Predictive Modelling of Dissolution Behaviour in Liquisolid Systems Based on Tablet Disintegration Kinetics

Abstract

Liquisolid systems (LSS) represent a promising approach for improving dissolution of poorly water-soluble drugs; however, the interplay between formulation variables, tablet disintegration and resulting drug release remains insufficiently understood. Therefore, this study evaluated the effect of tadalafil (TAD) concentration in dispersions (2.5; 5 and 10%) based on four non-volatile solvents, namely polyethylene glycol 200 (PEG 200), Transcutol® HP, propylene glycol and glycerol, on dissolution behaviour of liquisolid powders. All LSS improved TAD release compared to pure drug, while increasing drug concentration was associated with slower dissolution and less pronounced differences between solvents coinciding with formation of more concentrated suspensions and an increased fraction of undissolved drug. PEG 200 provided the most favourable overall performance and was selected for tablet development. Drug release from liquisolid tablets was influenced primarily by formulation composition rather than compression force. For tablets prepared from LSS containing lower fraction of undissolved drug, differences in dissolution profiles could be related to differences in tablet disintegration behaviour, whereas systems containing a higher fraction of undissolved drug required representation of multiple drug populations with distinct dissolution kinetics. Dynamic disintegration measurements combined with a physically grounded dissolution model enabled relating dissolution profiles across compaction conditions without re-adjustment of dissolution parameters. These findings provide mechanistic insight into drug release from LSS, allow distinguish between LSS formulation and tablet compression effects, and support disintegration-based modelling as a tool for formulation optimization.

Introduction

It has been currently reported that less than ten percent of novel drug candidates exhibit excellent permeability and solubility (Lipinski, 2002; Kumari et al., 2023). Furthermore, approximately half of all drug molecules are withdrawn during the development stage due to insufficient aqueous solubility, since its adequate solubility in gastrointestinal fluids is essential to achieve required therapeutic effect. The limited bioavailability of such compounds significantly increases formulation costs, as higher doses must be administered to reach therapeutic levels, which may in turn lead to undesirable toxicity (Kumari et al., 2023). For these reasons, various formulation strategies have been proposed to improve the solubility of poorly water-soluble drugs, including particle size reduction, co-solvents, surfactants, salt formation, amorphous solid dispersions, lipid-based systems and cyclodextrin inclusion complexes (Kumari et al., 2023). However, each of these approaches has specific limitations related to formulation complexity, scalability or applicability to individual drug molecules. In addition, these methods often require organic solvents, which present environmental and health risks. Among novel techniques, preparation of liquisolid systems (LSS) represents a volatile organic solvent-free method suitable for a wide range of poorly water-soluble drugs (Yadav et al., 2024; Taboon et al., 2022; Jaipakdee et al., 2022; Shah et al., 2024; Bhattacharyya et al., 2025).

The main principle of LSS preparation lies in the sorption of the drug in liquid form (liquid drug; drug solution, suspension or emulsion) onto a porous carrier, which is typically further coated with a material possessing a very fine particles with high specific surface area. In this way, a freely flowing, non-adherent powder suitable for subsequent processing into conventional solid dosage forms, such as capsules or tablets is obtained (Vraníková and Gajdziok, 2013). Recently, also liquisolid-based pellets have been introduced as a formulation approach combining enhanced drug dissolution with high flowability and a smooth pellet surface (Pezzini et al., 2016; Vasiljević et al., 2021).

From a biopharmaceutical perspective, the therapeutic efficacy of tadalafil (TAD) can be constrained by its low aqueous solubility and slow dissolution rate (Ali et al., 2022). Since dissolution represents the initial and critical step in drug absorption, this property poses a major limitation. Moreover, due to its very low pKa (0.85) (Alvani et al., 2019), TAD remains essentially non-ionized across the physiological pH range, precluding the use of ionization or salt formation strategies to enhance its solubility. The conversion of its stable crystalline form into an amorphous state is also challenging, further complicating formulation efforts. Tadalafil exhibits an ordered crystalline structure stabilized by supramolecular chains formed through intermolecular hydrogen bonding, which contributes to its high physicochemical stability. As a poorly water-soluble and highly hydrophobic drug, TAD shows a melting point of approximately 300 °C, significantly exceeding the processing temperatures of commonly used polymers for solid dispersion systems. This high thermal stability complicates conventional formulation approaches, as it limits the feasibility of various preparing (Školáková et al., 2019; Školáková et al., 2022).

Given these limitations, liquisolid systems (LSS) emerge as a particularly suitable and effective strategy. By transforming the drug into a molecularly dispersed state within a non-volatile solvent and subsequently converting it into a dry, free-flowing, and compressible powder, liquisolid formulations can significantly enhance the dissolution rate and apparent solubility of TAD, overcoming the constraints associated with its thermal properties and crystalline stability. TAD LSS have already been investigated by Lu et al. (2017); however, their formulation employed Avicel PH 102 as the carrier and PEG 400 as non-volatile solvent. It was shown previously (Vraníková and Gajdziok, 2015), that LSS based on magnesium aluminometasilicate Neusilin® US2 (NUS2) outperform those prepared with microcrystalline cellulose due to its significantly higher surface area and porosity, which enable superior liquid adsorption, improved flowability, higher liquid load factor, and better compressibility. In addition. selecting an appropriate non-volatile solvent, is crucial as it determines whether the drug is in solution or suspension form, thereby significantly impacting the overall drug release behaviour and formulation performance. According to Vasiljević et al. (2024), polyethylene glycols are the most frequently used non-volatile solvents in LSS, although other solvents such as propylene glycol, glycerol and Transcutol® HP have also been successfully employed (Sanka et al., 2014; Mehra et al., 2026; Saeedi et al., 2022; Jaydip et al., 2020).

These liquid vehicles play a key role in enhancing drug dissolution through several potential mechanisms, including an increased available surface area, improved wettability and enhanced apparent solubility of hydrophobic compounds. In addition, the improved intestinal permeation observed for LSS has been attributed to the presence of liquid vehicles, either indirectly via enhanced dissolution or directly through their intrinsic permeation-enhancing properties. Consequently, the type of liquid vehicle may significantly influence the extent of both dissolution and intestinal permeation enhancement (Yadav et al., 2024; Tabboon et al., 2022; Sanka et al., 2014; Komala et al., 2015). For this reason, one of the objectives of the presented study was to evaluate the effect of different solvents, namely PG, PEG 200, glycerol and T-HP, at different concentrations of TAD on the drug release rate from liquisolid powders. Despite the widespread use of LLS to enhance the dissolution of poorly soluble drugs, the mechanistic relationship between tablet disintegration and drug release remains insufficiently understood. LSS consist of well-defined particulate entities with reproducible physicochemical properties, leading to predictable intrinsic drug release behaviour at the particle level. When tablets are manufactured using identical LSS particles, differences in dissolution profiles are therefore expected to originate primarily from variations in tablet disintegration rather than from changes in particle-level dissolution kinetics. In such systems, tablet disintegration can be regarded as the rate-determining step governing drug release, as it controls the temporal availability of primary LSS particles in the dissolution medium. Based on these considerations, the central hypothesis of this study is that dissolution profiles of LSS-based tablets can be quantitatively linked and ultimately predicted using experimentally determined disintegration kinetics. Therefore, the aims of the present study were to investigate the effect of different non-volatile solvents and tadalafil concentrations on drug release from liquisolid systems and to establish a mechanistic relationship between tablet disintegration and drug dissolution that could serve as a predictive tool for formulation design.

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Materials

The model drug tadalafil was purchased from Biosynth (Biosynth Ltd, United Kingdom), mesoporous magnesium aluminometasilicate Neusilin® US2 used as a carrier material was obtained from Fuji Chemical Industry Co. (Fuji Chemical Industry Co., Ltd., Japan). Polyethylene glycol 200 (Dr. Kulich Pharma, Czech Republic), propylene glycol (Dr. Kulich Pharma, Czech Republic), glycerol (Dr. Kulich Pharma, Czech Republic) and Transcutol® HP (Gattefossé, France) were used as non-volatile solvents. To prepare liquisolid tablets cropovidone Kollidon CL-F (BASF SE, Germany), lactose Excipress SD (Armor Pharma™, France) and magnesium stearate (Merck KGaA, Germany) were used as superdisintegrant, filler and glidant, respectively.

Noemi Frigola Verhein, Radek Ludas, Tereza Školáková, Shuvagata Dhar, Eliška Straková, David Novák, Petr Zámostný, Barbora Vraníková, Predictive Modelling of Dissolution Behaviour in Liquisolid Systems Based on Tablet Disintegration Kinetics, Journal of Drug Delivery Science and Technology, 2026, 108848, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2026.108848.

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