An All-Round Excipient For Direct Compression - Pharmaceutical Technology

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An All-Round Excipient For Direct Compression
In the past, many efforts have been made to develop a single excipient that incorporates the properties of a binder, disintegrant and lubricant, and which can also be used for direct compression of an API. Using new co-processing technologies, the authors show that it is possible to formulate such an 'all-round' excipient.


Pharmaceutical Technology Europe
Volume 22, Issue 10


WJONES/GETTY IMAGES.
A classical powder mixture for the direct compression of tablets contains at least a binder and a lubricant, as well as, in some cases, a disintegrant and a glidant. Magnesium stearate is usually used as a lubricant, but this dramatically limits the blending time of a powder mixture,1 and also decreases tablet hardness and retards disintegration time.2 Moreover, magnesium stearate is incompatible with many APIs, mainly because of the electrophilic character of the Mg2+ ion and the basic reaction of the material itself.3,4

In the past, many efforts have been made to develop a single excipient that incorporates binding, disintegrating and lubricating properties, but none of these attempts were successful because of the limitations linked to magnesium stearate. However, new approaches to this challenge have been made possible using more hydrophilic lubricants such as stearic acid, glycerin monostearate and sodium stearyl fumarate.5 Because all of these materials show a higher watersolubility than magnesium stearate, it is easier to coprocess them in aqueous systems. Such lubricants have been used in pharmaceutical technology for many years and the advantages over magnesium stearate are very well known.6


The authors say...
To reduce the number of additives in a formulation and to overcome the problems associated with magnesium stearate, we have developed a coprocessed excipient that acts as a binder, disintegrant, lubricant and a glidant — an 'allround' commercial excipient called the PROSOLV EASYtab. We tested this product both in the laboratory and under production conditions. Overall, we found that this new material gives a much higher tablet output, particularly in highspeed rotary presses. Even at high tabletting speeds, the content uniformity of the coprocessed excipient was better than that of the physical mixture.

Materials and methods

Both, the 'allround' excipient and the physical mixture are composed from a binder (microcrystalline cellulose; VIVAPUR, JRS Pharma), a glidant (colloidal silicon dioxide; Aerosil, Evonik ), a disintegrant (sodium starch glycolate; VIVASTAR, JRS Pharma) and a lubricant (sodium stearyl fumarate; PRUV, JRS Pharma).


Figure 1: Physical mixture of microcrystalline cellulose, colloidal silicone dioxide, sodium starch glycolate and sodium stearyl fumarate. The components differ in appearance and can be easily distinguished. It is obvious that this powder mixture may have segregation. (MCC = microcrystalline cellulose, SSG = sodium starch glycolate, CSD = colloidal silicon dioxide, Lub = lubricant)
Tablets were compressed using a Fette 2090i (Fette Compacting, Germany) highspeed rotary press for the highspeed compression trials. A Schleuniger Pharmatron 8M (Dr. Schleuniger Pharmatron, Switzerland) was used to test tablet hardness. Both, the physical mixture of all four components and the coprocessed 'all-round' material were tested using the Fette 2090i system.


Figure 2: The single all-rounder excipient. The particles look very homogenous. All components from the physical mixture are well integrated.
The use of co-processing technology — a synergistic consolidation of all excipients into one to develop powders for direct compression — is becoming increasingly popular. Coprocessed powders generally give superior properties, mainly in flowability, but also in tablet hardness compared with physical mixtures.7,8 As such, coprocessing was used to manufacture the 'all-round' excipient. The ingredients were co-processed with a coprocessing technology based on a fluidbed granulation, which makes the particles more homogenous and less prone to segregation. Figure 1 and Figure 2 show the appearance of the starting material and the finished excipient, respectively.

The 'all-round' excipient was co-processed to create a medium particle size of 100 µm. The specific surface area was 6.4 m2/g for the co-processed excipient and 3.6 m2/g for the physical blend of the four components. In all trials, paracetamol tablets were pressed with 300 mg weight to a diameter of 13 mm. Tablets from the co-processed excipient contained 60% paracetamol and 40% PROSOLV EASYtab; tablets from the physical mixture were composed of 60% paracetamol, 38.6% of microcrystalline cellulose, 0.8% of colloidal silicon dioxide, 0.4% of sodium starch glycolate and 0.2% of sodium stearyl fumarate.

How is the excipient superior to the physical blend?

The bulk density was 340 g/L. After coprocessing of this physical mixture, the bulk density was 385 g/L. Compared with the physical blend, the coprocessed excipient is more condensed.


Figure 3: Tensile strength versus compression force of paracetamol tablets made using PROSOLV EASYtab and the physical mixture.
Figure 3 shows a comparison of the tensile strength of paracetamol tablets made using the co-processed excipient compared with paracetamol tablets made from the physical mixture of the raw materials. As can be seen from Figure 3, the tablets containing the single excipient demonstrates significantly greater tensile strength than the physical mixture.

For the co-processed excipient, the lubricant is integrated directly into the granulated particle itself rather than simply being free flowing in the powder mixture. This means that no fatty film is formed around the binding particles during blending, which ultimately leads to harder tablets than those made with the physical mixture.


Figure 4: Ejection force versus compression force of paracetamol tablets made using PROSOLV EASYtab and the physical mixture.
Because of the integrated lubricant, the ejection force is lower. Figure 4 shows the different ejection forces between the two paracetamol formulations. The coprocessed excipient shows a much lower ejection force compared with the physical mixture of the four components, which allows for an increase in the speed of the tablet press and a subsequent reduction in production costs. We conducted trials on the high-speed rotary press to test this. As an upper limit for the content uniformity a relative standard deviation of 2.5% was set. This was reached at an output of 240000 tablets/h with the coprocessed excipient and only 80000 tablets/h with the physical blend.9


Figure 5: Tensile strength of paracetamol tablets from the new co-processed excipient EASYtab (blue), the physical mixture lubricated with sodium stearyl fumarate (green), and the physical mixture lubricated with magnesium stearate (red).
The influence of blending time on tablet hardness was also studied. For low dosage formulations, a long blending time is essential for a good content uniformity. When we tested the coprocessed excipient we found that the mixing time did not influence tablet hardness — even after 60 min of mixing, the tablet hardness was the same as after 10 min. This is because the hydrophilic lubricant is implanted into the excipient and, thus, cannot affect the surface of the binding particles. The physical mixture using sodium stearyl fumarate as a lubricant, however, showed that tensile strength decreased with longer blending times. Using magnesium stearate the decrease in hardness was even higher (Figure 5).

In addition, the silicon dioxide, which is used as a glidant in the single excipient, is dispersed around the particles resulting in an increased material surface area. Silcon dioxide in a physical powder mixture produces a lot of dust in the production process. In the coprocessed excipient, the silicon dioxide is fixed on the surface of the particles which reduces the dust significantly.

Conclusion

The EASYtab excipient outperforms the physical mixture of the components in direct compression. It allows fast formulation and development, easy scaleup, because only the API and the single coprocessed excipient have influence on the process. Moreover, with the coprocessed excipient a high production output is achieved because tablets can be produced with high speed on the presses, ultimately lowering production costs. The single, 'allround' excipient also saves costs in the quality control procedure; instead of testing four starting materials only one has to be tested.

Reinhard Vollmer is Head of Technical Competence Center of JRS Pharma (Germany).

Edmont Stoyanov is Senior Scientist at JRS Pharma (Germany).

References

1. A.E. Butcher and T.M. Jones, J. Pharm. Pharmacol., 24, Suppl., 1-9 (1972).

2. J. Kikuta and N. Kimatori, Drug Dev. Ind. Pharm., 20(3), 343–355 (1994).

3. J.L. Ford and M.H. Rubinstein, Drug Dev. Ind. Pharm., 7(6), 675–682 (1981).

4. F.M. McDaid et al., Intern. J. of Pharmaceutics, 252(1-2), 235–240 (2003).

5. W.A. Ritschel and A. Bauer-Brandl, Die Tablette, Auflage 2nd edition (Editio Cantor Verlag; Aulendorf, Germany, 2007) pp 157.

6. A. Hölzer and J. Sjögren, Intern. J. of Pharmaceutics, 2, 145–153 (1979).

7. Y. Gonnissen, J.P. Remon, C. Vervaet, Eur. J. Pharm. Biopharm., 67, 220–226 (2007).

8. R. Christian Moreton, European Pharmaceutical Review, 2(3) (1997).

9. Data on file at JRS Pharma.

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