New Development in Understanding Drug–Polymer Interactions in Pharmaceutical Amorphous Solid Dispersions from Solid-State Nuclear Magnetic Resonance

Abstract

Pharmaceutical amorphous solid dispersions (ASDs) represent a widely used technology to increase the bioavailability of active pharmaceutical ingredients (APIs). ASDs are based on an amorphous API dispersed in a polymer, and their stability is driven by the presence of strong intermolecular interactions between these two species (e.g., hydrogen bond, electrostatic interactions, etc.). The understanding of these interactions at the atomic level is therefore crucial, and solid-state nuclear magnetic resonance (NMR) has demonstrated itself as a very powerful technique for probing API−polymer interactions. Other reviews have also reported exciting approaches to study the structures and dynamic properties of ASDs and largely focused on the study of API−polymer miscibility and on the identification of API−polymer interactions. Considering the increased use of NMR in the field, the aim of this Review is to specifically highlight recent experimental strategies used to identify API−polymer interactions and report promising recent examples using one-dimensional (1D) and two-dimensional (2D) experiments by exploiting the following emerging approaches of very-high magnetic field and ultrafast magic angle spinning (MAS). A range of different ASDs spanning APIs and polymers with varied structural motifs is targeted to illustrate new ways to understand the mechanism of stability of ASDs to enable the design of new dispersions.

Enhanced Oral Bioavailability of Rivaroxaban-Loaded Microspheres by Optimizing the Polymer and Surfactant Based on Molecular Interaction Mechanisms

“…In this study, we observed an approximately 160-fold increase in the solubility of RXB-loaded microspheres compared with that of the drug powder because of the synergistic effect of the PVP/SLS complex. In addition, to investigate the synergistic effect of the PVP/SLS complex, we investigated the effect of the drug–excipient ratio of the RXB-loaded microspheres on their solubility, dissolution, intermolecular interactions, and oral bioavailability. , In most solid dispersions, the solubility, dissolution rate, and bioavailability of poorly soluble drugs increased as the amount of excipients, such as polymers and surfactants, increased. − However, in this study, the solubility and dissolution rate of RXB were higher in the presence of a small amount of polymer (PVP) in the formulation. This was confirmed by a significant decrease in the solubility, dissolution rate, and bioavailability of RXB as the amount of PVP increased in the same SLS-containing formulation.…”

Probing Molecular Packing of Amorphous Pharmaceutical Solids Using X-ray Atomic Pair Distribution Function and Solid-State NMR

“…Experimental spectra are shown in black. The deconvoluted peaks in red and blue lines represent the HPMCAS carboxyl group in polymer alone and carboxyl group forming drug–polymer interaction, respectively; and (B) comparison between the population of the groups involved in the intermolecular interaction from the peak deconvolution (right y -axis: HPMCAS carboxyl group at 167–179 ppm in blue) and PCA scores (left y -axis: HPMCAS carboxyl group at 167–179 ppm in red and POSA C4 peak at 149–157 ppm in black); and (C) two examples of POSA-HPMCAS interactions identified in previous ssNMR studies. ,, …”

“…In order to quantitate the subtle change in S(q) and PDF, we would like to correlate to the molecular findings from ssNMR. 51,65,66 Specifically, the 1D 13 C ssNMR data of these ASD samples were previously collected. 51 A few interesting 13 C resonances, e.g., the HPMCAS carboxyl peak at 167−179 ppm and the POSA C4 peak at 149−157 ppm, exhibit systematic shifts with DL.…”

Microelectron Diffraction Reveals Contamination of Polymorphs by Structure Analysis of Microscale Crystals in a Novel Pharmaceutical Cocrystal

“…A crystal is a solid formed by highly ordered molecules arranged in a periodic pattern. − The properties affect solubility, dissolution rate, stability, and formulation processes, which pose a risk in drug development. ,, These properties are derived by stabilization through intermolecular interactions among the crystallized molecules in a crystal packing, , whereas the amorphous form is unstable owing to its higher energy and nonequilibrium state. , Crystallization properties are characterized for small molecules, and investigation of crystal forms is essential for the discovery and development of low-molecular-weight drugs. Crystallization is also commonly investigated in the manufacturing process for the quality control of drugs, and impurity purging is a frequently used method that determines the solubility difference between the drug and impurity. − …”