Nanoization and Characterization of Three Non-Steroidal Anti-inflammatory Drugs (Ketoprofen, Dexibuprofen and Indomethacin)

Abstract

The foremost challenge for pharmaceutical scientist is the poor bioavailability of drugs which is the derivative of poor water solubility. The nanocrystal has got prominent consideration in solving the bioavailability problem by increasing the aqueous solubility of the drugs. The nanocrystals can be prepared by bottom up and top down methods. In the current study nanonization has been accomplished by microchannel fluidic reactor (bottom up method) and media milling (top down method). The current research project has been conducted on three poor water soluble NSAIDs drugs (ketoprofen, dexibuprofen and indomethacin). In the bottom, up method, drug solutions and polymers solutions were mixed in microchannel fluidic reactor and subsequent emergent nanosuspensions were poured into vials having polymer solutions. Stable nanocrystals of the ketoprofen, dexibuprofen and indomethacin with particle sizes of 61 nm ± 3.0 with PDI of 0.25 ± 0.07, 45 nm ± 3.0 with PDI of 0.190 ± 0.06, 380 nm ± 5.0 with PDI of 0.290 ± 0.05 were produced. It was observed that antisolvent and solvent flow rate, inlet angle, mixing time and appropriate polymer with specific concentration were the key parameters which greatly affected yielded nanocrystals. The results obtained demonstrates that high antisolvent solvent volume to solvent volume ratio (2.0/0.5 ml/min) produced the relative smaller nanoparticles size. Moreover, it was originated that nanoparticle size increases while increasing the solvent volume and taking antisolvent volume constant. Similarly, at equal ratio of both antisolvent and solvent volumes, it was revealed that low ratio of both liquids produces comparatively smaller nanoparticle size. The mixing of the nanosuspensions for 60 minutes with subsequent ultra-sonication results in reduction of PDI and nanoparticle sizes. Moreover, small inlet angle 10° produced smaller nanocrystals in relation to inlet angle 50°. Poloxamer 407 was effective stabilizer for ketoprofen and dexibuprofen nanosuspensions while indomethacin nanosuspension was stabilized with HPMC-PVP-SDS polymer combination. Moreover, the imperative physicochemical characterization of the nanosuspensions were carried out and it was observed that the produced nanosuspensions were stable for two months. The crystallinity of the nanoparticles was confirmed by DSC and PXRD. Furthermore, Morphology examination was carried out through SEM and TEM and it has been substantiated that the produced nanocrystals were homogenously distributed with distinctive crystalline morphology. The produced nanocrystals proved significant dissolution rate correlated to marketed formulations and raw drugs. In the media milling method, coarse suspension of drug was prepared in the polymer and then was recycled in the milling machine (Dena®). Th effect of milling time on particle sizes of the model drugs was evaluated. The resulted particle sizes were 169 nm ± 1.98 with PDI of 0.194 ± 0.04, 298 nm ± 2.00 with PDI of 0.234 ± 0.05 and 161 nm ± 1.90 with PDI of 0.229 ± 0.06 for ketoprofen, dexibuprofen and indomethacin respectively. Moreover, the stability studies were carried out and the produced nanosuspensions were stable for two months. The crystallinity of the nanoparticles was established by DSC and PXRD. The Morphological examination was performed on SEM and TEM and it has been observed that the produced nanocrystals were having distinctive crystalline morphology and homogenously distribution. The dissolution studies revealed that produced nanocrystals have significant dissolution rate in relation to marketed formulations and raw drugs. At the end, this research project demonstrates that model drugs are successfully produced in nanocrystal form by Microchannel fluidic reactor and media milling methods.