«Dissertation Zur Erlangung des Doktorgrades der Naturwissenschaften Der Fakultät für Mathematik, Informatik und Naturwissenschaften der ...»
Tableting properties of silica aerogel and other silicates 45 Another silicate with exceptional properties is Neusilin® US2, a synthetic amorphous form of magnesium aluminometasilicate which is prepared by spray drying and thus provides an extremely large specific surface area and good flow and tableting properties. Co-grinding and preparation of solid dispersions with Neusilin® leads to a physical stabilization of amorphous drugs [57, 133] and thus enhanced drug release from formulations with these drugs [134-137]. The high porosity and large specific surface area of Neusilin® allow a high liquid adsorption capacity . This may be of interest especially for the preparation of solid oral dosage forms such as liquisolid compacts  and solid self-emulsifying drug delivery systems which both show fast drug release [139-141].
Co-grinding of drugs with Florite®, a calcium silicate  with large micropores and excellent tabletability, also leads to a physical stabilization of amorphous drugs with enhanced drug release . Moreover, it has been shown that this silicate is also suitable for adsorption of liquid  such as self-emulsifying drug delivery systems [139, 140] or liquid drugs.
However, in comparison to the application as glidant, the use of silicates as carrier materials requires higher amounts of silicate, ultimately leading to dosage forms containing just the drug adsorbed to the silicate. Therefore, as tablets represent widely used dosage forms, the objective of this study was to investigate the physical and tableting properties of the aforementioned silicates. As it was known from preliminary experiments that plain Aerosil® does not result in tablets of sufficient hardness, blends of microcrystalline cellulose and the respective silicate were prepared with varying silicate concentration.
Tableting properties of silica aerogel and other silicates 46
3.2 Materials and methods Materials Neusilin® Hydrophilic Silica Aerogel monoliths ; US2 (magnesium aluminometasilicate), Fuji Chemical Industry, Toyama, Japan; Aerosil® 200 (colloidal silica), Evonik, Darmstadt, Germany; Florite® (calcium silicate), Tokuyama, Tokyo, Japan; Avicel® PH102 (microcrystalline cellulose), FMC BioPolymer, Cork, Ireland;
Magnesium stearate, Baerlocher, Unterschleissheim, Germany. All other reagents used were of analytical grade.
Methods Preparation of Silica Aerogel Microparticles Hydrophilic Silica Aerogel monoliths prepared as described by Alnaief et al.  were milled with mortar and pestle and subsequently classified using a sieve shaker (AS 200, Retsch, Haan, Germany). A fraction of Aerogel particles between 63 µm and 160 µm mesh was selected for further investigation.
Determination of the specific surface area of the silicates
The specific surface area (SSA) of the silicates was quantified by gas adsorption using a Sorptomatic 1990 (Carlo Erba Instruments, Rodano, Italy). The samples were degassed under vacuum for 24 h and exposed to nitrogen at 77.4 K. According to the Brunauer-Emmet-Teller (BET) equation  the specific surface area of the silicates was determined within a relative pressure range p/p0 between 0.05 and 0.3. Surface areas were measured in triplicate.
Determination of the particle size of the silicates
The particle size distribution of the samples was determined in triplicate by laser diffraction using a dry dispersing system with a feeding air pressure of 1 bar (HELOS equipped with RODOS, Sympatec, Clausthal-Zellerfeld, Germany).
Tableting properties of silica aerogel and other silicates 47
Determination of the true density of the silicates
The true density of the silicates was determined in triplicate by helium pycnometry using a 10 cm³ sample cup equipped with a fritted filter cap (Accupyc 1330, Micromeritics, Aachen, Germany). Prior to testing the silicates were dried for 5 days over phosphorus pentoxide. Each measurement included 10 purge cycles followed by 10 measuring cycles.
Scanning electron microscopy of the silicates The silicates were coated with a thin carbon layer and analyzed using a LEO 1525 scanning electron microscope (LEO Elektronenmikroskopie, Oberkochen, Germany) at an accelerating voltage of 5 kV.
Determination of the moisture sorption isotherms The dynamic water sorption of the silicates was determined automatically by an adsorption test system (SPS 11, Projekt Messtechnik, Ulm, Germany) at 25 °C.
Approximately 200 mg of the silicates were equilibrated at 60 °C and 0 % R.H. for 48 h in the test apparatus prior to testing. The relative humidity range was 0 – 90 % R.H. in steps of 10 % each. At each humidity step, the samples were allowed to equilibrate until a weight change of 0.01 % / 30 min was reached.
Preparation of the tablets
Various powder blends with varying silicate concentration were prepared with Avicel® and the respective silicate. The ingredients were mixed for 5 min in a Turbula blender (T2F, Willy A. Bachofen, Muttenz, Switzerland) and compacted to tablets with an instrumented eccentric press (EXI, Fette, Schwarzenbek, Germany) equipped with flat faced punches of 10 mm diameter. External lubrication was performed by polishing the surface of the upper and lower punch as well as the die wall with magnesium stearate.
300 mg of the powder blends were filled manually into the die and compacted at a compaction speed of 16 strokes / min. For tablets consisting of 100 % silicate only 160 mg were compacted. All experiments were performed at 21 °C / 45 % R.H..
Tableting properties of silica aerogel and other silicates 48
Characterization of the tablets
Tablets were characterized after a relaxation time of at least 24 h. Crushing force, tablet diameter, and tablet thickness were determined using a hardness tester (TBH30, Erweka, Heusenstamm, Germany). The tensile strength was calculated according to Fell et al. . Tabletability was characterized by plotting the tensile strength versus the compaction pressure. For generation of the Heckel plot the porosities of the tablets at maximum compaction pressure in the die were used [112, 113]. From the Heckel plot the mean yield pressure, which represents the reciprocal value of the slope, may be determined .
Tableting properties of silica aerogel and other silicates 49
3.3 Results and discussion Characterization of the silicates The physical properties and the SEM pictures of the silicates are shown in Table 7 and Fig. 9, respectively. The specific surface area (SSA) and the structure of the investigated silicates differed significantly from each other. Florite® with its petaloid crystal structure and large micropores exhibited the smallest SSA which is slightly lower than that of Aerosil® with its loose particle aggregates. Neusilin® which is prepared by spray drying resulting in spherically shaped, porous, ultra light granules showed an almost 1.5 fold larger SSA than Aerosil®. The largest SSA by far was found with the Silica Aerogel. This extremely large SSA and the nano-sized open pore structure of Aerogels result from their unique manufacturing process .
Fig. 9: SEM pictures of the silicates
The mean particle size of Neusilin® was found to be twice larger than that of Florite®.
The particle size determined with Aerosil® represents the size of the loose aggregates formed by the nanometer-sized primary particles. The particle size of the Silica Aerogel microparticles was a result of the milling and sieving procedure of the Silica Aerogel monoliths. In contrast to Neusilin® and Silica Aerogel, Florite® and Aerosil® did not show free flowability due to their very small particle size and the resulting high cohesive forces . Moreover, the spherical shape of Neusilin®, a result of its Tableting properties of silica aerogel and other silicates 50 manufacturing process, supports good flowability. Recently, Alnaief et al.  developed the in situ production of spherical Aerogel microparticles which show even better flowability than the milled Aerogel microparticles due to their spherical shape.
True densities of the silicates were similar, whereat Aerosil® exhibited the highest and Silica Aerogel the lowest value.
Table 7: Physical properties of the silicates (means ± SD; n = 3)
In Fig. 10 the moisture sorption isotherms of the silicates are shown. Aerosil® and Florite® showed a relatively low moisture sorption over the whole range of investigated R.H., whereas Neusilin® and Silica Aerogel showed a pronounced moisture uptake beyond 70 % R.H.. Whereas Aerosil® and Florite® adsorbed only 11 and 17 % water vapor, respectively, Neusilin® and Silica Aerogel adsorbed 74 and 101 %, respectively, at 90 % R.H.. From these results it may be concluded, that the use of Neusilin® and Silica Aerogel require specified processing conditions. This is especially important for the extremely humidity-sensitive hydrophilic Aerogel, because high moisture results in a collapse of its porous structure and thus a loss of its characteristic properties.
Tableting properties of silica aerogel and other silicates 51 Fig. 10: Moisture sorption isotherms of the silicates Tableting properties of the silicates The influence of the silicate concentration on the tabletability of the investigated Avicel® / silicate powder blends is shown in Fig. 11. Obviously, the tableting properties of the powder blends were affected differently by the increase in silicate concentration.
The tensile strength of the Aerogel and Aerosil® compacts continuously decreased with increasing silicate concentration (Figs. 11a, b), whereas this decrease was more pronounced with Aerosil® than with Aerogel tablets. The tableting properties of Neusilin® blends remained unaffected by the addition of silicate (Fig. 11c) even up to a silicate concentration of 100 % (= plain Neusilin®). In contrast, according to the data shown in Fig. 11d the tensile strength of Florite® tablets increased with rising silicate concentration resulting in extremely hard tablets: for the manufacture of a sufficiently hard tablet with a tensile strength of 1.5 MPa a compaction pressure of less than 15 MPa is required with plain Florite®.
Tableting properties of silica aerogel and other silicates 52 Fig. 11: Tabletability of the Avicel® / silicate powder blends with varying silicate concentrations (means ± SD; n = 6)
a) Aerogel, b) Aerosil®, c) Neusilin®, d) Florite® These results show that even the plain silicates Neusilin®, Florite® and Aerogel can be compacted to tablets of acceptable tensile strength of 1.5 MPa. With Aerosil® blends a silicate concentration of up to 20 % resulted in a sufficient tensile strength at a compaction pressure of 100 MPa. Blends containing a silicate concentration of 30 % could not be compacted to tablets even at high pressures of 200 MPa.
To characterize the deformation process of the powder blends, the Heckel plot was recorded. The Heckel plot is used to determine the plastic deformation characteristics of a powder blend to be compacted [115, 116]. A high slope and thus a low mean yield pressure represent a high degree of plastic deformation . The Heckel plots of the investigated blends are shown in Fig. 12.
Tableting properties of silica aerogel and other silicates 53 Fig. 12: Heckel plots of the Avicel® / silicate powder blends with varying silicate concentrations (means ± SD; n = 6)
a) Aerogel, b) Aerosil®, c) Neusilin®, d) Florite® It is obvious with all blends that the slope of the Heckel plot decreases with increasing silicate concentration indicating a loss of plastic deformation behavior. However, this decrease was pronounced differently with the respective silicate blends. The influence of the silicate concentration on the mean yield pressure is displayed in detail in Fig. 13 for the different silicate blends.
Avicel® as microcrystalline cellulose shows a high degree of plastic deformation  manifesting itself in a low mean yield pressure (50 MPa). The addition of silicate led to a reduction of plastic deformation of the blends, which was most pronounced with Aerosil®, followed by Silica Aerogel and Neusilin®, whereas the addition of Florite® showed the lowest reduction. A relationship was found for the investigated silicates
between the tensile strength of the tablets and the mean yield pressure (Figs. 11, 13):
the higher the mean yield pressure and thus the lower the degree of plastic Tableting properties of silica aerogel and other silicates 54 deformation, the lower the resulting tablet hardness. Hardest tablets were obtained with Florite® which exhibited the lowest mean yield pressure, followed by Neusilin® and Aerogel, whereas tablets containing Aerosil® showed the highest mean yield pressure resulting in the lowest tablet strength.
Fig. 13: Influence of the silicate concentration on the mean yield pressure of the Avicel® / silicate powder blends However, the results also show that in addition to plastic deformation other bonding mechanisms within the silicates must be present. For instance, the tensile strength of Florite®-containing tablets was higher than that of plain Avicel® tablets although the mean yield pressure increased slightly with rising Florite® concentration. Further possible bonding mechanisms are mechanical interlocking of irregular particles, forces of attraction including Coulomb forces, hydrogen bonds, and van der Waals forces [145, 146].
Tableting properties of silica aerogel and other silicates 55
The physical properties and the structures of the investigated silicates differed significantly from each other. Silica Aerogel exhibited by far the largest specific surface area and Florite® the lowest. Silica Aerogel and Neusilin® showed free flowability due to the larger particle size in comparison to Florite® and Aerosil®. Moreover, Neusilin® and Silica Aerogel were more sensitive to moisture sorption than the other investigated silicates. The tabletability of the silicates improved in the following order: Aerosil® Silica Aerogel Neusilin® Florite®, whereas plastic deformation of all powder blends decreased with increasing silicate concentration. It was shown that compaction of plain Silica Aerogel, Neusilin® and Florite®, respectively, result in acceptable tablet hardness. Thus, these silicates are most suitable as tableting excipients, e.g. as carrier materials for liquid drugs or for amorphisation of drugs.