Ivan Marziano

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.

The metastability and nucleation thresholds of ibuprofen in ethanol and water-ethanol mixtures

To investigate the crystallization of ibuprofen [((RS)-2-(4-(2-methylpropyl) phenyl) propanoic acid)] from ethanol and water-ethanol mixtures it is necessary to know the nucleation limits of its solutions. In the absence of crystals, nucleation will seldom occur below the PNT (primary nucleation threshold). If crystals are present, nucleation will seldom occur until below the lower SNT (secondary nucleation threshold). Below the SNT, crystals will still grow with negligible nucleation. PNT and SNT values (expressed as relative supersaturation σ) have been measured at 10, 25, and 40°C for ibuprofen in ethanol and in a range of mixtures of different ethanol (E)/water (W) ratios. The induction times were determined from observing the times to nucleate for a range of different supersaturated solutions at a given temperature and E/W ratio. As expected, lowering the supersaturation leads to longer induction times. In ethanol, the SNT values are small and thus the secondary metastable zone width (MSZW) is relatively narrow with a 1 h SNT relative supersaturation typically about σ ~ 0.05. The 1 h PNT values are much larger with values for σ around 0.3. In aqueous ethanolic mixtures at 25°C, both the PNT and SNT decrease as the water content increases.