Susanne Florin Muschert, University of Lille
Tablet fabrication at low compaction pressures, the so-called “soft-tableting” is necessary to assure the effectiveness of treatments with pressure sensitive active ingredients [1], such as probiotics. Excipients like fillers with binding capacities during direct compression, offer the possibility to lower compaction forces and to obtain sufficient tablet hardness, low porosity and guarantee high probiotic survival [2]. The objective of the study was to identify suitable filler/binder excipients for soft tableting of Bifidobacterium longum.
Powder blends of 1 % magnesium stearate and several filler/binder (Ludiflash, Avicel PH302 & PH200 NF, Flowlac 100, Neosorb XTAB 200S, microcrystalline cellulose (MCC) 200L M, GalenIQ 720 & 721, Pearlitol 200SD, Prosolv SMCC 90 & HD 90, Emdex NON-GMO & Combilac) under optional addition of 10 % Bifidobacterium longum (freeze-dried powder, Lallemand, France) and/or 1, 3, 10 or 20 % Hydroxypropylcellulose (Klucel EXF) as a dry-binder, were prepared and directly compressed into tablets with a fully instrumented benchtop tablet press (Styl’One Nano, Medelpharm), equipped with flat-faced punches (diameter: 11.28 mm) at a compression speed of 10 mm/s and a fill shoe agitation of 10 Hz (optionally under inert nitrogen atmosphere). The mass of the tablets was kept constant at 500 mg and their hardness analyzed according to the Ph.Eur. (Schleuniger 5Y). Particle sizes of starter material were measured with the laser diffraction method (Mastersizer S, Malvern Panalytical) in air dispersion. Compressibility was evaluated with the in-die Heckel analysis (porosity against compaction pressure profile). Bacterial suspensions were obtained after dispersion of the tablets in 10 mL of phosphate-buffered saline, pH 7.4, ten-fold serial dilutions until 10-9 were prepared. 1 mL of each dilution was transferred into 3 Petri dishes and 20 mL culture media CM 151 Reinforced Clostridial Agar (Oxoid, UK) were tested. plates were anaerobically incubated at 37 °C for 48 h. and the colony forming units (CFU) per plate were counted.
The compressibility was evaluated by porosity versus applied pressure profiles and amongst the studied excipients the most promising compressibility was observed with both Prosolv types and Neosorb XTAB 200S. They were followed amongst others by Avicel PH200 NF, GalenIQ 720 and Avicel PH302 & Flowlac 100. The Heckel diagrams (-lnε as a function of compression pressure) the Heckel coefficient, (K) and its reciprocal value the yield pressure (Py), were determined via linear regression of the slope in the corresponding diagrams. Both K and Py describe the material’s compressibility or plastic deformation. Low values of Py and thus high values of K express better powder compressibility and higher plasticity. This analysis helped to further narrow down the selection of most suitable soft-tableting excipients. Generally, the addition of 10 % probiotic B. longum powder resulted in a very slight variation in compressibility. The compressibility profiles with & without 10 % B. longum addition show that the excipients mainly provide the compressibility and that their nature impacts the latter in a higher extend, compared to an addition of 10 % probiotic powder. Klucel EXF has been added to promising fillers in order to further improve tabletability. However, increasing binder amounts increased disintegration time and also the risk of powder sticking to the punches as observed here with Ludiflash based blends at high compression pressures.
Four promising formulations have been tested towards viable cells of B. longum after compression, based on Neosorb XTAB® 200S, Prosolv SMCC 90 & Avicel PH200 NF under binder addition. In all cases high amounts of viable material were found, with slightly lower values for tablets with slower disintegration due to high binder contents (Avicel PH200 NF + 20 % Klucel EXF). This shows the efficacy of the approach in general and of the identified filler/binder excipients to prevent B. longum from stress induced cell death.
REFERENCES:
1. Picker KM. Pharm Dev Technol. 2004;9(1):107-21. doi
2. Klayraung S, Viernstein H, Okonogi S. Int J Pharm 2009;370, 54-60. doi