Modeling the influence of the microbial loading level of fluidized bed granules on physical–mechanical and microbiological tablet properties

Abstract

In order to be able to administer efficient probiotic formulations, it is necessary to process the respective microorganisms gently into suitable dosage forms such as tablets maintaining their viability. In previous studies, the process chain consisting of fluidized bed granulation for life-sustaining drying of Saccharomyces cerevisiae as well as subsequent processing into tablets was investigated. Granules based on dicalcium phosphate (DCP), lactose (LAC) and microcrystalline cellulose (MCC) as carrier materials were produced and tableted, and physical–mechanical as well as microbiological tablet properties were evaluated. This revealed a carrier material-specific influence of granulation on both physical–mechanical and microbiological tablet characteristics. But the extent, to which this depends on the added cell mass, has not yet been investigated. This is addressed in the present study by examining the influence of the loading of the carriers with different amounts of yeast cells and the measurement of the resulting mechanical properties of the tablets and the survival of the microorganisms. Thereby, material-specific effects of loading on compressibility, compactibility and tabletability, but also on the survival of the yeast cells were found and related to the specific deformation mechanisms. Existing models for describing the physical–mechanical relationships are used, adapted and combined, which enables excellent correlations. In addition, empirical models are developed to describe the survival of the microorganisms during tableting the differently loaded granules.

Introduction

The production of pharmaceutical dosage forms containing living microorganisms is important for the efficient administration of probiotic microorganisms [1]. These are able to provide health benefits to the patient, in particular by interacting with the microbiome [2,3]. The possible mechanisms of action are manifold [4], but the presence of a sufficient dose of microorganisms and their viability is always crucial [2]. Here, it is not sufficient that the viability of the microorganisms is guaranteed during the production of the corresponding preparations, but also during storage until administration and beyond until they reach their target site. Long-term preservation of viability is possible by drying the microorganisms [1,[5], [6], [7], [8]].

However, drying itself is a critical step that can be accompanied by irreversible inactivation [9]. Therefore, gentle drying processes and parameters are required, as well as suitable formulations (protective additives) [9]. Various drying processes have been successfully used for the life-sustaining drying of microorganisms and are reviewed for example by Broeckx et al. (2016) [1]. These include in particular freeze drying, spray drying and fluidized bed drying or fluidized bed spray granulation. These processes are each associated with specific thermal and mechanical stresses on the microorganisms during drying [1]. In earlier studies, Saccharomyces cerevisiae was dried with the aim to maintain its viability [[6], [7], [8]].

Different additives were examined with regard to their effectiveness as protective substances and the combination of trehalose and skimmed milk powder was identified as particularly suitable across all processes [[6], [7], [8]]. Detailed information on their mechanisms can be found in our previously published work [7]. Dried microorganisms can be administered in powder form, e.g. packed in capsules, or in form of tablets. While hardly any critical stresses on the dried microorganisms are expected when filling capsules, tableting is a critical process due to the compression of the powder [10,11]. Nevertheless, the further processing of probiotic microorganisms in this form is often preferred, as the production is comparatively simple and inexpensive, and tablets are easy to handle, have a high dosing accuracy and high patient compliance.

The influence of compression of viable microorganisms was investigated in several studies. A higher compression stress is typically associated with a lower survival rate of the microorganisms [[6], [7], [8], [10], [12], [13], [14], [15], [16]]. However, sometimes only an initial loss of viability until a specific compression stress was reached was found and no further reduction was observed, if this compression stress level was exceeded [17,18] and in other studies even no losses at low compaction stresses [13,19] were reported. Fluidized bed spray granulation is an attractive drying process because granules with good tabletability can be produced when suitable carrier materials are used [7,10,16,20]. Survival of the microorganisms was found to be dependent on the carrier material used [7,10,16,20] and was attributed to the porosity reduction during compression [10,16].

However, it was also found that granulation of the carrier materials with yeast cells and protectants can also negatively influence properties such as compressibility, compactibility and tabletability [10]. The extend to which this depends on the loading has not yet been investigated and is the subject of this study. Similar investigations are published for other material systems [21], but not for living microorganisms. In particular, the simultaneous influence of the cell loading of the granules on survival during tableting is therefore completely unknown but crucial for enabling efficient process design for the manufacture of probiotic tablets. This is being investigated for the first time in this study. For this purpose, granules with different cell loads based on different carrier materials are compacted and the tablets are subjected to physical–mechanical and microbiological characterization. In order to better identify the respective influences, the experimental data is modeled using common models as a starting point for describing the physical–mechanical parameters. If necessary, a brief introduction can be found in the supplementary information. Since hardly models exist for the description of survival during tableting, suitable equations are determined in this work to allow a rational process design with reduced experimental effort in the future.

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Granulation procedure

For the granulation, typical excipients, namely dicalcium phosphate (DCP, DI-CAFOS A150, kindly provided by Chemische Fabrik Budenheim KG, Budenheim, Germany), lactose (LAC, Granulac 70, kindly provided by MEGGLE GmbH & Co. KG, Wasserburg am Inn, Germany) or microcrystalline cellulose (MCC, Vivapur 102, kindly provided by J. Rettenmaier & Söhne GmbH + Co KG, Rosenberg, Germany) were used as carrier material.

The granulation was performed as described previously [10]. In brief, fluidized bed granulation was performed on 1.0 kg scale (Solidlab 2, Syntegon Technology GmbH, Waiblingen, Germany) with an inlet temperature of 50 °C. Deviating from the procedure described before, the yeast cell load was varied by spraying different amounts of the cell suspension. Since the spray rate was kept constant, this was accompanied by corresponding changes in granulation duration. The particle size of the granules, as well as the ungranulated carrier material, was analyzed by dynamic image analysis (QICPIC with GRADIS dispersing unit and VIBRI dosing unit, Clausthal-Zellerfeld, Germany). The analysis was performed in triplicates with a minimum of 100,000 particles analyzed each time. The residual moisture of the granules was calculated based on weight loss after drying for 24 h at 105 °C.

Karl Vorländer, Lukas Bahlmann, Arno Kwade, Jan Henrik Finke, Ingo Kampen, Modeling the influence of the microbial loading level of fluidized bed granules on physical–mechanical and microbiological tablet properties, European Journal of Pharmaceutics and Biopharmaceutics, Volume 216, 2025, 114858, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2025.114858.

Read also our introduction article on Microcrystalline Cellulose here: