Mechanism of chemical degradation and determination of solubility by kinetic modeling of the highly unstable sesquiterpene lactone nobilin in different media.

The objective of this work was first to investigate the chemical degradation of the sesquiterpene lactone nobilin and determine its solubility under conditions of concurrent degradation for partially amorphous starting material; second, to determine the effect of biorelevant media used in the in vitro measurement of intestinal absorption on degradation and solubility of nobilin. Purely aqueous medium (aq-TMCaco ), fasted and fed state simulated intestinal fluid (FaSSIF-TMCaco and FeSSIF-TMCaco ), and two liposomal formulations (LiposomesFaSSIF and LiposomesFeSSIF ) with the same lipid concentration as FaSSIF-TMCaco and FeSSIF-TMCaco were used. Degradation products were identified by nuclear magnetic resonance and X-ray crystallography and the order of reaction kinetics was determined. Solubility was deduced with a mathematical model encompassing dissolution, degradation, and reprecipitation kinetics that took into account particle size distribution of the solid material. Degradation mechanism of nobilin involved water-catalyzed opening of the lactone ring and transannular cyclization resulting in five degradation products. Degradation followed first-order kinetics in aq-TMCaco and FaSSIF-TMCaco , and higher-order kinetics in FeSSIF-TMCaco and the two liposomal formulations, whereas degradation in the latter media was diminished. Solubility of nobilin increased in the order: aq-TMCaco < FaSSIF-TMCaco , < LiposomesFaSSIF < FeSSIF-TMCaco < LiposomesFeSSIF . Improvement of stability and solubility was consistent with the incorporation of the nobilin molecule into colloidal lipid particles. The developed kinetic model is proposed to be a useful tool for deducing solubility under dynamic conditions.

Tuning facial-meridional isomerisation in monometallic nine-co-ordinate lanthanide complexes with unsymmetrical tridentate ligands.

The unsymmetrical tridentate benzimidazole-pyridine-carboxamide units in ligands L1-L4 react with trivalent lanthanides, Ln(III), to give the nine-co-ordinate triple-helical complexes [Ln(Li)3]3+ (i = 1-4) existing as mixtures of C3-symmetrical facial and C1-symmetrical meridional isomers. Although the beta13 formation constants are 3-4 orders of magnitude smaller for these complexes than those found for the D3-symmetrical analogues [Ln(Li)3]3+ (i = 5-6) with symmetrical ligands, their formation at the millimolar scale is quantitative and the emission quantum yield of [Eu(L2)3]3+ is significantly larger. The fac-[Ln(Li)3]3+ <--> mer-[Ln(Li)3]3+ (i = 1-4) isomerisation process in acetonitrile is slow enough for Ln = Lu(III) to be quantified by 1H NMR below room temperature. The separation of enthalpic and entropic contributions shows that the distribution of the facial and meridional isomers can be tuned by the judicious peripheral substitution of the ligands affecting the interstrand interactions. Molecular mechanics (MM) calculations suggest that one supplementary interstrand pi-stacking interaction stabilises the meridional isomers, while the facial isomers benefit from more favourable electrostatic contributions. As a result of the mixture of facial and meridional isomers in solution, we were unable to obtain single crystals of 1:3 complexes, but the X-ray crystal structures of their nine-co-ordinate precursors [Eu(L1)2(CF3SO3)2(H2O)](CF3SO3)(C3H5N)2(H2O) (6, C45H54EuF9N10O13S3, monoclinic, P2(1)/c, Z = 4) and [Eu(L4)2(CF3SO3)2(H2O)](CF3SO3)(C4H4O)(1.5) (7, C51H66EuF9N8O(15.5)S3, triclinic, P1, Z = 2) provide crucial structural information on the binding mode of the unsymmetrical tridentate ligands.