Direct Compression of Probiotic Tablets with PROSOLV® EASYtab Nutra

Abstract

Although probiotics are mostly administered in the form of capsules, there are some advantages of tablets in terms of production effort, cost efficiency and stability of the probiotic bacteria. As probiotics are sensitive to high pressure and temperature, it is essential to select appropriate excipients for direct compression to ensure sufficient viability of the bacteria cells during production and storage. The aim of this study was to investigate the performance of the high functional excipient PROSOLV® EASYtab Nutra for direct compression of probiotic tablets. As PROSOLV® EASYtab Nutra is an all-in-one composite, only one mixing step is required before the compaction which makes the tableting process easy and comfortable. In order to evaluate the performance of PROSOLV® EASYtab Nutra, the survival rate of the bacteria and functional tablet properties were determined and compared to a lactose-based formulation. The study showed that PROSOLV® EASYtab Nutra is considerably better suited for direct compression of probiotic tablets because of the remarkable survival rate of 91.5 % of the bacteria cells as well as the quick disintegration within 18 seconds, which is almost 10 times faster compared to the lactose formulation. Furthermore PROSOLV® EASYtab Nutra is characterized by excellent compactability and an extremely low friability.

Introduction

There is an increasing demand for probiotic products worldwide and this trend is expected to continue in the following years. The global probiotic market was amounted to more than 34 billion USD in 2015 and an annual growth rate of 8 % from 2015 to 2020 was forecasted. The major applications are probiotic dietary supplements, food and beverages and animal feed probiotics.1,2,3,4 Probiotics were redefined as “live microorganisms, which when administered in adequate amounts, confer a health benefit on the host” by a FAO/WHO expert group in 2001. Probiotics provide a wide range of health benefits, including positive effects on immunological, digestive, and respiratory functions.5 The most common microorganisms used in probiotic formulations are bacteria belonging to the genera of Lactobacillus
and Bifidobacterium, but also yeasts such as Saccharomyces boulardii can be used as probiotics.6,7

As only living bacteria can have beneficial effects, it has to be ensured that the probiotic products contain viable bacteria in large enough numbers.5 The typically used delivery systems in the nutraceutical field are tablets and capsules, which provide increased storage stability compared to liquid preparations due to their low moisture content, as well as their easy and convenient admini-stration.6 Additionally, tablets are less-expensive, easy to manufacture and allow the highest dosage due to the strong compaction.8 However, the high compression forces and temperature increase during tablet production can destroy bacteria, leading to a reduced effectiveness of the probiotic products.6,9 In order to overcome these challenges, particular excipients are required, which are suitable for direct compression of probiotic tablets.

Study Design

The aim of this study was to develop a direct compression formulation for probiotic tablets with a viable cell count of at least 109 cfu per dose unit. As a model probiotic we selected a strain of Bifidobacteria, which is widely used in dietary supplements due to its positive impact on intestinal health and immune system. In order to reduce the mechanical stress for the sensitive probiotics and thus to improve the survival rate during manufacture, we chose PROSOLV® EASYtab Nutra, which is a high functional excipient especially for nutraceutical applications. The performance of
PROSOLV® EASYtab Nutra in probiotic tablets was compared to standard spray-dried lactose, which is also suitable for direct compression. Therefore, tablets with a crushing strength of 80 N were pressed and evaluated in terms of viability of the Bifidobacteria.

Further tested parameters were the compactibility and water activity of the powder mixture, as well as functional tablet characteristics, such as friability and disintegration.

Ingredients and Compactability

Selected Ingredients

The probiotic Bifidobacterium strain BB-12® (Bifidobacterium animalis subsp. lactis) was provided by Chr.
Hansen (Hoersholm, Denmark). The BB-12® bacteria cells were preserved by lyophilization, resulting in reduced water activity and therefore improved stability and viability of the bacteria.⁶ Numerous clinical studies and scientific publications have proven the beneficial effects of BB-12® on intestinal health and immune system, including a reduced risk of an upset stomach, improvement of the immune response, reduced respiratory tract infections, support of bowel function and alleviation of skin irritations.

PROSOLV® EASYtab Nutra is an all-in-one excipient, specifically developed for the nutraceutical industry. It
is composed of four components: microcrystalline cellulose as a binder, colloidal silicon dioxide as a glidant, crosscarmellose as a disintegrant, and saturated vegetable oil as a lubricant. The special coprocessing leads to a homogeneous distribution of the four components and synergistic effects in terms of functional performance. Because of the excellent compaction properties of PROSOLV® EASYtab Nutra it is possible to manufacture mechanically robust tablets at low compression forces resulting in reduced mechanical stress for sensitive ingredients such as probiotic bacteria. As PROSOLV® EASYtab Nutra is a ready-to-use composite, only one mixing step with the active is required before the compression process leading to a convenient and cost-e􀅨cient tableting process.

Lactose is widely used as a filler and diluent in solid dosage forms such as tablets and capsules11. For this study, we used spraydried lactose, which is characterized by its exceptional compactability compared to other lactose grades. Therefore, it is particularly suitable for direct compression applications.

Results and Discussion

Correlation between compaction force and viability

As outlined before, probiotics are sensitive to pressure, to which the microorganisms are exposed during tablet
manufacture. High compaction forces may damage the bacteria cells and therefore decrease their viability drastically depending on the robustness of the strain. Fig. 1 shows the correlation between the compaction force and the viability of the probiotic strain BB-12®.

Already at a moderate compression force of 10 kN only 63 % of the probiotic survived the tableting process. In order to maintain the viability of the probiotics at the best possible rate, an excipient with excellent compactibility is required, which enables suffcient tablet hardness at low compression forces.

Compactability of Single Ingredients

The compactability of each ingredient was evaluated by manufacturing placebo tablets at different compaction
forces (500 mg, 13 mm). The BB-12® itself was characterized by good flowability, but poor compactability. At a compaction force of 13 kN, the pure probiotic tablets showed insufficient crushing strength of 35 N. Furthermore,
the BB-12® powder is slightly sticky and therefore not suitable for direct compression in its pure form. A comparison of the selected excipients showed that PROSOLV® EASYtab Nutra provides considerably better compactability than the spray-dried lactose (Fig. 2).

In order to produce tablets with a crushing strength of 80 N, a compaction force of about 4 kN was necessary in case of PROSOLV® EASYtab Nutra . However, in the case of spray-dried lactose, a compaction force of about 19 kN was required, which is nearly fivefold the mechanical stress compared to the PROSOLV® EASYtab Nutra formulation. This indicates that probiotic tablets, produced with PROSOLV® EASYtab Nutra, may provide a higher survival rate of the bacteria cells than lactosebased tablets with the same crushing strength. The results of the study, which are shown below, confirm this hypothesis.

Evaluation of Probiotic Powder Mixture and Tablets

Two different formulations with 20 % of probiotic powder BB-12® were compacted into 500 mg tablets, corresponding to a theoretical bacterial count of about 1010 cfu per tablet. Formulation 1 contained spray-dried lactose as a binder, VIVASOL® GF LM (crosscarmellose, food grade, E 468) as a disintegrant, and magnesium stearate as a lubricant (Tab. 1). In formulation 2 the high functional excipient PROSOLV® EASYtab Nutra was used, which makes the use of further excipients unnecessary as PROSOLV® EASYtab Nutra itself includes a disintegrant and a lubricant. The water activity (aW) of both formulations showed appropriate values of 0.26 (PROSOLV® EASYtab Nutra) and 0.13 (spray-dried lactose) (Tab. 2). At higher aW values, the probiotics may be damaged due to undesired enzymatic processes; a
too low aW below 0.1 may also cause irreversible damage to the bacteria cells.12

The PROSOLV® EASYtab Nutra formulation resulted in a considerably higher survival rate of 91.5 % compared to
the lactose formulation, which had a viable cell count of 58.4 % after compaction (Tab. 2). This may be caused by the much better compactability of the PROSOLV® EASYtab Nutra formulation. In order to achieve a crushing strength of 80 N, a compression force of 9.8 kN was required in case of the PROSOLV® EASYtab Nutra formulation. Because of the lower compression force, the PROSOLV® EASYtab Nutra tablets had a more porous structure, leading to sufficient space for the microorganisms to survive (Pic. 1, left). In contrast, in the case of the lactose formulation, a compression
force of 30.5 kN was necessary to press tablets with a crushing strength of 80 N, resulting in a very dense and compact structure without much space for the probiotic bacteria (Pic. 1, right). An additional advantage of the porous structure is the much quicker tablet disintegration. The PROSOLV® EASYtab Nutra tablets disintegrate within 18 seconds and thus, almost 10 times faster than the lactose-based tablets. Furthermore, the PROSOLV® EASYtab Nutra tablets had a lower friability compared to the lactose tablets demonstrating the high robustness of PROSOLV® EASYtab Nutra (Tab. 2)

 

Conclusion

The high functional excipient PROSOLV® EASYtab Nutra is ideally suited for the manufacture of probiotic tablets containing the bacteria strain BB-12® because of its superiority over the lactose formulation in terms of survival rate of the probiotics, compactibility and further tablet characteristics, such as disintegration time and friability. In particular, the PROSOLV® EASYtab Nutra tablets are characterized by:

• Exceptionally high survival rate of over 90 %
• Excellent compactability, resulting in good tablet hardness at moderate compression forces
• Fast disintegration
• Low friability
• Appropriate water activity for usage in probiotic applications

Further advantages are the simple processing of PROSOLV® EASYtab Nutra with only one mixing step before the tablet compaction and the reduction of energy costs and tooling abrasion, as only moderate compression forces are necessary in order to form mechanically stable tablets.
In conclusion, PROSOLV® EASYtab Nutra is extremely well suited for direct compression of probiotic tablets because of the very high survival rate of bacteria cells during compaction and the excellent functional tablet parameters.

See the JRS whitepaper on Direct Compression of Probiotic Tabletswith PROSOLV® EASYtab Nutra:

 

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