**1. Introduction**

The growing number of active pharmaceutical ingredients (APIs) are characterized by poor water solubility. Currently, more than 70% of APIs under development are considered as poorly water soluble and almost 40% present in the pharmaceutical industry possesses aqueous solubility less than 100 μg/mL. Most of them belong to the second class of the Biopharmaceutical Classification System (BCS). These compounds are characterized by low solubility and high intestinal membrane permeability [1].

Given that the oral bioavailability of active pharmaceutical ingredients depends on their solubility and/or dissolution rate, many methods of solubility improvement have been developed [2]. They include chemical modifications, such as prodrugs [3,4] or salt formation [5], physical processes as micronization or polymorph transitions, as well as the preparation of drug-carrier systems, including solid dispersions (SD) [6,7] and complexes with cyclodextrins [8–11]. Solid dispersions are defined as drug-carrier systems in which a hydrophobic active pharmaceutical ingredient is either molecularly dispersed in a hydrophilic matrix or exists as micro-fine crystals [12]. The matrix can be made from low molecular weight compounds, or more frequently, hydrophilic polymers. They provide the dissolution rate improvement, particle size reduction, reduction of agglomeration, wettability improvement that are achieved by solid dispersion [13,14]. They possess different functional groups, molecular weight, melting temperatures (Tm), and glass transition temperatures (Tg). They can be crystalline (poly(vinyl alcohol)), semicrystalline (poly L-lactic acid), or amorphous (polyvinylpyrrolidone). Moreover, each polymer is characterized by different abilities to maintain molecular dispersion of active substances [15]. Drug-polymer solid dispersions are formed using evaporation methods, such as spray drying, and melting methods, including extrusion. These techniques often require high temperatures, which can influence the stability of the active substance, or high amounts of solvents, which may increase product toxicity and affect the environment [16]. These undesirable effects can be avoided by using supercritical fluid technology for solid dispersion preparation. The most commonly used gas is carbon dioxide, which is a non-toxic, non-flammable and widely available substance. In the supercritical state, i.e., above the critical temperature (31.4 ◦C) and pressure (74 bar), it is viscous and permeable like gaseous substances, while the density is comparable with liquids. It can act as a solvent and/or as a plasticizer for many substances. Also, it is easy to remove from the product after processing, so it is possible to obtain a solvent-free product without a dedicated solvent removal process [16–19].

Currently, tablets are the most popular dosage form. This is due to the ease of administration, neutral taste, appropriate stability and low cost of manufacturing [20–23]. Given that compression is an integral part of tableting, the effect of applied the compression force on the physical stability of the drug needs to be considered, especially in the case of the compounds undergoing mechanically induced activation [24,25]. One of such is bicalutamide, a non-steroidal antiandrogen, which belongs to class II of the Biopharmaceutics Classification System, exhibiting low aqueous solubility (below 5 μg/mL) and high lipophilicity (logP = 2.92) [26]. Th drug undergoes polymorph transition (from physically stable form I to metastable form II) or amorphization upon mechanical treatment as a consequence of a need for the relaxation of stress field applied during milling [27,28]. Drug amorphization was previously described upon milling and spray drying with polyviylpyrrolidone (PVP) [29,30]. Given that glassy bicalutamide recrystallizes easily upon grinding or scratching, the effect of increased pressure on physical stability needs to be investigated deeply. Although many papers describe the effect of temperature and humidity on the stability of amorphous drugs, the effect of pressure applied to solid dispersions during tableting was rarely described [31]. Also, only a few papers describe how the tableting and storage of solid dispersions affect the dissolution performance of bicalutamide.

The polymers chosen for this study were polyethylene glycol (Macrogol 6000, PEG6000,) and Poloxamer® 407 (PLX407). These excipients are commonly used for solid dispersion preparation due to their solubilizing effects, surface adsorption, and wetting enhancement. Macrogols are widely used as carriers due to their low melting point, fast solidification, and capability of forming solid drug solutions [32,33]. However, the presence of a crystalline form may result in unstable formulations and lower dissolution rates [32]. For some drug-active substances, the improvement in solubility enhancement by Poloxamer is more efficient than by Macrogols [34]. Poloxamers, also called pluronics, are amphiphilic block copolymers consisting of hydrophilic ethylene oxide blocks (EO) attached to a central polypropylene oxide unit (PO) of hydrophobic character. They are widely used as carriers, mostly due to a low melting point. Moreover, the differences in the solubility of the constituent blocks of poloxamer macromolecule lead to thermo-responsive self-assembly in an aqueous environment, which is the additional advantage for solubility enhancement [35].

In our studies, we evaluated the use of the supercritical carbon dioxide (scCO2) method as a way to obtain solid dispersions with bicalutamide, which were further (after mixing with excipients) compressed into tablets. The effect of tableting and storage in both normal and accelerated conditions was evaluated together with drug dissolution performance.

#### **2. Materials and Methods**
