Organic Nucleation: Water Rearrangement Reveals the Pathway of Ibuprofen.

The organic nucleation of the pharmaceutical ibuprofen is investigated, as triggered by the protonation of ibuprofen sodium salt at elevated pH. The growth and aggregation of nanoscale solution species by Analytical Ultracentrifugation and Molecular Dynamics (MD) simulations is tracked. Both approaches reveal solvated molecules, oligomers, and prenucleation clusters, their size as well as their hydration at different reaction stages. By combining surface-specific vibrational spectroscopy and MD simulations, water interacting with ibuprofen at the air-water interface during nucleation is probed. The results show the structure of water changes upon ibuprofen protonation in response to the charge neutralization. Remarkably, the water structure continues to evolve despite the saturation of protonated ibuprofen at the hydrophobic interface. This further water rearrangement is associated with the formation of larger aggregates of ibuprofen molecules at a late prenucleation stage. The nucleation of ibuprofen involves ibuprofen protonation and their hydrophobic assembly. The results highlight that these processes are accompanied by substantial water reorganization. The critical role of water is possibly relevant for organic nucleation in aqueous environments in general.

Molecular Characterization of Mesoporous Silica (Un)loading by Gemcitabine and Ibuprofen - An Interplay of Salt-Bridges and Hydrogen Bonds.

The molecular mechanisms of mesoporous silica nanomaterial (MSN) loading by gemcitabine and ibuprofen molecules, respectively, are elucidated as functions of pore geometry. Based on a small series of MSN archetypes, we use molecular dynamics simulations to systematically explore molecule-by-molecule loading of the carrier material. Apart from predicting the maximum active pharmaceutical ingredient (API) loading capacity, more detailed statistical analysis of the incorporation energy reveals dedicated profiles stemming from the interplay of guest-MSN salt-bridges/hydrogen bonding in concave and convex domains of the silica surfaces - which outcompete interactions among the drug molecules. Only after full coverage of the silica surface, we find secondary layer growth stabilized by guest-guest interactions exclusively. Based on molecular models, we thus outline a two-step type profile for drug release from MSN networks. Subject to the MSN structure, we find 50-75 % of the API within amorphous domains in the inner regions of the pores - from which drug release is provided at constant dissociation energy. In turn, the remaining 50-25 % of drug molecules are drastically hindered from dissociation.

Molecular Simulation Analyses of Polymorphism Control Factors by the Example of Carbamazepine Forms I-IV: A Blueprint for Industrial Drug Formulation?

We outline comparably simple molecular simulation techniques to elucidate the interactions that determine the polymorphism of carbamazepine. Starting from the established GAFF molecular mechanics model, only a small series of tailor-made improvements is needed to tackle the subtle differences in the interaction energies of polymorphs I - IV. On this basis, molecular dynamics simulations provide melting enthalpies at < 1 kcal/mol accuracy (0.2 kcal/mol for forms I-III) as compared to the experiment. Yet, the predicted stability ranking of III > I > II > IV only partially reproduces the experimentally observed III > I > IV > II series. Despite this limitation, we demonstrate how insights from molecular simulation offer the elucidation of possible factors for polymorph control. Apart from characterizing bulk crystals, we outline the evaluation of size-dependent profiles of crystallite formation energy. Contrasting the contributions of bulk, surface and edge terms to the formation energy of nano-scale precipitates, we suggest a multi-step nucleation mechanism leading from amorphous aggregates to crystallites. We argue that carbamazepine aggregates of less than ∼100 molecules adopt a spherical shape to minimize edge/surface energy - overcompensating the loss in bulk energy inherent to non-crystalline ordering in the inner core. In turn, for large crystallites polymorph form III is preferred, whilst suitable spatial confinement to crystallites of 100-500 carbamazepine molecules appears to promote form II.

On the Role of Silica Carrier Curvature for the Unloading of Small Drug Molecules: A Molecular Dynamics Simulation Study.

We present atomic scale models of differently shaped silica surfaces loaded by gemcitabine and ibuprofene molecules. Despite the dissimilar nature of the drug molecules, their association to silica carriers shows quite similar characteristics. We identify a well-defined contact layer that is stabilized by silica-molecule salt-bridges/hydrogen bonding in parallel to interactions among the drug molecules. Additional loading of the carriers leads to rough films with dynamically evolving asperities rather than layer-by-layer ordering. To elucidate the role of differently shaped silica surfaces, we compared planar slab models and spherical nanoparticles as 2 limiting cases. Despite the strong difference in the curvature of the silica surfaces, our molecular dynamics simulations show only small changes of the unloading characteristics. This suggests that the design of different pore shapes in mesoporous silica-based drug carriers mainly affects the migration kinetics rather than the energetics of drug loading and release.