X-ray crystallography and its role in understanding physicochemical properties of pharmaceutical cocrystals

YesProperties of a matter are intrinsically dependent upon the internal arrangement of molecules in the solid state. Therefore, knowledge of 3-dimensional structure of the matter is prerequisite for structure-property correlations and design of functional materials. Over the past century, X-ray crystallography has evolved as a method of choice for accurate determination of molecular structure at atomic resolution. The structural information obtained from crystallographic analysis paved the way for rapid development in electronic devices, mineralogy, geosciences, materials science, pharmaceuticals, etc. Knowledge of the structural information of active pharmaceutical ingredients (APIs) is prerequisite for rational drug design and synthesis of new chemical entities for development as new medicines. Over the past two decades, X-ray crystallography has played a key role in the design of pharmaceutical cocrystals-crystalline solids containing an API and one or more of pharmaceutically acceptable coformers. These materials have proved promising for fine-tuning several important properties of APIs. This short review highlights the history of crystallography, early breakthroughs, and the role of crystallography in understanding physicochemical properties of pharmaceutical cocrystals.S. Aitipamula gratefully acknowledges the financial support from the Institute of Chemical and Engineering Sciences of A*STAR (Agency for Science, Technology and Research), Singapore. V. R. Vangala thanks Royal Society of Chemistry for Researcher Mobility Grant (2015/17)

Indirect Wafer Bonding and Epitaxial Transfer of GaSb-Based Materials

Results from a study of indirect wafer bonding and epitaxial transfer of GaSb-based materials are presented. Benzocyclobutene (BCB) was used as a bonding agent to bond GaSb and epitaxial structures lattice matched to GaSb onto Si, GaAs, and sapphire carrier substrates. To better understand sources of stress during the bonding process, which can result in cracking and subsurface damage of the GaSb-based materials, BCB’s hardness and reduced elastic modulus were measured at various stages during the curing process. Based on the results of curing experiments, a bonding and epitaxial transfer process for GaSb-based materials was then developed. Following bonding, using an experimentally determined low-stress cure cycle, GaSb substrates were removed from epitaxial layers of InAsSb using a combination of mechanical thinning and polishing followed by selective chemical etching using a hydrofluoric and chromic acid solution. Etch selectivity data are also presented where selectivity greater than 100:1 is achieved for GaSb:InAsSb

Isomorphism: 'Molecular similarity to crystal structure similarity' in multicomponent forms of analgesic drugs tolfenamic and mefenamic acid

YesThe non-steroidal anti-inflammatory drugs mefenamic acid (MFA) and tolfenamic acid (TFA) have a close resemblance in their molecular scaffold, whereby a methyl group in MFA is substituted by a chloro group in TFA. The present study demonstrates the isomorphous nature of these compounds in a series of their multicomponent solids. Furthermore, the unique nature of MFA and TFA has been demonstrated while excavating their alternate solid forms in that, by varying the drug (MFA or TFA) to coformer [4-dimethylaminopyridine (DMAP)] stoichiometric ratio, both drugs have produced three different types of multicomponent crystals, viz. salt (1:1; API to coformer ratio), salt hydrate (1:1:1) and cocrystal salt (2:1). Interestingly, as anticipated from the close similarity of TFA and MFA structures, these multicomponent solids have shown an isomorphous relation. A thorough characterization and structural investigation of the new multicomponent forms of MFA and TFA revealed their similarity in terms of space group and structural packing with isomorphic nature among the pairs. Herein, the experimental results are generalized in a broader perspective for predictably identifying any possible new forms of comparable compounds by mapping their crystal structure landscapes. The utility of such an approach is evident from the identification of polymorph VI of TFA from hetero-seeding with isomorphous MFA form I from acetone–methanol (1:1) solution. That aside, a pseudopolymorph of TFA with dimethylformamide (DMF) was obtained, which also has some structural similarity to that of the solvate MFA:DMF. These new isostructural pairs are discussed in the context of solid form screening using structural landscape similarityDepartment of Science and Technology (DST/SJF/CSA-02/2014–15); Royal Pharmaceutical Society of Great Britain for seed corn funding (2018–19); INSPIRE fellowship from Department of Science and Technology, Government of India; IISER-Kolkata (instrumental facilities and fellowships

Funneling Light Through a Subwavelength Aperture with Epsilon-Near-Zero Materials

Integration of the next generation of photonic structures with electronic and optical on-chip components requires the development of effective methods for confining and controlling light in subwavelength volumes. Several techniques enabling light coupling to sub-wavelength objects have recently been proposed, including grating-, and composite-based solutions. However, experi-mental realization of these couplers involves complex fabrication with \sim 10nm resolution in three dimensions. One promising alternative to complex coupling structures involves materials with vanishingly small dielectric permittivity, also known as epsilon-near-zero (ENZ) materials. In contrast to the previously referenced approaches, a single at layer of ENZ-material is expected to provide effcient coupling between free-space radiation and sub-wavelength guiding structures. Here we report the first direct observation of bulk-ENZ-enhanced transmission through a subwavelength slit, accompanied by a theoretical study of this phenomenon. Our study opens the door to multiple practical applications of ENZ materials and ENZ-based photonic systems

Evidence of Nickel and Other Trace Elements and Their Relationship to Clinical Findings in Acute Mesoamerican Nephropathy: A Case-Control Analysis

BACKGROUND: Although there are several hypothesized etiologies of Mesoamerican Nephropathy (MeN), evidence has not yet pointed to the underlying cause. Exposure to various trace elements can cause the clinical features observed in MeN. METHODS AND FINDINGS: We measured 15 trace elements, including heavy metals, in renal case-patients (n = 18) and healthy controls (n = 36) in a MeN high-risk region of Nicaragua. Toenails clippings from study participants were analyzed using inductively coupled plasma mass spectrometry. A case-control analysis was performed, and concentrations were also analyzed over participant characteristics and clinical parameters. Nickel (Ni) concentrations were significantly higher in toenails from cases (1.554 mg/kg [0.176–42.647]) than controls (0.208 mg/kg [0.055–51.235]; p \u3c 0.001). Ni concentrations correlated positively with serum creatinine levels (p = 0.001) and negatively with eGFR (p = 0.001). Greater Ni exposure was also associated with higher leukocyte (p = 0.001) and neutrophil (p = 0.003) counts, fewer lymphocytes (p = 0.003), and lower hemoglobin (p = 0.004) and hematocrit (p = 0.011). CONCLUSIONS: Low-dose, chronic environmental exposure to Ni is a possible health risk in this setting. Ni intoxication and resulting systemic and renal effects could explain the clinical signs observed during early MeN. This study provides compelling evidence for a role of Ni in the acute renal impairment observed in this MeN high-risk population. Additional work to assess exposure levels in a larger and heterogeneous population, identify environmental sources of Ni and exposure pathways, and evaluate the link between Ni and MeN pathogenesis are urgently needed

Thermal and in situ x-ray diffraction analysis of a dimorphic co-crystal 1:1 caffeine-glutaric acid

YesSpurred by the enormous interest in co-crystals from the pharmaceutical industry, many novel co-crystals of active pharmaceutical ingredients have been discovered in recent years and this has in turn led to an increasing number of reports on polymorphs of co-crystals. Hence, a thorough characterization and understanding of co-crystal polymorphs is a valuable step during drug development. The purpose of this study is to perform in situ structural analysis and to determine thermodynamic stability of a dimorphic co-crystal system, 1:1 caffeine-glutaric acid (CA-GA, Forms I and II). We performed thermal and structural characterizations by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM), slurry and in situ variable temperature X-ray diffraction (VTXRD). For completeness, we have also re-determined crystal structures of CA-GA Forms I and II at 180 K using single crystal X-ray diffraction. Our results revealed that Form II is stable and Form I is metastable at ambient conditions. Further, the results suggest that the dimorphs are enantiotropically related and the transition temperature is estimated to be 79 Celcius degrees.This work was supported by Science and Engineering Research Council of A*STAR (Agency for Science, Technology and Research), Singapore

Fostering Community Preparedness to Cope with Drought: new initiatives and results from a study involving ODL and ICT from South Central India

Drought has emerged as a key concern in the context of climate variability induced by Climate Change processes and over a billion people are vulnerable, according to UN estimates. Drought preparedness is recognized as the preferred way to cope over relief, and information is the key. Improved access to contemporary ICT in the form of mobile phones and the Internet can help address the challenge of information deficiency in this matter. We have tried to develop an integrated approach for improving the capacity of rural communities by bringing together agricultural information with methods of ODL and effective exchange or delivery using video- conferencing. This has also enabled skill building among vulnerable rural communities in the use of color-coded maps derived from satellite imagery and GIS platforms. ICRISAT in partnership with a community based all- women micro-credit organization, the Adarsha Mahila Samaikhya (AMS), in South Central India has developed this blend of techniques to help the AMS and rural communities to anticipate how vulnerable their villages would be to drought in a season. This is an ongoing partnership, and we report here on joint studies carried out during March 2008- September 2009

AR2, a novel automatic muscle artifact reduction software method for ictal EEG interpretation: Validation and comparison of performance with commercially available software.

Objective: To develop a novel software method (AR2) for reducing muscle contamination of ictal scalp electroencephalogram (EEG), and validate this method on the basis of its performance in comparison to a commercially available software method (AR1) to accurately depict seizure-onset location. Methods: A blinded investigation used 23 EEG recordings of seizures from 8 patients. Each recording was uninterpretable with digital filtering because of muscle artifact and processed using AR1 and AR2 and reviewed by 26 EEG specialists. EEG readers assessed seizure-onset time, lateralization, and region, and specified confidence for each determination. The two methods were validated on the basis of the number of readers able to render assignments, confidence, the intra-class correlation (ICC), and agreement with other clinical findings. Results: Among the 23 seizures, two-thirds of the readers were able to delineate seizure-onset time in 10 of 23 using AR1, and 15 of 23 using AR2 (