All4Nutra
Abstract
We study the response of two twin-screw granulators of different barrel diameter to the variation of three process parameters (liquid-to-solid ratio, screw speed and throughput), while maintaining the same shear rate field along the screws. Various responses, including size distribution, porosity and content uniformity, were measured to determine granule characteristics. The set of experiments was based on a central composite design face-centered. Granules in both systems showed drug content consistent with expected values across varying process parameters. Relative granules size, normalized with the granulator gap, was larger for the equipment with the smaller gap. The liquid-to-solid ratio (LSR) was the most influential parameter affecting the granule size. Specifically, dimensional granule size increased with LSR values in both systems, consistent with previous studies. Elevated LSR values resulted in greater amounts of over-granulated material, whereas lower values produced exceedingly small (fines) or under-granulated material. The minimum amounts of both over- and under-granulated material were found at intermediate LSR values. Porosity varied differently between the systems, with a consistent reduction observed as LSR decreased from 0.3 to 0.4. Optimization studies revealed that central values of LSR and screw speed minimized fines and bigger granules while maximizing porosity, critical attributes for downstream processing. Granule size and porosity exhibited no significant correlation with tablet tensile strength across both systems. These findings offer valuable insights for optimizing pharmaceutical manufacturing processes to enhance product quality.
Highlights
Introduction
For over 50 years solid dosage forms, the most popular administration method, have been manufactured using a methodology known as batch production, an extensive process involving multiple discrete steps and the use of large-scale systems. After each step, production is typically halted for quality testing and the waiting times between production steps can significantly affect the production timeline. Alternatively, pharmaceutical products could be obtained through continuous manufacturing, an uninterrupted process in which raw materials are fed through a fully integrated assembly line, eliminating waiting times between steps. This method saves time, reduces human errors and drug shortages and can operate for longer periods to meet higher demand [[1], [2], [3]].
An important unit operation in the manufacturing of oral solid dosage forms is wet granulation (WG), typically used to improve critical material and product properties including flow, content uniformity, disintegration, dissolution and compressibility [4]. WG uses liquid as a binder to agglomerate fine particles into larger granules and both batch and continuous processes are available for wet granulation [4].
Twin screw granulators are especially well-suited for continuous pharmaceutical processes. Compared to other granulation technologies, twin screw granulation (TSG) allows for high drug loading and can process heat-sensitive materials with moderate energy requirements [4]. Screw elements (such as type, pitch and arrangement) and process parameters (e.g., screw speed, throughput, liquid-to-solid ratio and barrel temperature) can be selected depending on the application. These process parameters directly affect system parameters (working conditions) that in general cannot be controlled directly (such as power consumption, shear rate, powder feed number, specific mechanical energy, residence time distribution, fill level) [5,9,11,12]. Both, process and system parameters, impact the performance of the WG process and the final properties of the granules. The powder formulation also affects the granulation process and the selection of working parameters, such as the liquid-to-solid ratio (LSR). For example, hydrophobic drugs often require relatively high LSR values, in some cases up to 50 % [[5], [6], [7]].
After wet granulation, a drying step is required. Traditionally, this step is conducted as a batch process and interrupts the continuous character of the granulation workflow. In contrast, integrating the drying process directly into the granulation workflow makes WG a truly continuous technique. While recent advancements have led to the development of systems incorporating in-barrel drying, it is important to note that these systems often necessitate high temperatures, limiting their applicability to thermally stable materials [8]. Some continuous drying system coupled to granulators are currently available. Therefore, the ability to transfer a process from widely used twin screw granulators to different ones that provide in-line drying systems is important to achieve continuous WG processes.
The use of different granulators can lead to variations in granule characteristics, even when maintaining constant formulation, screw design and process parameters [10] while transfer of system parameters often proves to be challenging. Previous research on TSG has studied different system parameters as responses, as reviewed by Lute et al. [9]. However, it is still a significant challenge to ensure consistent granule properties across different granulators or scales for WG methods. Among system parameters, powder feed number (PFN) and shear rate have been proposed as important parameters in TSG scale-up. PFN represents the rate at which powder is fed into the barrel of the processing system relative to the screw turnover volume [13], and is related to the fill level [9,11]. Osorio et al. found that PFN is more useful as a scaling-out parameter (to increase the production rate) than to scale-up a process to a granulator of different dimensions. Shear stress depends on both the screw speed as well the rheological behavior of the granulated material. The shear stress exerted by the screw elements causes the wet mass to spread and create new interfaces, which aids in mixing and the shear rate measures the magnitude of this spreading process [5].
The aim of this study is to transfer the process between granulators of different scales without a specific focus on scaling up the process. For that, we compare the critical properties of ibuprofen granules produced by two different granulators designed for pharmaceutical applications. Ibuprofen, a hydrophobic model API extensively studied in WG processes [14], was granulated with a formulation that also includes lactose, microcrystalline cellulose and polyvinylpyrrolidone as excipients. Similar configurations were sought for both granulators. Screw speed, N, was adjusted to achieve comparable shear rates for both systems. Finally, liquid-to-solid ratio (LSR) and throughput (TP) were set to ensure an overlap in the parameter space, within the operational limits of the pumps, feeders and overall equipment performance. A central composite face-centered Design of Experiments (DoE) with three center points was performed for each granulator studied. Resulting granules were characterized by measuring their size distribution and porosity. Also, tensile strength and dissolution rate of tablets, made with them at same relative density, was assessed.
For the specific study of granules size, the presence of fines and large granules was quantified to assess the process yield (in this work, granules between 125 and 2000 μm). For each response, a fitting equation considering all statistically significant parameters and their interactions, was obtained.
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Materials
Ibuprofen 50 (BASF, Germany), lactose (Pharmatose 200 M, DFE Pharma, USA), microcrystalline cellulose (MCC, Avicel PH-101 NF, Dupont, USA), polyvinylpyrrolidone (PVP) average M.W. 50,000 (K30, Acros Organics, USA), sodium hydroxide (VWR, USA), potassium phosphate (VWR, USA), croscarmellose sodium (CCS, Spectrum Chemical MFG, US) and distilled water were used.
Nazareth E. Ceschan, María C. Balbi, Pablo Ravazzoli, German Drazer, Fernando Muzzio, Gerardo Callegari, Comparison of granules obtained with two twin-screw granulators of different diameter working at the same shear rate, Powder Technology, 2025, 121092, ISSN 0032-5910, https://doi.org/10.1016/j.powtec.2025.121092.
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