Industrial on-line analysis by nuclear magnetic resonance spectroscopy

[0002] The present invention relates to nuclear magnetic resonance phenomena and in particular to the use thereof in spectroscopic analysis.

[0003] The on-line analysis of chemical composition of samples undergoing continuous translational motion, for example through pipes or on conveyors is important throughout the food, chemical and pharmaceutical industries. To date, a number of spectroscopic and physical methods are used for on-line compositional analysis, including near infra-red spectroscopy (NIR), microwave sensors and ultrasonics.

[0004] However Nuclear Magnetic Resonance (NMR) has not hitherto been exploited in such an on-line mode on continuously moving objects, despite its well established analytical role in the off-line analytical laboratory. A possible exception to this statement is its use in the on-line analysis of slowly flowing liquids and pastes (C. Tellier and F. Mariette, Online applications in Food Science, Annual Reports on NMR spectroscopy, Vol. 31, 1995, 105-122).

[0005] However such applications use conventional NMR methodology and hardware and the fluid velocity is therefore limited by the restricted volume over which the magnetic field and/or radiofrequency field is homogeneous.

[0006] Another previous on-line analytical application is in the analysis of powders by NMR (C. I. Nicholls and A. De Los Santos, Hydrogen transient NMR for industrial moisture sensing, Drying Technology, vol 9, 1991, 849-873). But this is based on removing a sample of powder (e.g. with a piston arrangement) for analysis while it is stationary, using conventional NMR methods. There are several reasons for the failure to exploit NMR in a general way for on-line analysis of continuously moving samples.

[0007] First, most information is obtained in an NMR spectrum when the spectral peaks arising from different molecular species are well resolved. The spectrum is then easier to interpret and the spectral peak areas, which are related to the number of spins contributing to the peak, can be obtained from each resolved peak by simple integration. This has meant that, in off-line analytical laboratories, it is preferable to work with high (i.e. strong) magnetic fields, since the peak separation increases with increasing field strength. Unfortunately, creating high, spatially uniform magnetic fields (eg. above proton resonance frequencies of 100 MHz) requires the use of superconducting magnets. These magnets are very expensive and require regular filling with liquid nitrogen and liquid helium and are not therefore suitable for routine exploitation and use on the factory floor. If lower magnetic fields are used, such as those available with low-cost, robust, permanent magnets (with proton resonance frequencies less than approximately 20 MHz), the spectral peaks from different molecular species are not usually resolved in the NMR spectrum, making compositional analysis of the spectrum more complicated. This is probably one reason why low field NMR spectra have not yet been exploited for compositional analysis.

[0008] Another reason for the slow exploitation of conventional NMR in an on-line mode is the requirement of field homogeneity, both in the main magnetic field, B₀and in the radiofrequency field, B₁. Conventional hardware for generating spatially uniform radiofrequency fields based, for example, on Helmholtz coils, saddle coils and birdcage coils creates uniform radiofrequency radiation only over a limited volume. The NMR spectrum of the moving sample must therefore be acquired while the sample resides inside this limited volume. This severely limits the sample velocity and means that most NMR analysis is performed either in a side-line mode where the sample velocity is slowed, or in an off-line mode on stationary samples.

[0009] It is an object of the present invention to provide a method of obtaining magnetic resonance spectroscopic data and deriving chemical composition data therefrom.

[0010] It is a further object of the present invention to provide an apparatus which can maintain homogeneous B₀and B₁(RF) fields over a sufficient length of travel of an object undergoing translational motion to enable the collection of spectroscopic nuclear magnetic resonance data for determining chemical composition of the object.

[0011] According to one aspect, the present invention provides a method of nuclear magnetic resonance spectroscopy comprising the steps of:

[0012] conveying an object to be analysed through an NMR module at a predetermined velocity, v;

[0013] generating, within the NMR module, a spatially characterised, constant magnetic field B₀substantially parallel to the direction of the velocity, v;

[0014] generating, within the NMR module, a radiofrequency field B₁pulse transverse to field B₀;

[0015] detecting nuclear magnetic resonance signals weighted with at least one selected nuclear magnetic resonance parameter from said object;

[0016] generating a chemical shift resolved spectrum of the conveyed object within the NMR module.

[0017] According to a further aspect, the present invention provides apparatus for gathering spectroscopic nuclear magnetic resonance data comprising:

[0018] a first field generating means for generating a spatially characterised, constant magnetic field B₀in an NMR module volume having a predetermined length along a longitudinal axis thereof, the B₀field being parallel to said longitudinal axis;

[0019] a second field generating means for generating, within the NMR module volume, radiofrequency field B₁pulses transverse to field B₀;

[0020] receiver means for detecting nuclear magnetic resonance signals weighted with at least one selected nuclear magnetic resonance parameter from said object;

[0021] means for generating a chemical shift resolved spectrum of the conveyed object within the NMR module;

[0022] wherein at least said second field generating means comprises a coil having cylindrical geometry.

[0023] Embodiments of the present invention will now be described, by way of example, and with reference to the accompanying drawings in which:

[0024] FIG. 1 shows a schematic diagram showing principles of a nuclear magnetic resonance apparatus or module according to the present invention;

[0025] FIG. 2 shows a schematic diagram of an exemplary RF field generating unit suitable for use in the present invention;

[0026] FIG. 3 shows a schematic diagram of an exemplary G_xfield generating unit suitable for use in the present invention;

[0027] FIG. 4 shows examples of poorly resolved proton spectra for determining chemical composition in accordance with principles of the present invention;

[0028] FIG. 5 shows an arrangement for weighting motional echoes with T₁(low field) relaxation according to the present invention;

[0029] FIG. 6 shows a simulation of the magnetic field direction and strength as a function of x and z spatial co-ordinates for a G_xunit;

[0030] FIG. 7 shows a simulation of the magnetic field strength B_zalong the axis of a current loop as a function of z, at x=0, for the G_xunit of FIG. 6;

[0031] FIG. 8 shows a stimulation of the magnetic field strength B_zin the plane of a current loop as a function of x, at z=0, for the G_xunit of FIG. 6;

[0032] FIG. 9 shows a simulation of the square root of magnetic field strength B_z−1 in the plane of a current loop as a function of x, at z=0, for the G_xunit of FIG. 6.

[0033] A design of radiofrequency coil which permits the creation of uniform radiofrequency fields over extended volumes permits NMR to be carried out over much larger spatial volumes, and in particular over an extended length of a pathway of an object undergoing translational motion. This enables it to be used for on-line NMR compositional analysis.

[0034] This specification describes the development of a low-cost, robust, and fast, on-line nuclear magnetic resonance (NMR) spectrometer (and associated protocols) suitable for acquiring low-field, poorly resolved NMR spectra of solid (ie. non-fluid) samples undergoing continuous translational motion, although the apparatus can also be used for the analysis of semi-solid, fluid or powder samples similarly undergoing continuous translational motion. It also shows that, like NIR, a well-resolved NMR spectrum is not an essential requirement for compositional analysis so that low cost, robust, low-field permanent magnets (or electromagnets) can be used. Moreover, it exploits a new modified RF coil, together with a cylindrical-shaped low cost magnet, to extend the volume over which the field is spatially uniform thereby eliminating a major restriction on sample velocity.

[0035] Let us assume an object to be analysed is travelling with an instantaneous velocity, v(t), which need not be constant. Then, in the minimum time it takes to acquire an NMR signal, AQ (acquisition time), it travels a distance of at least L_mingiven by the integral,

[0036] L_min=∫₀^AQdt v(t)

[0037] This means that, for conventional NMR to be successful, the magnetic field, B₀and the radiofrequency field, B₁, are preferably both spatially homogeneous over a distance of at least L_min. This severely limits the range of velocities and acquisition times that can be used with conventional NMR protocols. The unique geometric feature of the apparatus of the present invention as described below, for generating the B₀, and radiofrequency field, B₁, is that they are both cylinders whose length can be extended indefinitely, at least in principle. They can therefore create spatially homogeneous B₀and B₁fields over any desired length, thereby removing the limitations of previous approaches.

[0038] We assume that the objects to be analysed are travelling down a conveyor tube, pneumatic tube, belt or other suitable means, schematically shown in FIG. 1 as conveyor 1. The conveyor 1 and all the objects 2 on it preferably move with a constant velocity v.

[0039] The hardware required to obtain an NMR spectrum consists of separate cylindrically-shaped units which enclose the conveyor 1 and which can be positioned at various positions along the conveyor. The conveyor carrying the objects then travels down the central axis of the cylindrical units. The modular nature of the hardware ensures greater adaptability to a plurality of applications.

[0040] Because the objects to be analysed are travelling with velocity v and it takes a finite time of AQ to acquire the NMR signal(s), it is necessary that the B₀field and radiofrequency field B₁are spatially homogeneous over a distance of at least v×AQ, along the conveyor. According to the preferred embodiment illustrated, the hardware devices as described below for generating the B₀field and radiofrequency field B₁are all cylindrically shaped with lengths that can be extended indefinitely, at least in principle. This distinguishes them from conventional NMR arrangements, such as U-shaped magnets, radiofrequency Helmholtz coils, birdcage coils etc. which would create homogeneous fields only over a limited distance along the conveyor.

[0041] The Polarizer Unit

[0042] This is illustrated in FIG. 1. We consider an object 2 moving with velocity, v(t). The first step in obtaining an image of the object is to induce longitudinal magnetization within it by application of a constant external magnetic field. This is done in a unit we have called the polarizer 3. If the object has a short T₁, then the polarizer 3 consists either of a single, straight, hollow, cylindrical permanent magnet 3aof length L, or a solenoid coil electromagnet 3aof length L. The object moves on a conveyor 1 down the central axis inside the cylindrical polarizer. The time spent inside the polarizer is L/v and for 100% polarization this should be at least 5T₁. However, 100% polarization is not an essential requirement of the on-line analyser and lower degrees of polarization can be considered. If T₁is long (several seconds), L may be impracticably large, in which case a series of solenoids or permanent magnets can be arranged in, for example, a spiral arrangement and the conveyor passed along the spiral.

[0043] Once the object is sufficiently polarized it passes with velocity v into the detector module which creates and detects an NMR signal from the moving object.

[0044] The Detector Module

[0045] Depending on the application, the detector module 4 consists of two different hardware units. These are called the B₀unit and the RF unit.

[0046] The B₀Unit

[0047] This is illustrated in FIG. 1. The polarized object 2 emerging from the polarizer 3 on the conveyor 1 passes into a spatially uniform, constant magnetic field, B₀within the detector module 4. Like the polarizer unit 3, the B₀field of the detector module 4 can be created by a hollow cylindrical permanent magnet or by a hollow cylindrical solenoid electromagnet, called, for convenience, the B₀unit.

[0048] The conveyor carrying the polarized sample then moves down the middle of the cylinder in a direction parallel to the cylinder axis, and preferably, along the cylinder axis. The direction of the polarized longitudinal magnetization in the sample leaving the polarizer should be in the same direction as B₀in the B₀unit The magnet can be of any desired length provided the B₀field everywhere in the object is spatially uniform. If the object T₁is sufficiently short, then the polarizer and B₀units can be combined into a single continuous unit. This is important for fluid objects to ensure that the magnetization is parallel to B₀.

[0049] The RF Unit

[0050] This is illustrated in FIG. 2. The on-resonance, radiofrequency field, B₁, which must be transverse to B₀, can be generated by a specially designed, cylindrical radiofrequency solenoid-like coil which we call the “RF unit”. Preferably, this also acts as a receiver coil and is fully described in the reference, “A solenoid-like coil producing transverse radiofrequency fields for MR imaging” by E. K. Jeong, D. H. Kim, M. J. Kim, S. H. Lee, J. S. Suh and Y. K. Kwong in J. Magn. Reson.127 (1997) 73-79, Article no. MN971172.

[0051] The RF unit 20 as described therein includes a pair of cylindrical coils: a first, outer coil 21 which has the plane of each loop 22 tilted with respect to the cylinder (z) axis to generate an RF field with a component perpendicular to the cylinder axis. A second, inner coil 23 acts as an eddy current coil which eliminates the longitudinal component of the RF field, leaving an RF field entirely perpendicular to the cylinder axis.

[0052] A special characteristic of this device is the generation of a uniform radiofrequency field over a long z distance. This distinguishes it from more conventional RF generators such as the standard saddle coil, birdcage or cavity resonator. Such conventional devices could be used for the purposes of the present invention, provided they are of sufficient size that their RF field is uniform over distances exceeding L_min. The solenoid-like RF unit coil 20aovercomes this limitation and can be easily situated inside and concentric with the B₀unit solenoid coil or permanent magnet. The RF unit 20 is interfaced with conventional electronic equipment and computers for control, acquisition and data processing.

[0053] The G_xUnit

[0054] This is illustrated schematically in FIG. 3. Where diffusion-weighted on-line spectroscopy is required, an optional third type of hardware unit comprising a single electric field coil 40 can be used which surrounds the B₀unit 41. The G_xunit creates a steady, spatially localized, non-uniform magnetic gradient G_xtransverse to B₀. The coil is wound around the gradient of RF solenoid unit at a single location. The magnetic fields generated by the coil 40 are simulated in FIGS. 6 to 9.

[0055] Triggering an NMR Pulse Sequence

[0056] With further reference to FIG. 1, this can be done electronically by arranging for the object to be analysed to cut a laser or infra-red beam traversing the conveyor 1 as the object 2 enters the detector unit 4. This is provided by suitable conventional light source 5 and a receiver unit 6 coupled to a control circuit 7. An electronic delay can then trigger an appropriate pulse sequence as required by the analysis method being used. If two laser beams are used spaced along the conveyor, the velocity v of the object can also be measured and this used to calculate the timing of radiofrequency pulses automatically.

[0057] On-Line Analysis Protocols

[0058] A) The Frequency Domain: On-line NMR Spectroscopy

[0059] The simple combination of the polarizer, B₀and RF units permits either a free induction decay (FID), spin echo or stimulated echo to be acquired “on-the-fly” from a moving sample. A simple Fourier transform of the FID, spin echo or stimulated echo will therefore create a chemical shift resolved spectrum of the moving sample. At low B₀field strengths and/or with samples having short transverse relaxation times, the spectral resolution may not be sufficient to resolve all the spectral peaks from different chemical constituents in the sample. In this case there are several protocols that can be used to analyse the chemical composition of the moving sample:

[0060] 1) Calibration Methods

[0061] The dependence of the spectral intensity at several frequencies on chemical composition can be used, with multivariate analysis, to determine the composition of the moving object. An analogous procedure is already used commercially in on-line NIR (Near Infra-Red) sensors. Appendix 2 outlines an example methodology.

[0062] An example of a poorly resolved proton spectrum is shown in FIG. 4. The spectra correspond to three different mousse samples of varying fat and starch content. Separate peaks of fat, water and starch protons are not resolvable, but appear as shoulders in the spectrum. By multivariate analysis of the intensities at three (or more) spectral frequencies (preferably corresponding to the peak maximum of each component) it is possible to create a calibration curve allowing the composition to be deduced from the spectrum.

[0063] 2) Spectral Weighting Methods

[0064] The different chemical constituents in the object can often be distinguished not only by differences in their chemical shifts but also by differences in other intrinsic NMR properties. These NMR properties include, for example the relaxation times T₂*, T₂, T₁, T_iρ, magnetization transfer rates or the self-diffusion coefficient, D. The following protocols describe how FID's and/or spin echoes or stimulated echoes can be used to create spectra weighted by each of these parameters. The calibration method described above can then be used with the parameter-weighted spectra.

[0065] T₂Weighted Spin Echo Spectroscopy

[0066] T₂weighted spectroscopy can be undertaken using spin echoes created by hard 180° pulses with a standard Hahn-echo or CPMG (Carr Purcell Meiboom Gill) pulse sequence applied to the moving object. T₂weighted spectroscopy is important because different chemical constituents in a food often have difference intrinsic transverse relaxation times. Acquiring spectra with different T₂weighting therefore permits different constituents to be distinguished.

[0067] T₂* Weighting in a Spectrum

[0068] In some samples, the signal is attenuated at a faster rate than that caused by simple transverse relaxation (T₂). This is caused by local field inhomogeneities and gives rise to relaxation with a time constant, T₂*. An FID created by a single 90° pulse is weighted by the relaxation time T₂*, so that the spectrum obtained by processing the FID will be weighted by T₂*.

[0069] T₁Weighting in the Spectrum

[0070] There are several possible ways of introducing T₁weighting into the spectra. The simplest is to use the inversion recovery sequence whereby the polarized magnetization, M(0) is inverted by a hard 180° pulse and allowed to recover for a fixed time, t₁, adjusted for each application. After the time delay t₁, an FID is created by a hard 90° pulse in the RF unit. An alternative pulse sequence which has the advantage of permitting two spectra to be obtained and compared, one with T₁weighting and the other without, involves the stimulated echo pulse sequence.

[0071] T₁(low field) Weighting in the Spectrum

[0072] Between the polarizer unit 3 and the detector module 4, the objects 2 being analysed contain longitudinal magnetization relaxing in the earth's magnetic field. By varying the length of time spent between the polarizer 3 and detector module 4, various amounts of T₁(low field) relaxation can be introduced. A suitable arrangement is shown in FIG. 5. As shown, the degree of residual magnetization at time t is given by the expression M_z(t)=M(0) exp[−t/T₁(ω=0)], where M(0) is the initial magnetization induced by the polarizer unit 3. The time t between the object leaving the polarizer unit 3 and arriving at the detector module 4 is, of course, determined by the length L=vT.

[0073] Diffusion Weighting in the Spectrum

[0074] Diffusion weighting can be created, explicifly, using two or more G_xunits. Each G_xunit creates a constant, localized, non-uniform gradient, G_xacross the solenoid axis and transverse to the B₀field. Motion of the object through these static G_xgradients is equivalent to imposing time-varying (pulsed) field gradients. The standard pulsed gradient spin echo or stimulated echo pulse sequences can then be used to weight the spectrum, which is obtained by Fourier transforming the spin echo or stimulated echo.

[0075] 3) On-line Compositional Analysis in a Moving Object by Difference Spectroscopy Using Spin and/or Stimulated Echoes

[0076] In some applications the acquisition of a single, parameter-weighted spectrum is insufficient to determine the chemical composition. In such eases it may be necessary to take the difference between a spectrum (called the first spectrum) acquired with an attenuation weighting which is insensitive to the presence of a particular component and a second spectrum weighted with a parameter (such as T₂*, T₂, T₁, or D) which is more sensitive to the presence of the chemical component. Taking suitably processed differences between the first and second spectra can then be used to determine the amount of the component in the food.

[0077] The first spectrum can be calculated from the FID generated by the first 90° pulse in the pulse sequences listed above. The second spectrum can be calculated from one (or more) of the spin echoes or stimulated echoes generated subsequently.

[0078] The difference protocol may, if necessary, be combined with spectrum registration software and/or signal processing software, such as Wiener filtering. All such operations can be performed in the least possible time using a fast computer, such as a 233 MHz PC.

[0079] B) The Time Domain

[0080] In some applications, it is not necessary to Fourier transform the time domain signal. For example, conventional solid/liquid ratios can be determined from the free induction decay in the time domain. Similarly, an on-line determination of emulsion droplet size distribution from the diffusion weighted stimulated echo is also possible. These protocols are standard techniques in off-line NMR analysis, but it has been recognized that these can also be applied in the on-line mode with the hardware described previously.

[0081] The present invention has thus far been described with reference to specific embodiments. It will be understood, however, that a number of modifications can be made thereto. For example, although the preferred embodiment requires that an object is undergoing continuous, uniform translational motion, in fact the object can be undergoing any non-zero velocity or finite acceleration.

[0082] This has particular significance where objects to be analysed are falling off the end of a conveyor belt, for example. In that situation, the motion of an object can be precisely characterised where it is undergoing continuous acceleration. Arrival of the object into the NMR system and/or determination of its translational motion can be determined by optical beams, as discussed earlier.

[0083] A number of examples of commercial applications of the on-line NMR spectrometer described above are now given. This list is purely illustrative and far from exhaustive.

[0084] Analysis of fat/water ratios. At a proton resonance frequency of 20 MHz, a chemical shift of 3 ppm (corresponding, approximately, to the chemical shift difference between lipid CH protons and water) is equivalent to 60 Hz, so provided the B₀field is sufficiently homogeneous to give linewidths of less than 60 Hz, separate fat and water peaks are normally resolvable. Even if they are not resolvable, either the fat or water signals can often be eliminated by the T₁-null method using the inversion recovery sequence or by use of T₂weighting created with a Hahn echo and a pulse spacing chosen to reduce or eliminate one or other of the chemical components. The signal intensity can then be used as an on-line monitor of the fat/water ratio.

[0085] On-line monitoring of protein/polysaccharide/water/sugar/lipid composition of food materials.

[0086] On-line detection of the degree of ripeness of fruit, especially if ripening is associated with changes of chemical composition, such as increased sugar content (sweetness) and reduced starch content (softening of the texture).

[0087] On-line monitoring of the particle sizes in powders. Different particle sizes are associated with different susceptibility gradients and hence different T₂* values. This causes differing spectral broadening.

[0088] On-line monitoring of the composition of flowing chemical mixtures in the chemical and pharmaceutical industries.

[0089] On-line measurements of solid/liquid ratios from the free induction decay.

[0090] On-line measurements of droplet size distributions in emulsions.

[0091] A MATLAB program has been written to calculate the magnetic field due to a circular current loop or coil centred at the origin in the xy-plane. This comprises “the G_xunit”. The results are shown in FIGS. 6 to 9. Note the non-linear G_xand G_zgradients created by this unit.

[0092] Example Methodology for Compositional Analysis Using a Poorly Resolved On-line NMR Spectrum

[0093] Here we show how it is, in principle, possible to analyze a mixture of chemical species using a poorly resolved on-line, low-field NMR spectrum such as that illustrated in FIG. 4.

[0094] 1. Consider a mixture of N chemical species, each species being labelled by the subscript, i, such that i=1, 2 . . . N.

[0095] 2. We assume that each chemical species is characterized by an NMR spectrum, I_i(ω), where ω is the NMR observation frequency. I_i(ω) can be measured for each pure chemical species in the on-line NMR spectrometer described in this patent. I_i(ω) would typically be a Lorentzian or Gaussian spectral lineshape, but this is not a necessary assumption.

[0096] 3. We further assume, for illustrative simplicity, that the functional form of I_i(ω) does not depend on the presence of other species, j, not the same as i. In other words, we assume simple additivity of component spectra in the mixture.

[0097] 4. The overall NMR spectrum, S(ω), observed for a mixture of N species is then the simple sum of the component spectra:

[0098] S(ω)=Σ_ix_iI_i(ω) i=1,2 . . . N.εΣ_ix_i=1.

[0099] To analyze the mixture composition, X₁, X₂, . . . X_N, we need only measure S(ω) at N different frequencies, ω_jfor j=1,2 . . . N. Then

[0100] S(ω_j)=Σ_ix_iI_i(ω_j)

[0101] This can be written in matrix form:

[0102] S=I.xwhere I_ijis the matrix element, I_j(ω_j)

[0103] The mixture composition is then obtained by simple matrix solution:

[0104] x=Γ¹.S

[0105] This shows that in order to analyze the mixture composition from a poorly resolved NMR spectrum it is only necessary to measure the intrinsic coefficients I_ij. This can be done by measuring the spectrum, I_i(ω), for a known amount of each pure species, i, under identical NMR spectrometer conditions.

[0106] The assumption of simple additivity can be removed at the expense of increased complexity, and requires additional calibration of interacting mixtures. A typical analytical method where there is non-additivity would be that of Principle Component Analysis as described, for example, in the book, “Factor Analysis in Chemistry”, 2^ndEdition, John Wiley and Sons, by E. R. Malinowski.