Influence of compression kinetics during tableting of fluidized bed-granulated microorganisms on microbiological and physical-mechanical tablet properties.

As tablets are convenient to administer to patients, ensure safe dosing and allow cost-effective production on a large scale, they are the favored dosage form for numerous active pharmaceutical ingredients but also for the administration of viable probiotic microorganisms. Granules with viable yeast cells (Saccharomyces cerevisiae) formed by fluidized bed granulation with dicalcium phosphate (DCP), lactose (LAC) or microcrystalline cellulose (MCC) as carrier materials were tableted using a compaction simulator. Besides the compression stress, the compression speed was systematically studied by varying consolidation time and dwell time. The microbial survival as well as physical properties of the tablets, e.g., porosity and tensile strength, were determined. Higher compression stresses result in lower porosities. While on the one hand this has a detrimental effect on microbial survival (due to increased pressure and shear stress during particle rearrangement / densification), on the other hand it results in higher tensile strengths. At the same compression stress, a prolonged dwell time resulted in lower porosity and thus in lower survival rates but higher tensile strength. Against that, consolidation time showed no significant influence on the considered tablet quality attributes. Since changes of the tensile strength related survival rate were negligible (due to opposite but balancing dependence on porosity), high production speeds could be used for tableting of these granules without additional loss of viability, as long as tablets with the same tensile strength are produced.

Tableting of fluidized bed granules containing living microorganisms.

Tablets are the favored dosage form for numerous active pharmaceutical ingredients, among others because they are easy to take, ensure safe dosing and allow cost-effective production on a large scale. This dosage form is also frequently chosen for the administration of viable probiotic microorganisms. Saccharomyces cerevisiae cells granulated in a fluidized bed process, with dicalcium phosphate (DCP), lactose (LAC) and microcrystalline cellulose (MCC) as carrier materials, were tableted using a compaction simulator, varying the compression stress. The tablets were analyzed regarding physical properties, e.g., porosity and tensile strength, as well as microbial survival. Carrier material and compression stress showed a significant influence on survival rate and physical tablet properties. The dependencies were related to material specific deformation characteristics and linked to mechanistic approaches to explain the different sensitivities.

Effect of Process Parameters, Protectants and Carrier Materials on the Survival of Yeast Cells during Fluidized Bed Granulation for Tableting.

The administration of living microorganisms is of special interest, with regard to probiotic microorganisms providing health benefits to the patient. Effective dosage forms require the preservation of microbial viability until administration. Storage stability can be improved by drying, and the tablet is an especially attractive final solid dosage form due to its ease of administration and its good patient compliance. In this study, drying of the yeast Saccharomyces cerevisiae via fluidized bed spray granulation is investigated, as the probiotic Saccharomyces boulardii is a variety of it. Fluidized bed granulation enables faster drying than lyophilization on the one hand and lower temperatures than spray drying on the other hand, which are the two predominantly used techniques for life-sustaining drying of microorganisms. Yeast cell suspensions enriched with protective additives were sprayed onto the carrier particles of common tableting excipients, namely, dicalcium phosphate (DCP), lactose (LAC) and microcrystalline cellulose (MCC). Different protectants, such as mono-, di-, oligo- and polysaccharides, but also skimmed milk powder and one alditol, were tested; as they themselves, or chemically similar molecules, are known from other drying technologies to stabilize biological structures such as cell membranes, and thus, improve survival during dehydration. With the combined use of trehalose and skimmed milk powder, survival rates were 300 times higher than without the use of protective additives. In addition to these formulation aspects, the influence of process parameters such as inlet temperature and spray rate were considered. The granulated products were characterized regarding their particle size distribution, moisture content and the viability of the yeast cells. It has been shown that thermal stress on the microorganisms is especially critical, which can be reduced, for example, by reducing the inlet temperature or increasing the spray rate; however, formulation parameters such as cell concentration also influenced survival. The results were used to specify the influencing factors on the survival of microorganisms during fluidized bed granulation and to derive their linkages. Granules based on the three different carrier materials were tableted and the survival of the microorganisms was evaluated and linked to the tablet tensile strength achieved. Using LAC enabled the highest survival of the microorganisms throughout the considered process chain.