjustments in process conditions. Thus, in this work, two continuous twin-screw extruders (QBcon1 from Bohle and Pharma 11 from ThermoScientific) were used to obtain granules and screw speed was varied in order to obtain the same shear rate in each equipment. Granules critical characteristics were studied and compared in order to optimize the process.

Materials and methods: Ibuprofen 50 (BASF), a high-dose, hydrophobic and poorly soluble drug, was used as an active pharmaceutical ingredient (API). Lactose (Pharmatose M200, DFE Pharma), microcrystalline cellulose (Avicel PH 101, Dupont) and polyvinylpyrrolidone (PVP K30, Acros Organics) were used as granulation excipients while DI water was used as liquid ligand. Materials were blended in a 4-liters V-blender at 25 rpm and using an intensifier bar (522 rpm). Materials concentration in the blend was: Ibuprofen, 60 %; PVP, 3 %; lactose, 25.9 % and MCC, 11.1 %. Lactose:MCC ratio was 70:30, in order to reduce liquid needed for granulation. Drug content uniformity in blends was studied by UV-spectroscopy (Cary 60, Agilent Technologies) at 220 nm. Screw configuration was kept constant in each equipment and as similar as possible between them. For that, a kneading zone (KZ) of 30° for Pharma 11 and of 22.5° for QBcon1 was assembled immediately after the liquid feed port. The slight difference in straggle angle is related to each equipment specific configuration element. A second KZ of 60° for Pharma 11 and of 67.5° for QBcon1 was assembled and separate from the first KZ using conveying elements and keeping the same number of pitches and similar proportional distance in each screw. In both equipment, a chopper was put at almost the end of the screw to reduce oversized granules size. A central composite design face centered DoE with three center points was used to optimize granules obtained with the two equipment. Each independent variable was studied at three different levels. Screw speed in both equipment were selected in order to provide the same shear rate, and varied between 250 and 450 rpm for Pharma 11 and between 180 and 320 rpm for QBcon1. Liquid to solid ratio (L/S) was 0.2, 0.3 and 0.4 for both equipment, while throughput was between 0.7 and 1.1 Kg/h for Pharma 11 and between 0.7 and 1.7 Kg/h for QbCon1. Each DoE experimental point was run during 2 minutes to allow conditions stabilization and during 10 minutes to collect granules for characterization. Samples were air dried until granules moisture content was similar to the original blend. Responses studied were: a) percentage of fines (granules < 125 μm); b) oversized granules (> 2000 μm); c) API content uniformity in granules; d) granules size distribution; e) granule porosity; f) compact tensile strength (all compacted to the same relative density); h) dissolution of API form tablets; i) wettability of tablets.

Results: Granules content uniformity was very close to the values obtained for the blends. Fine fraction increased when L/S ratio decreased, while oversized fraction increased by increasing L/S ratio. Higher amounts of fines and oversized granules were obtained in the Pharma 11 twin granulator compared to the QBcon1. Porosity (calculated by determining true and envelope density of granules with -10+18 ASTM mesh size) was between 0.373 and 0.521 for granules obtained with Pharma 11 and between 0.344 and 0.451 for QBcon1. As can be seen, less porous granules were obtained by using the QBcon1. Interestingly, highest porosity values were obtained with an L/S of 0.3 in both equipment. Tensile strength, determined in tablets with 0.91 relative porosity, was around 0.14 MPa for all granules studied. Pharmaceutical properties were adequate in each selected sample studied while tablet wettability was similar.

Conclusions: DoE allowed optimizing and comparing the production of granules carrying a high-dose, hydrophobic drug, keeping the same share rate in both equipment. Results demonstrate the effect of changing equipment and can be used, to some extent, for scale up.