Abstract
Nuclear magnetic resonance (NMR) in the form of both spectroscopy and imaging are powerful tools in most areas of scientific research. NMR spectroscopy yields quantitative information such as chemical species concentration and their three-dimensional molecular structure. The addition of pulsed magnetic field gradients to a spectroscopic experiment then provides non-invasive localised information in three spatial dimensions, i.e., a magnetic resonance image. This powerful combination of magnetic resonance imaging with NMR spectroscopy makes it possible to probe local chemical, physical and mass transport phenomena (in the form of diffusion and flow) and is particularly suited to study the dissolution behaviour of solid pharmaceutical dosage forms. This Chapter will focus on the fundamentals of the theory behind quantitative magnetic resonance spectroscopy and imaging, and highlights the importance of understanding the origins of the various magnetic resonance contrast mechanisms that are inherent in the systems discussed. Examples will be drawn from both model and real pharmaceutical solid dosage forms undergoing dissolution testing in a USP-IV dissolution cell under pharmacopeial conditions to illustrate the ideas discussed in the main text.
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Notes
- 1.
In terms of the spin populations shown in Fig. 18.1a, a 90° r.f. pulse equalises the populations of both the |α> and |β> energy states resulting in a non-equilibrium situation, i.e., the spin system has excess energy. Similarly a 180° r.f. inversion pulse would invert the initial equilibrium resulting in an excess population in the higher energy state.
- 2.
The 1D-profiling experiment is a very useful quick imaging experiment to ensure that the sample under investigation is suitably located with respect to its position inside both the r.f. coil and gradient coil set which is normally fixed inside the main magnet. Often researchers will use the 1D-profiling experiment in real time acquisition mode to physically position their sample in the r.f. coil and orientate the sample with respect to the laboratory frame of reference.
- 3.
Slice selection is achieved by applying a “soft” radio frequency pulse at the same time as an applied magnetic field gradient. The magnetic field gradient spreads out the Larmor precession frequencies and because of the narrow frequency bandwidth of the selective excitation pulse, only a limited region or “slice” of the samples Larmor frequencies is excited.
- 4.
Note the two-dimensional FT produces a frequency encoded spin density map in both orthogonal (xy) directions. The axes conversion to real space units is usually performed by the computer software from knowledge of the initial desired field of view (FOV) and digitisation rate.
- 5.
There are specialist pulse sequences such as zero echo time (ZTE, see for example Weiger et al. 2011) and ultra short echo time (UTE, see for example Robson et al. 2003) imaging that are considered quantitative in terms of spin density without correction, but they are not commonly used in non-clinical MR research.
- 6.
The can be avoided by choosing saturation recovery T 1 pre-conditioning over inversion-recovery T 1 preconditioning.
- 7.
In addition to UTE and ZTE imaging there are a number of MR pulse sequences that can begin to image solid matter, such as single point imaging (SPI) techniques, but again their use is not routine. The reader is refereed to (Mantle 2011) for a further discussion regarding SPI.
- 8.
In GE imaging a small tip angle is usually employed as one wants to make the acquisition of the image fast (sub-second) and free from T 1 relaxation artefacts. This is why the FLASH protocol is usually adopted for GE imaging.
- 9.
Often an additional “readout spoiler” gradient is applied after the digitiser has been switched off in order to destroy any spurious magnetisation. Similarly, r.f. spoiling is often also used in GE imaging.
- 10.
It is always very useful when working on any pulse sequence development to turn off all phase encoding gradients, i.e., set their values to zero, to see where and what form the echo signal takes using only the readout gradients. This “trick” is also used to ensure that the receiver gain is set correctly at the point where the center of k-space is acquired.
- 11.
It is a bonus that diffusion preconditioning will also yield velocity information if the data are processed in the correct way. Based on the SDC images obtained by D-RARE, the velocity of the flowing dissolution media can be obtained by tracking phase changes of the diffusion weighted images.
- 12.
For more than one spectral resonance peak, calculate Δν1/2 by subtracting the value of the FWHM of the left most and right most peaks. This will avoid chemical shift artefact (frequency aliasing) if sufficient bandwidth and gradient strength are available (which may not always be the case!).
- 13.
The factor of 2 in the expression below is due to the fact that the acquired readout data is complex, i.e., it has real and imaginary components.
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Acknowledgement
The author wishes to thank Dr Chen Chen (Charlie) for his assistance in preparing the manuscript and for expertly performing the data acquisition and processing of the results from the dissolution experiments on the model HPMC/TDFH dosage form.
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Mantle, M.D. (2016). Magnetic Resonance Imaging and Its Applications to Solid Pharmaceutical Dosage Forms. In: Müllertz, A., Perrie, Y., Rades, T. (eds) Analytical Techniques in the Pharmaceutical Sciences. Advances in Delivery Science and Technology. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-4029-5_18
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