Pharmaceutical Quality by Design Approach to Develop High-Performance Nanoparticles for Magnetic Hyperthermia.

Magnetic hyperthermia holds significant therapeutic potential, yet its clinical adoption faces challenges. One obstacle is the large-scale synthesis of high-quality superparamagnetic iron oxide nanoparticles (SPIONs) required for inducing hyperthermia. Robust and scalable manufacturing would ensure control over the key quality attributes of SPIONs, and facilitate clinical translation and regulatory approval. Therefore, we implemented a risk-based pharmaceutical quality by design (QbD) approach for SPION production using flame spray pyrolysis (FSP), a scalable technique with excellent batch-to-batch consistency. A design of experiments method enabled precise size control during manufacturing. Subsequent modeling linked the SPION size (6-30 nm) and composition to intrinsic loss power (ILP), a measure of hyperthermia performance. FSP successfully fine-tuned the SPION composition with dopants (Zn, Mn, Mg), at various concentrations. Hyperthermia performance showed a strong nonlinear relationship with SPION size and composition. Moreover, the ILP demonstrated a stronger correlation to coercivity and remanence than to the saturation magnetization of SPIONs. The optimal operating space identified the midsized (15-18 nm) Mn0.25Fe2.75O4 as the most promising nanoparticle for hyperthermia. The production of these nanoparticles on a pilot scale showed the feasibility of large-scale manufacturing, and cytotoxicity investigations in multiple cell lines confirmed their biocompatibility. In vitro hyperthermia studies with Caco-2 cells revealed that Mn0.25Fe2.75O4 nanoparticles induced 80% greater cell death than undoped SPIONs. The systematic QbD approach developed here incorporates process robustness, scalability, and predictability, thus, supporting the clinical translation of high-performance SPIONs for magnetic hyperthermia.

Tailoring the Photophysical Properties of a Homoleptic Iron(II) Tetra N-Heterocyclic Carbene Complex by Attaching an Imidazolium Group to the (C∧N∧C) Pincer Ligand─A Comparative Study.

We here report the synthesis of the homoleptic iron(II) N-heterocyclic carbene (NHC) complex [Fe(miHpbmi)2](PF6)4 (miHpbmi = 4-((3-methyl-1H-imidazolium-1-yl)pyridine-2,6-diyl)bis(3-methylimidazol-2-ylidene)) and its electrochemical and photophysical properties. The introduction of the π-electron-withdrawing 3-methyl-1H-imidazol-3-ium-1-yl group into the NHC ligand framework resulted in stabilization of the metal-to-ligand charge transfer (MLCT) state and destabilization of the metal-centered (MC) states. This resulted in an improved excited-state lifetime of 16 ps compared to the 9 ps for the unsubstituted parent compound [Fe(pbmi)2](PF6)2 (pbmi = (pyridine-2,6-diyl)bis(3-methylimidazol-2-ylidene)) as well as a stronger MLCT absorption band extending more toward the red spectral region. However, compared to the carboxylic acid derivative [Fe(cpbmi)2](PF6)2 (cpbmi = 1,1'-(4-carboxypyridine-2,6-diyl)bis(3-methylimidazol-2-ylidene)), the excited-state lifetime of [Fe(miHpbmi)2](PF6)4 is the same, but both the extinction and the red shift are more pronounced for the former. Hence, this makes [Fe(miHpbmi)2](PF6)4 a promising pH-insensitive analogue of [Fe(cpbmi)2](PF6)2. Finally, the excited-state dynamics of the title compound [Fe(miHpbmi)2](PF6)4 was investigated in solvents with different viscosities, however, showing very little dependency of the depopulation of the excited states on the properties of the solvent used.

How Rigidity and Conjugation of Bidentate Ligands Affect the Geometry and Photophysics of Iron N-Heterocyclic Complexes: A Comparative Study.

Two iron complexes featuring the bidentate, nonconjugated N-heterocyclic carbene (NHC) 1,1'-methylenebis(3-methylimidazol-2-ylidene) (mbmi) ligand, where the two NHC moieties are separated by a methylene bridge, have been synthesized to exploit the combined influence of geometric and electronic effects on the ground- and excited-state properties of homoleptic FeIII-hexa-NHC [Fe(mbmi)3](PF6)3 and heteroleptic FeII-tetra-NHC [Fe(mbmi)2(bpy)](PF6)2 (bpy = 2,2'-bipyridine) complexes. They are compared to the reported FeIII-hexa-NHC [Fe(btz)3](PF6)3 and FeII-tetra-NHC [Fe(btz)2(bpy)](PF6)2 complexes containing the conjugated, bidentate mesoionic NHC ligand 3,3'-dimethyl-1,1'-bis(p-tolyl)-4,4'-bis(1,2,3-triazol-5-ylidene) (btz). The observed geometries of [Fe(mbmi)3](PF6)3 and [Fe(mbmi)2(bpy)](PF6)2 are evaluated through L-Fe-L bond angles and ligand planarity and compared to those of [Fe(btz)3](PF6)3 and [Fe(btz)2(bpy)](PF6)2. The FeII/FeIII redox couples of [Fe(mbmi)3](PF6)3 (-0.38 V) and [Fe(mbmi)2(bpy)](PF6)2 (-0.057 V, both vs Fc+/0) are less reducing than [Fe(btz)3](PF6)3 and [Fe(btz)2(bpy)](PF6)2. The two complexes show intense absorption bands in the visible region: [Fe(mbmi)3](PF6)3 at 502 nm (ligand-to-metal charge transfer, 2LMCT) and [Fe(mbmi)2(bpy)](PF6)2 at 410 and 616 nm (metal-to-ligand charge transfer, 3MLCT). Lifetimes of 57.3 ps (2LMCT) for [Fe(mbmi)3](PF6)3 and 7.6 ps (3MLCT) for [Fe(mbmi)2(bpy)](PF6)2 were probed and are somewhat shorter than those for [Fe(btz)3](PF6)3 and [Fe(btz)2(bpy)](PF6)2. [Fe(mbmi)3](PF6)3 exhibits photoluminescence at 686 nm (2LMCT) in acetonitrile at room temperature with a quantum yield of (1.2 ± 0.1) × 10-4, compared to (3 ± 0.5) × 10-4 for [Fe(btz)3](PF6)3.

Ferrous and ferric complexes with cyclometalating N-heterocyclic carbene ligands: a case of dual emission revisited.

Iron N-heterocyclic carbene (FeNHC) complexes with long-lived charge transfer states are emerging as a promising class of photoactive materials. We have synthesized [FeII(ImP)2] (ImP = bis(2,6-bis(3-methylimidazol-2-ylidene-1-yl)phenylene)) that combines carbene ligands with cyclometalation for additionally improved ligand field strength. The 9 ps lifetime of its 3MLCT (metal-to-ligand charge transfer) state however reveals no benefit from cyclometalation compared to Fe(ii) complexes with NHC/pyridine or pure NHC ligand sets. In acetonitrile solution, the Fe(ii) complex forms a photoproduct that features emission characteristics (450 nm, 5.1 ns) that were previously attributed to a higher (2MLCT) state of its Fe(iii) analogue [FeIII(ImP)2]+, which led to a claim of dual (MLCT and LMCT) emission. Revisiting the photophysics of [FeIII(ImP)2]+, we confirmed however that higher (2MLCT) states of [FeIII(ImP)2]+ are short-lived (<10 ps) and therefore, in contrast to the previous interpretation, cannot give rise to emission on the nanosecond timescale. Accordingly, pristine [FeIII(ImP)2]+ prepared by us only shows red emission from its lower 2LMCT state (740 nm, 240 ps). The long-lived, higher energy emission previously reported for [FeIII(ImP)2]+ is instead attributed to an impurity, most probably a photoproduct of the Fe(ii) precursor. The previously reported emission quenching on the nanosecond time scale hence does not support any excited state reactivity of [FeIII(ImP)2]+ itself.

Photophysical Integrity of the Iron(III) Scorpionate Framework in Iron(III)-NHC Complexes with Long-Lived 2LMCT Excited States.

Fe(III) complexes with N-heterocyclic carbene (NHC) ligands belong to the rare examples of Earth-abundant transition metal complexes with long-lived luminescent charge-transfer excited states that enable applications as photosensitizers for charge separation reactions. We report three new hexa-NHC complexes of this class: [Fe(brphtmeimb)2]PF6 (brphtmeimb = [(4-bromophenyl)tris(3-methylimidazol-2-ylidene)borate]-, [Fe(meophtmeimb)2]PF6 (meophtmeimb = [(4-methoxyphenyl)tris(3-methylimidazol-2-ylidene)borate]-, and [Fe(coohphtmeimb)2]PF6 (coohphtmeimb = [(4-carboxyphenyl)tris(3-methylimidazol-2-ylidene)borate]-. These were derived from the parent complex [Fe(phtmeimb)2]PF6 (phtmeimb = [phenyltris(3-methylimidazol-2-ylidene)borate]- by modification with electron-withdrawing and electron-donating substituents, respectively, at the 4-phenyl position of the ligand framework. All three Fe(III) hexa-NHC complexes were characterized by NMR spectroscopy, high-resolution mass spectroscopy, elemental analysis, single crystal X-ray diffraction analysis, electrochemistry, Mößbauer spectroscopy, electronic spectroscopy, magnetic susceptibility measurements, and quantum chemical calculations. Their ligand-to-metal charge-transfer (2LMCT) excited states feature nanosecond lifetimes (1.6-1.7 ns) and sizable emission quantum yields (1.7-1.9%) through spin-allowed transition to the doublet ground state (2GS), completely in line with the parent complex [Fe(phtmeimb)2]PF6 (2.0 ns and 2.1%). The integrity of the favorable excited state characteristics upon substitution of the ligand framework demonstrates the robustness of the scorpionate motif that tolerates modifications in the 4-phenyl position for applications such as the attachment in molecular or hybrid assemblies.

Guest water hinders sodium-ion diffusion in low-defect Berlin green cathode material.

Among Prussian blue analogues (PBAs), NaxFe[Fe(CN)6]1-y·nH2O is a highly attractive cathode material for sodium-ion batteries due to its high theoretical capacity of ∼170 mA h g-1 and inexpensive raw materials. However, concerns remain over its long-term electrochemical performance and structural factors which impact sources of resistance in the material and subsequently rate performance. Refined control of the [Fe(CN)6] vacancies and water content could help in realizing its market potential. In this context, we have studied a low-defect Berlin green (BG) Na0.30(5)Fe[Fe(CN)6]0.94(2)·nH2O with varied water content corresponding to 10, 8, 6, and 2 wt%. The impact of water on the electrochemical properties of BG was systematically investigated. The electrodes were cycled within a narrow voltage window of 3.15-3.8 V vs. Na/Na+ to avoid undesired phase transitions and side reactions while preserving the cubic structure. We demonstrate that thermal dehydration leads to a significantly improved cycling stability of over 300 cycles at 15 mA g-1 with coulombic efficiency of >99.9%. In particular, the electrode with the lowest water content exhibited the fastest Na+-ion insertion/extraction as evidenced by the larger CV peak currents during successive scans compared to hydrated samples. The results provide fundamental insight for designing PBAs as electrode materials with enhanced electrochemical performance in energy storage applications.

Moisture-Driven Degradation Pathways in Prussian White Cathode Material for Sodium-Ion Batteries.

The high-theoretical-capacity (∼170 mAh/g) Prussian white (PW), NaxFe[Fe(CN)6]y·nH2O, is one of the most promising candidates for Na-ion batteries on the cusp of commercialization. However, it has limitations such as high variability of reported stable practical capacity and cycling stability. A key factor that has been identified to affect the performance of PW is water content in the structure. However, the impact of airborne moisture exposure on the electrochemical performance of PW and the chemical mechanisms leading to performance decay have not yet been explored. Herein, we for the first time systematically studied the influence of humidity on the structural and electrochemical properties of monoclinic hydrated (M-PW) and rhombohedral dehydrated (R-PW) Prussian white. It is identified that moisture-driven capacity fading proceeds via two steps, first by sodium from the bulk material reacting with moisture at the surface to form sodium hydroxide and partial oxidation of Fe2+ to Fe3+. The sodium hydroxide creates a basic environment at the surface of the PW particles, leading to decomposition to Na4[Fe(CN)6] and iron oxides. Although the first process leads to loss of capacity, which can be reversed, the second stage of degradation is irreversible. Over time, both processes lead to the formation of a passivating surface layer, which prevents both reversible and irreversible capacity losses. This study thus presents a significant step toward understanding the large performance variations presented in the literature for PW. From this study, strategies aimed at limiting moisture-driven degradation can be designed and their efficacy assessed.

A Stable Homoleptic Organometallic Iron(IV) Complex.

A homoleptic organometallic FeIV complex that is stable in both solution and in the solid state at ambient conditions has been synthesized and isolated as [Fe(phtmeimb)2 ](PF6 )2 (phtmeimb=[phenyl(tris(3-methylimidazolin-2-ylidene))borate]- ). This FeIV N-heterocyclic carbene (NHC) complex was characterized by 1 H NMR, HR-MS, elemental analysis, scXRD analysis, electrochemistry, Mößbauer spectroscopy, and magnetic susceptibility. The two latter techniques unequivocally demonstrate that [Fe(phtmeimb)2 ](PF6 )2 is a triplet FeIV low-spin S=1 complex in the ground state, in agreement with quantum chemical calculations. The electronic absorption spectrum of [Fe(phtmeimb)2 ](PF6 )2 in acetonitrile shows an intense absorption band in the red and near IR, due to LMCT (ligand-to-metal charge transfer) excitation. For the first time the excited state dynamics of a FeIV complex was studied and revealed a ≈0.8 ps lifetime of the 3 LMCT excited state of [Fe(phtmeimb)2 ](PF6 )2 in acetonitrile.

Influence of sodium content on the thermal behavior of low vacancy Prussian white cathode material.

Rechargeable sodium-ion batteries are the most attractive substitutes for lithium-ion batteries in large-scale energy storage devices due to wide spread reserves and low-cost of sodium resources and the similarities between sodium and lithium chemistry. However, finding a suitable cathode material is still a hurdle to be overcome. To date, Prussian white (PW), NaxFe[Fe(CN)6]y·nH2O has stood out as one of the most promising Na-host materials due to its low cost, facile synthesis and competitive electrochemical capacity. Despite this, there are concerns that this material will thermally decompose at relatively low temperatures to form cyanogen gas, which is a safety hazard. Thus, low vacancy NaxFe[Fe(CN)6]y·nH2O (x = 1.5, 1, 0.5 and 0) has been synthesized, and the influence of x on its thermal behavior systematically investigated. It is demonstrated that the thermal decomposition temperature, water content and moisture sensitivity of the samples strongly depend on the sodium content. The sample with x = 1.5 is found to be the most thermally stable and has the highest water content under the same experimental conditions. In addition, the sodium-rich samples (x = 1.5, 1 and 0.5) have higher surface water than the sodium-deficient one (x = 0). The local structure for this sample is also very different to the sodium-rich ones. Our findings offer new insights into the profound implications of proper material handling and safer operating conditions for practical Na-ion batteries and may be extended to analogous systems.

Luminescence and reactivity of a charge-transfer excited iron complex with nanosecond lifetime.

Iron's abundance and rich coordination chemistry are potentially appealing features for photochemical applications. However, the photoexcitable charge-transfer states of most iron complexes are limited by picosecond or subpicosecond deactivation through low-lying metal-centered states, resulting in inefficient electron-transfer reactivity and complete lack of photoluminescence. In this study, we show that octahedral coordination of iron(III) by two mono-anionic facial tris-carbene ligands can markedly suppress such deactivation. The resulting complex [Fe(phtmeimb)2]+, where phtmeimb is {phenyl[tris(3-methylimidazol-1-ylidene)]borate}-, exhibits strong, visible, room temperature photoluminescence with a 2.0-nanosecond lifetime and 2% quantum yield via spin-allowed transition from a doublet ligand-to-metal charge-transfer (2LMCT) state to the doublet ground state. Reductive and oxidative electron-transfer reactions were observed for the 2LMCT state of [Fe(phtmeimb)2]+ in bimolecular quenching studies with methylviologen and diphenylamine.

Influence of Cobalt Substitution on the Magnetic Properties of Fe5PB2.

The substitutional effects of cobalt in (Fe1-xCox)5PB2 have been studied with respect to crystalline structure and chemical order with X-ray diffraction and Mössbauer spectroscopy. The magnetic properties have been determined from magnetic measurements, and density functional theory calculations have been performed for the magnetic properties of both the end compounds, as well as the chemically disordered intermediate compounds. The crystal structure of (Fe1-xCox)5PB2 is tetragonal (space group I4/mcm) with two different metal sites, with a preference for cobalt atoms in the M(2) position (4c) at higher cobalt contents. The substitution also affects the magnetic properties with a decrease of the Curie temperature (TC) with increasing cobalt content, from 622 to 152 K for Fe5PB2 and (Fe0.3Co0.7)5PB2, respectively. Thus, the Curie temperature is dependent on composition, and it is possible to tune TC to a temperature near room temperature, which is one prerequisite for magnetic cooling materials.

A low-spin Fe(iii) complex with 100-ps ligand-to-metal charge transfer photoluminescence.

Transition-metal complexes are used as photosensitizers, in light-emitting diodes, for biosensing and in photocatalysis. A key feature in these applications is excitation from the ground state to a charge-transfer state; the long charge-transfer-state lifetimes typical for complexes of ruthenium and other precious metals are often essential to ensure high performance. There is much interest in replacing these scarce elements with Earth-abundant metals, with iron and copper being particularly attractive owing to their low cost and non-toxicity. But despite the exploration of innovative molecular designs, it remains a formidable scientific challenge to access Earth-abundant transition-metal complexes with long-lived charge-transfer excited states. No known iron complexes are considered photoluminescent at room temperature, and their rapid excited-state deactivation precludes their use as photosensitizers. Here we present the iron complex [Fe(btz)3]3+ (where btz is 3,3'-dimethyl-1,1'-bis(p-tolyl)-4,4'-bis(1,2,3-triazol-5-ylidene)), and show that the superior σ-donor and π-acceptor electron properties of the ligand stabilize the excited state sufficiently to realize a long charge-transfer lifetime of 100 picoseconds (ps) and room-temperature photoluminescence. This species is a low-spin Fe(iii) d5 complex, and emission occurs from a long-lived doublet ligand-to-metal charge-transfer (2LMCT) state that is rarely seen for transition-metal complexes. The absence of intersystem crossing, which often gives rise to large excited-state energy losses in transition-metal complexes, enables the observation of spin-allowed emission directly to the ground state and could be exploited as an increased driving force in photochemical reactions on surfaces. These findings suggest that appropriate design strategies can deliver new iron-based materials for use as light emitters and photosensitizers.

Structure Characterization and Properties of K-Containing Copper Hexacyanoferrate.

Copper hexacyanoferrate, Cu(II)[Fe(III)(CN)6]2/3·nH2O, was synthesized, and varied amounts of K(+) ions were inserted via reduction by K2S2O3 (aq). Ideally, the reaction can be written as Cu(II)[Fe(III)(CN)6]2/3·nH2O + 2x/3K(+) + 2x/3e(-) ↔ K2x/3Cu(II)[Fe(II)xFe(III)1-x(CN)6]2/3·nH2O. Infrared, Raman, and Mössbauer spectroscopy studies show that Fe(III) is continuously reduced to Fe(II) with increasing x, accompanied by a decrease of the a-axis of the cubic Fm3̅m unit cell. Elemental analysis of K by inductively coupled plasma shows that the insertion only begins when a significant fraction, ∼20% of the Fe(III), has already been reduced. Thermogravimetric analysis shows a fast exchange of water with ambient atmosphere and a total weight loss of ∼26 wt % upon heating to 180 °C, above which the structure starts to decompose. The crystal structures of Cu(II)[Fe(III)(CN)6]2/3·nH2O and K2/3Cu[Fe(CN)6]2/3·nH2O were refined using synchrotron X-ray powder diffraction data. In both, one-third of the Fe(CN)6 groups are vacant, and the octahedron around Cu(II) is completed by water molecules. In the two structures, difference Fourier maps reveal three additional zeolitic water sites (8c, 32f, and 48g) in the center of the cavities formed by the -Cu-N-C-Fe- framework. The K-containing compound shows an increased electron density at two of these sites (32f and 48g), indicating them to be the preferred positions for the K(+) ions.