Title : Formulation and Optimization of Furosemide Nanosuspension by Anti-solvent Precipitation

Authors : A. L. Marzan, R. Tabassum, B. Jahan, M. H. Asif, M. Kazi, M. De Matas, M. H. Shariare

Abstract : Purpose: Poor bioavailability is a major challenge for BCS class IV drug like Furosemide. To overcome this hurdle, nanosuspensions were prepared using antisolvent precipitation method for which a process optimization study was undertaken. Critical process parameters (CPP) and critical material attributes (CMA) were investigated using a factorial design to evaluate their impact on critical quality attributes (CQA) (particle size and polydispersity index (PDI). Methods: Furosemide nanosuspensions were prepared by adding a solution of furosemide dissolved in acetone, into water containing pluronic F68 and povidone K30, which were used as stabilizers. The impact of processing parameters (PP) and material attributes (MA) on the particle size and PDI of furosemide nanosuspensions was statistically evaluated using Minitab version 17 software. A full factorial design considering comprising factors [PP- injection rate, anti-solvent temperature, mixing rate and mixing time; MA - drug content, stabilizer type, solvent: anti-solvent and stabilizer: drug ratio] at two levels (high and low) was used to identify critical process parameter (CPP) and critical material attributes (CMA).The nanosuspension batches were characterized using an Inverted Phase Microscope, Scanning Electron Microscopy (SEM) and Malvern Zetasizer. Results: Microscopic and Zetasizer data showed that furosemide particles obtained were in the range of 80-350nm. Results (Figure 1) suggest that injection rate and stirring time were the most critical factors (p0.05) on the average particle size of nanosuspension batches (Figure1). However two-way interactions were found to be significant for MA (solvent: antisolvent ratio and Drug content; stabilizer: drug ratio and solvent: antisolvent ratio). When solvent: antisolvent ratio is low, particle size tends to be smallest (128.6±2.5) with low stabilizer: drug ratio. However, when solvent: antisolvent ratio increases, the opposite effect is observed with low stabilizer:drug ratio and particle size increases (330.3±28.9). Two way interactions were also found to be significant for process parameters (PP) (stirring time and antisolvent temperature). Interactions between processes parameters suggest that increased stirring times lead to larger particle (239.5±18.3) at high anti-solvent temperature. However effect of stirring time on particle size was not significant at low antisolvent temperature. Particle size distribution data (PDI) was found to be dependent mainly on stabilizer: drug ratio and the lowest PDI found in this study was 0.11±0.05. Conclusion: In this study, injection rate and stirring time were identified as CPPs, while interactions between MA were shown to be more effective to product quality than single material attributes in isolation. Control of both CPPs and CMAs, enables the delivery of nanosuspensions with low particle size, which might offer the opportunity to achieve enhanced dissolution and improved bioavailability for furosemide

Journal : Volume : Year : 2016 Issue :
Pages : City : Denver, Colorado, USA Edition : Editors :
Publisher : AAPS annual meeting and exposition , 2016 ISBN : Book : Chapter :
Proceeding Title : American Association of Pharmaceutical scientists (AAPS) Annual Meeting and Exposition, USA. Institution : Issuer : Number :