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«Dissertation Zur Erlangung des Doktorgrades der Naturwissenschaften Der Fakultät für Mathematik, Informatik und Naturwissenschaften der ...»

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Flow properties of the excipients were determined by measurement of the Hausner ratio and the powder flow rate. The Hausner ratio was calculated as the quotient of tap and bulk density. Bulk and tap densities were determined with a jolting volumeter (STAV 2003, J. Engelsmann, Ludwigshafen, Germany) according to the Pharmacopoeia Europaea. The mass-related powder flow rate in [g/s] was measured with a funnel (orifice diameter 7 mm) by recording the weight change over time with a precision balance (BL 1500 S, Sartorius, Göttingen, Germany). The volume-related powder flow rate in [cm³/s] was calculated as the quotient of the mass-related powder flow rate and the bulk density.

Tableting of the excipients

Tablets were prepared with an eccentric press (EXI instrumented with strain gauges and displacement transducer, Fette, Schwarzenbek, Germany) equipped with flat faced punches of 10 mm diameter. Tablet weight was adjusted to approximately 350 mg for the microcrystalline celluloses and 450 mg for the dicalcium phosphates.

Compaction speed was set to 16 rpm. All experiments were performed at 21 °C / 45 % R.H..

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. [109-111]. Tabletability of the excipients was evaluated by plotting the tensile strength versus the compaction force. From the Heckel plot [112, 113], i.e. the relationship between the logarithm of the reciprocal porosity and the compaction pressure, the mean yield pressure, which represents the reciprocal slope of the linear portion of the compression curve, was determined [114]. For determination of the mean yield pressure a pressure range from 50 to 120 MPa was Comparison of traditional and novel tableting excipients 34 selected for the microcrystalline celluloses and from 70 to 120 MPa for the dicalcium phosphates, respectively. The quantification of the mean yield pressure of each excipient included 10 measurements.

Investigation of the magnesium stearate sensitivity of the excipients For the investigation of lubricant sensitivity magnesium stearate at concentrations of 0.5, 1, 2 % [w/w] for MCC, SMCC, SGADCP and 1, 1.5, 2 % [w/w] for ADCP was added to the excipients by mixing in a Turbula blender for 5 min at 72 rpm. In this case compaction was performed with a rotary press (XL100, Korsch, Berlin, Germany) instrumented with strain gauges and equipped with flat faced punches of 10 mm diameter. Compaction speed was set to 20 rpm. Tabletability of the excipients was evaluated as described in the above mentioned subchapter.

Comparison of traditional and novel tableting excipients 35

2.3 Results and discussion Physical properties of the excipients The physical properties of the investigated excipients are shown in Table 5. It is obvious that the true densities of the microcrystalline celluloses are significantly lower than those of the dicalcium phosphates. The particle size of MCC was comparable to that of SMCC, whereas ADCP exhibited a 1.5 fold larger particle size than SGADCP.

The SSAs of the traditional and the novel excipients differed significantly from each other. Due to the silification process (SMCC) and the unique manufacturing process (SGADCP) [106] these novel excipients showed a much larger SSA: the SSA of SGADCP was more than 1.5 fold larger than that of ADCP with 20.7 m²/g, whereas the SSA of SMCC was more than 4 fold larger than that of MCC with 1.2 m²/g. This increased SSA of the novel excipients offers the possibility of special applications such as adsorption and uptake of liquids [107].

Table 5: Physical properties of the investigated excipients (means ± SD, n = 3)

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Flowability of the excipients The flowability of the excipients is shown in Table 6. Except for ADCP all bulk and tap densities of the excipients were similar. In contrast to the true densities of the dicalcium phosphates (Table 5), the bulk as well as tap densities of ADCP and SGADCP differed significantly from each other. The lower bulk and tap densities of Comparison of traditional and novel tableting excipients 36 SGADCP, which are comparable to those of MCC and SMCC, may be explained by its porous structure. SMCC showed no improvement in flow compared to MCC: neither a lower Hausner ratio, nor a higher powder flow rate was observed. Because of its spherical shape SGADCP exhibited better flowability compared to ADCP manifesting itself in a lower Hausner ratio and a higher volume-related powder flow rate. Due to its porous structure the mass-related powder flow rate of SGADCP is lower than that of ADCP.

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Tableting properties of the excipients In Fig. 6 the tabletability of the investigated excipients is shown. As expected, all excipients show an increase in tensile strength with increasing compaction force.

However, the tensile strength of the excipient compacts differed significantly from each other. For instance, at a compaction force of 10 kN, SMCC tablets showed a tensile strength of about 7 MPa, MCC tablets about 5 MPa, SGADCP tablets about 3 MPa, and ADCP tablets about 0.5 MPa. This means, that both novel excipients (SMCC and SGADCP) led to improved tabletability resulting in harder tablets in comparison to their Comparison of traditional and novel tableting excipients 37 traditional counterparts. The low tensile strength of ADCP tablets results from the poor binding properties of this dicalcium phosphate.





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To characterize the deformation process of the excipients, Heckel plots were recorded.

The Heckel plot is used to determine the plastic deformation properties of a powder to be compacted [115, 116]. A high slope of the linear portion of the compression curve and thus a low mean yield pressure represent a high degree of plastic deformation [114, 117]. The Heckel plots of the investigated excipients are shown in Fig. 7. It is obvious that the Heckel plot of MCC is similar to that of SMCC and the Heckel plot of ADCP is similar to that of SGADCP.

Comparison of traditional and novel tableting excipients 38 Fig. 7: Heckel plots of the investigated excipients (n = 1) compression curve: MCC, SMCC, ADCP, SGADCP decompression curve: no symbols The determination of the mean yield pressure resulted in a coefficient of determination R² of at least 0.998 in all cases. MCC exhibited a mean yield pressure of 79 ± 3 MPa, SMCC of 97 ± 1 MPa, ADCP of 440 ± 9 MPa, and SGADCP of 342 ± 5 MPa. It is apparant that the mean yield pressure of MCC and SMCC is much lower than that of ADCP and SGADCP. This confirms the plastic deformation properties of microcrystalline cellulose and the brittle fracture of anhydrous dicalcium phosphate [118-121].

Moreover, with the Heckel plot the degree of elastic deformation characteristics of a powder may be determined [122, 123]. High elastic energy causes a breaking of bonds and an increase of tablet porosity, which results in a reduced tensile strength of the tablets ultimately leading to capping [124]. Thus, a low elastic energy is favorable.

In contrast to the decompression curves of ADCP and SGADCP, those of MCC and SMCC were highly bent indicating a high degree of elastic recovery of the tablets [125]. As the decompression curves of ADCP and SGADCP were almost parallel to the x-axis, tablets of dicalcium phosphate did not show elastic recovery.

Comparison of traditional and novel tableting excipients 39

Magnesium stearate sensitivity of the excipients

The negative effect of magnesium stearate on the tabletability of powders is well known [126]. Film formation of the lubricant occurs during mixing, which causes a reduction of the interparticle bonding [127].

The influence of the magnesium stearate concentration on the tabletability of the respective excipients is shown in Fig. 8. The tensile strength of MCC and SMCC compacts decreased with increasing lubricant concentration (Figs. 8a, 8b). However, this lubricant sensitivity was less pronounced with SMCC than with MCC. The tableting properties of ADCP and SGADCP remained almost unaffected by addition of magnesium stearate (Figs. 8c, 8d). This may be explained by the different deformation properties of these excipients as described in the above mentioned subchapter: MCC and SMCC as microcrystalline celluloses show plastic deformation [128] whereas fragmentation is the main deformation mechanism of the dicalcium phosphates ADCP and SGADCP [105, 119]. Magnesium stearate as film forming lubricant causes a reduction of the interparticle bonding and thus the tensile strength of tablets consisting of plastically deforming compounds decreases with increasing magnesium stearate concentration. In contrast, with brittle excipients new contact areas free from magnesium stearate are formed during compaction and thus, the lubricant does not influence the tensile strength of these materials.

Comparison of traditional and novel tableting excipients 40 Fig. 8: Influence of magnesium stearate concentration on the tabletability of the investigated excipients (means ± SD, n = 10)

a) MCC, b) SMCC, c) ADCP, d) SGADCP Comparison of traditional and novel tableting excipients 41

2.4 Conclusion SMCC (Prosolv®) did not show improved flow properties in comparison to MCC (Avicel®), whereas the spherically shaped SGADCP (Fujicalin®) exhibited better flowability compared to ADCP (Anhydrous Emcompress®). The investigated novel tableting excipients showed better tableting properties than their traditional counterparts: harder tablets could be obtained at similar compaction forces. With the Heckel plot plastic deformation was confirmed as deformation property for the two types of microcrystalline cellulose and brittle fracture for the two types of dicalcium phosphate. Moreover, the two dicalcium phosphates did not show magnesium stearate sensitivity as observed with the two investigated microcrystalline celluloses.

Furthermore, the increased specific surface area of these novel excipients offers the option of special applications such as uptake of liquids.

Tableting properties of silica aerogel and other silicates 42

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Tableting properties of silica aerogel and other silicates Abstract In solid oral dosage forms silicates are commonly used as glidants in low concentration. However, due to their large specific surface area, silicates may also be used as carrier materials for drugs. Moreover, silicates allow amorphisation of drugs by co-grinding or processing with supercritical fluids.

The aim of this study was to investigate the physical and the tableting properties of Silica Aerogel (a special type of silica with an extremely large specific surface area), Neusilin® US2 (magnesium aluminometasilicate), Florite® (calcium silicate) and Aerosil® 200 (colloidal silica).

Powder blends of Avicel® PH102 (microcrystalline cellulose) and different amounts of the respective silicate were compacted and analyzed for their tabletability (tensile strength vs. compaction pressure) as well as their Heckel plot.

It was shown that with Neusilin® the tabletability appears to be independent of the silicate concentration, whereas with Florite® an increasing silicate concentration leads to a higher tensile strength. In contrast, the addition of Silica Aerogel and Aerosil® resulted in a decrease of the tensile strength. With Aerosil® a maximum tolerable concentration of 20 % [w/w] was determined. Plastic deformation of all powder blends decreased with increasing silicate concentration. This effect was most pronounced with Aerosil® and least with Florite®.

In conclusion, tablets with acceptable tensile strength were obtained with all plain silicates except for Aerosil®. Therefore, these silicates may be used in tablet formulations, e.g. as carrier materials for liquid or amorphous drugs.

Tableting properties of silica aerogel and other silicates 44

3.1 Introduction

In solid oral dosage forms silicates are commonly used as glidants. Glidants are substances that improve the flowability of cohesive powders and granules. Their mechanism of action is mainly the reduction of the interparticle cohesion and adhesion forces [129]. The van der Waals forces between particles in dry powders can be reduced by addition of silicates which may act as spacers and increase the interparticle distance. Moreover, glidants are believed to act as pore fillers on the surface of the particles or granules which thereby are prevented from interlocking and thus are allowed to flow faster. A third option for improving the flowability is the reduction of adsorbed moisture accompanied by a decrease of interparticle cohesion and adhesion. Silicates are well suited for that purpose because of their small particle size and large specific surface area [130]. One of the most frequently used glidants is colloidal silica (e.g. Aerosil® 200) which exhibits a very small particle size in the colloidal range and a large specific surface area of about 200 m²/g. With the application of silicates as glidants, attention should be paid to the silicate concentration: optimum concentrations of glidants are 1 % or lower. Excess of glidant should be avoided as higher concentrations lead to a decrease of the flowability due to large cohesive forces caused by the large specific surface area of these fine particles [131].

A further important field of application of silicates in solid oral dosage forms is their use as carrier materials. Due to the large specific surface area, silicates are well suited for the adsorption of solid (e.g. amorphous) as well as liquid drugs.

One of the most promising carrier materials is Silica Aerogel which is prepared from silicon dioxide using supercritical extraction [132]. The extremely large specific surface area and the open pore structure of the material make Aerogels an ideal candidate as carrier material. Adsorption of drugs to hydrophilic Silica Aerogels has been shown to be a promising technique for drug release enhancement [51-53]. Upon contact with fluids, the structure of hydrophilic Aerogels collapses and a fast release of the loaded drug takes place. Furthermore, this methodology allows a long-time stabilization of amorphous drugs also leading to fast drug release.



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