GB2434873A

GB2434873A - NMR determination of mass within a container

Info

Publication number: GB2434873A
Application number: GB0602188A
Authority: GB
Inventors: Jozef Antonius Willem M Corver; Johannes Van Veen
Original assignee: BOC Group Ltd
Current assignee: BOC Group Ltd
Priority date: 2006-02-03
Filing date: 2006-02-03
Publication date: 2007-08-08
Also published as: GB0602188D0

Abstract

Apparatus is described for determining a characteristic, such as the mass, of a sample contained within a container. The apparatus comprises a container inlet for receiving a container from an infeed conveyor, a container outlet located beneath the container inlet, means for applying a first magnetic field in a first direction in an interrogation zone located between the container inlet and the container outlet for creating a net magnetisation within a sample located within the interrogation zone, means for applying an alternating magnetic field in a second direction in the interrogation zone for temporarily changing the net magnetisation of the sample located therein, and means for monitoring energy emitted from the sample as the net magnetisation of the sample returns to its original state. A chute is used to transfer the container at least partially under gravity from the container outlet to an outfeed conveyor.

Description

METHOD OF DETERMINING THE MASS OF A SAMPLE

The present invention relates to a method of, apparatus for, determining the mass or other characteristic of a sample, and which may find use in the determination of the mass of a sample conveyed on a conveyor system, for example, between functions of a production line.

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 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 NMR techniques. The inspection station includes a magnet for creating a static magnetic field over an interrogation zone to produce a net pre-magnetisation within a vial located in the interrogation zone, and an RF probe for applying a pulsed, alternating magnetic field over the interrogation zone and orthogonal to the static magnetic field. The alternating magnetic field causes the net magnetisation of the sample contained within the vial to rotate about the axis of the alternating magnetic field, away from the direction of the static magnetic field.

After the pulse has been applied to the sample, the sample relaxes and emits electromagnetic energy at the Larmor frequency of the molecules of the sample. The magnetic component of the energy emitted from the sample * S **S *S* ISS * * S * S * S * S S S S S S S S S S S S S S S S S S S * * induces a signal, known as the free induction decay (FID), in the form of current in the RF probe. The amplitude of the induced current is considered to be directly proportional to the number of molecules in the sample. The amplitude of the induced current is then compared to that produced by a calibration sample with known mass to determine the mass of the sample under analysis.

Alternative 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 information concerning the product composition, the amount of ferrous particles within, or other contamination of, the sample.

In such known inspection stations, the RF probe for applying an alternating magnetic field over the interrogation zone 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 emitted from the sample.

Furthermore, the presence of metal needles would unduly influence the signal.

In a first aspect, the present invention provides apparatus for determining a characteristic, such as the mass, of a sample contained within a container, the apparatus comprising a container inlet for receiving a container from an infeed conveyor, a container outlet located beneath the container inlet, means for applying a first magnetic field in a first direction in an interrogation zone located between the container inlet and the container outlet for creating a net magnetisation within a sample located within the interrogation zone, means * * *** *** *** * S S S S * * * * * * * * S ** S S S S S * * * * S S S S S 5 5 S S for applying an alternating magnetic field in a second direction in the interrogation zone for temporarily changing the net magnetisation of the sample located therein, means for monitoring energy emitted from the sample as the net magnetisation of the sample returns to its original state, and means for transferring the container at least partially under gravity from the container outlet to an outfeed conveyor.

The apparatus can thus provide a convenient bench-top apparatus for determining the characteristic, such as mass, of a sample located within a container conveyed on a conveyor system, for example, of a production line.

The apparatus may be located beneath a first, infeed conveyor for conveying the containers, with a container being released or otherwise ejected from the conveyor when it is located above the container inlet of the apparatus, so that the container falls, slides or otherwise moves under gravity into the apparatus.

For example, each container may be clipped into a pocket located on the infeed conveyor, and subsequently physically dislodged from the pocket by a suitable reject mechanism when it is located above the container inlet.

Alternatively, each container may be releasably held on the infeed conveyor using one or more suction nozzles, which are de-activated to release a container when it is located above the container inlet. Another alternative for use with syringes is an infeed conveyor including a plurality of regularly spaced elongate apertures, each having a length longer than the width of a the heads of the plungers of the syringes and a width smaller that the width of the heads of the plungers. Each syringe is inserted into a respective aperture so that the ends of the head of the plunger rest on the upper surface of the conveyor, with the body of the syringe being suspended beneath the conveyor. When the syringe is located above the inlet, the plunger is rotated by a suitable mechanism, for example a friction element so that the head of the plunger passes through the aperture to release the syringe from the conveyor.

* * *** *** *** * * I * I * S * * I * * S S SI S * S I * S * S S S S S S *S S S S S The containers are preferably conveyed in an upright position on the infeed conveyor. The container inlet may be conical or otherwise shaped to have a relatively large mouth for receiving the containers. In the preferred embodiment, the sample is moved into and from the interrogation zone along the second direction, which is preferably substantially vertical.

As the container moves from the container inlet to the container outlet, it passes through an interrogation zone. Means such as a permanent magnet, electromagnets, current carrying coils or superconducting magnets, may be provided for applying a first magnetic field in a first direction in the interrogation zone for creating a net magnetisation within a sample located within the interrogation zone. Means such as a helical coil element surrounding the interrogation zone may be provided for applying an alternating magnetic field in a second direction in the interrogation zone for temporarily changing the net magnetisation of the sample located therein. By monitoring energy emitted from the sample as the net magnetisation of the sample returns to its original state, for example by monitoring the amplitude of a current induced in the coil element, an indication of the mass or other characteristic of the sample can be provided. For example, the alternating magnetic field may be applied to a sample a plurality of times. 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 application of pulse-sequences is also preferred for the measurement of the weight of solid material and in the case of liquids improves the accuracy of the measurement.

By allowing the samples to fall through the interrogation zone under gravity, rapid processing of a batch of samples may be conducted. Sensors may be provided for generating one or more light beams which are broken in turn as a container approaches the interrogation zone. This can be detected by position sensor electronics interfacing with the sensors. Based on this information, the speed of the container as it enters the interrogation zone can * * **. *** S..

* . . S * S * * S * S S S * S. * S * S S S S * S S S S S S S. S * * S be determined, and the application of the alternating magnetic field may be triggered to coincide with the subsequent passage of the container through the interrogation zone. Alternatively, the speed of the container as it enters the interrogation zone can be calculated in advance in the event that the container is released from a fixed position above the interrogation zone, with the application of the alternating magnetic field being triggering a predetermined period of time following the detection of a falling container.

As an alternative to allowing the container to move through the interrogation zone under gravity, the sample may be stationary within the interrogation zone during application of the alternating magnetic field. For example, a container may be retained within, and subsequently released from, the interrogation zone by a shutter mechanism or other means for releasably retaining the sample within the interrogation zone. Consequently, the aforementioned sensors and associated electronics for monitoring the position and/or speed of an approaching container may no longer be required. The movement of the shutter can be readily timed to release a container following the application of the alternating magnetic field thereto, and to restrain the next container passing through the container inlet. An advantage of this stationary phase in the movement of the container is that a stable magnetisation state is obtained. This stable state is less sensitive to ambient conditions such as temperature, and is not sensitive to timing related control systems. Furthermore, the alternating magnetic field may be readily applied to a stationary sample a plurality of times.

By providing a coil element that extends about the sample as it moves through the interrogation zone, the 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 element can be sized so that it has an internal diameter which is only slightly larger than the external diameter of the container containing the sample.

* * ..* S.. .55 * * I S S * S * S S * S * S S. S S S S I * a * . S S S S S. a * S * An ouffeed conveyor receives a container from the container outlet. The means for transferring the container at least partially under gravity from the container outlet to the outfeed conveyor may be conveniently provided by a chute located beneath the container outlet. The chute is preferably configured to change the direction of the movement of the containers leaving the apparatus from a substantially vertical direction to a substantially horizontal direction, with the outfeed conveyor being preferably configured to convey containers in a prone or horizontal position from the chute. Containers that have passed through the apparatus can therefore be individually identified on the ouffeed conveyor, and this can enable any container having a different mass or other characteristic to the other containers to be readily identified on, and rejected from, the ouffeed conveyor.

The present invention also provides a conveyor system comprising an infeed conveyor, apparatus as aforementioned for receiving containers from the infeed conveyor, and an outfeed conveyor for receiving containers from said apparatus.

In a further aspect, the present invention provides a method of determining a characteristic, such as the mass, of a sample contained within a container, the method comprising the steps of moving the sample into an interrogation zone from an infeed conveyor, applying a first magnetic field in a first direction in the interrogation zone for creating a net magnetisation within the sample located within the interrogation zone, applying an alternating magnetic field in a second direction in the interrogation zone for temporarily changing the net magnetisation of the sample located therein, monitoring energy emitted from the sample as the net magnetisation of the sample returns to its original state, and moving the sample at least partially under gravity from the interrogation zone to an outfeed conveyor.

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a. * . . S * * S a * * a * S. S S S a a a S -* * S C S *e C S S * The method and apparatus described above are particularly suitable for determining the mass of samples located within elongate containers, such as syringes or ampoules.

Features described above in relation to apparatus aspects of the invention are equally applicable to method 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 perspective view of a conveyor system including apparatus for determining the mass of a sample; Figure 2 illustrates a perspective view of the conveyor system of Figure 1 as a sample enters the apparatus, with the internal components of the apparatus partially exposed; Figure 3 is a close-up of part of Figure 2; Figure 4 is a similar view as Figure 2 illustrating a sample retained within the apparatus; Figure 5 is a block diagram illustrating a control system forming part of and controlling the apparatus; and Figure 6 is a similar view as Figure 2 illustrating a sample leaving the apparatus.

With reference first to Figure 1, a conveyor system 10 for conveying containers, for example between stations of a production line, comprises an infeed conveyor 12, measurement apparatus 14 for receiving a container from the infeed conveyor 12 and for determining a characteristic of a sample .. ss, es.

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contained within the container, and an outfeed conveyor 16 for subsequently receiving the container from the measurement apparatus 14. In this illustrated embodiment, the apparatus is used to determine the mass of pharmaceutical samples located within sterile glass or plastics syringes 18. 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 infeed conveyor 12 comprises a conveyor belt 20 generally comprising an endless chain driven by motor-driven gear wheels (not shown), which may be constructed from materials selected from a group including Kevlar , Teflon , polyester, polyurethane, aramide, glass, or other thermoplastic materials. The belt 20 has a series of spaced pockets (not shown) or other suitable holders into which the syringes are clipped for transportation by the belt 20 towards the measurement apparatus. Examples of a suitable belt 20 for conveying syringes and a handling unit for receiving syringes from the production line and for inserting the syringes 18 into the belt 20 are available from Robert Bosch GmbH.

With reference also to Figures 2 and 3, the measurement apparatus 14 is located beneath the infeed conveyor 12, and comprises a casing 24 having a container inlet 26 and a container outlet 28 located beneath the container inlet 26, in this embodiment immediately beneath the container inlet 26. The container inlet 26 may be selectively opened and closed by a first shutter mechanism comprising shutter 30, and the container outlet 28 may be selectively opened and closed by a second shutter mechanism comprising shutter 32.

A cylindrical, substantially vertical passageway 33 extends between the inlet 26 and the outlet 28 of the casing 24, and defines an interrogation zone of the measurement apparatus 14. A helical coil element 34 is located within the S S uS Sit Sit * . a S S S S $ ii S S a St i $ $ I a

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54 4 S a a casing 24 for surrounding a sample contained within a syringel 8 located within the passageway 33. The coil element 34 is preferably co-axial with the passageway so that the coil element 34 co-axially surrounds the sample contained within the syringe 18, and preferably extends substantially the entire length of the passageway 33. The coil element 34 preferably has an internal diameter that is only slightly larger than the external diameter of the head 36 of the plunger of a syringe 18.

The casing 24 also houses a magnetic assembly 36 for creating a homogenous direct current, or static, magnetic field in the x direction, as illustrated in Figure 3, through the interrogation zone 33. This has the effect of magnetising the sample contained within a syringe 18 located within the interrogation zone 33. The magnetic assembly 36 may be conveniently provided by a permanent magnet, electromagnets, current carrying coils or superconducting magnets.

In use, as a syringe 18 located on the infeed conveyor 12 approaches a position located immediately above the inlet 26 of the measurement apparatus 24, the first shutter mechanism is operated to open the container inlet 26, and the second shutter mechanism is operated to close the container outlet 28. When a syringe 18 is located immediately above the open container inlet 26, a reject mechanism is actuated to release the syringe 18 from the conveyor 20. For example, when the syringes 18 are clipped within pockets located on the conveyor 20, a reject mechanism may be actuated to push the syringe 18 from its pocket. The released syringe 18 falls under gravity through the open container inlet 26 into the interrogation zone 33, and is retained inside the interrogation zone by the shutter 32 of the second shutter mechanism.

With a syringe 18 retained within the interrogation zone, the shutter 30 of the first shutter mechanism is actuated to close the container inlet 26, and thereby isolate the syringe located within the interrogation zone 33, as illustrated in * S **S *** *** S * * S * S * * * S S S S S *. S * S S * e S S * * S. * S S * Figure 4. A pulse of alternating current at the sample's Larmor frequency is then applied to the helical coil element 34. This current causes an alternating magnetic field at the sample's Larmor frequency and oriented in the z direction, that is, orthogonal to the static magnetic field, to be applied to the sample contained within the syringe 18. This has the effect of exciting the sample by causing the sample's net magnetisation to rotate. After this pulse has been applied, the sample is in a high-energy, non-equilibrium state, from which the sample relaxes back to its equilibrium state. As the sample relaxes, electromagnetic energy at the Larmor frequency is emitted, the magnetic component of which induces a current in the coil element 34. The peak amplitude of the current varies with, among other things, the number of magnetic moments in the sample, and hence the number of molecules in the sample. Therefore, by monitoring the current induced in the coil element 34 as the net magnetisation of the sample returns to its original state, the mass of the sample contained within the syringe 18 may be determined.

Figure 5 is a block diagram illustrating a control system 40 forming part of and controlling the measurement apparatus 24. The control system 40 comprises a connection terminal 42 for connecting the control system 40 to the coil element 34. A switch 44 connects the terminal 42 to a signal generator 46 and a power amplifier 48 which are operable to generate and amplify respectively an AC pulse which can be applied to the coil element 34.

The connection terminal 42 is also connectable, through switch 44, to circuitry 50 for amplifying the signal received by the coil element 34 from the sample under analysis, and for removing noise components from that signal. The circuitry 50 also includes an ND converter for converting the signal to a digital signal before it is passed to a microprocessor 52. The microprocessor 52 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. As shown in Figure 5, the control system 40 may also comprise a user interface 53 for * S *IS *S* *S* * * * S S S S * S I * S S S S. S S I S S S S I S S S * S * S. S * S S -Il -allowing the user to input into the control system 40 the correct mass of each sample for a given batch of samples.

As shown by the dashed control lines 54, 56, the microprocessor 52 controls the operation of the signal generator 46 and the switch 44. This enables the microprocessor 52 to control the signal generator to generate an AC pulse when a syringe 18 containing a sample under analysis is located within the interrogation zone 33. For example, the microprocessor 52 may control the timing of the operation of the first and second shutter mechanisms 58, 60 and the reject mechanism 62 for releasing syringes 18 from the infeed conveyor 12, and may be configured to operate the signal generator 46 a predetermined time period after one of (i) the release of a syringe 18 from the infeed conveyor 12, and (ii) the closure of the container inlet by the first shutter mechanism 58 to isolate the syringe located within the interrogation zone 33.

Following the induction of the current in the coil element 34 as the net magnetisation of the sample returns to its original state, as illustrated in Figure 6 the second shutter mechanism is operated to open the container outlet to release the syringe 18 from the interrogation zone 33. The syringe falls through the container outlet 28 under gravity and is received by a chute 70 extending between the container outlet 28 and the ouffeed conveyor 16 to transfer the syringe 18 to the ouffeed conveyor 16. The outfeed conveyor 16 is preferably configured to convey syringes in a prone or horizontal position, and therefore the chute 70 is configured to change the direction of the movement of the syringe from a substantially vertical direction as it leaves the container outlet 28 to a substantially horizontal direction for receipt by the outfeed conveyor 16. The microprocessor 52 may control the outfeed conveyor 16 to index forward at the least the length of one syringe 18 as the container outlet 28 is opened so that the released syringe 18 does not dislodge any syringes already located on the outfeed conveyor 16.

* * *** S.. *S* * S S S S * S * S S S I S S S I S S * S S I S S I S * I. * 5. S -12 -Once the syringe 18 has been fully released from the interrogation zone 33, the second shutter mechanism is operated to close the container outlet 28, and the first shutter mechanism is operated to open the container inlet 26 in readiness for receiving another syringe 18 from the infeed conveyor 12. The infeed conveyor 12 may then be indexed forward, for example under the control of the microprocessor 52, to position another syringe 18 above the container inlet 26.

In the example described above, a single pulse is applied to the coil element 34 so that a determination of the mass of the sample contained within a syringe 18 may be made. Alternatively, a series of pulses may be applied to the syringe 18 retained within the interrogation zone 33 so that an alternating magnetic field is applied to the sample a plurality of times. 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 application of pulse-sequences is also preferred for the measurement of the weight of solid material and in the case of liquids improves the accuracy of the measurement.

In the above examples, the syringe 18 is stationary within the interrogation zone 33 when the pulse is applied thereto by the coil element 34.

Alternatively, the shutters 30, 32 may be maintained in an open position, or dispensed with altogether, and the pulse applied to the sample as the syringe falls through the interrogation zone 33 when it is released from the infeed conveyor 12. In this alternative, the signal generator 46 and switch 44 may be operated a predetermined time period following the release of the syringe 18 from the infeed conveyor 12. Alternatively, one or more sensors may be provided for generating one or more light beams which are broken in turn as a syringe approaches the interrogation zone 33 from the infeed conveyor 12.

This can be detected by position sensor electronics interfacing with the sensors. Based on this information, the speed of the syringe as it enters the interrogation zone 33 can be determined, and the application of the * * *** **S *S* * * S S S * S * S S S S * S 5 5 5 5 5 * * * S S S S S S 5* 5 5 S * -13-alternating magnetic field may be triggered to coincide with the subsequent passage of the syringe 18 through the interrogation zone 33.

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Claims

-14 -

CLAIMS

1. A method of determining a characteristic, such as the mass, of a sample contained within a container, the method comprising the steps of: moving the sample into an interrogation zone from an infeed conveyor; applying a first magnetic field in a first direction in the interrogation zone for creating a net magnetisation within the sample located within the interrogation zone; applying an alternating magnetic field in a second direction in the interrogation zone for temporarily changing the net magnetisation of the sample located therein; monitoring energy emitted from the sample as the net magnetisation of the sample returns to its original state; and moving the sample at least partially under gravity from the interrogation zone to an ouffeed conveyor.

2. A method according to Claim 1, wherein the sample is moved into the interrogation zone along the second direction.

3. A method according to Claim 2, wherein the second direction is substantially vertical.

4. A method according to any preceding claim, wherein the sample is stationary within the interrogation zone during application of the

alternating magnetic field.

5. A method according to Claim 4, wherein the sample is retained within, and subsequently released from, the interrogation zone by a shutter mechanism.

* * **. I.. *** * * * * S S * S * * S * S S. * S S * S S S * S * * S S * S. S * * I 6. A method according to any preceding claim, wherein the sample is moved from the interrogation zone to the outfeed conveyor along a chute.

7. A method according to any preceding claim, wherein the movement of the sample into the interrogation zone is at least partially under gravity.

8. A method according to any preceding claim, wherein the alternating magnetic field is applied by a coil element surrounding the interrogation zone.

9. Apparatus for determining a characteristic, such as the mass, of a sample contained within a container, the apparatus comprising: a container inlet for receiving a container from an infeed conveyor; a container outlet located beneath the container inlet; means for applying a first magnetic field in a first direction in an interrogation zone located between the container inlet and the container outlet for creating a net magnetisation within a sample located within the interrogation zone; means for applying an alternating magnetic field in a second direction in the interrogation zone for temporarily changing the net magnetisation of the sample located therein; means for monitoring energy emitted from the sample as the net magnetisation of the sample returns to its original state; and means for transferring the container at least partially under gravity from the container outlet to an outfeed conveyor.

10. Apparatus according to Claim 9, wherein the container outlet is located beneath the container inlet in the second direction.

* S **S eli C..

* S * * S I S * S I I * S S S. * * I I I * I I * S I * * * I. I I S S -16 - 11. Apparatus according to Claim 9 or Claim 10, wherein the second direction is substantially vertical.

12. Apparatus according to any of Claims 9 to 11, comprising means for releasably retaining the sample within the interrogation zone.

13. Apparatus according to Claim 12, wherein the means for releasably retaining the sample within the interrogation zone comprises a shutter mechanism.

14. Apparatus according to any of Claims 9 to 14, wherein the means for transferring the container to a outfeed conveyor comprises a chute.

15. Apparatus according to any of Claims 9 to 14, wherein the means for applying an alternating magnetic field comprises a coil element surrounding the interrogation zone.

16. A conveyor system comprising an infeed conveyor, apparatus according to any of Claims 9 to 15 for receiving containers from the infeed conveyor, and an outfeed conveyor for receiving containers from said apparatus.

17. A conveyor system according to Claim 16, wherein the infeed conveyor is configured to convey containers in an upright position.

18. A conveyor system according to Claim 16 or Claim 17, wherein the outfeed conveyor is configured to convey containers in a prone position.

* * .** *** *** * S * S * * * * S S S S * * S. * * S * S S S S S * * I * S *5 * S * .