pH-Induced Precipitation Behavior of Weakly Basic Compounds: Determination of Extent and Duration of Supersaturation Using Potentiometric Titration and Correlation to Solid State Properties

Abstract

This study showed that supersaturation behavior has significant correlation with the solid-state properties of the precipitate and that pH-metric titration methods can be utilized to evaluate the supersaturation behavior.

Initial Drug Dissolution from Amorphous Solid Dispersions Controlled by Polymer Dissolution and Drug-Polymer Interaction

“…To investigate the molecular mechanism of drug-polymer interaction in the solution state, solution 13 C NMR spectra of the pure KTZ, as well as the KTZ/polymer combinations were collected and compared. It's worth noting that we used chloroform as the solvent in the NMR analysis, because chloroform is one of a few solvents that can solubilize both drug and polymer without being likely to disrupt or induce intermolecular interactions between them.…”

“…Immediately upon contact with aqueous medium, amorphous drug usually dissolves much more rapidly compared with crystalline dose forms, due to the absence of crystal lattice, and the existence of water-soluble polymers. The solution drug concentration usually reaches various supersaturations depending on the physiochemical properties of the drug and the ASD formulation design (10)(11)(12)(13)(14). The initial drug dissolution is vividly termed as Bspring^ (15,16).…”

Impact of Solubilizing Additives on Supersaturation and Membrane Transport of Drugs

“…Amorphous solid dispersions (ASD), where the higher apparent solubility and dissolution rates of amorphous solids lead to supersaturated solutions (4,5) are a common formulation approach. Lipid based drug delivery systems (6), salts and weak bases (7) may also result in the formation of supersaturated solutions in vivo. From a thermodynamic perspective, the elevated solution concentrations obtained from supersaturated solutions are fundamentally different from those generated in the presence of solubilizing additives such as surfactants.…”

Using Environment-Sensitive Fluorescent Probes to Characterize Liquid-Liquid Phase Separation in Supersaturated Solutions of Poorly Water Soluble Compounds

“…Supersaturated solutions generated by methods other than dissolution of amorphous solid dispersions can also exhibit nano-aggregate formation. Thus highly supersaturated solutions generated by lipid digestion (6)(7)(8), following pH changes (9)(10)(11), and by solvent dilution (8,(10)(11)(12), e.g., during high throughput screening, have all been observed to contain non-crystalline drug aggregates. This phenomenon of aggregation is, in fact, a wellcharacterized physicochemical phase separation termed liquid-liquid phase separation (LLPS).…”