(M1530-09-56) Navigating Thermal Binder Selection for Rational Design of a Twin-Screw Melt Granulation Process

Purpose: Twin-screw melt granulation (TSMG), an alternative to conventional granulation methods has garnered significant attention due to its solvent-free nature and remarkable ability to enhance tabletability of poorly compressible powders. TSMG harnesses the heat and shear from the frictional and viscous dissipation of binder for granulation to occur. The thermal and mechanical stresses experienced by the material in the kneading zone, which cause granule growth, simultaneously induce undesired drug physicochemical changes, such as chemical degradation, crystal form change, and amorphization despite a short residence time of 30-60s. The local heat generation at the kneading zone is influenced by the binder’s rheological properties, drug-binder miscibility, and extent of granule growth thereby making binder type and level, one of the most critical factors in optimization. Preliminary investigation on TSMG of gabapentin with Klucel™ have highlighted the impact of binder level on degradation¹. The purpose of this study was to systematically design a TSMG process while carefully navigating through the influence of two different binders Soluplus™ and Plasdone™ on drug degradation and granule properties.

Methods: The selected binders Plasdone™ S630 Ultra and Soluplus™ have gained widespread adoption in twin-screw processing due to their distinct thermoplastic properties². Gabapentin (GABA) was chosen as a model drug, as it is a high-dose, poorly compressible drug that degrades upon melting (~174°C) to Gabalactam (GABA-L). Drug-binder blends at different ratios were run on a differential scanning calorimeter (DSC) at increasing isothermal times to simulate the thermal stresses experienced by the material in the extruder. GABA-L content in the processed blends was then quantified by reverse-phase HPLC with a limit of detection at 0.005%. Granulation was performed with a Leistritz Micro-18 twin-screw co-rotating extruder with a 25 L/D barrel configuration having a single 15 mm kneading block staggered at 30°. Binder level, feed rate and screw configuration were fixed. Factorial design was employed varying barrel temperature, screw speed and binder type. The resulting granules were used to quantify tensile strength using a single station hydraulic press along with % GABA-L content on the HPLC. The USP limit for GABA-L in finished product is 0.4%.

Results: Based on prior work (presented at AAPS 2022) involving TSMG of gabapentin with Klucel™, degradation kinetics elucidated through DSC enabled optimization of binder level while highlighting the accelerated degradation at higher temperatures ( >140 °C) at different isothermal times. DSC-based thermal stability testing with Soluplus™ and Plasdone™ revealed increased degradation at higher binder level forming the rationale to fix the binder level to 10% (Fig 1 and Fig 2). Degradation kinetics evaluated through DSC follows first order kinetics at low time intervals till 140 °C for both Plasdone™ and Soluplus™. Higher GABA-L content was observed with Plasdone™ than Soluplus™ at similar temperature profiles through DSC and the mechanism for the higher degradation is being investigated (Fig 1 and Fig 2). Granulation trials conducted by varying barrel temperature and screw speed pointed towards a high threshold barrel temperature of 130 °C and low screw speed of 50 rpm was required for granule growth. This was observed for both Plasdone™ and Soluplus™ as lower temperatures did not result in granule growth. The lack of granulation at lower temperatures can be attributed to the gentle screw configuration employed to reduce local heat generation and rely on degree of fill for granulation onset. With higher barrel temperature of 130 °C, Gaba-L content was 0.058% and 0.119% for Soluplus™ and Plasdone™, respectively, which was below the USP limit of 0.4%. Despite lower degradant level and granule growth, Soluplus™ did not improve the granule tabletability as tensile strength of 1.2 MPa was observed compared to 2.6 MPa with Plasdone™. As per the IPEC guidelines, a tensile strength of 2 MPa was required to withstand the stresses during manufacturing.

Conclusion: Despite the high barrel temperature, compressible granules of gabapentin were achieved with Plasdone™ with the most gentle screw configuration below the GABA-L limit of 0.4%. In the case of Soluplus™, a more aggressive screw configuration needs to be employed to attain compressible granules which may act as a double-edge sword increasing degradation. This work highlighted the importance of the complex interplay between binder properties, processing conditions on granule properties and degradation, further stressing the need for a deeper understanding of the rheological properties, moisture and chemical interactions between drug and binder in rational design of TSMG process.

References: 1. Adwait Pradhan, Nada Kittikunakorn, Fengyuan Yang, Thomas Durig, Feng Zhang et al., ‘How to Maintain Drug Stability During Twin-screw Melt Granulation?’, AAPS 2022, Boston.
2. Liu, T., Kittikunakorn, N., Zhang, Y., & Zhang, F. (2021). Mechanisms of twin screw melt granulation. Journal of Drug Delivery Science and Technology, 61, 102150.

Acknowledgements: This study was funded by Ashland Specialty Ingredients, Wilmington, DE

Figure 1. Degradation kinetics of gabapentin as a function of Soluplus level evaluated through DSC

Figure 2.Degradation kinetics of gabapentin as a function of Plasdone (S630 Ultra) level evaluated through DSC

Figure 3. % Gaba-L observed in TSMG granules processed at different conditions. (The value in the box is tensile strength of the tablets compressed at 215 MPa compression pressure from these granules)