Comprehensive Powder Rheological Characterization of Fifteen Lactose-Based Co-Processed and Single-Component Excipients Using FT4 Powder Rheometry and European Pharmacopoeia Methods: A Multi-Parameter Comparative and Correlative Study

Abstract

Background/Objectives: Co-processed excipients (CPEs) are designed for direct compression through particle engineering, yet comprehensive powder rheological profiles systematically comparing advanced and traditional characterization methods remain limited. This study characterized fifteen lactose-based excipients using European Pharmacopoeia (Ph. Eur.) methods and the complete Freeman FT4 Powder Rheometer measurement suite, establishing a correlation framework linking particle-level attributes to macroscopic flow behavior.

Methods: Fifteen excipients were characterized for bulk and tapped density, compressibility index, flow time (Ph. Eur. 2.9.16), and angle of repose (Ph. Eur. 2.9.36). Particle size and shape were measured by dynamic image analysis. FT4 measurements comprised stability and variable flow rate testing, consolidation, aeration, compressibility, permeability, shear cell, and wall friction at three surface roughness. Pearson correlation matrices were computed across all 53 parameters.

Results: Classical flow indices classified most CPE as good-to-satisfactory, failing to discriminate materials with fundamentally different dynamic flow profiles. FT4 testing revealed a fourfold range in Basic Flowability Energy (624–2107 mJ), a ninefold range in flow function coefficient (4.3–35.8), and wide aeration sensitivity differences (Aeration Ratio: 1.9–283.7). Strong correlations were identified between Specific Energy and compressibility index (r = 0.85), cohesion and Flow Rate Index (r = 0.79), and Normalized Aeration Sensitivity and pressure drop (r = 0.86). Within-family comparisons (Tablettose 70/80/100, FlowLac 90/100) revealed that particle size distribution breadth is a more critical flow determinant than median size alone.

Conclusions: Combining FT4 rheometry with pharmacopoeial testing provides substantially greater discriminating power than either approach alone, enabling rational excipient selection for direct compression formulation.

Introduction

Solid oral dosage forms remain the predominant pharmaceutical delivery route worldwide, and the choice of excipients fundamentally determines the manufacturability, stability, and performance of the final product. Direct compression (DC) has become the preferred tableting strategy owing to its simplicity, cost-effectiveness, and avoidance of moisture- and heat-sensitive processing steps [1]. However, DC imposes stringent requirements on excipient flowability, compressibility, and blend uniformity that individual raw materials—such as crystalline α lactose monohydrate or microcrystalline cellulose (MCC)—frequently fail to meet on their own [2,3].

Co-processed excipients (CPEs) address these limitations by combining two or more functional components through particle engineering techniques—including spray drying, co-agglomeration, roller drying, and wet granulation—to produce composite particles with synergistic properties that exceed those of simple physical mixtures [4,5]. The resulting improvements in flowability, compactibility, and dilution potential have been attributed to the intimate sub-particle integration of complementary functionalities: for instance, lactose provides compactibility and flavor masking, while MCC contributes deformability and disintegration [6]. Rojas et al. have demonstrated that co-processing generates enhanced DC functionality compared to physical blending at equivalent compositions [7].

The commercial landscape of lactose-based CPE has expanded considerably, with products from Meggle GmbH (Wasserburg am Inn, Germany) and BASF (Ludwigshafen am Rhein, Germany) representing diverse compositional and manufacturing approaches. Dominik et al. compared four of these products using classical flow and compression testing [8], while Haware et al. characterized MicroceLac 100 using a design-of-mixtures approach [9]. However, these studies relied exclusively on classical methods—compressibility index (CI), Hausner factor, angle of repose, and flow time—which are known to provide only a partial picture of powder behavior. The limitations of classical pharmacopoeial methods have been extensively documented. Shah et al. demonstrated the poor discriminating power of individual flow tests for pharmaceutical powders [10], while Krantz et al. showed that static and dynamic testing methods probe fundamentally different aspects of powder mechanics [11]. Lindberg et al. compared five flow measurement techniques and found substantial disagreement between methods for cohesive powders [12]. These findings underscore the need for multi-parameter characterization approaches.

The FT4 Powder Rheometer® (Freeman Technology, Tewkesbury, UK) provides precisely such a multi-faceted platform. By its patented rotating blade methodology, the FT4 quantifies dynamic flow resistance (Basic Flowability Energy, BFE), temporal stability (Stability Index, SI), sensitivity to flow rate changes (Flow Rate Index, FRI), and interparticulate cohesion (Specific Energy, SE) in a single instrument [13,14]. Complementary modules enable consolidated tapping, aeration, compressibility, permeability, shear cell, and wall friction measurements, providing over 20 independent flow descriptors per sample. The dynamics of the FT4 blade interaction have been characterized by Hare et al. using high-speed imaging and DEM simulation [15]; correcting numerical errors in that work does not affect the qualitative characterization cited here. Nan and Ghadiri systematically investigated the effects of air flow and particle shape on FT4 measurement [16,17].

Bharadwaj et al. used discrete element method (DEM) simulations to establish the mechanistic relationship between particle properties and FT4 flow energy [18]. Van Snick et al. published a landmark multivariate database of 55 raw materials with over 100 descriptors, demonstrating the utility of combining FT4 data with classical and particle-level measurements for in silico process design [19]. Their subsequent work extended this framework into a multivariate formulation and process development platform[20].

However, their datasets focus predominantly on single-component excipients and APIs, with limited representation of commercially available CPE. Navaneethan et al. used the FT4 to assess lubrication efficiency in pharmaceutical particulate systems [21], and Majerová et al. investigated the effect of colloidal silica on FT4 measured rheological properties of common excipients [22]. Ono and Yonemochi evaluated ibuprofen powder properties using the FT4 in the context of surface modification [23].

The present study addresses the existing knowledge gap by providing the first systematic, side-by-side characterization of fifteen lactose-based excipients—spanning coprocessed, spray-dried, spray-agglomerated, and specialty products—across the complete FT4 measurement suite and all relevant Ph. Eur. flow characterization methods. The primary objectives were (1) to establish comprehensive multi-dimensional rheological fingerprints for each material; (2) to quantify the additional information provided by FT4 parameters beyond classical pharmacopoeial methods; (3) to construct a correlation framework linking particle-level attributes to both traditional and advanced flow descriptors; (4) to investigate within-family effects of particle size distribution on flow behavior (Tablettose 70/80/100, FlowLac 90/100); and (5) to evaluate the relationship between measurement variability (standard deviation) and material cohesiveness. The resulting dataset and correlation framework can serve as a decision support tool for rational excipient selection in DC formulation development.

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Materials

Fifteen excipient samples representing five processing categories were investigated. Table 1 lists all materials with their declared compositions, manufacturing methods, typical particle morphology, and manufacturers. The materials were categorized as (i) multicomponent co-processed excipients (Cellactose 80, MicroceLac 100, Compaction Blend M, CombiLac, StarLac, RetaLac, MicrocelacPlus); (ii) roller-dried/milled anhydrous lactose (DuraLac); (iii) wet granulation product (Ludipress); (iv) spray-agglomerated single-component lactose (Tablettose 70, 80, 100); and (v) spray-dried products (Kollitab, FlowLac 90, FlowLac 100). All materials were used as received from their respective manufacturers without further processing.

Table 1. Overview of excipient materials, declared compositions, manufacturing methods, typical
particle morphology, and manufacturers. CPE = co-processed excipient; MCC = microcrystalline
cellulose; HPMC = hydroxypropyl methylcellulose; PVP = polyvinylpyrrolidone; RC = roller compaction; WG = wet granulation; SPA = spray agglomeration; SPD = spray drying.

Röttig, M.; Wolf, B.; Zwanzig, J.; Herz, F.; Priese, F. Comprehensive Powder Rheological Characterization of Fifteen Lactose-Based Co-Processed and Single-Component Excipients Using FT4 Powder Rheometry and European Pharmacopoeia Methods: A Multi-Parameter Comparative and Correlative Study. Pharmaceutics 2026, 18, 558. https://doi.org/10.3390/pharmaceutics18050558

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