Physical Stabilization of Pharmaceutical Glasses Based on Hydrogen Bond Reorganization under Sub-T_g Temperature

Abstract

Amorphous solid dispersions (ASDs) play a key role in the pharmaceutical industry through the use of high-energy amorphous state to improve solubility of pharmaceutical agents. Understanding the physical stability of pharmaceutical glasses is of great importance for their successful development. We focused on the anti-HIV agent, ritonavir (RTV), and investigated the influence of annealing at temperatures below the glass transition temperature (sub-T) on physical stability, and found that the sub-T annealing effectively stabilized RTV glasses. Through the atomic structure analyses using X-ray pair distribution functions and infrared spectroscopy, we ascertained that this fascinating effect of the sub-T annealing originated from strengthened hydrogen bonding between molecules and probably from a better local packing associated with the stronger hydrogen bonds. The sub-T annealing is effective as a physical stabilization strategy for some pharmaceutical molecules, which have relatively large energy barrier for nucleation.

Zeolitic intralayer microchannels of magadiite, a natural layered silicate, to boost green organic synthesis

“…Since the structure of magadiite was unknown, first, the initial structure model was prepared from the octosilicate structure25,26 to correspond to other data such as compositions, and NMR spectra and infrared spectra were investigated. The atomic coordinates of the structure model were moved to fit the experimental PDF data using a code running the real-space reverse Monte Carlo simulation37,40 implemented in the PDFfit2 program39 under bond length constraints (to retain SiO 4 tetrahedra by keeping the Si–O bond length in the range of 1.45–1.75 Å and the O–O distance in the range of 2.50–2.80 Å) using the PDFfit2 program as the fitting program. For the structure model reaching R w < 0.35, the symmetry of the structure was analyzed and then further refinements were carried out under the symmetry constraints.…”

Crystallization Tendency of Pharmaceutical Glasses: Relevance to Compound Properties, Impact of Formulation Process, and Implications for Design of Amorphous Solid Dispersions

“…Sub- T g annealing based on this strategy was found to be an effective strategy for stabilizing ritonavir glass [50]. For example, ritonavir glass annealed at 40 °C for two days was much more stable compared to fresh glass.…”

“…Structural analysis revealed a change in the packing volume and hydrogen-bonding pattern during the pre-annealing at 40 °C, which was the most likely source of the stabilization. Such pre-annealing strategy did not work for Classes 1 and 2 compounds [50].…”

Curved Fragmented Graphenic Hierarchical Architectures for Extraordinary Charging Capacities

“…The S ( Q ) in the scattering vector range of Q max = 20.6 Å −1 was treated with a revised Lorch function ( Δ = 1.0), and then converted into reduced PDF, G ( r ), where r is the interatomic distance. The structure of the materials was analyzed by the real‐space Reverse Monte Carlo (RMC) method using the PDFfit2 program modified by adding bond length restraints (±0.05 Å to the initial values), bond angle restraints (±5° to the initial values), and rigid body constraints to the CH bonds. The initial structure model was formed by optimizing a structure consisting of a 4 × 4 × 2 supercell of disorderly stacked graphite having carbon defects (60 C atoms and 12 H atoms) using a molecular mechanics simulation with the GULP program using the Brenner force field…”