An examination of binding motifs associated with inter-particle interactions between facetted nano-crystals of acetylsalicylic acid and ascorbic acid through the application of molecular grid-based search methods.

Grid-based intermolecular search methods using atom-atom force fields are used to assess the structural nature of potential crystal-crystal interfacial binding associated with the examination of representative pharmaceutical formulation components, viz acetylsalicylic acid (aspirin) and ascorbic acid (vitamin C). Molecular models of nano-sized molecular clusters for these two compounds, shaped in accordance with an attachment energy model of the respective particle morphologies, are constructed and used together with a grid-based search method to model the likely inter-particle interactions. The most-stable, mutual alignments of the respective nano-clusters based on their interaction energies are identified in the expectation that these are indicative of the most likely inter-particle binding configurations. The stable inter-particle binding configurations identified reveal that the number of interfacial hydrogen bonds formed between the binding particles is, potentially, an important factor in terms of the stability of inter-particle cohesion. All preferred inter-particle alignments are found to involve either the (1 0 0) or the (1 1 0) face of aspirin crystals interacting with a number of the growth forms of ascorbic acid. Four main types of interfacial hydrogen bonds are found to be associated with inter-particle binding and involve acceptor-donor interactions between hydroxyl, carbonyl, ester and lactone acceptor groups and hydroxyl donor groups. This hydrogen bonding network is found to be consistent with the surface chemistry of the interacting habit faces with, in general, the number of hydrogen bonds increasing for the more stable alignments. The likely usefulness of this approach for predicting solid-state formulation properties is reviewed.

The influence of tertiary butyl alcohol and volatile salts on the sublimation of ice from frozen sucrose solutions: implications for freeze-drying.

The purpose of this work was to investigate the phase behavior of tertiary butanol (TBA) and volatile ammonium salts in frozen mixtures with some commonly used excipients and the efficacy of such volatile additives in accelerating the sublimation of ice from frozen solutions. Differential scanning calorimetry was employed to determine first-order phase transformations and glass transition temperatures in binary and ternary mixtures. Ice sublimation rates were studied by conventional freeze-drying and mass loss with time. A eutectic temperature (268 K) was identified for the anhydrous TBA-sucrose system. In frozen ternary water-excipient-TBA systems, the relative amplitudes of the glass and phase transitions, as measured during warming scans, were found to depend critically on the previous cooling rates. Glass transitions of all the freeze-concentrated mixtures used were determined. The sublimation studies indicated an ability of all volatile additives to accelerate ice sublimation from amorphous, freeze-concentrated solutions, but no clear ranking order, applicable to all systems studied, could be established.