Transitioning Amiodarone Tablet Manufacturing: A Comparative Study of Batch and Continuous Wet Granulation

Abstract

Background/Objectives: The objective of this study was to design and optimize a continuous wet granulation process for Amiodarone hydrochloride tablets using a Design of Experiments approach. The study compared and evaluated the characteristics of granules and tablets produced via a high-shear mixer (batch process) and a twin-screw granulator (continuous process).

Methods: For process optimization, a central composite design was applied to establish a design space, defining screw speed and milling size as critical process parameters (X) and dissolution rate, flowability, assay, disintegration time, and friability as dependent variables (Y).

Results: Comparative results between the two processes revealed no significant differences in in-process control parameters, and all formulations successfully met the target dissolution profiles. Notably, the similarity factor (f₂) was calculated to be above 50, through which dissolution equivalence was successfully demonstrated with a high level of statistical certainty. Regarding process efficiency, lead time measurements confirmed that the continuous process dramatically reduced manufacturing time by more than 80% compared to the batch process.

Conclusions: This study validates the feasibility of converting batch-based drug manufacturing to a continuous platform without altering the formulation, presenting an effective process strategy for enhancing productivity and operational efficiency in the pharmaceutical industry.

Introduction

Recently, the pharmaceutical industry has been accelerating a paradigm shift from traditional batch manufacturing toward continuous manufacturing (CM) systems to simultaneously maximize production efficiency and ensure stringent quality control [1]. CM represents an innovative production methodology in which all stages—from raw material input to the final finished product—are executed within a seamless, integrated flow, emerging as a next-generation standard in the industry [2,3]. Unlike batch processes, where unit operations are conducted independently—often resulting in substantial time and resource expenditures due to inter-process lag times, material handling, and offline quality inspections—CM enables a dramatic reduction in production lead times and minimizes the risks of quality variability through the implementation of real-time monitoring and feedback control systems [4,5,6].

The cornerstone of a CM system hinges on the precise identification and control of critical Process Parameters (CPPs). By seamlessly integrating with process analytical technology (PAT), CM systems facilitate the real-time monitoring of critical material attributes (CMAs) and critical quality attributes (CQAs). This capability ensures product uniformity and process robustness by allowing for the real-time adjustment of CPPs in response to subtle in-process variations [7,8,9,10].

Furthermore, this technological framework paves the way for rapid mass production and flexible throughput adjustment in response to emergencies, such as supply chain disruptions or global pandemics. Ultimately, it enhances product reliability by minimizing human error and ensuring consistent quality throughout the production lifecycle [11,12,13].

In particular, since the transition of the wet granulation process profoundly influences the physical characteristics of granules and the subsequent drug dissolution behavior, a comprehensive understanding of the correlation between the batch-based high shear mixer (HSM) and the continuous twin screw granulation (TSG) is imperative.

Within the TSG-based continuous granulation process, various parameters such as screw configuration, liquid-to-solid (L/S) ratio, and feed rate must be considered. Among these, the twin-screw speed can serve as a dominant CPP depending on the formulation attributes, as it directly dictates the mechanical shear force and residence time distribution (RTD) of the granules [14,15,16,17].

Although the L/S ratio is highly critical as a dominant CPP in TSG, it was kept constant in this study to prevent any composition changes and preserve the validated batch formulation matrix. Under this constraint, subtle fluctuations in screw speed significantly affect granule density, particle size distribution (PSD), and tablet hardness. Therefore, establishing an optimized design space (DS) for this specific variable is a prerequisite for a successful transition to a continuous manufacturing system [18,19].

The primary objective of this study is to transition the established batch-based manufacturing process for Amiodarone hydrochloride (HCl) tablets to a CM system and comparatively evaluate the quality equivalence between the two processes. To this end, the physicochemical properties of granules and tablets manufactured by HSM and TSG were analyzed from multiple perspectives.

Specifically, this research aimed to systematically investigate the influence of twin-screw rotation speed, which was identified as a critical process parameter tailored to this specific formulation and a key success factor for the continuous process. To derive the interactions between process variables and establish optimal conditions, a Design of Experiment (DoE) approach based on central composite design (CCD) was implemented. Through these methodologies, the study seeks to validate the feasibility of the continuous manufacturing process and its potential to enhance production efficiency within the derived DS.

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Materials

Amiodarone HCl, the active pharmaceutical ingredient (API), was supplied by Zhejiang Hengkang Pharmaceutical Co., Ltd. (Taizhou, China). Additionally, Cordarone® Tablets (200 mg amiodarone hydrochloride, Handok Inc., Seoul, Republic of Korea) were purchased from a local commercial pharmacy and utilized as the reference drug in the comparative in vitro dissolution studies (Figure 2), maintaining continuity with the target reference product analyzed in our prior batch-mode study [10]. The excipients used in the formulation included pre-gelatinized starch (Starch 1500; Colorcon Korea, Suwon, Republic of Korea), lactose monohydrate (Lactose monohydrate 200M; DFE Pharma, Goch, Germany), and polyvinylpyrrolidone K25 (Povidone K25; BASF, Ludwigshafen, Germany). Colloidal silicon dioxide (Aerosil 200; Evonik, Essen, Germany) and magnesium stearate (Nitika Pharmaceutical Specialties Pvt. Ltd., Nagpur, India) were utilized as a glidant and a lubricant, respectively. Acetonitrile and methanol for analytical purposes were purchased from Duksan Co., Ltd. (Ansan, Republic of Korea), and all other chemicals used were of analytical reagent grade.

Immediate-release Amiodarone HCl tablets were manufactured using both batch-wise HSM and continuous TSG. To ensure a valid comparison between the two processes, the same formulation optimized in a previous study was applied.

Wet granules were prepared by adding purified water to a homogeneous blend of the API and excipients (lactose monohydrate, pre-gelatinized starch, and povidone K25). The resulting granules were dried in an oven at 65 °C until the loss on drying (LOD), measured at 105 °C using a moisture analyzer (MB-120, OHAUS, Seoul, Republic of Korea), reached 2.0% or less. The dried granules were then milled using a hammer mill (PX-MFC 90D, KINEMATICA, Malters, Switzerland) equipped with a 1.0 mm screen.

Subsequently, colloidal silicon dioxide and magnesium stearate, sieved through 35-mesh and 25-mesh screens, respectively, were added for final blending. The final mixture was compressed into tablets with a target weight of 350 mg using a rotary tablet press (PR-LM08, PTK Co., Ltd., Gimpo, Republic of Korea). As an online PAT strategy, the real-time compression pressure monitoring system of the rotary tablet press was utilized. This continuous feedback mechanism allowed for precise adjustment of consolidation forces, ensuring that continuous tablets maintained rigid structural equivalence to the batch process. Consistent compression pressure was maintained across both manufacturing methods to rigorously evaluate quality equivalence.

Yoon, J.-H.; Jeon, C.-W.; Kim, J.-E. Transitioning Amiodarone Tablet Manufacturing: A Comparative Study of Batch and Continuous Wet Granulation. Pharmaceuticals 2026, 19, 850. https://doi.org/10.3390/ph19060850