The hypothesis of the study was that (1) 3D printed drug delivery systems (DDS) could be characterized in situ during drug release using NMR/MRI techniques in terms of mass transport phenomena description (interfacial phenomena), particularly for systems dealing with two mobile phases (e.g., water and low molecular weight liquid polymer); (2) consequently, it could be possible to deduce how these interfacial mass transport phenomena influence functional properties of 3D printed DDS. Matrix drug delivery systems, prepared using masked stereolithography (MSLA), containing poly(ethylene glycol) diacrylate (PEGDA) and low molecular weight polyethylene glycol (PEG) with ropinirole hydrochloride (RH) were studied as example formulations. The PEGDA to PEG (mobile phase) concentration ratio influenced drug release. It was reflected in spatiotemporal changes in parametric T-2 relaxation time (T-2) and amplitude (A) images obtained using magnetic resonance imaging (MRI) and T-1-T-2 relaxation time correlations obtained using low-field time-domain nuclear magnetic resonance (LF TD NMR) relaxometry during incubation in water. For most of the tested formulations, two signal components related to PEG and water were assessed in the hydrated matrices by MRI relaxometry (parametric T-2/A images). The PEG component faded out due to outward PEG diffusion and was gradually replaced by the water component. Both components spatially and temporally changed their parameters, reflecting evolving water-polymer interactions. The study shows that dynamic phenomena related to bidirectional mass transport can be quantified in situ using NMR and MRI techniques to gain insight into drug release mechanisms from 3D printed DDS systems.

Hypothesis: Three-dimensional 1H UltraShort Echo Time magnetic resonance imaging (1H 3D UTE MRI) of the matrix tablet made of hydrophilic polymer hydrated in heavy water (D2O) will allow investigation of the hydration-induced spatiotemporal evolution of the material originally included in the matrix tablet during manufacturing (i.e., polymer chains and bound water).Experiments: The oblong-shaped sodium alginate matrix tablets were used to verify the hypothesis. The matrix was measured before and during hydration in D2O for up to 2 h using the 1H 3D UTE MRI. Five echo times (first at 20 & mu;s) were used, resulting in five three-dimensional images (one image for each echo time). In chosen cross-sections, two parametric images, i.e., amplitude and T2* relaxation time maps, were calculated using "pixel-by -pixel" mono-exponential fitting.Findings: The regions of the alginate matrix with T2* shorter than 600 & mu;s were analyzed before (air-dry matrix) and during hydration (parametric, spatiotemporal analysis). During the study, only hydrogen nuclei (protons) pre-existing in the air-dry sample (polymer and bound water) were monitored because the hydration medium (D2O) was not visible. As a result, it was found that morphological changes in regions having T2* shorter than 300 & mu;s were the effect of fast initial water ingress into the core of the matrix and subsequent polymer mobilization (early hydration providing additional 5% w/w hydration medium content relating to air-dry matrix). In particular, evolving layers in T2* maps were detected, and a fracture network was formed shortly after the matrix immersion in D2O. The current study presented a coherent picture of polymer mobilization accompanied by local polymer density decrease. We concluded, that the T2* mapping using 3D UTE MRI can effectively be applied as a polymer mobilization marker.

Hydrophilic polymers are widely used as drug carriers for modified/controlled release. But the hydration-related phenomena still need to be studied in depth. Various approaches exist to elucidate hydration-related phenomena in hydrophilic matrices (Caccavo et al., 2016). Most of them give a simplified picture of these phenomena. Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) techniques are also used for this purpose. But the vast majority of the studies are performed using H NMR/MRI during incubation in H2O. In this case, the signal from the hydration medium dominates the results, i.e., images and relaxation time distributions/maps (Baran et al., 2023). Only some research uses D2O as a hydration medium, but they present one-dimensional profiles in spatially restricted conditions (Dahlberg et al., 2007, Dahlberg et al., 2011). Sodium alginate based matrices containing sodium salicylate (ALG/SA), salicylic acid (ALG/SNA), and alginate placebo matrix have been studied recently in H2O. The results reflect the mobility of water molecules (Juszczyk et al. 2021a, Juszczyk et al. 2021b). However, an unexplored and interesting issue is to acquire images and T1-T2 relaxation time distributions of protons included originally in polymer and water bound to polymer chains in the unhydrated (air-dry) sample. The goal of the study was to approach the assessment of polymer mobilization and subsequent erosion using D2O as hydration media and a combination of imaging and relaxometric magnetic resonance techniques. Мaterials and methods

Sodium alginate is used in various industries, including food, pharmaceutical, and agriculture. Matrix systems, e. g., tablets, and granules, are macro samples with incorporated active substances. During hydration, they are neither equilibrated nor homogenous. Phenomena occurring during hydration of such systems are complex, determine their functional properties and hence require multimodal analysis. Still, there's a lack of compre-hensive view. The study aimed to obtain unique characteristics of the sodium alginate matrix during hydration, particularly considering polymer mobilization phenomena using low-field time-domain NMR relaxometry in H2O and D2O.An increase in total signal during 4 h of hydration in D2O of ca. 30 mu V resulted from polymer/water mobi-lization. Modes in T1-T2 maps and changes in their amplitudes reflected physicochemical state of the polymer/ water system: e.g. air-dry polymer mode (T1/T2 -600) and two mobilized polymer/water modes (at T1/T2 -40 and T1/T2 -20).The study describes the approach to evaluating the hydration of the sodium alginate matrix in terms of the temporal evolution of proton pools: those existing in the matrix before hydration and those entering the matrix from the bulk water. It provides data complementary to spatially resolved methods like MRI and microCT.

Current pharmaceutical production is not suitable for personalized medicines. Over the past few years, there has been a rapid increase in interest in 3D printing in pharmaceutical technology (Awad et al., 2018). The use of three-dimensional (3D) printing (additive manufacturing technology) in pharmacies could enable the production of patient-tailored batches of dosage forms with different dosing and release characteristics (Azad et al., 2020; Trenfield et al., 2018). Understanding the physicochemical processes occurring during the printing process and drug release from the pharmaceutical products can help to design them consciously. The 3D Vat Polymerization technology seems to be one of the promising methods used in pharmacy (Stanojevic et al., 2021). On the other hand, one of the methods of spatiotemporal characterization of pharmaceutical matrices in situ are magnetic resonance methods including magnetic resonance imaging. These methods allow for the assessment of mass transport phenomena at the molecular and macro-level without disturbing the processes taking place inside this material (Baran et al., 2023; Kulinowski et al., 2015).

There are two typical ranges of temperature observed in mobility of molecules in confinement of eg. zeolite structure: translational mobility above T-S, and localized molecules below T-S. NMR spectra and relaxation for acetone-d(6) in D-ZSM-5 were obtained in a wide temperature range. NMR results were analyzed and compared with previous results for acetone-d6 in NaX and NaY zeolites. A lot of attention was dedicated to internal rotation of methyl groups, both above and below T-S. An evidence was given for existence of acetone dimers in confinement of D-ZSM-5 in the temperature range 267 K-151.5 K.

The purpose was to show, using destructive/nondestructive methods, that the interplay between water, tablet structure, and composition determine the unique spatiotemporal hydration pattern of polymer-based matrices. The tablets containing a 1:1 w/w mixture of sodium alginate with salicylic acid (ALG/SA) or sodium salicylate (ALG/SNA) were studied using Karl Fischer titration, differential scanning calorimetry, X-ray microtomography, and magnetic resonance imaging. As the principal results, matrix specific features were detected, e.g., "locking" of the internal part of the matrix (ALG/SA); existence of lamellar region associated with detection of free/freezing water (ALG/SA); existence of water penetrating the matrix forming specific region preceding infiltration layer (ALG/SNA); switch in the onset temperature of endothermic water peak associated with an increase in the fraction of non-freezing water weight per dry matrix weight in the infiltration layer (ALG/SNA). The existence of complicated spatiotemporal hydration patterns influenced by matrix composition and molecular properties of constituents has been demonstrated.

Wound dressings when applied are in contact with wound exudates in vivo or with acceptor fluid when testing drug release from wound dressing in vitro. Therefore, the assessment of bidirectional mass transport phenomena in dressing after application on the substrate is important but has never been addressed in this context. For this reason, an in vitro wound dressing stack model was developed and implemented in the 3D printed holder. The stack was imaged using magnetic resonance imaging, i.e., relaxometric imaging was performed by means of T-2 relaxation time and signal amplitude 1D profiles across the wound stack. As a substrate, fetal bovine serum or propylene glycol were used to simulate in vivo or in vitro cases. Multi-exponential analysis of the spatially resolved magnetic resonance signal enabled to distinguish components originating from water and propylene glycol in various environments. The spatiotemporal evolution of these components was assessed. The components were related to mass transport (water, propylene glycol) in the dressing/substrate system and subsequent changes of physicochemical properties of the dressing and adjacent substrate. Sharp changes in spatial profiles were detected and identified as moving fronts. It can be concluded that: (1) An attempt to assess mass transport phenomena was carried out revealing the spatial structure of the wound dressing in terms of moving fronts and corresponding layers; (2) Moving fronts, layers and their temporal evolution originated from bidirectional mass transport between wound dressing and substrate. The setup can be further applied to dressings containing drugs.

Methods of spatiotemporal characterization of nonequilibrated polymer based matrices are still immature and imperfect. The purpose of the study was to develop the methodology for the spatiotemporal characterization of water transport and properties in alginate tablets under hydration. The regions of low water content were spatially and temporally sampled using Karl Fisher and Differential Scanning Callorimetry (spatial distribution of freezing/nonfreezing water) with spatial resolution of 1 mm. In the regions of high water content, where sampling was infeasible due to gel/sol consistency, magnetic resonance imaging (MRI) enabled characterization with an order of magnitude higher spatial resolution. The minimally hydrated layer (MHL), infiltration layer (IL) and fully hydrated layer (FHL) were identified in the unilaterally hydrated matrices. The MHL gained water from the first hour of incubation (5%–10% w/w) and at 4 h total water content was 29%–39% with nonfreezing pool of 28%–29%. The water content in the IL was 45%–47% and at 4 h it reached ~50% with the nonfreezing pool of 28% and T2 relaxation time < 10 ms. The FHL consisted of gel and sol layer with water content of 85%–86% with a nonfreezing pool of 11% at 4 h and T2 in the range 20–200 ms. Hybrid destructive/nondestructive analysis of alginate matrices under hydration was proposed. It allowed assessing the temporal changes of water distribution, its mobility and interaction with matrices in identified layers.

Polyvinyl butyral (PVB) is an amorphous polymer employed in many technological applications. In order to highlight the relationships between macroscopic properties and dynamics at a microscopic level, motions of the main-chain and of the propyl side-chains were investigated between Tg − 288 °C and Tg + 55 °C, with Tg indicating the glass transition temperature. To this aim, a combination of solid state Nuclear Magnetic Resonance (NMR) methods was applied to two purposely synthesized PVB isotopomers: one fully protonated and the other perdeuterated on the side-chains. 1H time domain NMR and 1H field cycling NMR relaxometry experiments, performed across and above Tg, revealed that the dynamics of the main-chain corresponds to the α-relaxation associated to the glass transition, which was previously characterized by dielectric spectroscopy. A faster secondary relaxation was observed for the first time and ascribed to side-chains. The geometry and rate of motions of the different groups in the side-chains were characterized below Tg by 2H NMR spectroscopy.

We studied deuteron NMR spectra and spin - lattice relaxation of deuterated acetone-d(6), adsorbed into zeolites NaX (1.3) and NaY(2.4) at 100% coverage of sodium cations. At temperatures roughly below 160 K the deuterons are localized and their NMR characteristics are determined by CD3 rotation and rotational oscillations of acetone molecules. In NaX the CD3 rotation and rotational oscillations about the twofold axis of acetone dominate the spectra below 100 K, while above it oscillations also about other axes become important. In NaY dominant features are related to methyl tunnelling and to a smaller extent to rigid acetones, before the rotational oscillations about twofold axis start to prevail above 40 K. The analysis of the strongly non-exponential magnetization recovery was done by applying the recently introduced method (Ylinen et al., 2015 [12]), improved here to take into account the limited fast recovery at the level crossings, 10% at omega(t) =omega(0) and 28% at omega(t) = 2 omega(0). At first the experimental recovery is fitted by three exponentials with adjustable weights and decay rates. Then these quantities are calculated from activation energy distributions and known expressions for the deuteron relaxation rate. In NaY two distinctly separate activation energy distributions were needed, the dominant one being very broad. The use of three distributions, two of them covering practically the same energies as the broad one, lead to a somewhat better agreement with experiment. In general the theoretical results agree with experiment within experimental scatter. As the final result the mean activation energies and widths are obtained for activation energy distributions.

Our published and new experimental results by means of deuteron NMR spectroscopy in studies of molecular mobility in confinement are summarized and annalysed. Conclusions about limits of applicability of methods in disclosing several features are achieved. A set of molecules: D2, CD4, D2O, ND3, CD3OD and (CD3)2CO was chosen and introduced into zeolites with faujasite structure. Measurements of deuteron spectra and relaxation in function of loading and temperature provide a wealth of cases. A tranistion from translational into rotational mobility on decreasing temperature was a common obsevation. Fast magnetization exchange between two subsystems with different mobility was considered as a model. Existence of D2O clusters and trimers of CD3OD was a particularly significant evidence for importance of mutual ineractions. Evolution of spectral components, derivation of the activation energy and T1/T2 ratio are among analysed features. Choice of the zeolite, eg. NaY or NaX, introduces specific inertactions with the zeolite framework. Temperature at wich molecules become immobilized on cage walls is related to the strength of the interactions. On increasing temperature we may observe features like for layers of liquid on cage walls and gaseus state. In general properly chosen molecules may be used for characterization of host microporous systems.

The main aim of our approach is to gain a comprehensive view of mobility of small molecules in confinement as reported by H-2 NMR spectroscopy. The spectra and spin lattice relaxation were measured in a wide range of temperature. A set of molecules, D-2,CD4,D2O,ND3,CD3OD and (CD3)(2)CO, was chosen and introduced into NaX and NaY zeolites. A wide range of loadings provides another dimension in studies of molecular mobility in confinement. Observed features reflect evolution on decreasing temperature of molecular dynamics from gaseous state over liquid-like rotational phase to immobilized molecules. Molecules become immobilized below the temperature T-s, which appears to be an important parameter related to the strength of interactions with zeolite framework. For chosen zeolites, NaX and NaY, hydrogen bonding, and electrostatic interaction dominate, respectively. We restrict ourselves in reporting results above T-s, as below molecular mobility is reduced to when possible. The existence of D2O clusters and trimers of CD3OD gave particularly significant evidence for importance of their mutual interactions. A transition from translational to rotational mobility on decreasing temperature was a common observation, with transition temperature T-TR as a significant parameter. Fast magnetization exchange between these two mobilities was considered as a model in analysis of the relaxation temperature dependence. We point out the effective value of the quadrupole coupling constant as justification for using the exchange model. A wealth of observed features proves particular sensitivity of H-2 NMR spectroscopy in studies of molecular dynamics.

Deuteron NMR spectra and spin-lattice relaxation were studied experimentally in zeolite NaY(2.4) samples containing 100% or 200% of CD3OH or CD3OD molecules of the total coverage of Na atoms in the temperature range 20-150K. The activation energies describing the methyl and hydroxyl motions show broad distributions. The relaxation data were interpreted by improving a recent model (Stoch et al., 2013 [16]) in which the nonexponential relaxation curves are at first described by a sum of three exponentials with adjustable relaxation rates and weights. Then a broad distribution of activation energies (the mean activation energy A0 and the width σ) was assumed for each essentially different methyl and hydroxyl position. The correlation times were calculated from the Arrhenius equation (containing the pre-exponential factor τ0), individual relaxation rates computed and classified into three classes, and finally initial relaxation rates and weights for each class formed. These were compared with experimental data, motional parameters changed slightly and new improved rates and weights for each class calculated, etc. This method was improved by deriving for the deuterons of the A and E species methyl groups relaxation rates, which depend explicitly on the tunnel frequency ωt. The temperature dependence of ωt and of the low-temperature correlation time were obtained by using the solutions of the Mathieu equation for a threefold potential. These dependencies were included in the simulations and as the result sets of A0, σ and τ0 obtained, which describe the methyl and hydroxyl motions in different positions in zeolite.

We report on density functional theory computations combined with the results of measurements of the quadrupole coupling constants for O-17, hydroxyl deuterons, and adsorbed water deuterons in DX zeolite (n(Si)/n(Al) = 1). Calculations are performed for the crystalline periodic model of the DX zeolite. The local structural parameters are found for various oxygen positions at equilibrium. The quadrupole coupling constants for 170 are in the range C-Q(O-17) = 7.75 +/- 0.5 and 3.75 +/- 0.5 MHz for (Si- OD Al) and (Si-O-Al) substructures, respectively. Related values of the asymmetry parameter eta fall in the ranges of 0.9 +/- 0.5 and 0.15 +/- 0.1, respectively. The quadrupole coupling constant for deuterons depends on the OD distance according to the relation C-Q(D)[MHz] = -2.732d(OD)[MHz/angstrom] + 2.938 MHz. Deuterons are assigned to labeled oxygen positions according to the decreasinng quadrupole coupling constant C-Q(D) as O1 >= O4 >= O2 >= O3, with their relative abundances of 54.4, 7.6, 26.6, and 11.4%, respectively. The binding energy of deuteron in hydroxyl groups and for adsorbed water molecules is analyzed. Formation of the water hexamer in the plane of the 12-ring window was confirmed. Results of the calculations are compared with NMR experimental data for O-17 and D.

Deuteron NMR spectra and spin-lattice relaxation were measured for D2O confined in NaX, NaY, and DY faujasites with various loadings at temperatures ranging from 200 to 310 K with the aim to study molecular mobility of confined water. Hysteresis of spin-lattice relaxation was observed for both DY and NaY(2.4) samples at 500% loading (280 water molecules per unit cell) in a heating-cooling cycle between 264.5 and 277.7 K. The hysteresis is most likely reflecting formation and decomposition of water clusters at different temperature. Spin-lattice relaxation rates obtained from the experiment are consistent with a picture of the fast magnetization exchange between two dynamically different deuteron populations. The observed relaxation behavior as a function of temperature and loading is most likely an effect of interplay between translational and rotational diffusion. Translational diffusion of water molecules is found to be related to the strength of the electrostatic interaction of water oxygen atoms to faujasite sodium cations, whereas water molecule reorientations seem to depend on the strength of hydrogen bonding to faujasite oxygen atoms and the strength of hydrogen bonds between water molecules, at outer and inner positions in water clusters, respectively.

Deuteron NMR spectra were measured for D2O confined in NaX, NaY, and DY faujasites with various D2O loadings at temperatures ranging from T = 70 K to T = 200 K with the aim to study the molecular mobility of confined water as a function of Si/Al ratio and loading. The recorded spectra were fitted with linear combinations of representative spectral components. At low loading, with the number of water molecules per unit cell close to the abundance of sodium cations, a component related to π-jumps of water deuterons about the 2-fold symmetry axis dominated. For loadings at levels 3 times and 5 times higher than the initial loading level, Pake dublets due to rigid water deuterons dominated the recorded spectra. A set of the quadrupole coupling constant values of localized water deuterons was derived from the analysis of the Pake dublets. Their values were attributed to deuteron positions corresponding to the locations at oxygen atoms in the faujasite framework and locations within hydrogen-bonded water clusters inside faujasite cages. The contributions of the different spectral components were observed to change with increasing temperature according to the Arrhenius law with a characteristic dynamic crossover point at T = 165 K. Below T = 165 K a spectral component was observed whose contribution changed with temperature, yielding the activation energy of about 2 kJ/mol, characteristic for jumps between inversion-related water positions in clusters.

A new method is introduced for analyzing deuteron spin–lattice relaxation in molecular systems with a broad distribution of activation energies and correlation times. In such samples the magnetization recovery is strongly non-exponential but can be fitted quite accurately by three exponentials. The considered system may consist of molecular groups with different mobility. For each group a Gaussian distribution of the activation energy is introduced. By assuming for every subsystem three parameters: the mean activation energy E0, the distribution width σ and the pre-exponential factor τ0 for the Arrhenius equation defining the correlation time, the relaxation rate is calculated for every part of the distribution. Experiment-based limiting values allow the grouping of the rates into three classes. For each class the relaxation rate and weight is calculated and compared with experiment. The parameters E0, σ and τ0 are determined iteratively by repeating the whole cycle many times. The temperature dependence of the deuteron relaxation was observed in three samples containing CD3OH (200% and 100% loading) and CD3OD (200%) in NaX zeolite and analyzed by the described method between 20K and 170K. The obtained parameters, equal for all the three samples, characterize the methyl and hydroxyl mobilities of the methanol molecules at two different locations.

Nuclear magnetic resonance (NMR) provides means to investigate molecular dynamics at every state of matter. Features characteristic for the gas phase, liquid-like layers and immobilized methanol-d4 molecules in NaX and NaY zeolites were observed in the temperature range from 300 K down to 20 K. The NMR spectra at low temperature are consistent with the model in which molecules are bonded at two positions: horizontal (methanol oxygen bonded to sodium cation) and vertical (hydrogen bonding of hydroxyl deuteron to zeolite framework oxygen). Narrow lines were observed at high temperature indicating an isotropic reorientation of a fraction of molecules. Deuteron spin–lattice relaxation gives evidence for the formation of trimers, based on observation of different relaxation rates for methyl and hydroxyl deuterons undergoing isotropic reorientation. Internal rotation of methyl groups and fixed positions of hydrogen bonded hydroxyl deuterons in methyl trimers provide relaxation rates observed experimentally. A change in the slope of the temperature dependence of both relaxation rates indicates a transition from the relaxation dominated by translational motion to prevailing contribution of reorientation. Trimers undergoing isotropic reorientation disintegrate and separate molecules become localized on adsorption centers at 166.7 K and 153.8 K for NaX and NaY, respectively, as indicated by extreme broadening of deuteron NMR spectra. Molecules at vertical position remain localized up to high temperatures. That indicates the dominating role of the hydrogen bonding. Mobility of single molecules was observed for lower loading (86 molecules/uc) in NaX. A direct transition from translation to localization was observed at 190 K.