WO2007144206A2

WO2007144206A2 - Method of determining the mass of a plurality of samples by means of nmr

Info

Publication number: WO2007144206A2
Application number: PCT/EP2007/005436
Authority: WO
Inventors: Josef Antonius Willem Maria Corver; Klaus-Dieter Schmalbein; Diether C. Maier; Andreas Kamlowski; Franciscus Antonius Damen
Original assignee: The Boc Group Plc; Bruker Biospin Gmbh
Priority date: 2006-06-14
Filing date: 2007-06-14
Publication date: 2007-12-21
Also published as: GB0611745D0; WO2007144206A3

Abstract

A method is described for determining a characteristic, such as the mass, of each of a plurality of samples. The method comprises the steps of providing a plurality of coil elements each for surrounding a respective sample, causing the samples to enter an interrogation zone, each sample being surrounded by a respective coil element when it is located within the interrogation zone, applying a magnetic field in a first direction in the interrogation zone for creating in a pre-polarised state a net nuclear magnetisation of a nuclear spin species within a sample located in the interrogation zone, applying, by each coil element surrounding a respective sample located in the interrogation zone, an RF field in a second direction for temporarily changing the net nuclear magnetisation of the nuclear spin species in the sample, detecting RF energy emitted from that sample as the net nuclear magnetisation of the nuclear spin species in the sample relaxes, and, from the detected RF energy, determining the characteristic of each sample located in the interrogation zone.

Description

METHOD OF DETERMINING THE MASS OF A PLURALITY OF SAMPLES

The present invention relates to a method of determining the mass or other characteristic of a plurality of samples, and finds use in the determination of the mass of samples conveyed on a conveyor system, for example, between functions of a production line. The invention may also be used to analyse the contents of containers from stock that has already been sealed.

In-line filling machines for dispensing products, such as liquid and/or powder drug samples, into containers or vials typically include a conveyor system for conveying the containers between functions. A filling station receives empty vials from the conveyor system, sequentially fills the vials with an accurate amount of one or more products and closes the thus-filled vials with closure members, for example, stoppers. The conveyor system then conveys the closed vials to an inspection station which checks that the vials have been correctly filled. A reject station is provided downstream from the inspection station for removing incorrectly filled vials from the production line. A sealing station may also be provided downstream or upstream from the reject station for sealing the vials.

It is known to utilise an inspection station that checks the mass of vials on a production line using Nuclear Magnetic Resonance (NMR) techniques. Usually, the magnetic resonance characteristics of the nuclei of hydrogen atoms (protons) form the basis of these NMR measurements. In special cases, other nuclei may also be used. In the following, we will limit the discussion to protons. The inspection station includes a magnet for creating a static magnetic field over an interrogation zone to produce a net polarisation of the magnetic moments associated with the proton nuclear spins within a sample contained within a vial located in the interrogation zone, and an RF probe for applying an RF field over the interrogation zone with a field component orthogonal to the static magnetic field. An RF field applied in resonance causes the net proton nuclear magnetisation of the sample contained within the vial to rotate about the axis of the RF field, away from the direction of the static magnetic field into the plane perpendicular to the direction of the static magnetic field. "In resonance" means that the RF frequency corresponds to the Larmor precession frequency of the proton nuclear magnetic moments in the applied magnetic field. Further, the RF field is applied only temporarily, i.e., as a pulse which is switched on and off to precisely turn the proton nuclear magnetisation, for example, by 90°.

After the RF pulse has been applied, the proton nuclear magnetisation is in a non-equilibrium state, thus it will eventually relax with characteristic time- constants back to thermal equilibrium, i.e., so that the proton nuclear magnetisation is parallel to the static magnetic field axis. Due to this process electromagnetic energy is emitted by the protons at their Larmor frequency. The magnetic component of the electromagnetic RF field emitted from the sample induces a RF voltage in the RF probe, known as the free induction decay (FID). The initial amplitude of the resulting RF voltage is proportional to the number of hydrogen nuclei in the sample. The amplitude of the voltage is then compared to that produced by a calibration sample with known mass to determine the mass of the sample under analysis.

Alternative NMR techniques also exist for determining the characteristics of samples other than just mass (or weight). For example, by supplying a train of pulses and monitoring the responses, usually referred to as "echoes", from the sample, it is possible to obtain further information concerning for example the amount of ferrous particles within, or other contamination like moisture, of the sample.

In such known inspection stations, the RF probe extends over and about the interrogation zone, so that the samples under analysis pass beneath the probe. For the detection of the mass of samples contained in elongate containers such as syringes, this would result in a relatively tall and bulky probe for the mass of the samples under analysis. Due to disproportionate size of the probe in relation to the sample, this would result in a relatively small signal to noise ratio in the energy detected by the probe. Furthermore, the presence of metal needles would unduly influence the signal.

In a first aspect, the present invention provides a method of determining a characteristic, such as the mass, of each of a plurality of samples, the method comprising the steps of: providing a plurality of coil elements each for surrounding a respective sample; causing the samples to enter an interrogation zone, each sample being surrounded by a respective coil element when it is located within the interrogation zone; applying a magnetic field in a first direction in the interrogation zone for creating in a pre-polarised state a net nuclear magnetisation of a nuclear spin species within a sample located in the interrogation zone; applying, by each coil element surrounding a respective sample located in the interrogation zone, an RF field in a second direction for temporarily changing the net nuclear magnetisation of the nuclear spin species in the sample; detecting RF energy emitted from that sample as the net nuclear magnetisation of the nuclear spin species in the sample relaxes; and from the detected RF energy, determining the characteristic of each sample located in the interrogation zone.

By providing a coil element for each sample which extends about the sample when it is located within the interrogation zone, the RF energy emitted from the sample can have an acceptable signal to noise ratio, as the size of the coil element can be proportionate to the size of the sample under analysis. For instance, the coil elements can be sized such that they have an internal diameter which is only slightly larger than the external diameter of the samples. This leads to a large filling factor. Furthermore, the individual coil - A -

elements may be inductively decoupled from each other, leading to minimal cross-over of the signals.

In one embodiment, the RF energy emitted from a sample may induce an RF voltage in the coil element surrounding that sample, with the characteristic of the sample being determined directly from the RF voltage induced in the coil element. The coil element thus forms part of a receiving and transmitting device for both applying the RF field to the samples, and detecting the RF energy subsequently emitted from the samples. In this embodiment, each coil element forms part of a resonance circuit tuned to the Larmor frequency of a particular nuclear spin species contained in the samples. The resonance circuits of the coil elements may be permanently connected to a detecting and digitising system or other device for determining the characteristic of the samples. As an alternative to permanently connecting the resonance circuits of the coil elements to a detection and digitising system with leads or other connectors, the signal may also be transferred by other means. Examples include inductive or capacitive coupling, or mercury contacts. In this case, there is no requirement to provide leads or other connectors between the coil elements and the device for determining the characteristic of the samples.

Alternatively, the RF energy may cause an RF voltage to be induced in an RF coil separate from the coil elements, with this RF coil instead forming part of the aforementioned resonance circuit tuned to the Larmor frequency of a particular nuclear spin species contained in the samples. This RF coil may be located beneath or above the interrogation zone. This RF coil may thus form part of the receiving and transmitting device instead of the coil elements, in that a pulse of alternating current is applied to the RF coil to induce a similar alternating current in the coil element surrounding a sample. The energy subsequently emitted from the sample induces an RF voltage in the coil element surrounding that sample, which RF voltage in turn induces a voltage in the RF coil, with the characteristic of the sample being determined from the voltage induced in the RF coil. Other alternatives are possible. For example, the RF coil, in conjunction with an electronic resonant circuit, may be a transmitting device only, with the characteristic of the sample being determined directly from the RF voltage induced in the coil element surrounding the sample, which serves as a receiving device for the energy emitted from the sample.

The plurality of samples may be either sequentially or simultaneously located inside within the interrogation zone.

The coil elements may be stationary within the interrogation zone, with the plurality of samples being inserted into, and subsequently removed from, the coil elements. However, in the preferred embodiments the samples are moved at a controlled velocity through the interrogation zone, each sample having a respective coil element located thereabout and moving therewith as it moves through the interrogation zone.

In one embodiment, the coil elements are located within a sample holder comprising a plurality of apertures, each aperture having a respective coil element extending thereabout and a respective sample inserted therein, and wherein the sample holder is moved through the interrogation zone at a controlled velocity. Such a sample holder can provide a convenient mechanism for locating the coil elements relative to the samples, and for providing coil elements having a size that closely matches the size of the samples. The sample holder can be relatively cheap to manufacture, and may be either re-usable or disposable. This embodiment can be used for inspection of samples of stock prior to release.

In view of this, in a second aspect the present invention provides a method of determining a characteristic, such as the mass, of each of a plurality of samples, the method comprising the steps of: providing a sample holder comprising a plurality of apertures, each aperture having a respective coil element extending thereabout; inserting each sample within a respective aperture; causing the sample holder to move at a controlled velocity through an interrogation zone; applying a magnetic field in a first direction in the interrogation zone for creating in a pre-polarised state a net nuclear magnetisation of a nuclear spin species within a sample located in the interrogation zone; applying, by each coil element surrounding a respective sample located in the interrogation zone, an RF field in a second direction in the interrogation zone for temporarily changing the net nuclear magnetisation of the nuclear spin species in the sample; detecting the RF energy emitted from that sample as the net nuclear magnetisation of the nuclear spin species in the sample relaxes; and from the detected RF energy, determining the characteristic of each sample located in the interrogation zone.

The coil elements are preferably arranged in a row extending in said first direction as the sample holder moves through the interrogation zone. An RF field is preferably applied to each of the coil elements located in a row of coil elements by a respective RF coil and electronic resonance circuit, that is, RF fields are applied using a row of excitation coils and electronic resonance circuits extending in said first direction. This can enable a plurality of samples to be simultaneously analysed. Alternatively, or additionally, RF fields may be applied to specific samples at will using selected RF coils.

The sample holder may comprise a plurality of rows of coil elements, with an RF field being simultaneously applied to samples located in a row of coil elements as that row moves through the interrogation zone.

The first magnetic field may be generated by a magnet system comprising a permanent magnet, electromagnets, current carrying coils or superconducting magnets. The first magnetic field may include a gradient field. For example, a separate pair of coils may be located on either side of the interrogation zone, and which operate to provide a magnetic field gradient across the interrogation zone. As a result of this gradient, the static magnetic field experienced by each of the samples contained within a row of coil elements will be different, and therefore the respective Larmor frequency of each of the samples will be different. Consequently, each sample can be interrogated separately and simultaneously by applying to the sample a different narrow band RF pulse at the appropriate frequency. Alternatively, a broad-band RF excitation pulse may excite all nuclear spins in one row simultaneously followed by individual detection of the different FIDs at each different Larmor frequency of the samples.

In another embodiment, relative movement is effected between the coil elements and the samples to locate the coil elements about the samples. In one preferred example, the coil elements are movable relative to the moving samples. Each coil element is moved towards its respective sample as it approaches the interrogation zone so that the coil element extends about the sample as it passes through the interrogation zone. The coil element can then be moved away from the sample following the energy emission from the sample as the net nuclear magnetisation of the nuclear species of the sample relaxes, and re-positioned for location about another sample as it approaches the interrogation zone. A large number of samples can therefore be analysed using only a small number of moveable coil elements.

In view of this, in a third aspect the present invention provides a method of determining a characteristic, such as the mass, of each of a plurality of samples, the method comprising the steps of: causing the samples to move at a controlled velocity through an interrogation zone; effecting relative movement between a plurality of coil elements and the moving samples so that each coil element extends about a respective sample and moves at said velocity as that sample moves through the interrogation zone, wherein each coil element is part of a resonance circuit tuned to the Larmor frequency of a particular nuclear spin species contained in the samples; applying a magnetic field in a first direction in the interrogation zone for creating in a pre-polarised state a net nuclear magnetisation of said nuclear spin species within a sample located in the interrogation zone; applying an RF field in a second direction in the interrogation zone for temporarily changing the net nuclear magnetisation of said nuclear spin species in the sample located in the interrogation zone; detecting by each coil element surrounding a respective sample located in the interrogation zone the RF energy emitted from that sample as the net nuclear magnetisation of said nuclear spin species in the sample relaxes; and from the detected RF energy, determining the characteristic of each sample located in the interrogation zone.

The coil elements are preferably mounted on a moveable carriage, with the carriage being moved relative to the moving samples to cause the coil elements to surround the samples as they move through the interrogation zone. The coil elements may be excited sequentially as they are moved through the interrogation zone. This solution is applicable only when the magnetic field in the first direction is sufficiently homogeneous, because the effective interrogation zone will be different for each syringe. In case the magnet field is not sufficiently homogeneous, a constant interrogation zone can be effectuated by applying a rotating wheel with coil elements at the end of each spoke.

The RF field may be applied a plurality of times to each sample as it moves through the interrogation zone. By subsequently monitoring the RF energy emitted from the sample as it returns to its original state, a characteristic of the sample other than mass, such as the level of contamination of the sample, may be determined. Each sample may be pre-polarised before entering the interrogation zone. The process of aligning the nuclear spins to the stationary magnetic field can be characterised by a time constant, namely the spin-lattice relaxation time, T-i. This is the time needed for the alignment to reach 63% of the full saturation. The longer the time the sample spends in the stationary field, the better the alignment (pre-polarisation). The higher the polarisation, the higher the signal strength of the response to the RF field. Therefore, the application of an additional stationary magnetic field prior to the interrogation zone can improve the quality of the measurement of the characteristic of the sample.

The methods described above are particularly suitable for determining the mass of samples located within elongate containers, such as syringes or ampoules.

In a fourth aspect the present invention provides apparatus for determining a characteristic, such as the mass, of each of a plurality of samples, the apparatus comprising: means for moving the samples into an interrogation zone; means for applying a magnetic field in a first direction in the interrogation zone for creating in a pre-polarised state a net nuclear magnetisation of a nuclear spin species within a sample located in the interrogation zone; means for applying an RF field in a second direction in the interrogation zone for temporarily changing the net nuclear magnetisation of the nuclear spin species within a sample located in the interrogation zone; means for detecting RF energy emitted from that sample as the net nuclear magnetisation of the nuclear spin species within the sample relaxes; and means for determining from the detected RF energy the characteristic of each sample; wherein the RF field applying means comprises a plurality of coil elements each for surrounding a respective sample located within the interrogation zone.

In a fifth aspect, the present invention provides apparatus for determining a characteristic, such as the mass, of each of a plurality of samples, the apparatus comprising: a sample holder comprising a plurality of apertures each for receiving a respective sample; means for moving the sample holder at a controlled velocity through an interrogation zone; means for applying a magnetic field in a first direction in the interrogation zone for creating in a pre-polarised state a net nuclear magnetisation of nuclear spin species within samples located in the interrogation zone as the holder moves through the interrogation zone; means for applying an RF field in a second direction in the interrogation zone for temporarily changing the net nuclear magnetisation of the nuclear spin species within a sample located in the interrogation zone, means for detecting RF energy emitted from a sample located in the aperture as the net nuclear magnetisation of the nuclear spin species within the sample relaxes; and means for determining from the detected RF energy the characteristic of each sample; wherein the RF field applying means comprises a plurality of coil elements located in the holder and each surrounding a respective aperture.

In a sixth aspect, the present invention provides apparatus for determining a characteristic, such as the mass, of each of a plurality of samples, the apparatus comprising: means for moving the samples at a controlled velocity through an interrogation zone; means for applying a magnetic field in a first direction in the interrogation zone for creating in a pre-polarised state a net nuclear magnetisation of the nuclear spin species within a sample as it moves through the interrogation zone; a plurality of coil elements each for applying an RF field in a second direction in the interrogation zone for temporarily changing the net nuclear magnetisation of the nuclear spin species of a sample located in the interrogation zone, and for detecting RF energy emitted from that sample as the net nuclear magnetisation of the nuclear spin species of that sample relaxes, each coil element being part of a resonance circuit tuned to the Larmor frequency of a particular nuclear spin species contained in the samples; means for effecting relative movement between the plurality of coil elements and the moving samples so that each coil element extends about a respective sample and moves at said velocity as that sample moves through the interrogation zone; and means for determining from the detected RF energy the characteristic of each sample.

Features described above in relation to method aspects of the invention are equally applicable to apparatus aspects, and vice versa.

Preferred features of the present invention will now be described, by way of example only, with reference to the accompanying drawings, in which:

Figure 1 illustrates a first embodiment of an apparatus for determining the mass of moving samples;

Figure 2 is a close-up of part of the apparatus of Figure 1 ;

Figure 3 is a block diagram illustrating a control system forming part of and controlling the apparatus of Figure 1 ; Figure 4 illustrates a second embodiment of an apparatus for determining the mass of moving samples, with the coil elements spaced from the samples;

Figure 5 is a block diagram illustrating the control system of the apparatus of Figure 4;

Figure 6 illustrates the apparatus of Figure 4, with the coil elements having been moved to surround the samples before they enter the interrogation zone of the apparatus;

Figure 7 illustrates the apparatus of Figure 4, with the coil elements having been moved with the samples as they pass through the interrogation zone;

Figure 8 illustrates the apparatus of Figure 4, with the coil elements having been moved away the samples for return to the position shown in Figure 4;

Figure 9 illustrates a third embodiment of an apparatus for determining the mass of moving samples, with the coil elements spaced from the samples;

Figure 10 illustrates the apparatus of Figure 9, with the coil elements having been moved to surround the samples before they enter the interrogation zone of the apparatus;

Figure 11 illustrates the apparatus of Figure 9, with the coil elements having been moved with the samples as they pass through the interrogation zone; and

Figure 12 illustrates the apparatus of Figure 9, with the coil elements having been moved away the samples for return to the position shown in Figure 9. Figure 1 illustrates a first embodiment of an apparatus for determining the mass of moving samples. In each of the preferred embodiments described below, the apparatus is used to determine the mass of pharmaceutical samples located within sterile glass or plastics syringes 10. However, the apparatus is also suitable to use with containers of other shapes and sizes, such as vials and ampoules, and to determine the mass of other types of sample, for example biological samples, industrial chemicals and food products.

The syringes 10 are located within one or more sample holders 12. In this embodiment, each sample holder 12 is in the form of a cassette, preferably formed from material that does not influence the determined mass of the samples or does not interfere with the NMR measurement. The cassette 12 comprises a base 14 and opposing side walls 16, 18 depending orthogonally from the base 14. Each side wall 16, 18 terminates with an inwardly- projecting flange 20.

An array of tubular syringe holders 22 is provided in the base 14 of the cassette 12. The array of syringe holders 22 comprises a plurality of rows of syringe holders 22, each row extending along the z direction illustrated in Figure 1 and with adjacent rows being spatially separated along the x direction orthogonal to the z direction. In this example, each cassette 12 can hold 60 syringes, although the cassette may be modified to hold more or less syringes as required.

With reference also to Figure 2, each syringe holder 22 comprises a cylindrical aperture 24 for receiving the barrel 26 of a syringe 10. The aperture 24 passes orthogonally through the base 14, and is defined on either side of the base 14 by the bores of first and second co-axial sleeves 28, 30 integral with the base 14 and each extending orthogonally from a respective surface of the base 14. At least the first sleeve 28 projecting from the upper (as illustrated) surface of the base 14 is sized so that, in use, part of the plunger 32 of a syringe 10 located in the syringe holder 22 rests on the upper surface of the first sleeve 28.

A helical coil element 34 is located within the aperture 24 of each syringe holder 22 for surrounding a sample contained within a syringe 10 inserted into the aperture 24. The coil element 34 is preferably co-axial with the aperture 24 so that the coil element 34 co-axially surrounds the sample contained within the syringe 10, and preferably extends substantially the entire length of the aperture 24. The coil element 34 preferably has an internal diameter that is only slightly larger than the external diameter of the barrel 26 of the syringe 10.

Returning to Figure 1 , the cassette 12 is located on a conveyor 36 for moving the cassette 12 at a controlled, preferably constant, velocity in the x direction. In this example, the conveyor 36 comprises a pair of spaced, parallel conveyor belts 38 upon which the inwardly-projecting flanges 20 of the cassette 12 are seated when the cassette 12 is located on the conveyor 36. Each belt 38 generally comprises an endless chain extending about and driven by a pair of motor-driven rotational drums 40 located at opposite ends of the conveyor 36, and may be constructed from materials selected from a group including Kevlar®, Teflon®, polyester, polyurethane, aramide, glass, or other thermoplastic materials.

The conveyor 36 conveys the cassette 12 through an interrogation zone 42, illustrated in Figure 2, to determine the mass of the samples contained within the syringes 10. This interrogation zone 42 preferably extends in the z direction, that is substantially orthogonal to the direction of motion of the cassette 12 on the conveyor 36, between the arms 44 of a preferably U- shaped magnet 46 for creating a homogenous direct current, or static, magnetic field in the z direction through the interrogation zone 42. This has the effect of creating a net nuclear magnetisation along the z axis of the nuclear spin species within samples contained within the syringes 10 as they are moved through the interrogation zone 42. The U-shape has the advantage of being open to three sides in order to allow also laminar air flow from the top.

A row of RF coils 48 is located beneath the interrogation zone 42 and extending in the z direction. As illustrated in Figures 1 and 2, the RF coils 48 are housed within a cassette 50 located upon two L-shaped brackets 52, each bracket 52 being mounted on the inner surface of a respective arm 44 of the permanent magnet 46. Application of a pulse of alternating current at the sample's Larmor frequency to each RF coil 48 induces a similar alternating current in the coil element 34 passing over the RF coil 48 as the pulse is applied thereto. This current causes an RF field at the sample's Larmor frequency and oriented along the y axis orthogonal to the static magnetic field (which is oriented along the z axis) to be applied to the sample contained within the syringe 10 located within the coil element 34. This has the effect of exciting the sample by causing the net nuclear magnetisation of the nuclear spin species to rotate away from the z axis. After this pulse has been applied, the sample is in a high-energy, non-equilibrium state, from which the net nuclear magnetisation of the nuclear spin species relaxes back to its equilibrium state along the z axis.

As this nuclear magnetisation relaxes, RF energy at the Larmor frequency of the nuclear spin species is emitted, the magnetic component of which induces an RF voltage in the RF coil 48. The peak amplitude of the RF voltage varies with, among other things, the number of nuclear magnetic moments in the sample, and hence the number of hydrogen protons in the sample. Therefore, by monitoring the RF voltage induced in the RF coil 48 as the net nuclear magnetisation of the hydrogen protons in the sample relaxes, the mass of the sample contained within the syringe 10 may be determined.

Figure 3 is a block diagram illustrating a control system 60 forming part of and controlling the apparatus for determining the mass of the samples. The control system 60 comprises a plurality of connection terminals 62 (only two shown in Figure 3) for connecting the control system 60 to each RF coil 48. A switch 64 connects each terminal 62 to a signal generator 66, a power amplifier 68 and respective matching and tuning capacitors 69, each of which, together with an RF coil 48, form a resonant circuit which is operable to generate and amplify respectively an RF pulse which can be applied to each of the RF coils 48.

Each connection terminal 62 is also connectable, through its respective switch 64, to circuitry 70 for amplifying the signal received by the RF coil 48 from the sample under analysis, and for removing noise components from that signal. The circuitry 70 also includes an A/D converter for converting the signal to a digital signal before it is passed to a microprocessor 72. The microprocessor 72 compares the peak amplitude of the signal with the peak amplitude of a signal recorded before under otherwise identical conditions from a calibration sample with a known mass (or weight), to determine the mass (or weight) of the sample under analysis. As shown in Figure 3, the control system 60 may also comprise a user interface 73 for allowing the user to input into the control system 60 the correct mass of each sample for a given batch of samples.

As shown by the dashed control lines 74, 76, the microprocessor 72 controls the operation of the signal generator 66 and the switches 64. This enables the microprocessor 72 to control the generation of an RF pulse when a syringe 10 containing a sample under analysis is located directly above one of the RF coils 48. For example, one or more sensors (not illustrated) may be located in front of the permanent magnet 46 for generating a light beam which is broken as the cassette 12 passes therethrough. This can be detected by position sensor electronics 78 interfacing with the sensors, which in turn provides a signal to the microprocessor 72 indicating that the light beam has been broken. Based on this information and the speed of the conveyor belts 38, which can be provided to the microprocessor 72 from a conveyor controller 80, the microprocessor 72 determines the optimum timing for the generation of a series of RF pulses to excite each row of coil elements 34 of the cassette 12 in turn as they pass over the RF coils 48, and signals the signal generator 66 accordingly. Through control of the switches 64, the microprocessor 72 can select which of the RF coils 48 are to receive an RF pulse, enabling one or more of the coil elements 34 in each row to be selectively excited as required.

In a modification of this embodiment, the static magnetic field includes a gradient field. For example, a separate pair of coils (not shown) may be located on either side of the interrogation zone 42, and which operate to provide a magnetic field gradient across the interrogation zone. As a result of this gradient, the static magnetic field experienced by each of the samples contained within a row of syringe holders 22 will be different, and therefore the respective Larmor frequency of each of the samples will be different. Consequently, each sample can be interrogated separately and simultaneously by detecting from and/or applying to the sample a different narrow band RF pulse at the appropriate frequency. Each pulse may be generated by a respective signal generator 66 and resonant circuit (69, 48), each signal generator being connected to a respective switch 64 by a power amplifier 68 and resonant circuit (69, 48), and being controlled by signals received over a respective control line 76 from the microprocessor 72.

In another modification of this embodiment, the samples may be pre-polarised before entering the interrogation zone, for example by causing the syringes to pass through an additional stationary magnet prior to the measurement zone. This can improve the quality of the measurement of the characteristic of each sample.

Through use of the apparatus illustrated in Figure 1 , the mass of each syringe within an array of 60 syringes may be rapidly analysed to determine whether the syringes have been correctly filled. The array of syringes may be randomly selected from amongst a batch of syringes produced by a production line. Alternatively, a number of syringes may be periodically removed from the production line for analysis and subsequent return to the production line. In the event that one or more discrete signals received from an RF system, which in this embodiment is provided by the RF coils 48 and the excitation coils 34, indicates that a syringe has been incorrectly filled, or if an average signal received from an RF coil 48 over a period of time indicates that one or more of the syringes has been incorrectly filled, the microprocessor 72 may generate an alert for display on the user interface 73 to alert the user to the incorrect filling of the syringes. The user can then choose to reject the entire batch of syringes, or, to avoid rejection of the entire batch, subject further arrays of syringes from that batch to mass analysis to identify when the incorrect filling of the syringes began.

A second embodiment of an apparatus for determining the mass of moving samples is illustrated in Figure 4. This second embodiment is suitable for determining the mass of samples contained within syringes as they are conveyed between stations of a production line, for example between a filling station and a reject station for rejecting any syringes which have not been correctly filled. This can enable both incorrect filing of the syringes to be rapidly detected, and any incorrectly filled syringes to be individually rejected from the stock of syringes produced on the production line.

In this second embodiment, a conveyor 100 for conveying the syringes individually through the interrogation zone comprises a conveyor belt 102 generally comprising an endless chain driven by motor-driven gear wheels (not shown), and, as in the first embodiment, may be constructed from materials selected from a group including Kevlar®, Teflon®, polyester, polyurethane, aramide, glass, or other thermoplastic materials. The belt 102 has a series of pockets 104 or other suitable holders for holding the syringes 10 such that the samples contained in the syringes 10 are located above the belt 102. The pockets 104 have a regular pitch on the belt 102. A first device (not shown) is provided at one end of the belt 102 for receiving the syringes from the production line and inserting the syringes 10 into the pockets 104. A second device (not shown) is provided at the other end of the belt 102 for removing the syringes from the pockets 104 and returning the syringes 10 to the production line.

The conveyor 100 moves the syringes 10 at a controlled, preferably constant velocity in the x direction illustrated in Figure 4 through the interrogation zone (not indicated in Figure 4). As in the first embodiment, the interrogation zone preferably extends in the z direction, that is substantially orthogonal to the direction of motion (x) of the syringes 10 on the conveyor 100, between the arms 108 of a preferably U-shaped permanent magnet 110 for creating a homogenous direct current, or static, magnetic field in the z direction through the interrogation zone. This has the effect of creating a net nuclear magnetisation of the nuclear spin species of the samples contained within the syringes 10 as they are moved through the interrogation zone.

The apparatus includes a row of preferable helical coil elements 112 extending in the y direction and mounted on a transport unit 114 for effecting relative movement between the coil elements 112 and the syringes 10. The transport unit 114 comprises an elongate carriage 116 extending in the x direction and from which the coil elements 112 downwardly depend. Each coil element 112 is housed in a sleeve 118 integral with the carriage 116. The pitch of the coil elements 112 on the carriage 116 is the same as the pitch of the pockets 104 on the belt 102. In this second embodiment, each coil element 112 has an internal diameter that is larger than the maximum radius of the plungers 32 of the syringes 10 to enable the coil elements 112 to fit around the barrels 26 and plungers 32 of the syringes 10, and thus substantially co-axially surround the samples contained within the syringes 10.

In this embodiment, the carriage 116 is connected to, or integral with, one end of an arm 120 extending orthogonally from the carriage 116 in the z direction. The other end of the arm 120 is slidably mounted on a first rail 122 extending in the y direction and which has one end thereof slidably mounted on a second rail 124 extending in the x direction. Linear actuators (not shown) or other suitable actuators are provided for actuating sliding movement of the first rail 122 along the second rail 124, and for actuating sliding movement of the arm 120 along the first rail 122.

Figure 5 is a block diagram illustrating a control system 130 forming part of and controlling the apparatus for determining the mass of the samples. The control system 130 is similar to that control system 60 described above with reference to Figure 3. Features 62 to 80 of the control system 60 are replicated in the control system 130, and so those features will not be explained again here. However, it is to be noted that, in this embodiment, each matching and tuning capacitor 69 forms a resonant circuit with a coil element 112, which circuit is operable to generate and amplify respectively an RF pulse which can be applied to the coil element 112.

In addition to those features, the control system 130 includes a controller 132 for controlling the linear actuators. Each of the terminals 62 (two only shown in Figure 5) is connected to a respective coil element 112.

In use, with the conveyor 100 operated to convey the syringes 10 through the interrogation zone in the direction indicated by arrow 140 in Figure 4, the carriage 116 is initially positioned above the syringes 10. As in the first embodiment, one or more sensors (not illustrated) may be located in front of the permanent magnet 110 for generating a light beam which is intermittently broken as the syringes 10 pass therethrough. This can be detected by the position sensor electronics 78 interfacing with the sensors, which in turn provides a signal to the microprocessor 72 indicating that the light beam has been broken. Based on this information and the speed of the conveyor belt 102, which can be provided to the microprocessor 72 from the conveyor controller 80, the microprocessor 72 controls the linear actuators to actuate movement of the transport unit 114. The transport unit 114 is actuated to cause the carriage 116 to move horizontally, that is, in the z direction, at the same speed as the conveyor belt 102 and so that each coil element 112 moves immediately above a respective syringe 10, and simultaneously to move vertically downwards, that is, in the y direction, to cause each coil element 112 to move towards its respective syringe 10 as it approaches the interrogation zone and at such a speed that, as illustrated in Figure 6, each coil element 112 extends fully around the sample contained within its respective syringe 10 before the syringe 10 enters the interrogation zone.

From the position illustrated in Figure 6, the carriage 116 is moved horizontally at the same speed as the belt 102 so that each coil element 112 passes through the interrogation zone with its respective syringe 10. As each coil element 112 passes through the interrogation zone, the microprocessor 72 outputs control signals to the signal generator 66 and the switch 64 associated with that coil element 112 to supply a pulse of alternating current (RF pulse) at the sample's Larmor frequency to the coil element 112. This current causes an RF field at the sample's Larmor frequency and oriented orthogonal to the static magnetic field to be applied to the sample contained within the syringe 10 located within the coil element 112. As discussed above, this has the effect of exciting the sample by causing the net nuclear magnetisation of the nuclear spin species to rotate away from the z axis. After this pulse has been applied, the sample is in a high-energy, non- equilibrium state, from which the net nuclear magnetisation of the nuclear spin species relaxes back to its equilibrium state along the z axis.

As this nuclear magnetisation relaxes, RF energy at the Larmor frequency of the nuclear spin species is emitted, the magnetic component of which induces an RF voltage in the coil element 112. The signal output from the coil element 112 is received by the circuitry 70 associated with the switch 64, which amplifies the signal, removes noise components from the signal and converts the signal to a digital signal before it is passed to the microprocessor 72. The microprocessor 72 compares the peak amplitude of the signal with the peak amplitude of a signal received from a calibration sample with a known mass (or weight), to determine the mass (or weight) of the sample under analysis.

When all of the coil elements 112 mounted on the carriage 116 have passed through the interrogation zone (as illustrated in Figure 7), the carriage 116 is vertically raised with further horizontal movement of the carriage 116 to the position illustrated in Figure 8 so that the ends of the sleeves 118 are clear from the upper surfaces of the plungers 32 of the syringes 10. The carriage 116 can then be returned rapidly to the position illustrated in Figure 4 to enable the mass of another plurality of samples to be determined. This solution is applicable only when the stationary magnet field is sufficiently homogeneous, because the effective interrogation zone will be different for each syringe. In case the magnet field is not sufficiently homogeneous, a constant interrogation zone can be effectuated by applying a rotating wheel (not illustrated) with coil elements at the end of each spoke.

Alternative transport units may be provided for causing the movement of the carriage 116 described above. For example, in the third embodiment of apparatus for determining the mass of moving samples illustrated in Figures 9 to 12, the transport unit 150 replaces the rails 122 and 124 of the transport unit 114 with four pivotally connected drive members 152, 154, 156,158. Drive members 152, 154 each have one end pivotally connected to the end of the arm 120, and drive members 156, 158 each have one end pivotally connected to a stationary member 160 providing pivot 162. The other ends of drive members 152, 156 are pivotally connected to pivot 164, and the other ends of drive members 154, 158 are pivotally connected to pivot 166. By controlling the movement of the pivots 164, 166, the carriage 116 may be caused to move in the same manner described above with reference to Figures 9 to 12. It is to be understood that the foregoing represents three embodiment of the invention, others of which will no doubt occur to the skilled addressee without departing from the true scope of the invention as defined by the claims appended hereto.

For example, in each of the above embodiments the microprocessor 72 may control the signal generator 66 to generate a series of pulses to excite each coil element a plurality of times as it moves through the interrogation zone. By subsequently monitoring the energy emitted from the sample as it returns to its original state, a characteristic of the sample other than mass, such as the level of contamination of the sample, may be determined. The arrangements of Figs. 4, and Figs. 6 to 12 could also be upside down.

Claims

1. A method of determining a characteristic, such as the mass, of each of a plurality of samples, the method comprising the steps of: providing a plurality of coil elements each for surrounding a respective sample; causing the samples to enter an interrogation zone, each sample being surrounded by a respective coil element when it is located within the interrogation zone; applying a magnetic field in a first direction in the interrogation zone for creating in a pre-polarised state a net nuclear magnetisation of a nuclear spin species within a sample located in the interrogation zone; applying, by each coil element surrounding a respective sample located in the interrogation zone, an RF field in a second direction for temporarily changing the net nuclear magnetisation of the nuclear spin species in the sample; detecting RF energy emitted from that sample as the net nuclear magnetisation of the nuclear spin species in the sample relaxes; and from the detected RF energy, determining the characteristic of each sample located in the interrogation zone.

2. A method according to Claim 1 , wherein the RF energy emitted from a sample induces an RF voltage in the coil element surrounding that sample, and wherein the characteristic of the sample is determined from the RF voltage induced in the coil element.

3. A method according to Claim 1 or Claim 2, wherein each coil element is part of a resonance circuit tuned to the Larmor frequency of a particular nuclear spin species contained in the samples.

4. A method according to Claim 1 , wherein the RF energy causes an RF voltage to be induced in an RF coil separate from the coil elements, wherein the RF coil is part of a resonance circuit tuned to the Larmor frequency of a particular nuclear spin species contained in the samples.

5. A method according to Claim 4, wherein the RF coil is located beneath or above the interrogation zone.

6. A method according to Claim 4 or Claim 5, wherein the energy emitted from a sample induces an RF voltage in the coil element surrounding that sample, which RF voltage in turn induces a voltage in the RF coil, and wherein the characteristic of the sample is determined from the voltage induced in the RF coil.

7. A method according to any preceding claim, wherein the plurality of samples are sequentially located within the interrogation zone.

8. A method according to any of Claims 1 to 6, wherein the plurality of samples are simultaneously located within the interrogation zone.

9. A method according to any preceding claim, wherein the coil elements are stationary within the interrogation zone, and wherein the plurality of samples are inserted into, and subsequently removed from, the coil elements.

10. A method according to any of Claims 1 to 8, wherein the samples are moved at a controlled velocity through the interrogation zone, each sample having a respective coil element located thereabout and moving therewith as it moves through the interrogation zone.

1 1 . A method according to Claim 10, wherein the coil elements are located within a sample holder comprising a plurality of apertures, each aperture having a respective coil element extending thereabout and a respective sample inserted therein, and wherein the sample holder is moved through the interrogation zone at a controlled velocity.

12. A method of determining a characteristic, such as the mass, of each of a plurality of samples, the method comprising the steps of: providing a sample holder comprising a plurality of apertures, each aperture having a respective coil element extending thereabout; inserting each sample within a respective aperture; causing the sample holder to move at a controlled velocity through an interrogation zone; applying a magnetic field in a first direction in the interrogation zone for creating in a pre-polarised state a net nuclear magnetisation of a nuclear spin species within a sample located in the interrogation zone; applying, by each coil element surrounding a respective sample located in the interrogation zone, an RF field in a second direction in the interrogation zone for temporarily changing the net nuclear magnetisation of the nuclear spin species in the sample; detecting the RF energy emitted from that sample as the net nuclear magnetisation of the nuclear spin species in the sample relaxes; and from the detected RF energy, determining the characteristic of each sample located in the interrogation zone.

13. A method according to Claim 1 1 or Claim 12, wherein the coil elements are arranged in a row extending in said first direction as the sample holder moves through the interrogation zone.

14. A method according to Claim 13, wherein an RF field is applied to each of the coil elements located in the row of coil elements by a respective RF coil.

15. A method according to Claim 14, wherein each RF coil is part of a resonance circuit tuned to the Larmor frequency of a particular nuclear spin species contained in the samples.

16. A method according to any of Claims 13 to 15, wherein the first magnetic field includes a gradient field, whereby different magnetic fields are applied to each of the samples located in the row of coil elements.

17. A method according to any of Claims 11 to 16, wherein the sample holder comprises a plurality of rows of coil elements, and wherein an

RF field is simultaneously applied to samples located in a row of coil elements as that row moves through the interrogation zone.

18. A method according to Claim 10, wherein each coil element is moved relative to its respective sample as it approaches the interrogation zone so that the coil element extends about the sample as it moves through the interrogation zone.

19. A method of determining a characteristic, such as the mass, of each of a plurality of samples, the method comprising the steps of: causing the samples to move at a controlled velocity through an interrogation zone; effecting relative movement between a plurality of coil elements and the moving samples so that each coil element extends about a respective sample and moves at said velocity as that sample moves through the interrogation zone, wherein each coil element is part of a resonance circuit tuned to the Larmor frequency of a particular nuclear spin species contained in the samples; applying a magnetic field in a first direction in the interrogation zone for creating in a pre-polarised state a net nuclear magnetisation of said nuclear spin species within a sample located in the interrogation zone; applying an RF field in a second direction in the interrogation zone for temporarily changing the net nuclear magnetisation of said nuclear spin species in the sample located in the interrogation zone; detecting by each coil element surrounding a respective sample located in the interrogation zone the RF energy emitted from that sample as the net nuclear magnetisation of said nuclear spin species in the sample relaxes; and from the detected RF energy, determining the characteristic of each sample located in the interrogation zone.

20. A method according to Claim 18 or Claim 19, wherein the coil elements are moved towards the moving samples as they approach the interrogation zone, and are moved away from the moving samples following the energy emission from the samples.

21 . A method according to Claim 20, wherein the coil elements are subsequently re-positioned for location about different samples.

22. A method according to any of Claims 18 to 21 , wherein the coil elements are mounted on a moveable carriage, and wherein the carriage is moved relative to the moving samples to cause the coil elements to surround the samples as they move through the interrogation zone.

23. A method according to any of Claims 18 to 22, wherein the coil elements are excited sequentially as they are moved through the interrogation zone to apply the RF field to the samples.

24. A method according to any preceding claim, wherein the RF field is applied a plurality of times to each sample located within the interrogation zone.

25. A method according to any preceding claim, wherein each sample is pre-polarised before entering the interrogation zone.

26. Apparatus for determining a characteristic, such as the mass, of each of a plurality of samples, the apparatus comprising: means for moving the samples into an interrogation zone; means for applying a magnetic field in a first direction in the interrogation zone for creating in a pre-polarised state a net nuclear magnetisation of a nuclear spin species within a sample located in the interrogation zone; means for applying an RF field in a second direction in the interrogation zone for temporarily changing the net nuclear magnetisation of the nuclear spin species within a sample located in the interrogation zone; means for detecting RF energy emitted from that sample as the net nuclear magnetisation of the nuclear spin species within the sample relaxes; and means for determining from the detected RF energy the characteristic of each sample; wherein the RF field applying means comprises a plurality of coil elements each for surrounding a respective sample located within the interrogation zone.

27. Apparatus according to Claim 26, wherein the coil elements form part of the RF energy detecting means, and wherein the determining means is configured to determine the characteristic of a sample from the RF voltage induced in the surrounding coil element by RF energy emitted from the sample.

28. Apparatus according to Claim 26 or Claim 27, wherein each coil element is part of a resonance circuit tuned to the Larmor frequency of a particular nuclear spin species contained in the samples.

29. Apparatus according to Claim 26, wherein the RF energy detecting means comprises an RF coil, separate from the coil elements, within which an RF voltage is induced by RF energy emitted from a sample, the RF coil forming part of a resonance circuit tuned to the Larmor frequency of a particular nuclear spin species contained in the samples, and wherein the determining means is configured to determine the characteristic of the sample from the RF voltage induced in the RF coil.

30. Apparatus according to Claim 29, wherein the excitation coil is located beneath or above the interrogation zone.

31 . Apparatus according to Claim 29 or Claim 30, wherein the RF energy emitted from a sample induces a RF voltage in the coil element surrounding that sample, which RF voltage in turn induces a voltage in the RF coil, and wherein the determining means is configured to determine the characteristic of the sample from the voltage induced in the RF coil.

32. Apparatus according to any of Claims 26 to 31 , wherein the moving means is configured to sequentially locate samples within the interrogation zone.

33. Apparatus according to any of Claims 26 to 31 , wherein the moving means is configured to simultaneously locate a plurality of samples within the interrogation zone.

34. Apparatus according to any of Claims 26 to 33, wherein the coil elements are stationary within the interrogation zone, and wherein the moving means is configured to insert the plurality of samples into, and subsequently remove the plurality of samples from, the coil elements.

35. Apparatus according to any of Claims 26 to 33, wherein the moving means is configured to move the plurality of samples at a controlled velocity through the interrogation zone, each sample having a respective coil element located thereabout and moving therewith as it moves through the interrogation zone.

36. Apparatus according to Claim 35, wherein the coil elements are located within a sample holder comprising a plurality of apertures each for receiving a respective sample and having a respective coil element extending thereabout, and wherein the moving means is arranged to move the sample holder through the interrogation zone at said controlled velocity.

37. Apparatus for determining a characteristic, such as the mass, of each of a plurality of samples, the apparatus comprising: a sample holder comprising a plurality of apertures each for receiving a respective sample; means for moving the sample holder at a controlled velocity through an interrogation zone; means for applying a magnetic field in a first direction in the interrogation zone for creating in a pre-polarised state a net nuclear magnetisation of nuclear spin species within samples located in the interrogation zone as the holder moves through the interrogation zone; means for applying an RF field in a second direction in the interrogation zone for temporarily changing the net nuclear magnetisation of the nuclear spin species within a sample located in the interrogation zone, means for detecting RF energy emitted from a sample located in the aperture as the net nuclear magnetisation of the nuclear spin species within the sample relaxes; and means for determining from the detected RF energy the characteristic of each sample; wherein the RF field applying means comprises a plurality of coil elements located in the holder and each surrounding a respective aperture.

38. Apparatus according to Claim 36 or Claim 37, wherein the apertures are arranged in a row extending in said first direction as the sample holder moves through the interrogation zone.

39. Apparatus according to Claim 38, wherein the RF field applying means comprises a plurality of RF coils arranged in a row extending in said first direction for applying an RF field to a row of coil elements.

40. Apparatus according to Claim 39, wherein the plurality of RF coils form part of the RF energy detecting means, and within each of which an RF voltage is induced by RF energy emitted from a sample, each RF coil forming part of a resonance circuit tuned to the Larmor frequency of a particular nuclear spin species contained in the samples, and wherein the determining means is configured to determine the characteristic of a row of samples from the RF voltages induced in the RF coils.

41 . Apparatus according to any of Claims 36 to 40, wherein the sample holder comprises a plurality of rows of apertures.

42. Apparatus according to Claim 25, comprising means for moving each coil element relative to its respective sample as it approaches the interrogation zone so that the coil element extends about the sample as it moves through the interrogation zone.

43. Apparatus for determining a characteristic, such as the mass, of each of a plurality of samples, the apparatus comprising: means for moving the samples at a controlled velocity through an interrogation zone; means for applying a magnetic field in a first direction in the interrogation zone for creating in a pre-polarised state a net nuclear magnetisation of the nuclear spin species within a sample as it moves through the interrogation zone; a plurality of coil elements each for applying an RF field in a second direction in the interrogation zone for temporarily changing the net nuclear magnetisation of the nuclear spin species of a sample located in the interrogation zone, and for detecting RF energy emitted from that sample as the net nuclear magnetisation of the nuclear spin species of that sample relaxes, each coil element being part of a resonance circuit tuned to the Larmor frequency of a particular nuclear spin species contained in the samples; means for effecting relative movement between the plurality of coil elements and the moving samples so that each coil element extends about a respective sample and moves at said velocity as that sample moves through the interrogation zone; and means for determining from the detected RF energy the characteristic of each sample.

44. Apparatus according to Claim 42 or Claim 43, wherein the coil element moving means is arranged to move the coil elements towards the moving samples as they approach the interrogation zone, and to move the coil elements away from the moving samples following the energy emission from the samples.

45. Apparatus according to Claim 44, wherein the coil element moving means is arranged to subsequently re-position the coil elements for location about different samples.

46. Apparatus according to any of Claims 42 to 45, wherein the coil element moving means comprises a carriage upon which the coil elements are mounted, and means for moving the carriage relative to the moving samples to cause the coil elements to surround the samples as they move through the interrogation zone.