Study of the Influence of Pharmaceutical Excipients on the Solubility and Permeability of BCS Class II Drugs
Abstract
Most novel active pharmaceutical ingredients have low water solubility; therefore, solubility-enhancing methods are applied. The aim of the present investigation is to study the impact of nine commonly used pharmaceutical excipients (fillers, surfactants, cyclodextrins, polymers) on solubility, permeability and their relationship. This is crucial for ensuring optimal bioavailability. Carbamazepine, naproxen and pimobendan were chosen as model compounds due to their different acid–base properties. Equilibrium solubility was measured by the traditional shake flask method. Effective permeability was determined by the PAMPA model. Measurements of ionizable compounds were carried out at three pH values. The pH-dependent change in the investigated parameters is maintained even in the presence of excipients. Fillers resulted in a slight or no effect, while the impact of other excipients showed a significant concentration dependence. The impact of excipients was influenced by the structure and ionization state of the molecules. The dominance of the ionized form moderates the impact of excipients. The changes in solubility were more pronounced than in the case of permeability. By examining the effect of the ionization state and interactions with excipients, this work supports the development of formulations that enhance solubility with minimal impacts on permeability. Additionally, it can serve as good basis for preformulation studies and design optimization.
Introduction
Oral drug administration remains the preferred route for drug delivery due to its non-invasive nature, ease of dosing, cost-effectiveness and high patient compliance [1,2]. However, the efficacy and bioavailability of orally administered drugs are highly influenced by two physicochemical properties: the water solubility and the intestinal permeability. The dissolved form of the active pharmaceutical ingredient (API) is essential for the absorption from the gastrointestinal tract (GI), while adequate permeability ensures transport through the membranes [3,4].
Poor aqueous solubility is a common issue, as it affects approximately 40% of commercial drugs and 70–90% of new drug candidates; thus, they belong to Biopharmaceutical Classification System (BCS) II (low solubility, high permeability) or BCS IV (low solubility, low permeability) [5,6].
Consequently, the development of solubility-enhancing techniques has become a major focus of research over the years. As a result, various formulation strategies, including particle size reduction, amorphous solid dispersions, lipid-based and self-emulsifying systems, have been applied to improve solubility [1,7,8]. In addition to the above-mentioned techniques, formulations contain various types of excipients to enhance drug solubility (complexing agents, surfactants), dissolution rate (disintegrants), and the stability of APIs (polymers) to ensure optimal bioavailability [9,10].
While solubility enhancement has been a primary research focus, its effect on permeability remained mainly overlooked until the pioneering work of Dahan and Miller [11]. Their investigation established an inverse relationship between equilibrium solubility and effective permeability (Pe), both in vitro and in vivo. It highlights the potential for reduced bioavailability, when permeability changes are not considered [12,13]. Such a phenomenon was reported by Beig et al., for example, in the case of carbamazepine in the presence of polyethylene glycol (PEG), as well as etoposide in the presence of sodium lauryl sulphate (SLS) and hydroxypropyl-β-cyclodextrin (HPβCD) [14,15,16]. However, in some cases, the solubility–permeability trade-off is not so obvious. SLS at low concentrations (~10 mM) enhances solubility via micelle formation. At the same time, it decreases the permeability by lowering the free fraction of the drug available for passive transport, which demonstrates the interplay between solubility and permeability [17]. However, at higher concentrations, SLS can solubilize intestinal epithelial cells, leading to the damage of the intestinal barrier, which results in increased permeability [18]. Cyclodextrins (CDs), by contrast, may enhance permeability by facilitating drug transport across aqueous media via complex formation [19].
These findings highlight the crucial role of the solubility–permeability interplay in formulation development, which is confirmed by a recently demonstrated novel formulation development strategy based on this trade-off [20,21,22]. However, in most cases the emphasis is placed on a single drug–excipient interaction instead of a holistic study [11,23,24]. Extended investigations are necessary to systematically evaluate the role of solubility enhancers in modulating both parameters across different concentrations and types of excipients. Furthermore, studies at several pH values are necessary to determine the effect of species distribution on the influencing effect of excipients in the case of ionizable molecules.
The aim of this work is to investigate the impact of nine commonly used excipients on equilibrium solubility, permeability, and their interplay using validated methods. During the selection of excipients, the goal was to identify the most frequently applied categories of excipients by prioritizing those commonly utilized in solubility-enhancing research and present in marketed formulations. To achieve this, two excipients were selected from each category. Thus, the final selection included sugars and sugar alcohols—mannitol and sorbitol—which also exhibit hydrotropic properties, along with lactose, a completely inert filler. Cyclodextrins were represented by hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobutyl-ether-β-cyclodextrin (SBEβCD), known for their ability to form inclusion complexes. Among the surfactants, Tween 80 (Polysorbate 80) and sodium lauryl sulphate (SLS) were selected due to their amphiphilic nature and their frequent application in solubilization.
Finally, polymers were represented with polyvinylpyrrolidone K25 (PVP-K25) and polyvinylpyrrolidone/vinyl acetate 64 (PVPVA 64), which are commonly used as solubility enhancers and stabilizers. The occurrence of the excipients was also checked in the FDA database [25]. It contains information (application route, used amount, etc.) about inactive ingredients in drug products approved by the FDA. In formulations, different excipients are applied in various concentrations due to their different functions. While in most cases the concentration of fillers is higher than that of the APIs, the amount of other excipients (e.g., surfactants) is lower. Due to this, 1:0.5, 1:1 and 1:3 mass ratios (APIs:excipients) were investigated during the measurements to model both cases. To ensure a comprehensive analysis, three, BCS II model compounds were chosen: carbamazepine (CAR), naproxen (NAP) and pimobendan (PIMO).
Our aim was to examine compounds with different acid–base properties, and to ensure that the pKa value of the ionizable ones would fall within the pH interval of the GI section (pH = 1.0–6.8), so the protonation state would play a decisive role in their absorption [26]. Due to this, three biorelevant pH values were applied, pH = 3.0, pH = 5.0 and pH = 6.5, which simulate the pH of fed stomach, fed intestine and fasted intestine [27,28]. Hence, in addition to excipient effects, the influence of pH was also investigated. Consequently, the main goal of this research is to conduct a comprehensive, multi-factorial investigation to establish a good basis for formulation design.
For the permeability measurements, Parallel Artificial Membrane Permeability Assay (PAMPA) was applied. Due to its high throughput and low material requirements, it is a suitable technique for studies where several measuring layouts are possible [29,30]. Thermodynamic solubility was measured by the saturation shake flask method (SSF) [31,32,33].
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Materials
CAR (purity >97%) was from TCI Chemical (Tokyo, Japan), NAP (purity 98–102%), and PIMO (purity 98%) was purchased from Sigma-Aldrich Co. LLC. (St. Louis, MO, USA). Table 1 contains some of the most important physicochemical properties and the structures of the APIs. Lactose-monohydrate, sorbitol, mannitol, SLS, PVPVA 64, PVP-K25, and Tween-80 were received from Sigma-Aldrich Co. LLC. (St. Louis, MO, USA), and HPβCD (with the degree of substitution ~4.5) and SBEβCD (with the degree of substitution ~7) were obtained from Cyclolab R&D Ltd. (Budapest, Hungary). The structures of the excipients are presented in Table S1. The buffer components (acetic acid (99–100%), phosphoric acid (>85%), boric acid, sodium hydroxide) were supplied by Molar Chemicals Ltd. (Halásztelek, Hungary). HEPES (2-[4-(2-hydroxyethyl)-1-piperazinyl] ethanesulfonic acid, 238.30 g/mol, purity >99%) was purchased from TCI Chemicals (Tokyo, Japan). GIT lipid was received from Pion Inc. (Billerica, MA, USA).
Bárdos, V.; Szolláth, R.; Tőzsér, P.; Mirzahosseini, A.; Sinkó, B.; Angi, R.; Takács-Novák, K. Study of the Influence of Pharmaceutical Excipients on the Solubility and Permeability of BCS Class II Drugs. Sci. Pharm. 2025, 93, 19. https://doi.org/10.3390/scipharm93020019
Read also our introduction article on Sorbitol here:
