Twin-Screw Melt Granulation with Mannitol: High-Drug-Loaded Immediate-Release Tablets of Caffeine

Abstract

High drug-loaded immediate-release formulations can be produced using a solvent-free and continuous melt-granulation method with a twin-screw extruder. Known and widely used high-molecular-weight and hydrophobic melt-binders result in weak tablets and negatively influence the disintegration and dissolution of tablets. Thus, this work aimed to probe mannitol as a melt-binder at a concentration of 30 wt.% and to investigate the effect of twin-screw melt granulation processing temperature and screw speed on the preparation of high drug-loaded immediate-release caffeine tablets with superior mechanical properties. A two-level design of experiment with three center points was used for the screening of the effect of barrel temperature and screw speed on granules and tablets properties. Model drug caffeine was mixed with mannitol (Parteck® M100), while a Pharma 11 extruder with helix feed screw elements and without a nozzle was used for twin-screw melt granulation. Processing conditions were found to significantly influence the solid state of ingredients and the quality of granules. Mannitol, as a melt-binder at a concentration of 30 wt.% at given processing conditions, was proven as an efficient melt-binder for high drug-loaded immediate-release tablets with superior mechanical properties.

Introduction

High drug-loaded formulations are in high demand for the manufacture of oral tablets, especially for high dose products. They allow a reduction in the overall tablet size which facilitates swallowing. However, raw drug substances usually possess poor flowability and compactibility. Thus, usually, high-drug-loaded formulations are not applicable for direct compression. To achieve desirable tablet mass uniformity and drug content uniformity, prevent segregation and achieve desirable flowability, high drug-loaded formulations are usually produced using different granulation methods, including dry, melt, or wet granulation [1,2,3].

Wet granulation represents the oldest granulation method, which for immediate-release and high-drug loaded oral solid dosage forms, it is the most often used method. Low-shear wet granulation is the oldest traditionally used method, while high-shear granulation with mixer-granulators followed by fluid-bed granulators appeared later. Therefore, for the realization of wet granulation these types of equipment are most often applied in industry. Upon the evolution of pharmaceutical technology, the batch approach for high-shear and fluid-bed granulation was successfully implemented for melt granulation process. Melt granulation is the method of choice if the drug is thermally stable [4, 5]. Due to the equipment constructive features such as heating via the heating jacket of the high-shear granulator and process organization with the pumping of molten binder into the fluid bed, the maximum attainable heating temperatures are limited. Thus, binders with melting points below 100℃ were used for melt granulation [6].

Conventionally, melt granulation was performed using batch equipment like a high-shear mixer granulator or fluid-bed processor and low-melting excipients as binders. Nevertheless, the transition from batch to continuous and/or solvent-free processes is a rising trend [6, 7]. As such, melt extrusion technologies (specifically co-rotating twin-screw hot melt extruders because of enhanced mixing capabilities) have gained more interest over the last decades and have been used for melt-granulation [8, 9]. These are accompanied by other advantages of continuous manufacturing, such as enhanced process control, relatively small equipment footprint and flexible batch size [6, 10, 11]. Despite the abovementioned advantages, extrusion-based melt granulation relies on the same established low-melting binders historically used for batch granulation processes. These include binders with melting temperature (Tm) below 100℃ as solid polyethylene glycols (Kollisolv® PEG 3350 and 8000), poloxamers, palmitic acid, glyceryl tripalmitate (Dynasan® 116), glyceryl monostearate, stearic acid, glycerol distearate (Precirol® ATO 5), glyceryl tri stearate (Dynasan® 118), glyceryl di behenate (Compritol® 888 ATO), and waxes [12,13,14,15,16]. It is well known that melt granulation with these low-melt binders results in high granulation efficiency but weak tablets [17]. Specifically, despite improved rheological properties of powders (e.g. flowability), melt-granulated formulations with PEG 8000 showed higher plasticity and resulted in tablets with weaker tensile strength in comparison to tablets obtained by direct compression [18,19,20]. Notwithstanding, PEG (such as PEG 6000 and PEG 8000; Fig. 1) is still the most frequent binder in melt granulation, including twin-screw melt granulation (TSMG). Another disadvantage related to hydrophobic melt binders (such as waxes, fatty acids, and glycerol esters of fatty acids) is their negative effect on the tablet disintegration and dissolution – increased disintegration/dissolution time [21].

Compared to fluid-bed and high-shear melt granulation, melt extrusion with reproducible thermal and mechanical history of processed samples opens the possibility to use melt binders which require a higher processing temperature. The maximum processing temperature during melt granulation should be limited to the degradation temperature of formulation components, which is above 220℃, based on our observations, for most organic components. Therefore, some soluble polymers, such as hydroxypropyl cellulose (HPC), Soluplus®, polyvinyl alcohol, Plasdone® S630, have recently been reported in the scientific literature as promising melt binders for TSMG [15, 22,23,24,25,26,27]. It should be mentioned that drug release kinetics decrease when increasing the polymer concentration in the formulation [25, 28]. Soluble polymer binders form viscous gels during dissolution, which slows down the tablet disintegration and dissolution [29].

By analogy with wet granulation, melt granulation can be divided into two groups in accordance with the way of melt binder is introduced [30]. In the first group, the melt binder is completely molten, has fully lost the shape of parent particles, and is distributed (more or less homogeneously), in the powder bed [31,32,33]. In the second group, the melt binder is partly molten, retains some features of the initial binder particles and can represent granule cores [18]. To achieve the results of the first group, in TSMG, mixing and kneading screw elements are used; while to achieve the results of the second group, conveying elements are used [34]. In both cases, granules are formed upon cooling down and solidification of the molten material [14]. Depending on the binder properties and processing conditions, solidification can happen either inside the barrel [31, 35, 36] or after exiting the extruder onto the conveyor belt (Fig. 2) [37].

Melt granulation can pursue different reasons, including drug-excipient physicochemical interactions and solid-state modification [38, 39]. It can be used to increase the apparent intestinal solubility, which results in increased bioavailability for class II and IV drugs in accordance with the biopharmaceutical classification system (BCS). Apart from BCS class II and IV drugs, TSMG is also highly used for BCS class I and III drugs which are mostly formulated as immediate release tablets. Rapid release is especially important for BCS class III drugs [40, 41] considering their limited intestinal transit time and low permeability, thus, their bioavailability depends on the rate and completeness of drug release [41]. Recent investigations have underlined the importance of immediate release for class III drugs and highlighted the limitations of existing pharmacopeial disintegration and dissolution methods [42, 43]. It was shown that in fasted conditions, the available volume for the disintegration and dissolution of media in the stomach is dynamic and relatively small [44]. While in postprandial conditions, the viscosity of the media is relatively high [45]. In both cases, these circumstances are increasing the disintegration and dissolution time, while pharmacopeial methods provide us with biased/non-biorelevant results. Formulation-wise, the best disintegration in the limited volume and dissolution results at the simulated postprandial viscosity of the stomach compartment were obtained with tablet excipients as polyols [46].

Polyols (sugar alcohols), such as sorbitol, mannitol, and isomalt, are known to possess excellent compaction properties and are widely used to improve the mechanical properties of tablets [47, 48]. Thanks to their relatively low molecular weight and high number of hydroxyl groups, polyols have high aqueous solubility [49]. In addition, they have favorable organoleptic characteristics [50, 51]. Depending on their chemical and crystal structure [52], polyols have different melting points and recrystallization behavior upon cooling down (Fig. 3) [37]. Thus, in melt granulation, formulations with different polyols should be processed at different temperatures. Although polyols have been proposed to be used in TSMG [37], their application as melt binders is still under-investigation.

Successful TSMG can be obtained as a result of the balance between the processing temperature and screw speed which controls material residence time in the extruder barrel [17, 53,54,55,56]. Hereby this study aimed to probe mannitol as a melt-binder in the concentration of 30 wt.% and to investigate the effect of TSMG processing temperature (T) and screw speed (SS) on the preparation of high drug-loaded immediate-release caffeine tablets.

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Materials

In this study, caffeine (Farmalabor Srl, Canosa di Puglia, Italy) was used as a model substance, mannitol (#EQ98Q; Parteck® M100; Roquette, Lestrem, France) as a melt-binder, croscarmellose sodium (Kiccolate™; Asahi-Kasei, Tokyo, Japan) as a disintegrant, and magnesium stearate (MgSt; batch no.299546; Magnesia 4264; Magnesia GmbH, Lüneburg, Germany) as a lubricant.

Buczkowska, E.M., Kukuls, K., Horváth, Z.M. et al. Twin-Screw Melt Granulation with Mannitol: High-Drug-Loaded Immediate-Release Tablets of Caffeine. AAPS PharmSciTech 27, 238 (2026). https://doi.org/10.1208/s12249-026-03464-w

Read also our introduction article on Mannitol here: