Process monitoring and visualization solutions for hot-melt extrusion : a review

Objectives: Hot-melt extrusion (HME) is applied as a continuous pharmaceutical manufacturing process for the production of a variety of dosage forms and formulations. To ensure the continuity of this process, the quality of the extrudates must be assessed continuously during manufacturing. The objective of this review is to provide an overview and evaluation of the available process analytical techniques which can be applied in hot-melt extrusion. Key Findings: Pharmaceutical extruders are equipped with traditional (univariate) process monitoring tools, observing barrel and die temperatures, throughput, screw speed, torque, drive amperage, melt pressure and melt temperature. The relevance of several spectroscopic process analytical techniques for monitoring and control of pharmaceutical HME has been explored recently. Nevertheless, many other sensors visualizing HME and measuring diverse critical product and process parameters with potential use in pharmaceutical extrusion are available, and were thoroughly studied in polymer extrusion. The implementation of process analytical tools in HME serves two purposes: (1) improving process understanding by monitoring and visualizing the material behaviour and (2) monitoring and analysing critical product and process parameters for process control, allowing to maintain a desired process state and guaranteeing the quality of the end product. Summary: This review is the first to provide an evaluation of the process analytical tools applied for pharmaceutical HME monitoring and control, and discusses techniques that have been used in polymer extrusion having potential for monitoring and control of pharmaceutical HME

Systematic review and quality analysis of emerging diagnostic measures for calcium pyrophosphate crystal deposition disease.

ObjectivesCalcium pyrophosphate crystal deposition disease (CPPD) is common, yet prevalence and overall clinical impact remain unclear. Sensitivity and specificity of CPPD reference standards (conventional crystal analysis (CCA) and radiography (CR)) were meta-analysed by EULAR (published 2011). Since then, new diagnostic modalities are emerging. Hence, we updated 2009-2016 literature findings by systematic review and evidence grading, and assessed unmet needs.MethodsWe performed systematic search of full papers (PubMed, Scopus/EMBASE, Cochrane 2009-2016 databases). Search terms included CPPD, chondrocalcinosis, pseudogout, ultrasound, MRI, dual energy CT (DECT). Paper selection, data abstraction, EULAR evidence level, and Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 bias and applicability grading were performed independently by 3 authors.ResultsWe included 26 of 111 eligible papers, which showed emergence in CPPD diagnosis of ultrasound (U/S), and to lesser degree, DECT and Raman spectroscopy. U/S detected CPPD crystals in peripheral joints with sensitivity >80%, superior to CR. However, most study designs, though analytical, yielded low EULAR evidence level. DECT was marginally explored for CPPD, compared with 35 published DECT studies in gout. QUADAS-2 grading indicated strong applicability of U/S, DECT and Raman spectroscopy, but high study bias risk (in ∼30% of papers) due to non-controlled designs, and non-randomised subject selection.ConclusionsThough CCA and CR remain reference standards for CPPD diagnosis, U/S, DECT and Raman spectroscopy are emerging U/S sensitivity appears to be superior to CR. We identified major unmet needs, including for randomised, blinded, controlled studies of CPPD diagnostic performance and rigorous analyses of 4 T MRI and other emerging modalities

Ultrasound delivery of Surface Enhanced InfraRed Absorption active gold-nanoprobes into fibroblast cells: a biological study via Synchrotron-based InfraRed microanalysis at single cell level

Ultrasound (US) induced transient membrane permeabilisation has emerged as a hugely promising tool for the delivery of exogenous vectors through the cytoplasmic membrane, paving the way to the design of novel anticancer strategies by targeting functional nanomaterials to specific biological sites. An essential step towards this end is the detailed recognition of suitably marked nanoparticles in sonoporated cells and the investigation of the potential related biological effects. By taking advantage of Synchrotron Radiation fourier transform infrared micro-spectroscopy (SR-microftiR) in providing highly sensitive analysis at the single cell level, we studied the internalisation of a nanoprobe within fibroblasts (NIH-3T3) promoted by low-intensity US. To this aim we employed 20 nm gold nanoparticles conjugated with the IR marker 4-aminothiophenol. The significant Surface Enhanced Infrared Absorption provided by the nanoprobes, with an absorbance increase up to two orders of magnitude, allowed us to efficiently recognise their inclusion within cells. Notably, the selective and stable SR- microftiR detection from single cells that have internalised the nanoprobe exhibited clear changes in both shape and intensity of the spectral profile, highlighting the occurrence of biological effects. Flow cytometry, immunofluorescence and murine cytokinesis-block micronucleus assays confirmed the presence of slight but significant cytotoxic and genotoxic events associated with the US-nanoprobe combined treatments. our results can provide novel hints towards US and nanomedicine combined strategies for cell spectral imaging as well as drug delivery-based therapies

Use of ultrasound attenuation spectroscopy to determine the size distribution of clay tactoids in aqueous suspensions

The dispersion processes of aqueous samples of clay are studied using ultrasound attenuation spectroscopy. The attenuation spectra that are acquired in the frequency range $10-100$ MHz are used to determine the particle size distributions (PSDs) for different concentrations and ages of the clay suspensions. Our analysis, using equivalent spherical diameter (ESD) for circular discs under Stokes drag in samples of concentrations greater than 1.5\% w/v, shows that a substantial fraction of the aggregates in suspension are actually tactoids that are composed of more than one platelet. This is in contrast to the general belief that clay disperses into individual platelets in the concentration range where their suspensions exhibit glassy behavior. We conclude that the incomplete fragmentation of the clay tactoids arises from the rapid enhancement of the inter-tactoid Coulombic repulsion.Comment: 21 pages, 6 figure

Measuring Dislocation Density in Aluminum with Resonant Ultrasound Spectroscopy

Dislocations in a material will, when present in enough numbers, change the speed of propagation of elastic waves. Consequently, two material samples, differing only in dislocation density, will have different elastic constants, a quantity that can be measured using Resonant Ultrasound Spectroscopy. Measurements of this effect on aluminum samples are reported. They compare well with the predictions of the theory.Comment: 4 pages, 2 figure

Transport, Magnetic and Vibrational Properties of Chemically Exfoliated Few Layer Graphene

We study the vibrational, magnetic and transport properties of Few Layer Graphene (FLG) using Raman and electron spin resonance spectroscopy and microwave conductivity measurements. FLG samples were produced using wet chemical exfoliation with different post-processing, namely ultrasound treatment, shear mixing, and magnetic stirring. Raman spectroscopy shows a low intensity D mode which attests a high sample quality. The G mode is present at $1580$ cm$^{-1}$ as expected for graphene. The 2D mode consists of 2 components with varying intensities among the different samples. This is assigned to the presence of single and few layer graphene in the samples. ESR spectroscopy shows a main line in all types of materials with a width of about $1$ mT and and a $g$-factor in the range of $2.005-2.010$. Paramagnetic defect centers with a uniaxial $g$-factor anisotropy are identified, which shows that these are related to the local sp$^2$ bonds of the material. All kinds of investigated FLGs have a temperature dependent resistance which is compatible with a small gap semiconductor. The difference in resistance is related to the different grain size of the samples

Time-resolved fluorescence observation of di-tyrosine formation in horseradish peroxidase upon ultrasound treatment leading to enzyme inactivation

The application of ultrasound to a solution can induce cavitional phenomena and generate high localised temperatures and pressures. These are dependent of the frequency used and have enabled ultrasound application in areas such as synthetic, green and food chemistry. High frequency (100 kHz to 1 MHz) in particular is promising in food chemistry as a means to inactivate enzymes, replacing the need to use periods of high temperature. A plant enzyme, horseradish peroxidase, was studied using time-resolved fluorescence techniques as a means to assess the effect of high frequency (378 kHz and 583 kHz) ultrasound treatment at equivalent acoustic powers. This uncovered the fluorescence emission from a newly formed species, attributed to the formation of di-tyrosine within the horseradish peroxidase structure caused by auto-oxidation, and linked to enzyme inactivation