Statistical analysis and comparison of a continuous high shear granulator with a twin screw granulator: Effect of process parameters on critical granule attributes and granulation mechanisms Wei Meng a , Lalith Kotamarthy b , Savitha Panikar b , Maitraye Sen c , Shankali Pradhan d , Michaelis Marc f , James D. Litster d,e , Fernando J. Muzzio a,b , Rohit Ramachandran, Dr. b, * a Department of Pharmaceutics, Rutgers University, Piscataway, NJ 08854, USA b Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ 08854, USA c Eli Lilly and Company, Indianapolis, IN 46225, USA d School of Chemical Engineering, Purdue University, West Lafayette, IN 47907, USA e Department of Chemical and Biological Engineering, The University of Sheffield, Sheffield S10 2TN, UK f Hüttlin GmbH – A Bosch Packaging Technology Company, 79650 Schopfheim, Germany A R T I C L E I N F O Article history: Received 23 May 2016 Received in revised form 25 August 2016 Accepted 10 September 2016 Available online 12 September 2016 Keywords: Continuous manufacturing High shear granulation Twin screw granulation Design of experiments Design space Granulation mechanism A B S T R A C T This study is concerned with identifying the design space of two different continuous granulators and their respective granulation mechanisms. Performance of a continuous high shear granulator and a twin screw granulator with paracetamol formulations were examined by face-centered cubic design, which focused on investigating key performance metrics, namely, granule size, porosity, flowability and particle morphology of granules as a function of essential input process parameters (liquid content, throughput and rotation speed). Liquid and residence time distribution tests were also performed to gain insights into the liquid-powder mixing and flow behavior. The results indicated that continuous high shear granulation was more sensitive to process variation and produced spherical granules with monomodal size distribution and distinct internal structure and strength variation. Twin screw granulation with such a particular screw configuration showed narrower design space and granules were featured with multimodal size distribution, irregular shape, less detectible porosity difference and tighter range of strength. Granulation mechanisms explored on the basis of nucleation and growth regime maps revealed that for most cases liquid binder was uniformly distributed with fast droplet penetration into the powder bed and that granule consolidation and coalescence mainly took place in the nucleation, steady growth and rapid growth regimes. ã 2016 Elsevier B.V. All rights reserved. 1. Introduction Wet granulation is a particle design process where formulation design (primary particles and liquid properties) and process design (granulator type and operation condition) are combined to produce granulated materials with desirable attributes. While granulation is traditionally considered as a size enlargement process, other particle properties such as porosity, flowability, compressibility and shape can be modified simultaneously to meet specific use requirements. This in turn is driven by the rates of several macroscopic granulation mechanisms: wetting and nucleation, consolidation and coalescence, breakage and attrition (Iveson et al., 2001). In secondary pharmaceuticals manufacturing, wet granulation has been widely carried out to modulate the attributes of in-process intermediates (granules), enabling exqui- site control of finished drug product quality (Tan et al., 2014). For decades, most commercial granulation processes were carried out by batch-wise operation of tumbling, fluidized bed or mixer granulators, largely due to the high profit margins, stringent regulatory framework and limited material throughput (Vervaet and Remon, 2005). Although batch manufacturing still predom- inates in pharmaceutical industry, nowadays continuous processes are advancing in leaps and bounds, with the imperative necessity to speed up and de-risk process and product development under reduced capital expenditure. Regulatory authorities, such as U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), are also encouraging this paradigm transformation * Corresponding author at: Department of Chemical and Biochemical Engineer- ing, Rutgers University, 98 Brett Road, Piscataway, NJ 08854, USA. E-mail address: rohitrr@rci.rutgers.edu (R. Ramachandran). http://dx.doi.org/10.1016/j.ijpharm.2016.09.041 0378-5173/ã 2016 Elsevier B.V. All rights reserved. International Journal of Pharmaceutics 513 (2016) 357–375 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsev ier.com/locate /ijpharm