Polymorphs, Salts, and Cocrystals: What's in a Name?

The December 2011 release of a draft United States Food and Drug Administration (FDA) guidance concerning regulatory classification of pharmaceutical cocrystals of active pharmaceutical ingredients (APIs) addressed two matters of topical interest to the crystal engineering and pharmaceutical science communities: (1) a proposed definition of cocrystals; (2) a proposed classification of pharmaceutical cocrystals as dissociable ``API-excipient'' molecular complexes. The Indo U.S. Bilateral Meeting sponsored by the Indo-U.S. Science and Technology Forum titled The Evolving Role of Solid State Chemistry in Pharmaceutical Science was held in Manesar near Delhi, India, from February 2-4, 2012. A session of the meeting was devoted to discussion of the FDA guidance draft. The debate generated strong consensus on the need to define cocrystals more broadly and to classify them like salts. It was also concluded that the diversity of API crystal forms makes it difficult to classify solid forms into three categories that are mutually exclusive. This perspective summarizes the discussion in the Indo-U.S. Bilateral Meeting and includes contributions from researchers who were not participants in the meeting.

Influence of growth ambience and doping on the structural properties of multiferroic DyMnO3

We report on the single crystal growth of 50% Sr and Y doped multiferroic DyMnO3 using optical floating zone technique. A comparison of the effect of growth ambience and of chemical substitution on the crystal structure of DyMnO3 is attempted. It is observed that DyMnO3 adopts Pm3m cubic structure with 50% Sr doping whereas with 50% Y doping, the crystal structure is hexagonal P6(3)cm. Orthorhombic Pnma structure is adopted by DyMnO3 when grown in air, whereas hexagonal P6(3)cm structure is obtained when grown under the ambience of argon. The structural polymorphism is discussed in terms of difference in ionic sizes of Sr, Y and Dy, comparable Gibbs free energies and coordination schemes of surrounding oxygens for hexagonal and orthorhombic structures of DyMnO3. (C) 2012 Elsevier B.V. All rights reserved.

Study of the Formation of Nano-Networks in Colloidal Particles

The authors studied the formation of a wafer-scale network of connected colloidal beads by reactive ion etching. The dimensions of the connections have been studied as a function of etching time for colloidal beads of different sizes, and could be well controlled. The authors have found that the nano-network forms and disappears for the same time of etching independent of the diameter of the polystyrene beads. With recent interest of connected colloidal networks in various optical sensing applications, such as photonic crystals, as surface-enhanced Raman scattering substrates, the studies have potential uses in the development of wafer-scale nanophotonic sensors.

Ship-Mounted Real-Time Surface Observational System on board Indian Vessels for Validation and Refinement of Model Forcing Fields

A network of ship-mounted real-time Automatic Weather Stations integrated with Indian geosynchronous satellites Indian National Satellites (INSATs)] 3A and 3C, named Indian National Centre for Ocean Information Services Real-Time Automatic Weather Stations (I-RAWS), is established. The purpose of I-RAWS is to measure the surface meteorological-ocean parameters and transmit the data in real time in order to validate and refine the forcing parameters (obtained from different meteorological agencies) of the Indian Ocean Forecasting System (INDOFOS). Preliminary validation and intercomparison of analyzed products obtained from the National Centre for Medium Range Weather Forecasting and the European Centre for Medium-Range Weather Forecasts using the data collected from I-RAWS were carried out. This I-RAWS was mounted on board oceanographic research vessel Sagar Nidhi during a cruise across three oceanic regimes, namely, the tropical Indian Ocean, the extratropical Indian Ocean, and the Southern Ocean. The results obtained from such a validation and intercomparison, and its implications with special reference to the usage of atmospheric model data for forcing ocean model, are discussed in detail. It is noticed that the performance of analysis products from both atmospheric models is similar and good; however, European Centre for Medium-Range Weather Forecasts air temperature over the extratropical Indian Ocean and wind speed in the Southern Ocean are marginally better.

Infrared spectrum of formamide in the solid phase

Infrared spectra of solid formamide are reported as a function of temperature. Solid formamide samples were prepared at 30 K and then annealed to higher temperatures (300 K) with infrared transmission spectra being recorded over the entire temperature range. The NH2 vibrations of the formamide molecule were found to be particularly very sensitive to temperature change. The IR spectra revealed a phase change occurring in solid formamide between 155 and 165 K. Spectral changes observed above and below the phase transition may be attributed to a rearrangement between formamide dimers and the formation of polymers is proposed at higher temperatures.

The dynamics between forward citations and price of singleton patents

In recent years, business practitioners are seen valuing patents on the basis of the market price that the patent can attract. Researchers have also looked into various patent latent variables and firm variables that influence the price of a patent. Forward citations of a patent are shown to play a role in determining price. Using patent auction price data (of Ocean Tomo now ICAP patent brokerage), we delve deeper into of the role of forward citations. The successfully sold 167 singleton patents form the sample of our study. We found that, it is mainly the right tail of the citation distribution that explains the high prices of the patents falling on the right tail of the price distribution. There is consistency in the literature on the positive correlation between patent prices and forward citations. In this paper, we go deeper to understand this linear relationship through case studies. Case studies of patents with high and low citations are described in this paper to understand why some patents attracted high prices. We look into the role of additional patent latent variables like age, technology discipline, class and breadth of the patent in influencing citations that a patent receives.

A novel adeno-associated virus serotype (AAV)-8 capsid mutant improves human coagulation factor IX expression in vivo

Recombinant AAV-8 vectors have shown significant promise for hepatic gene therapy of hemophilia B. However, the theme of AAV vector dose dependent immunotoxicity seen with AAV2 vectors earlier seem to re-emerge with AAV8 vectors as well. It is therefore important to develop novel AAV8 vectors that provide enhanced gene expression at significantly less vector doses. We hypothesized that AAV8 during its intracellular trafficking, are targeted for destruction in the cytoplasm by the host-cellular kinase/ubiquitination/proteasomal degradation machinery and modification of specific serine/threonine kinase or ubiquitination targets on AAV8 capsid (Fig.1A) may improve its transduction efficiency. To test this, point mutations at specific serine (S)/threonine (T) > alanine (A) or lysine (K)>arginine (R) residues were generated on AAV8 capsid. scAAV8-EGFP vectors containing the wild-type (WT) and each one of the 5 S/T/K-mutant(S276A, S501A, S671A, T251A and K137R) capsids were evaluated for their liver transduction efficiency at a dose of 5 X 1010 vgs/ animal in C57BL/6 mice in vivo. The best performing mutant was found to be the K137R vector in terms of either the gene expression (46-fold) or the vector copy numbers in the hepatocytes (22-fold) compared to WT-AAV8 (Fig.1B). The K137R-AAV8 vector that showed significantly decreased ubiquitination of the viral capsid had reduced activation of markers of innate immune response [IL-6, IL-12, tumor necrosis factor α, Kupffer cells and TLR-9]. In addition, animals injected with the K137R mutant also demonstrated decreased (2-fold) levels of cross-neutralizing antibodies when compared to animals that received the WT-AAV8 vector. To study further the utility of the novel AAV8-K137R mutant in a therapeutic setting, we delivered human coagulation factor IX (h.FIX) under the control of liver specific promoters (LP1 or hAAT) at two different doses (2.5x10^10 and 1x10^11 vgs per mouse) in 8-12 weeks old male C57BL/6 mice. As can be seen in Fig.1C/D, the circulating levels of h.FIX were higher in all the K137R-AAV8 treated groups as compared to the WT-AAV8 treated groups either at 2 weeks (62% vs 37% for hAAT constructs and 47% vs 21% for LP1 constructs) or 4 weeks (78% vs 56% for hAAT constructs and 64% vs 30% for LP1 constructs) post hepatic gene transfer. These studies demonstrate the feasibility of the use of this novel vector for potential gene therapy of hemophilia B.

Wafer scale fabrication of porous three-dimensional plasmonic metamaterials for the visible region: chiral and beyond

We report on a wafer scale fabrication method of a three-dimensional plasmonic metamaterial with strong chiroptical response in the visible region of the electromagnetic spectrum. The system was comprised of metallic nanoparticles arranged in a helical fashion, with high degree of flexibility over the choice of the underlying material, as well as their geometrical parameters. This resulted in exquisite control over the chiroptical properties, most importantly the spectral signature of the circular dichroism. In spite of the large variability in the arrangement, as well as the size and shape of the constituent nanoparticles, the average chiro-optical response of the material remained uniform across the wafer, thus confirming the suitability of this system as a large area chiral metamaterial. By simply heating the substrate for a few minutes, the geometrical properties of the nanoparticles could be altered, thus providing an additional handle towards tailoring the spectral response of this novel material.

Taming of large diameter triaxial setup

Triaxial tests are essential to estimate the shear strength properties of the soil or rock. Normally triaxial tests are carried out on samples of 38 mm diameter and 76 mm height. Granular materials, predominantly used in base/sub-base construction of pavements or in railways have size range of 60-75 mm. Determination of shear strength parameters of those materials can be made possible only through triaxial tests on large diameter samples. This paper describes a large diameter cyclic triaxial testing facility set up in the Geotechnical Engineering lab of Indian Institute of Science. This setup consists of 100 kN capacity dynamic loading frame, which facilitates testing of samples of up to 300 mm diameter and 600 mm height. The loading ram can be actuated up to a maximum frequency of 10 Hz, with maximum amplitude of 100 mm. The setup is capable of carrying out static as well as dynamic triaxial tests under isotropic, anisotropic conditions with a maximum confining pressure of 1 MPa. Working with this setup is a difficult task because of the size of the sample. In this paper, a detailed discussion on the various problems encountered during the initial testing using the equipment, the ideas and solutions adopted to solve them are presented. Pilot experiments on granular sub-base material of 53 mm down size are also presented.

Glycidyl azide polymer crosslinked through triazoles by click chemistry: curing, mechanical and thermal properties

Glycidyl azide polymer (GAP) was cured through click chemistry by reaction of the azide group with bispropargyl succinate (BPS) through a 1,3-dipolar cycloaddition reaction to form 1,2,3-triazole network. The properties of GAP-based triazole networks are compared with the urethane cured GAP-systems. The glass transition temperature (T-g), tensile strength, and modulus of the system increased with crosslink density, controlled by the azide to propargyl ratio. The triazole incorporation has a higher T-g in comparison to the GAP-urethane system (T-g-20 degrees C) and the networks exhibit biphasic transitions at 61 and 88 degrees C. The triazole curing was studied using Differential Scanning Calorimetry (DSC) and the related kinetic parameters were helpful for predicting the cure profile at a given temperature. Density functional theory (DFT)-based theoretical calculations implied marginal preference for 1,5-addition over 1,4-addition for the cycloaddition between azide and propargyl group. Thermogravimetic analysis (TG) showed better thermal stability for the GAP-triazole and the mechanism of decomposition was elucidated using pyrolysis GC-MS studies. The higher heat of exothermic decomposition of triazole adduct (418kJmol(-1)) against that of azide (317kJmol(-1)) and better mechanical properties of the GAP-triazole renders it a better propellant binder than the GAP-urethane system.

Valence band electronic structure of Nd1-xYxMnO3 using X-ray absorption, photoemission and GGA plus U calculations

The electronic structures of Nd1-xYxMnO3 (x=0-0.5) were studied using X-ray absorption near-edge structure (XANES) at the Mn L-3,L-2- and O K-edge along with valence-band photoemission spectroscopy (VB-PES). The systematic increase in white-line intensity of the Mn L-3,L-2-edge with doping, suggests a decrease in the occupancy of Mn 3d orbitals. The O K-edge XANES shows a depletion of unoccupied states above the Fermi energy. The changes in the O K-edge spectra due to doping reflects an increase in the Jahn-Teller distortion. The VB-PES shows broadening of the features associated with Mn 3d and O 2p hybridized states and the shift of these features to a slightly higher binding energy in agreement with our GGA + U calculations. The system shows a net shift of the occupied and unoccupied states away from the Fermi energy with doping. The shift in theoretical site-projected density of states of x=0.5 composition with respect to x=0 suggest a subtle change from a charge transfer to Mott-Hubbard type insulator. (C) 2013 Elsevier B.V. All rights reserved.

Glassy dielectric response in Tb2NiMnO6 double perovskite with similarities to a Griffiths phase

Results of frequency-dependent and temperature-dependent dielectric measurements performed on the double-perovskite Tb2NiMnO6 are presented. The real (epsilon(1)(f,T)) and imaginary (epsilon(2)(f,T)) parts of dielectric permittivity show three plateaus suggesting dielectric relaxation originating from the bulk, grain boundaries and the sample-electrode interfaces, respectively. The epsilon(1)(f,T) and epsilon(2)(f,T) are successfully simulated by a RC circuit model. The complex plane of impedance, Z'-Z `', is simulated using a series network with a resistor R and a constant phase element. Through the analysis of epsilon(f,T) using the modified Debye model, two different relaxation time regimes separated by a characteristic temperature, T*, are identified. The temperature variation of R and C corresponding to the bulk and the parameter alpha from modified Debye fit lend support to this hypothesis. Interestingly, the T* compares with the Griffiths temperature for this compound observed in magnetic measurements. Though these results cannot be interpreted as magnetoelectric coupling, the relationship between lattice and magnetism is markedly clear. We assume that the observed features have their origin in the polar nanoregions which originate from the inherent cationic defect structure of double perovskites. Copyright (C) EPLA, 2013

Trends in aerosol optical depth over Indian region: Potential causes and impact indicators

The first regional synthesis of long-term (back to similar to 25 years at some stations) primary data (from direct measurement) on aerosol optical depth from the ARFINET (network of aerosol observatories established under the Aerosol Radiative Forcing over India (ARFI) project of Indian Space Research Organization over Indian subcontinent) have revealed a statistically significant increasing trend with a significant seasonal variability. Examining the current values of turbidity coefficients with those reported similar to 50 years ago reveals the phenomenal nature of the increase in aerosol loading. Seasonally, the rate of increase is consistently high during the dry months (December to March) over the entire region whereas the trends are rather inconsistent and weak during the premonsoon (April to May) and summer monsoon period (June to September). The trends in the spectral variation of aerosol optical depth (AOD) reveal the significance of anthropogenic activities on the increasing trend in AOD. Examining these with climate variables such as seasonal and regional rainfall, it is seen that the dry season depicts a decreasing trend in the total number of rainy days over the Indian region. The insignificant trend in AOD observed over the Indo-Gangetic Plain, a regional hot spot of aerosols, during the premonsoon and summer monsoon season is mainly attributed to the competing effects of dust transport and wet removal of aerosols by the monsoon rain. Contributions of different aerosol chemical species to the total dust, simulated using Goddard Chemistry Aerosol Radiation and Transport model over the ARFINET stations, showed an increasing trend for all the anthropogenic components and a decreasing trend for dust, consistent with the inference deduced from trend in Angstrom exponent.