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

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With the melting method the drug is added to the molten carrier and the mixture is stirred until a homogenous melt is obtained. With the solvent method drug and carrier are dissolved in small amounts of solvent with final solvent evaporation. The higher release rates of solid dispersions may be ascribed to a number of factors which include formation of the amorphous form of the drug, reduction of particle size to nearly the molecular level, improved wetting properties, and solubilisation of the drug by the carrier [61, 65-70]. The advantages of this methodology are the molecular dispersion of the drug within the hydrophilic carrier and the comparably high drug stability. However, for the preparation of solid dispersions usually special equipment is needed such as a spray dryer or a fluid bed apparatus.

Self-emulsifying drug delivery systems (SEDDS) are isotropic mixtures of oil, surfactant, cosolvent and drug, which emulsify spontaneously to produce oil in water emulsions when introduced into an aqueous phase under gentle agitation [71].

Generally, SEDDS are either administered as liquid dosage forms or as soft gelatin capsules. Basically, solid dosage forms are preferred over liquid preparations for many reasons including ease of manufacture, patient compliance, dosage uniformity, and stability. Liquid SEDDS may be transformed to solid self-emulsifying systems Liquisolid Technology 25 (SSEDDS) by addition of powder carriers [72-75]. The liquisolid technology may be used to transform liquid SEDDS into acceptably flowing and compressible powders.

One of the drawbacks of this technique is the high surfactant concentration [45].

1.6.2 Technologies for the retardation of drug release There are several retardation principles for oral sustained release dosage forms including inert insoluble matrices, hydrophilic colloid matrices, membrane-controlled drug delivery systems, ion exchange resins, and osmotic systems [76, 77].

In a matrix tablet the drug is dispersed in either an insoluble or a soluble carrier which forms the matrix [78, 79]. Carrier materials for insoluble matrices are water insoluble polymers, fats, and waxes. From insoluble matrices the drug is released as soon as a solvent enters the matrix and dissolves the particles. The addition of channelling agents increases drug release by leaving tortuous capillaries after leaching [80, 81].

The empty matrix (ghost matrix) is excreted with the feces. Carrier materials for hydrophilic colloid matrices are water swellable or erodible polymers such as hydroxypropyl methylcellulose of different molecular weight [43, 82]. In contact with water the polymer either swells and forms a hydrated matrix layer through which the drug has to diffuse or erodes resulting in a zero order drug release kinetic [83]. Matrix formulations are widely used due to their simple manufacturing process, a high maximum possible drug load, low production costs, and low risk of dose dumping.

Oral dosage forms coated with water insoluble film forming polymers show a membrane-controlled drug diffusion. Hydration of the coating film increases the permeability of the film and facilitates diffusion of the drug. Typical polymers used include ethylcellulose and polymethacrylates, e.g. Eudragit® RS, RL and NE grades [84-88]. To modify the release characteristics of the film water soluble substances may be added as pore forming agents increasing the release rate [89]. However, manufacture of coated dosage forms requires special equipment, the process is timeconsuming, and dose dumping may occur with single-unit systems as a result of film failure or damage.

Liquisolid Technology 26 Cationic or anionic drugs may be bound to an ion exchange resin due to its ionic structure [90, 91]. Drug release from these complexes depends on the pH and electrolyte concentration in the gastrointestinal tract. Release is faster in the acidic environment of the stomach than in the luminal contents of the small intestine [92]. Of course, this mechanism of sustained drug release can only be adopted to ionic drugs.

An osmotic pump system is composed of a core tablet surrounded by a semipermeable membrane with a hole generated by a laser beam. The core tablet consists of the drug, a water soluble polymeric osmotic agent and/or a salt [93, 94]. The semipermeable membrane allows water to diffuse into the core tablet and to dissolve the drug and osmotic agent. As the osmotic pressure inside the dosage form increases, the drug solution or suspension is pumped out of the hole following a zero order kinetic. However, attention has to be paid to the integrity and consistency of the coating film and the accurate size of the hole [95].

Liquisolid Technology 27

1.7 Conclusion

Nowadays, new chemical entities often possess a high molecular weight and a high lipophilicity. Especially poorly soluble and highly permeable active pharmaceutical ingredients represent a technological challenge, as their poor bioavailability is solely caused by poor water solubility, which may result in low drug absorption. Numerous methods have been described to improve water solubility and drug release, respectively, among which the liquisolid technology is one of the most promising approaches. With this technology liquids such as solutions or suspensions of poorly soluble drugs in a non-volatile liquid vehicle are converted into acceptably flowing and compressible powders by simple physical blending with selected excipients named the carrier and the coating material. As highest drug release rates are observed with liquisolid compacts containing a drug solution as liquid portion, liquisolid compacts may be optimized by selection of the liquid vehicle and the carrier and coating materials. Moreover, the addition of disintegrants may further accelerate drug release from liquisolid compacts.

The liquisolid technology may also be used for the preparation of sustained release formulations with zero order release pattern. Thus, a constant plasma level will be reached, which is maintained throughout the dosing interval. For sustained release liquisolid compacts, the selection and the concentration of the excipients such as liquid vehicle, retarding agent (matrix forming material) as well as carrier and coating material play an important role.

The liquisolid approach is a promising technology because of the simple manufacturing process, low production costs and the possibility of industrial manufacture due to the good flow and compaction properties of liquisolid formulations.

Comparison of traditional and novel tableting excipients 28

–  –  –

Abstract Novel tableting excipients are continuously developed and advertised with superior flow and compaction characteristics.

The objective of this study was to compare two traditionally used and two novel tableting excipients with regard to their physical and tableting properties as well as their magnesium stearate sensitivity. Avicel® PH102 (microcrystalline cellulose) was compared to the novel co-processed excipient Prosolv® SMCC90 (silicified microcrystalline cellulose), whereas Anhydrous Emcompress® (anhydrous dicalcium phosphate) was compared to the novel spherically granulated excipient Fujicalin® (anhydrous dicalcium phosphate).

True density was determined with a helium pycnometer, particle size via laser diffraction and specific surface area by gas adsorption. Flowability was characterized by the Hausner ratio and the powder flow rate. Tableting properties were characterized by tabletability (tensile strength vs. compaction force) and mean yield pressure derived from the Heckel Plot. The magnesium stearate sensitivity of the excipients was investigated by determination of the tensile strength of tablets containing different magnesium stearate concentrations.

Due to the silification process in the case of Prosolv® and the unique manufacturing process in the case of Fujicalin®, the novel excipients showed a comparably larger specific surface area. Hardest tablets by far could be obtained with Prosolv®, followed by Avicel® and Fujicalin®. Emcompress® tablets showed the lowest hardness values.

Avicel® and Prosolv® were sensitive to magnesium stearate, whereas Fujicalin® and Emcompress® did not show lubricant sensitivity. This confirms the plastic deformation behavior of microcrystalline cellulose and the brittle fracture of anhydrous dicalcium phosphate.

In conclusion, compared to the traditional excipients the investigated novel tableting excipients were advantageous with regard to their specific surface area with the option of liquid adsorption and their tableting properties.

Comparison of traditional and novel tableting excipients 30

2.1 Introduction

Direct compaction of powder blends is usually preferred over compaction of granules due to the comparably simple and more economical manufacturing process: less equipment is needed, processing times are reduced, and energy costs are lower.

Furthermore, during direct compaction no solvents or heat are needed, which could affect product stability. However, various problems may occur during direct compaction, e.g. poor flowability and/or binding properties and a lack of content uniformity. Therefore, improved excipients with better functionality are needed.

One approach in the development of new excipients with improved properties is coprocessing of two or more materials [96]. Co-processing usually results in a material, which shows better flow and compaction properties than the physical blend of its components.

The co-processed silicified microcrystalline cellulose Prosolv® SMCC, a high functionality excipient, was developed to reduce some of the known disadvantages of conventional microcrystalline cellulose such as low bulk density, poor flowability, and high lubricant sensitivity. Prosolv® is a combination of a filler/binder and a glidant consisting of 98 % microcrystalline cellulose and 2 % colloidal silica. It exhibits better flowability and tabletability than plain microcrystalline cellulose [97-99]. Moreover, Prosolv® shows less lubricant sensitivity [100, 101] and higher prevention of sticking [102]. With FT-IR, C-NMR, powder X-ray diffraction, mercury porosimetry, helium pycnometry, scanning electron microscopy, and particle size analysis it has been shown that silification affects neither the chemical structure nor the polymorphic properties of microcrystalline cellulose [103, 104]. Thus, in the case of the application of silicified microcrystalline cellulose in solid oral dosage forms the regulatory approval process may be sped up because microcrystalline cellulose and colloidal silica are commonly used excipients that are known to be safe.

Another novel excipient with interesting properties is Fujicalin®, an innovative anhydrous dicalcium phosphate with improved tabletability and flowability compared to conventional anhydrous dicalcium phosphate. The unique synthesis process of Comparison of traditional and novel tableting excipients 31 Fujicalin® consists of a restricted crystal growth of anhydrous dicalcium phosphate followed by spray drying of an aqueous dispersion of these microcrystals. Thereby, porous spherical particles cotaining microcrystals of anhydrous dicalcium phosphate are obtained [105, 106]. Due to its high porosity and large specific surface area, Fujicalin® has a high liquid adsorption capacity [107].

As novel tableting excipients are continuously developed and advertised with superior properties, the objective of this study was to compare two traditionally used and two novel tableting excipients with regard to their physical and tableting properties as well as their potential advantages during tablet manufacture. Avicel® PH102 was compared to the novel co-processed excipient Prosolv® SMCC90, whereas Anhydrous Emcompress® was compared to the novel spherically granulated excipient Fujicalin®.

Moreover, the magnesium stearate sensitivity of the excipients was investigated and compared to the different deformation characteristics of the excipients.

Comparison of traditional and novel tableting excipients 32

2.2 Materials and methods Materials Avicel® PH102 (microcrystalline cellulose, MCC), FMC BioPolymer, Cork, Ireland;

Prosolv® SMCC90 (silicified microcrystalline cellulose, SMCC), JRS Pharma, Rosenberg, Germany; Anhydrous Emcompress® (anhydrous dicalcium phosphate, ADCP), JRS Pharma, Rosenberg, Germany; Fujicalin® (spherically granulated anhydrous dicalcium phosphate, SGADCP), Fuji Chemical Industry, Toyama, Japan;

Magnesium stearate (MgSt), Baerlocher, Unterschleissheim, Germany.

Methods Determination of the specific surface area of the excipients The specific surface area (SSA) 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.

Determination of the particle size of the excipients The particle size distribution of the samples was determined via laser diffraction using a dry dispersing system with a feeding air pressure of 1 bar (HELOS equipped with RODOS, Sympatec, Clausthal-Zellerfeld, Germany).

Determination of the true density of the excipients The true density of the excipients was determined by helium pycnometry using a 10 cm³ sample cup equipped with a fritted filter cap (Accupyc 1330, Micromeritics, Aachen, Germany). Prior to testing the excipients were dried for 5 days over phosphorus pentoxide. Each measurement included 10 purge cycles followed by 10 measuring cycles.

Comparison of traditional and novel tableting excipients 33

Flowability of the excipients

Prior to the flowability tests the excipients were mixed with magnesium stearate (0.5 % [w/w]: MCC, SMCC, SGADCP; 1 % [w/w]: ADCP) for 5 min in a Turbula blender (T2F, Willy A. Bachofen, Muttenz, Switzerland) at 72 rpm.

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