Direct Compaction Drug Product Process Modeling

Abstract

Most challenges during the development of solid dosage forms are related to the impact of any variations in raw material properties, batch size, or equipment scales on the product quality and the control of the manufacturing process. With the ever pertinent restrictions on time and resource availability versus heightened expectations to develop, optimize, and troubleshoot manufacturing processes, targeted and robust science-based process modeling platforms are essential. This review focuses on the modeling of unit operations and practices involved in batch manufacturing of solid dosage forms by direct compaction. An effort is made to highlight the key advances in the past five years, and to propose potentially beneficial future study directions.

Keywords: direct compaction; drug product; pharmaceutical technology; process engineering; process modeling.

Fig. 1

Order of direct compaction unit operations

Fig. 2

Comparison of the instantaneous discharge rates as a function of hopper outlet radius. Measured data refers to lab-scale experiments using Mikro PVC powder of d₅₀ ≈ 4 μm and ff_c ≈ 1-2; for compared Models refer to [–22]. Figure reproduced from [16]

Fig. 3

Simulation snapshots of powder transfer system showing API loading for an actual API/excipient particle size distribution demonstrating significant segregation with superpotent tablets at the start of the batch. Figure reproduced from [10]

Fig. 4

Relative airflow (arrows), air pressure (left half), and absolute particle velocity (right half) at steady state for varying hopper angles from CFD-DEM simulations; dead zones (particle velocity < 4 cm/s) are emphasized [34]

Fig. 5

a Shear predicted by DEM as the mean distance particles traveled as a function of the discharged mass; b Compact tensile strength considering varying impeller sizes. Reproduced from [35]

Fig. 6

a Flow function of silanized glass powder (d₅₀ = 8 μm) with a concentration of 0.01 mol/L. b Chemical formulas of the used hydrophobic silane coatings —(1) PFOTES: Perfluorooctyltriethoxysilane; (2) FPTS: Trifluoropropyltrimethoxysilane; (3) CDMPS: Chlorodimethylphenylsilane; (4) CDMOS: Chlorodimethyloctylsilane; (5) CTMS: Trimethylchlorosilane; Piranha – peroxymonosulfuric acid. c Flow function coefficients of the silanized particles at major principal stress of 10 kPa. Reproduced from [41]

Fig. 7

Experimentally measured restitution coefficients a marble articles of sizes 2–6 mm; reproduced from 59, b MCC pellets (d₅₀ = 1 mm) with 20-μm-thick HPMC and Eudragit based coatings, containing different moisture contents (represented here by pore saturation degree ‘S’) and stressed at different contact forces; reproduced from [60]

Fig. 8

Schematic representations of lamination in a powder compacts suggested by Train (image adapted from [125]) and b capping and lamination failures as suggested by Long (image adapted from [126]). Radial stress is given by σ_r

Fig. 9

Contours of shear stress within the compacts during partial ejection from a straight a and a tapered die b. The graph in c shows the variation of the shear stresses along the outer edge of the compact. σ_xy is shear stress (figure reproduced from [127])

Fig. 10

Modified Drucker–Prager/Cap model: yield surface in p–q plane with experimental procedures for determining the shear failure surface F_s and the cap surface F_c. [Image adapted from [134]]

Fig. 11

Example family of yield loci for various relative densities

Fig. 12

Schematic of the force-displacement contact model developed by Luding for two particles in contact

Fig. 13

Schematic diagram of the normal force-displacement behavior in the proposed contact model

Fig. 14

Incorrect prediction of strength anisotropy for transversely confined and uniaxially compressed powders (figure reproduced from [178])

Fig. 15

A schematic of the tablet coating process highlighting several key physical phenomena. Reproduced from Ketterhagen et al. [181] with permission