Fenofibrate Nanocrystals Coated Microcrystalline Cellulose, A Solidification Strategy for Nanocrystalline Suspension

Abstract

The nanocrystalline suspensions (NCS) are aqueous colloidal dispersions susceptible to Ostwald ripening and particle aggregation during processing and storage. Although conventional drying methods freeze-drying (FD) and spray-drying (SD) are successful, their practical implications are still limited. Longer processing time, elevated costs, batch-to-batch variability, and a lack of a continuous approach limit the drying process. The current work aims to develop a solidification strategy for aqueous NCS of the BCS II molecule, fenofibrate (FNF). The NCS was formulated using combinations of stabilizers to achieve effective particle size reduction (∼300 nm) via wet media milling followed by converting it to solid powder using spray coating onto various grades of microcrystalline cellulose (MCC). The NCS batches prepared using HPMC E5: Kolliphor® TPGS (1:5) and Kollidon® VA64: Dowfax 2A1 (1:5) were spray coated onto MCC, i.e., PH102, KG1000, and Prosolv. The nanospray coating was performed using a sprinkling nozzle pan coater, and the effect of viscosity on spray deposition was examined. The solid-state characterization was performed to assess the crystalline nature of the FNF throughout the process. The flow property analysis demonstrated that all the nanospray coated granules (NSG) exhibited good flowability and compressibility. The morphological assessment provided evidence that the nanocrystals (NC) were effectively coated on the surface of MCC. Kollidon® VA64: Dowfax 2A1 (1:5) nanospray coated PH102 granules showed a ∼90% drug release within 120 mins compared with other MCC. These findings demonstrate that the nanospray coating is a robust solution that mitigates the limitations associated with FD.

Introduction

As drug discovery advances with new techniques, solubility remains a critical constraint for newly developed BCS Class II and IV drug molecules. Development of solid oral dosage forms for such drug molecules is challenging due to its poor aqueous solubility. The poor solubility of the drug also limits the dissolution and bioavailability affecting its therapeutical efficacy. To address these challenges, numerous formulations have been developed, altering both physical and chemical properties of drug molecules with respect to the surrounding i.e., salt formation, complexation, pH-based solubilization, Amorphous solid dispersion, cyclodextrins, etc., [1], [2]. The aforementioned strategies have been extensively discussed in previously reported work for enhancing solubility; nevertheless, individual methods have their limitations due to the added complexity in continuous manufacturing. Therefore, this creates a demand for new techniques, nanocrystal (NC) technology is one among them which represents a scalable approach capable of enhancing the solubility and dissolution of numerous BCS class II and IV drug candidates.

Leveraging the use of NC technology, wherein crystals are dispersed in solvent-free aqueous media known as nanocrystalline suspension (NCS). This aqueous medium contains drug molecules with a particle size in the nanometers (nm) range without the matrix carrier but surrounded by a stabilizer layer. The presence of a stabilizer layer minimizes Ostwald ripening and prevents aggregation. By carefully screening stabilizers and the manufacturing process, NC can achieve high drug content. The principle of solubility enhancement of NC is explained by theories such as the Noyes-Whitney, which elucidates that as the reduction in particle size leads to an increase in effective surface area, resulting in an enhanced dissolution rate [3]. Kelvin’s theory states that an increase in the colloidal particle curvature increases the dissolution pressure, thereby shifting the equilibrium towards dissolution, increasing the saturation solubility [4], [5].

NC manufacturing technologies are classified into two categories: the top-down approach, the bottom-up approach, [6]. The most commonly applied techniques of top-down approaches comprise microfluidization or high-pressure homogenization (HPH), dual centrifugation (DC) wet media milling, etc. Wet media milling was discovered by Liversidge et al. in 1992 [7] and proven to be a commercially feasible approach as a solvent-free method to achieve uniform particle size reduction and high drug content. This method is compatible even with thermally unstable drugs with maximum scalability [8]. The formulated NC are in liquid state and essentially converted into a dry powder for a solid oral tablet. NC formed after milling has a high surface area, imposing a high free energy on the system. This results in the physical instability of NCS in liquid form over time, as it enhances the risk of a system reverting to a lowered energy state by the formation of agglomerates. [9]. Consequently, solidification of NCS is needed and is accomplished by variety of methods including freeze-drying (FD), spray drying (SD) and fluid-bed granulation, etc. Among the aforementioned techniques, FD is appropriate for small-scale production of thermally unstable molecules. However, it is often less preferred for large-scale batches due to long processing times, the need for process optimization, and the potential of amorphization of the final FD powder. If a suitable cryoprotectant is not utilized, FD may also results in low bulk-density powders with poor flowability and larger particle sizes [10], [11]. Similarly, SD causes lower process yields and minimal sprayable drug content due to the incorporation of substantial amounts of dispersant [12], [13].

Fenofibrate (FNF) is a BCS class II molecule with a very poor water solubility of < 0.1 μg /mL, and a neutral molecule that will not exhibit any pH-dependent solubility, leading to incomplete absorption throughout the GIT, and shows submaximal clinical effects [14], [15]. Marketed formulation Lypanthia NT 145® (Tricor®) has a dosage of 140 mg a micronized product that showed an improved bioavailability but experiences a food effect. The irregular bioavailability led to variable low-dose (40-60 mg) and standard high-dose (120-200 mg) requirements [16]. Subsequently, NC-based formulations of FNF have been marketed with minimal food effects due to their enhanced dissolution rate. Also, the reduced particle sizes may facilitate uptake by epithelial cells in the GIT, improving oral bioavailability [17]. Although NC enhance bioavailability, the formulated NCS in the liquid state exhibits rapid agglomeration and gradual Ostwald ripening during storage [18]. Hence, FD was employed, but it results in hygroscopic and less compressible powders. During the process of FD, a change in physical state may also occur and may affect the final dissolution behavior of FNF[19]. Beyond FD and SD, several alternative downstream solidification strategies have been investigated to convert drug NCS into solid oral dosage intermediates, with fluid bed–based processes being widely reported. In the context of FNF , Tran et al. demonstrated a scalable granulation approach using Fluorite® as a porous carrier to solidify FNF NCS, thereby improving dissolution performance [20]. Similarly, Azad et al. employed fluidized bed coating to deposit FNF onto lactose-based carriers, highlighting the influence of carrier size on dissolution enhancement [21]. Wang et al. reported wet-milled layering of FNF onto sugar spheres to produce multiparticulate pellets, thereby improving dissolution rate and oral bioavailability [22]. Collectively, these studies demonstrate that fluidized granulation and layering techniques as efficient downstream processing strategies for converting FNF NCS into solid dose [23], [24]. Nanospray coating can also be a newer solidification approach, as reported in our previous study, Albendazole nanosuspension was developed and spray-coated onto microcrystalline cellulose carriers (MCC) to form NSG. These granules were further filled in EUDRACAP® for colon-specific targeting [25]. Similarly, Saikishore et al. performed NCS spray granulation of irbesartan on mannitol and microcrystalline cellulose, to achieve fast dissolution [26]. The same research group had developed NC spray-coated granules and prepared low-dose micro tablets [27]. Jadhav et al. formulated diclofenac acid NCS into sprayed granules [28].

The current investigation aims to develop a solid oral dosage form of FNF-NCS. The particle size reduction was accomplished by DC wet media milling integrating steric and electrostatic stabilizers. The optimized liquid FNF-NCS was further assessed for short-term stability, followed by a nanospray coating of finalized FNF-NCS over the surface of inert MCC. Additionally, the study evaluates the influence of various carriers on the nanospray coating, particularly Avicel PH102, KG1000, and Prosolv. The resulting NSG will be characterized by its flow properties, solid-state properties, microscopic examination, and in-vitro drug release. Facilitating the development of highly compressible granules with superior flow characteristics as a viable alternative for FD with a continuous manufacturing approach (Fig. 1).

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Materials

FNF was procured from AK Scientific (Union City, CA, USA). Hydroxypropyl methylcellulose E5 (METHOCEL™ E5; E5) and alkyldiphenyloxide disulfonate (Dowfax 2A1; DW) were gifted from Dow Chemicals (Midland, MI, USA). The copolymer 1-vinyl-2-pyrrolidone and vinyl acetate (Kollidon® VA64; VA), Sodium lauryl sulphate (Kolliphor® SLS; SLS), and d-alpha tocopherol polyethylene glycol 1000 succinate (Kolliphor® TPGS; TPGS) were obtained from BASF (Tarrytown, NY, USA). Avicel PH102, was received from BASF.

Shashank Reddy Pasika, Henis J. Patel, Yi Guo, Ketan Patel, Fenofibrate Nanocrystals Coated Microcrystalline Cellulose, A Solidification Strategy for Nanocrystalline Suspension., Journal of Drug Delivery Science and Technology, 2026, 108672, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2026.108672.

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