The objective of present study was to optimize spray drying of Risperidone (RIS) nanosuspension for achieving lower particle size, higher yield and good compressibility of spray dried powder using Quality by design approach. RIS nanosuspension was prepared by anti-solvent precipitation technique using poloxamer 68 and Poloxamer 127 as stabilizers. 3 level 2 factorial design was applied using two independent factor variables viz., X1: feed pump speed (RPM) and X2: inlet temperature (degrees C) and their effect upon dependent variables viz., Y1: Size, and Y2: %Entrapment efficiency was determined at three different levels. Spray dried powder was further characterized for bulk level properties and formulated as an orally dispersible tablet (ODT). The developed ODT were characterized by various parameters like wetting time, disintegration time, hardness, friability, weight variation and dissolution for comparison. Size and PDI of formulated RIS Nanosuspension were found to be 200.00 +/- 0.40 nm and 0210 +/- 0.03 respectively. Optimized process parameters for spray dryer were obtained from design space, which gave critical quality attributes (CQA) response of lowest size and highest yield of 214.21 +/- 2.01 nm and 61.85 +/- 1.02% respectively. FTIR, DSC, XRD and AFM studies of spray dried RIS nanosuspension revealed that crystallinity of RIS was altered during spray drying process. Bulk density, Tapped density, Hausner ratio, Compressibility index and Angle of repose of spray dried RIS was found to be 0.588 +/- 0.12 g/mL, 0.641 +/- 0.20 g/mL, 1.09 +/- 0.26, 8.33 +/- 0.32 and 32.40 degrees +/- 0.98 degrees respectively. ODT formulated using optimized spray dried nanosuspension showed higher dissolution than marketed ODT formulation which may be due to increase in solubility of Risperidone during spray drying of nanosuspension. (C) 2018 Elsevier B.V. All rights reserved.