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

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In contrast to Avicel®, Fujicalin® and Neusilin® blends show improved flowability far beyond 8 % liquid drug content (Figs. 16b and 16c). The high porosity and high specific surface area of these excipients allow penetration of the liquid into the particle pores and thus, a high liquid load. The flowability improvement can be attributed to a sponge-like liquid uptake into these porous excipients resulting in a weight gain of the individual particles accompanied by better flow properties.

The liquid oversaturation is not yet reached for the Fujicalin® blends and the Neusilin® blends with a TA content of 20 % and 55 %, respectively.

Carrier and coating materials for liquisolid compacts 66 Fig. 16: Flowability of TA liquisolid powder blends containing Aerosil® as coating material (means ± SD, Hausner ratio: n = 3, powder flow rate: n = 5)

a) Avicel® blends, b) Fujicalin® blends, c) Neusilin® blends Carrier and coating materials for liquisolid compacts 67 b. Tabletability The influence of tocopherol acetate on the tableting properties of the investigated blends is shown in Fig. 17. Obviously, the tableting properties of the blends are affected differently by the increase in liquid drug content.

The tensile strength of the Avicel® compacts continuously decreases with increasing liquid drug content (Fig. 17a), whereas the tableting properties of Fujicalin® blends remain almost unaffected by the addition of liquid drug up to 12 % (Fig. 17b). This may

be explained by the different deformation characteristics of these two excipients:

Avicel® as microcrystalline cellulose shows plastic deformation [128] whereas fragmentation is the main deformation mechanism of the dicalcium phosphate Fujicalin® [105]. With a brittle excipient new contact areas form instantaneously during compaction and thus, the liquid drug does not influence the tabletability at a low liquid content.

As with Fujicalin®, Neusilin® formulations are insensitive to liquid addition up to a certain liquid content. With the Neusilin® formulations this insensitivity is even extended up to 40 % liquid content (Fig 17c).

In conclusion, tablets with acceptable mechanical properties are obtained with a maximum TA content of 8 % for the Avicel® compacts, 12 % for the Fujicalin® compacts and 50 % for the Neusilin® compacts.

With higher liquid drug contents the tablet hardness decreases significantly and the tensile strength is independent of the compaction force. The adhesive properties of the drug itself cause sticking of the compressed particles resulting in a constant low tensile strength.

These results show that with the investigated novel carrier materials a higher liquid drug content of the liquisolid compacts can be achieved while maintaining good tableting properties. The superior liquid adsorption capacity of Neusilin® and Fujicalin® can be explained by their porous structure and high specific surface area.

Carrier and coating materials for liquisolid compacts 68 Fig. 17: Tabletability of TA liquisolid compacts containing Aerosil® as coating material (means ± SD, n = 5)

a) Avicel® compacts, b) Fujicalin® compacts, c) Neusilin® compacts *containing additional 6 % Kollidon® CL Carrier and coating materials for liquisolid compacts 69 c. Disintegration In Fig. 18 the disintegration of the Avicel® and Fujicalin® compacts is shown. As expected, all tablets show an increase in disintegration time with increasing drug content due to the lipophilic nature of TA and thus, a decreased wettability of the compacts. Moreover, the disintegration time is strongly dependent on the excipient used. In comparison to Fujicalin® (Fig. 18b), Avicel® compacts disintegrate much faster (Fig. 18a). This may be explained by an extremely fast water penetration into microcrystalline cellulose tablets caused by wicking and subsequent widening of the pores [148]. The very fast disintegration of Neusilin® compacts ( 1 min) is solely caused by the addition of the superdisintegrant Kollidon® CL.

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Variation of the coating material As Neusilin® turned out to be the most effective carrier (Figs. 16 and 17) this silicate was used for further studies as carrier material to look for the most effective coating material. In the following subchapters the results of the flowability and tabletability of the formulations containing Neusilin® as carrier material, Aerosil®, Florite® or Neusilin® as coating material (Table 8) and tocopherol acetate as liquid drug are presented. The disintegration times of the compacts are not discussed because of the very fast disintegration of the Neusilin®-containing compacts (see above).

a. Flowability

All blends containing Neusilin® as carrier material show good flowability at high TA contents of 50 and 55 % (Table 9). Moreover, a slight improvement of the powder flow rate is observed with all blends with an increasing drug content from 50 to 55 %. This can be explained by the above mentioned sponge-like liquid uptake of Neusilin® and thus, a weight gain of the individual particles. Among these free flowing powder blends the formulation containing Neusilin® as carrier as well as coating material exhibits the best flow properties with the lowest Hausner ratio and the highest powder flow rate resulting from the spherical shape of this silicate.





Flowability of TA liquisolid powder blends containing Neusilin® as carrier

Table 9:

material (means ± SD, Hausner ratio: n = 3, powder flow rate: n = 5)

–  –  –

b. Tabletability In Fig. 19 the tabletability of tocopherol acetate liquisolid compacts containing Neusilin® as carrier material is shown. As mentioned above for the Neusilin®- and Aerosil®-containing compacts, tablets with acceptable mechanical properties are obtained with a maximum TA content of 50 % (Figs. 17c, 19a). The replacement of Aerosil® by Florite® or Neusilin® as coating material allows a higher liquid loading capacity. With Neusilin® and Florite® as coating material an increase of the liquid content up to 55 % is possible resulting in acceptable tablet hardness (Figs. 19b and 19c). Therefore, Florite® and Neusilin® turned out to be more suitable as coating materials than the commonly used Aerosil®. This higher liquid loading capacity is accompanied by better tableting properties of Florite® and Neusilin® than Aerosil®: The tensile strength of the Aerosil® compacts is considerably lower than that of the respective Florite® and Neusilin® compacts.

In conclusion, compared to the commonly used carrier and coating materials Avicel® and Aerosil® (Fig. 17a) the liquid adsorption capacity of the formulation containing Neusilin® as carrier as well as coating material (Fig. 19c) is increased by a factor of seven (from 8 to 55 % TA).

Carrier and coating materials for liquisolid compacts 72 Fig. 19: Tabletability of TA liquisolid compacts containing Neusilin® as carrier material (means ± SD, n = 5)

a) Aerosil® compacts, b) Florite® compacts, c) Neusilin® compacts *containing additional 6 % Kollidon® CL Carrier and coating materials for liquisolid compacts 73

4.4 Conclusion It could be shown that the selection of the carrier and coating materials strongly affects the liquid adsorption capacity of liquisolid formulations. Replacement of the commonly used carrier and coating materials by excipients with high specific surface areas and good flow and tableting properties allows considerably higher liquid adsorption capacities. If Neusilin® is used as carrier as well as coating material instead of Avicel® and Aerosil®, the tocopherol acetate adsorption capacity is increased by a factor of seven. This higher liquid adsorption capacity leads to a significant improvement of the liquisolid technology: the use of this effective excipient enables the preparation of liquisolid compacts of high dose, poorly soluble drugs where high amounts of liquid vehicle are needed. Thus, tablet weights are reduced in comparison to the commonly used carrier and coating materials. Furthermore, Neusilin® simplifies the preparation of liquisolid formulations as it acts as carrier as well as coating material.

Moreover, as solid dosage forms are preferred over liquid preparations due to improved patient compliance, dosage uniformity, and stability highly adsorptive tableting excipients provide a wide field of application for liquid drugs, liquid nutritional supplements or liquid SEDDS.

Drug release enhancement from hydrophilic aerogels and liquisolid compacts 74

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Enhancement of griseofulvin release from hydrophilic aerogel formulations and liquisolid compacts Abstract The potential of hydrophilic aerogel formulations and liquisolid systems to improve the release of poorly soluble drugs was investigated using griseofulvin as model drug. The in vitro release rates of this drug formulated as directly compressed tablets containing crystalline griseofulvin were compared to aerogel tablets with the drug adsorbed onto hydrophilic silica aerogel and to liquisolid compacts containing the drug dissolved or suspended in PEG 300. Furthermore, the commonly used carrier and coating materials in liquisolid systems Avicel® and Aerosil® were replaced by Neusilin®, an amorphous magnesium aluminometasilicate with an extremely high specific surface area to improve the liquisolid approach.

Both the liquisolid compacts containing the drug dissolved in PEG 300 and the aerogel tablets showed a considerably faster drug release than the directly compressed tablets. With liquisolid compacts containing the drug suspended in PEG 300 the release rate increased with rising percentage of dissolved drug in the liquid portion. It could be shown that Neusilin® with its extremely high liquid adsorption capacity allows the production of liquisolid formulations with lower tablet weights.

Drug release enhancement from hydrophilic aerogels and liquisolid compacts 76

5.1 Introduction

Since the implementation of combinatorial chemistry and high throughput screening for the investigation of new chemical entities the molecular weight and lipophilicity of drugs increase and this in turn decreases water solubility [149]. Especially poorly soluble, highly permeable active pharmaceutical ingredients (BCS Class II drugs) represent a technological challenge, as their poor bioavailability is solely caused by poor water solubility resulting in low drug absorption [147]. Therefore, new technologies increasing the solubility and thus drug release are looked for. Release enhancement of poorly soluble drugs may be achieved by an increase of the drug

solubility, the drug surface area, or by formulating the drug in its dissolved state:

Several methodologies such as micronization [48], co-grinding [55, 56], formulation of inclusion complexes [61], solid dispersions [65, 70] and lipid based formulations [71] such as self-emulsifying drug delivery systems (SEDDS) have been introduced with different success.

Adsorption of drugs onto hydrophilic silica aerogels has been shown to be a promising technique for drug release enhancement [52, 53]. This methodology also allows a long-time stabilization of amorphous drugs. Upon contact with fluids, the structure of hydrophilic aerogels collapses and a fast release of the loaded drug takes place.

One of the most promising approaches for release enhancement is the liquisolid technology [3, 5, 11, 14, 19, 30]. Liquisolid systems are composed of a non-volatile, water soluble liquid vehicle, solid drug particles and selected excipients, named the carrier and coating materials. The drug may be dissolved or suspended in the liquid vehicle. Subsequently, this liquid portion is transformed into a free flowing, readily compressible and apparently dry powder by simple physical blending with the carrier and coating materials. Liquisolid compacts of poorly soluble drugs containing the drug dissolved or suspended in a solubilising liquid vehicle provide enhanced drug release due to an increased aqueous solubility of the drug, an increased surface area of the drug, and an improved wettability of the drug particles [4, 6]. Accordingly, this optimized drug release allows an improved drug absorption in the gastrointestinal tract and thus a higher oral bioavailability [9, 10].

Drug release enhancement from hydrophilic aerogels and liquisolid compacts 77 Besides drug release enhancement, the liquisolid approach is a promising technique because of the simple manufacturing process, low production costs and the possibility of industrial manufacture due to good flow and compaction properties of the liquisolid formulations.

To calculate the required amount of powder excipients (carrier and coating materials) a mathematical approach for the formulation of liquisolid systems has been developed by Spireas [1].

Depending on the excipient ratio R of the powder substrate an acceptably flowing and compressible liquisolid system can be obtained only if a maximum liquid load, named “liquid load factor” (Lf), is not exceeded.

The terms “acceptable flow” and “acceptable compressibility” imply the desired and thus preselected flow and compaction properties, which must be met by the final liquisolid formulation.

R represents the ratio between the mass of the carrier (Q) and the coating (q)

materials present in the formulation:

–  –  –

With the desired amount of liquid, the amount of carrier and coating material can be calculated if the liquid load factor Lf is known.



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