Browsing by Author "Botana, Adolfo"
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Item Open Access Artemisinin Cocrystals for Bioavailability Enhancement. Part 1: Formulation Design and Role of the Polymeric Excipient(ACS, 2021-11-01) Kaur, Manreet; Yardley, Vanessa; Wang, Ke; Masania, Jinit; Botana, Adolfo; Arroo, R. R. J.; Li, M.Artemisinin (ART) is a most promising antimalarial agent, which is both effective and well-tolerated in patients, though it has therapeutic limitations due to its low solubility, bioavailability and short half-life. The objective of this work was to explore the possibility of formulating ART cocrystals, i.e., artemisinin-orcinol (ART-ORC) and artemisinin-resorcinol (ART2-RES) as oral dosage forms to deliver ART molecules for bioavailability enhancement. This is the first part of the study, aiming to develop a simple and effective formulation which can then be tested on an appropriate animal model (i.e. mouse selected for in vivo study) to evaluate their preclinical pharmacokinetics for further development. In the current work, the physicochemical properties (i.e., solubility and dissolution rate) of ART cocrystals were measured to collect information necessary for the formulation development strategy. It was found that the ART solubility can be increased significantly by its cocrystals, i.e., 26-fold by ART-ORC and 21-fold by ART2-RES respectively. Screening a set of polymers widely used in pharmaceutical products, including Polyvinylpyrrolidone, Hydroxypropyl Methylcellulose and Hydroxypropyl Methylcellulose Acetate Succinate, based on the powder dissolution performance parameter analysis, revealed that Polyvinylpyrrolidone/vinyl Acetate (PVP-VA) was the most effective crystallisation inhibitor. The optimal concentration of PVP-VA at 0.05 mg/mL for the formulation was then determined by a dissolution/permeability method which represented a simplified permeation model to simultaneously evaluate the effects of a crystallization inhibitor on the dissolution and permeation performance of ART cocrystals. Furthermore, experiments, including surface dissolution of single ART cocrystals monitored by Raman spectroscopy and SEM and diffusion properties of ART in solution measured by 1H and diffusion-ordered spectroscopy (DOSY) nuclear magnetic resonance (NMR) spectroscopy, provided insight into how the excipient affects the ART cocrystal dissolution performance and bioavailability.Item Metadata only Explorations of the chemical constitution and aqueous solution status of caries-arresting silver(I)-diammine fluoride and silver(I)-fluoride products using high-resolution 19F NMR analysis. Spectroscopic and SEM investigations of their interactions with human saliva: evidence for the in vivo salivary-catalysed autoconstruction of Ag/AgCl-based nanoparticles (IV-SCAN)—part I(Frontiers, 2024-06-12) Hunwin, Kayleigh; Page, Georgina; Edgar, Mark; Botana, Adolfo; Armitage, Rachel; Desai, Unmesh; Bhogadia, Mohammed; Chan, Wyman; Duffin, Steven; Duffin, Marcus; Grootveld, MartinIntroduction: Silver(I)-diammine fluoride (SDF) and silver(I)-fluoride (SF) complexes have been successfully employed for the arrest of dental caries for many years. However, to date there are very few studies available reporting on the molecular structural compositional and solution status of these agents [typically applied as highly-concentrated 38% (w/v) solutions]. Here, we explored the solution status and chemical constitution of commercially-available SDF and SF products, and secondly investigated the multicomponent interplay of these products with biomolecules present in intact human whole-mouth salivary supernatants (WMSSs) in vitro. Methods: High-resolution 19F NMR analysis was employed to explore SDF and SF product solutions, and to determine WMSS fluoride (F−) concentrations, whereas ammonia (NH3) release form SDF was tracked by 1H NMR spectroscopy. SEM and thin-film FTIR-ATR analyses were employed to explore the atomic and molecular compositions of sequentially-generated AgCl deposits and chromophoric Ag/AgCl nanoparticles (CSNPs); the time-dependent generation of the latter was followed spectrophotometrically. Results: 19F NMR spectra of aqueous SF solutions contained a very broad F− signal (Δv1/2 70 Hz), demonstrating that much of its solvated F− content was rapidly exchanging with Ag(I) on the NMR timescale, but those of SDF had a much sharper resonance, similar to that of “free” F− (4 Hz). Moreover, further NMR results revealed that a popular SDF product contained high molar excesses of both F− and NH3. Treatment of WMSSs with SDF and SF generated an off-white precipitate, which slowly developed into CSNPs at 23°C; SEM demonstrated high contents of both silver and chloride in this material (ca.1:1 atomic content ratio). FTIR-ATR analysis found that the CSNPs formed contained a range of salivary biomolecules, which appear to encapsulate the Ag/AgCl core (significant thiocyanate contents were also found). In conclusion, NMR results acquired demonstrated that SF, but not SDF, product solutions feature rapidly-exchanging F− between its “free” and Ag(I)-bound forms, and that SDF contains large excesses of both F− and its NH3 ligands. Characterised AgCl deposits and CSNPs were sequentially produced from the interactions of these complexes with WMSS biomolecules. Discussion: In view of their well-known microbicidal and cariostatic properties, the observed autobioconstruction of CSNPs involving salivary catalysis is of much therapeutic significance.Item Open Access Insight into the Precipitation Inhibition of Polymers within Cocrystal Formulations in Solution Using Experimental and Molecular Modeling Techniques(ACS, 2025-02-28) Alinda, Peace; Botana, Adolfo; Li, M.This study investigated the role of various polymers as precipitation inhibitors in solutions of flufenamic acid (FFA) and its cocrystals with theophylline (FFA-TP) and nicotinamide (FFA-NIC). Through a combination of NMR spectroscopy, molecular dynamics simulations, and nucleation studies using Crystal16, we evaluated the effects of polyethylene glycol (PEG), polyvinylpyrrolidone-vinyl acetate (PVP-VA), and Soluplus (SOL), both individually and in combinations, on the nucleation, diffusion, and self-association of FFA molecules in solution. 1H NMR and DOSY measurements revealed that while PEG was highly effective in reducing molecular mobility, thus significantly delaying nucleation, PVP-VA facilitated nucleation by enhancing FFA diffusion and aggregation. SOL provided a balance, enhancing molecular mobility but maintaining a delayed nucleation effect, likely due to micellar encapsulation, as evidenced by line broadening in 1H NMR. Combination systems such as PVP-VA-PEG and PVP-VA-SOL showed synergistic effects, with PVP-VA-SOL proving particularly effective in inhibiting FFA nucleation across all systems. Molecular dynamics simulations supported these findings by highlighting changes in intermolecular interactions and aggregation tendencies in the presence of each polymer. This comprehensive analysis suggested that selecting appropriate polymeric excipients, or combinations thereof, can finely tune the nucleation behaviours of drug solutions, offering a strategic approach to optimizing the stability of supersaturated drug solutions.Item Metadata only Physicochemical properties, biological chemistry and mechanisms of action of caries-arresting diammine-silver(I) fluoride and silver(I)-fluoride solutions for clinical use: a critical review(Frontiers, 2024-07-23) Hunwin, Kayleigh; Page, Georgina; Edgar, Mark; Botana, Adolfo; Armitage, Rachel; Bhogadia, Mohammed; Desai, Unmesh; Duffin, Steven; Duffin, Marcus; Chan, Wyman; Grootveld, MartinThis paper serves as a Part II follow-up of our research investigations performed on the molecular structures of silver(I)-fluoride (SF) and diammine-silver(I) fluoride (SDF) complexes in solution-based commercial products for clinical application, their precise chemical compositions, and their nature in aqueous solution, the latter including rapid fluoride-exchange processes at the silver(I) ion centre monitored by 19F NMR analysis (Part I). Part I of this series also explores the mechanisms of action (MoA) of these complexes, and is therefore largely focused on their chemical reactions with constituents of human saliva, which has access to their sites of application. Such reactions were found to slowly promote the generation of potentially physiologically-active Ag/AgCl nanoparticles from primarily-generated discoloured silver(I) chloride (AgCl) precipitates, a process involving salivary electron-donors such as thiocyanate and L-cysteine. Since this research has shed new light on potential MoAs for these products, in this accompanying report (Part II), we have performed a critical review of scientific literature in order to rationalize our results in relation to current views on these mechanisms for SF and SDF products employed for the successful clinical arrest of dental caries. Following an Introduction to the subject matter ( Section 1), this paper comprises a generalized overview of silver coordination chemistry ( Section 2), which is followed by a section focused on the aqueous solution status and equilibria involved in SF chemistry ( Section 3), the latter including results acquired from an original simulation of the electronic absorption spectra of coloured SF complexes in aqueous solution (Section 3.1). Section 4 then investigates detailed rationales for the biologically-relevant ligand-exchange and redox chemistries, disposition and fates of SF, SDF and silver(I)-nitrate when employed for the treatment of dental caries, with emphasis placed on their therapeutic MoAs. This Section is supported by the provision of valuable information centralized on (1) relevant biomolecular chemistry involved in solution- and solid-state matrices ( Section 4.1); (2) SF and perhaps silver(I)-nitrate as more cost-effective alternatives to SDF therapies ( Section 4.2); and (3) the potential therapeutic benefits and effects offered by silver-based nanoparticles and their associated MoAs ( Section 4.3). Recommendations for future investigations in this area are proposed.