(T1330-09-51) Klucel Fusion™ HPC Facilitating Continuous Melt Granulation in a GEA ConsiGma® Granulator

Tuesday, October 22, 2024

1:30 PM – 2:30 PM MT

Presenting Author(s)

QS

Quyen Schwing, MS

Senior Team Leader, Global Pharmaceutical R&D
Ashland Specialty Ingredients
Wilmington, Delaware, United States

Main Author(s)

QS

Quyen Schwing, MS

Senior Team Leader, Global Pharmaceutical R&D
Ashland Specialty Ingredients
Wilmington, Delaware, United States

Co-Author(s)

CB

Chloe Borza, BS (she/her/hers)

Process Engineer
GEA Process Engineering, Inc.
Columbia, Maryland, United States
JZ

Jessica Zombek, MS

Director, Engineering and Process Technology
GEA Process Engineering, Inc.
Columbia, Maryland, United States
QS

Quyen V. Schwing, BS

Staff Scientist
Ashland Specialty Ingredients
Wilmington, Delaware, United States
QS

Quyen V. Schwing, MS

Global OSD Leader
Ashland Specialty Ingredients
Wilmington, Delaware, United States
Andrew Birkmire, BS

Senior Process Scientist and OSD Sales Support Manager
GEA Process Engineering, Inc.
Columbia, Maryland, United States
Thomas Durig, n/a

Sr Director, Head of Innovation
Ashland Life Sciences
Wilmington, Delaware, United States

Purpose: Twin-screw melt granulation is rapidly emerging as a central process and enabler of continuous manufacturing of oral solid dosage forms. An essential advantage of this process technology is eliminating the need for water or organic solvents, thus eliminating the often rate-limiting drying step and the associated environmental impact. Since many pharmaceutical ingredients (API) have low density and poor flowability, granulation is practiced extensively for ease of handling. Klucel fusion™ is a new hydroxypropyl cellulose (HPC) polymer that is expressly designed to optimize performance in twin screw melt granulation (TSMG). This study explored high-dose acetaminophen (APAP) formulations at different binder levels and process factors such as temperature, screw speed, and feed rate in a continuous twin-screw melt granulation process using GEA ConsiGma® granulator.

Methods: An experimental design approach was implemented to study the impact of screw (300-600rpm) speeds, feed rates (5-10kg/h), and barrel temperatures (85°C-105°C) on acetaminophen formulations (Table 1) comprising Klucel fusion™ x HPC using the GEA ConsiGma® GD 25/80 twin screw granulator for continuous melt granulation. The collected granules were co-milled using 0.991 mm screen. The milled granules were characterized for particle size, morphology, and powder flowability. The milled acetaminophen granulation of each batch was blended with 5% Polyplasdone™ plus, a co-processed excipient containing crospovidone type b, sodium stearyl fumarate, and fumed silica and compressed into 500 mg dose tablets at various compression forces on a Styl’One simulating Fette 2090 using 0.687 X0.2812 capsule shape tooling. All tablets were characterized for dimensions, hardness, friability, and drug release profiles. Dissolution testing was conducted in 900 mL of Phosphate buffer pH 5.8 maintained at 37°C with USP Apparatus 1 (baskets) at 50 RPM.

Results: Robust Acetaminophen granules were produced under most experimental conditions. Insufficient granule growth was observed at a low binder level of 5% and at a low temperature of 85°C. A binder level of 7.5% is needed to form granules at a low processing temperature of 85°C, and strong flaky granules were formed at high binder levels or high temperatures (Figure 1). Acceptable bulk density and powder flowability were obtained, and uniformity binder distribution across granules ranged between 80-101%. Higher binder levels generated stronger tablets. However, the impact was diminished over 7.5% at the binder level. Overall, Klucel fusion™ x enabled melt granulation at 85 -105°C, generating the strongest tablets compared to wet-granulated APAP tablets (Figure 2).

Conclusion: Although not primarily designed for melt extrusion, the GEA ConsiGma® GD 25/80 granulator provides good mixing intensity and temperature control allowing the Klucel fusion™ enabled granules to yield tablets with excellent strength, low friability and comparable dissolution to tablets made by traditional wet granulation. The process was run at temperature comparable to those used for drying wet granulations, but with significantly shorter residence time.

Table 1: Acetaminophen tablet formulations

Figure 1: Effect of binder level and temperature on APAP extrudates

Figure 2: Impact of tablet hardness on binder level