Elucidating the Molecular Mechanism of Drug–Polymer Interplay in a Polymeric Supersaturated System of Rifaximin

Abstract

Supersaturated drug delivery system (SDDS) enables the solubility and sustained membrane transport of poorly water-soluble drugs. SDDS provides higher drug concentration in the dispersed phase and equilibrium in the continuous phase, which corresponds to amorphous solubility of the drug. Rifaximin (RFX) is a nonabsorbable BCS class IV drug approved for the treatment of irritable bowel syndrome and effective against Helicobacter pylori. RFX shows slow crystallization and precipitation in an acidic pH of 1.2−2, leading to obliteration of its activity in the gastrointestinal tract. The objective of the present study is to inhibit the precipitation of RFX, involving screening of polymers at different concentrations, using an in-house developed microarray plate method and solubility studies which set forth hydroxypropyl methylcellulose (HPMC) E15, Soluplus, and polyvinyl alcohol to be effective precipitation inhibitors (PIs). Drug− polymer precipitates (PPTS) are examined for surface morphology by scanning electron microscopy, solid-phase transformation by hot stage microscopy, the nature of PPTS by polarized light microscopy, and drug−polymer interactions by Fourier transform infrared and nuclear magnetic resonance spectroscopy. Besides, the unfathomed molecular mechanism of drug−polymer interplay is discerned at the air−water interface using sum-frequency generation spectroscopy to correlate the interfacial hydrogen bonding properties in bulk water. Surprisingly, all studies disseminate HPMC E15 and Soluplus as effective PIs of RFX.

Amorphous Salts Solid Dispersions of Celecoxib: Enhanced Biopharmaceutical Performance and Physical Stability

“…The increase of the plasma concentration of CEL in initial periods (0.5 to 6 h) may be ascribed to the gradual increase in the solubilization of ASSDs in the low pH environment encountered in the gastric and small intestinal regions. Moreover, it can also be ascribed to the generation and maintenance of supersaturation for a more extended period, leading to increased absorption from the supersaturated solution over that period . Binary ASD also achieved a greater plasma concentration up to 12 h that again might be due to a lower rate of solubilization in a lower pH environment and the formation of colloidal structures with polymers in the intestinal pH .…”

Hydrolysis and Condensation of Tetraethyl Orthosilicate at the Air–Aqueous Interface: Implications for Silica Nanoparticle Formation

“…The SFG spectrometer (Ekspla, Lithuania) was employed to probe the structure of TEOS and its interaction with solvents, and the schematic of this system is shown in Figure . The details of the SFG experimental setup utilized for the current work are described previously. ,,− Briefly, this system consists of a passively mode-locked Nd:YAG laser (Ekspla PL2231). It produces an output of 30 ps pulse output with the energy of 40 mJ at a wavelength of 1064 nm having a repetition rate of 50 Hz (Figure ).…”

Comparative analysis of drug-salt-polymer interactions by experiment and molecular simulation improves biopharmaceutical performance

“…However, none of these studies estimated the strength of drug-drug interactions in the presence and absence of polymer, or in the presence of ions in addition to polymer. Although molecular level mechanistic studies elucidating the drug-polymer interplay in both solution and solid state have been performed using high-end analytical techniques [6, 28, 32] , the intermolecular interactions in an aqueous environment that correlate with the in vivo drug fate of a drug are until now largely unexplored experimentally, but are particularly amenable to investigation by MD simulation.…”

“…It is known that intermolecular drug-polymer interactions can significantly impact the biopharmaceutical performance 8,9,28 and physical stability 29,30 of a drug. Indeed, the general rationale for experimental screening of polymers to identify excipients for a particular drug is to identify thermodynamically miscible systems that possess adhesive interactions (specific hydrogen bonding, hydrophobic or van der Waals interactions), between the drug and the polymer in order to hinder drug-drug aggregation 31,32 , and thereby prevent nucleation and crystal growth in the supersaturated solution during dissolution. The traditional methods to predict drug-polymer miscibility involve the calculation of solubility parameters and Flory-Huggins (F-H) interaction parameters [33][34][35] .…”

“…However, none of these studies estimated the strength of drug-drug interactions in the presence and absence of polymer, or in the presence of ions. Although molecular level mechanistic studies to elucidate the drug-polymer interplay in both solution and solid state have been performed using high-end analytical techniques 6,28,32 , the intermolecular interactions in an aqueous environment that correlate with the in vivo fate of a drug remain largely unexplored, but are particularly amenable to investigation by MD simulation.Here, MD simulations of neutral and anionic forms of CEL with different polymers, in aqueous solution, representing the in vivo environment, were performed, and compared with experimental measurements for novel supersaturated ASSDs that have the potential to address the aforementioned problems of drug-drug aggregation and crystallization. We find that hindrance of drug aggregation is attributable to stronger drug-polymer interactions in the ionized drug state in ASSDs compared to the non-ionized drug in conventional ASDs.…”