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

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Carrier and coating materials for liquisolid compacts 56

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Abstract The liquisolid technology is a promising technique for release enhancement of poorly soluble drugs. With this approach liquids such as solutions or suspensions of poorly soluble drugs in a non-volatile liquid vehicle are transformed into acceptably flowing and compressible powders. As fast release liquisolid compacts require a high amount of liquid vehicle more effective tableting excipients for liquid adsorption are needed to reduce tablet weight.

The aim of this study was to investigate the suitability of various novel tableting excipients as carrier and coating materials for liquisolid compacts.

Liquisolid compacts containing the liquid drug tocopherol acetate as model drug and various excipients were prepared. The effect of liquid drug content on the flowability and tabletability of the liquisolid powder blends as well as the disintegration of the liquisolid compacts was studied. From this data, the maximum liquid adsorption capacity of the respective mixtures of carrier and coating materials could be determined.

It was shown that the liquid adsorption capacity depends on the specific surface area of the investigated excipients. Fujicalin® (spherically granulated dicalcium phosphate anhydrous) and especially Neusilin® (magnesium aluminometasilicate) are more effective carrier materials for liquid adsorption than Avicel® (microcrystalline cellulose) which is often used for liquisolid systems. Moreover, Florite® (calcium silicate) and Neusilin® turned out to be more suitable as coating materials than the commonly used Aerosil® (colloidal silica) due to their better tableting properties.

In conclusion, if Neusilin® is used as carrier and coating material instead of Avicel® (carrier material) and Aerosil® (coating material) the tocopherol acetate adsorption capacity is increased by a factor of seven.

Carrier and coating materials for liquisolid compacts 58

4.1 Introduction

Poorly soluble, highly permeable active pharmaceutical ingredients (BCS Class II drugs) represent a technological challenge as their poor bioavailability is only caused by poor water solubility resulting in low drug absorption [147]. Numerous methods for increasing water solubility and drug release, respectively, are used such as micronization [48], adsorption onto high surface area carriers [52, 53], co-grinding [56], formulation of inclusion complexes [61], solid dispersions [65, 66, 70] and lipid based formulations [71] for instance self-emulsifying drug delivery systems (SEDDS). One of the most promising approaches is the liquisolid technology [11, 14, 29].

The concept of “liquisolid systems“ as defined by Spireas [1] may be used to convert a liquid into a free flowing, readily compressible and apparently dry powder by simple physical blending with selected excipients named the carrier and coating material. The liquid portion which can be a liquid drug, a drug suspension or a drug solution in suitable non-volatile liquid vehicles is incorporated into the porous carrier material (Fig. 14). Once the carrier is saturated with liquid, a liquid layer is formed on the particle surface which is instantly adsorbed by the fine coating particles [2]. Thus, an apparently dry, free flowing, and compressible powder is obtained. Usually, microcrystalline cellulose is used as the carrier material and amorphous silicon dioxide as the coating material.

Fig. 14: Schematic representation of liquisolid systems [2] Carrier and coating materials for liquisolid compacts 59 Liquisolid compacts of poorly soluble drugs containing a drug solution or drug suspension in a solubilising vehicle provide enhanced drug release characteristics due to an increased surface area of drug available for release, an increased aqueous solubility of the drug, and an improved wettability of the drug particles [3-6].

Accordingly, this improved drug release may result in a higher drug absorption in the gastrointestinal tract and thus an improved oral bioavailability [9, 10].

The liquisolid technology has been successfully applied to low dose poorly soluble drugs [14, 29]. However, the formulation of a high dose poorly soluble drug is one of the limitations of this technique. The release rates are directly proportional to the fraction of molecularly dispersed drug in the liquid portion [11, 14]. Thus, a higher drug dose requires a higher amount of liquid vehicle to obtain a faster drug release. As a powder can retain only limited amounts of liquid while maintaining acceptable flow and compression properties, high amounts of carrier and coating materials are needed.

This results in an increase in tablet weight ultimately leading to an unacceptably high tablet size.

A potential approach to minimize tablet weight is to increase the liquid adsorption capacity by either adding binders such as povidone or hypromellose to the liquid portion [18] or by using carrier and coating materials with a high specific surface area (SSA). The higher the specific surface area of an excipient, the higher the liquid load factor [2].

For instance, the liquid adsorption capacity of microcrystalline cellulose (SSA: 1.18 m²/g) is higher than that of lactose (SSA: 0.35 m²/g), starch (SSA:

0.6 m²/g) and sorbitol (SSA: 0.37 m²/g) [4].

The aim of this study was to investigate novel porous tableting excipients with a high specific surface area with regard to their suitability of liquid adsorption while maintaining acceptable flow and tableting properties. The following excipients were

compared to the commonly used carrier and coating materials Avicel® and Aerosil®:

Fujicalin®, a spherically granulated dicalcium phosphate anhydrous [105, 106] with a high porosity and high specific surface area resulting in good flowability and tabletability, Neusilin® US2, a synthetic amorphous form of magnesium aluminometasilicate [141] prepared by spray drying with an extremely high specific surface Carrier and coating materials for liquisolid compacts 60 area and good flowability and tabletability, and Florite®, a calcium silicate [142] with large micropores and excellent tabletability.

In the present study the influence of liquid drug content on the flowability and tabletability of various liquisolid powder blends was analyzed. Tocopherol acetate was used as the liquid model substance. The objective was to identify the most effective carrier and coating material for liquid uptake while maintaining acceptable flow and tableting properties. Therefore, in the first part of the study various carrier materials were investigated and compared to Avicel® and in the second part the commonly used coating material Aerosil® was replaced by novel excipients to further optimize the liquid adsorption capacity.

Carrier and coating materials for liquisolid compacts 61

4.2 Materials and methods Materials Tocopherol acetate, BASF, Ludwigshafen, Germany; Avicel® PH200 (microcrystalline Neusilin® cellulose), FMC BioPolymer, Cork, Ireland; US2 (magnesium aluminometasilicate), Fuji Chemical Industry, Toyama, Japan; Fujicalin® (spherically granulated dicalcium phosphate anhydrous), Fuji Chemical Industry, Toyama, Japan;

Aerosil® 200 (colloidal silica), Evonik, Darmstadt, Germany; Florite® (calcium silicate), Tokuyama, Tokyo, Japan; Kollidon® CL (crospovidone), BASF, Ludwigshafen, Germany; Magnesium stearate, Baerlocher, Unterschleissheim, Germany. All other reagents used were of analytical grade.

Methods Determination of the specific surface area of the excipients The specific surface area of the excipients was determined 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 [108] the specific surface area of the excipients was evaluated within a relative pressure range p/p0 between 0.05 and 0.3.

Each excipient was measured in triplicate.

Scanning electron microscopy of the excipients The excipients were coated with a thin carbon layer and analyzed using a LEO 1525 scanning electron microscope (LEO Elektronenmikroskopie, Oberkochen, Germany) and an accelerating voltage of 5 kV.

Preparation of the liquisolid powder blends Liquisolid powder blends of varying content of tocopherol acetate (TA) (expressed as percent [w/w] referred to the total weight of TA, carrier and coating materials) were prepared with a Bohle Mini Granulator (BMG, Bohle, Ennigerloh, Germany). The liquid Carrier and coating materials for liquisolid compacts 62 drug was added as acetonic solution to binary mixtures of carrier and coating materials (Table 8). Carrier and coating materials were used in a ratio of 20 : 1 (R-value) according to the recommendation of Spireas et al. [29]. Mixing was performed until the powder appeared visibly dry. To remove solvent residues, the blends were subsequently oven-dried (2 h, 40 °C) and stored at 21 °C / 45 % R. H. before use.

Prior to tableting Neusilin® blends were mixed with Kollidon® CL (6 % [w/w]) for 5 min in a Turbula blender (T2F, Willy A. Bachofen, Muttenz, Switzerland) to ensure tablet disintegration.

Table 8: Excipient composition of various tocopherol acetate liquisolid compacts

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R - Excipient ratio (carrier material : coating material) *6 % [w/w] referring to the weight of the liquisolid formulation Flowability of the liquisolid powder blends Flow properties of the liquisolid powder blends were characterized 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) equipped with a 50 ml measuring cylinder according to the Pharmacopoeia Europaea. The powder flow rate was measured by recording the weight change over time with a precision balance Carrier and coating materials for liquisolid compacts 63 (BL 1500 S, Sartorius, Göttingen, Germany). The orifice diameter of the funnel was 7 mm.

Tableting of the liquisolid powder blends Tablets were produced with an instrumented eccentric press (EXI, Fette, Schwarzenbek, Germany) equipped with flat faced punches of 10 mm diameter.

External lubrication was performed with magnesium stearate. The required amount of powder was filled manually into the die and compressed at a compaction speed of 16 strokes / min. All experiments were performed at 21 °C / 45 % R. H..

Characterization of the liquisolid compacts

Tablets were characterized after a relaxation time of at least 24 hours after tablet manufacture. 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]. Tabletability of the liquisolid compacts was evaluated by plotting tensile strength versus compaction force. A minimum tensile strength of 1.5 MPa was regarded as sufficient tablet hardness.

Disintegration time was measured with a disintegration tester (ZT 72, Erweka, Heusenstamm, Germany) according to the conditions of the Ph. Eur. for uncoated tablets.

Carrier and coating materials for liquisolid compacts 64

4.3 Results and discussion Characterization of the excipients The specific surface area (SSA) and the structure of the investigated excipients differ

significantly from each other. For instance, the specific surface area of Fujicalin® (SSA:

32 ± 1 m²/g) is 32 times higher than that of Avicel® (SSA: 1 ± 0 m²/g). This difference becomes apparent in Fig. 15. Whereas the spherically granulated dicalcium phosphate anhydrous (Fujicalin®) shows a high porosity, microcrystalline cellulose (Avicel®) exhibits a smooth surface. From the excipients investigated in this study the silicates provide by far the highest specific surface areas. Florite® with its petaloid crystal structure and large micropores exhibits a SSA of 142 ± 7 m²/g, whereas Aerosil® with its loose agglomerates formed by the nanometer-sized primary particles exhibits a

SSA of 201 ± 7 m²/g. The highest specific surface area by far shows Neusilin® (SSA:

339 ± 1 m²/g) which is prepared by spray drying resulting in spherically shaped, porous, ultra light granules.

Fig. 15: SEM pictures of the excipients Variation of the carrier material In the following subchapters the results of the flowability, tabletability, and tablet disintegration of the formulations containing Aerosil® as coating material, Avicel®, Fujicalin® or Neusilin® as carrier material (Table 8) and tocopherol acetate as liquid drug are presented.

Carrier and coating materials for liquisolid compacts 65 a. Flowability In Fig. 16 the influence of liquid drug content on the flowability of the liquisolid powder formulations is shown. The flowability of the investigated blends was affected differently by the increase in liquid drug content.

For all three formulations the blends without TA show poor flowability manifesting itself in a high Hausner ratio and a low powder flow rate. This can be attributed to the high amount of very fine Aerosil® coating particles leading to large cohesive and adhesive forces caused by the high specific surface area of these fine particles. It is shown for all formulations that the addition of the liquid drug improves the flowability (decrease of the Hausner ratio and increase in powder flow rate). The liquid drug is initially adsorbed by the carrier surfaces and subsequently covered by the fine Aerosil® coating particles resulting in particles with better flowability due to a decrease of interparticle forces.

For Avicel® blends this flowability improvement could only be observed with up to 8 % liquid drug content (Fig. 16a). With higher liquid drug contents (12 and 16 %) the flowability decreases because the liquid drug content was too high. The high amount of liquid could not be completely adsorbed by the carrier and coating materials and thus, sticky agglomerates were formed. The blend with 20 % TA was not measurable because of pronounced sticking. Therefore, best flowability of the Avicel® blends is observed with a liquid drug content of 8 %.

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