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

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The aim of the present study was to compare drug release from several griseofulvin tablet formulations. The poorly soluble antifungal drug was formulated as conventional tablets containing crystalline griseofulvin, as aerogel tablets containing the drug adsorbed to hydrophilic silica aerogel and as liquisolid compacts containing the drug dissolved in PEG 300. Liquisolid compacts containing the drug suspended in PEG 300 were investigated with regard to the influence of drug content in the liquid portion on drug release. Furthermore, the commonly used carrier and coating materials in Drug release enhancement from hydrophilic aerogels and liquisolid compacts 78 liquisolid systems Avicel® and Aerosil®, respectively, were replaced by Neusilin® to improve the liquisolid approach. Due to its extremely high specific surface area as well as its good flow and tableting properties this magnesium aluminometasilicate was assumed to allow a considerably higher liquid load factor, thereby enabling the preparation of liquisolid compacts with lower tablet weights.

Drug release enhancement from hydrophilic aerogels and liquisolid compacts 79

5.2 Materials and methods Materials Griseofulvin, Fagron, Barsbüttel, Germany; Carbon dioxide (purity 99.9 %), AGA Gas, Hamburg, Germany; hydrophilic silica aerogel microspheres, mean particle size 300 µm [144]; polyethylene glycol 300 (PEG 300), glycerol, and propylene glycol, Fagron, Barsbüttel, Germany; Avicel® PH200 (microcrystalline cellulose), FMC BioPolymer, Cork, Ireland; Aerosil® 200 (colloidal silica), Evonik, Darmstadt, Germany;

Neusilin® US2 (magnesium aluminometasilicate), Fuji Chemical Industry, Toyama, Japan; Kollidon® CL (crospovidone), BASF, Ludwigshafen, Germany. All other reagents used were of analytical grade.

Methods Loading of silica aerogel microspheres with griseofulvin A weighed amount of drug and aerogel microspheres, each wrapped in a filter paper were placed in an autoclave (250 ml, built at the Hamburg University of Technology, Germany). The autoclave was sealed, heated to 40 °C and carbon dioxide was pumped inside until a pressure of 180 bar was reached [143, 150]. After 48 hours under these conditions the pressure was released and the drug-loaded aerogel microspheres (300 µm) were removed. To determine the drug concentration in the loaded aerogel a weighed amount of aerogel microspheres was dispersed in methanol. The solution was stirred for at least 20 min to ensure complete dissolution of the drug. The concentration of the drug in methanol was analyzed spectrophotometrically at 291 nm (1 cm quartz cells, 8453, Agilent Technologies, Santa Clara, USA). Based on these data the drug concentration in the loaded aerogel was calculated. Each experiment was carried out in triplicate.

Solubility studies The solubility of griseofulvin in three non-volatile liquid vehicles which are commonly used for the formulation of liquisolid compacts, namely, propylene glycol, polyethylene Drug release enhancement from hydrophilic aerogels and liquisolid compacts 80 glycol 300 (PEG 300), and glycerol were determined by preparation of saturated solutions of the drug in these solvents and measuring their drug concentration: excess griseofulvin was stirred in the above mentioned solvents for 48 h at 21 °C. Accurately weighed quantities of the filtered supernatants were further diluted with methanol and analyzed spectrophotometrically at 291 nm for their drug content. From these results the solubility of griseofulvin (in percent [w/w]) in the respective liquid vehicle was calculated. Each experiment was carried out in triplicate.

Preparation of directly compressed tablets

A conventional tablet formulation with micronized griseofulvin and an aerogel tablet formulation with griseofulvin adsorbed to hydrophilic silica aerogel were prepared with each tablet containing Kollidon® CL as disintegrant, Avicel® as binder, and 1.5 mg of drug. The drug concentration of the hydrophilic silica aerogel microspheres was determined to 3.0 ± 0.1 % [w/w] and therefore each tablet contained 50 mg of drugloaded silica aerogel. To ensure that tablet disintegration is not the rate-limiting step and drug release is not hindered by slow disintegration of the dosage form, 5 % [w/w] Kollidon® CL were added to all formulations. All ingredients were mixed for 5 min in a Turbula blender (T2F, Willy A. Bachofen, Muttenz, Switzerland) and compressed into tablets with an instrumented single punch press (EXI, Fette, Schwarzenbek, Germany) equipped with flat faced punches of 10 mm diameter. For each tablet 300 mg of the powder blends were filled manually into the die and compressed at a compaction speed of 16 strokes / min. The compaction force was adjusted to achieve a minimum tensile strength of 1 MPa [109]. All experiments were performed at 21 °C / 45 % R.H..

Preparation of liquisolid compacts

Several liquisolid formulations with each sample unit containing 3 mg of griseofulvin (corresponding to 2 – 5 tablets) were prepared by addition of the liquid portion (0.9 – 2.3 % drug in PEG 300) to the carrier and coating material and mixing in a mortar (Table 10). Finally, Kollidon® CL was added and the formulations were mixed for 5 min in a Turbula blender. The liquisolid formulations LS-1 – LS-10 consisted of Avicel® as carrier and Aerosil® as coating material. Carrier and coating materials were used in a weight ratio of 20 : 1 (= R-value) according to the recommendation of Spireas et al.





[29]. A liquid load factor of 0.22 was used in these formulations resulting in acceptable Drug release enhancement from hydrophilic aerogels and liquisolid compacts 81 flowability of the blends (maximum angle of slide 33 °C) and sufficient tablet hardness (minimum tensile strength 1 MPa). For the liquisolid formulation LS-N with Neusilin® as carrier as well as coating material a liquid load factor of 1.58 was used. Despite such a high liquid load factor, the formulation fulfills the required flowability and tablet hardness. The high liquid loading capacity of this magnesium aluminometasilicate may be explained by its extremely high specific surface area of 339 ± 1 m²/g as well as its good flow and tableting properties [107].

The liquisolid formulations were compacted as described for the directly compressed tablets. However, for the liquisolid compacts the required amount of powder blend for one tablet was between 300 and 434 mg (Table 10).

Formulations LS-2 – LS-10 contained drug suspensions as liquid portion in contrast to LS-1and LS-N which contained a drug solution. For suspensions the percentage of dissolved drug in the liquid portion is calculated by the ratio of the drug's solubility in the liquid vehicle PEG 300 and the total drug content in the liquid portion present in each formulation (Table 10).

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

Eur. for uncoated tablets.

Drug release studies

–  –  –

5.3 Results and discussion Solubility of griseofulvin in various non-volatile liquid vehicles Griseofulvin was found to be poorly soluble in glycerol (0.004 ± 0.000 [% w/w]) and propylene glycol (0.13 ± 0.00 [% w/w]). Its solubility in PEG 300 (0.95 ± 0.00 [% w/w]) was much higher. Thus, to minimize the required amount of liquid, PEG 300 was chosen as liquid vehicle for preparation of griseofulvin liquisolid compacts.

Disintegration of the investigated tablets

The disintegration times of the liquisolid and the directly compressed tablets are shown in Table 11. Obviously, all formulations (except for formulation LS-N) disintegrated within less than 15 seconds. This very fast tablet disintegration may be explained by the presence of the superdisintegrant Kollidon® CL [151] as well as the microcrystalline cellulose Avicel® leading to an extremely fast water penetration into the tablets caused by wicking and subsequent widening of the pores [148]. Thus, drug release was not hindered by slow disintegration of the dosage form. Tablets containing Neusilin (LS-N) disintegrated within 4.5 min because of the poor disintegration properties of this silicate.

Table 11: Disintegration times of the investigated tablets (means ± SD, n = 3)

–  –  –

Drug release from the investigated tablet formulations Drug release profiles of the conventional and the aerogel tablets as well as the liquisolid compact formulation LS-1 are shown in Fig. 20. It is obvious that drug release from the liquisolid compacts was much faster than that from the conventional tablets although both formulations disintegrated rapidly (Table 11): within 5 min, only 37 % of griseofulvin were released from the conventional tablets as compared to the LS-1 compacts with 95 % drug release. Even though the liquisolid compacts LS-1 represent solid dosage forms, the drug is dissolved in the liquid vehicle within the powder matrix. Thus, drug release from LS-1 compacts was solely dependent on the disintegration of the tablets and the miscibility of the liquid portion with the dissolution medium. The comparatively slow drug release from conventional tablets may mainly be explained by the poor water solubility of griseofulvin and thus a low drug dissolution rate.

Fig. 20: Drug release profiles of the conventional tablets, the aerogel tablets, and the liquisolid compacts LS-1 (means ± SD; n = 3) In comparison to the liquisolid compacts LS-1, the aerogel tablets showed a slightly slower drug release. However, compared to the conventional tablets the drug release rate from the aerogel tablets was much higher with more than 73 % within 5 min. This faster drug release from hydrophilic aerogels was also observed by Smirnova et al.

[52] who investigated different methods for drug release enhancement of griseofulvin, namely micronization of drug by milling, by rapid expansion from supercritical Drug release enhancement from hydrophilic aerogels and liquisolid compacts 85 solutions (RESS), and drug adsorption to hydrophilic aerogels. The faster drug release of the aerogel tablets may be explained by both an increase in the specific surface area of the drug resulting from the adsorption to the aerogel microspheres and possibly an amorphous state of the drug. X-ray diffraction patterns confirmed the hypothesis that no crystalline structures of the drug are present in drug-loaded aerogel formulations and no long-range order is established upon adsorption of the drug to silica aerogels [51, 53]. The faster drug release from aerogel tablets may also be caused by fast wetting of the hydrophilic aerogel and an immediate collapse of its structure in aqueous media [51, 52].

In Fig. 21 drug release profiles of several liquisolid compacts with varying drug contents in the liquid portion are shown. It is apparent that the drug content in the liquid portion had an effect on drug release from liquisolid compacts.

Fig. 21: Drug release profiles of several liquisolid compacts and the conventional tablets (means ± SD; n = 3) With increasing drug content in the liquid portion exceeding the solubility limit and thus a decreasing percentage of dissolved drug in the liquid portion the release rate decreased. This effect is illustrated in detail in Fig. 22 where the drug content in the liquid portion of the compacts LS-1 – LS-10 is plotted versus drug release at 20 min.

This decrease of drug release is attributed to the increasing amount of undissolved drug.

Drug release enhancement from hydrophilic aerogels and liquisolid compacts 86 Fig. 22: Influence of the drug content in the liquid portion of liquisolid compacts on the released drug at 20 min (means ± SD; n = 3) In Fig. 23 the percentage of released drug from the liquisolid compacts LS-1 – LS-10 and the conventional tablets at 20 min are plotted versus the corresponding percentage of dissolved drug in the liquid portion. It is obvious that there was no difference in the percentage of released drug at 20 min between the conventional tablets and the liquisolid compacts LS-8 – LS-10 with all formulations showing a release of about 67 %. Accordingly, the rising percentage of dissolved drug in these three liquisolid compacts did not lead to the expected increase in drug release. With higher percentages of dissolved drug in the liquid portion above 50 % the released drug at 20 min increased linearly (slope = 0.64, R² = 0.995). Therefore, the percentage of released drug from liquisolid compacts may be predicted, a fact that was also observed by Spireas et al. [11, 14].

Drug release enhancement from hydrophilic aerogels and liquisolid compacts 87 Fig. 23: Influence of the percentage of dissolved drug in the liquid portion of liquisolid compacts on the released drug at 20 min (means ± SD; n = 3);

data of the conventional tablets In summary, if fast release rates are desired, the liquid portion of liquisolid compacts must contain a high percentage of dissolved drug. However, a liquid portion with a high percentage of dissolved drug might require a high amount of liquid vehicle depending on the solubility of the drug in the liquid vehicle and the required drug dose.

As the powder excipients can only adsorb limited amounts of liquid while maintaining good flow and tableting properties, tablet weight will increase with higher amounts of liquid vehicle (Table 10). For instance, the sample unit weight of the fast release formulation LS-1 was more than 2 g, whereas that of LS-10 was only about 800 mg.

However, this lighter formulation contained a comparatively high percentage of undissolved drug in the liquid portion and thus showed a significantly lower drug release compared to the heavy formulation LS-1.

As the liquid load factor is dependent on the carrier and coating materials used, a further aim of this study was to optimize the liquisolid technology by replacing the commonly used carrier and coating materials Avicel® and Aerosil® by Neusilin® US2.

This magnesium aluminometasilicate with its extremely high specific surface area allowed a considerably higher liquid load factor of 1.58 and thus the production of Drug release enhancement from hydrophilic aerogels and liquisolid compacts 88 liquisolid formulations with lower tablet weights. Replacement of Avicel® and Aerosil® by Neusilin® led to a reduction of the weight of the sample unit containing 3 mg of griseofulvin dissolved in PEG 300 from 2026 mg to 600 mg (Table 10).



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