Polymer-inducing chemical degradation of amorphous solid dispersions driven by drug-polymer interactions for physical stabilization.

Intermolecular interactions between active pharmaceutical ingredients (APIs) and carrier polymers are important for the long-term physical stability of amorphous solid dispersions (ASDs). However, the negative impact of intermolecular interactions on chemical stability has rarely been reported. In this study, the relationship between intermolecular interactions and physical and chemical stability was investigated using two ASDs composed of API and hydroxypropyl methylcellulose acetate succinate (HPMCAS) with different stabilities: ASD1 was physically stable but chemically unstable, whereas ASD2 was physically unstable but chemically stable.

Molecular-Level Structural Analysis of siRNA-Loaded Lipid Nanoparticles by H NMR Relaxometry: Impact of Lipid Composition on Their Structural Properties.

H NMR relaxometry was applied for molecular-level structural analysis of siRNA-loaded lipid nanoparticles (LNPs) to clarify the impact of the neutral lipids, 1,2-distearoyl--glycero-3-phosphocholine (DSPC) and cholesterol, on the physicochemical properties of LNP. Incorporating DSPC and cholesterol in ionizable lipid-based LNP decreased the molecular mobility of ionizable lipids. DSPC reduced the overall molecular mobility of ionizable lipids, while cholesterol specifically decreased the mobility of the hydrophobic tails of ionizable lipids, suggesting that cholesterol filled the gap between the hydrophobic tails of ionizable lipids.

Nanostructure and Molecular-Level Characterization of Aminoalkyl Methacrylate Copolymer and the Impact on Drug Solubilization Ability.

The effects of pH changes and saccharin (SAC) addition on the nanostructure and mobility of the cationic aminoalkyl methacrylate copolymer Eudragit E PO (EUD-E) and its drug solubilization ability were investigated. Small-angle X-ray scattering performed using synchrotron radiation and atomic force microscopy showed that the EUD-E nanostructure, which has a size of approximately several nanometers, changed from a random coil structure at low pH (pH 4.0-5.

Structural Evaluation of the Choline and Geranic Acid/Water Complex by SAXS and NMR Analyses.

Recently, choline and geranic acid (CAGE), an ionic liquid (IL), has been recognized to be a superior biocompatible material for oral and transdermal drug delivery systems (DDS). When CAGE is administered, CAGE would be exposed to various types of physiological fluids, such as intestinal and intradermal fluids. However, the effect of physiological fluids on the structure of CAGE remains unclear.

Effect of Drug-Polymer Interactions through Hypromellose Acetate Succinate Substituents on the Physical Stability on Solid Dispersions Studied by Fourier-Transform Infrared and Solid-State Nuclear Magnetic Resonance.

The present study evaluated the specific intermolecular interactions between carbamazepine (CBZ) and substituents of hypromellose acetate succinate (HPMC-AS), as well as the mechanism of inhibition of recrystallization of solid dispersions (SDs) using Fourier-transform infrared (FTIR) and solid-state nuclear magnetic resonance (NMR) spectroscopy. CBZ and HPMC derivatives, including HPMC, hypromellose acetate (HPMC-A), and hypromellose succinate (HPMC-S), were spray-dried to prepare CBZ/polymer spray-dried samples (SPDs). CBZ/HPMC SPD and CBZ/HPMC-A SPD recrystallized within 10 days at 60 °C and 0% relative humidity, whereas CBZ/HPMC-S SPD maintained its amorphous state for a longer period.

Discovery of Novel 5-(Piperazine-1-carbonyl)pyridin-2(1)-one Derivatives as Orally eIF4A3-Selective Inhibitors.

Starting from our previous eIF4A3-selective inhibitor , a novel series of (piperazine-1-carbonyl)pyridin-2(1)-one derivatives was designed, synthesized, and evaluated for identification of orally bioavailable probe molecules. Compounds and showed improved physicochemical and ADMET profiles, while maintaining potent and subtype-selective eIF4A3 inhibitory potency. In accord with their promising PK profiles and results from initial in vivo PD studies, compounds and showed antitumor efficacy with T/C values of 54% and 29%, respectively, without severe body weight loss.