Structural variability within, and polymorphic stability of, nano-crystalline molecular clusters of l-glutamic acid and D-mannitol, modelled with respect to their size, shape and ‘crystallisability’

Abstract

The molecular and intermolecular structure and energetic stability of nano-sized molecular clusters for two polymorphic forms of L-glutamic acid (L-GA) and two of D-mannitol (D–M) are assessed. Molecular modelling, using empirical force-fields and the atom-atom method, is applied to examine the relative stability of both facetted and spherical clusters. Clusters are built on the basis of their crystallographic structures and then monitored following minimisation of the inter-molecular packing and relaxation of the intra-molecular conformations. Examination of energetic stability of the clusters reveals that at small cluster sizes (<250 molecules for LGA and <35 molecules for D–M) fully relaxed and facetted molecular clusters of the bulk metastable phase are more energetically stable than clusters derived from the stable solid-form crystal structures. The effect is, in general, found to be less pronounced for spherical compared to the facetted clusters particularly for L-GA (<100 molecules for L-glutamic acid) albeit following relaxation of D–M clusters the effect is slightly more pronounced (<50 molecules). A comparison between the molecular conformations present in the pairs of polymorphs of L-GA and D–M and the conformations of the energy-minimised, isolated molecules is used to probe the transition pathway from isolated molecule through to molecules with the conformation manifested in the respective polymorphs. This reveals that the solid-state intermolecular forces, associated with crystallisation, effect a distortion of the molecular conformations away from the equilibrium conformations with, interestingly, smaller conformational changes being predicted for the metastable forms of both compounds. Structural optimisation of all the molecules within the clusters, with respect to their original crystallographic structures, reveals the variation in molecular conformation to be greater for smaller compared to larger cluster sizes and slightly less for the ‘metastable’ compared to the ‘stable’ phases. The results are discussed with reference to Ostwald's rule of Stages (see e.g. W. Ostwald, Zeitschrift fur Physikalische Chemie (Leipzig), 1897, 22, 289–329) and related to the development of potential approaches for predicting both appropriate crystallisation conditions to achieve a desired polymorphic form and for the assessment of the inherent ‘crystallisability’ of a given material.