The effect of filler particle size on API homogeneity of controlled release formulations via continuous twin-screw wet granulation

Abstract

Previous research has shown that controlled release (CR) formulations with hydrox- ypropyl methylcellulose (HPMC) as hydrophilic matrix former produced via twin-screw wet granulation (TSWG) yield granules with an inhomogeneous active pharmaceutical ingredient (API) distribution (Denduyver et al., 2024). This was attributed to the fast hydration and swelling behaviour of HPMC upon addition of granulation liquid, limiting granule breakage and continuous exchange of particles during granule growth. Altering the liquid-to-solid ratio (L/S-ratio), using a more aggressive screw configuration or using fillers with different sol- ubility did not yield granules with a homogeneous API distribution. Therefore, the effect of the filler particle size on the content uniformity and granule growth mechanism of CR granules was studied using filler grades with a smaller and larger particle size distribution (PSD) than the API. As granule growth in TSWG occurs spatially along the granulator unit, a compartmental analysis was performed to collect granules from each zone. The small particle size fillers yielded a more homogeneous API distribution compared to the large particle size fillers in each compartment throughout the granulator unit. However, for lactose-, mannitol- and dicalcium phosphate (DCP)-based formulations, underdosing in the fines fraction (<150 µm) was observed. The small particle size microcrystalline cellulose (MCC)-based formulation yielded a homogeneous API distribution. The inter- play of the swelling behavior of MCC and the smaller particle size facilitated wetting, favoring the homogeneous API distribution over the granule sieve fractions.

Introduction

As a continuous manufacturing technique, twin-screw wet granulation (TSWG) offers numerous benefits. The flexible screw configuration and liquid addition ports in com- bination with granule growth occurring spatially along the granulator unit facilitate the development of granules with the desired properties (Dhenge et al., 2012, El Hagrasy et al., 2013). In addition, its continuous nature enables easy scale-up, improves product quality by real-time quality assurance, and reduces floor space and investment costs (Kleinebudde et al., 2017). Controlled release (CR) formulations are established in the pharmaceutical industry as they enable constant drug plasma levels, improve patient compliance and avoid adverse drug effects (Larsson, 2010). Although the production of CR formulations via TSWG may present challenges (process failures and limited design space) due to high polymer fraction, recent research demonstrated its potential. The effect of formulation and process parameters on process performance (torque, residence time dis- tribution), granule quality attributes (granule size distribution, shape and strength, bulk and flow properties and content uniformity) or tablet quality attributes (tensile strength and dissolution profile) was investigated in different studies (Thompson and O’Donnell, 2015, Vanhoorne et al., 2016, Vanhoorne et al., 2016, Kim et al., 2017, Kotamarthy et al., 2022, Zidan et al., 2022, Sierra-Vega et al., 2023). Ad- ditionally, the transfer from a high shear granulation (HSG) to a TSWG process for CR formulations was investigated and critical parameters were identified (Kim et al., 2017, Kotamarthy et al., 2022).

In the studies of Vanhoorne et al. (Vanhoorne et al., 2016) and Denduyver et al. (Denduyver et al., 2024), the content uniformity of CR granules with hydroxypropyl methylcellulose (HPMC) as hydrophilic matrix former was investigated. In both studies, an inhomogeneous active pharmaceutical ingredient (API) distribution over granule sieve fractions was observed for formulations containing different HPMC grades. This could result in content uniformity issues during downstream processing by preferential adherence of the fines fraction to the drying unit filters or lay- ering of equipment parts. In the study of Denduyver et al. (Denduyver et al., 2024); it was elucidated that the hydrophilic matrix former HPMC is the root cause of the non-homogeneous API dis- tribution due to its fast hydration and swelling behavior upon addition of granulation liquid, preventing granule breakage and the exchange of particles during granule growth. Altering the liquid-to-solid ratio (L/S-ratio) or using a more aggressive screw configura- tion did not significantly improve the API distribution over the different granule sieve fractions. When fillers with different solubility and dissolution rate were included in the formulations, differences in the distribution of API were detected, but these observations could not be entirely attributed to the solubility properties of the filler. It was hypothesized that the primary particle size of the filler could play a role in the degree of API inhomogeneity.

Therefore, this study aims to gain more knowledge about the effect of filler particle size on the API distribution in CR granules produced via TSWG. Two distinct filler grades with a particle size distribution (PSD) smaller and larger than the API were investigated for water-soluble and water-insoluble fillers. A compartmental analysis was performed to collect granules from the different zones since the granule growth occurs spatially along the granulator barrel (Verstraeten et al., 2017). In addition, the granule growth mechanism along the different zones for all formulations was studied to gain insight about the obtained API distribution. Finally, the effect of filler type on tabletability and drug release profile of tablets produced via CR formulations was studied.

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Materials

Theophylline anhydrous 200 M (Siegfried, Zofingen, Switserland) as API was com- bined with HPMC 90SH-4000SR (substitution type 2208; ShinEtsu, Tokyo, Japan) as hydrophilic matrix former and four different fillers. For each filler, two grades with a dis- tinct PSD were included in the study: a grade with a PSD smaller than theophylline and a grade with a PSD larger than theophylline.

Analysis of filler particle size distributions

The PSDs of the small and large particle size fillers are shown in Fig. 2 and had respectively a slightly smaller (Fig. 2a) and a larger (Fig. 2b) PSD compared to theophylline. In the category of the small particle size fillers, the dicalcium phosphate (DCP) grade (Emcompress Anhydrous Powder) had the smallest PSD and the mannitol grade (Pearlitol 25C) the largest. The microcrystalline cellulose (MCC) grade (Avicel pH 105) had the narrowest PSD (span of 1.90) and the mannitol grade the widest

Phaedra Denduyver, Chris Vervaet, Vaĺerie Vanhoorne, The effect of filler particle size on API homogeneity of controlled release formulations via continuous twin-screw wet granulation, International Journal of Pharmaceutics,
2024, 124990, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124990.

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