Influence of crystallisation environment on the nucleation and growth of single crystals of (RS)-ibuprofen

The crystal growth of ibuprofen as a function of crystallisation environment is presented. Measurement of solubility as a function of solvent (ethanol 95%, ethyl acetate, acetonitrile and toluene) and temperature using UV/Vis spectroscopy and gravimetric analysis reveals less than ideal behaviour, consistent with strong solute-solute interactions, particularly in the case of acetonitrile. Examination of the nucleation kinetics reveals a comparatively small metastable zone width (MSZW) (ΔT = 10.0 - 13.9oC) with interfacial tensions in the range 2.56 – 5.52.10-3 (J/m2).
The growth rates for the {001} and {011} faces of spontaneously nucleated single crystals are precisely measured in-situ using optical microscopy revealing that their growth rates increase with increasing supersaturation to different extents, depending on the solvent type with concomitant impact on the crystal habit. For similar supersaturations, the growth rate of {011} is lowest in ethanol and highest in acetonitrile, whilst that of {001} is lowest in toluene and highest in ethanol. The aspect ratios, as a function of supersaturation, are generally higher at the 15 mL than the 0.5 mL crystalliser scale size. The data is consistent with a 2-D Birth and Spread growth model for both surfaces and scale sizes. This is in good agreement with the calculated surface entropy α factor.
The measured growth rate dispersion for these faces is much less for these spontaneously nucleated crystals in stagnant, supersaturated solutions when compared to the literature data obtained for a stirred batch crystalliser. Additional higher index re-entrant faces are found at high levels of supersaturation consistent with their alignment either parallel to the {012} or {112} face.
The growth rate in the non-agitated jacketed vessel is found to be slightly higher than that for the agitated reactors with both being in quite in a good agreement with literature data suggesting that these results on single crystals will have utility in representative the growth rates of a population of crystals in an agitated crystallizer.
Observations are is rationalised using molecular and crystallographic modelling revealing e.g. that polar protic solvents inhibit the growth rate of faces containing
available hydrogen bonding binding sites, such as carboxylic acid groups. Molecular conformational searching reveals the molecular structure in the solid-state to be close to that of molecules minimum intra-molecular energy. Conformer population analysis as a function of solvent reveals no significant solvent effect on the low energy conformer distribution indicative a low likelihood of polymorphic behaviour for this compound in good agreement with literature.