Effect of polyoxylglycerides-based excipients (Gelucire®) on ketoprofen amorphous solubility and crystallization from the supersaturated state

Abstract

Introduction

Supersaturating drug delivery systems (SDDS) is an effective approach to improve the solubility and dissolution rate of poorly water-soluble compounds. These formulations are able to generate drug supersaturation after dispersion or dissolution in gastrointestinal fluids and maintain it for a physiologically relevant time, thus representing a boost for drug absorption. In SDDS, the drug can be either in solution (e.g., cosolvent systems, lipid-based formulations) or in a high-energy solid form (e.g., amorphous forms, crystalline salt forms, co-crystals and amorphous solid dispersions (ASD) like) (Brouwers et al., 2009). In both cases, supersaturation is achieved when drug molecules are dissolved at a concentration above the equilibrium crystalline solubility (Dahan et al., 2016).

It has been shown that highly supersaturated solutions undergo phase separation when the amorphous solubility of the drug is exceeded, with formation of drug rich-droplets dispersed within the aqueous phase. This phenomenon is known as liquid–liquid phase separation (LLPS) and it has been extensively studied by the research group of Taylor and co-workers (Ilevbare and Taylor, 2013, Raina et al., 2015). When a supersaturated solution undergoes LLPS, a metastable equilibrium takes place between free drug in the bulk aqueous solution and the non-crystalline, water-saturated, drug-rich phase (Miao et al., 2019). The interest in studying this phenomenon arises from the recognition of its role as “drug reservoir” maintaining the maximum drug concentration in the bulk solution while the permeation through the intestinal membrane occurs. However, the dispersed drug-rich phase is thermodynamically unstable, and thus there is a constant driving force toward crystallization to lower the system’s free energy by reducing the concentration of free drug (Indulkar et al., 2020). When crystallization occurs, nucleation followed by crystal growth rapidly depletes drug supersaturation up to a drug concentration that approaches the crystalline equilibrium solubility.

Various studies have shown that excipients might affect both the maximum supersaturation (amorphous solubility) and the crystallization tendency from supersaturated solution. The role of polymers as crystallization inhibitors is well studied. Some polymers are able to delay or inhibit drug crystallization either from solution or in a solid matrix. They can impact either nucleation by interacting with the drug aggregates that form crystal nuclei, or growth by being adsorbed onto the developing crystal surfaces (Indulkar et al., 2020). In addition to polymers, surface active materials might also impact the crystallization processes by influencing nucleation and crystal growth (Dai et al., 2008, Chen et al., 2015) or accelerating solution-mediated polymorph transformation (Semjonova and Bērziņš, 2022). However, the mechanisms underlying these effects are still poorly understood. Furthermore, the amount of amphiphilic excipients (whether above or below the critical micelle concentration, CMC) is a determining factor, as the monomeric and micellar forms can interact differently with the drug-rich droplets and the crystal nuclei in supersaturated drug solutions (Indulkar et al., 2020).

Polyoxylglycerides-based solid mixtures, commercially known as Gelucire® with high Hydrophylic Lipophylic Balance (HLB), are a widespread class of excipients for developing self-emulsifying and/or supersaturating drug delivery systems aimed at improving the bioavailability of poorly water soluble drugs (Bertoni et al., 2020, Bertoni et al., 2019, Qi et al., 2010). These semicrystalline carriers, classified as GRAS, are composed of polyethylene glycol (PEG) esters of long chain fatty acids, mono-, di- and triglycerides (Panigrahi et al., 2018). They have low melting temperatures and are thus suitable to be processed by solvent-free manufacturing technologies such as hot melt extrusion (Uttreja et al., 2024), melt granulation (Sarabu et al., 2021), spray congealing (Bertoni et al., 2019, Qi et al., 2010) and 3D printing (Daravath, 2021, Vithani et al., 2019). They have been used either alone (Aldosari et al., 2021) or in combination with polymers, oils and surfactants to produce different types of dosage forms (Shin et al., 2019, Goo et al., 2021). Due to their amphiphilic character, Gelucire® excipients with high HLB have excellent solubilizing properties and have proved to be efficient bioavailability enhancers for drugs. A number of studies have demonstrated their effectiveness in the development of formulations with improved performance in terms of in vitro solubility and dissolution rate (Bertoni et al., 2020, Sarabu et al., 2021, Albertini et al., 2015), as well as in vivo oral bioavailability (Bertoni et al., 2019, Aldosari et al., 2021, Shin et al., 2019).

Despite the interest in using these excipients, their effect on solutions containing hydrophobic drugs above crystalline solubility has not yet been explored. The goal of this study was to investigate the influence of high-HLB Gelucire® on supersaturated solutions of poorly water-soluble drugs. Specifically, two commercial Gelucire® excipients with high HLB values (Gelucire®50/13 and Gelucire®48/16) mixed at 1:1 wt ratio (hereinafter referred to as Gel-mix) were used and evaluated regarding their influence on:

• (i) the drug crystalline solubility (i.e., solubilization in the aqueous bulk phase);
• (ii) the drug amorphous solubility (i.e., LLPS onset);
• (iii) the properties of the colloidal drug-rich phase formed when amorphous solubility is exceeded;
• (iv) drug crystallization from supersaturated solutions.

Ketoprofen (KET), which belongs to class II of the BCS, was selected as model drug. First, KET crystalline and amorphous solubility were determined in the presence of several Gel-mix concentrations. The impact of Gelucire® excipients on the properties of the KET-rich colloidal phase formed at concentrations above the amorphous solubility was investigated. In parallel, the influence of Gelucire® on KET crystallization from supersaturated solutions was evaluated.

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Materials

Ketoprofen (KET) was purchased from Merck (Darmstadt, Germany). Gelucire®50/13 and Gelucire®48/16 were kindly supplied from Gattefossè (Milan, Italy). Methocel E5 (HPMC) was a gift of Colorcon and PVP K-30 (Kollidon®30) was kindly supplied by BASF S.p.A. (Ludwigshafen, Germany). In order to have the drug molecule in non-ionised form, the aqueous medium used for all experiments was NaCl/HCl buffer (0.2 M, pH 1.2). All other chemicals and solvents used were of analytical grade.

Serena Bertoni, Beatrice Albertini, Nadia Passerini, Effect of polyoxylglycerides-based excipients (Gelucire®) on ketoprofen amorphous solubility and crystallization from the supersaturated state, International Journal of Pharmaceutics, Volume 669, 2025, 125030, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.125030.

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