The purpose of this study was to investigate the influence of spiral jet-milling process on the physicochemical characteristics of alpha polymorphic active pharmaceutical ingredient, using Carbamazepine form III as a model drug, and taking into consideration Quality by Design (QbD) approach to pharmaceutical development. A 2((4-1)) factorial screening design was implemented to identify the spiral jet-milling process variables that significantly affect the particle size distribution of milled samples. Diameter of injector nozzles, diameter of ring nozzles and air pressure were selected for further analysis using a 2((3-1)) factorial experimental design. Particle size distribution of additional samples was determined, while physicochemical properties were examined by differential scanning calorimetry (DSC), hot-stage polarized microscopy (HSPM), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), and compared to those of un-milled drug. The gathered results shown that applied experimental design approach is capable to predict material behavior and could help in better understanding of material behavior during jet-milling process. Created design space (DS) provides assurance of product quality, expressed as the powder particle sizes lower than 5 mu m, as well as, in initial polymorph form existence after jet-milling through combination and interaction of input variables. (C) 2013 The Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.