Evolution of regulatory aspects of genotoxic impurities in pharmaceuticals: Survival of the fittest

The genotoxic impurities (GIs) are carcinogenic hence its management during synthesis of pharmaceuticals is very important to be detected even in trace level for the safe use of the drugs. The presence of drug substance/drug product DNA-reactive impurities poses a significant problem for drug regulators as well as industry. There are several regulatory guidelines and position papers focused on controlling the amount of impurities within the specified limits. The present compilation gives an account of updated information about GIs and reviews the regulatory aspects for GIs in active pharmaceutical ingredients/drug formulations. A detailed discussion about control strategies in the context of GIs is also described precisely. The analysis of GIs is a challenging and complex aspect of the drug development process. Control and determination of these impurities at ppm or ppb levels are significant challenges for analysts, therefore the approaches for the analysis of GIs have also been discussed.     

Critical needs of fringe-order accuracies in two-color holographic interferometry

Two-color holographic interferometry is a promising technique for separating simultaneous concentration and temperature variations in solution for crystal-growth experiments on earth and in microgravity conditions in space. The ultimate success depends on two linearly independent fringe patterns due to the different wavelengths. With available practical lasers and typical crystal-growth experimental conditions the two interference fringe patterns (other than scale effects) may not be too different. The slight error in the measured fringe order can then yield large uncertainty in temperature and concentration determination. This aspect is analytically considered for the first time in this article. A simple cell (rectangular parallelpiped) is considered containing the fluid. For simplicyt, we assume a constant field along the object-wave-propagation direction in the cell. The two reconstructed fringe patterns are then represented in terms of temperature and concentration variations. Solving two equations theoretically yields the desired temperature and concentration. However, once the fringe-postition measurement error is introduced, error in the temperature and concentration results. These errors are analytically determined. A particular case of TGS (triglycine sulfate) aqueous solution with HeNe (λ=632.8 nm) and HeCd (λ=441.6 nm) lasers for holography is critically discussed. It is found that a high degree of accuracy in the fringe order is required in this particular case. To improve fringe-position measurements, special techniques such as electronic phase measurement or heterodyne detection may be necessary. The study provides the analytical guidelines for designing the experiments and critical needs of desired physical parameters. Paper was presented at the 1990 SEM Fall Conference on Experimental Mechanics held in Baltimore, MD on November 5–8.     

An improved method for calculating flow past flapping and hovering airfoils

A method is reported here for calculating unsteady aerodynamics of hovering and flapping airfoil for two-dimensional flow via the following improved methodologies: (a) a correct formulation of the problem using stream function (ψ) and vorticity (ω) as dependent variables; (b) calculating loads and moment by a new method to solve the governing pressure Poisson equation (PPE) in a truncated part of the computational domain on a nonstaggered grid; (c) accurate solution using high accuracy compact difference scheme for the vorticity transport equation (VTE) and (d) accelerating the computations by using a high-order filter after each time step of integration. These have been used to solve Navier–Stokes equation for flow past flapping and hovering NACA 0014 and 0015 airfoils at typical Reynolds numbers relevant to the study of unsteady aerodynamics of micro air vehicle (MAV) and insect/bird flight.     

Dynamic shearing resistance of molten metal films under high pressures and extremely high shearing rates

In the present study plate-impact pressureshear experiments have been conducted to study the dynamic shearing resistance of molten metal films at shearing rates of approximately 10⁷ s⁻¹. These molten films are generated by pressure-shear impact of relatively low melt-point metals such as 7075-T6 Al alloy with high hardness and high flow-strength tool-steel plates. By employing high impact speeds and relatively smooth impacting surfaces, normal interfacial pressures ranging from 1–3 GPa and slip speeds of over 100 m/s are generated during the pressure-shear loading. The resulting friction stress (∼100 to 400 MPa) combined with the high slip speeds generate conditions conductive to interfacial temperatures approaching the fully melt temperature regime of the lower melt-point metal (7075-T6 aluminum alloy) comprising the tribo-pair. During pressure-shear loading, laser interferometry is employed to measure normal and transverse motion at the rear surface of the target plate. The normal component of the particle velocity provides the interfacial normal traction while the transverse component provides the shearing resistance of the interface as it passes through melt. In order to extract the critical interfacial parameters, such as the interfacial slip-speed and interfacial temperatures, a Lagrangian finiteelement code is developed. The computational procedure accounts for dynamic effects, heat conduction, contact with friction, and full thermo-mechanical coupling. At temperatures below melt the flyer and target materials are described as an isotropic thermally softening elastic-viscoplastic solid. For material elements with temperatures in excess of the melt point, a purely Newtonian fluid constitutive model is employed. The results of this hybrid experimental-computational study provide insights into the dynamic shearing resistance of molten metal films at high pressures and extremely high shearing rates.     

Syntheses of (−)-gabosine A, (+)-4-epi-gabosine A, (−)-gabosine E, and (+)-4-epi-gabosine E

(+)-4-epi-Gabosine A 1 and (−)-gabosine A 2 have been synthesized starting from methyl α,d-glucopyranoside and methyl α,d-mannopyranoside, respectively, by utilizing Pd(0) catalyzed Stille coupling as the key step. On the other hand, syntheses of (+)-4-epi-gabosine E 3 and (−)-gabosine E 4 have been accomplished from methyl α,d-glucopyranoside and from methyl α,d-mannopyranoside, respectively, by utilizing DMAP catalyzed Morita-Baylis-Hillman reaction as the key step. Presence of acetyl group at C-6 position of sugar derived cyclic enone prevented the aromatization of MBH adduct. A plausible mechanism is also described.     

He 2++ molecular ion in a strong time-dependent magnetic field: a current-density functional study

The He molecular ion exposed to a strong ultrashort time‐dependent (TD) magnetic field of the order of 10⁹ G is investigated through a quantum fluid dynamics (QFD) and current‐density functional theory (CDFT) based approach using vector exchange‐correlation (XC) potential and energy density functional that depend not only on the electronic charge‐density but also on the current density. The TD‐QFD‐CDFT computations are performed in a parallel internuclear‐axis and magnetic field‐axis configuration at the field‐free equilibrium internuclear separation R = 1.3 au with the field‐strength varying between 0 and 10¹¹ G. The TD behavior of the exchange‐ and correlation energy of the He is analyzed and compared with that obtained using a [B‐TD‐QFD‐density functional theory (DFT)] approach based on the conventional TD‐DFT under similar computational constraints but using only scalar XC potential and energy density functional dependent on the electronic charge‐density alone. The CDFT based approach yields TD exchange‐ and correlation energy and TD electronic charge‐density significantly different from that obtained using the conventional TD‐DFT based approach, particularly, at typical magnetic field strengths and during a typical time period of the TD field. This peculiar behavior of the CDFT‐based approach is traced to the TD current‐density dependent vector XC potential, which can induce nonadiabatic effects causing retardation of the oscillating electronic charge density. Such dissipative electron dynamics of the He molecular ion is elucidated by treating electronic charge density as an electron‐“fluid” in the terminology of QFD. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011     

Ideal rate of collision of cylinders in simple shear flow

The collision of particles influences the behavior of suspensions through the formation of aggregates for adhesive particles or through the contributions of solid-body contacts to the stress for nonadhesive particles. The simplest estimate of the collision rate, termed the ideal collision rate, is obtained when particles translate and rotate with the flow but have no hydrodynamic or colloidal interactions. Smoluchowski calculated the ideal collision frequency of spherical particles in 1917. So far, little work has been done to understand rate of collision for nonspherical particles. In this work, we calculate the ideal collision rate for cylindrical particles over a broad range of particle aspect ratios r defined as the ratio of length to diameter. Monte Carlo simulations are performed with initial relative positions and orientations that model the rate of approach of noninteracting particles following Jeffery orbits with several choices of the orbit distribution. The role of rotational motion of particles on collision frequency is elucidated by comparing the ideal collision rate calculations with similar calculations for nonrotating particles. It is shown that the ratio of the collision rate of cylinders to that of spheres that circumscribe the cylinders is proportional to 1/rr(e) for r ? 1 and r(e) for r ? 1. Here, r(e) is the effective aspect ratio defined as the aspect ratio of a spheroid having the same period of rotation as the cylinder. The effective aspect ratio of the cylindrical particles was determined using finite element calculations of the torque on nonrotating cylinders with their axes parallel to the velocity and velocity gradient directions. In addition to deriving the total collision rate, we categorize collisions as side-side, edge-side, and face-edge based on the initial point of contact. Most collisions are found to be side-edge for r ? 1 and face-edge for r ? 1, suggesting that nonlinear aggregates will develop if particles stick at the point of first contact.     

Single mode phonon energy transmission in functionalized carbon nanotubes

Although the carbon nanotube (CNT) features superior thermal properties in its pristine form, the chemical functionalization often required for many applications of CNT inevitably degrades the structural integrity and affects the transport of energy carriers. In this article, the effect of the side wall functionalization on the phonon energy transmission along the symmetry axis of CNT is studied using the phonon wave packet method. Three different functional groups are studied: methyl (-CH(3)), vinyl (-C(2)H(3)), and carboxyl (-COOH). We find that, near Γ point of the Brillouin zone, acoustic phonons show ideal transmission, while the transmission of the optical phonons is strongly suppressed. A positive correlation between the energy transmission coefficient and the phonon group velocity is observed for both acoustic and optical phonon modes. On comparing the transmission due to functional groups with equivalent point mass defects on CNT, we find that the chemistry of the functional group, rather than its molecular mass, has a dominant role in determining phonon scattering, hence the transmission, at the defect sites.     

Computational studies on tetrazole derivatives as potential high energy materials

The tetrazole is an important functionality of the most of energetic materials due to 80% nitrogen content, stability, and high enthalpy of formation. The present structure–property relationship study focuses on the optimized geometries of tetrazole derivatives obtained from density functional theory (DFT) calculations at B3LYP/6-31G* levels. The heat of formation (HOF) of tetrazole derivatives have been calculated by designing the appropriate isodesmic reactions. The increase in nitro groups on azole rings shows the remarkable increase in HOF. Density has been predicted by using CVFF force field. Increase in the nitro group increases the density. Detonation properties of the designed compounds were evaluated by using the Kamlet–Jacobs equation based on predicted densities and HOFs. Designed tetrazole derivatives show detonation velocity (D) over 8 km/s and detonation pressure (P) of about 32 GPa. Thermal stability was evaluated via bond dissociation energies (BDE) of the weakest C–NO₂ bond at B3LYP/6-31G* level. Charge on the nitro group has been used to assess the sensitivity correlation. Overall, the study implies that designed compounds of this series are found to be stable and expected to be the novel candidates of high energy materials (HEMs).