Complications in investigations of the swelling of hydrogel matrices due to the presence of trapped gas.

In recent studies, NMR imaging has been used to investigate the swelling of hydroxypropylmethylcellulose (HPMC) tablets and to determine polymer concentration distributions in the swollen matrix. The total amount of polymer in the system was computed from these distributions and was up to 35% greater than the known weight of HPMC in the tablet. This deviation was traced to the presence of air bubbles in the swollen matrix which occupied a significant volume previously assumed to be occupied by polymer and water. When the air in the tablet was removed by vacuum, the swollen gel contained no evidence of air bubbles and the calculated total polymer weights from the HPMC distributions were equal to the amount of HPMC in the tablet.

Quantitative NMR imaging study of the mechanism of drug release from swelling hydroxypropylmethylcellulose tablets.

NMR imaging has been used to study the release behavior of two model drugs, triflupromazine-HCl and 5-fluorouracil, from swelling hydroxypropylmethylcellulose (HPMC) tablets. Preliminary experiments were performed on equilibrium mixtures of drug, polymer and water to determine how properties such as NMR relaxation parameters and self-diffusion were affected by the drug and polymer concentrations. The tablet swelling was restricted to one dimension and distributions of the water and model drugs were obtained by 1H and 19F imaging, respectively. The HPMC distribution at each time in the swelling process was determined indirectly from its effect on the relaxation parameters of the water and the drugs. In the one-dimensional swelling tablet, distributions of drug and polymer were compared to determine what factors influenced the release of drug from the swelling tablet. The distributions for triflupromazine-HCl and HPMC paralleled each other and the drug was only released at the eroding edge of the tablet where the HPMC concentration dropped below 10%. In contrast, 5-fluorouracil was released much more rapidly from the tablet and appeared to escape by diffusion from regions as high as 30% HPMC. An empirical measure of the rate of tablet edge movement can be obtained from plots of the edge position as a function of the square root of time. For HPMC, the rate of tablet expansion was determined in this way to be (2.4+/-0.8)x10(-6) cm(2) s(-1). The self-diffusion of triflupromazine-HCl in equilibrated mixtures of similar composition to the eroding tablet edge is approximately 3x10(-6) cm(2) s(-1) while the self-diffusion coefficient of 5-fluorouracil remained higher than this value until the HPMC concentration reached about 30%. This comparison of 'diffusion' properties may be useful in predicting the mechanism of drug release from other swelling hydrophilic matrix systems.

NMR imaging investigations of drug delivery devices using a flow-through USP dissolution apparatus.

A system for performing NMR imaging experiments on drug delivery devices within a flow-through dissolution apparatus, USP Apparatus 4, has been developed. The system was used to image the physical changes that occur in solid dosage forms during dissolution in the flow-through apparatus. Simultaneous cumulative drug release measurements were also made. The NMR images obtained under these conditions and the drug release data provide a better understanding of the processes involved in the release of drugs from drug delivery systems based on diffusion, dissolution and osmosis mechanisms.

Use of NMR imaging in the optimization of a compression-coated regulated release system.

Nuclear magnetic resonance (NMR) imaging is routinely used to detect the protons of mobile water molecules within samples. In this investigation, this non-destructive, non-invasive technique was used to determine the cause for faster than predicted drug release from a dissolution-based regulated-release tablet. The NMR images of tablets, from two different formulations, taken at various intervals of time while immersed in static USP dissolution medium showed that the tablet with faster than predicted drug release had a porous coating. The porous coat exposed more of the core surface area to the dissolution medium than desired and this caused an increase in the rate of dissolution of the core. The data presented in this paper demonstrate the usefulness of NMR imaging in solid dosage form development.

Magnetic resonance imaging evaluation of photodynamic therapy-induced hemorrhagic necrosis in the murine M1 tumor model.

Proton magnetic resonance imaging (MRI) and histological methods were used to evaluate photodynamic therapy (PDT)-induced hemorrhagic necrosis in the murine M1 tumor within 72 h of treatment of male DBA/2 mice. The effects of three photosensitizing drugs were investigated: Photofrin (n = 4), Zn (II) phthalocyanine (n = 7) and benzoporphyrin derivative monoacid ring A (n = 11). As noted in previous studies of PDT using MRI, MRI makes possible serial, noninvasive, in vivo observation of tissue response to PDT. Our serial study of MRI and histological data confirms that tumors responded in the same way to PDT treatment using the three photosensitizing drugs: vascular damage followed by hemorrhagic necrosis. Most importantly and unlike previous MRI studies of PDT, we used a very high field magnet that enhanced the effect of magnetic susceptibility on image signal when blood is processed by the body after PDT-induced hemorrhagic necrosis. This last finding demonstrates the utility of high field magnets and the importance of localized, serial experiments in future magnetic resonance studies of PDT.

Investigation of fluorocarbon blowing agents in insulating polymer foams by 19F NMR imaging.

Currently, there is no reliable and readily accessible technique with which the distribution and diffusion of blowing agents in rigid insulating foams can be detected and monitored. In this paper, we demonstrate that 19F NMR microscopic imaging together with 19F solid-state MAS NMR spectroscopy is ideally suited for such measurements and yield quantitatively reliable information that will be critical to the development and fabrication of optimized insulating materials with alternative blowing agents. Polystyrene (PS) and polyurethane (PU) foam samples were investigated with the objective of determining quantitatively the amount of blowing agents in the gaseous phase and dissolved in the polymer phase, and to determine and monitor the distribution of the blowing agents in aged foams as a function of time and temperature. The concentrations of the gaseous blowing agents in the cells and dissolved in the solid were simultaneously and quantitatively measured by 19F MAS NMR spectroscopy. An unfaced 1-yr-old PS foam filled with CH3CF2Cl has about 13% of total HCFCs dissolved in the solid; while there is about 24% of HCFCs in the solid of a faced 3-mos-old PU foam filled with CH3CCl2F. The data from 19F NMR imaging demonstrate that the distributions of the blowing agents in an aged foam are quite uniform around the center part (2 cm away from any edge) of a foam board; however, a gradient in blowing agent concentration was found as a function of distance from the initial factory cut edge. The effective diffusion coefficients of the blowing agents can be directly calculated from the imaging data. Quantitative diffusion constants and activation barriers were determined. Additionally, a foam treated with a second blowing agent was monitored with chemical shift selective imaging and the diffusion of the second gas into the foam and the out-diffusion of the original gas were determined.

Harvesting and climate effects on organic matter characteristics in British Columbia coastal forests.

As part of investigations into the effects of harvesting old-growth forest, we characterized carbon in five organic matter pools in eight forest chronosequences of coastal British Columbia. Each chronosequence comprised stands in four seral stages from regeneration (3-8 yr) to old-growth (>250 yr), with second-growth stands mostly of harvest origin. Stands were located in two biogeoclimatic subzones with contrasting climate (wetter, slightly cooler conditions on the west coast of Vancouver Island than on the east). Carbon concentrations in fine woody debris (FWD), forest floor (LFH), fine roots from LFH, and two water-floatable fractions from 10 to 30 cm mineral soil (MIN-ROOT, 2-8 mm and MIN-FLOAT, <2 mm) showed no significant effects due to climate, seral stage, or site. There were some significant differences in N concentrations, but none related to seral stage. Carbon-13 cross-polarization with magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectra with principal component analysis of relative areas also showed little harvesting effect, but greater variation related to input of coarse woody debris (CWD) vs. roots high in tannin. Overall, there tended to be more spectral features associated with wood and lignin in the west; whereas some MIN-ROOT samples from the drier east side had aromatic intensity attributed to charcoal. The minimal effects of one harvest on organic matter are most likely due to the large legacy effect; however, more intensive management will probably result in less CWD retention, less charcoal input, and less microsite variability in these pools of poorly decomposed organic matter.

Anti-inflammatory steroids, lysosomal stabilization and parachor.

Parachor is an additive constitutive property of a molecule and is related to the molar volume and the surface tension. The parachor of a steroid can be calculated from its constituent atoms and bonds. The parachor of a biologically active molecule is related to the ability of that molecule to permeate hydrophobic regions of cells, especially cellular membranes. An examination of the parachor values of a large number of steroids shows that these values are correlated with a number of different biological activities, from independent sources. The ability of steroids to release lysosomal enzymes from isolated lysosomes in vitro is inversely related to the parachor of the steroid. A similar relationship holds for the release of lysosomal beta-glucoronidase (EC 3.2.1.31) from isolated lysosomes of rat preputial gland following in vivo administration of steroids. The relative anti-inflammatory potencies of steroids by several assay methods are directly proportional to their parachors. The relative ability of corticosteroids to uncouple oxidative phosphorylation and to swell isolated mitochondria in vitro show a direct proportionality with the steroidal parachor. The percutaneous absorptions of steroids show good correlation with parachors, stratum corneum-water partition coefficients and amylcaproate-water partition coefficients; but not with hexadecane-water partition coefficients. The application of parachor as a structure-activity correlation parameter in drug design is likely to yield useful information. The advantages and limitations of the calculated parachor method are discussed.

PIP: Molecular parachor values of individual steroids were calculated by the addition of atomic or group parachors in an investigation to determine correlation between lysosomal stabilization in vitro and in vivo antiinflammatory potency, glucocorticoid potency, percutaneous absorption, and the parachors of the steroids. The ability of steroids to release lysosomal enzymes from isolated lysosomes in vitro is inversely related to the parachor of the steroid. A similar relationship has been found for the release of lysosomal Beta-glucoronidase from isolated lysosomes of rat preputial gland following in vivo administration of steroids. The relative antiinflammatory potencies of steroids by several assay methods are directly proportional to their parachors. Also in direct proportion to their parachors is the relative ability of corticosteroids to uncouple oxidative phosporylation and to swell isolated mitochondria in vitro. Good correlation with parachors, stratum corneum-water partition coefficients, and amylcaproate-water partition coefficients have been shown with the percutaneous absorptions of steroids; hexadecane-water partition coefficients have failed to show a good correlation. Useful information may be found if parachor as a structure-activity correlation parameter is applied to drug design.

Solid-state NMR detection, characterization, and quantification of the multiple aluminum environments in US-Y catalysts by (27)Al MAS and MQMAS experiments at very high field.

The detection of all of the aluminum present in steamed zeolite H-Y catalysts by (27)Al MAS NMR at 14.4 T (600 MHz for (1)H) and 18.8T (800 MHz for (1)H) is reported. Further, it is shown that it is possible by (27)Al MAS and MQMAS NMR measurements to clearly identify four separate aluminum environments which are characteristic of these materials and to unambiguously assign their coordinations. Average chemical shift and quadrupolar coupling parameters are used to accurately simulate the (27)Al MAS NMR spectra at 9.4 T (400 MHz for (1)H), 14.4 T (600 MHz for (1)H) and 18.8 T (800 MHz for (1)H) in terms of these four aluminum environments. In addition, these average chemical shift and quadrupolar coupling parameters are used to calculate peak positions in the (27)Al MQMAS isotropic dimension that are in good agreement with the experimental data acquired at 9.4 and 18.8 T.

Solid-state NMR characterization of the mineral searlesite and its detection in complex synthesis mixtures.

The mineral searlesite (NaBSi(2)O(5)(OH)(2)) was synthesized and characterized by (1)H, (11)B, (23)Na, and (29)Si magic-angle spinning (MAS) NMR spectroscopy. From these spectra, the (11)B and (23)Na quadrupole coupling parameters and isotropic chemical shifts and the (29)Si chemical shift anisotropies have been precisely determined. These parameters are all consistent with the local environments obtained from the crystal structure for searlesite from X-ray diffraction, and they demonstrate that the synthetic sample has a high degree of both short- and long-range order. Furthermore, these anisotropic parameters are found to provide a unique fingerprinting of searlesite in complex mixtures where the presence of this mineral is not anticipated. This is demonstrated for product mixtures formed in attempts to incorporate boron in the structures of the layer silicates magadiite and kenyaite. These mixtures have been investigated by (11)B, (23)Na, and (29)Si MAS NMR which clearly reveal that the samples are mixtures of searlesite and magadiite/kenyaite and that searlesite production consumes all of the boron in these synthesis mixtures. However, the (29)Si MAS NMR spectra of these mixtures indicate that the presence of boron in the reaction mixtures nevertheless has an important influence on the quality of the magadiite and kenyaite layer silicates produced.

Measurement of cryoprotective solvent penetration into intact organ tissues using high-field NMR microimaging.

Existing methods are not able to monitor accurately the penetration of cryoprotective solvents (CPS) into intact tissues. In this study, NMR imaging is shown to be a noninvasive nondestructive way to measure penetration rates and effective diffusion coefficients of Me2SO into samples of rat kidney and rat liver tissues. This new method is unique in that the measurements obtained are not averaged over the entire tissue volume but may be made at any site in the tissue. Measurements of penetration rates yield values which are similar to literature values, and the effective diffusion coefficients fall within the expected range. The images also suggest an explanation of why CPSs fail to completely protect organs from freezing damage.

Pressure-induced changes in the nuclear magnetic resonance spectra of a biopolymer in aqueous solution.

High resolution proton nuclear magnetic resonance spectra of the poly(amino acid)poly[N5-(3-hydroxypropyl)-L-glutamine], of degrees of polymerization 685 and 137, were measured in a mixed D2O and H2O solvent, at pressures from 1.03 to 1968.5 kg/cm2, and at temperatures of 2 and 10 degrees C. Increasing the pressure appeared to cause an increased mobility of the side chain hydrocarbon residues, and also of the alpha-hydrocarbon residue of the polymer chain. This is interpreted to imply the occurrence of a volume decrease on unfolding of the polymer from a helix to a random coli, with subsequent exposure of hydrophobic groups to the solvent.

1D and 2D solid state NMR investigations of the framework structure of As-synthesized AlPO4-14.

The framework structure of As-synthesized AlPO4-14 has been investigated with a combination of different one-dimensional 27Al and 31P solid state NMR techniques and 27Al/31P double resonance methods. The results are found to be fully consistent with the assumed structural model. 27Al MAS and DOR experiments at three different magnetic field strengths together with simulations show the presence of two tetrahedral sites, one pentacoordinated and one octahedral aluminum site. The 27Al quadrupolar coupling constants and the 31P isotropic chemical shifts of the tetrahedral sites correlate well with tetrahedral shear-strain parameters and mean P-O-Al bond angles, respectively. These correlations allow one to assign all of the NMR resonances to specific T-sites in the proposed framework structure. The assignments are then further confirmed by the application of three different two-dimensional heteronuclear correlation methods (i.e., 27Al-->31P TEDOR, CP, and INEPT) which reveal the connectivities between AlOx and PO4 polyhedra. The two-dimensional INEPT experiment is applied here for the first time in the solid state.