20 research outputs found
Simultaneous differential scanning calorimetry â synchrotron X-ray powder diffraction : a powerful technique for physical form characterisation in pharmaceutical materials
© 2016 American Chemical Society. We report a powerful new technique: hyphenating synchrotron X-ray powder diffraction (XRD) with differential scanning calorimetry (DSC). This is achieved with a simple modification to a standard laboratory DSC instrument, in contrast to previous reports which have involved extensive and complex modifications to a DSC to mount it in the synchrotron beam. The high-energy X-rays of the synchrotron permit the recording of powder diffraction patterns in as little as 2 s, meaning that thermally induced phase changes can be accurately quantified and additional insight on the nature of phase transitions obtained. Such detailed knowledge cannot be gained from existing laboratory XRD instruments, since much longer collection times are required. We demonstrate the power of our approach with two model systems, glutaric acid and sulfathiazole, both of which show enantiotropic polymorphism. The phase transformations between the low and high temperature polymorphs are revealed to be direct solid-solid processes, and sequential refinement against the diffraction patterns obtained permits phase fractions at each temperature to be calculated and unit cell parameters to be accurately quantified as a function of temperature. The combination of XRD and DSC has further allowed us to identify mixtures of phases which appeared phase-pure by DSC
Mechanistic in situ and ex situ studies of phase transformations in molecular co-crystals
Coâcrystallisation is widely explored as a route to improve the physical properties of pharmaceutical active ingredients, but little is known about the fundamental mechanisms of the process. Herein, we apply a hyphenated differential scanning calorimetryâXâray diffraction technique to mimic the commercial hot melt extrusion process, and explore the heatâinduced synthesis of a series of new coâcrystals containing isonicotinamide. These comprise a 1:1 coâcrystal with 4âhydroxybenzoic acid, 2:1 and 1:2 systems with 4âhydroxyphenylacetic acid and a 1:1 crystal with 3,4âdihydroxyphenylactic acid. The formation of coâcrystals during heating is complex mechanistically. In addition to coâcrystallisation, conversions between polymorphs of the coâformer starting materials and coâcrystal products are also observed. A subsequent study exploring the use of inkjet printing and milling to generate coâcrystals revealed that the synthetic approach has a major effect on the coâcrystal species and polymorphs produced
Stabilisation of metastable polymorphs: the case of paracetamol form III
YesThe design of a melt synthesis of the first air-stable formulation of the metastable form III of paracetamol is derived from thermo-spectroscopic and thermo-diffraction experiments. Melt crystallisation in the presence of ÎČ-1,4-saccharides produces form III selectively and the excipients appear to act as stabilising âactiveâ templates of the metastable polymorph.This article is part of themed collection: Pharmaceutical Solids
The National Early Warning Score and its subcomponents recorded within ±24 hours of emergency medical admission are poor predictors of hospital-acquired acute kidney injury
YesBackground: Hospital-acquired Acute Kidney Injury (H-AKI) is a common cause of avoidable morbidity and mortality.
Aim: To determine if the patientsâ vital signs data as defined by a National Early Warning Score (NEWS), can predict H-AKI following emergency admission to hospital.
Methods: Analyses of emergency admissions to York hospital over 24-months with NEWS data. We report the area under the curve (AUC) for logistic regression models that used the index NEWS (model A0), plus age and sex (A1), plus subcomponents of NEWS (A2) and two-way interactions (A3). Likewise for maximum NEWS (models B0,B1,B2,B3).
Results: 4.05% (1361/33608) of emergency admissions had H-AKI. Models using the index NEWS had the lower AUCs (0.59 to 0.68) than models using the maximum NEWS AUCs (0.75 to 0.77). The maximum NEWS model (B3) was more sensitivity than the index NEWS model (A0) (67.60% vs 19.84%) but identified twice as many cases as being at risk of H-AKI (9581 vs 4099) at a NEWS of 5.
Conclusions: The index NEWS is a poor predictor of H-AKI. The maximum NEWS is a better predictor but seems unfeasible because it is only knowable in retrospect and is associated with a substantial increase in workload albeit with improved sensitivity.The Health Foundatio
Mechanistic in situ and ex situ studies of phase transformations in molecular coâcrystals
A kinetic and mechanistic study into the formation of the CuâCr layered double hydroxide
The formation of the layered double hydroxide [Cu2Cr(OH)6]Cl·yH2O from the reaction between CuO and aqueous CrCl3·6H2O was explored using synchrotron X-ray diffraction and ex situ analyses. The use of hard X-rays permitted time-resolved in situ studies to be performed as the reaction proceeded under a range of conditions. Additional information was obtained from ex situ experiments in which aliquots of the reaction mixture were removed, quenched, and subsequently analysed by laboratory X-ray diffraction, IR, UV-visible, and atomic emission spectroscopies. On the basis of these data, it is proposed that the reaction involves three steps. First, the solid CuO starting material is hydrolysed to give Cu(OH)2 chains, releasing Cu(2+) ions into solution. The Cu hydroxide chains subsequently condense with aqueous Cr(3+) species, Cl(-) ions and water molecules to give a hydrated form of the LDH. This material then extrudes some water to form a phase with a reduced interlayer spacing
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Polymorphic Phase Transitions in Carbamazepine and 10,11âDihydrocarbamazepine
Temperature-induced phase transitions in carbamazepine (CBZ) and 10,11-dihydrocarbamazepine (DHC) were studied by simultaneous differential scanning calorimetryâX-ray diffraction in this work. The transitions generally involve a transitional melt phase which is quickly followed by recrystallisation. The expansions of the unit cell as a function of temperature could be quantified and allow us to determine a directional order of stability in relation to the lattice constants. Dihydrocarbamazepine formâ
II undergoes a conversion to formâ
I by a localised melt phase. Carbamazepine (CBZ) formâ
IV converts to formâ
I at 182â°C, again by a localised intermediate melt phase. CBZ formâ
II converted to formâ
I at 119â°C by a pathway that appears to have included some melting, and formâ
III underwent a part melt-recrystallisation and a part sublimation-recrystallisation to formâ
I
Drug repurposing in neurological diseases: an integrated approach to reduce trial and error
Lessons Learned from Co-Evolution of Software Process and Model-Driven Engineering
Software companies need to cope with permanent changes in market. To stay competitive it is often inevitable to improve processes and adopt to new technologies. Indeed, it is well know that software processes and model-driven engineering (MDE) are subject to evolution. Simultaneously, it is known that MDE can affect process tailoring, which makes it possible that evolution in MDE triggers process evolution and vice versa. This can lead to undesired process changes and additional cost, when process adaptations constitute a need for further investments in MDE tooling. However, there is little knowledge so far whether this co-evolution exists and how it looks like. In this chapter, we present two industrial case studies onco-evolution of MDE and software process. Based on these case studies, we present an initial list of co-evolution drivers and observations made on co-evolution of softwareprocesses and MDE. Furthermore, we compile our lessons learned to directly help process managers dealing with co-evolution