Exploration of solubilisation effects facilitated by the combination of Soluplus® with ionic surfactants

Introduction

Preclinical formulation scientists frequently face substantial challenges presented by drugs with poor aqueous solubility, which complicates achieving required exposure for effective testing of emerging drug candidates. Particularly in preclinical rodent studies, the volumes of administration are small which necessitates high dose loaded enabling formulation to ensure sufficient in vivo exposure (Shah et al., 2014). Given sufficient solubilisation capacity, solution formulations are usually preferred over solid dosage forms or suspensions, as they are less susceptible to issues associated with dosing, dissolution, physical instability and non-uniformity (Neervannan, 2006). Formulating an aqueous solution of the drug candidate using surfactants is a well established method to improve the solubility of poorly water soluble drugs (Kuentz et al., 2007). However, the demand for novel solubility enhancing formulations during preclinical testing is continuously increasing to cope with the rise of poorly-water soluble drugs in drug discovery programs (O’Driscoll and Griffin, 2008, Holm et al., 2023).

Surfactants are amphiphilic molecules that, above their critical micelle concentration (CMC), assemble to colloidal species called micelles. This allows the micellar solubilisation of drugs to increase their apparent solubility (Maher et al., 2023). They represent a heterogeneous class of molecules which can be classified based on various aspects, including their state of ionization, water-dispersibility, -solubility and by their hydrophilic-lipophilic balance (HLB) (Rangel-Yagui et al., 2005). Based on these attributes, they exert different properties of relevance to formulation scientist (Koehl et al., 2020, Saal et al., 2018).

One particularly noteworthy surfactant is the polymeric excipient Soluplus® (BASF), which has drawn significant interest for its potential use in the hot melt extrusion (HME) process of preparing amorphous solid dispersions (ASDs) (Hardung et al., 2010, Linn et al., 2012). Soluplus® is a graft copolymer composed of polyvinylcaprolactam and polyvinylacetate grafted to polyethylene glycol 6000, which confers bifunctional characteristics that make it amenable as both a hydrophilic matrix carrier for ASDs and a potent solubilizer due to its ability to form colloidal polymeric structures (Pignatello et al., 2022). Given its amphiphilic properties and notable solubilisation capacity for poorly water-soluble drugs, Soluplus® has been shown to be a viable preclinical solubiliser for drugs exhibiting high preclinical dose numbers (Tanida et al., 2016, Alopaeus et al., 2019).

It has been previously reported that the addition of other excipients to non-ionic polymers may alter their solution properties by influencing their supramolecular assembly (Shi et al., 2016, Liu et al., 2016). These changes in aggregation behaviour can affect clouding, viscosity, and most importantly, solubilisation of the system by adsorption and redistribution of the ionic surfactant between polymer and bulk phase (Hansson and Lindman, 1996, Holmberg et al., 1997). Thus far, research has primarily concentrated on poloxamers and non-ionic cellulose derivatives (Clulow et al., 2020, Qi et al., 2012). Interactions for the latter have been described through the ’pearl-necklace’ model. This model illustrates the cooperative, non-covalent interactions between the hydrophobic elements of a polymer and the surfactant’s tailgroup, resulting in the formation of clusters of surfactant molecules around the hydrophobic parts of polymer coils (Qi et al., 2012, Persson et al., 1996, Nilsson, 1995). Notably, these interactions have recently demonstrated their relevance in poly(vinylpyrrolidone-vinyl acetate) 64 (PVP-VA 64) systems as well, as reported by Liu et al. (2016).

The effect of combining a polymeric surfactant with an additive on solubility has been categorized as either additive, synergistic, or non-synergistic (Clulow et al., 2020, Feng et al., 2018, Nishikido, 2020). Additive behavior is observed when the drug’s solubility in the excipient combination matches the solubilisation provided by the micelles formed by the excipients independently (Clulow et al., 2020). If the behavior is synergistic, the solubilisation is greater than the sum of the individually determined solubility values, which indicates that the interactions between the polymer and the additive result in the formation of assemblies with a higher affinity for the drug. If colloids of lower affinity assemble, a decrease in solubility over the separately measured solubility values would be expected (Clulow et al., 2020).
Another method for analyzing a drug’s affinity for solubilisation is to consider the slope derived from plotting the solubilised drug concentration against the concentration range of the introduced co-excipient. If the mode of association as a function of added excipient is concentration independent, a constant slope would be expected across the concentration gradient. Any apparent non-linearity would indicate that the mode of association between the excipients is subject to change as a function of co-excipient introduced (Clulow et al., 2020).

Attempts to incorporate ionic surfactants into polymers may reveal challenges in adapting to solution formulations due to the restricted solubilisation ability of prevalent non-ionic polymers. Moreover, studies thus far typically concentrated on diluted systems (Liu et al., 2016, Qi et al., 2012). The influence of mixed non-ionic surfactant systems and sodium dodecyl sulfate (SDS) – non-ionic surfactant systems was investigated by Feng et al. (2018), and it was concluded for a set of eight compounds that mixed non-ionic surfactants in aqueous solutions follow additive behavior, whereas the combination of non-ionic surfactants with SDS negatively influenced solubility, albeit forming mixed micellar systems. Notably, the non-ionic surfactants investigated encompassed different chemical characteristics, spanning from ethoxylated fatty acids, to ethoxylated polysorbates and higher molecular weight polymers such as Lutrol® F 127.

In this context, Soluplus® remains relatively unexplored and given it confers both, micellar and polymeric characteristics, it may exhibit advantages over other conventional polymeric excipients. Thus far, most studies primarily focused on its use as a hydrophilic matrix carrier for ASDs. Special attention has been given to the effects of incorporating ionic surfactants on solid-state physical stability, and supersaturation-precipitation kinetics (Baghel et al., 2018, Xia et al., 2016). Recent studies focusing on liquid state by Xia et al. (2016) highlighted the effect of adding SDS to Soluplus® in the context of supersaturation maintenance of cyclosporin A, where a higher degree of apparent supersaturation was maintained by the introduction of SDS due to the formation of Soluplus®-SDS complexes. Simultaneously, the complexities arising from this combination were noted by Thiry et al. (2016) during dissolution testing of Soluplus® – itraconazole extrudates. It was found that SDS increased the hydrophobicity of Soluplus®, which prevented the material from eroding and releasing from the ASD matrix.

SDS, dioctyl sodium sulfosuccinate (DOSS) and sodium oleate (NaOleate) represent frequently utilized excipients in oral formulation development. In addition, NaOleate is considered a highly biocompatible dietary substrate (Maher et al., 2023). This study aimed to investigate a systematically narrow range of ionic surfactant concentrations added to Soluplus® to enhance the solubilisation of poorly water-soluble drugs. Additionally, the aim was to explore the formation of various colloidal assemblies as a function of the incorporated ionic surfactant.

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Materials

Soluplus® was provided by BASF (Ludwigshafen, Germany). SDS and DOSS were sourced by Sigma-Aldrich (VT, USA) with a purity of 99.9%, respectively. NaOleate exhibited a purity of 97.0% and was purchased from Tokyo Chemical Industry Co. LTD. (Tokyo, Japan). Acetonitrile was obtained from Sigma-Aldrich (LiChrosolv; Supelco; gradient grade for liquid chromatography, VT, USA). To investigate solubilisation by Soluplus®-ionic surfactant systems, seven model drugs exhibiting poor aqueous solubility were investigated. Apart from RO1, all drugs were commercially obtained as specified in Table 1. A representative chemical diversity was targeted with the selected drugs regarding their physicochemical properties, focusing on lipophilicity expressed as calculated logP, melting point, and molecular weight.

Justus Johann Lange, Lukas Enzner, Martin Kuentz, Patrick J. O’Dwyer, Wiebke Saal, Brendan T. Griffin, Nicole Wyttenbach, Exploration of solubilisation effects facilitated by the combination of Soluplus® with ionic surfactants,
European Journal of Pharmaceutical Sciences, 2024, 106957, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2024.106957.

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