(T1030-12-82) A Novel Binder Designed to Enable Widespread Adoption of Twin Screw Melt Granulation (TSMG)

Purpose: Manufacturing immediate-release granulation, especially (but not only) in the context of continuous manufacturing, is attractive as it removes the rate-limiting and energy-intensive granulation drying step, thus reducing the need for sophisticated drying equipment and reducing process and control complexity while potentially increasing productivity. There is also evidence that melt granulation with suitable binders can improve tablet strength over traditional granulation. Despite the potential benefits, concerns relating to increase in-process API degradation and impurity formation, especially in thermolabile drugs, have held back the widespread commercial adoption of TSMG. This study introduces a purpose-designed tablet binder that allows for low extrusion process temperatures (50°C- 80°C) and low shear levels at low binder level of 5%. The performance of this new binder klucel™ Fusion hydroxypropyl cellulose (HPC) was compared against commercially available klucel™ HPC EXF and Polyethylene glycol (PEG) 8000 using Gabapentin as an extreme example of a highly thermolabile drug.

Methods: Melt viscosity and mechanical properties of klucel™ Fusion HPC and commercial klucel™ EXF HPC were determined using a TA Instruments Discovery Hybrid Rheometer DHR‑3 and a Dynamic Mechanical Analyzer DMA-Q800. Binary blends of 95% Gabapentin (a thermally labile drug with poor compaction properties) and 5% klucel™ fusion HPC, klucel™ HPC EXF, or PEG 8000 were prepared. The granulation was carried out on a Leistritz 18 mm twin-screw extruder, using the different polymer types at different temperatures, barrel fills, and screw speeds (Table 1). Tablets containing 600mg Gabapentin were made using each granulation and characterized for friability, hardness, and drug dissolution. The degradation product Gaba-lactam was quantified using HPLC.

Results: This new melt granulation binder showed significantly lower melt viscosity, lower storage modules, and higher Tan (δ) than commercial HPC, indicating enhanced thermoplasticity and processability compared to the commercial HPC grade at 50-180°C. (Figure 1). Compared to other binders, klucel™ Fusion HPC performed exceptionally well across a wide range of processing conditions, yielding stronger granules than HPC EXF and PEG 8000 in TSMG of Gabapentin (Figure 2). In addition, the formulation with the klucel™ Fusion HPC formed the lowest degradant level of the studied formulations and lower levels than the commercial product, Neurontin™ 600mg film-coated tablets. Klucel™ Fusion granulations produced under all conditions delivered the strongest tablets with acceptable friability. The formulation processed with PEG 8000 at high temperature had the highest impurity level and yielded the softest tablets. Immediate-release dissolution behavior was not impacted.

Conclusion: The klucel™ Fusion HPC exhibited better processability and stability of Gabapentin than the commercial HPC EXF grade and PEG 8000 due to its low melting temperature and complex viscosity. To move beyond traditional batch processing (e.g., wet and fluid bed granulation) to continuous processing technology using melt granulation, the klucel™ Fusion HPC is the best polymer choice due to the ease of processing and protection of moisture-sensitive and thermolabile drugs.

References: Effects of thermal binders on chemical stabilities and tabletability of gabapentin granules prepared by twin-screw melt granulation, Nada Kittikunakorn a, J. Joseph Koleng III b, Tony Listro c, Changquan Calvin Sun d, Feng Zhang, International Journal of pharmaceutics, Volume 599, 25 March 2019, Pages 37- 47

Table 1: Study design of Gabapentin melt granulation parameters

Figure 1: Complex viscosity & Tan delta of klucel™ fusion vs commercial klucel™ EXF HPC grade

Figure 2: Gabapentin melt granulation processing Window of klucel™ fusion, klucel™ EXF HPC, and PEG 8000