Release optimisation of indomethacin microspheres obtained by ultrasonic spray-congealing technique.

INTRODUCTION Indomethacin (IMC) is a potent and safe non steroidal anti-inflammatory drug (NSAID) endowed with good analgesic properties, but its very low water solubility (0.40 mg 100 mL-1 at 25°C) can give rise to formulation problems and limits its therapeutic applications and biovailability. Moreover IMC, used orally for the treatment of acute and chronic rheumatoid arthritis, causes irritation in the gastrointestinal tract, and especially in the stomach [1]. The purpose of this research is to study the possibility of increasing the dissolution rate of the indomethacin by co-evaporation with hydrophilic polymers such as poly-vinylpyrrolidone (PVP) and successively using IMC/PVP co-evaporate product to prepare enteric coating microparticles with stearic acid by ultrasound spray-congealing technique. EXPERIMENTAL METHODS Materials IMC was purchased from Sigma Chemical Co. (St. Louis, MO); PVP of different molecular weights (Kollidon 12 PF, 30 F, and 90 F) were kindly supplied by BASF (Ludwigshafen, Germany) and used as received. IMC was sieved and only < 200 μm fraction was used. Stearic acid was purchased from Polichimica, Bologna, Italy. All other materials were of analytical grade. Kollidon 12 PF was used for all the samples examined. Different PVP were used only for co-evaporated preparation. Preparation of co-evaporates Co-evaporates IMC and PVP (Kollidon 12 PF, 30 F, and 90 F) at 1:1 fixed weight ratio were prepared using alcohol as solvent by the solvent method with temperature not exceeding 50°C. The residue was dried for 24 h under vacuum at room temperature, ground, sieved, and stored in a dessiccator at room temperature Preparation microspheres Using the PVP 12/IMC coevaporated powder (<200 micron), a suspension was prepared in molten stearic acid at 60°C. The mixture has been used to prepare stearic acid co-evaporated PVP-IMC. This microparticles were produced using the ultrasonic atomizer described in detail in a previous paper. For comparison were produced also IMC stearic acid microspheres (for all microspheres – theroretical drug loading 10 % w/w). Sample characterization At each step the material was evaluated using particle size analysis, scanning electron microscopy (SEM), energy dispersion analysis by X-rays (EDAX), evaluation of drug content, differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), X-ray diffraction (XRD) and in vitro dissolution test. RESULTS AND DISCUSSION · Co-evaporated products The three co-evaporated products (PVP 12/IMC, PVP 30/IMC and PVP 90/IMC) appear, as obtained, from a unique solidified mass, which, on breaking, leaves smaller particles with sharp edges and conchoids surfaces. In each case, the two components crystallized together in an apparently homogeneous one-phase system. From dissolution tests of the three co-evaporated materials at pH 7.4, release rate of the drug were improved with respect to the pure IMC, reaching 70% of the IMC dissolved after 2-3 min. In the following tests only PVP 12/IMC co-evaporate has been used because this PVP in solution is less viscous and therefore suitable for ultrasonic spray-congealing technique. · Microspheres Using ultrasound spray-congealing apparatus, it was possible obtain IMC/SA and PVP12/IMC/SA microparticles with a theoretical drug loading of 10% (w/w). The determination of drug content showed that theoretical and experimental values are quite similar and the drug was found uniformly distributed in all the size fractions as documented by EDAX spectra. A) B) Indomethacin Figure 1: EDAX spectra: A) IMC; B) IMC/PVP/SA microspheres The shape and morphology of the samples were examined using SEM. SEM analysis revealed that it was possible obtain spherically shaped and non-aggregated microparticles and in particularly co-evaporated PVP/IMC stearic acid microspheres (at low and high magnifications) sh..