Patent ID: 12188871

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Referring toFIG.1, there is shown schematically apparatus10for spectral or other optical analysis of pharmaceutical dosage forms12, and in particular of oral solid dosage forms such as tablets or capsules, although other types of dosage forms or indeed other kinds of objects altogether may be analysed using the apparatus.

The apparatus10is arranged and operated to provide improved consistency of spectral or other optical analysis across a batch of such dosage forms which are intended to be substantially identical. Dosage forms of a batch may typically be superficially identical or very similar, for example in terms of shape, size and composition, but may still comprise defects and/or variations especially in internal chemical content and composition. It may be important to detect such defects and variations as part of a manufacturing process or other test scenario.

Pharmaceutical tablets are manufactured in a variety of shapes, sizes and colours. Some tablets may be of multiple different colours. Tablet shapes include cylindrical or elliptical prism forms, often with bevelled edges, spherical, ovoid, lozenge forms and so forth. Tablets are frequently embossed or debossed with markings such as alphanumeric codes and other symbols, slots to assist breaking into parts, and other surface features. Some tablets carry printed surface markings, for example including alphanumeric codes and other symbols. Tablets are manufactured both in coated forms in which a surface layer comprises different components to an underlying tablet core, and in uncoated forms.

Pharmaceutical capsules, of which gel capsules are one particular form, typically comprise an encapsulating sleeve containing pharmaceutical powders or sometimes gels or fluids. A typical shape for a capsule is cylindrical with rounded ends, but other geometries are sometimes used, for example flattened cylindrical forms. The encapsulating sleeve is typically formed by joining two opposing end sections, which are frequently of different colours. Capsules are often printed with surface markings such as alphanumeric codes and other symbols.

The inventors have found that various physical features of dosage forms such as those mentioned above can affect the consistency of results of optical analysis between a number of such dosage forms of the same type or batch even if these are superficially identical. It has been determined that consistency may be reduced for example if such dosage forms are presented for optical analysis in different orientations or rotational states of those features with respect to the optical analysis equipment. Very few dosage forms which it might be desirable to analyse optically are essentially devoid of any such features or asymmetries, although some dosage forms may be sufficiently symmetric about one axis of rotational symmetry such that rotation of the dosage form about that axis is difficult to detect at least visually for example by a machine vision system, in which case rotation about this axis does not contribute in any effective way to consideration of rotational state of the dosage form during handling for subsequent optical analysis.

The apparatus as illustrated inFIG.1can be used to provide for automatic and sequential optical analysis of a plurality of such superficially identical or similar dosage forms, with improved consistency of optical analysis.

Typical application areas may be for monitoring chemical composition of dosage forms sampled from a production line or other manufacturing process. Determined properties of the dosage forms may include measurements or concentrations or quantities of one or more active ingredients or other components, as well as measurements or concentrations or quantities of polymorph forms, hydrated forms, solvate forms, salt forms, and degrees of crystallinity of one or more such active ingredients or components. The presence or concentration of impurities may similarly be detected.

The apparatus illustrated inFIG.1is particularly arranged to carry out Raman spectral analysis of dosage forms12, although other types of spectral or more generally optical analysis could also or instead be implemented. To this end the apparatus comprises a Raman analysis station20which is arranged to detect Raman spectral features33in probe light scattered within a dosage form12when positioned in a test location22of the station.

The Raman analysis station20ofFIG.1comprises a laser source24arranged to generate a laser beam of probe light, typically of infrared light, delivery optics26arranged to direct the probe light to a dosage form12in the test location22, collection optics30arranged to receive probe light following scattering, including Raman scattering, within the dosage form12, and a detector32arranged to detect Raman spectral features33of the dosage form present in the scattered probe light.

Typically, the laser source24may operate in the near infrared, for example around 700 to 1000 nm, either as a continuous wave or pulsed source. Suitable average optical output power delivered to the dosage form12may be around 50 to 1200 mW, and a suitable spot diameter of the probe light beam at the dosage form12may be in the region of around 1 to 10 mm. Particularly small spot sizes may be avoided due to risks of heat damage to the dosage form under test.

When implementing Raman spectral techniques, the collection optics30and/or detector32are usually designed to incorporate very good suppression of the wavelength band (i.e. fundamental wavelength) of the probe light as emitted by the laser source24. Raman scattering cross sections are very small, so without such suppression the fundamental wavelength is likely to adversely affect accurate detection of the Raman spectral features, even though these may be spaced by tens of nanometers or more in wavelength from the laser wave band. This suppression may be achieved using one or more optical filters such as holographic notch filters in the collection optics30to suppress the laser waveband light which has been elastically scattered through or around the pharmaceutical solid dosage form to be tested.

Suppression of the laser waveband light in the collection optics30when detecting Raman spectral features33reduces the need to avoid stray probe light reflecting or scattering around the dosage form12and into the collection optics, as would usually be necessary if using infrared absorption spectroscopy and some other spectroscopic techniques. As a result, the dosage form to be tested can be suspended at the test location22without particular need for a carrier or other structure providing an optical seal around the sides of the dosage form between the delivery optics26and collection optics30to prevent such stray light. The dosage form can therefore be suspended between the deliver and collection optics without requiring to be seated within any holder or carrier.

The dosage form12may therefore be held in the test location22in a “free space” configuration without need for particular optical barriers or optical sealing around the dosage form. In turn, this enables some increased design flexibility in how the dosage form is carried to, held in, and removed from the test location22, for example using a mechanical gripper to hold the dosage form through all of these steps, as discussed in more detail below. Similarly, the mechanical gripper discussed below need not be provided with any light blocking baffles for example in the form of elastically yielding material.

A dosage form12may be presented in the test location22at a particular fixed position and state of rotation (orientation/alignment) for the duration of optical testing, or may be moved/rotated between a number of discrete positions with optical testing taking place at each discrete position, and/or may be moved (including either or both of translational movement and rotation) with optical testing taking place during the course of that movement, such as in a scanning action. Such movements may be implemented using the dosage handler described in more detail below, for example by movement of the dosage form within the test location using a gripper90. However, this geometry of the optical analysis may instead or additionally be varied between discrete testing geometries and/or by scanning using by movement or adjustment of delivery optics26and/or collection optics30of the Raman analysis station used to deliver probe light to the dosage form and to collect scattered light from the dosage form, or a combination of these aspects.

Multiple optical measurements obtained in such ways during the presentation of a particular dosage form may be combined for example to obtain a more representative optical measurement of the dosage form. For example, by testing a particular dosage form with a laser spot directed at multiple different locations and/or scanned across a range of locations, the optical measurements may better represent the entire bulk of a dosage form. Such techniques may also permit a smaller and/or more consistent laser spot size on the dosage form to be used.

The detector32may be implemented in various ways, for example as a spectrometer covering a suitable waveband to detect the desired Raman spectral features33, for example a Kaiser Optical Technologies Holospec device. Coupling of laser light from the laser source24to the delivery optics26, and between the collection optics30and the detector32may typically be achieved using optical fibres, although free space transmission arrangements could be used as well or instead.

Spectral data describing at least aspects of the detected Raman spectral features33may be passed from the detector32to an analyser34which is arranged to determine properties of the dosage form from the spectral data, such as the various chemical properties mentioned above. The spectral data may typically take the form of a readout from a CCD or other imaging component of the detector32, and the analyser34may then be arranged to detect aspects such as the magnitudes of particular Raman spectral peaks and other features which represent particular chemical components expected or looked for in the dosage form under test, broader spectral matches to spectra or multiple spectral features of such components, and so forth, for example with reference to one or more data libraries defining expected spectra and/or particular spectral features of such components.

Spectral data and/or determined properties of the tested dosage form may be used in various ways, for example being stored locally and/or remotely, transmitted across a network, further analysed, used to control a process such as a manufacture process used to create the dosage form under test, and so forth. InFIG.1a local personal computer36is shown as receiving the determined properties, and may for example provide output of aspects of the determined properties to a person monitoring the apparatus10, for example in the form of displays of deviations of determined properties from expected values, audible or visible alerts to bring the attention of such a person to sufficiently significant deviations, and so forth.

Typically, the probe light may be directed by the delivery optics26to a first surface40of a dosage form12located in the test location22, and probe light scattered within the dosage form may then be collected from a second surface41spaced from the first surface. In this way, the collected probe light will have been scattered at depth within the dosage form12under test, and detected Raman spectral features33will be representative of bulk properties of the dosage form.

Generally, the second surface41may be spaced from the first surface40in such a manner that forward scattering of Raman scattered elements of the probe light are transmitted to the second surface to be collected and detected, so that the dosage form is analysed in a transmission or forward scattering geometry. Although different arrangements are possible, typically the second surface41may be on an opposite side of the dosage form to the first surface40. An example of this is illustrated for a tablet dosage form12′ shown in expanded view inFIG.1, in which the first surface40is a first flat surface of the tablet dosage form12′, and the second surface41is a second flat surface of the tablet dosage form12′ which is opposite the first surface40. For some dosage forms and more commonly for tablet forms, each of the first and second surfaces may be substantially parallel, often circular, and spaced from each other by a sidewall.

Some ways in which the Raman analysis station20may be arranged and operated to implement analysis using such transmission or forward scattering geometries are described in WO2007/113566, the contents of which are incorporated herein by reference for all purposes.

In some other arrangements, the Raman analysis station20may also or instead be arranged to carry out Raman spectral measurements of the dosage form12in other geometries and modes, for example using a spatially offset Raman spectroscopy (SORS) mode of operation. In such a mode, probe light is delivered by the delivery optics26to one or more entry surface regions of the dosage form12, and the collection optics30are used to collect scattered probe light from one or more collection surface regions that are laterally spaced from the entry region(s). Raman spectral features13are then detected in the collected light by detector32.

The depth profile of the Raman scattering which gives rise to the Raman spectral features13in the collected light is then dependent on the lateral spacing. A single spacing between entry and collection surface regions can be used, or Raman spectral features from multiple spacings can be combined to provide more detailed depth dependent measurements, for example a profile of Raman scattering and consequent spectral features as a function of depth within the dosage form. This technique and various implementation details are discussed for example in WO2006/061565 and GB2541110, the contents of which are incorporated herein in their entirety for all purposes.

The Raman analysis station10may as well or instead be arranged to implement Raman analysis of a dosage form using other geometries, arrangements or techniques, and in some embodiments other spectral techniques such as ultraviolet, visible, or infrared absorption or reflection spectral techniques, fluorescence techniques, and so forth may be used as well or instead or Raman spectroscopy. In some such modes of optical analysis, delivery and collection optics may be separate or combined or be provided in other more complex forms, with backscatter, transmission or of other types of geometries being used.

As already mentioned above, various asymmetries and features of a dosage form under test, such as overall shape, surface, colour features, debossing and embossing, and printed markings, can affect the results of optical analysis, and very few dosage forms which it might be desirable to analyse optically are essentially devoid of any such asymmetries and features.

When carrying out optical analysis of a dosage form12, for example using the Raman analysis station20described above implementing a transmission geometry, variations in the orientation as well as the position of the dosage form within the test location22are found to give rise to variations and errors in the detected Raman spectral features33and therefore also in the detected properties of the dosage form under test. Variations in orientation of the dosage form under test can give rise not only to overall changes in intensity of the collected light, but also variations in the relative strengths and apparent wavelengths of various spectral features, for example due to interactions with geometries and properties of the delivery optics, collection optics, and the detector. Different orientations of the dosage form can also give rise to different distributions of both elastic and Raman scattering within the volume of the dosage form.

To achieve more consistent results of optical analysis between similar or essentially identical dosage forms it has been found beneficial to present each such dosage form for optical analysis in the same orientation. Some particular example situations are:if a batch of dosage forms comprises tablets with a particular debossing or printing or other markings on one flat face, then those markings should be consistently oriented for testing, for example always facing upwards, or always facing downwards, and always rotated in the horizontal plane to the same orientation;if a batch of dosage forms comprises capsules each with two ends of different colours, those ends should be consistently oriented in the same way; andif a batch of dosage forms comprises capsules with printing along a cylindrical side wall then that printing should be consistently oriented.

The apparatus ofFIG.1comprises a dosage source42which is arranged to provide dosage forms to a dosage handler60. For example, the dosage source may comprise or be arranged to accept one or more singulator hoppers43, each singulator hopper being arranged to release one dosage form at a time under control of a controller50. In this way multiple batches of dosage forms may be loaded for analysis, each in a separate singulator hopper43containing perhaps tens to hundreds of such dosage forms, and the controller can then provide automatic, scheduled processing of these batches. Each such batch, or each of two or more of the singulator hoppers, may conveniently contain a different type of dosage form, for example different in terms of any of geometry (size, shape etc.), pharmaceutical content, markings, colour, and so forth. The described apparatus is particularly beneficial in being able to handle such different types of dosage forms without any particular physical change or modification to the apparatus, so that multiple different batches of dosage forms can be processed in a single operating session without user intervention.

The singulator hopper or hoppers may be arranged to deliver each dosage form to a feed mechanism44. The feed mechanism44could for example comprise a carousel having multiple peripheral apertures each for receiving one such dosage form12, the carousel rotating to transfer received dosage forms to be released one at a time from the dosage source42to the dosage handler60.

The dosage handler60receives a series of dosage forms of the same type or batch from the dosage source42, and is then automatically operated by the controller50to consistently set at least some aspects of the rotational state of each such dosage form for presentation at the test location22of the Raman analysis station20(for example alignment of a dosage axis of the dosage form into a preferred direction and/or orientation of the dosage form about that dosage axis). In this way, potential errors and variations in detected properties of the dosage forms which could otherwise arise due to inconsistencies in rotational state at the test location22can be minimised or reduced. To this end, the controller may comprise or be provided with alignment/orientation data52defining a predefined or preferred rotational state such as alignment and/or orientation for each type or batch of dosage forms which may be delivered to the dosage handler60by the dosage source, to be used as described in more detail below.

Following the optical analysis, the dosage handler60carries out an output operation. Typically, the output operation should permit each optically tested dosage form to be uniquely and accurately located or identified for possible further testing or analysis. To this end, the dosage handler60may deposit each tested dosage form in a different cell of an output tray45, in such a manner that the cell used for that particular dosage form can later be identified either manually or as part of a further automatic process.

FIG.2illustrates schematically how the dosage handler60ofFIG.1may be implemented to provide the desired improved consistency of alignment and/or orientation in optical analysis of a plurality of dosage forms of a single type or batch. The dosage handler60comprises a handling table70which provides a table surface72on which each dosage form12delivered from dosage source42can be manipulated. The table surface72may preferably be level, i.e. substantially horizontal. The table surface72may be smooth, or may be textured in some way, either in one or more regions or across the whole table surface72. For example, a surface texture may be provided which permits a dosage form12to be pushed or slid across the table surface72but which prevents or reduces unwanted rolling or other movement of a dosage form. Suitable surface textures may for example comprise small repeated protrusions such as in pyramid or conical forms, small repeated indentations or dimples and so forth. Such features may for example have a height or depth, and a repeat period, of less than about 1 mm.

The dosage handler60illustrated inFIG.2comprises a rotation stage74having a rotation stage surface75which is arranged to receive and rotate a dosage form12to a predetermined, preferred alignment, for subsequent grasping for carrying to and analysis by Raman analysis station20. The rotation stage surface75may typically be flush with, or form part of, the table surface72of the handling table (and therefore typically also level or substantially horizontal) to enable a dosage form12to be pushed across the table surface72and onto the rotation stage surface75as discussed in more detail below. The rotation stage surface75is arranged to rotate about a rotation stage axis77which is substantially perpendicular to the rotation stage surface and the table surface, so typically approximately vertical if the table surface is approximately horizontal. In other words, the rotation stage used to rotate the dosage form about a typically vertical axis to achieve the desired rotational alignment about that axis.

To achieve the preferred alignment, the dosage handler60also comprises a machine vision system80to detect at least some aspects of rotational state of the dosage form for example when present on the rotation stage surface75, and to pass the detected aspects to the controller50so that the preferred alignment of the dosage form can be achieved by rotating the rotation stage74by suitable control of a rotation stage motor76(which may be considered to be comprised in the rotation stage74in some embodiments). For example, the machine vision system80may detect a starting alignment of a dosage form on the rotation stage surface, and pass this starting alignment to the controller which then rotates the rotation stage to bring the dosage form into the preferred alignment. In other embodiments the machine vision system may monitor the alignment of the dosage form as the rotation stage is rotated, and the controller is then arranged to stop the rotation when the preferred alignment is achieved.

The machine vision system80may comprise at least one camera82having a field of view comprising at least part of the rotation stage surface75, typically looking downwards at the rotation stage, and a machine vision processor84arranged to receive one or more images of a dosage form12located on the rotation stage surface and to detect desired properties of the dosage form12, including aspects of rotational state such as alignment and orientation, from the images. Although depicted as a separate entity inFIG.2, the machine vision processor84may be provided as part of the controller50if desired.

The machine vision processor84may detect other properties of the dosage form12in addition to aspects of rotational state, for example location of the dosage form on the rotation stage surface75, and positive or negative identification of the dosage form as being of a particular type or from a particular batch, for example using features such as those described above which may include shape, size, printed markings, surface embossing and debossing markings, colour areas and so forth, and pass such detected properties to the controller50, analyser34, personal computer36or other suitable element. For example, the controller50may control the dosage handler60to handle a dosage form differently depending on what type of dosage form is detected, for example orienting the dosage form in a manner specific to that type for optical analysis.

The machine vision system80may also be used to determine dimensions of a dosage form (it may be required to check these against desired dimensions), such as a diameter of a dosage form of round plan view, or more specific length and width dimensions of dosage forms of other plan forms such as ellipses, rectangles, or capsule forms. Other suitable measures could include plan view surface area. Thickness of a dosage form between two largely planar opposing surfaces, such as thickness of a tablet may also be determined by the machine vision system, although this may require some specific manipulation of the dosage form to ensure that the dosage form edge is suitably presented to the camera82. In some cases the machine vision system may take sufficient dimensional and/or area measurements to enable a volume of the dosage form to be calculated.

For a particular type or batch of dosage form, the preferred alignment may be defined (for example in the alignment/orientation data52available to the controller) with reference to a dosage axis of the dosage form, which can be predefined and at least implicitly recognised from imagery of such a dosage form using the machine vision system80. Rotation of a dosage form on the rotation stage to a preferred alignment then equates to rotation of a predefined dosage axis of the dosage form into alignment with a target axis parallel with the rotation stage surface, where the target axis may typically be fixed with respect to the dosage handler60or one or more other parts of the apparatus10.

FIG.3ashows how a dosage axis13and therefore a preferred alignment (i.e. rotational orientation) of a dosage form may be defined. In this case, an essentially cylindrical capsule12″ is shown as having a dosage axis13which corresponds in this case to the axis of rotational symmetry of the cylinder. A preferred alignment of this capsule may be when the dosage axis13is parallel with a target axis (not shown in the figure). If the capsule12″ or other dosage form is not symmetrical under a reversal of direction or reflection along this dosage axis, for example having different coloured ends or other asymmetric features as shown in the figure, then the preferred alignment may require the dosage axis to specifically be parallel or anti-parallel to the target axis.

Because the alignment of the dosage form on the rotation stage may determine how the dosage form is grasped for carrying to the test location, selection of the dosage axis may also take into account the expected stability of hold by a gripper when grasped along, or in an orientation defined relative to, this axis.

If additionally the capsule12″ includes features which make it asymmetric in rotation about the dosage axis13, such as the printed characters shown in the figure, then as well as rotating the dosage axis to a preferred alignment it may be desirable to rotate the dosage form about the dosage axis, or another axis substantially parallel to the surface of the rotation stage, to a preferred orientation of rotation, for example using the gripper described in more detail below.

FIG.3bshows another example of how a dosage axis13may be defined, in this case for a tablet12″′ having an debossed snap line feature or break line14on one of the two opposing circular faces of the tablet12″′. In this case, a preferred orientation of rotation about the dosage axis could be to have the snap line facing in a particular direction, for example either upwards or downwards, or possibly either facing to the left or right in the figure.

Referring back toFIG.2, the dosage handler60also comprises an element for moving the rotated dosage form to the testing location. InFIG.2, this element is provided by a gripper90which is arranged to grasp the dosage form12after rotation into the preferred alignment using the rotation stage, and to carry the grasped dosage form to the testing location22of the Raman analysis station20, with these actions being carried out under control by the controller50.

In being carried from a position where the dosage form on the rotation stage is grasped by the gripper, to a position where the dosage form is presented for analysis at the testing location22, the alignment and optionally other aspects of the orientation of the dosage form may remain fixed, or they may be changed in a controlled and known manner so as to achieve a consistent alignment and/or orientation of the dosage form at the testing location. However, following optical analysis there will usually be little or no need to retain a known or accurate alignment or orientation of the dosage form during the subsequent output operation.

The gripper90may also be arranged to rotate a grasped dosage form about a gripper rotation axis96, which may for example be an axis parallel to the rotation stage surface75(so typically a horizontal axis), to a preferred orientation of rotation. This may be achieved by using the gripper to grasp the dosage form, lift the dosage form above the rotation stage surface75, rotate the dosage form, and return the dosage form to the rotation stage surface75, and release the dosage form. Such a sequence could be used if it is preferred for the gripper to return to another rotation and/or translation condition before grasping the dosage form again for carrying to the testing location. Alternatively, the gripper could rotate the dosage form following grasping and lifting, without again placing the dosage form onto the rotation stage surface, for example as part of the movement to carry the dosage form to the testing location, or indeed at the testing location. As another alternative, such lifting and/or replacing of the dosage form by the gripper could take place on one or more other parts of the table surface away from the rotation stage, and in some arrangements or operations there may be no need to lift the dosage form before carrying out the rotation, for example if the rotation is about an axis of symmetry of a cylindrical form.

Typically, the gripper90may comprise opposing jaws92,94which are arranged to close towards each other and onto a dosage form to thereby grasp the dosage form. Although the dosage axis may be defined in various ways in order to fulfil the requirement of rotation using the rotation stage to a preferred alignment as discussed above, the dosage axis may conveniently be defined as an axis along which the gripper jaws approach so as to close onto the dosage form for grasping and carrying the dosage form to the test location.

As illustrated inFIG.2, the gripper rotation axis96may also be parallel to the axis along which the gripper jaws close, and therefore also the target axis mentioned above which is the same as the dosage axis when the dosage form is in the preferred alignment on the rotation stage74.

Each gripper jaw92,94may be designed to function in a satisfactory manner for all anticipated dosage forms without need to customise shape or change gripper jaw for any particular dosage form or class of dosage form. To this end, each gripper jaw may comprise a concave surface98, these concave surfaces being opposed to each other and presented to a dosage form for grasping the dosage form when the jaws approach each other. Each concave surface may have a suitable radius of curvature for providing a more secure grasp of a typical dosage form to be handled, for example with a radius of curvature of between about 3 and 10 mm.

More generally, methods of operating the apparatus may comprise the dosage handler delivering each of a plurality of dosage forms of a first geometry (for example shape, size etc.) to the test location for optical analysis, and then delivering each of a plurality of dosage forms of a second, different geometry to the test location for optical analysis without changing or modifying the gripper jaws.

In order to control the gripper to rotate the dosage form to a preferred orientation of rotation, for example as defined by the alignment/orientation data52, the machine vision system80is also arranged to detect orientation of rotation of the dosage form for example about the gripper rotation axis and/or the dosage axis and to pass this detected orientation to the controller. This could be done either as a starting orientation from which the controller can determine a required amount of gripper rotation, as an ongoing detection of the orientation as gripper rotation takes place, or in other ways.

Translational movement of the gripper90as a whole is provided by multi-axis staging100, typically having three translational axes so as to enable the gripper to move to a position on the table to grasp as dosage form, to lift the dosage form from the table, to carry the dosage form to the test location22, and to complete the output operation. To this end, the machine vision system80is also arranged to detect a lateral position of the dosage form on the rotation stage, and to pass the detected lateral position to the controller for controlling the gripper to grasp the dosage form in the detected lateral position both by suitable control of the multi-axis staging100and of the gripper jaws92,94.

The gripper may be arranged such that both gripper jaws move relative to the multi-axis staging100as the jaws close towards each other. Alternatively, one jaw may be stationary relative to the staging100(for example the distal jaw92which is further from the staging100inFIG.2), while the other jaw is arranged to translate relative to the staging (for example the proximal jaw94which is closer to the staging100inFIG.2).

In addition to the rotation stage74and rotation stage surface75, the handling table70may comprise other structures and areas for handling, analysing and otherwise processing a dosage form. For example, as illustrated inFIG.2, the handling table70may also comprise a weighing scale110comprising a weighing scale surface112. The weighing scale surface112is preferably flush with or forms part of the table surface72, so that a dosage form can be slid or pushed across the table surface72and onto the weighing scale surface112. The weighing scale is coupled to the controller50so that the weight of a dosage form can be received from the weighing scale, for example for reporting to the personal computer36or other parts of the apparatus. The determined weight of a dosage form can be used, for example in conjunction with other properties determined by the machine vision system, and/or analyser34to help determine whether the dosage form meets particular required specifications, or to help determine if the dosage form is of the expected type or from the correct batch.

Although depicted as separate inFIG.2, in some embodiments the weighing scale may be incorporated into rotation stage.

The handling table surface72as shown inFIG.2also comprises a drop zone120, which is a region of the table surface72onto which the dosage form source is arranged to deposit a dosage form for manipulation and analysis. Providing such a drop zone120which is separate from the weighing scale surface means that impact of a dosage form dropping onto the drop zone120does not adversely affect the accuracy of the weighing scale. Once the dosage form has been dropped onto the drop zone120by the dosage source, it can be moved for example by sliding or pushing for subsequent weighing by the weighing scale110.

Some or all of the rotation stage surface75could in principle be used as the drop zone, but robotic layout and workflow considerations make it advantageous for these areas to be kept separate.

The dosage handler60may also comprise an element for pushing or sliding a dosage form across the table surface72. InFIG.2this is illustrated as a box slider130which, in the plane of the table surface72or from a top view surrounds a dosage form when in position to or in the process of pushing or sliding the dosage form, although other forms of slider which do not necessarily surround the dosage form could be used. The illustrated box slider130shown inFIG.2provides a closed rectangular perimeter around the dosage form to be moved, but other forms can be used subject to the slider being useful for accurate positioning of a dosage form where required on the table surface72. The box slider ofFIG.2has lateral dimensions of about 30 to 60 mm along each side.

In particular the box slider130may be controlled by the controller50to move to the drop zone120so as to receive a dosage form within the box slider130from the dosage source42. The box slider is then controlled to move the received dosage form to the weighing scale surface112for weighing, and then on to the rotation stage surface75for alignment and/or orientation before being transported by the gripper90to the test location22.

In order to leave a dosage form at the rotation stage surface73, the box slider130is provided with an axis of translation perpendicular to the table surface72, typically in a vertical direction, so that it can be lifted sufficiently to clear the dosage form. Additionally, the box slider130will typically be provided with two axes of translation so as to be able to move a dosage form to a variety of locations on the table surface72as may be required by the manipulation process to be carried out.

Conveniently, the box slider may be mounted to the same multi-axis staging100as the gripper90. For constructional efficiency and use, the dosage handler60may then be arranged such that the drop zone120, weighing scale surface112, and rotation stage surface75are generally disposed in that order along a process axis125of the dosage handler60generally indicated inFIG.2, and the test location22of the Raman analysis station may then also be disposed generally further along the same process axis125from the rotation stage surface75. The multi-axis staging100used to move the position of the gripper90may also provide the required movement of the box slider130along the process axis125between the drop zone120, the weighing scale110and the rotation stage74.

The process axis125may correspond to a principle axis of motion of the multi-axis staging100, for example by movement of the multi-axis staging along a rail102or similar structure which extends along or parallel to the process axis125. In practice, three separate axes of motion may be commonly provided to both the gripper and box slider by the multi-axis staging. In the arrangement ofFIG.2these axes would provide movement along the process axis, in a perpendicular depth direction across the table surface, and vertically. However, in some arrangements one or more of these axes could be separately provided for each of the gripper90and the box slider130, for example with each of the gripper and box slider being provided with separate vertical or separate depth control axes.

FIGS.4a,4band5use flow diagrams to illustrate some ways in which the apparatus described above may be automatically operated, for example by controller50, so as to present a dosage form in a consistent rotational state such as alignment and/or orientation at the test location22of the Raman analysis station20or other spectral or optical analysis arrangement. Although particular sequences of process steps are illustrated and discussed, subsets of these steps may be used without all of the other steps, and the steps need not necessarily be used in the described and illustrated order.

In step410ofFIG.4a, a dosage form is received on a rotation stage74. The dosage form may be received on the rotation stage in various ways, for example as discussed above, and below in connection withFIG.5.

At step415the rotation stage is rotated so as to rotate the dosage form about an axis of rotation77of the rotation stage, typically a vertical or substantially vertical axis, into a preferred alignment or orientation about that axis. As discussed above, the amount of rotation required to achieve the preferred alignment of the dosage form may be determined using a machine vision system80comprising a camera having a field of view which includes some or all of the rotation stage74. The preferred alignment of the dosage form may be achieved by aligning a predefined dosage axis13of the dosage form which can be identified using the machine vision system with a target axis typically fixed with reference to non-moving parts of the apparatus such as the machine vision system.

The dosage form is then grasped using the gripper90, in the preferred alignment, at step418, and picked up from the rotation stage. The dosage form is then carried by the gripper90to the test location22of the optical analysis station, at step425, for optical analysis at step430. An optional step shown as step420inFIG.4amay also be carried out after, or in some cases before, rotation of the dosage form to a preferred alignment using the rotation stage. This additional step comprises using the gripper90to rotate the dosage form about a gripper rotation axis92to a preferred orientation. The gripper rotation axis92is typically oblique or substantially perpendicular to the rotation stage axis77, so may typically be horizontal or substantially horizontal, and/or parallel to a surface72of the rotation stage on which the dosage form is supported.

Rotation to the preferred orientation may for example take place in part or whole while the dosage form is still on or just above the rotation stage, and/or during movement to the test location, and/or on arrival at the test location, as demonstrated by the three alternative time points (a), (b) and (c) inFIG.4a.

In this way, the preferred alignment and/or orientation of the dosage form is preserved, albeit with any known subsequent rotations due to controlled movement of the gripper, until an optical interrogation at the test location has been completed, following which the dosage form can be released from the grasp of the gripper.

Optical interrogation of the dosage form is carried out at step430, and in particular this may be Raman interrogation to determine Raman spectral features, or other types of spectral or optical analysis as discussed elsewhere in this document. The optical interrogation may in particular be carried out in a transmission configuration, for example by directing laser probe light to a first surface region of the dosage form, collecting elements of the laser probe light scattered within the dosage form from a second surface region of the dosage form, the second surface region being on an opposite side of the dosage form from the first surface region, and detecting Raman or other spectral features in the collected light.

As already noted above, the dosage form may be presented using the gripper in the test location22at a particular fixed position and state of rotation (orientation/alignment) for the duration of optical testing, or may be moved/rotated between a number of discrete positions with optical testing taking place at each discrete position, and/or may be moved (including either or both of translational movement and rotation) with optical testing taking place during the course of that movement, such as in a scanning action.

Finally, properties of the dosage form are determined at step435. Such properties may be chemical properties of the dosage form such as the presence or proportions of particular chemical species or forms, and such properties can be determined from the detected Raman or other spectral features. Various notifications and/or alerts can then automatically be generated for the attention of an operator of the apparatus, for example alerts indicating properties of one or more dosage forms lying outside preferred ranges.

By using a transmission geometry, and by using Raman spectral analysis, various useful chemical and constitutional properties of the internal bulk, rather than just from the surface regions of the dosage form, can be determined. However, such transmission analysis can be sensitive to the precise rotational state such as alignment/orientation of a dosage form in the test location22, and by carrying out a suitable alignment/orientation using the rotation stage and/or gripper, and preserving that rotational state using the gripper (albeit with subsequent known rotations), more consistent results of the Raman spectral analysis can be achieved.

The gripper may be used for other operations and actions in addition to those described above and illustrated inFIG.4a. For example, it may be required to “flip” a dosage form over so that a preferred face of the dosage form is facing upwards and towards the camera82, either before or after the dosage form is rotated to the preferred alignment. Such an operation could enable the machine vision system80to better determine or control a correct alignment of the dosage form, for example if suitable markings are only seen on one main face of a dosage form, in which case such a flip operation may be undertaken by the gripper before the rotation stage operation. In another example as discussed below the gripper may be used in presenting an edge of a dosage form to the machine vision system in order to assist in determination of a thickness of the dosage form.

The machine vision system80may be used to obtain various dimensional measurements of a dosage form when the form is lying on the rotation stage and/or held by the gripper. Typically, the machine vision system may comprise a camera82having a downward view onto the rotation stage as shown inFIG.2. If the dosage form has two opposing major faces, as is typical for tablets and some other forms, then although plan view dimensions may easily be obtained when the dosage form is lying flat with such a major face on the rotation stage using a downward view camera, it may also be desirable for the machine vision system80to determine a thickness between the two opposing major faces, and this dimension will be hidden from the camera in such a view. Such a dosage form may typically be a tablet or similar comprising two opposing circular faces with a side wall of approximately constant width extending between these faces, but other face shapes and geometries may be used.

To this end, the gripper90may also be used, under control of the controller and with use of the machine vision system80, to present an edge face or side wall of the dosage form to the camera82of the machine vision system80so that a thickness of the dosage form can be determined, for example by the machine vision processor84. This may be carried out before or after step415inFIG.4a, for example depending on whether a particular rotational state of the dosage form is required for it to be picked up by the gripper.

In some examples, the gripper may be used to lift and rotate the dosage form, for example through 90 degrees, before replacing it on edge on the rotation stage. The gripper then releases the dosage form and can also be moved out of the way in order to provide the machine vision system with a clearer view of the dosage form. In other examples, the gripper may rotate the dosage form, for example through 90 degrees, to present an edge view to the machine vision system while retaining grasp of the dosage form and without placing the dosage form on edge on the rotation stage. For some designs of gripper90particular rotations might be required to ensure that a sufficiently clear view of the dosage form edge is still obtained.

In either case, the machine vision system is then used to acquire and output suitable dimensional data of the dosage form from the edge view in order to determine a thickness of the dosage form.

If the dosage form is placed on edge onto the rotation stage for determination of thickness following a rotation step415ofFIG.4a, then it may be possible to use the gripper to pick up the dosage form again from this position and proceed with steps425,430and435ofFIG.4a, and optionally also step420. However, the process of placing the dosage form on edge may instead require the dosage form to be returned to a state on the rotation stage where a major face is flat on the stage, either by direct handling using the gripper, or knocking the dosage form over in some manner, such that rotation of the stage under step415may needed to be repeated after the edge thickness determination.

Some ways in which the above dimensions measurements may be implemented are shown inFIG.4b. At step450a dosage form having opposing major faces separated by an edge face is received beneath the machine vision system camera82, which in the context ofFIG.4amay be step410where the dosage form is received on the rotation stage, but may be on some other surface or part of handling table70. At step455the machine vision system camera82is used to detect dimensions of the major face of the dosage form which is in plan view beneath the camera. Such dimensions could be a diameter of a circular dosage form, length and width dimensions of an ellipsoidal or rectangular tablet, a plan view surface area, and so forth. If the dosage form is also being manipulated according to a scheme such as that ofFIG.4athen step455may take place before or after s step415of rotating the dosage form into a preferred alignment.

At step460the gripper90is used to grasp the dosage form and rotate the dosage form to present the edge face to the machine vision system camera82. For example a portion of the edge face closest to the camera may be rotated to be substantially horizontal, but other angles of presentation relative to the camera could be used which give sufficient accuracy of measurement. The gripper might then either put down the dosage form on edge and move away to give the machine vision system a clear view of the dosage form, or might retain grip of the dosage form if this still provides a sufficiently clear view. At step465the machine vision system is used to detect a thickness of the dosage form using the visible width of the edge face. If the dosage form is also being manipulated according to a scheme such as that ofFIG.4athen step460may be followed by repositioning the dosage form to lie on a major face before carrying out, or carrying out again rotation step415if necessary, or step465might be followed by step425(and optionally step420) in which the dosage form is carried to the test location without necessarily needing to be put down by the gripper again on the rotation stage.

FIG.5shows steps which may be implemented automatically, for example under control of a controller50, in order to provide a dosage form to the rotation stage74so that a method such as that ofFIG.4acan be carried out.

In step510a dosage form is received at a drop zone120of a handling table70which also comprises the rotation stage74. The handling table70may also comprise a weighing scale110, and the rotation stage and weighing scale may be flush or form part of the handling table such that a dosage form can be pushed or slid across the handling table between these stations. The drop zone is provided separately on the handling table70to the weighing scale if provided, so that dropping of the dosage form onto the handling table does not affect subsequent performance of the weighing scale which could take some time to return to an equilibrium if the dosage form was dropped directly onto the weighing scale, thereby slowing down the handling and optical analysis process.

The dosage form may be delivered to the drop zone120by a dosage source42as described elsewhere in this document, which may itself comprise or be arranged to accept one or more singulator hoppers43each capable of carrying a batch of tens or hundreds of dosage forms of the same type and to be tested in the same way, and of delivering one such dosage form at a time to the drop zone.

At step515the dosage form received at the drop zone is moved by sliding or pushing across the handling table onto the weighing scale110, if provided. The dosage form is then weighed at step520, and then moved by sliding or pushing across the handling table onto the rotation stage at step525. At this point, the steps ofFIG.4amay then be carried out.

The sliding or pushing of the dosage form across the handling table may be carried out by a slider element, for example the box slider130illustrated inFIG.2. Such a box slider which surrounds the dosage form in all horizontal directions permits the dosage form to be dropped by the dosage source42in step510without risking the dosage form bouncing away from an expected location or off the handling table altogether. The box slider form then also permits the dosage form to be moved accurately in any horizontal direction under control of the controller50, to any desired position for example at the centre of the weighing scale or the centre of the rotation stage.

The described apparatus may also be used to carry out an automated series of tests on the same or a series of dosage forms of the same type. Such a series of tests can be used for example to determine operating characteristics of the apparatus, such as accuracy and repeatability of the presentation of a dosage form at the test location22, and therefore also of the resulting optical analysis and determined properties of such a type of dosage form. To this end, the described apparatus may for example be used to carry out a method as outlined inFIG.6.

InFIG.6, a dosage form is received at the handling table70in step610, for example at a drop zone120of the handling table. The dosage form is then manipulated using the dosage handler apparatus at step620, for example including use of one or more of the box slider130, weighing scale110, rotation stage74, gripper90, and multi-axis staging100as described above. The dosage form is then presented at the test location22in step630in one or more preferred rotational states (combinations of orientations and alignments as required) and/or translational positions by the gripper90for optical interrogation by detection of Raman spectral features using the Raman analysis station20. As discussed above, such rotational states and/or positions may include just a single such rotational state and position, or movement between multiple such configurations with optical analysis being carried out at each such configuration and/or continuously during such movement in the form a scanning operations.

If the series of tests is complete at decision point640then the data received from the series of optical interrogations may be analysed to determine one or more parameters of the handling, presentation and analysis process at step650, but otherwise the dosage form may be returned to the handling table70in step660, for example using the gripper90to return the dosage form to the drop zone120, following which the steps of manipulation and presentation to the Raman analysis station20are repeated using the same dosage form.

Instead of handling and presenting the same dosage form each time to the Raman analysis station20, a presented dosage form could be discarded and a new dosage form of the same type used for the next test sequence ofFIG.6. Instead of presenting a dosage form each time in the same orientation, alignment and position, the dosage handler could instead present a dosage form in a range of different such configurations.

The step650of determining parameters of the handling, presentation, and analysis process could take various forms. If a dosage form is presented in the Raman analysis station20each time using a supposedly identical rotational state, alignment and position, then the parameters may comprise one or more parameters representing measures of variance of a property of the dosage form such as the absolute content of an active pharmaceutical ingredient under these supposedly identical configurations.

If aspects such as rotational state and position of the dosage form at the time of optical interrogation are varied from one presentation to the next in order to test a range of such aspects, then the parameters determined in step650may represent how adjusting such aspects affects the results of the optical analysis. Such parameters or results can then be used to design an improved or optimised scheme for presenting dosage forms of the same or similar types at the test location22.

The described apparatus can therefore be used to test the impact of variance and determine precision of the results of the optical measurements due to various different factors including variance in the handling and presentation of the dosage forms and variance in the optical measurements. The described apparatus can also be used to establish an improved or optimised scheme or handling and presentation of the dosage forms.

An apparatus10as described above and arranged to carry out handling and analysis of pharmaceutical dose forms as discussed may typically be capable of carrying out Raman spectral interrogation of a single dosage form in around a few seconds to a few tens of seconds, with this time period depending on the required signal to noise ratio of Raman spectral feature detection and consequent accuracy of determined chemical properties, on what power level of laser beam irradiation of each dosage form is acceptable, and other factors such as the types of optics and optical detectors used. Consequently, the dosage handler should be arranged to handle a series of dosage forms at the same rate or faster in order to make best use of the optical analyser. For example, if the dosage source can be loaded with ten singulator hoppers each carrying a hundred dosage forms then around a thousand dosage forms may easily be analysed fully automatically within a few hours, with the improved accuracy of optical analysis resulting from aspects of the invention discussed above.

Some aspects of the described apparatus and methods may be implemented using computer program code executing on one or more suitable computer systems. Such computer systems will typically comprise one or more microprocessors to execute such computer program code, memory to store such programs and related data, and suitable input and output facilities including for example wired or wireless data connections, non-volatile storage, visual displays, and input device such as keyboards and mice.

The controller50for example may comprise one or more suitable computer systems programmed to carry out the described operations by control of the dosage source, gripper, rotation stage, multi-axis staging and other components in response to data received from the machine vision system, weighing scale, analyser, and other sources. Some or all of the image and data processing aspects of the machine vision system may be implemented in a separate computer system or may be implemented within the same computer system or systems used to provide the data processing required of the controller50. In some embodiments, the machine vision system may make use of the LabVIEW software (Laboratory Virtual Instrument Engineering Workbench) provided by National Instruments of Austin, Tex., to implement aspects such as identification of a particular type of dosage form, and various aspects of position and orientation of a dosage form.

The analyser may similarly be implemented using one or more computer systems using suitable software to receive a spectral data signal from the detector32, analyse and process that spectral data signal in various ways for example to reduce noise, transform into desired forms, and determine or measure particular spectral features, and to match detected spectral features with those of known or expected components or characteristics of the dosage form under test. Libraries of spectral features which may be used for such comparisons are available for example from S.T. Japan or Sigma-Aldrich.

It has been discussed above how the gripper90may be used to move a dosage form12during presentation in the test location, with multiple optical measurements being taken across a range of alignments (variations in translational position and/or rotational orientation) of the dosage form so as to obtain a more representative optical measurement of the dosage form. To this end,FIG.7illustrates a dosage form12which has been grasped by the gripper, for example while lying on the rotation stage74or other part of the handling table surface72, and which has been carried by the gripper90to the test location22provided within the Raman analysis station20. These and other actions and motions by the gripper90may be effected by a controller such as controller50depicted inFIGS.1and2, in combination with suitable motion providing elements such as the multi-axis staging depicted inFIG.2.

More particularly,FIG.7depicts the delivery optics26and collection optics30already described above, with the dosage form12being located at a test location22between the two. The delivery optics26are then arranged to direct a beam of probe light27to a first surface region710of the dosage form, and the collection optics30are arranged to receive probe light from a second surface region712of the dosage form following scattering, or more particularly forward scattering, through the dosage form12from the first surface region to the second surface region.

In particular, the first surface region710and second surface region712may be on opposite sides or opposite faces of the dosage form12, for example on respective first and second surfaces40and41as already depicted inFIG.1, such that the dosage form is tested using a forward scattering or transmission configuration, although other configurations may be used such as other configurations discussed above.

The detector32already illustrated inFIG.1and discussed above is arranged to receive the collected probe light from the collection optics30and to detect Raman spectral features in the collected probe light, for example Raman spectral features representing the magnitudes of a number of Raman spectral peaks, or more generally a full Raman spectrum representing a detected intensity or power as a function of wavenumber or wavelength. This data is then passed to the analyser34, also discussed above, which is arranged to determine one or more properties of the dosage form under test using the Raman spectral features, such as relative concentration of a particular constituent of interest such as an active pharmaceutical ingredient.

In some embodiments, a particular dosage form12is positioned at the test location and held stationary in a single configuration or alignment between the delivery and collection optics while Raman spectral features are measured, and the Raman spectral features for that single alignment are then used for determining one or more properties of the dosage form. However, the inventors have noted that there may be several benefits in moving the dosage form within the test location while under test so that Raman spectral features are detected for a plurality of different such alignments or configurations. Such measurements of Raman spectral features may be taken at each of a plurality of discrete and typically stationary alignments, during one or more movements of the dosage form, or a combination of the two. Typically, all such alignments may be used for obtaining Raman spectral features without removing the dosage form from the test location, but in some embodiments in may be desirable or appropriate to remove the dosage form from the test location between some alignments or groups of alignments. One such situation could be, following use of one or more alignments, to replace the dosage form on a surface such as the table surface72so as to rotate the gripper, pick the dosage form up again with the gripper in the rotated position, invert the dosage form using the gripper, and present the dosage form in the test location in the inverted (upside down) state for use of one or more further alignments.

Different alignments or configurations of the dosage form at the test location22, whether discrete such alignments, or continuous movements through ranges of such alignments, may be provided in particular by rotation of the dosage form about one or more chosen axes, translation in one or more directions, or a combination of the two. Such changes in alignment of the dosage form at the test location result in corresponding changes in the positions on the dosage form of one or both of the first and second surface regions710,712, and therefore changes in the scattering paths of probe light between the first and second surface regions, and therefore also changes in the representative volume of the dosage form being tested in each alignment.

Moving the gripper to present the dosage form in a plurality of alignments between the delivery optics and the collection optics, and for each alignment, collecting probe light from said second surface, therefore allows a range of different scattering geometries through, and representative volumes of the dosage form to be tested. The analyser may then use the Raman spectral features from the various alignments in a number of ways, determining one or more properties of the dosage form using the Raman spectral features detected during some or all of the alignments.

For example, in one mode of operation the analyser may process the detected Raman spectral features for each alignment or each of a plurality of groups or ranges of alignment to derive a separate dosage form property for each such alignment, group, or range, and then average or combine the obtained dosage form properties to obtain a single average dosage form property which is more representative of the whole dosage form.

In another mode of operation, the analyser may instead average or otherwise combine together the Raman spectral features from each alignment or each of a plurality of groups or ranges of alignment, to determine a more representative set of Raman spectral features for the whole dosage form, from which a more representative dosage form property for the whole dosage form can be derived.

In other modes of operation, a separate value of a property of the dosage form may be determined for each of a plurality of different alignments, or group or range of alignments, for example so as to determine a separate value of a property of the dosage form for each of two or more different parts of the dosage form. For example, such modes of operation may for example be used to detect a separate value for each of two or more frangibly separable parts of a pharmaceutical tablet, typically defined by one or more break lines14or grooves in one or more faces of the tablet, such as the debossed snap line feature seen inFIG.3b.

Multiple alignments of a dosage form at the test location can be achieved more readily using the described arrangements because of the use of Raman spectroscopy which permits the dosage form to be held at the test location without requiring light baffles or other arrangements to strongly prevent probe light from passing around the dosage form to the probe light collection optics. This is in contrast to the use of infrared absorption spectroscopy where leakage of probe light around the dosage form is of much more concern, making that type of optical testing of the dosage form over a range of alignments (translations and/or rotations) much more difficult because the dosage form will usually need to be held in some kind of light tight surround. To this end, and as discussed elsewhere, the gripper used in the present embodiments may be arranged to suspend the dosage form in essentially free space between the delivery optics and collection optics of the Raman analysis station, without any baffles or other particular light blocking structures being needed.

Referring back toFIG.7, the mechanical gripper (represented by cross sections through opposing jaws94) is controlled to translate the dosage form12laterally between the delivery and collection optics, so that the first surface region710translates across an upper surface40of the dosage form12, and at the same time the second surface region712translates across a lower surface41of the dosage from. The dosage form may be held stationary in each of two or more particular such alignments, and Raman spectral features detected for each such discrete alignment, and/or Raman spectral features may be detected during one or more episodes of continuous movement of the dosage form12.

The depicted lateral translation allows a larger volume of the dosage form to be sampled, while retaining use of a probe light beam27(and therefore first surface region710) of modest diameter which may be easier to provide in an optically consistent manner, and using a second surface region of modest diameter which can also improve consistency of light collection. In order to improve consistency of probe light delivery and collection it may be preferable to use optics with fixed probe light spot size on the dosage form12, and a fixed collection spot size, and to avoid telescope or other moving optics arrangements. For example, a desirable first surface region710or delivery light spot size may be less than about 3 mm, or less than about 2 mm in diameter.

Although an essentially lateral translation is depicted inFIG.7between two or more positions, these positions could be distributed in various ways, for example in a straight line across the dosage form, in a spiral form, using a two dimensional array of evenly spaced sampling points and so forth. Although the translation inFIG.7is depicted as being lateral, some vertical movement (towards/away from the delivery optics/collection optics) may also be desirable, for example to ensure that the second surface region is maintained at a substantially constant distance from the collection optics. This may particularly be desirable to maintain the second surface region at a suitable focal distance from the collection optics so as to maintain constant light collection characteristics.

InFIG.8the gripper is seen to be controlled to rotate the dosage form12about one or more axes, which could be perpendicular to the optical axes of the delivery and collection optics as depicted inFIG.8, or could be or include other axes. As forFIG.7, the dosage form may be held stationary in each of two or more particular such alignments, and Raman spectral features detected for each such discrete alignment, and/or Raman spectral features may be detected during one or more episodes of continuous movement of the dosage form12. InFIG.7the degree of rotation depicted in around thirty degrees, but a range of alignments over a much smaller range of angles may be used, or over a larger range of angles. In some embodiments, the dosage form may be completely inverted or turned over between alignments, so that one or more alignments involve probe light scattering through the sample in one direction, and one or more alignments involve the probe light scattering through the sample in the other direction.

One or more such rotational movements may be combined with one or more translational movements (for example as depicted inFIG.7) to provide a number of different alignments, in each of which at least one of the position of the first surface region on the dosage form and the position of the second surface region on the dosage form is different, thereby providing a different optical path for scattering of the probe light through the sample for analysis as discussed above.

If translation is used then the range of translation of the dosage form involved in providing the plurality of alignments may typically be of the order of a few mm, for example at least 2 mm. If rotation is used then the range of rotation of the dosage form involved in providing the plurality of alignments may vary widely, for example being at least a few degrees or at least 10 degrees. One or more full inversions of the dosage form may involve a range of rotation of about 180 or about 360 degrees.

FIG.9is similar toFIGS.7and8but depicts the translation of a dosage form12″′ similar to that ofFIG.3bin which a break line14or debossed snap line feature is provided across a surface of the dosage form to facilitate breaking the dosage form into two parts, such as two half doses. In this case, one or more alignments in which Raman spectral features are measured provide for first and second surface regions in one half dose, and one or more alignments in which Raman spectral features are measured provide for first and second surface regions in the other half dose. In this way, one or more properties of the dosage form can be separately determined for each half dose. Of course, some dosage forms may be similarly structured for breaking into three or more separate doses, and one or more alignments corresponding to each such dose may be used to determine one or more properties for each such dose.

FIG.10provides in perspective view a detailed drawing of apparatus implementing the dosage handler60and some other aspects illustrated inFIGS.1and2. For clarity and convenience however,FIG.10does explicitly show any of the dosage source42, the controller50, the analyser34, or the personal computer36seen in the earlier figures.

The dosage handler is generally depicted within the dashed balloon labelled60. The multi-axis staging depicted generally within the dashed balloon100provides movement of the gripper90and box slider130as required to implement the handling processes described above in relation to the handling table70. The horizontal table surface72of the handling table70comprises the drop zone120where the dosage source (not shown) drops a dosage form into the box slider130, the weighing scale surface112of weighing scale110to which the box slider130moves the dosage form for weighing, and the rotation stage surface75of rotation stage74, to which the box slider130moves the dosage form after weighing. The rotation stage74is driven by the rotation stage motor76.

The machine vision system includes the machine vision camera82which has a field of view covering some or all of the rotation stage surface75by virtue of machine vision mirror83, so that the machine vision system can detect at least an alignment of a dosage form lying in the plane of the handling table surface such that the dosage form can be aligned to a preferred alignment by rotation of the rotation table. The machine vision system preferably also detects further orientation information of the dosage form so that it can be rotated by the gripper90about the gripper rotation axis92to a desired orientation of rotation, the gripper axis being parallel to the table surface72. InFIG.10rotation of the gripper is driven by a gripper rotation motor99through a belt drive.

The Raman analysis station is generally depicted within dashed balloon20, and comprises a laser source24to generate a probe beam27of laser light, delivery optics26, collection optics30, and detector32. The test location22inFIG.10is located close above the handling table70. The drop zone120, weighing scale surface112, and rotation stage surface75are generally distributed along a process axis125, and the test location22is conveniently located along the same axis beyond the rotation stage surface75. The probe beam27of laser light is directed downwards by delivery optics26towards the test location22which is above an aperture73through the handling table70. A dosage form is held by the gripper90for optical analysis at the test location above the aperture73, and the collection optics70which are partly located beneath the handling table receive the probe light scattered within the held dosage form through the aperture73, to thereby achieve a transmission configuration for optical analysis.

The multi-axis staging100is arranged to run along a rail102which is parallel to the process axis125so as to provide the required access by the box slider130to the drop zone120, weighing scale surface112and rotation stage surface75, and the required access by the gripper90to the rotation stage surface75and the test location22. Vertical motion of the gripper90and box slider130is provided by a common vertical axis mechanism of the multi-axis staging100, and depth motion across the table surface perpendicular to the process axis125is provided by a common depth axis mechanism of the multi-axis staging.

While particular embodiments of the invention have been described with reference to the drawings, the skilled person will be aware of various modifications and changes can be made to these embodiments without departing from the scope of the invention.