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

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Es konnte gezeigt werden, dass die Auswahl des Carrier- und des Coating-Materials einen großen Einfluss auf die Flüssigkeitsaufnahmekapazität der Liquisolid-Formulierungen hat. Der Austausch der gewöhnlich verwendeten Carrier- und CoatingMaterialien durch Hilfsstoffe mit einer großen spezifischen Oberfläche und guten Fließ- und Kompaktiereigenschaften wie Fujicalin® und Neusilin® führte zu einer beträchtlichen Erhöhung der Flüssigkeitsaufnahme. Bei Verwendung von Neusilin® sowohl als Carrier- als auch Coating-Material anstelle der gewöhnlich verwendeten Materialien Avicel® (Carrier) und Aerosil® (Coating) konnte die Flüssigkeitsaufnahmekapazität sogar um das siebenfache gesteigert werden.

Schließlich wurde festgestellt, dass die schnellste Wirkstofffreisetzung mit LiquisolidTabletten beobachtet wird, die eine Arzneistofflösung als flüssigen Anteil enthalten.

Dies bedeutet für eine schnell freisetzende Arzneiform große Mengen an flüssigem Vehikel falls der Arzneistoff hoch dosiert bzw. die Wirkstofflöslichkeit in dem Vehikel gering ist. Folglich werden in diesem Fall hohe Mengen an Carrier- und CoatingMaterial benötigt, was wiederum zu einer Zunahme der Tablettenmasse führt. Der Ersatz der üblicherweise verwendeten Carrier- und Coating-Materialien durch das hochadsorptive Neusilin® ermöglicht die Reduktion der Tablettenmasse.

Contents V Contents

1. Liquisolid technology – a method to enhance and prolong drug release 1

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1.1 Introduction With the liquisolid technology as described by Spireas [1] a liquid may be transformed 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. 1).

Inert, preferably water-miscible organic solvent systems with high boiling point such as propylene glycol, liquid polyethylene glycols, or glycerine are best suitable as liquid vehicles. 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 carrier material and amorphous silicon dioxide (colloidal silica) as coating material.

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Various excipients such as lubricants and disintegrants (immediate release) or matrix forming materials (sustained release) may be added to the liquisolid system to produce liquisolid compacts (Fig. 2).

Fig. 2: Schematic outline of the steps involved in the preparation of liquisolid compacts [1] Liquisolid compacts of poorly soluble drugs containing a drug solution or drug suspension in a solubilising vehicle show enhanced drug release 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 [3-8]. Accordingly, this improved drug release may result in a higher drug absorption in the gastrointestinal tract and thus, an improved oral bioavailability [9, 10].

As shown in Fig. 3, drug release from liquisolid compacts is significantly faster than that from their directly compressed counterparts. Here, liquisolid compacts with hydrocortisone containing a 5 % [w/w] drug solution in polyethylene glycol 400 were investigated using microcrystalline cellulose and colloidal silica as carrier and coating materials, respectively [11].

Liquisolid Technology 4 Fig. 3: Hydrocortisone release profiles from liquisolid compacts containing a 5 % [w/w] drug solution in polyethylene glycol 400 ( ) and from directly compressed tablets ( ) with the same drug dose of 10 mg [11] Moreover, the liquisolid technology may also be used to prolong dissolution rate [1, 8, 12, 13]. Sustained release oral dosage forms are beneficial with regard to patient compliance because of the reduced dosing frequency. Ideally, a sustained release dosage form leads to therapeutic plasma levels, which are maintained throughout the dosing interval. It has been shown that with hydrophobic carriers such as Eudragit® RL and RS instead of hydrophilic carriers, sustained release systems may be obtained [13]. Sustained release from liquisolid compacts with the conventional carrier and coating materials may also be observed after addition of a matrix forming material such as hydroxypropyl methylcellulose [1].

With the liquisolid technology it is possible to prepare sustained release tablets with a zero order drug release pattern (Fig. 4). Here, liquisolid compacts with nifedipine containing a 30 % [w/w] drug suspension in polyethylene glycol 400 were prepared using microcrystalline cellulose and colloidal silica as carrier and coating materials, respectively [1]. In addition, 22 % [w/w] of the matrix former hydroxypropyl methylcellulose with a viscosity grade of 15 mPa·s was added to obtain sustained drug release.

Liquisolid Technology 5

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1.2 Theory of Liquisolid systems A powder can retain only limited amounts of liquid while maintaining acceptable flow and compression properties. To calculate the required amounts of powder excipients (carrier and coating materials) a mathematical approach for the formulation of liquisolid systems has been developed by Spireas [1, 14]. This approach is based on the flowable (Ф-value) and compressible (Ψ-number) liquid retention potential introducing constants for each powder/liquid combination.

The Ф-value of a powder represents the maximum amount of a given non-volatile liquid that can be retained inside its bulk [w/w] while maintaining an acceptable flowability. The flowability may be determined from the powder flow or by measurement of the angle of repose.

The Ψ-number of a powder is defined as the maximum amount of liquid the powder can retain inside its bulk [w/w] while maintaining acceptable compactability resulting in compacts of sufficient hardness with no liquid leaking out during compression [15].

The compactability may be determined by the so-called “pactisity” [1, 15] which describes the maximum (plateau) crushing strength of a one-gram tablet compacted at sufficiently high compression forces.

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

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 on the carrier material is not exceeded. This liquid/carrier ratio is termed “liquid load factor L f “ [w/w] and is defined as the weight ratio of the liquid formulation (W) and the

carrier material (Q) in the system:

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where Φ and φ are the Ф-values of the carrier and coating material, respectively.

Similarly, the liquid load factor for production of liquisolid systems with acceptable

compactability ( Ψ L f ) can be determined by:

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where Ψ and ψ are the Ψ-numbers of the carrier and coating material, respectively.

In Table 1 examples of liquisolid formulation parameters of various powder excipients with commonly used liquid vehicles are listed.

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*included as coating material in carrier/coating powder systems As soon as the optimum liquid load factor is determined, the appropriate quantities of carrier (Qo) and coating (qo) material required to convert a given amount of liquid formulation (W) into an acceptably flowing and compressible liquisolid system may be

calculated as follows:

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1.3 Liquisolid formulations for enhanced drug release Many poorly soluble drugs have been formulated as liquisolid systems showing enhanced drug release. Different liquid vehicles, carrier and coating materials were used to formulate these drug delivery systems (Table 2).

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*: drug solution dispersed on various silicas (no compacts) PEG: polyethylene glycol PG: propylene glycol Synperonic® PE/L 81: polyoxyethylene-polyoxypropylene block copolymer Cremophor® EL: polyoxyl 35 castor oil MCC: microcrystalline cellulose HPMC: hydroxypropyl methylcellulose Liquisolid Technology 11

1.3.1 Mechanisms of enhanced drug release from liquisolid systems

In the literature several mechanisms of enhanced drug release have been postulated for liquisolid systems. The three main suggested mechanisms include an increased surface area of drug available for release, an increased aqueous solubility of the drug, and an improved wettability of the drug particles. Formation of a complex between the drug and excipients or any changes in crystallinity of the drug could be ruled out using DSC and XRPD measurements [4, 18, 28].

a. Increased drug surface area

If the drug within the liquisolid system is completely dissolved in the liquid vehicle it is located in the powder substrate still in a solubilized, molecularly dispersed state.

Therefore, the surface area of drug available for release is much greater than that of drug particles within directly compressed tablets [3-5, 11, 14].

Accordingly, with increasing drug content exceeding the solubility limit and thus, increasing fraction of undissolved drug in the liquid vehicle the release rate decreases.

With various drugs it could be shown that the release rates are directly proportional to the fraction of the molecularly dispersed drug (FM) in the liquid formulation [3, 5, 11, 14]. FM is defined by Spireas as the ratio between the drug's solubility (Sd) in the liquid vehicle and the actual drug concentration (Cd) in this vehicle carried by each system [11].


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In Fig. 5 the effect of the fraction of the molecularly dispersed drug (FM) on the release rate of hydrocortisone formulated as liquisolid compacts containing various drug concentrations in varying amounts of propylene glycol as liquid vehicle is shown. It is obvious that the drug release rate increases linearly with increasing FM. Interestingly, this linear increase may be observed only above a certain FM-limit.

Fig. 5: Effect of the fraction of molecularly dispersed drug (FM) on the hydrocortisone release rate at 30 min of liquisolid compacts (means ± SD, n = 3) [11]

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b. Increased aqueous solubility of the drug In addition to the first mechanism of drug release enhancement it is expected that Cs, the solubility of the drug, might be increased with liquisolid systems. In fact, the relatively small amount of liquid vehicle in a liquisolid compact is not sufficient to increase the overall solubility of the drug in the aqueous dissolution medium. However, at the solid/liquid interface between an individual liquisolid primary particle and the release medium it is possible that in this microenvironment the amount of liquid vehicle diffusing out of a single liquisolid particle together with the drug molecules might be sufficient to increase the aqueous solubility of the drug if the liquid vehicle acts as a cosolvent [3-5, 11, 14]. The overall increase in the solubility of drugs caused by liquisolid systems was confirmed by Yadav et al. [6, 16, 20, 33].

c. Improved wetting properties

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1.3.2 Optimization of liquisolid formulations with enhanced drug release The liquisolid technology has been successfully applied to low dose, poorly water soluble drugs. The formulation of a high dose, poorly soluble drug is one of the limitations of the liquisolid technology. As the release rates are directly proportional to the fraction of molecularly dispersed drug (FM) in the liquid formulation a higher drug dose requires higher liquid amounts for a desired release profile. Moreover, to obtain liquisolid systems with acceptable flowability and compactability high levels of carrier and coating materials are needed. However, this results in an increase in tablet weight ultimately leading to tablet sizes which are difficult to swallow. Therefore, to overcome this and various other problems of the liquisolid technology several formulation parameters may be optimized (Table 3).

Table 3: Optimization of formulation parameters for liquisolid systems with immediate drug release

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In various studies the effect of different types of non-volatile liquid vehicles has been investigated. The results suggest that the selection of a liquid vehicle with a high solubilizing capacity for the drug and thus, an increased FM, leads to enhanced release profiles [5, 14, 17, 23, 28]. That means that by selection of a liquid vehicle with optimum solubilizing properties the amount of liquid and thus, the weight and size of the liquisolid compacts can be reduced. However, in addition to the drug solubility in the liquid vehicle other physicochemical characteristics of the liquid vehicles such as polarity, viscosity, molecular weight, chemical structure, and lipophilicity may also have an effect on drug release [14].

A further approach to minimize tablet weight is to increase the liquid load factor by using carrier and coating materials with a high specific surface area or by adding PVP to the liquid formulation. It was found that 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 (1.18 m²/g) is higher than that of lactose (0.35 m²/g), starch (0.6 m²/g), and sorbitol (0.37 m²/g) [4]. Fujicalin® (30 m²/g), a spherically granulated dicalcium phosphate anhydrous, and Neusilin® US2 (300 m²/g), a magnesium aluminometasilicate, turned out to be very effective excipients for liquid adsorption while maintaining acceptable flow and compaction properties [34, 35].

Khaled [25] noticed precipitation and consequently retention of the drug in the cavities of porous excipients upon contact of the liquid formulation with the release medium.

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