Spray drying as a reliable route to produce metastable carbamazepine form IV

Carbamazepine is an active pharmaceutical ingredient used in the treatment of epilepsy that can form at least five polymorphic forms. Metastable form IV was originally discovered from crystallisation with polymer additives however has not been observed from subsequent solvent only crystallisation efforts. This work reports the reproducible formation of phase pure crystalline form IV by spray drying of methanolic carbamazepine solution. Characterisation of the material was carried out using diffraction, SEM and DSC. In situ Raman spectroscopy was used to monitor the spray dried product during the spray drying process. This work demonstrates spray drying provides a robust method for the production of form IV carbamazepine and the combination of high supersaturation and rapid solid isolation from solution overcomes the apparent limitation of more traditional solution crystallisation approaches to produce metastable crystalline forms

Temperature correction of spectra to improve solute concentration monitoring by in situ ultraviolet and mid-infrared spectrometries towards isothermal local model performance

Changes in temperature can significantly affect spectroscopic-based methods for in situ monitoring of processes. As varying temperature is inherent to many processes, associated temperature effects on spectra are unavoidable, which can hinder solute concentration determination. Ultraviolet (UV) and mid-infrared (IR) data were acquired for l-ascorbic acid (LAA) in MeCN/H2O (80:20 w/w) at different concentrations and temperatures. For both techniques, global partial least squares (PLS) models for prediction of LAA concentration constructed without preprocessing of the spectra required a high number of latent variables to account for the effects of temperature on the spectra (root mean square error of cross validation (RMSECV) of 0.18 and 0.16 g/100 g solvent, for UV and IR datasets, respectively). The PLS models constructed on the first derivative spectra required fewer latent variables, yielding variable results in accuracy (RMSECV of 0.23 and 0.06 g/100 g solvent, respectively). Corresponding isothermal local models constructed indicated improved model performance that required fewer latent variables in the absence of temperature effects (RMSECV of 0.01 and 0.04 g/100 g solvent, respectively). Temperature correction of the spectral data via loading space standardization (LSS) enabled the construction of global models using the same number of latent variables as the corresponding local model, which exhibited comparable model performance (RMSECV of 0.06 and 0.04 g/100 g solvent, respectively). The additional chemometric effort required for LSS is justified if prediction of solute concentration is required for in situ monitoring and control of cooling crystallization with an accuracy and precision approaching that attainable using an isothermal local model. However, the model performance with minimal preprocessing may be sufficient, for example, in the early phase development of a cooling crystallization process, where high accuracy is not always required. UV and IR spectrometries were used to determine solubility diagrams for LAA in MeCN/H2O (80:20 w/w), which were found to be accurate compared to those obtained using the traditional techniques of transmittance and gravimetric measurement. For both UV and IR spectrometries, solubility values obtained from models with LSS temperature correction were in better agreement with those determined gravimetrically. In this first example of the application of LSS to UV spectra, significant improvement in the predicted solute concentration is achieved with the additional chemometric effort. There is no extra experimental burden associated with the use of LSS if a structured approach is employed to acquire calibration data that account for both temperature and concentration

The FLUXNET2015 dataset and the ONEFlux processing pipeline for eddy covariance data

The FLUXNET2015 dataset provides ecosystem-scale data on CO2, water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe (over 1500 site-years, up to and including year 2014). These sites, independently managed and operated, voluntarily contributed their data to create global datasets. Data were quality controlled and processed using uniform methods, to improve consistency and intercomparability across sites. The dataset is already being used in a number of applications, including ecophysiology studies, remote sensing studies, and development of ecosystem and Earth system models. FLUXNET2015 includes derived-data products, such as gap-filled time series, ecosystem respiration and photosynthetic uptake estimates, estimation of uncertainties, and metadata about the measurements, presented for the first time in this paper. In addition, 206 of these sites are for the first time distributed under a Creative Commons (CC-BY 4.0) license. This paper details this enhanced dataset and the processing methods, now made available as open-source codes, making the dataset more accessible, transparent, and reproducible.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Investigation of premixed sooting flames by combined laser induced incandescence and laser induced fluorescence

This study applies the techniques of laser induced incandescence (LII) and laser induced fluorescence (LIF) to investigate laminar sooting flames of premixed ethylene air. The approach involves using three different excitation wavelengths, together with temporally and spectrally resolved detection, generating a rich dataset concerning the formation of soot and polycyclic aromatic hydrocarbons (PAHs). Both prompt and delayed detection are used to perform LII when exciting with short wavelengths, both with issues involved. Delayed detection gives an underestimation of soot volume fraction at low heights in the flame, as a result of particle size effects. Prompt detection gives overestimation of soot volume fraction due to fluorescence in the measurement volume. It is shown that care must be taken with either method and through evaluation of the associated errors this study shows delayed detection provides a more accurate measure of soot volume fraction. The ability to obtain the fluorescence signals over a range of heights above burner and stoichiometries is demonstrated. The approach relies on heating the soot particles equivalently with three excitation wavelengths so the LII contribution to the signals can be subtracted, leaving only fluorescence. Fluorescence profiles obtained show similar features to those seen in the literature for invasive measurements, including a reduction in the fluorescence signal generated by 283 nm excitation at intermediate heights above the burner surface followed by a re-increase. Although the data do not allow species-selective measurements of PAHs, these in-situ measurements allow inferences to be drawn about changing concentration of different size classes of these precursors to soot formation. Finally the method of obtaining subtracting the LII contribution to signals was used to obtain fluorescence spectra both for 283 nm and 532 nm excitation. This showed the possibility that fluorescence can yield useful information that it is otherwise impossible to obtain in-situ under sooting conditions.This study applies the techniques of laser induced incandescence (LII) and laser induced fluorescence (LIF) to investigate laminar sooting flames of premixed ethylene air. The approach involves using three different excitation wavelengths, together with temporally and spectrally resolved detection, generating a rich dataset concerning the formation of soot and polycyclic aromatic hydrocarbons (PAHs). Both prompt and delayed detection are used to perform LII when exciting with short wavelengths, both with issues involved. Delayed detection gives an underestimation of soot volume fraction at low heights in the flame, as a result of particle size effects. Prompt detection gives overestimation of soot volume fraction due to fluorescence in the measurement volume. It is shown that care must be taken with either method and through evaluation of the associated errors this study shows delayed detection provides a more accurate measure of soot volume fraction. The ability to obtain the fluorescence signals over a range of heights above burner and stoichiometries is demonstrated. The approach relies on heating the soot particles equivalently with three excitation wavelengths so the LII contribution to the signals can be subtracted, leaving only fluorescence. Fluorescence profiles obtained show similar features to those seen in the literature for invasive measurements, including a reduction in the fluorescence signal generated by 283 nm excitation at intermediate heights above the burner surface followed by a re-increase. Although the data do not allow species-selective measurements of PAHs, these in-situ measurements allow inferences to be drawn about changing concentration of different size classes of these precursors to soot formation. Finally the method of obtaining subtracting the LII contribution to signals was used to obtain fluorescence spectra both for 283 nm and 532 nm excitation. This showed the possibility that fluorescence can yield useful information that it is otherwise impossible to obtain in-situ under sooting conditions