A systematic comparison of four pharmacopoeial methods for measuring powder flowability

Powder flow is one of the crucial factors affecting several pharmaceutical manufacturing processes. Problems due to insufficient powder flow reduce production process efficiency and cause suboptimum product quality. The U.S. Pharmacopoeia has specified four methods to evaluate the flowability of pharmaceutical powders, including angle of repose (AoR), compressibility index (CI) and Hausner ratio (HR), Flow through an orifice, and shear cell. Comparison within and between those methods with 21 powders (covering a wide range of flowability) was performed in this study. Strong correlation was observed between fixed base cone AoR, and fixed height cone AoR (R² = 0.939). CI and HR values calculated from a tapped density tester (meeting USP standards), manual tapping, and Geopyc® correlated strongly (R² > 0.9). AoR, CI/HR, minimum diameter for flowing through an orifice (d_min), and shear cell results generally correlate strongly for materials with flowability worse than Avicel® PH102. Both shear cell and CI/HR methods can reliably distinguish powders exhibiting poor flow. For materials with good flow, the ability to distinguish powders follows the order of AoR ≈ CI/HR > shear cell > d_min. The systematic comparison of the four common methods provides useful information to guide the selection of methods for future powder flow characterization. Given the limitations observed in all four methods, we recommend that multiple techniques should be used, when possible, to more holistically characterize the flowability of a wide range of powders.

Introduction

Powder flow plays an important role in various pharmaceutical manufacturing processes, such as tablet and capsule production. Insufficient powder flow due to inherently poor flowability or suboptimal process design causes problems, such as flow obstruction, segregation, and uneven flow (Buanz, 2021, Schulze, 2021, Staniforth, 2001). Such problems can, in turn, reduce production process efficiency and cause suboptimum product quality. For example, poorly flowing powders can exhibit inconsistent tablet or capsule filling, resulting in poor content uniformity, large weight variation, and variable tablet mechanical strength, disintegration, and drug release performance (Chattoraj et al., 2011, Gaisford and Saunders, 2012, Staniforth, 2001, Sun, 2010, Thalberg et al., 2004). Moreover, industrial production frequently requires powder transportation from one manufacturing plant to another or one operation unit to another within the same manufacturing site. A key requirement towards effectively controlling powder flow behaviors or solving flow-related problems during manufacturing is clear understanding of powder flow properties based on appropriate characterization of powders using established techniques.

The onset of powder flow requires the motion of individual particles within the powder, which is induced by a state of non-equilibrium forces. Depending on the nature of the material and surrounding environment, forces acting on a particle in a powder bed at rest may include gravitational force, adhesion and cohesion force, electrostatic force, magnetic force, water bridges, friction, or forces due to mechanical interlocking (Gaisford and Saunders, 2012, Staniforth, 2001). The interplay among these forces depends on several factors, such as particle size and size distribution, particle shape, environmental conditions (e.g., humidity, temperature, acceleration, and gravitational constant), as well as some other factors, such as the angle of inclination, mass of the powder pile, and applied load (Gaisford and Saunders, 2012, Goh et al., 2018, Schulze, 2021, Staniforth, 2001).

Methods for characterizing powder flow properties can be broadly categorized as static and dynamic (Krantz et al., 2009). A static method is generally performed on a static powder bed, such as angle of repose (AoR), shear cell, tapped and untapped bulk density, critical orifice diameter. A dynamic method characterizes powders in motion under well-defined conditions, including the measurement of hopper flow rate, and flow rate by a recording flow meter (Staniforth, 2001, Taylor and Aulton, 2021). For pharmaceutical powders, the U.S. pharmacopoeia has specified four methods, i.e., AoR, compressibility index (CI) and Hausner ratio (HR), flow through an orifice, and shear cell, in the monograph <1174> “powder flow” (USP, 2020a). Other useful techniques for flowability evaluation of powders are both dynamic, e.g., fluidization method (Krantz et al., 2009, Leturia et al., 2014, Lüddecke et al., 2021), avalanching method using a rotating drum (such as Aeroflow® device) (Hancock et al., 2004, Lavoie et al., 2002, Taylor et al., 2000, Thalberg et al., 2004), powder rheometry (FT4 powder rheometer) (Bharadwaj et al., 2010, Freeman, 2007) and static, e.g., ball indentation method (Hassanpour et al., 2019, Zafar et al., 2015).

Given the complexity of powder flow, each of these methods focuses only on one or some aspects of the properties of powder flow. Hence, evaluating a powder using different methods simultaneously is highly beneficial to gain a holistic understanding of powder flowability (USP, 2020a). For examples, several excipients were studied using AoR, CI, HR, and shear cell methods in the context of capsule filling (Tan and Newton, 1990). Flowability of powders for inhalation were characterized by HR, AoR, avalanching, and shear tester methods (Thalberg et al., 2004). Effects of particle size and shape on flowability of a few drug formulations were studied using AoR, HR, powder rheometry, shear cell, and avalanching methods (Goh et al., 2018). Flowability of several metal powders were characterized by flow rate, HR, AoR, shear cell, and rheometer (Marchetti and Hulme-Smith, 2021). Effects of particle size, morphology, and density on flowability of microcrystalline cellulose powders were investigated using a shear cell method and CI (Hou and Sun, 2008). However, to our knowledge, there is not yet a report that systematically compared the four methods in the U.S. Pharmacopoeia monograph < 1174 > using several powders that cover a wide range of flowability (cohesive to excellent flow). Hence, this study was carried out to fill the knowledge gap.

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Materials

Five grades of microcrystalline cellulose (MCC), including Avicel® PH105, PH101, and PH102 (International Flavors & Fragrances, Philadelphia, PA) and Comprecel® M101 and M102 (Mingtai Chemical, Taoyuan, Taiwan), milled alpha-lactose monohydrate (Pharmatose® 200 M; DMV-Fonterra Excipients, Goch, Germany), spray dried lactose (Fast-flo®; Foremost Farm Middleton, WI, USA), spray dried lactose (FlowLac ®100, Meggle GmbH & Co. KG, Wasserburg am Inn, Germany).

Weeraya Tharanon, Yiwang Guo, Jomjai Peerapattana, Changquan Calvin Sun, A systematic comparison of four pharmacopoeial methods for measuring powder flowability, International Journal of Pharmaceutics, 2024, 124454, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124454.