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The present study was aimed to develop the Glimepiride (GLM) loaded nanosuspension by different methods for increasing the solubility of GLM. Twelve formulations were prepared by combination method (FG), which included antisolvent precipitation method followed by sonication (Method 1) selecting drug and polymer in ratio of 1:10, 1:20 and 1:30. Further 6 formulations were prepared by nanoprecipitation method (Fg) (Method 2) selecting drug and polymer in ratio of 1:10, 1:20 by using different polymers like polyvinyl pyrolidone (PVP K30), and poly(ethylene glycol) (PEG) such as PEG 6000 and PEG 400. The GLM nanosuspensions prepared by different techniques were evaluated by optical microscopy, percent entrapment efficiency (%EE), particle size analysis, zeta potential, transmission electron microscopy (TEM) and in vitro dissolution. FG1 formulation was found to be better formulation showing 82.04% EE, 129–180 nm particle size range, 30.16 mV zeta potential, 0.253 polydispersity index (PDI) and 86.76% drug release as compared to Fgii formulation having %EE, average particle size, zeta potential, PDI value and drug release as 80.03%, 72–383 nm, -22.19 mV, 0.358 and 74.77%, respectively. On the basis of results obtained from different studies, it can be concluded that GLM nanosuspension prepared by combination technique (FG) shows good solubility and dissolution than those prepared by nanoprecipitation technique (Fg), hence the combination technique is found to be a preferred technique to prepare GLM nanosuspension over nanoprecipitation technique.