MATERIALS AND METHODS USED

Materials:

Ibuprofen was obtained from Resfar (Milan, Italy); colloidal silicone dioxide (Syloid 244) and talc of pharmaceutical grade were from Prodotti Gianni (Milan, Italy); hydroxypropyl cellulose (HPC LF) was from Eigenmann & Veronelli SpA (Milan, Italy); Eudragit L30D was from Röhm GmbH (Darmstadt, Germany); polyvinylpyrrolidone K30 (PVP K30) was from Basf (Lundmingshafen, Germany); sucrose spheres (30 mesh) were from Gelfipharma International Srl (Milan, Italy). All other material and solvents of the highest purity grade were from Fluka (Buchs, Switzerland).

Physical Characterization of the Starting Materials

Carr’s index determination. The Carr’s compressibility index was determined as an indirect method to assess the powder flow properties from bulk densities. Particularly, the compressibility index of a powder was calculated according to the following equation:

compressibility index (%) = D_f , D_o × 100 Df

where Do is the fluff or poured bulk density and Df is the tapped or consolidated bulk density. The obtained values were then interpreted according to the Carr table reporting the generalized relationship occurring between powder flow properties and compressibilty index.

Contact angle measurements. The contact angle of the compacted powder was measured by a wettability tester (Lorentzen-Wattre apparatus, Sweden).

Rheological studies of binder solutions. Rheological measurements have been carried out using a Rheometrics International rheometer (Rheometrics, Possum Town, NY, USA) equipped with 14w and 24 geometries coaxial cylinders according to the DIN system.

Measurements were conducted at room temperature in the range of shear rate between 0 and 350 s-¹.

Ibuprofen size distribution determination

The size distribution of ibuprofen particles was determined by laser diffraction (Galai-cis-1, Tecnogalenica, Italy) after dispersing the powder in an aqueous 0.1% polysorbate 80 solution saturated with ibuprofen.

Powder Layering Technique

Layered pellets were prepared using GS HP/25 equipment (GS Coating System, Italy). This pilot plant is a multifunction system used to process different dosage forms such as tablets, capsules, pellets, and microgranules, using the same pan.

Sugar spheres were poured into the coating pan, then intermittently treated with a nebulized binder solution applied by spray guns and with a finely dispersed drug powder applied by a specially designed powder feeding unit. The powder feeding unit is a patented system developed by GS Coating System in which two synergic mechanical actions, the vibration applied to the powder feeding unit and the rotary movement of the helical conveyor, allow an extremely precise dosage of the powder. At the end of each cycle of wetting and powder application, the sphere bed was dried to remove the solvent completely, in this way forming the intraparticellar solid bridges between the spheres.

The powder used to obtain the pellets was prepared as follows. The drug was sieved through a 200 μm mesh sieve and then mixed with the excipients. Afterwards, the obtained mixture was passed again through the 200 μm mesh sieve. The application rate of the powder was between 200 and 300 g/min.

The weight ratio between powder and sprayed binding solution was 1,1.25:200. At the end of the layering process the obtained pellets were subjected to a screening operation using a Weston model 503 sieve (Vibrowest, Cormano, Italy).

Particle Morphology

The shape and surface characteristics of the ibuprofen-containing pellets were evaluated by scanning electron microscopy using a Stereoscan 360 microscope (Cambridge Instruments, Cambridge, UK).

Determination of Pellet Moisture Content

In order to assess the performance of the drying process, the residual moisture present in the pellets was determined by weighing the samples before and after the drying process using a thermobalance LJ 16 Mettler Toledo (Schwerzenbach, Switzerland).

Pellet Friability Test

Resistance to abrasion was determined using a Roche TAR 10 frabilator (Erweka, Ensenstam, Germany). To this end, 10 g of pellets were mixed with 25 glass spheres (5μm in diameter)and uniformly tumbled for 10 min at 25 rpm. Weight loss from the tablet was measured afterwards.

Determination of Pellet Ibuprofen Content

Ibuprofen determination was performed as follows. One g of pellets was solubilized in 20 mL of a mixture constituted by a 1% Tween 20 aqueous solution and ethanol 90:10 (vol/vol). Afterwards, samples were centrifuged at 4000 rpm for 10 min and the supernatant was subjected to high-performance liquid chromatography (HPLC) analysis. The HPLC determination of ibuprofen was performed using a system consisting of a Bruker LC21-C chromatographic pump (Bruker, Bremen, Germany), a Rheodyne 7125 sample injection valve equipped with a 50- mL loop (Rheodyne, Cotati, USA), and a Chrom-A-Scope rapid scan ultraviolet detector (Carlo Erba Strumentazione, Milan, Italy) able to measure and store 10 spectra per minute. The elution solvent was degassed by a double-way automatic degasser Erma ERC-3311 degasser (Erma Inc., Tokio, Japan). Samples were chromatographed on a 250 x 4.6 mm reverse-phase stainless steel column packed with 5μ m particles (Model BDS Hypersil C-18, Hewlett Packard, USA), eluted isocratically at room temperature using as mobile phase acetonitrile:water 60:40 vol/vol at a flow rate of 1 mL/min. Ibuprofen was monitored at 263 nm.

Enteric Coating

The enteric coating was carried out using the same HP/25 pan by means of a constant and homogeneous one-way air flow into the core bed combined with a suitable spraying system for the coating material. The composition of the enteric coating suspension was as follows: Eudragit L 30 D-55 (30% aq), 33.2%; talc, 5.0%, titanium dioxide, 3.5%; triethyl citrate, 1.0%; methylene blue, 0.5%; water, 43.2%. The process conditions employed for the enteric coating were as follows: product temperature, 37°C; spray rate, 25 mL/min; inlet air quantity, 100 cm/h; inlet air temperature, 75°C; pan speed, 17 rpm; air cap, n.1; nozzle, 1.4 mm; nebulization pressure, 0.8 bar.

Drug Release Test

The disintegration time and the drug release rate from enteric coated and uncoated pellets were determined according to the procedures reported in the USP XXIII, method A, page 1795 (apparatus 2, 100 rpm, 37°C, acid stage: 750 mL of 0.1 N hydrochloric acid for 2 hours and buffer stage: add 250 mL of 0.2 M tribasic sodium phosphate and adjust to a pH of 6.8).