Modification of indomethacin crystals using supercritical and aqueous antisolvent crystallizations

Abstract Indomethacin, a non-steroidal anti-inflammatory medicine, was crystallized from an organic solution using supercritical and aqueous antisolvents. Carbon dioxide and water were used as antisolvents for the crystallization of indomethacin in acetone. When the drug solution and antisolvent were brought into contact, solid crystals precipitated. Sebacic acid and urea were employed as habit-modifying agents in the supercritical and aqueous antisolvent experiments, respectively. As the drug concentration in acetone increased from 0.01 to 0.07 g/mL, the average particle size of indomethacin decreased from 26.0 to 7.0 μm (supercritical) and from 2.3 to 0.7 μm (aqueous). Increasing the temperature by 20 °C increased the particle size by 97 (supercritical) and 28% (aqueous). The aspect ratio of the indomethacin crystals decreased from 13 to 2 when habit-modifying agents were added to the system (up to 0.851 wt%). Crystals obtained from the supercritical antisolvent experiments were of the α + γ-form, while the crystals produced from the aqueous antisolvent experiments existed in the α-form. The use of habit-modifying agents did not influence the DSC or XRD profiles of the original indomethacin crystals.