Origin of profound changes in powder properties during wetting and nucleation stages of high-shear wet granulation of microcrystalline cellulose Limin Shi a , Yushi Feng b , Changquan Calvin Sun a, ⁎ a Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA b Eli Lilly and Company, Indianapolis, IN 46285, USA abstract article info Article history: Received 11 October 2010 Received in revised form 16 December 2010 Accepted 14 January 2011 Available online 22 January 2011 Keywords: High-shear wet granulation Wetting and nucleation Tabletability Flow property Surface smoothing Shape rounding The aim of this work was to understand the evolution of powder tabletability and flowability during wetting and nucleation stages of high-shear wet granulation (HSWG). Microcrystalline cellulose (MCC) was granulated with water using a high-shear process. Granule morphology, surface texture, size, porosity, specific surface area, tabletability, and flowability were characterized. MCC granulated with 5% water showed no change in tabletability but significantly improved flowability, corresponding to smoother surfaces and lower surface area. From 5% to 25% water, tabletability decreased by 1/4 but flowability remained unchanged. Granule shape and porosity remained unchanged while surfaces were smoothened, leading to decreased surface area. From 25% to 35% water, MCC granules became more round. There was another sharp decrease in tabletability but powder flowability remained unchanged. Forty-five percent of water led to more particle rounding and commencement of nucleation, which only slightly impacted tabletability and flowability. From 0% to 45% water, granule size decreased slightly and could not explain the significant changes in powder tabletability and flowability. Deteriorated tabletability was instead caused by surface smoothing, granule densification, and granule rounding. Enhanced powder flowability was caused mostly by surface smoothing with granule rounding as a minor contributor. © 2011 Elsevier B.V. All rights reserved. 1. Introduction A high-shear wet granulation process (HSWG) involves spraying a granulating fluid onto powders as it is being vigorously mixed under high shear [1]. Benefits of HSWG include improved flow, easier handling, reduction of dust and fines, increased bulk densities, better uniformity, and reduced powder segregation during subsequent processing. Because of these benefits, HSWG has been routinely implemented in a wide range of fields, including pharmaceutical, agricultural, detergent, food, and mine industries to enhance powder processibility [2–6]. While improving certain powder properties, HSWG can also lead to undesirable changes in other powder properties. For example, HSWG can cause drastic reduction in powder tabletability to such an extent that sufficiently strong tablets cannot be made by compaction, a phenomenon known as over-granulation [7–12]. Classically, the HSWG process is divided into three distinct stages: (i) wetting and nucleation where granulating liquid contacts the powder to form nuclei; (ii) granules grow from nuclei primarily due to intergranular collisions and consolidation; and (iii) attrition and breakage of granules due to impact, wear, or compaction [13–18]. While significant advancements in our understanding of the physics of HSWG have been made [19–22], a vast majority of the work has focused on changes in processibility of final granules as a function of changes in powder compositions or process parameters. It has been known that particle properties, such as initial particle size, chemical compositions, and powder wettability, can influence HSWG process and properties of resulted granules. However, very little has been known about how powder properties change during the stage of wetting and nucleation, despite their obvious importance in mech- anistic understanding of the HSWG process. Recently, we observed profound reduction in the tabletability of microcrystalline cellulose (MCC) before the HSWG process advanced to the granule growth stage, i.e., no appreciable size enlargement occurred. Compared to the starting MCC powder, the HSWG granules exhibited a three-fold reduction in tabletability without any detectable size enlargement, which could lead to deteriorated tabletability of HSWG granules [11]. Thus, factors other than granule size enlargement must be explored to understand the profound changes in powder properties. We exam- ined changes in structure and properties of granules and linked them with changes in powder properties as required by the principle of materials science tetrahedron (MST) [23]. Mechanistic understanding of any observation or phenomenon is critical for achieving true quality-by-design [24]. In this study, we aim at systematically characterizing changes in granule properties during the wetting and nucleation stage of HSWG for attaining mechanistic understanding. Powder Technology 208 (2011) 663–668 ⁎ Corresponding author at: Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 9-127B Weaver-Densford Hall, 308 Harvard Street S.E., Minneapolis, MN 55455, USA. Tel.: +1 612 624 3722; fax: +1 612 626 2125. E-mail address: sunx0053@umn.edu (C.C. Sun). 0032-5910/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2011.01.006 Contents lists available at ScienceDirect Powder Technology journal homepage: www.elsevier.com/locate/powtec