High-drug-loaded immediate-release tablets of caffeine prepared by twin-screw melt granulation with mannitol

This poster has been presented at the 15th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, which took place in Prague, Czech Republic.

High-drug-loaded immediate-release tablets of caffeine prepared by twin-screw melt granulation with mannitol

Introduction

• Trivially, melt granulation was performed using batch equipment like a high-shear mixer granulator or fluid-bed processor and low-melting excipients as binders. In the last decades, melt extruders with a continuous processing way have become more popular. Twin-screw melt granulation is a promising method for the preparation of high-drug-loaded immediate-release (IR) tablets. Nevertheless, most often the same lowmelting excipients are used as binders in the melt granulation process. It was shown that these excipients lead to tablets with poor mechanical properties [1]. In contrast with the mentioned batch equipment, continuously processing melt extruders can efficiently control the residence time of material in the extruder barrel, thermal, and mechanical history. These circumstances are opening the opportunity to investigate additional excipients, such as polyols as melt binders, to achieve superior mechanical properties and desirable drug release of high-drug-loaded immediate-release tablets.
• This study aimed to investigate the effect of twin-screw melt granulation (TSMG) processing temperature and screw speed on the properties of granules and tablets using caffeine as a model drug and mannitol as a melt-binder.

Materials & Methods

• Particle size distribution (PSD). The PSD was determined by a laser diffraction particle size analyser using an ‘Aero S’ module for dry dispersions (Mastersizer 3000, Malvern Instruments, Malvern, UK).
• TSMG. Caffeine (Farmalabor Srl, Italy; Fig. 1) with an average particle size of 72.4 μm (Fig. 2) and a melting temperature of 275℃ in combination with mannitol with an average particle size of 80.0 μm and a melting temperature of 174℃ (Parteck M100; Roquette, Lestrem, France; Fig. 3) were mixed (70:30, w/w) and melt-granulated using twin-screw extruder Pharma 11 (Thermo Electron Corporation, Karlsruhe, Germany) without a nozzle (Fig. 4) The residence time of material in the barrel for every formulation was determined [2] (Table 1).
• Obtained granules were calibrated via a 1.6 mm sieve and characterised in terms of angle of repose (AoR) and flowability (GTB 2; Erweka GmbH, Langen, Germany), bulk and tap density (SVM II; Erweka GmbH, Langen, Germany), and particle size distribution by sieving (AS 200 digit cA; Retsch GmbH, Haan, Germany).
• Tablet composition. To be focused on the process conditions’ effect on the tablet properties, no components such as disintegrants and glidants were added to the formulation. Granules were lubricated with 1.3 wt.% of magnesium stearate (Magnesia 4264; Magnesia GmbH, Lüneburg, Germany) for 4 minutes at 30 rpm with a double cone blender (DVC Developer; Comasa, Barcelona, Spain).
• Tableting. Using punches with a diameter of 5 mm and a concave surface (cap depth of 0.25 mm), tablets with a target dose of 50 mg of caffeine and a target weight of 72.5 mg (Table 2) were prepared with a compaction simulator (STYL’One Nano; Medelpharm, Beynost, France). Tableting cycles of a small rotary press at a speed of 70 rpm, a precompression pressure of 50 MPa and a compression pressure of 200 MPa were implemented.
• Tablet Hardness Measurement and Tensile Strength Calculation. The tablet thickness (h) and diameter (d), as well as tablet hardness (breaking force,F) were measured (n=10) by a tablet tester (ST50 WTDH; Sotax AG, Aesch, Switzerland) immediately after the compaction. The tensile strength (τ, MPa) was calculated by employing the following equation: τ= (2 F)/(π d h)
• A dissolution test was performed USP-2 (paddle at 50 rpm) in 900 mL of media (pH 1.2; Eur.Ph.) and drug concentration in the dissolution medium was quantified with HPLC-UV.
• Statistically based design of experiments (DoE). A two-level full factorial design with three centre-points was applied (Table 1) using DoE software MODDE® Pro (ver. 13.1.0.687; Sartorius AG, Umeå, Sweden).

Results

• Mannitol (Fig. 3) with a melting point of 174℃ (Fig. 5) was used for TSMG of caffeine (Fig. 1) with a melting point of 237℃.
• Only conveying elements were used for TSMG (Fig. 4). Thermal processing conditions were set in the range of 185-225℃ to avoid caffeine melting (Fig. 4 and Table 1).
• The residence time for all conditions was found in the range of 33-54 seconds (Table 1).
• Upon mannitol crystallisation (Fig 5), granule solidification took place inside the extruder barrel (Fig. 4).
• Screw speed (residence time) was the dominant factor affecting the granule size (Fig. 6).
• The bulk and tapped density of the obtained granules were dependent on both screw speed and processing temperature (Fig. 7 and Fig. 8).
• The tensile strength of tablets was found in the range of 1.5 and 2.3 MPa.
• The friability of tablets was comparable and not more than 0.23 wt.%.
• The amount of drug released in 30 minutes decreased with temperature and screw speed increases (Fig. 9 and Fig. 10).

Conclusion

• High-drug-loaded immediate-release tablets of caffeine with excellent mechanical properties were successfully prepared by twin-screw melt granulation with mannitol (30 wt.%).
• Screw speed emerged as the main factor to influence the apparent density of granulated material, and temperature showed the highest effect on drug release from tablets.
• Supposedly, this is due the fact that granule porosity decreases along with an increase in temperature and screw speed.
• The selection of process parameters allowed us to obtain immediate-release tablets without the need for a disintegrant.
• The optimal conditions for achieving an immediate drug release were found to be at the lowest processing temperature and screw speed. Intermediate conditions (205℃/80 rpm) provided a balance between mechanical strength, rapid disintegration, and immediate-release dissolution.

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Source: Buczkowska EM, Kukuls K, Horváth ZM, Frolova AJ, Petersone L, Dadou S, et al. High-drug-loaded immediate-release tablets of caffeine prepared by twin-screw melt granulation with mannitol. 15th PBP; Prague, Czech Republic, 2026.03.23-26; DOI: 10.13140/RG.2.2.36011.40489

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