Władysław P. Węglarz

Magnetic Resonance Microscopy for Assessment of Morphological Changes in Hydrating Hydroxypropylmethyl Cellulose Matrix Tablets In Situ

ABSTRACTPurposeTo resolve contradictions found in morphology of hydrating hydroxypropylmethyl cellulose (HPMC) matrix as studied using Magnetic Resonance Imaging (MRI) techniques. Until now, two approaches were used in the literature: either two or three regions that differ in physicochemical properties were identified.MethodsMultiparametric, spatially and temporally resolved T2 MR relaxometry in situ was applied to study the hydration progress in HPMC matrix tablets using a 11.7 T MRI system. Two spin-echo based pulse sequences—one of them designed to specifically study short T2 signals—were used.ResultsTwo components in the T2 decay envelope were estimated and spatial distributions of their parameters, i.e. amplitudes and T2 values, were obtained. Based on the data, five different regions and their temporal evolution were identified: dry glassy, hydrated solid like, two interface layers and gel layer. The regions were found to be separated by four evolving fronts identified as penetration, full hydration, total gelification and apparent erosion.ConclusionsThe MRI results showed morphological details of the hydrating HPMC matrices matching compound theoretical models. The proposed method will allow for adequate evaluation of controlled release polymeric matrix systems loaded with drug substances of different solubility.

An understanding of modified release matrix tablets behavior during drug dissolution as the key for prediction of pharmaceutical product performance - case study of multimodal characterization of quetiapine fumarate tablets.

Motivation for the study was the lack of dedicated and effective research and development (R&D) in vitro methods for oral, generic, modified release formulations. The purpose of the research was to assess multimodal in vitro methodology for further bioequivalence study risk minimization. Principal results of the study are as follows: (i) Pharmaceutically equivalent quetiapine fumarate extended release dosage form of Seroquel XR was developed using a quality by design/design of experiment (QbD/DoE) paradigm. (ii) The developed formulation was then compared with originator using X-ray microtomography, magnetic resonance imaging and texture analysis. Despite similarity in terms of compendial dissolution test, developed and original dosage forms differed in micro/meso structure and consequently in mechanical properties. (iii) These differences were found to be the key factors of failure of biorelevant dissolution test using the stress dissolution apparatus. Major conclusions are as follows: (i) Imaging methods allow to assess internal features of the hydrating extended release matrix and together with the stress dissolution test allow to rationalize the design of generic formulations at the in vitro level. (ii) Technological impact on formulation properties e.g., on pore formation in hydrating matrices cannot be overlooked when designing modified release dosage forms.

Air Gun Impactor—A Novel Model of Graded White Matter Spinal Cord Injury in Rodents

Understanding mechanisms of spinal cord injury and repair requires a reliable experimental model. We have developed a new device that produces a partial damage of spinal cord white matter by means of a precisely adjusted stream of air applied under high pressure. This procedure is less invasive than standard contusion or compression models and does not require surgical removal of vertebral bones. We investigated the effects of spinal cord injury made with our device in 29 adult rats, applying different experimental parameters. The rats were divided into three groups in respect to the applied force of the blast wave. Functional outcome and histopathological effects of the injury were analyzed during 12-week follow-up. The lesions were also examined by means of magnetic resonance imaging (MRI) scans. The weakest stimulus produced transient hindlimb paresis with no cyst visible in spinal cord MRI scans, whereas the strongest was associated with permanent neurological deficit accompanied by pathological changes resembling posttraumatic syringomyelia. Obtained data revealed that our apparatus provided a spinal cord injury animal model with structural changes very similar to that present in patients after moderate spinal cord trauma.

A volume microstrip RF coil for MRI microscopy.

Quantitative magnetic resonance imaging (MRI) studies of small samples such as a single cell or cell clusters require application of radiofrequency (RF) coils that provide homogenous B(1) field distribution and high signal-to-noise ratio (SNR). We present a novel design of an MRI RF volume microcoil based on a microstrip structure. The coil consists of two parallel microstrip elements conducting RF currents in the opposite directions, thus creating homogenous RF field within the space between the microstrips. The construction of the microcoil is simple, efficient and cost-effective. Theoretical calculations and finite element method simulations were used to optimize the coil geometry to achieve optimal B(1) and SNR distributions within the sample and predict parameters of the coil. The theoretical calculations were confirmed with MR images of a 1-mm-diameter capillary and a plant obtained with the double microstrip RF microcoil at 11.7 T. The in-plane resolution of MR images was 24 μm × 24 μm.

Multimodal approach to characterization of hydrophilic matrices manufactured by wet and dry granulation or direct compression methods

PURPOSE OF THE RESEARCH The purpose of the research was to investigate the effect of the manufacturing process of the controlled release hydrophilic matrix tablets on their hydration behavior, internal structure and drug release. Direct compression (DC) quetiapine hemifumarate matrices and matrices made of powders obtained by dry granulation (DG) and high shear wet granulation (HS) were prepared. They had the same quantitative composition and they were evaluated using X-ray microtomography, magnetic resonance imaging and biorelevant stress test dissolution. PRINCIPAL RESULTS Principal results concerned matrices after 2 h of hydration: (i) layered structure of the DC and DG hydrated tablets with magnetic resonance image intensity decreasing towards the center of the matrix was observed, while in HS matrices layer of lower intensity appeared in the middle of hydrated part; (ii) the DC and DG tablets retained their core and consequently exhibited higher resistance to the physiological stresses during simulation of small intestinal passage than HS formulation. MAJOR CONCLUSIONS Comparing to DC, HS granulation changed properties of the matrix in terms of hydration pattern and resistance to stress in biorelevant dissolution apparatus. Dry granulation did not change these properties-similar hydration pattern and dissolution in biorelevant conditions were observed for DC and DG matrices.

The Relationship Between the Evolution of an Internal Structure and Drug Dissolution from Controlled-Release Matrix Tablets

In the last decade, imaging has been introduced as a supplementary method to the dissolution tests, but a direct relationship of dissolution and imaging data has been almost completely overlooked. The purpose of this study was to assess the feasibility of relating magnetic resonance imaging (MRI) and dissolution data to elucidate dissolution profile features (i.e., kinetics, kinetics changes, and variability). Commercial, hydroxypropylmethyl cellulose-based quetiapine fumarate controlled-release matrix tablets were studied using the following two methods: (i) MRI inside the USP4 apparatus with subsequent machine learning-based image segmentation and (ii) dissolution testing with piecewise dissolution modeling. Obtained data were analyzed together using statistical data processing methods, including multiple linear regression. As a result, in this case, zeroth order release was found to be a consequence of internal structure evolution (interplay between region’s areas—e.g., linear relationship between interface and core), which eventually resulted in core disappearance. Dry core disappearance had an impact on (i) changes in dissolution kinetics (from zeroth order to nonlinear) and (ii) an increase in variability of drug dissolution results. It can be concluded that it is feasible to parameterize changes in micro/meso morphology of hydrated, controlled release, swellable matrices using MRI to establish a causal relationship between the changes in morphology and drug dissolution. Presented results open new perspectives in practical application of combined MRI/dissolution to controlled-release drug products.

ZTE imaging of tight sandstone rocks at 9.4T - Comparison with standard NMR analysis at 0.05T.

Zero echo time (ZTE) imaging at 9.4T was used to assess local water saturation level in the tight sandstone rocks. The results were compared with the industry standard porosity estimation basing on T2 relaxation analysis at 0.05T. A linear dependence between the two was achieved. This suggests the possibility to use 3D ZTE method for assessment of local amount of water in rocks. The method can be applicable in investigation of water saturation processes in tight rocks, where imaging methods based on spin echo like RARE failed due to short T2, while single point imaging (SPI) is impractical due to long acquisition time.

Novel method for screening of enteric film coatings properties with magnetic resonance imaging

The aim of the study is to present the concept of novel method for fast screening of enteric coating compositions properties without the need of preparation of tablets batches for fluid bed coating. Proposed method involves evaluation of enteric coated model tablets in specially designed testing cell with application of MRI technique. The results obtained in the testing cell were compared with results of dissolution studies of mini-tablets coated in fluid bed apparatus. The method could be useful in early stage of formulation development for screening of film coating properties that will shorten and simplify the development works.

Altered electroencephalography spectral profiles in rats with different patterns of experimental brain dysplasia

BACKGROUND Malformations of cortical development, such as focal cortical dysplasia, are commonly associated with intractable epilepsy. Multiple animal models were created in attempts to recapitulate features of human malformations of cortical development. These manipulations give rise to various focal or diffuse anatomical abnormalities, accompanied by altered susceptibility to epileptic seizures. Both in humans and in models of dysplasia, the question of timing of the initiating insult is important. METHODS Here, we used a rat model of cerebral dysplasia elicited by prenatal irradiation at gestational days (E) 13, 15, 17, or 19. Previous results suggest these animals are characterized by different patterns of dysplasia as well as different reactivity to seizurogenic stimuli in several seizure models. Rats were implanted with telemetric electroencephalography (EEG) transmitters. We compared EEG data from freely moving animals with anatomical observations obtained with MRI, as well as Western blotting and immunohistochemistry. RESULTS We performed spectral analyses of EEG signal, revealing differential regulation of specific bands (including delta, theta, alpha-beta, gamma) in animals with different patterns of dysplasia. Relative contribution of low-frequency activity in delta band is the lowest in E15 and the highest in E19. Conversely, higher frequency bands, corresponding to alpha/beta and gamma components, are reduced in E15 versus E19. This is accompanied by altered expression of glial markers in the E19 group. CONCLUSION To our knowledge, this constitutes the first quantitative description of power spectral properties in this experimental model, providing insight into mechanisms underlying the anatomical and electrophysiological abnormalities associated with brain dysplasia of different types. Birth Defects Research, 110:303-316, 2018.

ZTE MRI in high magnetic field as a time effective 3D imaging technique for monitoring water ingress in porous rocks at sub-millimetre resolution

Zero echo time magnetic resonance imaging (ZTE MRI) at 9.4T was used to assess the local distribution of water in dolomite rocks under different saturation conditions. The results were compared with the industry standard Single Point Imaging (SPI) at 0.6T. 3D maps of the local amount of water saturating heterogeneous rock were obtained from the imaging data, and correlated with the corresponding structural images from high resolution micro-CT (μCT). The method can be applicable in the investigation of spatial kinetics of water saturation processes in porous, heterogeneous rocks where imaging methods based on spin echo, such as RARE, have failed due to short T2, while SPI is often impractical due to its long acquisition time.