In Situ Monitoring of Competitive Coformer Exchange Reaction by 1H MAS Solid-State NMR.

In a competitive coformer exchange reaction, a recent topic of interest in pharmaceutical research, the coformer in a pharmaceutical cocrystal is exchanged with another coformer that is expected to form a cocrystal that is more stable. There will be a competition between coformers to form the most stable product through the formation of hydrogen bonds. This will cause destabilization of the pharmaceutical products during processing or storage. Therefore, it is important to develop a mechanistic understanding of this transformation by monitoring each and every step of the reaction, employing a technique such as 1H nuclear magnetic resonance (NMR). In this study, an in situ monitoring of a coformer exchange reaction is carried out by 1H magic angle spinning (MAS) solid-state NMR (SSNMR) at a spinning frequency of 60 kHz. The changes in caffeine maleic acid cocrystals on addition of glutaric acid and caffeine glutaric cocrystals on addition of maleic acid were monitored. In all of the reactions, it has been observed that caffeine glutaric acid Form I is formed. When glutaric acid was added to 2:1 caffeine maleic acid, the formation of metastable 1:1 caffeine glutaric acid Form I was observed at the start of the experiment, indicating that the centrifugal pressure is enough for the formation. The difference in the end product of the reactions with a similar reaction pathway of 1:1 and 2:1 reactant stoichiometry indicates that a complete replacement of maleic acid has occurred only in the 1:1 stoichiometry of the reactants. The polymorphic transition of caffeine glutaric acid Form II to Form I at higher temperatures was a crucial reason that triggered the exchange of glutaric acid with maleic acid in the reaction of caffeine glutaric acid and maleic acid. Our results are novel since the new reaction pathways in competitive coformer exchange reactions enabled understanding the remarkable role of stoichiometry, polymorphism, temperature, and centrifugal pressure.

Insights into the Structure of Sucralfate by Advanced Solid- and Liquid-State NMR.

Sucralfate, which is a sucrose octasulfate aluminum complex, is an active pharmaceutical ingredient (API) falling in the category of cytoprotective agents which are very effective for gastric and duodenal ulcers. On interaction with stomach acid, it ionizes into aluminum and sucrose octasulfate ions to form a protective layer over the ulcerated region inhibiting further attack from acid. The mechanism of action of sucralfate in the context of its structure is not well understood. Considering that at least two forms of this API are available in the market, there are no reports on the various forms of sucralfate and differences in their pharmacological action. We characterized the two forms of sucralfate using multinuclear, multidimensional solid-state NMR, and the results show significant structural differences between them arising from variation in the aluminum environment and the level of hydration. The impact of structural differences on pharmacological action was examined by studying acid-induced Al release by 27Al liquid-state NMR. The sucralfate, European pharmaceutical standard, Form I, undergoes faster disruption in acid compared to Form II. The difference is explained on the basis of structural differences in the two forms which gives significant insights into the action of sucralfate in relation to its structure.

A solid-state NMR method for characterization of pharmaceutical eutectics.

Pharmaceutical eutectics are extremely useful for designing formulations, and currently, there are no techniques other than differential scanning calorimetry (DSC) that can confirm their formation. In this study, we demonstrate that 1H fast magic angle spinning (MAS) solid-state NMR (SSNMR) experiments can confirm the formation of eutectics by detecting their intermolecular hydrogen bonding interactions.

Single-Fraction Stereotactic Ablative Body Radiotherapy for Primary and Extracranial Oligometastatic Cancers.

Stereotactic ablative body radiotherapy (SABR) consists of delivering high doses of ionising radiation, typically across three to eight fractions with high precision and conformity. SABR has become increasingly commonplace throughout the last quarter of a century and is offered for the treatment of various primary and metastatic tumour types. Delivering SABR in a single fraction has arisen as an appealing possibility for several reasons. These include fewer hospital visits, greater patient convenience, improved sustainability and lower costs. However, these factors must be balanced against considerations such as toxicity, side-effects and, most importantly, progression-free and overall survival. In this review we seek to analyse the results of studies looking at the efficacy of single-fraction SABR for lung, prostate, renal and pancreas primary tumours, as well as oligometastases. The tumour type to be most widely treated with single-fraction SABR is lung, but its remit continues to expand. We also look at the biological rationale underpinning SABR and how this can be extended to single-fraction regimens. Finally, we turn our attention towards the future directions of SABR and specifically single-fraction regimens. These include the possibility of combining SABR with immunotherapy and technological advances in the field, which could serve to expand the scope of SABR. We conclude by summarising the current clinical studies of single-fraction SABR.

An investigation of Al2O3 induced variations in the structural parameters in strontium borosilicate glasses using solid state NMR.

The physical properties of oxide glasses are crucially dependent on the atomistic structural speciation. In this study, we investigate the variation in the local ordering in the glass network of strontium borosilicate glasses (34.82 SrO, 51.84 B2O3, 13.34 SiO2 in mol%) with a progressive substitution of B2O3 by Al2O3 and estimate the structural parameters: the oxygen packing fraction, and the average network coordination number. The coordination of the network forming cations at various glass compositions is determined using 11B, 27Al, and 29Si solid-state nuclear magnetic resonance (SSNMR). The SSNMR reveals that at the higher substitution of B2O3 by Al2O3 in the glass composition, the coordination network of Al3+ exists predominantly in the 4 coordinated state, the network forming B3+ cations transform from a tetrahedral BO4 to a trigonal BO3 structure, and the Q4 form of silicates is dominant. The average coordination number and the oxygen packing fraction were calculated using the parameters obtained from the SSNMR results, and it is observed that the average coordination number decreases, and the oxygen packing fraction increases on incorporating Al. It is interesting to note that some of the thermophysical properties of these compositions closely follow the pattern shown by the average coordination number and the oxygen packing fraction.

Effect of oxalic acid and sulphuric acid hydrolysis on the preparation and properties of pineapple pomace derived cellulose nanofibers and nanopapers.

Nanocellulose is the "green magnet" which attracts a wide spectrum of industries towards it due to its availability, biodegradability, and possible smart applications. For the first time, pineapple pomace was being explored as an economic precursor for cellulose nanofibers. Nanofiber isolation was accomplished using a chemo-mechanical method and solution casting was adopted for the development of nanopapers. Moreover, the study examines the structural, optical, crystalline, dimensional, and thermal features of nanofibers isolated using different acid hydrolysis (oxalic acid and sulphuric acid) methods. Fourier-transform infra-red spectroscopy, 13C solid-state nuclear magnetic resonance spectroscopy, and X-ray diffraction analysis indicated the presence of type I cellulose. The transmittance, crystallinity index, and thermal stability of PPNFS (sulphuric acid treated fiber) were greater than PPNFO (oxalic acid treated fiber). The transmission electron microscopy and dynamic light scattering analysis confirmed the nanodimension of PPNFO and PPNFS. While comparing the optical and mechanical properties of nanopapers, PPNFS outperforms PPNFO. The tensile strength of the prepared nanopapers (64 MPa (PPNFO) and 68 MPa (PPNFS)) was found to be high compared to similar works reported in the literature. The prepared nanopaper is proposed to be used for food packaging applications.

Chlorine-free extraction and structural characterization of cellulose nanofibers from waste husk of millet (Pennisetum glaucum).

This study aims to extract cellulose nanofibers (CNFs) from a sustainable source, i.e. millet husk, which is an agro-waste worthy of consideration. Pre-treatments such as mercerisation, steam explosion, and peroxide bleaching (chlorine-free) were applied for the removal of non-cellulosic components. The bleached millet husk pulp was subjected to acid hydrolysis (5% oxalic acid) followed by homogenization to extract CNFs. The extracted CNFs were characterized using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), Dynamic Light Scattering (DLS), Energy Dispersive X-ray Spectroscopy (EDX), Thermogravimetry (TG and DTG), Differential scanning calorimetry (DSC), and Solid state 13C nuclear magnetic resonance spectroscopy (solid state 13C NMR). The isolated CNFs show a typical cellulose type-I structure with a diameter of 10-12 nm and a crystallinity index of 58.5%. The appearance of the specific peak at 89.31 ppm in the solid state 13C NMR spectra validates the existence of the type-I cellulose phase in the prepared CNFs. The prepared CNFs had a maximum degradation temperature (Tmax) of 341 °C, that was 31 °C greater than raw millet husk (RMH). The outcome of the study implies that the nanofibers are prominent alternatives for synthetic fibers for assorted potential applications, especially in manufacturing green composites.

Results of a single-arm pilot study of 32P microparticles in unresectable locally advanced pancreatic adenocarcinoma with gemcitabine/nab-paclitaxel or FOLFIRINOX chemotherapy.

BACKGROUND: Unresectable locally advanced pancreatic cancer (LAPC) is generally managed with chemotherapy or chemoradiotherapy, but prognosis is poor with a median survival of ∼13 months (or up to 19 months in some studies). We assessed a novel brachytherapy device, using phosphorous-32 (32P) microparticles, combined with standard-of-care chemotherapy. PATIENTS AND METHODS: In this international, multicentre, single-arm, open-label pilot study, adult patients with histologically or cytologically proven unresectable LAPC received 32P microparticles, via endoscopic ultrasound-guided fine-needle implantation, planned for week 4 of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) or gemcitabine/nab-paclitaxel chemotherapy, per investigator's choice. The primary endpoint was safety and tolerability measured using Common Terminology Criteria for Adverse Events version 4.0. The lead efficacy endpoint was local disease control rate at 16 weeks. RESULTS: Fifty patients were enrolled and received chemotherapy [intention-to-treat (ITT) population]. Forty-two patients received 32P microparticle implantation [per protocol (PP) population]. A total of 1102 treatment-emergent adverse events (TEAEs) were reported in the ITT/safety population (956 PP), of which 167 (139 PP) were grade ≥3. In the PP population, 41 TEAEs in 16 (38.1%) patients were possibly or probably related to 32P microparticles or implantation procedure, including 8 grade ≥3 in 3 (7.1%) patients, compared with 609 TEAEs in 42 (100%) patients attributed to chemotherapy, including 67 grade ≥3 in 28 patients (66.7%). The local disease control rate at 16 weeks was 82.0% (95% confidence interval: 68.6% to 90.9%) (ITT) and 90.5% (95% confidence interval: 77.4% to 97.3%) (PP). Tumour volume, carbohydrate antigen 19-9 levels, and metabolic tumour response at week 12 improved significantly. Ten patients (20.0% ITT; 23.8% PP) had surgical resection and median overall survival was 15.2 and 15.5 months for ITT and PP populations, respectively. CONCLUSIONS: Endoscopic ultrasound-guided 32P microparticle implantation has an acceptable safety profile. This study also suggests clinically relevant benefits of combining 32P microparticles with standard-of-care systemic chemotherapy for patients with unresectable LAPC.

Radiotherapy Advances in Paediatric Medulloblastoma Treatment.

Radiotherapy is an essential element in the multidisciplinary management of children with medulloblastoma and postoperative craniospinal axis radiotherapy is considered to be the cornerstone of curative treatment. With modern multidisciplinary management, more than 80% of children with standard-risk medulloblastoma and up to 70% of children with high-risk medulloblastoma are long-term survivors. Current clinical trials are evaluating risk-adapted radiotherapy in standard-risk medulloblastoma to reduce long-term sequelae, whereas the research approach in high-risk medulloblastoma is to improve clinical outcome with dose-intensification of chemotherapy and the use of hyperfractionated radiotherapy regimens. Technological advances, such as tomotherapy, volumetric modulated arc therapy and proton therapy, may further improve the therapeutic ratio by reducing radiotherapy toxicities. A selected group of children with recurrent disease after treatment for standard-risk medulloblastoma may be considered for re-irradiation.

Radiotherapy in the Management of Paediatric Low-Grade Gliomas.

Paediatric low-grade (World Health Organization grade I-II) gliomas (LGGs) represent a spectrum of primary central nervous system tumours. Local tumour control is the cornerstone in the general management of childhood gliomas. Surgery is the primary treatment of choice in the majority. Non-surgical treatments are recommended for progressive or symptomatic inoperable disease. Although chemotherapy is increasingly used as first non-surgical treatment, radiotherapy remains standard as salvage treatment or as primary treatment in selected cases in which surrounding normal tissue can be optimally preserved. The role of targeted therapies is currently under investigation in clinical trials. Modern high-precision radiotherapy techniques, including proton therapy, have the potential to improve long-term toxicities. There is therefore an urgent need for prospective studies to compare the efficacy and safety of modern radiotherapy with systemic treatment in children with LGGs. New information on molecular genetic patterns in LGGs may also have an impact on the selection and sequencing of radiotherapy.

Correction: One pot ligand exchange method for a highly stable Au-SBA-15 catalyst and its room temperature CO oxidation.

Correction for 'One pot ligand exchange method for a highly stable Au-SBA-15 catalyst and its room temperature CO oxidation' by Yogita Soni et al., Chem. Commun., 2018, DOI: 10.1039/c8cc06887a.