The use of biocompatible crystalline substrates for the heterogeneous nucleation and polymorphic selection of indomethacin

Abstract

A heteroepitaxial nucleation approach was applied to control the nucleation rates and to selectively nucleate a single form of indomethacin (IMC). Six organic functional crystalline substrates, L-glutamic acid (GLU), L-threonine (THR), allantoin (ALT), xanthine (XAN), biotin (BIO) and L-histidine (HIS) were selected as substrates. The efficacy of each substrate in promoting the nucleation of IMC was examined with a high throughput microscopic method. The polymorphic selectivity of each substrate towards the stable γ-form and the metastable α-form of IMC was investigated with a combination of microscopy, Raman spectroscopy, and powder X-ray diffraction. Induction experiments in ethanol demonstrated that all used substrates were highly effective in enhancing the nucleation rates of IMC. GLU showed complete selectivity towards the formation of γ-IMC, and HIS increased the phase selectivity towards the metastable form by 33% compared to the homogeneous nucleation in ethanol. The combinatorial effect of the presence of HIS and supersaturation of the solvent in promoting the polymorphic selection towards the metastable form was also investigated. Furthermore, Raman spectroscopy-based crystal face indexing was conducted to identify the in contact faces for the substrate and IMC and demonstrated that the major driving force for phase selective epitaxial growth in these organic molecular systems is the level of the functional group match at the substrate–solute interface.