The rapid expansion of a supercritical solution (RESS) process was used to produce submicron Paracetamol (=Acetaminophen), Mefenamic acid, Nabumetone and Tolbutamide particles. These model drugs have been chosen since different numbers of polymorphs (I & II, I III and I V) have been reported in literature. Thus, the aim of this investigation was twofold: to examine the possibility of using the RESS process to produce submicron drug particles and to control the polymorphic properties of drug micro particles. The unprocessed and micronized particles are characterized by scanning electron microscopy, X-ray diffraction and differential scanning calorimetry. A significant reduction was observed in the particle size and size distribution of the particles produced by RESS. The mean particle size of the processed particles increased in the following order: Mefenamic acid (0.08 mu m <= x(50) <= 0.16 mu m) < Paracetamol (0.16 mu m <= x(50) <= 0.34 mu m) < Tolbutamide (0.34 mu m <= x(50) <= 0.45 mu m) < Nabumetone (0.75 mu m <= x(50) <= 0.81 mu m). Under certain temperature (333 and 353 K) and pressure (15, 20, 25 and 30 MPa) conditions, it was possible to form the favorable Tolbutamide polymorphic form II. Thus, this study demonstrates that the polymorphic characteristics of submicron Tolbutamide particles produced by RESS can be controlled by varying the pre-expansion conditions while the simple static treatment with supercritical CO2 does not induce polymorphic conversion of the drugs investigated. (C) 2016 Elsevier B.V. All rights reserved.