Magnetic resonance spectroscopic methods for the assessment of metabolic functions in the diseased brain.

Magnetic resonance spectroscopy (MRS) is a non-invasive technique that can be used to detect and quantify multiple metabolites. This chapter will review some of the applications of MRS to the study of brain functions. Typically, (1)H-MRS can detect metabolites reflecting neuronal density and integrity, markers of energy metabolism or inflammation, as well as neurotransmitters. The complexity of the proton spectrum has however led to the development of other nuclei-based methods, such as (31)P- and (13)C-MRS, which offer a broader chemical shift range and therefore can provide more detailed information at the level of single metabolites. The versatility of MRS allows for a wide range of clinical applications, of which neurodegeneration is an interesting target for spectroscopy-based studies. In particular, MRS can identify patterns of altered brain chemistry in Alzheimer's patients and can help establish differential diagnosis in Alzheimer's and Parkinson's diseases. Using MRS to follow less abundant neurotransmitters is currently out of reach and will most likely depend on the development of methods such as hyperpolarization that can increase the sensitivity of detection. In particular, dynamic nuclear polarization has opened up a new and exciting area of medical research, with developments that could greatly impact on the real-time monitoring of in vivo metabolic processes in the brain.

Polymer swelling, drug mobilization and drug recrystallization in hydrating solid dispersion tablets studied by multinuclear NMR microimaging and spectroscopy.

Despite the advantages offered by solid dispersions, the marketed products based on this technology are few. The most frequent concern is the stability of the amorphous drug. The state of the drug in solid dispersions is, in general, poorly characterized as the number of characterization techniques available to monitor nanometer-sized drug particles embedded in a matrix are limited. Here we present a combination of localized NMR spectroscopic and NMR imaging techniques which allow in situ monitoring of the state of the drug during tablet disintegration and dissolution. (19)F NMR relaxation is shown to be sensitive to both the crystalline/amorphous state and the size of the model nanoparticles made of the drug substance flutamide. The time course of drug mobilization and recrystallization is detected with spatial resolution within swelling solid dispersion tablets. Comparing results from spatially resolved (19)F, (2)H and (1)H NMR experiments, recrystallization is related to its enabling factors such as local hydration level and local mobility of the polymer matrix. The initially amorphous drug may recrystallize either by nanoparticle coalescence or by ripening of crystalline grains.

Relationships between solid dispersion preparation process, particle size and drug release--an NMR and NMR microimaging study.

Solid dispersion tablets prepared by either spray drying or rotoevaporation and exhibiting different grain and pore sizes were investigated under the process of hydration-swelling-gelation. (2)H and (1)H NMR microimaging experiments were used to selectively follow water penetration and polymer mobilization kinetics, respectively, while the drug release kinetics was followed by (1)H NMR spectroscopy. The obtained data, in combination with morphological information by scanning electron microscopy (SEM), reveal a complex process that ultimately leads to release of the drug into the aqueous phase. We find that the rate of water ingress has no direct influence on release kinetics, which also renders air in the tablets a secondary factor. On the other hand, drug release is directly correlated with the polymer mobilization kinetics. Water diffusion into the originally dry polymer grains determines the rate of grain swelling and the hydration within the grains varies strongly with grain size. We propose that this sets the stage for creating homogeneous gels for small grain sizes and heterogeneous gels for large grain sizes. Fast diffusion through water-rich sections of the inhomogeneous gels that exhibit a large mesh size is the factor which yields a faster drug release from tablets prepared by rotoevaporation.

Polymer-drug interactions and wetting of solid dispersions.

We demonstrate the ability of drugs to influence the wetting of solid dispersion tablets in unexpected ways. Five model drugs of different water solubility and ability to interact with the involved polymers were incorporated in hydrophilic polymer matrices, made of either hydroxypropyl methylcellulose (HPMC) or polyvinyl pyrrolidone (PVP). The physical mixtures of all combinations of drug and polymer presented surface hydrophobicities, as measured by the equilibrium advancing contact angle of water, which are expected for materials that do not influence the interactions of each other with water. However, the solid dispersions containing HPMC deviated from this regular behaviour and displayed contact angles below those of the pure compounds involved, either drug or polymer. This behaviour is explained by changed surface exposure of HPMC side groups, as a result of changes in intermolecular hydrogen bonds. In addition to water contact angle measurements, we employed NMR imaging to monitor the time course of water ingress and swelling.

Surface composition and contact angle relationships for differently prepared solid dispersions.

Solid dispersions are promising drug delivery forms which offer the possibility to disperse a hydrophobic drug in a hydrophilic matrix and thereby improve the dissolution behavior and the bioavailability of the drug. One important aspect and a prerequisite in understanding the drug dissolution mechanism from solid dispersions is a better analytical monitoring of the solid dispersion surface properties, such as powder surface composition and water adsorption properties. In this paper, we have considered chemical and structural surface analysis data for solid dispersions processed by spray drying or roto-evaporation and compared these data with information obtained by contact angle measurements. Firstly, we establish the usefulness and suitability of X-ray photoelectron spectroscopy (XPS) for determination of surface chemical composition and scanning electron microscopy (SEM) for determining the structure of solid dispersions composed of different types of carriers, drugs and drug concentrations. Secondly, we measure contact angles of solid dispersions to describe wettability, to finally establish a link between the surface chemical composition, the powder structure and the wetting behavior. These experimental methods offer a rapid screening tool for the selection of carrier, drug concentration and/or process in early development. In addition, they provide a useful tool for investigating structural aspects of solid dispersions which have intrinsic relevance for drug dissolution and stability.

Polymer mobilization and drug release during tablet swelling. A 1H NMR and NMR microimaging study.

The objective of this study was to investigate the swelling characteristics of a hydroxypropyl methylcellulose (HPMC) matrix incorporating the hydrophilic drug antipyrine. We have used this matrix to introduce a novel analytical method, which allows us to obtain within one experimental setup information about the molecular processes of the polymer carrier and its impact on drug release. Nuclear magnetic resonance (NMR) imaging revealed in situ the swelling behavior of tablets when exposed to water. By using deuterated water, the spatial distribution and molecular dynamics of HPMC and their kinetics during swelling could be observed selectively. In parallel, NMR spectroscopy provided the concentration of the drug released into the aqueous phase. We find that both swelling and release are diffusion controlled. The ability of monitoring those two processes using the same experimental setup enables mapping their interconnection, which points on the importance and potential of this analytical technique for further application in other drug delivery forms.