Non-destructive Determination of Disintegration Time and Dissolution in Immediate Release Tablets by Terahertz Transmission Measurements

Purpose The aim of this study was to establish the suitability of terahertz (THz) transmission measurements to accurately measure and predict the critical quality attributes of disintegration time and the amount of active pharmaceutical ingredient (API) dissolved after 15, 20 and 25 min for commercial tablets processed at production scale. Methods Samples of 18 batches of biconvex tablets from a production-scale design of experiments study into exploring the design space of a commercial tablet manufacturing process were used. The tablet production involved the process steps of high-shear wet granulation, fluid-bed drying and subsequent compaction. The 18 batches were produced using a 4 factor split plot design to study the effects of process changes on the disintegration time. Non-destructive and contactless terahertz transmission measurements of the whole tablets without prior sample preparation were performed to measure the effective refractive index and absorption coefficient of 6 tablets per batch. Results The disintegration time (R$^{2}$ = 0.86) and API dissolved after 15 min (R$^{2}$ = 0.96) linearly correlates with the effective refractive index, neff, measured at terahertz frequencies. In contrast, no such correlation could be established from conventional hardness measurements. The magnitude of neff represents the optical density of the sample and thus it reflects both changes in tablet porosity as well as granule density. For the absorption coefficient, αeff, we observed a better correlation with dissolution after 20 min (R$^{2}$ = 0.96) and a weaker correlation with disintegration (R$^{2}$ = 0.83) compared to neff. Conclusion The measurements of neff and αeff provide promising predictors for the disintegration and dissolution time of tablets. The high penetration power of terahertz radiation makes it possible to sample a significant volume proportion of a tablet without any prior sample preparation. Together with the short measurement time (seconds), the potential to measure content uniformity and the fact that the method requires no chemometric models this technology shows clear promise to be established as a process analyser to non-destructively predict critical quality attributes of tablets.We would like to thank GlaxoSmithKline for providing the sets of samples and sharing their valuable experience and advice. D.M. and J.A.Z. would like to acknowledge the the U.K. Engineering and Physical Sciences Research Council (EPSRC) for funding (EP/L019922/1). J.S. participated in this study as a undergraduate summer student visiting from the Friedrich-Schiller-University Jena and would like to thank the German Academic Exchange Service (DAAD) RISE Worldwide programme for supporting her visit (GB-PH-1870)

Correcting pervasive errors in RNA crystallography through enumerative structure prediction

Three-dimensional RNA models fitted into crystallographic density maps exhibit pervasive conformational ambiguities, geometric errors and steric clashes. To address these problems, we present enumerative real-space refinement assisted by electron density under Rosetta (ERRASER), coupled to Python-based hierarchical environment for integrated 'xtallography' (PHENIX) diffraction-based refinement. On 24 data sets, ERRASER automatically corrects the majority of MolProbity-assessed errors, improves the average Rfree factor, resolves functionally important discrepancies in noncanonical structure and refines low-resolution models to better match higher-resolution models

Evaluation of a communication skills seminar for students in a Japanese medical school: a non-randomized controlled study

BACKGROUND: Little data exist for the effectiveness of communication skills teaching for medical students in non-English speaking countries. We conducted a non-randomized controlled study to examine if a short intensive seminar for Japanese medical students had any impact on communication skills with patients. METHODS: Throughout the academic year 2001–2002, a total of 105 fifth-year students (18 groups of 5 to 7 students) participated, one group at a time, in a two-day, small group seminar on medical interviewing. Half way through the year, a five-station objective structured clinical examination (OSCE) was conducted for all fifth-year students. We videotaped all the students' interaction with a standardized patient in one OSCE station that was focused on communication skills. Two independent observers rated the videotapes of 50 students who had attended the seminar and 47 who had not. Sixteen core communication skills were measured. Disagreements between raters were resolved by a third observer's rating. RESULTS: There was a statistically significant difference in proportions of students who were judged as 'acceptable' in one particular skill related to understanding patient's perspectives: asking how the illness or problems affected the patient's life, (53% in the experimental group and 30% in the control group, p = .02). No differences were observed in the other 15 core communication skills, although there was a trend for improvement in the skill for asking the patient's ideas about the illness or problems (60% vs. 40%, p = .054) and one of the relationship building skills; being attentive and empathic nonverbally (87% vs. 72%, p = .064). CONCLUSION: The results of this study suggest that a short, intensive small group seminar for Japanese medical students may have had a short-term impact on specific communication skills, pertaining to understanding patient's perspectives

Experimental long-lived entanglement of two macroscopic objects

Entanglement is considered to be one of the most profound features of quantum mechanics. An entangled state of a system consisting of two subsystems cannot be described as a product of the quantum states of the two subsystems. In this sense the entangled system is considered inseparable and nonlocal. It is generally believed that entanglement manifests itself mostly in systems consisting of a small number of microscopic particles. Here we demonstrate experimentally the entanglement of two objects, each consisting of about 10^12 atoms. Entanglement is generated via interaction of the two objects - more precisely, two gas samples of cesium atoms - with a pulse of light, which performs a non-local Bell measurement on collective spins of the samples. The entangled spin state can be maintained for 0.5 millisecond. Besides being of fundamental interest, the robust, long-lived entanglement of material objects demonstrated here is expected to be useful in quantum information processing, including teleportation of quantum states of matter and quantum memory.Comment: Submitted to Nature, June 9, 2001, 11 pages, 3 figures. Contents changed following referees' suggestion

The regions within the N-terminus critical for human glucagon like peptide-1 receptor (hGLP-1R) cell Surface expression

The hGLP-1R is a target for the treatment of type 2 diabetes and belongs to the class B family of GPCRs. Like other class B GPCRs, the GLP-1R contains an N-terminal signal peptide (SP) and undergoes N-linked glycosylation, which are important for its trafficking and maturation. This study analysed the role of the SP, the hydrophobic region after the SP (HRASP), glycosylation and the conserved residues within the N-terminus in GLP-1R trafficking. HGLP-1R targeted to the cell surface showed no SP, and the SP deleted mutant, but not the mutants defective in SP cleavage, showed cell surface expression, demonstrating the importance of SP cleavage for hGLP-1R cell surface expression. The N-terminal deletions of hGLP-1R revealed that the HRASP, not the SP, is essential for cell surface expression of GLP-1R. Further, inhibition of hGLP-1R glycosylation prevented cell surface expression of the receptor. Mutation of Trp39, Tyr69 and Tyr88, which are required for agonist binding, in the GLP-1R abolished cell surface expression of the receptor independent of the SP cleavage or N-linked glycosylation. In conclusion, the N-terminus of hGLP-1R regulates receptor trafficking and maturation. Therefore this study provides insight into the role of hGLP-1R N-terminus on the receptor cell surface expression

Magnetism, FeS colloids, and Origins of Life

A number of features of living systems: reversible interactions and weak bonds underlying motor-dynamics; gel-sol transitions; cellular connected fractal organization; asymmetry in interactions and organization; quantum coherent phenomena; to name some, can have a natural accounting via $physical$ interactions, which we therefore seek to incorporate by expanding the horizons of `chemistry-only' approaches to the origins of life. It is suggested that the magnetic 'face' of the minerals from the inorganic world, recognized to have played a pivotal role in initiating Life, may throw light on some of these issues. A magnetic environment in the form of rocks in the Hadean Ocean could have enabled the accretion and therefore an ordered confinement of super-paramagnetic colloids within a structured phase. A moderate H-field can help magnetic nano-particles to not only overcome thermal fluctuations but also harness them. Such controlled dynamics brings in the possibility of accessing quantum effects, which together with frustrations in magnetic ordering and hysteresis (a natural mechanism for a primitive memory) could throw light on the birth of biological information which, as Abel argues, requires a combination of order and complexity. This scenario gains strength from observations of scale-free framboidal forms of the greigite mineral, with a magnetic basis of assembly. And greigite's metabolic potential plays a key role in the mound scenario of Russell and coworkers-an expansion of which is suggested for including magnetism.Comment: 42 pages, 5 figures, to be published in A.R. Memorial volume, Ed Krishnaswami Alladi, Springer 201

Whole genome analysis of linezolid resistance in Streptococcus pneumoniae reveals resistance and compensatory mutations

<p>Abstract</p> <p>Background</p> <p>Several mutations were present in the genome of <it>Streptococcus pneumoniae </it>linezolid-resistant strains but the role of several of these mutations had not been experimentally tested. To analyze the role of these mutations, we reconstituted resistance by serial whole genome transformation of a novel resistant isolate into two strains with sensitive background. We sequenced the parent mutant and two independent transformants exhibiting similar minimum inhibitory concentration to linezolid.</p> <p>Results</p> <p>Comparative genomic analyses revealed that transformants acquired G2576T transversions in every gene copy of 23S rRNA and that the number of altered copies correlated with the level of linezolid resistance and cross-resistance to florfenicol and chloramphenicol. One of the transformants also acquired a mutation present in the parent mutant leading to the overexpression of an ABC transporter (spr1021). The acquisition of these mutations conferred a fitness cost however, which was further enhanced by the acquisition of a mutation in a RNA methyltransferase implicated in resistance. Interestingly, the fitness of the transformants could be restored in part by the acquisition of altered copies of the L3 and L16 ribosomal proteins and by mutations leading to the overexpression of the spr1887 ABC transporter that were present in the original linezolid-resistant mutant.</p> <p>Conclusions</p> <p>Our results demonstrate the usefulness of whole genome approaches at detecting major determinants of resistance as well as compensatory mutations that alleviate the fitness cost associated with resistance.</p

Just Click Here : A Brief Glance at Absurd Electronic Contracts and the Law Failing to Protect Consumers

As e-commerce explodes around the world, consumers’ rights have been left behind. Before the completion of virtually every transaction on the Internet, the onus is placed on consumers to read and agree to an onslaught of terms and conditions. Often hidden in the middle of this extremely lengthy list of terms are massive exemption and limitation of liability clauses that deny consumers most if not all of their rights as “equal” trading partners. The common law principle that all onerous clauses in a contract need to be brought to the attention of the consumer for them to be binding seems to have been lost with the invention of the “click here to agree” button for signing online contracts. As the courts in Canada have not provided clear guidance on this issue thus far, other means must be pursued in order to protect consumers from the near-tyrannical control of unencumbered electronic standard form contracts in e-commerce. This paper will describe the principle of sufficiency of notice as it applies to paper contracts, and then contrast it with the newer jurisprudence that has refused to apply the principle to electronic contracts. The reasons for the refusal will be explored, followed by an examination of why the principle of sufficiency of notice needs to be applied and strengthened to respond to the increasingly onerous provisions hidden in electronic contracts. Finally, some other options for achieving the goal of consumer protection from hidden onerous clauses will be briefly explored. These other options include introducing stiffer consumer protection legislation domestically, the creation of international treaties, developing voluntary standards of contracting, and relying on Internet self-regulation

Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery

To commemorate the auspicious occasion of the 30th anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review and discuss the history of IPC, its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics discussed at this special meeting and underscores the huge importance and impact, the discovery of IPC has made in the field of cardiovascular research