(303b) Investigation and Modeling of Key Process Parameters of High-Shear Wet Granulation

High-shear wet granulation (HSWG) is a commonly used unit operation in many solid oral dosage drug products to improve material flowability and reduce segregation tendency, especially when cohesive drug substance is involved. Previous literature has provided a comprehensive understanding on development of different aspects of this unit operation, such as process control, agglomeration and breakage mechanics, mathematical modeling, simulation, and scale-up strategies [1-7]. In this research, a full-factorial DoE with 3 factors (spray rate, amount of water added, and impeller speed) was designed and executed in order to understand the influence of these factors on the granulation performance.

Batches were manufactured using HSWG with the same formulation. Several material properties of dried granules were then tested, such as bulk/tap density, granule particle size distribution using Malvern Mastersizer 2000, flowability using Jenike & Johanson ring shear tester, and compressibility using the Huxley Bertram Compaction Simulator. It was observed that various granule properties were tightly correlated with the process parameters. For example, batches with low moisture content during granulation produced granules with poor flowability (Carr’s index > 30%, and flow index < 10). Also, batches with high moisture content and high number of revolution led to over-granulation and produced dense granules (bulk density was 0.06g/cc higher than the control) with coarser particle size (d₅₀ was 160 microns larger than control) and poor compressibility (maximum hardness was 2.7 kp lower than control). These observations were confirmed through statistical modeling on the data of granule properties, which showed that moisture content and total number of impeller revolution were the most significant indices: 1) moisture content influenced Carr’s index of dry granule (p-value = 0.0095), while 2) total number of impeller revolution influenced more on d₅₀(p-value = 0.0221) and maximum hardness (p-value = 0.0441). Results indicated practical guidance on the selection of granulation process parameters, and provided suggestions on good quality control of granule properties through process development of drug product. 

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