Intelligent automation of high-performance liquid chromatography method development by means of a real-time knowledge-based approach

We describe the development, attributes and capabilities of a novel type of artificial intelligence system, called LabExpert, for automation of HPLC method development. Unlike other computerised method development systems, LabExpert operates in real-time, using an artificial intelligence system and design engine to provide experimental decision outcomes relevant to the optimisation of complex separations as well as the control of the instrumentation, column selection, mobile phase choice and other experimental parameters. LabExpert manages every input parameter to a HPLC data station and evaluates each output parameter of the HPLC data station in real-time as part of its decision process. Based on a combination of inherent and user-defined evaluation criteria, the artificial intelligence system programs use a reasoning process, applying chromatographic principles and acquired experimental observations to iteratively provide a regime for a priori development of an acceptable HPLC separation method. Because remote monitoring and control are also functions of LabExpert, the system allows full-time utilisation of analytical instrumentation and associated laboratory resources. Based on our experience with LabExpert with a wide range of analyte mixtures, this artificial intelligence system consistently identified in a similar or faster time-frame preferred sets of analytical conditions that are equal in resolution, efficiency and throughput to those empirically determined by highly experienced chromatographic scientists. An illustrative example, demonstrating the potential of LabExpert in the process of method development of drug substances, is provided.     

Ultrafast dynamics for electron photodetachment from aqueous hydroxide

Charge-transfer-to-solvent reactions of hydroxide induced by 200 nm monophotonic or 337 and 389 nm biphotonic excitation of this anion in aqueous solution have been studied by means of pump-probe ultrafast laser spectroscopy. Transient absorption kinetics of the hydrated electron, e(aq) (-), have been observed, from a few hundred femtoseconds out to 600 ps, and studied as function of hydroxide concentration and temperature. The geminate decay kinetics are bimodal, with a fast exponential component ( approximately 13 ps) and a slower power "tail" due to the diffusional escape of the electrons. For the biphotonic excitation, the extrapolated fraction of escaped electrons is 1.8 times higher than for the monophotonic 200 nm excitation (31% versus 17.5% at 25 degrees C, respectively), due to the broadening of the electron distribution. The biphotonic electron detachment is very inefficient; the corresponding absorption coefficient at 400 nm is <4 cm TW(-1) M(-1) (assuming unity quantum efficiency for the photodetachment). For [OH(-)] between 10 mM and 10 M, almost no concentration dependence of the time profiles of solvated electron kinetics was observed. At higher temperature, the escape fraction of the electrons increases with a slope of 3x10(-3) K(-1) and the recombination and diffusion-controlled dissociation of the close pairs become faster. Activation energies of 8.3 and 22.3 kJ/mol for these two processes were obtained. The semianalytical theory of Shushin for diffusion controlled reactions in the central force field was used to model the geminate dynamics. The implications of these results for photoionization of water are discussed.     

Thermodynamic profiles for CO photodissociation from heme model compounds: effect of proximal ligands

Here we present a comprehensive study of the thermodynamic parameters (enthalpy, entropy, and volume changes) associated with carbon monoxide photodissociation and rebinding to Fe(II) microperoxidase-11 (Fe(II)MP11) and Fe(ll) tetrakis(4-sulfonatophenyl)porphine complex (FeII4SP) with water and 2-methylimidazole as proximal ligands. CO photodissociation from FeII4SP complexes is accompanied by a positive volume change of approximately 17 mL mol(-1). A smaller volume change of approximately 12 mL mol(-1) was observed for CO dissociation from Fe(II)MP-11. We attribute the positive volume change to cleavage of the Fe-CO covalent bond and to solvent reorganization due to the low-spin to high-spin transition. CO binding is an exothermic reaction with an enthalpy change of -17 kcal mol(-1) for the CO-FeII4SP complexes and -13 kcal mol(-1) for the CO-Fe(II)MP11 complex. In all cases, the ligand recombination occurs as a single-exponential process indicating that CO dissociation is followed by direct CO rebinding to a high-spin five-coordinate complex without concomitant dissociation of the proximal base. In addition, observed negative activation entropies and volumes for ligand binding to (2-Melm)FeII4SP and MP-11, respectively, suggest that CO rebinding can be described by an associative mechanism with bond formation being the rate-limiting step.     

Structural properties of a series of photochromic fluorinated indolylfulgides

Fluorinated indolyl­fulgides are a class of photochromic organic compounds that meet many of the requirements for use as optical memory media and optical switches. The X‐ray crystal structures of a series of five photochromic fluorinated indolyl­fulgides have been determined, namely (3Z)‐3‐[1‐(1,2‐di­methyl‐1H‐indol‐3‐yl)‐2,2,2‐tri­fluoro­ethyl­idene]‐4‐(1‐methyl­ethyl­idene)­dihydrofuran‐2,5‐dione (tri­fluoro­methyl­iso­propyl­idene­indolyl­fulgide), C₁₉H₁₆F₃NO₃, (I), (3Z)‐3‐[1‐(1,2‐dimethyl‐1H‐indol‐3‐yl)‐2,2,3,3,3‐penta­fluoro­propyl­idene]‐4‐(1‐methyl­ethyl­idene)­dihydrofuran‐2,5‐dione (penta­fluoro­ethyl­iso­propyl­idene­indolyl­fulgide), C₂₀H₁₆F₅NO₃, (II), (3Z)‐3‐[1‐(1,2‐di­methyl‐1H‐indol‐3‐yl)‐2,2,3,3,4,4,4‐hepta­fluoro­butyl­idene]‐4‐(1‐methyl­ethyl­idene)­dihydrofuran‐2,5‐dione (hepta­fluoro­propyl­iso­propyl­idene­indolyl­fulgide), C₂₁H₁₆F₇NO₃, (III), (3Z)‐3‐[1‐(1,2‐di­methyl‐1H‐indol‐3‐yl)‐2,2,2‐tri­fluoro­ethyl­idene]‐4‐(tri­cyclo­[3.3.1.1^3,7]­decyl­idene­)dihydrofuran‐2,5‐dione (tri­fluoro­methyl­adamantyl­idene­indolyl­fulgide), C₂₆H₂₄F₃NO₃, (IV), and (3Z)‐3‐[1‐(1,2‐di­methyl‐1H‐indol‐3‐yl)‐2,2,3,3,4,4,4‐hepta­fluoro­butyl­idene]‐4‐(tri­cyclo­[3.3.1.1^3,7]­decyl­idene­)dihydrofuran‐2,5‐dione (hepta­fluoro­propyl­adamantylidenein­dolyl­fulgide), C₂₈H₂₄F₇NO₃, (V). The photochromic property of fulgides is based on the photochemically allowed electrocyclic ring closure of a hexatriene system to form a cyclo­hexa­diene. For each fulgide examined, the bond lengths within the hexatriene system alternate between short and long, as expected. Comparing the structures of the five fulgides with each other demonstrates no significant difference in bond lengths, bond angles or dihedral angles within the hexatriene systems. The distance between the bond‐forming C atoms at each end of the hexatriene system does vary. Correlations of structural properties with optical properties are addressed.     

Comparison of experimental and calculated peak shapes for three cylindrical geometry FAIMS prototypes of differing electrode diameters

High-field asymmetric waveform ion mobility spectrometry (FAIMS) separates ions at atmospheric pressure and room temperature based on the difference of the mobility of ions in strong electric fields and weak electric fields. This field-dependent mobility of an ion is reflected in the compensation voltage (CV) at which the ion is transmitted through FAIMS, at a given asymmetric waveform dispersion voltage (DV). Experimental CV, relative peak ion intensity, and peak width data were compared for three FAIMS prototypes with concentric cylindrical electrodes having inner/outer electrode radii of: (1) 0.4/0.6 cm, (2) 0.8/1.0 cm, and (3) 1.2/1.4 cm. The annular analyzer space was 0.2 cm wide in each case. A finite-difference numerical computation method is described for evaluation of peak shapes and widths in a CV spectrum collected using cylindrical geometry FAIMS devices. Simulation of the radial distribution of the ion density in the FAIMS analyzer is based upon calculation of diffusion, electric fields, and the electric fields introduced by coulombic ion-ion repulsion. Excellent agreement between experimental and calculated peak shapes were obtained for electrodes of wide diameter and for ions transmitted at low CV.     

Low-dimensional intrinsic material functions for nonlinear viscoelasticity

Rheological material functions are used to form our conceptual understanding of a material response. For a nonlinear rheological response, the possible deformation protocols and material measures span a high-dimensional space. Here, we use asymptotic expansions to outline low-dimensional measures for describing leading-order nonlinear responses in large amplitude oscillatory shear (LAOS). This amplitude-intrinsic regime is sometimes called medium amplitude oscillatory shear (MAOS). These intrinsic nonlinear material functions are only a function of oscillatory frequency, and not amplitude. Such measures have been suggested in the past, but here, we clarify what measures exist and give physically meaningful interpretations. Both shear strain control (LAOStrain) and shear stress control (LAOStress) protocols are considered, and nomenclature is introduced to encode the physical interpretations. We report the first experimental measurement of all four intrinsic shear nonlinearities of LAOStrain. For the polymeric hydrogel (polyvinyl alcohol - Borax) we observe typical integer power function asymptotics. The magnitudes and signs of the intrinsic nonlinear fingerprints are used to conceptually model the mechanical response and to infer molecular and microscale features of the material.     

Synthesis of N-(1-Keto-) and N-(1-Hydroxy-5-Indansulfonyl)-N′-(4-Chlorophenyl)Urea,Two Major Metabolites of the Antitumor Agent Sulofenur (LY186641)

A brief (3–4 step), large-scale synthesis of two major metabolites of the antitumor agent sulofenur was developed. The required intermediate, 1-keto-5-indansulfonamide, was prepared in only two steps, utilizing a novel method for converting an aromatic chloride to a sulfonamide.     

DERIVATION OF THE LEHNERT FIELD EQUATIONS FROM GAUGE THEORY IN VACUUM: SPACE CHARGE AND CURRENT

It is shown that the Lehnert field equations in vacuum, with concomitant space charge and current, can be derived straightforwardly from standard gauge theory applied in vacuum, using the concept of covariant derivative and Feynman's universal influence. The Lehnert and Proca field equations are shown to be inter-related through the well-known de Broglie theorem, in which the photon mass can be interpreted as finite. These ideas go some way towards addressing the inconsistency inherent in Maxwell's famous displacement current, which has no concomitant vacuum space charge.     

Linear stability of radially-heated circular Couette flow with simulated radial gravity

The stability of circular Couette flow between vertical concentric cylinders in the presence of a radial temperature gradient is considered with an effective “radial gravity.” In addition to terrestrial buoyancy − ρg e _z we include the term − ρg _m f(r)e _r where g _m f(r) is the effective gravitational acceleration directed radially inward across the gap. Physically, this body force arises in experiments using ferrofluid in the annular gap of a Taylor–Couette cell whose inner cylinder surrounds a vertical stack of equally spaced disk magnets. The radial dependence f(r) of this force is proportional to the modified Bessel function K ₁(κr), where 2π/κ is the spatial period of the magnetic stack and r is the radial coordinate. Linear stability calculations made to compare with conditions reported by Ali and Weidman (J. Fluid Mech., 220, 1990) show strong destabilization effects, measured by the onset Rayleigh number R, when the inner wall is warmer, and strong stabilization effects when the outer wall is warmer, with increasing values of the dimensionless radial gravity γ = g _m /g. Further calculations presented for the geometry and fluid properties of a terrestrial laboratory experiment reveal a hitherto unappreciated structure of the stability problem for differentially-heated cylinders: multiple wavenumber minima exist in the marginal stability curves. Transitions in global minima among these curves give rise to a competition between differing instabilities of the same spiral mode number, but widely separated axial wavenumbers.