Quantitative magnetic resonance micro-imaging methods for pharmaceutical research

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Abstract

The use of magnetic resonance imaging (MRI) as a tool in pharmaceutical research is now well established and the current literature covers a multitude of different pharmaceutically relevant research areas. This review focuses on the use of quantitative magnetic resonance micro-imaging techniques and how they have been exploited to extract information that is of direct relevance to the pharmaceutical industry. The article is divided into two main areas. The first half outlines the theoretical aspects of magnetic resonance and deals with basic magnetic resonance theory, the effects of nuclear spin–lattice (T1), spin–spin (T2) relaxation and molecular diffusion upon image quantitation, and discusses the applications of rapid magnetic resonance imaging techniques. In addition to the theory, the review aims to provide some practical guidelines for the pharmaceutical researcher with an interest in MRI as to which MRI pulse sequences/protocols should be used and when. The second half of the article reviews the recent advances and developments that have appeared in the literature concerning the use of quantitative micro-imaging methods to pharmaceutically relevant research.

Graphical abstract

This is a set of images acquired at 3.5 h after the start of dissolution of a swelling matrix tablet. The images give quantitative maps of the water concentration, water mobility and diffusion, and water movement around tablet. All four images are acquired in only 5 min, and they give a story of all these events happening cocurrently during the dissolution process.

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Introduction

The use of magnetic resonance imaging (MRI) as a tool in pharmaceutical research dates back to the work of Rajabisiahboomi et al. (1994) who used traditional spin–echo magnetic resonance imaging to investigate the swelling of hydrating hydroxypropylmethylcellulose (HPMC) tablets. Since then there has been a vast amount of work published in the literature concerning the use of magnetic resonance imaging and its application to pharmaceutical systems. Recently, there have been several excellent reviews (Melia et al., 1998, Nott, 2010, Richardson et al., 2005, Zeitler and Gladden, 2009) on the aforementioned subject which, collectively, cover a wide variety of pharmaceutically relevant research. The aim of this review is two fold: (i) to focus on the use of quantitative magnetic resonance techniques and how they have been used to extract information that is of direct relevance to pharmaceutical research; (ii) to provide some guidelines for the pharmaceutical researcher with an interest in MRI as to which MRI pulse sequences/protocols should be used and when. The second aim may seem somewhat unusual but there is a good reason for including this. In the last 2–3 years the emergence of commercially available so-called “bench-top” MRI systems has made the use of MRI much more attractive to pharmaceutical research companies, primarily because of the fact that ench-top systems do not require expensive high field superconducting magnets as part of their hardware. In addition, bench-top systems are extremely compact and require only a moderate amount of space in a laboratory. Moreover, a standard United States Pharmacopeia (USP-4) dissolution cell can now be incorporated into a bench-top system (Malaterre et al., 2009, Nott, 2010) and thus permits a direct comparison of MRI data with that from a industry standard USP-4 dissolution apparatus under well defined universally accepted protocols. However, the bench-top phenomenon is still in its infancy in terms of “user friendliness” of the software and MRI pulse programming interfaces, which make the rapid implementation of new techniques cumbersome. Nevertheless, it is likely that bench-top MRI systems will be routinely used by non-MRI specialists in the pharmaceutical industry with increasing frequency, and thus it is prudent to provide some guidelines that will aid the choice of which MRI protocols to use and when.

So, what is meant by “quantitative” in terms of magnetic resonance data? One of the defining beauties of the magnetic resonance phenomenon whether it be from an imaging or spectroscopy viewpoint, is that the acquired signal is, in theory, proportional to the number of active nuclei in a particular sample of interest. So in its simplest form magnetic resonance tells us “how much?” of a particular substance we have and thus it can, in principle, be used to spatially map, for example, the concentration of an active pharmaceutical ingredient (API) in a solid dosage form, or the concentration of water or drug in a gel layer. In addition to the question of “how much?”, MRI data can also be acquired and manipulated to give quantitative information regarding “how fast? (or indeed how slow?)” molecules of interest move. For example, of particular interest to pharmaceutical research community is quantifying the rate of ingress of dissolution media into swellable matrices, the rate of formation and expansion of gels layers and the rate at which an API is dissolved and subsequently transported from its existence within a gel layer to a surrounding dissolution medium. The answers to the questions of “how much?” and “how fast?” for many pharmaceutically relevant research areas using MRI techniques is sometimes possible, but it is imperative, for the accurate interpretation of data, that the information within the MRI image has been corrected for signal losses that result from so called T1, and T2-relxation, diffusion and flow losses. Fyfe and Blazek (1997) and Hyde and Gladden (1998) were amongst the first to note that previous MRI investigations of liquid ingress into polymers were not quantitative as they lacked information from both the liquid and the polymer. Fyfe and Blazek (1997) presented the first fully quantitative study of a pharmaceutically relevant system, namely HPMC swelling by water, using a combination of conventional T1/T2 relaxation NMR spectroscopy (for calibration) and T2 weighted one dimensional non-slice selective imaging/profiling. It is thus timely at this stage to review the basics behind the nuclear magnetic resonance (NMR) and magnetic resonance imaging experiments and highlight some of the more important issues that may cause errors in such measurements of “how much?” of a substance we have and “how fast?” is it moving with a particular focus on the applicability of magnetic resonance micro-imaging methods to pharmaceutical drug delivery systems.

Section snippets

Nuclear magnetic resonance (NMR) and MRI theory

The complete theory of NMR and MRI is complex but well established and the reader is referred to several excellent texts on the subject for a thorough treatment (Callaghan, 1993, Haacke, 1999, Levitt, 2001, Liang and Lauterbur, 2000). The basic principles behind the NMR experiment and the origins of T1 and T2 relaxation and how they can effect the quantitative interpretation of data are included. In addition, the theory behind spatial resolution in magnetic resonance, to give a magnetic

Magnetic resonance imaging

So far, the discussion on NMR theory has been limited to spectroscopic measurements, i.e. ones that are made on the whole sample. This type of measurement has been, and still is, the staple diet of chemists and biochemists whose common goal is essentially to determine the structure, bonding and dynamic properties of molecules. To continue, we will need to introduce the theory behind the formation of an image from a sample, i.e. how can we obtain local, as opposed to whole or bulk, information

Rapid imaging techniques

Sections 3.0 and A.1 discussed how an image was formed in a magnetic resonance experiment by the simultaneous use of r.f. pulses and magnetic field gradients. It was also stated in Section 2.2.1 that in order to avoid T1 relaxation contrast the magnetisation in any magnetic resonance experiment should be recycled in a time three to five times greater than the longest T1 relaxation constant in the sample to give data that is between 95% and 99.9% T1 contrast free respectively. However, the

Quantitative magnetic resonance imaging in pharmaceutically relevant research

In the last twenty years there have been many NMR and MRI research papers that have focused on studying both non-swelling and swelling matrix type controlled / sustained drug delivery dosage forms. Section 1.0 indicated that several recent reviews (Melia et al., 1998, Nott, 2010, Richardson et al., 2005, Zeitler and Gladden, 2009) essentially cover most of these works to date. The aim of this section is to review the literature that is concerned primarily with quantitative MRI studies of

Summary remarks

The aim of this review (and the supplementary material) was firstly to describe in some detail the theoretical basis behind NMR/MRI signal quantitation and how one must consider the effects of T1 and T2 relaxation and diffusion in order to obtain optimised quantitative results. A second aim was to give some relatively simple guidelines to aid the experimentalist in choosing/identifying suitable MRI protocol(s) for pharmaceutically relevant research. A current review of the literature showed

Acknowledgements

MDM wishes to thank Dr Andrew Sederman for useful discussions during the preparation of this review.

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