Improved Dissolution of Poorly Water-Soluble Rutin via Solid Dispersion Prepared Using a Fluid-Bed Coating System

Abstract

Background/Objectives: Rutin, a bioactive flavonol glycoside known for its antioxidant, anti-inflammatory, and anticancer activities, faces limited clinical application due to its poor aqueous solubility and low oral bioavailability. This study aimed to enhance the dissolution of rutin by preparing solid dispersions (SDs) using a fluid-bed coating system and formulating the resulting SDs into tablet dosage forms.

Methods: Rutin was dissolved in methanol and sprayed onto various carriers, including lactose monohydrate, mannitol, microcrystalline cellulose, silicon dioxide, and calcium carbonate.

Results: Among the carriers tested, lactose monohydrate produced the highest dissolution enhancement, achieving complete drug release within 15 min versus approximately 60% for free rutin. Further investigation into the effect of the rutin-to-lactose ratio on dissolution enhancement identified 1:10 as the most effective. Characterization by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) confirmed a marked reduction in rutin crystallinity, while scanning electron microscopy (SEM) revealed reduced particle size and successful adsorption onto the carrier. Fourier transformed infrared (FT-IR) analysis suggested hydrogen bonding interactions between rutin and lactose monohydrate, which contributed to improved dissolution. The optimal SD was incorporated into tablets containing 50 mg of rutin via wet granulation, and the inclusion of sodium lauryl sulfate further enhanced dissolution. Stability testing demonstrated that the optimized tablets maintained their dissolution profile after 6 months under accelerated conditions (40 °C and 75% RH).

Conclusions: These findings indicate that fluid-bed coating is an effective approach for preparing SDs to improve the dissolution of rutin and may be extended to other natural polyphenolic compounds.

Introduction

Poor aqueous solubility presents a significant hurdle for numerous drug candidates, profoundly impacting their absorption and subsequent bioavailability [1]. Since oral administration remains the most convenient and commonly used route for drug delivery, the dissolution of a drug in gastrointestinal fluids is a crucial step for achieving effective absorption [2]. Drugs with low solubility often exhibit incomplete or erratic absorption, leading to suboptimal therapeutic concentrations in systemic circulation and high inter-patient variability [3]. This pervasive problem is estimated to affect nearly 40% of currently marketed drugs and up to 70–90% of compounds under development, underscoring its critical impact on modern pharmaceutical research and development [4].

Rutin, a flavonol glycoside identified as 3,3′,4′,5,7-pentahydroxy flavones-3-rutinoside, is also known as quercetin-3-rutinoside or vitamin P. This compound is widely distributed in nature, appearing in plants such as buckwheat, asparagus, and citrus fruits [5].

Structurally, it consists of the flavonol quercetin combined with the disaccharide rutinose, whose molecular structure is shown in Figure 1. This natural compound is renowned for its diverse pharmacological activities, exhibiting antioxidant, anti-inflammatory, and anticarcinogenic properties, making it a promising candidate for various therapeutic applications such as antihypertensive, cardioprotective, neuroprotective, and anti-cancer treatments [6]. Despite its significant therapeutic potential, rutin’s clinical application and oral delivery efficiency are severely limited by its poor aqueous solubility, which poses a substantial hurdle in drug development [7].

Rutin is classified as a Biopharmaceutical Classification System (BCS) class II compound, indicating its low solubility and high permeability [8,9]. For this reason, strategies to enhance rutin’s aqueous solubility are crucial for unlocking its full therapeutic potential and enabling its effective incorporation into pharmaceutical products.

To improve the solubility and dissolution of rutin, various formulation strategies have been explored, including cocrystallization [10], cyclodextrin complexation [11,12], self-emulsifying systems [13], nanoemulsions [14,15], solid dispersions (SDs) [8,16], and nanoparticulate delivery systems [17,18]. Some of which have shown that enhanced solubility and/or dissolution translated into improved oral bioavailability in preclinical animal studies [10,13]. Among these, SD techniques have emerged as an effective approach, involving the dispersion of a drug within a polymeric carrier matrix. This approach is recognized as a promising strategy to enhance the dissolution rate and bioavailability of poorly water-soluble drugs. The improvement in drug dissolution is typically attributed to several mechanisms, such as particle size reduction, enhanced wettability, and the partial or complete conversion of the crystalline drug into an amorphous form [19].

SDs can be prepared using various conventional methods, such as melting or solvent evaporation [20]. In the melting method, the drug and carrier are melted together and then rapidly cooled to solidify the mixture. The solvent evaporation method involves dissolving both components in a common solvent, which is subsequently removed. However, the melting method requires high processing temperatures, making it unsuitable for thermolabile drugs like rutin [21]. Solvent evaporation methods, while avoiding thermal degradation, typically demand large volumes of solvent and often yield SDs with poor flowability and compressibility, leading to operational challenges during large-scale production. Therefore, there is an ongoing need to develop innovative methods to prepare SDs of poorly water-soluble drugs to enhance their scalability and manufacturability. One effective and practical approach is to utilise fluid-bed coating technology for preparing SDs. In this method, the drug is first dissolved in a suitable solvent and then sprayed onto excipients or beads, referred to as substrates [4]. Solvent evaporation and SD deposition occur simultaneously, resulting in the formation of SD granules with improved flowability and compressibility. Another advantage of this approach is that the resulting granules can be easily processed into final dosage forms, such as tablets or capsules, suitable for commercialization. To the best of our knowledge, this approach has not yet been applied to prepare rutin-loaded SDs for enhanced dissolution.

The aims of this study were to (1) improve the dissolution of rutin by preparing the SD using a fluid-bed coating system and (2) to further formulate the prepared SD into a tablet dosage form. The type of carrier and the drug-to-carrier ratio were investigated for their effects on the dissolution enhancement in the SD. The drug crystallinity was significantly reduced in the SD, as evidenced by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) data, together with reduced particle size shown in scanning electron microscopy (SEM) images. Changes in these physical properties can be explained by the intermolecular hydrogen bonding interactions between the drug and the carrier shown in Fourier-transformed infrared (FT-IR) spectra. The prepared SD proved to enhance the dissolution compared to the free drug and was subsequently formulated into a tablet dosage form with enhanced dissolution and a good stability profile over 6 months of storage in accelerated conditions. This scalable SD strategy via fluid-bed coating technology shows potential for improved dissolution of poorly water-soluble rutin, which can subsequently improve its oral bioavailability.

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Materials

Rutin (Shaanxi Ruiwo Phytochem Co., Ltd., Ankang, China), lactose monohydrate (Tablettose® 100, Meggle, Wasserburg am Inn, Germany), mannitol (Pearlitol® 50 C, Roquette, Lestrem, France), microcrystalline cellulose (Avicel PH-101, FMC International, Cork, Ireland), silicon dioxide (Syloid® 244 FP, Grace GmbH, Worms, Germany), calcium carbonate (Xilong Chemical, Shantou, China), sodium lauryl sulfate (SLS, Sigma Aldrich, St. Louis, MO, USA), and polyvinyl pyrrolidone K30 (PVP K30, Ashland Chemical, Wilmington, DE, USA) were purchased for use. Distilled water was deionised by reverse osmosis with a Milli-Q water Millipore Purification System™ (Millipore Corp., Bedford, MO, USA). All other chemicals and solvents were of analytical-grade standard.

Nguyen, H.V.; Nguyen, N.T.-T.; Tran, H.K.-T.; Huynh, T.T.-N.; Vo, V.H.-B.; Le, C.T.-T.; Saha, T. Improved Dissolution of Poorly Water-Soluble Rutin via Solid Dispersion Prepared Using a Fluid-Bed Coating System. Pharmaceutics 2025, 17, 1559. https://doi.org/10.3390/pharmaceutics17121559

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