(M1230-11-65) Local Heat Generation at Kneading Zone in Continuous Twin-Screw Melt Granulation: Exploring the Interplay of Processing Parameters and Binder Level for a Novel Thermal Binder

Monday, October 21, 2024

12:30 PM – 1:30 PM MT

Presenting Author(s)

NK

Niyati Kodange, MS

Graduate Research Assistant
University of Texas at Austin
Austin, Texas, United States

Main Author(s)

NK

Niyati Kodange, MS

Graduate Research Assistant
University of Texas at Austin
Austin, Texas, United States

Co-Author(s)

AP

Adwait Pradhan, MS (he/him/his)

Graduate Research Assistant
University of Texas at Austin
Austin, Texas, United States
KK

Kapish Karan, MS

Global OSD leader, Pharmaceutical R&D
Ashland Specialty Ingredients
Wilmington, Delaware, United States
QS

Quyen Schwing, MS

Senior Team Leader, Global Pharmaceutical R&D
Ashland Specialty Ingredients
Wilmington, Delaware, United States
Thomas Durig, n/a

Sr Director, Head of Innovation
Ashland Life Sciences
Wilmington, Delaware, United States
Feng Zhang, Ph.D.

Associate professor
University of Texas at Austin
Austin, Texas, United States

Purpose: Twin-screw melt granulation (TSMG) is a continuous manufacturing process used to produce granules for oral solid dosage forms. It has been used in several commercial products (e.g., Eucreas, Oriahnn, and Orilissa). However, its adoption is lagging due to perceived concerns of thermally induced drug degradation. TSMG is carried out at an elevated temperature, and the molten thermal binder functions as the liquid binder. The granule formation primarily relies on the energy input to the powder from rotating screws in form of specific mechanical energy (SME) and heated barrel in form of thermal energy. Most of the energy input takes place at the kneading section via viscous and frictional heat dissipation. The objective of this study is to understand the correlation between process parameters and local heat generation (ΔT_local), which is represented as granule temperature minus set barrel temperature at various binder levels using Klucel Fusion™ hydroxypropyl cellulose (HPC) as a novel thermal binder. A mechanistic understanding of the local heat generation at the kneading zone would help clear any misconceptions about TSMG, ultimately fostering broader adoption of this enabling technology.

Methods: Klucel Fusion^TMHPC was used as the thermal binder, and Acetaminophen (APAP, d90= 47 microns) is used as the model drug. APAP is a poorly compressible drug and shows miscibility with HPC at elevated temperatures. Klucel Fusion^TM HPC is the first purpose-designed binder with excellent thermoplastic properties (low melt viscosity and higher tan δ), enabling low processing temperatures ( < 90°C) while delivering excellent compressibility at a low usage level. Aerosil® 200 (0.05%) was added to improve the flow of the powder blend. Granulation was carried out using a Leistritz^® ZSE 18 twin-screw co-rotating extruder with a 25 L/D configuration. To understand the local temperature, a single 15 mm kneading block (5 mm disc width) was placed close to the end of the barrel. Preliminary granulation trials were conducted to identify critical composition, process variables and their design space. ΔT_local, granule size, and granule tabletability were measured as responses. Granule temperature was recorded as radiometric data using a Teledyne FLIR E54 camera gun, and data was processed using Thermal Studio Pro™ software. Granule size was analyzed using CamSizer^®. Statistical analysis was performed using JMP software. To assess tabletability, the granules were compressed into tablets using a hydraulic press, and tensile strength was determined.

Results: Based on the preliminary granulation trials, we have identified four critical parameters and two levels for each variable: binder level (5 and 10%), disc offset angle (60 and 90°) of the kneading block, specific rate (Q/N) (0.01 and 0.025 Kg.hr^-1.rpm^-1), and barrel temperature (80 and 100 ºC). Two levels for specific rate were achieved by maintaining a constant screw speed (N) of 100 rpm while varying the feed rate (Q) (1.0 and 2.5 Kg.hr^-1). The granulation run was considered successful when the tensile strength of tablets could reach 2 MPa. The granulation runs are given in Table 1. Most of the granulation was achieved at a high specific rate of 0.025 Kg.hr^-1.rpm^-1, which resulted in a high degree of fill. The granule temperature for the successful runs ranged from 92.7 to 109.7 °C. The mean residence time of all these successful runs was in the range of 20 to 40 seconds. We believe that most drugs would be stable with such a short exposure to this elevated temperature. The standard least squares regression analysis indicated that the specific rate and disc offset angle of the kneading block had a significant impact on the local heat generation (p < 0.05) (Table 2). Both higher specific rate and more restrictive kneading element (90° angle) enhanced interactions between the binder and drug. This resulted in greater granule growth and, hence, generation of more local heat at the kneading block. Granulation was achieved with 5% Klucel Fusion™ using 90° kneading element. At a high specific rate, 10% binder and 90º kneading block resulted in increased frictional heat dissipation, leading to an increase in granule size (d90). As the granules grew larger, their movement at the kneading block became further restricted, contributing to ΔT_local. Compared to 100 ºC barrel temperature, a higher SME was observed at 80 ºC barrel temperature. With a lower barrel temperature, less thermal energy was conducted from the barrel, resulting in less softening of Klucel Fusion™. This rheological attribute of the powder blend caused rotating screws to input SME in the form of viscous heat dissipation at the kneading zone, leading to increased ΔT_local (Figure 1).

Conclusion: Material was exposed to elevated temperature (92.7 to 109.7 °C) for a short duration (20-30 seconds) during TSMG. Granulation can be achieved with 5% Klucel Fusion^TMHPC when the formulation is processed with a 90º kneading block at a high specific rate. The lower barrel temperature, higher binder level, higher specific rate, and larger disc angle of the kneading block contributed to high ΔT_local.

References: 1. Liu T, Paul S, Beeson BT, Alexander J, Yang F, Bi V, et al. Effect of Hydroxypropyl Cellulose Level on Twin-Screw Melt Granulation of Acetaminophen. AAPS PharmSciTech. 2020;21:1–14.
2. Pradhan A, Costello M, Yang F, Bi V, Durig T, Zhang F. Using twin-screw melt granulation to co-process mannitol and hydroxypropylcellulose. J Drug Deliv Sci Technol. 2022;77.

Acknowledgements: This work is funded and supported by Ashland Specialty Ingredients, Wilmington, Delaware

Table 1: Granulation runs with different processing conditions (successful granulation runs are highlighted in green) with its corresponding ΔTlocal and SME.

Table 2: Statistical analysis of ΔTlocal for different parameters (p < 0.05 indicates statistical significance).

Figure 1: Correlation between granule size d90, ΔTlocal and SME at high specific rate of 0.025 Kg hr-1 rpm-1.