Emerging technologies for the non-invasive characterization of physical-mechanical properties of tablets

The density, porosity, breaking force, viscoelastic properties, and the presence or absence of any structural defects or irregularities are important physical-mechanical quality attributes of popular solid dosage forms like tablets. The irregularities associated with these attributes may influence the drug product functionality. Thus, an accurate and efficient characterization of these properties is critical for successful development and manufacturing of a robust tablets. These properties are mainly analyzed and monitored with traditional pharmacopeial and non-pharmacopeial methods. Such methods are associated with several challenges such as lack of spatial resolution, efficiency, or sample-sparing attributes. Recent advances in technology, design, instrumentation, and software have led to the emergence of newer techniques for non-invasive characterization of physical-mechanical properties of tablets. These techniques include near infrared spectroscopy, Raman spectroscopy, X-ray microtomography, nuclear magnetic resonance (NMR) imaging, terahertz pulsed imaging, laser-induced breakdown spectroscopy, and various acoustic- and thermal-based techniques. Such state-of-the-art techniques are currently applied at various stages of development and manufacturing of tablets at industrial scale. Each technique has specific advantages or challenges with respect to operational efficiency and cost, compared to traditional analytical methods. Currently, most of these techniques are used as secondary analytical tools to support the traditional methods in characterizing or monitoring tablet quality attributes. Therefore, further development in the instrumentation and software, and studies on the applications are necessary for their adoption in routine analysis and monitoring of tablet physical-mechanical properties

Cortical depth dependent functional responses in humans at 7T: improved specificity with 3D GRASE

Ultra high fields (7T and above) allow functional imaging with high contrast-to-noise ratios and improved spatial resolution. This, along with improved hardware and imaging techniques, allow investigating columnar and laminar functional responses. Using gradient-echo (GE) (T2* weighted) based sequences, layer specific responses have been recorded from human (and animal) primary visual areas. However, their increased sensitivity to large surface veins potentially clouds detecting and interpreting layer specific responses. Conversely, spin-echo (SE) (T2 weighted) sequences are less sensitive to large veins and have been used to map cortical columns in humans. T2 weighted 3D GRASE with inner volume selection provides high isotropic resolution over extended volumes, overcoming some of the many technical limitations of conventional 2D SE-EPI, whereby making layer specific investigations feasible. Further, the demonstration of columnar level specificity with 3D GRASE, despite contributions from both stimulated echoes and conventional T2 contrast, has made it an attractive alternative over 2D SE-EPI. Here, we assess the spatial specificity of cortical depth dependent 3D GRASE functional responses in human V1 and hMT by comparing it to GE responses. In doing so we demonstrate that 3D GRASE is less sensitive to contributions from large veins in superficial layers, while showing increased specificity (functional tuning) throughout the cortex compared to GE

Impact of incomplete ventricular coverage on diagnostic performance of myocardial perfusion imaging.

In the context of myocardial perfusion imaging (MPI) with cardiac magnetic resonance (CMR), there is ongoing debate on the merits of using technically complex acquisition methods to achieve whole-heart spatial coverage, rather than conventional 3-slice acquisition. An adequately powered comparative study is difficult to achieve given the requirement for two separate stress CMR studies in each patient. The aim of this work is to draw relevant conclusions from SPECT MPI by comparing whole-heart versus simulated 3-slice coverage in a large existing dataset. SPECT data from 651 patients with suspected coronary artery disease who underwent invasive angiography were analyzed. A computational approach was designed to model 3-slice MPI by retrospective subsampling of whole- heart data. For both whole-heart and 3-slice approaches, the diagnostic performance and the stress total perfusion deficit (TPD) score-a measure of ischemia extent/severity-were quantified and compared. Diagnostic accuracy for the 3-slice and whole-heart approaches were similar (area under the curve: 0.843 vs. 0.855, respectively; P = 0.07). The majority (54%) of cases missed by 3-slice imaging had primarily apical ischemia. Whole-heart and 3-slice TPD scores were strongly correlated (R2 = 0.93, P < 0.001) but 3-slice TPD showed a small yet significant bias compared to whole-heart TPD (- 1.19%; P < 0.0001) and the 95% limits of agreement were relatively wide (- 6.65% to 4.27%). Incomplete ventricular coverage typically acquired in 3-slice CMR MPI does not significantly affect the diagnostic accuracy. However, 3-slice MPI may fail to detect severe apical ischemia and underestimate the extent/severity of perfusion defects. Our results suggest that caution is required when comparing the ischemic burden between 3-slice and whole-heart datasets, and corroborate the need to establish prognostic thresholds specific to each approach

Quantitative planar and volumetric cardiac measurements using 64 mdct and 3t mri vs. Standard 2d and m-mode echocardiography: does anesthetic protocol matter?

Cross‐sectional imaging of the heart utilizing computed tomography and magnetic resonance imaging (MRI) has been shown to be superior for the evaluation of cardiac morphology and systolic function in humans compared to echocardiography. The purpose of this prospective study was to test the effects of two different anesthetic protocols on cardiac measurements in 10 healthy beagle dogs using 64‐multidetector row computed tomographic angiography (64‐MDCTA), 3T magnetic resonance (MRI) and standard awake echocardiography. Both anesthetic protocols used propofol for induction and isoflourane for anesthetic maintenance. In addition, protocol A used midazolam/fentanyl and protocol B used dexmedetomedine as premedication and constant rate infusion during the procedure. Significant elevations in systolic and mean blood pressure were present when using protocol B. There was overall good agreement between the variables of cardiac size and systolic function generated from the MDCTA and MRI exams and no significant difference was found when comparing the variables acquired using either anesthetic protocol within each modality. Systolic function variables generated using 64‐MDCTA and 3T MRI were only able to predict the left ventricular end diastolic volume as measured during awake echocardiogram when using protocol B and 64‐MDCTA. For all other systolic function variables, prediction of awake echocardiographic results was not possible (P = 1). Planar variables acquired using MDCTA or MRI did not allow prediction of the corresponding measurements generated using echocardiography in the awake patients (P = 1). Future studies are needed to validate this approach in a more varied population and clinically affected dogs

Computerized Analysis of Magnetic Resonance Images to Study Cerebral Anatomy in Developing Neonates

The study of cerebral anatomy in developing neonates is of great importance for the understanding of brain development during the early period of life. This dissertation therefore focuses on three challenges in the modelling of cerebral anatomy in neonates during brain development. The methods that have been developed all use Magnetic Resonance Images (MRI) as source data. To facilitate study of vascular development in the neonatal period, a set of image analysis algorithms are developed to automatically extract and model cerebral vessel trees. The whole process consists of cerebral vessel tracking from automatically placed seed points, vessel tree generation, and vasculature registration and matching. These algorithms have been tested on clinical Time-of- Flight (TOF) MR angiographic datasets. To facilitate study of the neonatal cortex a complete cerebral cortex segmentation and reconstruction pipeline has been developed. Segmentation of the neonatal cortex is not effectively done by existing algorithms designed for the adult brain because the contrast between grey and white matter is reversed. This causes pixels containing tissue mixtures to be incorrectly labelled by conventional methods. The neonatal cortical segmentation method that has been developed is based on a novel expectation-maximization (EM) method with explicit correction for mislabelled partial volume voxels. Based on the resulting cortical segmentation, an implicit surface evolution technique is adopted for the reconstruction of the cortex in neonates. The performance of the method is investigated by performing a detailed landmark study. To facilitate study of cortical development, a cortical surface registration algorithm for aligning the cortical surface is developed. The method first inflates extracted cortical surfaces and then performs a non-rigid surface registration using free-form deformations (FFDs) to remove residual alignment. Validation experiments using data labelled by an expert observer demonstrate that the method can capture local changes and follow the growth of specific sulcus

An evaluation of morphological and functional multi-parametric MRI sequences in classifying non-muscle and muscle invasive bladder cancer

Objectives: Our goal is to determine the ability of multi-parametric magnetic resonance imaging (mpMRI) to differentiate muscle invasive bladder cancer (MIBC) from non-muscle invasive bladder cancer (NMIBC). Methods: Patients underwent mpMRI before tumour resection. Four MRI sets, i.e. T2-weighted (T2W) + perfusion-weighted imaging (PWI), T2W plus diffusion-weighted imaging (DWI), T2W + DWI + PWI, and T2W + DWI + PWI + dif-fusion tensor imaging (DTI) were interpreted qualitatively by two radiologists, blinded to histology results. PWI, DWI and DTI were also analysed quantitatively. Accuracy was determined using histopathology as the reference standard. Results: A total of 82 tumours were analysed. Ninety-six percent of T1-labeled tumours by the T2W + DWI + PWI image set were confirmed to be NMIBC at histopathology. Overall accuracy of the complete mpMRI protocol was 94% in differentiating NMIBC from MIBC. PWI, DWI and DTI quantitative parameters were shown to be significantly different in cancerous versus non-cancerous areas within the bladder wall in T2-labelled lesions. Conclusions: MpMRI with DWI and DTI appears a reliable staging tool for bladder cancer. If our data are validated, then mpMRI could precede cystoscopic resection to allow a faster recognition of MIBC and accelerated treatment pathways. Key Points: • A critical step in BCa staging is to differentiate NMIBC from MIBC. • Morphological and functional sequences are reliable techniques in differentiating NMIBC from MIBC. • Diffusion tensor imaging could be an additional tool in BCa staging