Noninvasive characterization (EPR, µCT, NMR) of 3D PLA electrospun fiber sponges for controlled drug delivery.

Highly porous 3D-scaffolds, made from cut, electrospun PLA fibers, are relatively new and promising systems for controlled drug-delivery applications. Because knowledge concerning fundamental processes of drug delivery from those scaffolds is limited, we noninvasively characterized drug-loading and drug-release mechanisms of these polymer-fiber sponges (PFS). We screened simplified PFS-implantation scenarios with EPR and µCT to quantify and 3D-visualize the absorption of model-biofluids and an oil, a possible drug-loading liquid. Saturation of PFS (6 × 8 mm, h x d) is governed by the high hydrophobicity of the material and air-entrapment. It required up to 45 weeks for phosphate-buffered saline and 11 weeks for a more physiological, surface-active protein-solution, indicating the slow fluid-uptake of PFS as an effective mechanism to substantially prolong the release of a drug incorporated within the scaffold. Medium-chain triglycerides, as a good wetting liquid, saturated PFS within seconds, suggesting PFS potential to serve as carrier-vessels for immobilizing hydrophobic drug-solutions to define a liquid's 3D-interface. Oil-retention under mechanical stress was therefore investigated. 1H NMR permitted insights into PFS-oil interaction, confirming surface-relaxation and restricted diffusion; both did not influence drug release from oil-loaded PFS. Results facilitate better understanding of PFS and their potential use in drug delivery.

The role of chelating agents and amino acids in preventing free radical formation in bleaching systems.

The control of bleaching reaction is important in hair bleaching and laundry detergents to ensure quality of the final product. A better understanding of the reaction mechanisms is needed to minimize product failures. 31P NMR-spectroscopy-based spin trap technique was employed to detect and quantify the free radical species that were generated in different bleaching solutions. These solutions contained the key actives in an alkaline hair colorant/bleaching product, an ammonium salt and hydrogen peroxide at pH = 10. Generally, the main radical species detected in hair oxidative coloring or bleaching processes, were hydroperoxyl/superoxide radicals HO2·/O2.-, amino radicals ·NH2 and hydroxyl radicals ·OH. Their amounts showed a variation based on the chemical composition of the bleaching systems and the metal ion content. The generation of free radicals from reactions between transition metal ions, such as copper, and hydrogen peroxide at pH = 10 was evaluated. In the absence of chelating agents, the copper ions generated a significant level of hydroxyl radicals in a Fenton-like reaction with hydrogen peroxide at pH = 10. Besides that, an increase in copper ion content led to an increase of amino radical ·NH2, whereas the concentration of superoxide radical O2·- decreased which was not yet well reported in the previous literature. The effect of chelating agents like ethylenediaminetetraacetic acid (EDTA), tetrasodium-iminodisuccinate (IDS), a mixture of basic amino acids and dicarboxylic acid on free radical formation was investigated in the presence of binary Cu2+-Ca2+ bleaching systems. As expected, in the binary Cu2+-Ca2+ ion system EDTA did not suppress hydroxyl radical formation effectively, but the mixture containing sodium succinate, lysine and arginine reduced hydroxyl radical formation, whereas IDS (nearly) completely inhibited hydroxyl radical formation. The results indicated that each bleaching solution has its characteristic performance and damage profile. Whereas the reactivity can be controlled by the usage of chelating agents.

Synthesis, Characterization, and Nanoencapsulation of Tetrathiatriarylmethyl and Tetrachlorotriarylmethyl (Trityl) Radical Derivatives­A Study To Advance Their Applicability as in Vivo EPR Oxygen Sensors.

Tissue oxygenation plays an important role in the pathophysiology of various diseases and is often a marker of prognosis and therapeutic response. EPR (ESR) is a suitable noninvasive oximetry technique. However, to reliably deploy soluble EPR probes as oxygen sensors in complex biological systems, there is still a need to investigate and improve their specificity, sensitivity, and stability. We reproducibly synthesized various derivatives of tetrathiatriarylmethyl and tetrachlorotriarylmethyl (trityl) radicals. Hydrophilic radicals were investigated in aqueous solution mimicking physiological conditions by, e.g., variation of viscosity and ionic strength. Their specificity was satisfactory, but the oxygen sensitivity was low. To enhance the capability of trityl radicals as oxygen sensors, encapsulation into oily core nanocapsules was performed. Thus, different lipophilic triesters were prepared and characterized in oily solution employing oils typically used in drug formulations, i.e., middle-chain triglycerides and isopropyl myristate. Our screening identified the deuterated ethyl ester of D-TAM (radical 13) to be suitable. It had an extremely narrow single EPR line under anoxic conditions and excellent oxygen sensitivity. After encapsulation, it retained its oxygen responsiveness and was protected against reduction by ascorbic acid. These biocompatible and highly sensitive nanosensors offer great potential for future EPR oximetry applications in preclinical research.

Benchtop MRI for pharmacokinetic evaluation of two aqueous-based nano-scaled formulations of oleic acid stabilized magnetite nanocrystals.

BACKGROUND: The interplay between numerous factors, including the size, shape, coating, surface charge and composition of particles is known to affect the pharmacokinetics and biodistribution of superparamagnetic iron oxides (SPIOs). This makes understanding the role of each factor independently quite challenging. METHODS: In the present study, the in vivo magnetic resonance imaging (MRI), biodistribution and hepatic clearance evaluations of two SPIOs Formulations A and B developed from ∼13.5 nm hydrophobic oleic acid stabilized monodisperse magnetite nanocrystals core and lipid-based amphiphilic stabilizers were performed using a prototype benchtop MR imager (22 MHz) and pulsed nuclear magnetic resonance (NMR) system (20 MHz), respectively. Formulation A was composed of mPEG-2000-DSPE and Formulation B was composed of Phospholipon-100H, sucrose ester M-1695 and Cremophor RH-40. RESULTS: The in vivo MRI investigations showed that both formulations were safe and effective as potential liver MR contrast agents with sustained liver contrast for at least seven days. In addition, ex vivo relaxometric investigations revealed that the formulations predominantly distribute to the liver and spleen following I.V. injection. The hepatic clearance kinetics determined based on the relaxometric quantification method indicated that both formulations exhibited a biphasic clearance process with a slow terminal clearance half-life of 11.5 and 12.7 days, respectively, for Formulations A and B. CONCLUSIONS: The results of this study showed the potential biomedical applications of the investigated magnetopharmaceutical formulations as MRI contrast agents.

Novel semisolid SNEDDS based on PEG-30-dipolyhydroxystearate: development and characterization.

The aim of the current study is to explore the potential of PEG-30-dipolyhydroxystearate (Cithrol(®) DPHS) and Soluplus(®) as ingredients in novel semisolid self-nanoemulsifying drug delivery systems (SNEDDS). Semisolid SNEDDS consisting of Cithrol(®) DPHS, Capmul(®) MCM and Kolliphor(®) HS 15 were successfully prepared. The formulations were comprehensively characterized by photon correlation spectroscopy (PCS), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), electron spin resonance (ESR) and proton nuclear magnetic resonance ((1)H NMR). All formulations were semisolid at room temperature and melted at body temperature. The hydrodynamic diameter of the dispersions was less than 25 nm. The ratio Cithrol(®) DPHS:Capmul(®) MCM was found to be critical for the dispersibility and the stability of the formed nanoemulsion.

Toward a detailed characterization of oil adsorbates as "solid liquids".

Solid lipid formulation systems are used to overcome oral bioavailability problems of poorly water-soluble drugs. One promising process is the conversion of a liquid lipid system in a free flowing powder by use of adsorbing excipients. The aim of this study was the detailed characterization of solid-liquid interactions in oil adsorbed to Fujicalin and Neusilin which were manufactured by means of dual asymmetric centrifugation or conventional mortar/pestle blending. The adsorption strength of the excipients was investigated by Benchtop-NMR and ESR spectroscopy revealing the highest adsorption power for the Neusilin products. The adsorbate production methods as well as the storage of the excipients impact their adsorption properties. Environmental scanning electron microscopy (ESEM) and confocal laser scanning microscopy (CLSM) show that dual asymmetric centrifugation leads to a smoothing of the particle surface, whereas the mortar/pestle blending results in an uneven surface and particle destruction. The oil distribution at the particles is inhomogeneous for both production methods. The micropolarity of the adsorbed oil was investigated by ESR spectroscopy and multispectral fluorescence imaging. The adsorbing process on Neusilin leads to an increased micropolarity of the oil component. The release of the oil component in aqueous media could be verified by Benchtop-NMR and multispectral fluorescence imaging.

Lecithin-based microemulsions for targeted delivery of ceramide AP into the stratum corneum: formulation, characterizations, and in vitro release and penetration studies.

PURPOSE: To improve the solubility and penetration of Ceramide AP (CER [AP]) into the stratum corneum that potentially restores the barrier function of aged and affected skin. METHODS: CER [AP] microemulsions (MEs) were formulated using lecithin, Miglyol® 812 (miglyol) and water-1,2 pentandiol (PeG) mixture as amphiphilic, oily and hydrophilic components, respectively. The nanostructure of the MEs was revealed using electrical conductivity, differential scanning calorimeter (DSC) and electron paramagnetic resonance (EPR) techniques. Photon correlation spectroscopy (PCS) was used to measure the sizes and shape of ME droplets. The release and penetration of the CER into the stratum corneum was investigated in vitro using a multi-layer membrane model. RESULTS: The MEs exhibited excellent thermodynamic stability (>2 years) and loading capacity (0.5% CER [AP]). The pseudo-ternary phase diagrams of the MEs were obtained and PCS results showed that the droplets are spherical in shape and bigger in size. In vitro investigations showed that the MEs exhibited excellent rate and extent of release and penetration. CONCLUSIONS: Stable lecithin-based CER [AP] MEs that significantly enhance the solubility and penetration of CER [AP] into the stratum corneum were developed. The MEs also have better properties than the previously reported polyglycerol fatty acid surfactant-based CER [AP] MEs.

Polyglycerol fatty acid ester surfactant-based microemulsions for targeted delivery of ceramide AP into the stratum corneum: formulation, characterisation, in vitro release and penetration investigation.

Ceramide AP (CER [AP]) is an integral component of the stratum corneum (SC) lipid matrix and is capable of forming tough and super stable lamellae. It may help to restore the barrier function in aged and affected skin. However, its effectiveness from conventional dosage forms is limited due to its poor solubility and penetration into the SC. Therefore, stable polyglycerol fatty acid ester surfactant (SAA)-based CER [AP] microemulsions (MEs) were formulated and characterised to enhance its solubilisation and penetration into the SC. TEGO® CARE PL 4 (TCPL4: polyglycerol-4-laurate), isopropyl palmitate (IPP) and water-1, 2 pentandiol (PeG) were used as amphiphilic, oily and hydrophilic components, respectively. The effects of HYDRIOL® PGMO.4 (HPGMO4: polyglyceryl-4-oleate) as a co-surfactant (co-SAA) and linoleic acid (Lin A) as part of the oil component on the stability and characteristics of the MEs were investigated. EPR results were used for the first time to reveal MEs nanostructures. The release and penetration behaviour of the MEs was assessed in vitro by using a multi-layer membrane model. The results obtained showed that HPGMO4 and Lin A increased stability and expanded the ME region considerably. The formulations were stable for 10 to >24 months. Dynamic light scattering (DLS) results showed that the droplets were bigger and asymmetric, which might be helpful to localise the CER into the upper layers of the epidermis. Release and penetration from the MEs was superior as compared to the hydrophilic cream (DAB). The rate and extent of CER [AP] released and penetrated from O/W MEs was better than W/O MEs.

Application of Benchtop-magnetic resonance imaging in a nude mouse tumor model.

BACKGROUND: MRI plays a key role in the preclinical development of new drugs, diagnostics and their delivery systems. However, very high installation and running costs of existing superconducting MRI machines limit the spread of MRI. The new method of Benchtop-MRI (BT-MRI) has the potential to overcome this limitation due to much lower installation and almost no running costs. However, due to the low field strength and decreased magnet homogeneity it is questionable, whether BT-MRI can achieve sufficient image quality to provide useful information for preclinical in vivo studies. It was the aim of the current study to explore the potential of BT-MRI on tumor models in mice. METHODS: We used a prototype of an in vivo BT-MRI apparatus to visualise organs and tumors and to analyse tumor progression in nude mouse xenograft models of human testicular germ cell tumor and colon carcinoma. RESULTS: Subcutaneous xenografts were easily identified as relative hypointense areas in transaxial slices of NMR images. Monitoring of tumor progression evaluated by pixel extension analyses based on NMR images correlated with increasing tumor volume calculated by calliper measurement. Gd-BOPTA contrast agent injection resulted in a better differentiation between parts of the urinary tissues and organs due to fast elimination of the agent via kidneys. In addition, interior structuring of tumors could be observed. A strong contrast enhancement within a tumor was associated with a central necrotic/fibrotic area. CONCLUSIONS: BT-MRI provides satisfactory image quality to visualize organs and tumors and to monitor tumor progression and structure in mouse models.

Benchtop-MRI for in vivo imaging using a macromolecular contrast agent based on hydroxyethyl starch (HES).

Magnetic resonance imaging (MRI) is a powerful non-invasive diagnostic tool in the clinical setting. However, the wide spread use of small animal MRI instruments for preclinical research purposes has been limited by the need for strong magnets operating in the range of 4.7-11.7T. To obtain such strong and homogenous magnetic fields, superconducting electromagnets cooled with liquid helium are used, which highly increases the costs for research studies. Here we report on the use of a pilot 0.5T benchtop MRI (BT-MRI) operating with a permanent magnet and designed for in vivo imaging of mice. It was used to evaluate a novel macromolecular MRI contrast agent based on a Gd-chelate of hydroxyethyl starch (Gd-HES). Images obtained by the BT-MRI showed the high contrast enhancement of Gd-HES, its longevity in the circulation, as well as its utility for tumor diagnosis, urography and angiography. These results demonstrate the potential of the new BT-MRI as a useful research tool, as well as that of Gd-HES as a new MRI contrast agent.

Water dynamics in bolaamphiphile hydrogels investigated by 1H NMR relaxometry and diffusometry.

The dynamical properties of water in hydrogels formed by the bolaamphiphiles dotriacontane-1,32-diyl-bis[2-(trimethylammonio)ethylphosphate] (PC-C32-PC) and its head group derivative dotriacontane-1,32-diyl-bis[2-(dimethylammonio)ethylphosphate] (Me(2)PE-C32-Me(2)PE) were investigated by determining the transverse relaxation times and the mean diffusion coefficients of the water protons. T(2) distributions obtained for hydrogels containing only 1 mg/mL of PC-C32-PC or Me(2)PE-C32-Me(2)PE were found to be almost unchanged compared to that of pure deionized water. In a hydrogel containing 30 mg/mL PC-C32-PC, a small dynamical perturbation of the water molecules could be observed, since the obtained major peak in the T(2) distribution was found to be slightly broadened and shifted to lower T(2) values with respect to pure water. Moreover, a slightly decreased mean diffusion coefficient of the water molecules was determined for the hydrogel with 30 mg/mL PC-C32-PC. For 30 mg/mL Me(2)PE-C32-Me(2)PE at pH 5, the dynamical properties of water are significantly influenced by the presence of the bolaamphiphiles. Whereas the mean diffusion coefficient of water was again only slightly decreased, the relaxation behavior was found to be considerably changed. At room temperature, the major T(2) peak obtained for 30 mg/mL Me(2)PE-C32-Me(2)PE at pH 5 was significantly broadened and shifted to lower T(2) values compared to pure buffer. This broad monomodal peak becomes bimodal when the temperature is decreased to 5 °C. Increasing the temperature revealed that the structural changes of the bolaamphiphilic self-assemblies at 45 °C are reflected in the determined mean relaxation times (T(2m)). These results indicate the presence of a significant degree of structural heterogeneity in a hydrogel formed by 30 mg/mL Me(2)PE-C32-Me(2)PE at pH 5. By comparing the mean diffusion coefficients with the mean transverse relaxation times, the distance scale of these heterogeneities could be estimated to be in the range of 50 to 120-140 µm. They can most probably be ascribed to the existence of a considerable number of lamellar domains being formed besides the nanofibers in hydrogels with 30 mg/mL Me(2)PE-C32-Me(2)PE at pH 5. Upon storage, the phenomenon of syneresis was observed for this hydrogel, which corresponds to a growth of the lamellar domains to sizes between 140 and 190 µm.

Application of electron paramagnetic resonance (EPR) spectroscopy and imaging in drug delivery research - chances and challenges.

Electron Paramagnetic Resonance (EPR) spectroscopy is a powerful technique to study chemical species with unpaired electrons. Since its discovery in 1944, it has been widely used in a number of research fields such as physics, chemistry, biology and material and food science. This review is focused on its application in drug delivery research. EPR permits the direct measurement of microviscosity and micropolarity inside drug delivery systems (DDS), the detection of microacidity, phase transitions and the characterization of colloidal drug carriers. Additional information about the spatial distribution can be obtained by EPR imaging. The chances and also the challenges of in vitro and in vivo EPR spectroscopy and imaging in the field of drug delivery are discussed.

Non-invasive MRI detection of individual pellets in the human stomach.

MRI is a powerful and non-invasive method to follow the fate of oral drug delivery systems in humans. Until now, most MRI studies focused on monolithic dosage forms (tablets and capsules). Small-sized multi-particulate drug delivery systems are very difficult to detect due to the poor differentiation between the delivery system and the food. A new approach was developed to overcome the described difficulties and permit the selective imaging of small multi-particulate dosage forms within the stomach. We took advantage of the different sensitivities to susceptibility artefacts of T(2)-weighted spin-echo sequences and T(2)-weighted gradient echo pulse sequences. Using a combination of both methods within a breath hold followed by a specific mathematical image analysis involving co-registration, motion correction, voxel-by-voxel comparison of the maps from different pulse sequences and graphic 2D-/3D-presentation, we were able to obtain pictures with a high sensitivity due to susceptibility effects caused by a 1% magnetite load. By means of the new imaging sequence, single pellets as small as 1mm can be detected with high selectivity within surrounding heterogeneous food in the human stomach. The developed method greatly expands the use of MRI to study the fate of oral multi-particulate drug delivery systems and their food dependency in men.

Non-invasive in vivo evaluation of in situ forming PLGA implants by benchtop magnetic resonance imaging (BT-MRI) and EPR spectroscopy.

In the present study, we used benchtop magnetic resonance imaging (BT-MRI) for non-invasive and continuous in vivo studies of in situ forming poly(lactide-co-glycolide) (PLGA) implants without the use of contrast agents. Polyethylene glycol (PEG) 400 was used as an alternative solvent to the clinically used NMP. In addition to BT-MRI, we applied electron paramagnetic resonance (EPR) spectroscopy to characterize implant formation and drug delivery processes in vitro and in vivo. We were able to follow key processes of implant formation by EPR and MRI. Because EPR spectra are sensitive to polarity and mobility, we were able to follow the kinetics of the solvent/non-solvent exchange and the PLGA precipitation. Due to the high water affinity of PEG 400, we observed a transient accumulation of water in the implant neighbourhood. Furthermore, we detected the encapsulation by BT-MRI of the implant as a response of the biological system to the polymer, followed by degradation over a period of two months. We could show that MRI in general has the potential to get new insights in the in vivo fate of in situ forming implants. The study also clearly shows that BT-MRI is a new viable and much less expensive alternative for superconducting MRI machines to monitor drug delivery processes in vivo in small mammals.

Characterization of scaffolds for tissue engineering by benchtop-magnetic resonance imaging.

Several publications have shown approaches for the optimization of tissue engineering constructs by magnetic resonance imaging (MRI). However, the technology is still scarcely used, probably because of the poor spatial resolution of clinical scanners and their temporally limited availability for many researchers. The new benchtop- MRI (BT-MRI) equipment used in the present study is much more affordable, for example, because of the low static magnetic field strength of 0.5 T and the absence of a helium cooling system. In this study, the method of BT-MRI was evaluated for the characterization of a tissue engineering scaffold. Hollow cylinder scaffolds were made of hydroxyapatite (HA), collagen, and chitosan and wrapped in a polyglycolic acid mesh. Mass transport between construct and surrounding medium was investigated by dynamic contrast agent-enhanced MRI with gadolinium(III)-diethylaminepentaacetic acid. The results demonstrate that BT-MRI permits detailed, space-resolved insights into diffusion processes within the three-dimensional matrices, enabling a comparison of the mass transport inside different scaffold types. Inhomogeneities of the HA distribution in scaffolds caused by the fabrication were also visible in MR images. The fate of cells, labeled with superparamagnetic iron oxide nanoparticles and seeded on the scaffold surface, was monitored. For the first time, it was shown that mass transport, inhomogeneities of the HA distribution, and localization of superparamagnetic iron oxide nanoparticle-labeled cells are accessible in a tissue engineering scaffold by BT-MRI. Hence, it is demonstrated that BT-MRI is a powerful analytic method for the noninvasive evaluation of tissue engineering constructs.

The motional dynamics in bolaamphiphilic nanofibers and micellar aggregates: an ESR spin probe study.

The aggregation behavior of the bolaamphiphilic hydrogelators dotriacontane-1,32-diyl-bis[2-(trimethylammonio)ethylphosphate] (PC-C32-PC) and the pH-sensitive dotriacontane-1,32-diyl-bis[2-(dimethylammonio)-ethylphosphate] (Me2PE-C32-Me2PE) was characterized before using different methods. Dependent on the temperature, pH, and concentration, these bolaamphiphiles self-asssemble into long nanofibers or other aggregates, such as short rods or micelles. In order to obtain information about the motional dynamics and microscopic order inside of these aggregates, we carried out a systematic ESR spin probe study. The spectra obtained with the spin probes 5-, 12- and 16-doxyl stearic acid (n-DSA) were found to be highly sensitive to changes in the bolaamphiphilic arrangement. Rotational correlation times and order parameters were obtained from full ESR line shape simulations with the programs EasySpin and EPRSIM. The maximum hyperfine splitting, 2Amax, was used to determine the transition temperatures, which are in agreement with the DSCdata. By comparison of 5-DSA and 12-DSA, which are residing at different positions in the alkyl chain region of the aggregates, it was found that trans-gauche isomerization is predominantly occurring in the outer region of the aggregates. For Me2PE-C32-Me2PE at pH 10, our ESR data indicate that micelles are short rods rather than being spherical in shape. Therefore, increasing the concentration from 1 to 10 mg/mL leads only to a one-dimensional growth of these micelles.

Benchtop-magnetic resonance imaging (BT-MRI) characterization of push-pull osmotic controlled release systems.

The mechanism of drug release from push-pull osmotic systems (PPOS) has been investigated by Magnetic Resonance Imaging (MRI) using a new benchtop apparatus. The signal intensity profiles of both PPOS layers were monitored non-invasively over time to characterize the hydration and swelling kinetics. The drug release performance was well-correlated to the hydration kinetics. The results show that (i) hydration and swelling critically depend on the tablet core composition, (ii) high osmotic pressure developed by the push layer may lead to bypassing the drug layer and incomplete drug release and (iii) the hydration of both the drug and the push layers needs to be properly balanced to efficiently deliver the drug. MRI is therefore a powerful tool to get insights on the drug delivery mechanism of push-pull osmotic systems, which enable a more efficient optimization of such formulations.

Modulating pH-independent release from coated pellets: effect of coating composition on solubilization processes and drug release.

The aim of the study was to clarify the influences of three coating parameters on the drug release from chlorpheniramine maleate (CPM) pellets, coated with blends of poly(vinyl acetate) (PVAc) and poly(vinyl alcohol)-poly(ethylene glycol) (PVA-PEG) graft copolymer. A central composite design was implemented to investigate the effect of the polymer blend ratio, the film coat thickness and the plasticizer concentration on the drug release. The solubilization inside the pellets was monitored by EPR spectroscopy. The blending ratio of both the polymers and the film thickness were found to have a major influence on the drug release and the solubilization speed, in contrast to the plasticizer concentration. A pH-independent release profile was adjustable via modulating the polymer blend ratio and the coating thickness. A mathematical model was developed, providing a good predictability of the release profile, based on the film coat composition. This model offers the possibility to achieve a defined drug-release profile by selective adaptation of the film coat composition, in view of process times, feasibility or polymer costs.

Benchtop-NMR and MRI--a new analytical tool in drug delivery research.

During the last years, NMR spectroscopy and NMR imaging (magnetic resonance imaging, MRI) have been increasingly used to monitor drug delivery systems in vitro and in vivo. However, high installation and running costs of the commonly used superconducting magnet technology limits the application range and prevents the further spread of this non-invasive technology. Benchtop-NMR (BT-NMR) relaxometry uses permanent magnets and is much less cost intensive. BT-NMR relaxometry is commonly used in the food and chemical industry, but so far scarcely used in the pharmaceutical field. The paper shows on several examples that the application field of BT-NMR relaxometry can be extended into the field of drug delivery, including the characterisation of emulsions and lipid ingredients (e.g. the amount and physicochemical state of the lipid) and the monitoring of adsorption characteristics (e.g. oil binding of porous ingredients). The most exciting possibilities of BT-NMR technology are linked with the new development of BT-instruments with imaging capability. BT-MRI examples on the monitoring of hydration and swelling of HPMC-based monolayer and double-layer tablets are shown. BT-MRI opens new MRI opportunities for the non-invasive monitoring of drug delivery processes.

Do in situ forming PLG/NMP implants behave similar in vitro and in vivo? A non-invasive and quantitative EPR investigation on the mechanisms of the implant formation process.

Electron paramagnetic resonance (EPR) spectroscopy was applied to monitor non-invasively the formation of in situ forming implants in vitro and in vivo after the administration of poly(lactide-co-glycolide) (PLGA)/N-methyl-pyrrolidone (NMP) solutions. The nitroxide spin probe 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TB) was incorporated in polymer solutions and samples were incubated in 0.1 M phosphate buffer (pH 7.4) at 37 degrees C or injected subcutaneously in the femoral of BALB/c mice. EPR permitted the direct and continuous determination of the NMP-water exchange during implant formation both in vitro and in living mice. The formation of the implant structure followed a two phase mechanism: over 75% of the polymer precipitated immediately after injection within the first 30 min and formed a solid shell. The subsequent moderate solidification of the implants was governed by diffusion and was completed after 24 h. The replacement of the organic solvent NMP by water was determined by polarity shifts within the implant and could be quantified. Both the kinetic of NMP-water exchange and polymer precipitation showed good in vitro-in vivo correlation.