Enhancing the Solubility and Dissolution of Apigenin: Solid Dispersions Approach

Abstract

Apigenin (APG), a bioactive flavonoid with promising therapeutic potential, suffers from poor water solubility, which limits its bioavailability. To address this, solid dispersions of APG were prepared using ball milling with sodium alginate (SA), Pluronic^® F-68 (PLU68), Pluronic^® F-127 (PLU127), PVP K30, and PVP VA64 as polymeric excipients. These dispersions were screened for apparent solubility in water and buffers with pH 1.2, 5.5, and 6.8. Based on improved solubility after 60 min, APG–PLU68 and APG–PLU127 dispersions were selected for further study. DSC and FT-IR analysis confirmed molecular interactions between APG and the polymer matrices, contributing to enhanced solubility and dissolution rates. Dissolution rate studies showed that APG–PLU127 achieved 100% solubility at pH 6.8, suggesting its potential use in environments such as the small intestine. Additionally, APG–PLU127 exhibited 84.3% solubility at pH 1.2, indicating potential for solid oral dosage forms, where APG could be absorbed in the acidic conditions of the stomach. The stability study confirmed that storage for one year under ambient conditions does not cause chemical degradation but affects the physical state and solubility of the dispersion. Antioxidant activity was assessed using the ABTS assay. Freshly obtained APG–PLU127 showed 68.1% ± 1.94% activity, whereas APG–PLU127 stored for one year under ambient conditions exhibited 66.2% ± 1.62% (significant difference, p < 0.05). The difference was related to a slight decrease in the solubility of APG in the solid dispersion (T0 = 252 ± 1 μg∙mL⁻¹, T1 = 246 ± 1 μg∙mL⁻¹). The findings demonstrate the superior performance of PLU127 as a carrier for enhancing the solubility, release, and antioxidant activity of APG.

Introduction

Modern pharmacology and medicine face numerous challenges, among which one of the most critical is improving the bioavailability of drugs. A key factor influencing bioavailability is the solubility of a drug in water, as only the dissolved fraction of the active substance can be absorbed by the body and exert the desired therapeutic effects [1,2]. The issue of poor solubility affects nearly 90% of newly developed drugs, posing a significant challenge for the pharmaceutical industry [3]. Promising results can be achieved through chemical and physical modifications of the medicinal compound, as well as by incorporating appropriate excipients into the final drug formulation. Chemical methods include salt formation, complexation, and prodrug design, while physical methods focus on drug delivery systems—modifications that alter the physical form of the substance without changing its molecular structure [4,5,6]. These methods primarily include particle size reduction, amorphization, and the creation of solid dispersions or cocrystals [7].
Apigenin (APG, Figure 1), a flavone, demonstrates significant lipophilicity, which allows it to penetrate biological membranes; however, its low solubility in water (1.35 µg/mL) [8] limits its application despite many biological properties, including anti-inflammatory, antioxidant, and antibacterial effects [9,10].

Despite the potential beneficial therapeutic properties of APG, it is not widely used in medicine due to limitations resulting from low bioavailability. APG belongs to Class II of the BCS system, which means that despite good permeability through membranes, its activity is limited by water solubility [11]. For this reason, attempts are being made to increase bioavailability by creating APG delivery systems. Table 1 summarizes the APG delivery systems described so far in the scientific literature.

(click table to enlarge)

Solid dispersions in polymer matrices offer a promising approach to enhancing the solubility and bioavailability of medicinal compounds [12,13,14,15,16]. Therefore, in this study, we aim to create a solid dispersion of APG with sodium alginate, Pluronic® F-68, Pluronic F-127®, PVP K30, and PVP VA64. The ball milling method (BM) was used to obtain them. Our previous study confirmed that BM enables effective particle size reduction, resulting in very fine drug particles with increased specific surface area [28]. Additionally, the mechanical action of the ball mill ensures high dispersion uniformity, yielding a product with more controlled physicochemical properties. Achieving similar uniformity can be challenging with other techniques, such as spray drying. Another significant advantage of the ball mill is that it operates without the need for high temperatures. This eliminates the risk of thermal degradation of the drug, which is sensitive to heat, unlike methods such as spray drying that may lead to the decomposition of bioactive compounds. Furthermore, the ball mill is relatively simple to operate and has low operating costs. The milling process also enhances the stability of the dispersion. Milling can be conducted in the presence of stabilizers or carriers, which help prevent recrystallization or aggregation of active pharmaceutical ingredients (APIs), making the ball mill particularly effective for preparing stable dispersions. Moreover, the process is highly flexible, allowing for adjustments to parameters such as milling speed, duration, and ball size to optimize the final product properties. In comparison to other techniques, such as precipitation or ultrasonic methods, the ball mill often provides superior control over particle size and distribution, translating to better functional properties of API dispersions. Moreover, dry milling is considered an environmentally friendly method for preparing dispersions. One of the primary environmental benefits of this technique is that it does not require the use of solvents or other chemical agents, reducing the environmental impact associated with solvent disposal and contamination. This solvent-free process eliminates the need for hazardous or toxic chemicals, making it a safer and more sustainable alternative compared to liquid-based techniques, such as solvent evaporation or precipitation, which typically involve the use of large amounts of solvents [29,30,31].

These advantages highlight the ball mill as a versatile and efficient method for preparing APG dispersions for various applications. The results of this research may contribute to the development of new pharmaceutical formulations containing APG, which could be effectively used in the treatment of multiple diseases. Additionally, this work represents a contribution to the advancement and application of mechanochemical pharmaceutical technologies in line with sustainable development principles, which is of critical importance in the context of global environmental challenges.

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Materials

The following reagents were used in the experiments: apigenin (Sigma Aldrich, St. Louis, MO, USA)), ethanol (POCH, Gliwice, Poland)), acetonitrile (HPLC grade, POCH, Gliwice, Poland), 96% formic acid (POCH, Gliwice, Poland), 0.1 N hydrochloric acid (Alfa Chem sp. z o.o., Poznan, Poland), potassium dihydrogen phosphate (POCH, Gliwice, Poland), sodium hydroxide (POCH, Gliwice, Poland), polyvinylpyrrolidone (PVP30, BASF SE, Ludwigshafen am Rhein, Germany), copolymer of vinylpyrrolidone and vinyl acetate (PVPVA64, BASF SE, Ludwigshafen am Rhein, Germany), sodium alginate (SA, Sigma Aldrich, St. Louis, MO, USA), Pluronic® F-68 (PLU68, BASF SE, Ludwigshafen am Rhein, Germany), and Pluronic® F-127 (PLU127, Sigma Aldrich, St. Louis, MO, USA).

Rosiak, N.; Tykarska, E.; Miklaszewski, A.; Pietrzak, R.; Cielecka-Piontek, J. Enhancing the Solubility and Dissolution of Apigenin: Solid Dispersions Approach. Int. J. Mol. Sci. 2025, 26, 566. https://doi.org/10.3390/ijms26020566

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