The present study systematically and simultaneously investigates the influence of process variables of spray-drying on the properties of solid self-microemulsifying drug delivery system (SmeddS) using design of experiment (DOE) and optimizes them in order to produce solid-SMEDDS satisfying pre-defined powder quality attributes. Flurbiprofen-loaded liquid-SMEDDS was dispersed in dextran and spray-dried. After preliminary screening, the independent factors selected according to three-factor, three-level Box-Behnken design were inlet temperature (X 1 ), feed rate (X 2 ) and carrier concentration (X 3 ). The responses used to compute the effects of independent factors were moisture content (Y 1 ), yield (Y 2 ), drug content (Y 3 ) and droplet size (Y 4 ) of the micro-emulsion. SMEDDS powder characteristics such as morphology, thermal behavior, crystallinity and flowability were also considered. Models were developed and model fitting analysis showed an adequate fit for all responses, indicating good predictability. Significant effects of processing parameters on powder characteristics were observed. The spray-drying process parameters were optimized as inlet temperature (134°C), feed rate (5%) and carrier concentration (0.6%) to produce solid-SMEDDS with acceptable moisture content (0.72±0.02%), yield (58.5±2.9%), drug content (70.1±2.7 mg/g) and droplet size (166.8±13.8 nm). Validation of the optimization process in five batches showed experimental value very close to the predicted one, ensuring the reproducibility of the developed models. Furthermore, optimized parameters resulted a highly crystalline flurbiprofen changed to an amorphous form. In conclusion, this study demonstrated the applicability of the DOE approach for optimizing the process parameters to manufacture solid-SMEDDS with desired quality attributes.Key words design of experiment; Box-Behnken design; optimization; self-microemulsifying drug delivery system; spray-drying Self-microemulsifying drug delivery system (SMEDDS) has been emphasized in recent years for its ability to improve the solubility and bioavailability of poorly water-soluble drugs. Conventionally, SMEDDS are prepared as liquid formulations that are either delivered in soft or hard gelatin capsules 1) However, a liquid form of SMEDDS has several potential drawbacks in manufacturing scale-up such as less stability due to the precipitation of active ingredients, especially at lower temperatures, interactions of formulation components with the capsule shells, and leakage from the capsules.2,3) In order to overcome these limitations, the liquid-based dispersion must be converted into a dry product. In addition, a solid form of SMEDDS formulation combines the advantages of enhanced solubility and bioavailability with a higher stability compared to its corresponding liquid formulation. 4) Solidification can be achieved by dispersion of liquid SMEDDS into a suitable inert solid carrier in an aqueous medium, followed by elimination of the water via several techniques such as spray-drying. Th...