*2.1. Materials*

Itraconazole (ITR, 1-(butan-2-yl)-4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-[(1H-1,2,4-triazol-1 -yl)methyl]-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-4,5-dihydro-1H-1,2,4-triazol-5-one, 99.8%, Henan Tianfu Chemical Co., Ltd., Zhengzhou, China) served as a model drug. Poly(vinyl alcohol) (PVA, Parteck ® MXP, Merck ®- KGaA, Darmstadt, Germany), copovidone (K/VA, Kollidon ® VA64, BASF ®, Ludwigshafen, Germany), crospovidone (K/CL, Kollidon ® CL-M, BASF ®, Ludwigshafen, Germany) were utilized as the matrix-forming polymers to prepare both filaments and 3D printed tablets. Talc (Fagron ®, Kraków, Poland) and magnesium stearate (Avantor ® Performance Materials, Gliwice, Poland) were added to tablets prepared by compression in tablet press. Hydrochloric acid (Merck ® KGaA, Darmstadt, Germany) and potassium chloride (Avantor ® Performance Materials, Gliwice, Poland) were used as dissolution media ingredients. Water used in all experiments was produced by Elix 15UV Essential reversed osmosis system (Merck ® KGaA, Darmstadt, Germany).

#### *2.2. Preparation of Drug-Loaded Filaments*

Filaments were extruded using a 40D, 12-mm co-rotating twin-screw extruder (RES-2P/12A Explorer, Zamak Mercator ®, Skawina, Poland) equipped with a gravimetric feeder MCPOWDER ® (Movacolor ®, Sneek, The Netherlands) and an air-cooled conveying belt (Zamak Mercator ®, Skawina, Poland). The mixtures of itraconazole and matrix-forming polymers, of the composition presented in Table 1, and the total mass equal to 200 g were extruded through a 1.75 mm die at 160 ◦C. The feeding rate was set to approximately 70 g/h, which resulted in the linear filament extrusion speed of 25 m/h. The barrel temperature varied from 40 to 190 ◦C. The optimized temperature profile and screw configuration are presented in Figure 1.


**Table 1.** Composition of the filaments.

**Figure 1.** Screw configuration and temperature profile.

#### *2.3. Evaluation of Filament Properties*

The diameter uniformity of the obtained filament was evaluated using a Mitutoyo ® micrometer screw (Kawasaki, Japan). Six randomly selected points were measured. Mechanical properties were assessed in stretching test performed with an EZ-SX tensile tester (Shimadzu ®, Kioto, Japan). The measurements were performed six times for each type of filament. Randomly selected pieces of filament, 100 mm in length, were placed in the tensile tester's jaws and stretched up to breakage. Hardness and elasticity of the filaments were determined based on the measurements of tensile strength and Young's modulus.

#### *2.4. Determination of Itraconazole Content in the Obtained Filament*

Six randomly selected and accurately weighed pieces of filament were placed in conical flasks filled with 25 mL of a mixture of methanol and 0.1 M HCl of pH 1.2 (1:1 v/v) and shaken for 24 h using a Memmert ® water bath (WNB 22, Schwabach, Germany). The drug concentration was assayed at λ = 255 nm using a Shimadzu ® UV-1800 spectrophotometer (Kioto, Japan). The specificity of the analytical method was verified. There was no sign of interference between the drug and excipients at the analytical wavelength.

#### *2.5. Preparation of 3D Printed Tablets*

The Blender ® 2.79b software was used to design the models of the oblong tablets (Blender Foundation, Amsterdam, The Netherlands). The basic model was 20 mm long and 10 mm wide. The model height varied from 2.4 to 3.65 mm, which was related to the number of 3D printed layers. Voxelizer ® slicing software (version 1.4.18, ZMorph ®, Wroclaw, Poland) was applied to define the height and the width of the single layer path. The 3D model was imported in stl format and divided into layers before printing. The thickness of the first layer was equal to 0.2 mm to improve the adhesion of the print to the printer bed, whereas the height of the subsequent layers was 0.15 mm. The path width was equal to the diameter of the printing nozzle, i.e., 0.4 mm. One outline and rectilinear infill (density of 20%, 35%, and 60%) were designed for the printing process. Each tablet was composed of 50 mg of ITR and 200 mg of polymer carriers (Table 1). The tablets were printed by an FDM ZMorph ® 2.0 S personal fabricator (Wroclaw, Poland) equipped with a 1.75 mm commercially available printhead. Printing temperature was 205 ◦C. The tablets were printed with a 10–15 mm/s printing speed. The temperature of building platform was 40 ◦C.

#### *2.6. Preparation of Tablets by Filament Compression (HME Tablets)*

For comparison purposes, filament milled in a Tube Mill 100 control (IKA ®, Staufen, Germany) and raw compounds were compressed in a Korsch ® EK0 single-punch tablet press (Berlin, Germany). The composition of the tablets was similar to 3D printed tablets; each tablet was composed of 50 mg of ITR and 200 mg of polymer mixture. Additionally, the blends contained 12.5 mg of a talc and magnesium stearate mixture (9:1 w/w), which played the role of glidant and lubricant, respectively.

#### *2.7. Preparation of Directly Compressed Tablets (DC Tablets)*

Powder blends composed of 3DP tablet ingredients with the addition of the talc and magnesium stearate mixture (9:1 w/w) were compressed using Korsch ® EK0 single-punch tablet press (Berlin, Germany) for comparison purposes, to investigate the impact of technological processes on the ITR dissolution profile.

## *2.8. Micro-Computed Tomography*

Micro-computed tomography (μ-CT) analysis was performed using a SkyScan ® 1172 microtomograph (Bruker ®, Billerica, MA, USA). It was applied to examine the structure of the 3DP tablets with 20%, 35%, and 60% of infill and to verify the repeatability of printing process (the data collected for three tablets with 35% of infill were compared). The image pixel size was 6.9 μm for measurements of all samples. A cone beam reconstruction software program (Nrecon SkyScan ®, Bruker ®, Billerica, MA, USA) based on the Feldkamp algorithm was used for the reconstruction of the projections. A CT-Analyser ® (SkyScan ®, Bruker ®, Billerica, MA, USA) was used for binarization purposes. The procedure was based on density distribution histograms collected for the whole sample volume. A CT-Analyser ® was also used for the characterization of the morphological features of the tablets, their volume, and surface. CTVox ® software (Bruker ®, Billerica, MA, USA) was applied to present the 3D results.

#### *2.9. Di*ff*erential Scanning Calorimetry (DSC)*

Thermodynamic properties of neat ITR, PVA, K/VA, K/CL, and their mixtures in the form of filaments and 3DP tablets were examined using a DSC 1 STARe System (Mettler-Toledo ®, Greifensee, Switzerland) equipped with an HSS8 ceramic sensor with 120 thermocouples and liquid nitrogen cooling station. Zinc and indium standards were used for the temperature and enthalpy calibration. The samples were measured in an aluminum, pinned crucible (40 mL). The samples were heated with a rate of 10 K/min. The experiments were performed in nitrogen atmosphere with a gas flow of 60 mL/min.

#### *2.10. X-Ray Powder Di*ff*raction (XRD)*

A Rigaku Denki ® D/MAX Rapid II-R (Tokyo, Japan) equipped with a rotating Ag anode and an image plate detector in the Debye–Scherrer geometry was used for the X-ray di ffraction measurements. Graphite (002) crystal was used to monochromatize the incident radiation (λKα = 0.5608 Å). The width of the X-ray beam at the sample was 0.3 mm. The samples were pulverized before the experiment and measured at room temperature, in glass capillaries with a diameter of 1.5 mm and wall thickness of 0.01 mm. The background intensity from empty capillary was subtracted. The obtained two-dimensional di ffraction patterns were converted into one-dimensional functions of intensity versus the scattering vector.

#### *2.11. Dissolution Studies*

The dissolution of ITR from tablets was determined in 1000 mL of 0.1 M HCl with the addition of KCl, in the pharmacopeial paddle apparatus (Vision ® G2 Elite 8, Hanson Research ®, Chatsworth, CA, USA) equipped with a VisionG2 AutoPlus autosampler. Stainless steel, spring-like sinkers were used to prevent tablet floating. The samples were filtered and analyzed on-line at 255 nm at predetermined periods using a UV-1800 spectrophotometer (Shimadzu ®, Kioto, Japan) equipped with flow-through cuvettes. Three repetitions for each sample were carried out. The results represent the averaged results and the standard deviations (mean ± SD).

## *2.12. Solubility Study*

An excess of physical mixture (PM), extrudate (HME), and printed systems (3DP) were dispersed in 20 mL of 0.1 MHCl and shaken at ambient temperature using a KS 130 basic orbital shaker (IKA ®, Staufen im Breisgau, Germany). After 48h, the samples were filtered through a 0.45 μm Chromafil ® Xtra CA-45/25 membrane filter and analyzed spectrophotometrically at λ = 255 nm (UV-1800 Shimadzu ®, Kioto, Japan). The reported data represent the averages from three series of measurements with standard deviations (SD).
