Crystallization kinetics of ibuprofen from ethanol and aqueous ethanol

Ibuprofen [2-(4-isobutyl-phenyl)-propionic acid] is a common analgesic pharmaceutical. It is substantially insoluble in water but quite soluble in organic solvents. Ibuprofen here has been crystallized from ethanol and aqueous ethanol. Batch experiments were undertaken from 10 to 40 oC to measure the solubility, the width of the metastable zone and the growth kinetics. The solubility in ethanol varies markedly with temperature. Generally solubilities fall as the water content increases for aqueous ethanol. At 40 oC, saturated solutions with solvent water contents from 35 to 65 % w/w show a phase separation into two liquid layers. The metastable zone width for primary nucleation is substantial, but is much narrower for secondary nucleation. None the less, growth rates in this narrow secondary metastable zone are still significant and this region, with care, can be used for non-nucleating seeded batch crystallizations. Crystal growth rates were found to be first order with supersaturation, with growth rate constants increasing with temperature [activation energy = 23.4 (±50%) kJ/mol] and within the accuracy of measurement not changing with the solvent water content