Atomic-level structure determination of amorphous molecular solids by NMR.

Structure determination of amorphous materials remains challenging, owing to the disorder inherent to these materials. Nuclear magnetic resonance (NMR) powder crystallography is a powerful method to determine the structure of molecular solids, but disorder leads to a high degree of overlap between measured signals, and prevents the unambiguous identification of a single modeled periodic structure as representative of the whole material. Here, we determine the atomic-level ensemble structure of the amorphous form of the drug AZD4625 by combining solid-state NMR experiments with molecular dynamics (MD) simulations and machine-learned chemical shifts. By considering the combined shifts of all 1H and 13C atomic sites in the molecule, we determine the structure of the amorphous form by identifying an ensemble of local molecular environments that are in agreement with experiment. We then extract and analyze preferred conformations and intermolecular interactions in the amorphous sample in terms of the stabilization of the amorphous form of the drug.

Supersaturated formulations of poorly soluble weak acid drugs evaluated in rodents; a case study.

In the present study we describe a way of working to overcome oral administration challenges in an early preclinical project. As candidate drugs were obtained, the preclinical delivery route was replaced by the intended route of the product and resources were allocated to optimize the oral absorption. Two main approaches were followed in order to formulate a selected weak acid, AZ'403, for oral administration in large scale toxicological studies and the early clinical phases. Both approaches relies on the suppression of precipitation from obtained supersaturated solutions achieved either by amorphous solid dispersions (using hydroxypropyl methylcellulose acetate succinate, HPMC-AS) or crystalline salts (sodium and potassium salts). In vivo studies in rodents were performed to evaluate oral AZ'403 absorption from amorphous and crystalline formulations, using nano- and micro crystalline particles of the neutral form, as references. The oral absorption of AZ'403 formulated using both approaches was significantly higher compared with the references. The improvements in overall exposures were 7-100 times during the investigated conditions. The pharmacokinetic profiles implied that both solid dispersions and crystalline salts of AZ'403 generated supersaturation in the small intestine in rodents and indicated that both approaches may be ways forward for subsequent late stage product development.