Evaluation of binders in twin-screw wet granulation – Optimization of tabletability

The influence of hydroxypropyl cellulose type (HPC-SSL SFP, HPC-SSL), concentration (2 %, 3.5 %, 5 %) and filler (lactose, calcium hydrogen phosphate (DCP)/microcrystalline cellulose (MCC)) on twin-screw wet granulation and subsequent tableting was studied. The aim was to identify the formulation of the highest tabletability which still fulfills the requirements of the disintegration. Lactose combined with 5 % binder enabled a higher tabletability and a faster disintegration than DCP/MCC. It was found that tabletability of lactose formulations can be increased by higher binder concentration and higher compression pressure while tabletability of DCP/MCC formulations can be only increased by higher compression pressure. It was observed that batches containing DCP/MCC failed the disintegration test, if the highest binder concentration and the highest compression pressure were used. To ensure a fast disintegration, the compression pressure or at least the binder concentration had to be low. Changing the disintegrant and its localization improved the DCP/MCC formulation, resulting in faster disintegration than lactose tablets. However, it also resulted in a lower tabletability. In this study best tablets were achieved with 3.5 % or 5 % binder and lactose as filler. These tablets presented the highest tabletability but still disintegrated in less than 500 s.

Introduction

The tabletability describes the ability of a material to form a tablet of sufficient mechanical strength after compression (Sun, 2011). An adequate mechanical strength is important to enable further processing as well as transport. The mechanical strength can be measured as tensile strength, where often a tensile strength of at least 2 MPa is targeted (Sun et al., 2009). To increase the mechanical strength of tablets, binders are used to improve the interactions between the particles. Already in an upstream granulation they enhance the product quality (e.g., particle size distribution and granule friability) forming a cohesive network between the different substances in the formulation (Vandevivere et al., 2020). Many binders are described to be useful in the different manufacturing methods.

In the case of twin-screw wet granulation a former study showed the increase of tabletability if povidone, copovidone, hydroxypropyl methylcellulose or hydroxypropyl cellulose (HPC) were used in an upstream granulation process (Köster et al., 2021). Several factors are described to be able to influence the tabletability. Beside the properties of the starting material like the plasticity or porosity (Wang et al., 2022), also the properties of the intermediate product can have an impact. The size (Arndt and Kleinebudde, 2018, Arndt et al., 2018, Skelbæk-Pedersen et al., 2021, Sun and Himmelspach, 2006), shape (Osei-Yeboah et al., 2014a), surface (Osei-Yeboah et al., 2014a), hardness (Skelbæk-Pedersen et al., 2021), porosity (Badawy et al., 2006, Nordström and Alderborn, 2015, Osei-Yeboah et al., 2014a, Tao et al., 2015, van den Ban and Goodwin, 2017) and bulk density (van den Ban and Goodwin, 2017) of the granules were found as influential. Moreover, the granulation method (Nordström and Alderborn, 2015) as well as all process parameters like L/S in wet granulation (Osei-Yeboah et al., 2014a, Tao et al., 2015) or the screw configuration or screw speed (Khorsheed et al., 2019) in twin-screw granulation which cause the listed granule properties can influence the tabletability. During subsequent compression, the tableting speed (Tye et al., 2005) and lubrication (Badawy et al., 2006, Mosig and Kleinebudde, 2014) are known to be of importance.

Nonetheless, fulfilling the dissolution of the active pharmaceutical ingredient is imperative, and disintegration of the tablet may be necessary to facilitate the process. A binder will decelerate the disintegration of the tablet (Joneja et al., 1999). Substances which accelerate the disintegration are disintegrants like croscarmellose sodium, crospovidone and sodium starch glycolate. The mentioned substances are also named as superdisintegrants because already low concentrations between one and four percent are sufficient to ensure a fast disintegration (Fahr and Voigt, 2015). However, the disintegrant type, its localization and concentration have to be chosen carefully dependent on both formulation and process parameters (Köster and Kleinebudde, 2023).

This study aimed to identify a suitable HPC concentration to assure a sufficient tabletability but still allow a disintegration which meets the requirements. The study was performed orientated towards a former study where a suitable disintegrant and its localization were investigated (Köster and Kleinebudde, 2023). Two different fillers were examined. As granulation is a typical manufacturing step before tableting (Khorsheed et al., 2019) but only a few studies investigate the tabletability after wet granulation, this study should help to expand the knowledge about this manufacturing technique. Twin-screw granulation is predestined for continuous production which is a process of great interest caused by less scale-up difficulties, shorter development time and automatic production lines, for instance (Dhenge et al., 2010, Keleb et al., 2004) and results in different granules than other, non-continuous wet granulation techniques like fluid-bed granulation and high-shear granulation (Arndt et al., 2018, Arndt and Kleinebudde, 2018, Pandey et al., 2018). Thus, this study aims to expand the understanding of twin-screw granulation.

Material

Product name	Substance	Supplier	Abbreviation/ Name in study	Function
Avicel PH-101	Microcrystalline Cellulose	Dupont, Wilmington, USA	MCC	DM / Filler
DI-CAFOS A 60	Calcium hydrogen phosphate anhydrate	Chemische Fabrik Budenheim, Budenheim, Germany	DCP
Granulac® 200	Alpha-lactose monohydrate	Meggle, Wasserburg am Inn, Germany	Lactose (L)	Filler
HPC-SSL SFP	Hyprolose	Nippon Soda, Tokyo, Japan	SSL SFP	Binder
HPC-SSL	Hyprolose	Nippon Soda, Tokyo, Japan	SSL	Binder
Kollidon® CL-SF	Crospovidone	BASF, Ludwigshafen, Germany	xPVP	Disintegrant
Primellose®	Croscarmellose sodium	DFE Pharma, Goch, Germany	xCMC	Disintegrant
Parteck LUB MST	Magnesium stearate	Merck, Darmstadt, Germany	MgSt	Lubricant

 

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Claudia Köster, Peter Kleinebudde, Evaluation of binders in twin-screw wet granulation – Optimization of tabletability,
International Journal of Pharmaceutics, 2024, 124290, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124290.

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Read also our introduction article on Binders here: