A Versatile Method of Ambient-Temperature Solvent Removal.

Isolation of heat-sensitive reaction products in post-synthesis workup procedures often requires ambient-or low-temperature solvent removal. In the method demonstrated here, solvent evaporation is driven by the pressure gradient between a distillation flask and a chilled receiver in an evacuated closed system containing a minimal amount of residual noncondensable gas. Using an all-glass apparatus, the method is exemplified by evaporation of solvent samples from a distillation flask containing 50 mL of either dimethylformamide, dimethyl sulfoxide (DMSO), or N-methylpyrrolidone (NMP). The distillation flask is suspended in a water bath at temperatures of 18-28 °C, the evaporated solvent is collected in a receiver chilled with liquid nitrogen, and the entire process is completed in 90-140 min. The practicality of this method is further illustrated on a bench-chemistry scale by DMSO and NMP solvent removal from solutions of benzophenone, monitored by gravimetric and 1H NMR methods. Modification of the demonstrated method to mimic freeze-drying conditions (by reducing heat flow to the distillation flask) can be used for recovery of water-soluble compounds including polymers and biopolymers. We propose the name "cryovap" for this solvent removal method.

Tenacic Acids: A New Class of Tenacious Binders to Metal Oxide Surfaces.

The backbone of 2-hydroxyisophthalic acid was identified as a potential metal oxide anchor because of the perfect alignment of all three of its donor groups for binding to inorganic surfaces. It can therefore be used in the design of organic linkers for metal oxide based hybrid materials. Optimized and scalable methods for the synthesis of 2-hydroxyisophthalic acid (1) and its 5-substituted derivatives: 5-bromo- (2), 5-sulfooxy- (3), 5-hydroxy- (4), and 5-PEG600 (5) are presented. Dynamic light scattering (DLS) demonstrated that compound 2 inhibits Fe(OH)3 precipitation when FeIII aqueous solutions are titrated with NaOH, while similar titrations in the presence of the structurally-related isophthalic and salicylic acids, both missing the third donor group, show turbidity at pHs as low as 2.3 and 3.5, respectively. The adduct synthesized from 4.5 nm γ-Fe2 O3 nanoparticles and 5 is water-, alcohol- and CH2 Cl2 -soluble, and forms stable aqueous colloids in the pH range of 4.4-8.7. Moreover, at a pH close to neutral these colloids survive at 100 °C, demonstrating the high practicality of 2-hydroxyisophthalic acid for nanoparticulate inorganic/organic hybrid material design.

Optimization of PEGylated nanoemulsions for improved pharmacokinetics of BCS class II compounds.

The objective of the study was the optimization of nanoemulsion formulations to prevent their rapid systemic clearance after intravenous administration. An amphiphilic PEG derivative DSPE-PEG (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(polyethylene glycol) with different chain lengths and concentration was used as a nanoemulsion droplet surface modifier. The danazol loading in all nanoemulsions was kept on the same level of ∼2 mg/mL. In the present investigation, PEGylated and non-PEGylated nanoemulsions were compared in vitro phagocytosis by incubating with lung macrophages and in vivo after intravenous administration in rats. Danazol-containing nanoemulsions (NE) modified with various PEG chain lengths (2000-10 000) and concentrations (3-12 mg/mL) were prepared and characterized. Nanoemulsion droplets were reproducibly obtained in the size range of 213-340 nm. The non-PEGylated NE had the surface charge of -25.4 mV. This absolute charge value decreased with increasing chain length and concentration. With increase in chain length and density the macrophage uptake decreased which could be due to decrease in surface charge and hydrophilicity of droplets. The greatest shielding of the NE droplets was reached with DSPE-PEG5000 at the concentration of 6 mg/mL where the surface charge changed to -1.27 mV. Following intravenous administration a maximum danazol exposure (401 ± 68.2 h ng/mL) was observed with the lowest clearance rate (5.06 ± 0.95 L/h/kg) from 6 mg/mL DSPE-PEG5000 nanoemulsion. PEG5000 and PEG10000 altered the pharmacokinetic of danazol by decreasing clearance and volume of distribution which is likely explained by the presence of hydrophilic shields around the droplets that prevent their rapid systemic clearance and tissue partitioning.

Synthesis of 5-Substituted Derivatives of Isophthalic Acid as Non-Polymeric Amphiphilic Coating for Metal Oxide Nanoparticles.

In the course of development of novel capping ligands with variable steric factor, which will be used as an organic coating for metal oxide nanoparticles, a base-catalyzed nucleophilic oxirane ring-opening addition reaction between dimethyl 5-hydroxyisophthalate and allyl glycidyl ether was studied. The allyl-terminated 1-1, 1-2 and 1-3 adducts and dihydroxylated derivative of the 1-1 adduct, 5-diglyceroxy isophthalic acid, were synthesized. The latter binds to the surface of 5 nm γ-Fe2O3 nanoparticles in reaction with their surfactant-free diethylene glycol colloids.

Evaluation of a nanoemulsion formulation strategy for oral bioavailability enhancement of danazol in rats and dogs.

The objective of this study was to determine whether nanoemulsion formulations constitute a viable strategy to improve the oral bioavailability of danazol, a compound whose poor aqueous solubility limits its oral bioavailability. Danazol-containing oil-in-water nanoemulsions (NE) with and without cosurfactants stearylamine (SA) and deoxycholic acid (DCA) were prepared and characterized. Nanoemulsion droplets size ranging from 238 to 344 nm and with surface charges of -24.8 mV (NE), -26.5 mV (NE-DCA), and +27.8 mV (NE-SA) were reproducibly obtained. Oral bioavailability of danazol in nanoemulsions was compared with other vehicles such as PEG400, 1% methylcellulose (MC) in water (1% MC), Labrafil, and a Labrafil/Tween 80 (9:1) mixture, after intragastric administration to rats and after oral administration of NE-SA, a Labrafil solution, or a Danocrine® tablet to dogs. The absolute bioavailability of danazol was 0.6% (PEG400), 1.2% (1% MC), 6.0% (Labrafil), 7.5% (Labrafil/Tween80), 8.1% (NE-DCA), 14.8% (NE), and 17.4% (NE-SA) in rats, and 0.24% (Danocrine), 6.2% (Labrafil), and 58.7% (NE-SA) in dogs. Overall, danazol bioavailability in any nanoemulsion was higher than any other formulation. Danazol bioavailability from NE and NE-SA was 1.8- to 2.2-fold higher than NE-DCA nanoemulsion and could be due to significant difference in droplet size.

Superparamagnetic iron oxide nanoparticles with variable size and an iron oxidation state as prospective imaging agents.

Magnetite nanoparticles in the size range of 3.2-7.5 nm were synthesized in high yields under variable reaction conditions using high-temperature hydrolysis of the precursor iron(II) and iron(III) alkoxides in diethylene glycol solution. The average sizes of the particles were adjusted by changing the reaction temperature and time and by using a sequential growth technique. To obtain γ-iron(III) oxide particles in the same range of sizes, magnetite particles were oxidized with dry oxygen in diethylene glycol at room temperature. The products were characterized by DLS, TEM, X-ray powder diffractometry, TGA, chemical analysis, and magnetic measurements. NMR r(1) and r(2) relaxivity measurements in water and diethylene glycol (for OH and CH(2) protons) have shown a decrease in the r(2)/r(1) ratio with the particle size reduction, which correlates with the results of magnetic measurements on magnetite nanoparticles. Saturation magnetization of the oxidized particles was found to be 20% lower than that for Fe(3)O(4) with the same particle size, but their r(1) relaxivities are similar. Because the oxidation of magnetite is spontaneous under ambient conditions, it was important to learn that the oxidation product has no disadvantages as compared to its precursor and therefore may be a better prospective imaging agent because of its chemical stability.

The metamorphosis of heterometallic trinuclear antiferromagnetic complexes into nano-sized superparamagnetic spinels.

Thermal decomposition of the trinuclear heterometallic oxoacetates [Fe(2)M(µ(3)-O)(CH(3)COO)(6)(H(2)O)(3)] has been used as a single-precursor method for synthesis of the spinel-structured ternary oxides MFe(2)O(4) (M = Mn(II), Co(II), and Ni(II)). This facile process occurring at 320 °C results in the formation of nanocrystalline, (7-20 nm) highly pure stoichiometric ferrites in quantitative yield. The magnetic properties of these nanoparticulate ferrites were studied in the 10-300 K temperature range, revealing superparamagnetic behaviour for the Ni and Mn particles and ferromagnetic behavior for the Co ones at room temperature. Their blocking temperatures follow the order: CoFe(2)O(4) > MnFe(2)O(4) > NiFe(2)O(4).

Synthesis of ultrasmall magnetic iron oxide nanoparticles and study of their colloid and surface chemistry.

Colloidal nanoparticles of Fe(3)O(4) (4 nm) were synthesized by high-temperature hydrolysis of chelated iron (II) and (III) diethylene glycol alkoxide complexes in a solution of the parent alcohol (H(2)DEG) without using capping ligands or surfactants: [Fe(DEG)Cl(2)](2-) + 2[Fe(DEG)Cl(3)](2-) + 2H(2)O + 2OH(-) → Fe(3)O(4) + 3H(2)DEG + 8Cl(-) The obtained particles were reacted with different small-molecule polydentate ligands, and the resulting adducts were tested for aqueous colloid formation. Both the carboxyl and α-hydroxyl groups of the hydroxyacids are involved in coordination to the nanoparticles' surface. This coordination provides the major contribution to the stability of the ligand-coated nanoparticles against hydrolysis.

Reactivity of 3d transition metal cations in diethylene glycol solutions. Synthesis of transition metal ferrites with the structure of discrete nanoparticles complexed with long-chain carboxylate anions.

Study of the reactivity of 3d transition metal cations in diethylene glycol solutions revealed several key features that made it possible to develop a new method for synthesis of the nanocrystalline transition metal ferrites. The 3-7 nm particles of [MFe2O4]n[O2CR]m, where M = Mn, Fe, Co, Ni, and Zn, ligated on their surface with long-chain carboxylate anions, have been obtained in an isolated yield of 75-90%. The key features are the following. Complexation of the first-row transition metal cations with diethylene glycol at a presence of alkaline hydroxide is sufficient to enable control over the rate of their hydrolysis. The reaction of hydrolysis leads to the formation of metal oxide nanocrystals in colloidal solution. The nanoparticles growth is terminated by an added long-chain carboxylic acid, which binds to their surface and acts as a capping ligand. The isolated nanocrystalline powders are stable against agglomeration and highly soluble in nonpolar organic solvents.