2.1. Materials
Dexketoprofen trometamol (DXKT) (Lusochimica SpA, Lomagna, LC, Italy), glyceryl distearate (GDS) (Gattefossè, Saint-Priest, France), colloidal silica (Evonik, Wesseling, Germany), mannitol (Roquette Freres, Beinheim, France), and sucralose (Merk, KGaA, Darmstadt, Germany) were a generous gift from Menarini Manufacturing Logistic and Services s.r.l., Florence, Italy. All other reagents were of technical grade.
2.2. Wet Granulation in a High-Shear Mixer (HSM)
Drug powder was subjected to wet granulation with a HSM using the GMXB-LAB mini GRANUMEIST
® Bottom Drive (Freund Vector, Marion, IA, USA), equipped with a 6-L mixing bowl. Water was used as a granulating solution. The drug powder was previously mixed with colloidal silica, which was added to limit adhesion between particles during the process [
18,
19]. To obtain the necessary amount of DKXT granules, various batches of 1 Kg were produced and then collected together. For each batch, 97.5% of the active ingredient and 2.5% of the colloidal silica were processed in the HSM in three stages: powder mixing, wetting, and massing. In the first step, the powders were mixed for 1 min with an impeller speed of 400 rpm and a chopper speed of 600 rpm. During the wetting stage (5 min), water was added at a constant flow rate of 15 mL/min; the amount of water was 75 mL; the impeller speed was set at 400 rpm and the chopper speed at 600 rpm for 3.5 min; then, the chopper speed was increased to 1500 rpm, remaining constant for the rest of the process. The final stage of massing allowed granule growth thanks to the conjunctive action of the impeller (400 rpm) and chopper (1500 rpm). The massing time was 1 min to avoid overwetting phenomena. The wet granules were obtained using the Erweka AR 400 oscillating granulator, equipped with a 1.5 mm net size (GPI Equipment Group, Jefferson Valley, NY, USA). The obtained granules were dried in a static oven (FD 250 F 9 Vismara s.r.l., Vallemare, PE, Italy) at 50 °C for 2 h, until 1.5% of the residual moisture was reached. The moisture was checked using the loss on drying (LOD) test using the moisture analyzer Mettler HR 83 (Mettler Toledo AG, Nänikon, Switzerland). The granules were then screened with a vibrating test sieve (Retsch GmbH, Haan, Germany) to obtain three different granulometric fractions: the biggest one (B), greater than 850 μm; the medium one (M), between 180 and 850 μm; and the smallest one (S), lower than 180 μm. All the batches were stored in a HDPE (high-density polyethylene) drum with a double bag liner and desiccant bags.
2.7. Solid-State Characterization
Samples of pure DXKT powder, pure GDS powder, and coated and uncoated DXKT granules were characterized at the solid state using the following techniques: X-ray powder diffractometry and differential scanning calorimetry analysis were performed in order to examine whether any change in drug solid-state properties occurred during the granulation process.
X-ray powder diffractometry (XRPD): The instrument used was a theta–theta Bruker D8-advance Powder Diffractometer apparatus (Silberstreifen, Germany) using Cu Kα radiation and a graphite monochromator. The samples were analyzed at room temperature in the 3–30° 2θ range, with the following experimental conditions: step = 0.03-time scan = 1 s, i = 40 mA, V = 40 kV, and λ = 1.54018 Ả.
Differential scanning calorimetry (DSC): Samples (5 to 10 mg) were exactly weighed with a Mettler MX5 microbalance (Mettler-Toledo, Greinfensee, Switzerland) and put in sealed Al pans with pierced lid. Analyses were conducted on a Mettler TA 4000 Stare system (Mettler Toledo, Greifensee, Switzerland) using the following parameters: scanning in a temperature range between 30 and 300 °C, a static air atmosphere, and a scanning speed of 10 °C/min.
Scanning electron microscopy (SEM): SEM was used to examine the morphologies of the coated and uncoated DXKT granules. The samples were analyzed under high vacuum and underwent a preliminary treatment of metallization; that is, they were coated with a metallic film (silver) to better appreciate their morphological characteristics. The samples were analyzed using a FIB-SEM GAIA 3 instrument (Tescan, Brno, Czech Republic).
Specific surface area (SSA): SSA was evaluated with Micromeritics ASAP 2010 equipment (Micromeritics Norcross, GA, USA) according to the BET (Brunauer-Emmett-Teller) method, which involves measuring the amount of inert gas absorbed by a monomolecular layer of the solid under investigation. This was carried out by degassing the sample and then adding controlled amounts of nitrogen gas into a burette connected to an analytical station under vacuum. The nitrogen adsorption isotherm was measured by adding nitrogen gas, and the nitrogen desorption isotherm was measured by withdrawing nitrogen gas. The equilibrium pressure in the burette was measured after each sampling.
Particle size analysis using sieves: Particle size analysis using sieves was used to separate the different fractions of uncoated and coated granules. The used instrument was a vibratory sieve shaker equipped with sieves of 850 μm and 180 μm (Retsch GmbH, Haan, Germany).
Laser diffractometry: The particle size and particle size distribution of the samples were measured through laser diffractometry using Mastersizer 3000 equipment (Malvern Panalytical Ltd., Worcestershire, UK). The operating parameters used were: dispersant = Tegiloxan 3; stirrer speed = 2800 rpm; background measurement time = 15.00 s; sample measurement time = 5.00 s; and light obscuration = 16.48%.
Loss on drying (LOD): LOD values of uncoated DXKT granules were measured following a two-hour stay in an oven at 50 °C; granules with a moisture content of less than 1.5% were considered acceptable. LOD analyses were performed by setting the temperature at 80 °C until the loss of weight was constant for 20 s. Approximately 3 g of granules were weighed to perform the LOD measurement. The results were expressed as percent mass lost (% w/w) relative to the initial weight. A Mettler HR 83 infrared balance (Mettler-Toledo, Greinfensee, Switzerland) was used.
Near infrared spectroscopy (NIR): NIR spectra were acquired between 900 and 1700 nm in the diffuse reflectance mode (200 scan count and 7.8 ms integration time) using a Micro NIR PAT-W Spectrometer (Viavi Solution Inc., Chandler, AZ, USA). A 99% reflectance sample was used as a reference. The spectral acquisition and data elaboration were performed using Unscrambler X 10.3.1 lite Software (Oslo, Norway). This technique was used as an in-line analysis, with the aim of monitoring the coating process and highlighting any differences.
Data elaboration: For data collection, elaboration, and analysis, Excel and JMP Software 17.2.0 (SAS Institute Inc., Cary, NC, USA) were used.