Raman analysis of pharmaceutical dosage forms

Abstract

Methods and apparatus for automated analysis of pharmaceutical dosage forms are disclosed. In some aspects, the dosage form can be gripped by a gripper that is used to transport the dosage form to an inspection location and present the dosage form at multiple different alignments between delivery and collection optics. Probe light scattered through the dosage form is collected during each alignment. The collected probe light for the multiple alignments is then used for Raman spectral analysis of the dosage form. In other aspects, a rotational stage is used to rotate the dosage form onto the stage to a preferred alignment before being gripped by the gripper. The gripper is then used to transport the dosage form to the inspection location for optical analysis.

Description

[Technical field]

[0001] The present invention relates to an apparatus and method for Raman or other optical or spectroscopic analysis of pharmaceutical dosage forms, including oral solid dosage forms such as tablets or capsules. For example, such dosage forms can be analyzed using Raman spectroscopy in a transmission configuration. [Background technology]

[0002] In various situations, such as production line sampling, it is desirable or necessary to test pharmaceutical dosage forms to ensure that they comply with certain specifications. Such specifications may prescribe absolute amounts of one or more active pharmaceutical ingredients (APIs), as well as narrow tolerances for other aspects of the dosage form, such as shape, size, and content of other chemical ingredients, as well as chemical properties.

[0003] One method of determining such quantities and chemical characteristics is to individually grind each sample dosage form into a powder, dissolve in a solvent, and feed into a liquid chromatograph, mass spectrometer, or similar device. However, when a large number of dosage forms need to be individually tested, this process can be time consuming and difficult to effectively automate. It becomes difficult to accurately track the identity of each dosage form sample through such an analytical process, and the physical characteristics and identification of the original dosage form's markings are lost in the process.

[0004] Spectroscopic examination of pharmaceutical dosage forms for quantitative analysis is described, for example, in US Pat. No. 5,399,623 and US Pat. No. 5,499,623. Dosage forms can take the form of tablets, capsules and other pharmaceutical preparations. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Patent Application No. PCT / SE96 / 01637 [Patent Document 2] International Publication No. 2007 / 113566 Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention addresses the problems and limitations of the related prior art. [Means for solving the problem]

[0007] Aspects of the invention provide an apparatus and method for automatically handling and presenting dosage form samples for optical analysis with minimal or zero operator input, and can be configured to handle many different sizes and shapes of dosage forms, switch between different samples or dosage form types without user input, and automatically process different types of dosage forms stored in different hoppers, for example, without user intervention. Dosage forms can be tracked and managed through the handling and analysis process with minimal or zero scope for handling errors or incorrect sample loading. Physical dimensions and markings of the dosage form can be determined and matched to expected values ​​and patterns.

[0008] Aspects of the invention also allow for accurate weighing of individual dosage forms. Because optical analyses such as transmission configuration Raman techniques typically provide proportional content measurements such as percentage active pharmaceutical ingredient content (% API), having the dosage weight allows for a more accurate absolute measure of API dosage to be determined for the sample being tested.

[0009] Aspects of the present invention also allow for flexible manipulation of individual dosage forms such that inconsistencies in the results of optical analysis can be avoided due to improved consistency of sample presentation during optical analysis.

[0010] Each pharmaceutical dosage form may be a tablet, coated tablet, capsule, gel capsule, or any of a variety of other forms. Such dosage forms may be described as solid dosage forms, and while some such solid dosage forms may contain liquids or gels therein, solid dosage forms may be individually manipulated, such as by a mechanical gripper. Such dosage forms may also be described as oral dosage forms intended for ingestion by swallowing.

[0011] Dosage forms processed by the above methods and apparatus may display one or more of the following: surface markings, debossing (e.g., features pressed into the dosage form during manufacture), embossing (raised features on the dosage form), multiple surface regions each having a different color, printed markings, etc. It has been found that the presence of such features can affect the results of optical analysis, particularly spectral analysis, of such dosage forms, and therefore consistency in the presentation of optical interrogations is desirable to achieve consistency in the quantitative analysis of the dosage forms.

[0012] In particular, aspects of the invention provide an apparatus for analyzing pharmaceutical dosage forms, the apparatus comprising a dosage handler configured to bring the dosage form into a predetermined and preferred rotational state or orientation (such as alignment of a defined axis of the dosage form to a preferred direction and / or orientation of the dosage form about that axis) in response to detection of the dosage form by a machine vision system, and an optical analysis station for inspecting the dosage form. Various configurations can be provided that ensure that the dosage form remains in a preferred rotational state or orientation when presented to the optical analysis station for inspection, although other changes in the known rotation or alignment may be made as needed within the optical analysis station when moving the dosage form to the optical analysis station and thereafter.

[0013] The dosage form handler may, for example, comprise a rotary stage or turntable configured to rotate the dosage forms located on the stage. The rotation is controlled in response to data received from a machine vision system. The rotary stage may provide a substantially horizontal or flat, usually circular, upper surface on which the dosage forms are located and may therefore be used to rotate the dosage forms about a vertical axis. The dosage form handler may additionally or alternatively comprise a mechanical gripper or other manipulator configured to perform one or more of the following: rotation of the dosage forms in response to the machine vision system, for example about an axis inclined or perpendicular to the axis of rotation of the rotary stage, and thus usually a horizontal axis, and transporting the dosage forms to an optical analysis station for inspection. The dosage form handler may also comprise a weighing scale configured to weigh the dosage forms located on the weighing scale, usually prior to rotation and / or manipulation as described above. Such a weighing scale may be provided adjacent to the rotary stage, for example by both the rotary stage and the weighing scale being provided on a surface of a handling table.

[0014] The optical analysis station can typically be configured to perform Raman spectral interrogation of the dosage form, for example in a transmission configuration, while still being held by a mechanical gripper or other manipulator after collection of light from a rotational stage or other part of the dosage form handler.

[0015] Another aspect of the invention provides an apparatus for analyzing a pharmaceutical dosage form comprising a rotational stage having a rotational stage surface configured to receive a dosage form, a gripper or manipulator configured to grip the dosage form, an optical analysis station having an inspection location and configured to detect spectral features in probe light scattered within the dosage form when positioned at the inspection location, and a controller configured to control rotation of the rotational stage to rotate the dosage form into a preferred alignment, orientation or rotation while on the stage surface, control the gripper to grip the dosage form in the preferred alignment, orientation or rotation, and control the gripper to transport the gripped dosage form to the inspection location for spectral interrogation and analysis.

[0016] This allows each dosage form to be presented at the optical analysis station with a consistent and preferred alignment, orientation, or rotation, thereby reducing presentation bias that may otherwise result in significant variability in the results of the optical analysis, particularly when the dosage forms have significant asymmetries or markings such as colored areas, debossing, etc. The rotating stage surface may be typically circular and may be in the form of a substantially flat, horizontal surface upon which the dosage forms rest to be placed above the surface.

[0017] The optical analysis station may in particular be a Raman analysis station configured to detect Raman spectral features of the inspected dosage form. The Raman analysis station may comprise a delivery optics configured to direct a probe light to a first surface region of the dosage form when located at the inspection location, a collection optics configured to receive said scattered probe light from a second surface region of the dosage form, the second surface region being spaced apart from the first surface region, and a detector configured to detect Raman spectral features in the received probe light. The Raman analysis station may thereby interrogate the dosage form using a transmission geometry to obtain spectral measurements representative of the bulk of the dosage form, for example as described in US Pat. No. 5,399,992.

[0018] The second surface region can be an area on an opposite side of the dosage form from the first surface region to help maximize the volume of the dosage form represented by the results of the spectral analysis.

[0019] The apparatus can be configured such that the gripper holds the dosage form at an inspection location for Raman analysis in free space without other structures, such as, for example, a carrier provided as part of the Raman analysis station, or an optical baffle between the delivery and collection optics. Moreover, because Raman techniques are used for analysis in which the detected spectral features are spectrally separated from the fundamental laser frequency, there is no need to provide the gripper with a light-blocking baffle, for example in the form of an elastically bending material or a more rigid holder or mount.

[0020] More specifically, it is not necessary for a holder or mount to be provided that provides a tight fit around the dosage form at the inspection location to prevent the laser light from scattering around or passing through the dosage form, nor is it necessary for the dosage form to rest or be disposed within such a tight fit holder or mount, although such a holder or mount may still be provided if desired.

[0021] The device may further comprise an analyzer configured to determine one or more properties of the dosage form, such as the percentage content of an active pharmaceutical ingredient (API), the proportional content of other chemical ingredients, etc., from the detected Raman spectral features. Such proportional measures, when combined with a determined weight of the dosage form, which may be obtained using a weighing scale of the device as discussed below, may be used to determine an absolute content measure, e.g., the amount of API.

[0022] The apparatus may further comprise a machine vision system configured to detect the alignment of the dosage form when on the rotating stage surface and pass the detected alignment of the dosage form to the controller to control the rotation of the rotating stage to rotate the dosage form into a preferred alignment. For example, the machine vision system may be configured to detect the alignment or orientation of a predefined dosage axis of the dosage form, the preferred alignment or orientation comprising the preferred alignment or orientation of the dosage axis. To this end, the machine vision system may be provided in advance with the geometric details and optionally surface marking details of the dosage form to be manipulated, which may explicitly or implicitly include such predefined dosage axis.

[0023] The gripper or manipulator can be configured to rotate the gripped dosage form about the gripper rotation axis, and the controller is configured to subsequently control the gripper to rotate the dosage form about the gripper rotation axis while gripping the dosage form in a preferred rotational orientation. If the dosage form has already been rotated to a preferred alignment by the rotation stage, the gripper rotation axis can be parallel to the preferred alignment of the dosage form axis. Typically, the gripper rotation axis can be parallel to the rotation stage surface and therefore is also typically perpendicular to the axis of rotation of the rotation stage. This rotation by the gripper is also typically performed using data from a machine vision system. To this end, the machine vision system can also be configured to detect the rotational orientation of the dosage form about the gripper rotation axis and pass the detected rotational orientation to the controller in order to control the gripper when rotating the dosage form to the preferred rotational orientation.

[0024] The machine vision system can also be configured to detect the lateral position of the dosage form on the rotating stage surface and pass the detected lateral position to the controller for controlling the gripper to grip the dosage form at the detected lateral position.

[0025] The machine vision system can be further configured to determine one or more dimensions of the dosage form, such as a length, width, diameter, or other dimension of the dosage form in a plan view when positioned on the rotation stage. If the dosage form has opposing major surfaces separated by an edge surface, to determine the thickness of the dosage form between the opposing major surfaces, the controller can be configured to control the gripper to rotate the dosage form to present an edge of the dosage form in a plan view to the machine vision system, rather than the major surfaces, and the machine vision system is then configured to determine the thickness of the dosage form from a plan view of the presented edge.

[0026] In some examples, detection of the edge surface by the machine vision system can be accomplished while the dosage form is being held by the gripper, although in other examples, the controller can be configured to control the gripper to place the dosage form edge-down on the rotating stage and release the dosage form at that position in order to determine the thickness of the dosage form by the machine vision system. This can be useful, for example, when the gripper would otherwise obscure the machine vision system's view of the edge.

[0027] Using a gripper to present the dosage form edge-on to a machine vision system can be particularly useful when the machine vision system uses one or more downward-looking cameras overlooking the rotating stage, but no cameras looking sideways across the rotating stage are provided, which in principle could detect the thickness of the dosage form but would add cost and complexity to the system.

[0028] Although different types of manipulators or grippers may be used, the gripper may comprise opposing jaws configured to grip the dosage form between the jaws. The opposing jaws may be configured to grip the dosage form by closing on the dosage form along at least one of an axis parallel to the rotating stage surface and an axis along the gripper rotation axis. In particular, the gripper is typically provided with three translational axes of movement, although the orientation of the gripper rotation axis may be fixed, thereby simplifying the construction of the apparatus.

[0029] The gripper can be configured to remain in a preferred alignment when the dosage form is held at the inspection location for Raman analysis. It should be noted that the direction of preferred alignment as achieved using the rotation stage can be changed to different directions when held at the inspection location, so long as the change is known and precisely controllable.

[0030] Each jaw of the gripper can include a concave surface that is presented to the dosage form to grip the dosage form when the jaw grips the dosage form.

[0031] The controller can be configured to control the gripper or manipulator to place the dosage form in a predetermined cell in an output tray or other output structure or device following detection of a Raman spectral feature in the probe light scattered within the dosage form while positioned at the inspection location.

[0032] The apparatus may include a handling table for use in the manipulation and other testing of each dosage form. For example, the rotating stage surface may form part of the table surface of the handling table. The apparatus may include a weighing machine having a weighing machine surface forming part of the table surface and configured to weigh the dosage form when positioned on the weighing machine surface. The weight of the dosage form may be combined with the results from the spectral analysis to determine and output one or more absolute measures of the content of the dosage form, such as a measure of API weight or other absolute amount.

[0033] The apparatus may further comprise a dosage form source, the dosage form source configured to deposit the dosage form in a drop zone of the table surface. To avoid temporary degradation of the accuracy of the weighing device, the drop zone may typically be separate from the weighing device and may optionally be separate from the rotating stage surface. The dosage form source may comprise multiple hoppers, the apparatus configured to select a dosage form from a particular hopper for analysis. In this way, dosage forms of different types or specifications may be loaded into each hopper by a user, after which the apparatus can automatically perform the required handling and optical analysis of multiple different types of dosage forms without further user intervention.

[0034] The apparatus may further include a slider configured to slide the dosage form across the table surface under the control of the controller, for example, the controller may be configured to control the slider to slide the dosage form from the drop zone to a meter surface for metering, and from the meter surface to a rotation stage surface for alignment and any other required orientation.

[0035] The slider can be a box slider configured to surround the dosage form for sliding across the table surface. Providing slider walls surrounding the dosage form, for example, in a rectangular or square configuration, can avoid loss of the dosage form from control by the device, for example, when the dosage form is dropped from the dosage form source onto the table surface. The slider is typically provided with three axes of translational movement, including a vertical axis that allows the slider to rise above the height of the dosage form so that the dosage form can be left stationary on the table surface and the slider moved away.

[0036] The gripper and slider can both be coupled to multi-axis staging that provides common motion for both the gripper and slider, for example, the multi-axis staging can provide movement along a process axis under the control of a controller to move the slider between a drop zone, a meter surface, and a rotary stage surface, and move the gripper between the rotary stage surface of a Raman analysis station and an inspection location.

[0037] The present invention also provides methods such as methods of handling, manipulation, inspection, optical interrogation, analysis, and quantitative analysis of dosage forms, including methods of controlling aspects of the devices described herein.

[0038] According to one aspect, the present invention provides a method of automatically analyzing a pharmaceutical dosage form, the method including receiving the dosage form on a rotating stage, rotating the rotating stage to rotate the dosage form about a rotational stage axis into a preferred alignment or orientation, transporting the dosage form from the rotating stage to an inspection location of a spectral analysis station, and optically interrogating the dosage form at the inspection location.

[0039] The optical interrogation may include spectral interrogation of the dosage form, for example detecting one or more Raman spectral features of light scattered by the dosage form, and the method may further include determining one or more properties of the dosage form, such as quantitative properties of chemical components, from results of the spectral interrogation.

[0040] Performing spectral interrogation can include using a transmission geometry, for example, directing laser probe light to a first surface region of the dosage form, collecting components of the laser probe light scattered within the dosage form from a second surface region of the dosage form opposite the first surface region, and detecting Raman spectral features in the collected light.

[0041] The transporting can be accomplished by gripping the dosage form using a gripper or other manipulator when in a preferred alignment or orientation, transporting the gripped dosage form using the gripper to an inspection location, performing spectral interrogation of the gripped dosage form, and only after this releasing the dosage form from the gripper's grip.

[0042] The gripper can also be used to rotate the dosage form about the gripper rotation axis to a preferred orientation about that axis, thereby further reducing bias in the presentation of the dosage form during optical interrogation. Rotation of the dosage form about the gripper rotation axis can typically be performed after rotation of the dosage form about the rotation stage axis using the rotation stage such that the dosage form is already in the desired alignment for gripping by the gripper, although more than one step of rotation using the rotation stage can be used, for example both before and after rotation by the gripper.

[0043] The method may further include receiving the dosage form at a drop zone of a handling table, the handling table also comprising a weighing scale and a rotation stage, sliding the dosage form from the drop zone across the handling table to the weighing scale, weighing the dosage form using the weighing scale, sliding the dosage form across the handling table from the weighing scale to the rotation stage, rotating it to a preferred alignment or orientation, and then transporting it to an inspection location.

[0044] Also provided are methods of determining aspects such as variability in handling and optical interrogation of a dosage form, for example, by repeating the above steps on a single dosage form or multiple dosage forms of the same type to perform multiple such optical interrogations and comparing results of the multiple optical interrogations to determine at least one measure of variability in handling and optical interrogation of the dosage form.

[0045] A method for automatically analyzing a plurality of pharmaceutical dosage forms may also include loading a plurality of dosage forms each of a plurality of dosage form types, with each type of dosage form being loaded into a separate hopper, and performing descriptive manipulation and optical analysis of each dosage form, wherein receiving a particular dosage form at a rotary stage or other portion of the dosage form handler includes receiving the dosage form from the hopper in which the dosage forms are loaded.

[0046] The present invention also provides methods and apparatus for improved optical inspection of dosage forms during presentation, for example, by a gripper or other handling element at a Raman analysis station or other inspection location. Improved sampling of the dosage form can be achieved by adjusting the alignment of the dosage form to determine Raman spectral features for a range of such alignments, including translation and / or rotation of the dosage form. This can involve detecting Raman spectral features for such ranges of alignments to determine properties of the dosage formulation that are more representative of the dosage formulation as a whole, and / or can involve determining values ​​of properties of different portions of the same formulation, such as divisible subdoses of a tablet.

[0047] Multiple such alignments can be more easily achieved using the described configuration because of the use of Raman spectroscopy, which allows the dosage form to be held at the inspection location without light baffles or other devices that strongly prevent the probe light from being directed around the dosage form and towards the probe light collection optics. This is in contrast to the use of infrared absorption spectroscopy, where leakage of the probe light around the dosage form is a much greater concern and therefore optical inspection of the dosage form over a range of alignments (translational and / or rotational) is much more difficult.

[0048] To this end, the present invention provides a method of automated analysis of a pharmaceutical dosage form comprising gripping the dosage form using a gripper, moving the gripper to carry the dosage form to an inspection location between delivery optics configured to direct probe light to a first surface region of the dosage form and collection optics configured to receive the probe from a second surface region of the dosage form after scattering through the dosage form, moving the gripper to present the dosage form in a plurality of alignments between the delivery optics and the collection optics, collecting the probe light from the second surface for each alignment, and detecting Raman spectral features of the received probe light for each of the plurality of alignments.

[0049] One or more properties of the dosage form, such as the relative concentration of the active pharmaceutical ingredient, can then be determined using the Raman spectral features detected during some or all of the alignments. The Raman spectral features from all of the alignments can be used, for example, to determine an improved average property of the formulation as a whole. However, in other embodiments, different values ​​of a particular property can be determined for each of two or more portions of the dosage form using one or more alignments corresponding to each such portion of the dosage form. This technique can be useful for determining the value of a property for each of multiple frangible portions of a dosage form, where the two or more portions of the tablet may typically be defined by a dividing line provided on the surface of the tablet.

[0050] The multiple alignments of the dosage form can be understood to provide for a change in 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 between each alignment. To this end, between each alignment, the gripper can move the dosage form through one or both of translation and rotation. However, it should be noted that one or both of discrete alignments and continuous movement through one or more ranges of alignment can be used. Thus, at least some of the alignments can form one or more continuous ranges of alignment during movement of the dosage form in which Raman spectral features are detected in the received probe light.

[0051] The optical inspection can use a transmission configuration in which the second surface region is on an opposite side of the dosage form from the first surface region. As noted elsewhere, the pharmaceutical dosage form can be one or more of a tablet, a coated tablet, a capsule, a gel capsule, a solid dosage form, and an oral dosage form. The range of movement of the dosage form when providing multiple alignments can include at least one of translating the dosage form over a distance of at least 2 mm and rotating the dosage form through at least 10 degrees.

[0052] The present invention provides a corresponding apparatus for providing optical inspection of dosage forms using multiple alignments, such as an apparatus for automated analysis of pharmaceutical dosage forms, comprising a mechanical gripper configured to grip the dosage form, a Raman analysis station having an inspection location and configured to detect Raman spectral features in probe light scattered within the dosage form when positioned at the inspection location, a controller configured to control the gripper to present the dosage form in multiple alignments within the inspection location, collect the probe light scattered within the dosage form at each of the alignments, and control the Raman analysis station to detect Raman spectral features in the collected probe light, and an analyzer configured to determine one or more characteristics of the dosage form from the detected Raman spectral features.

[0053] The present invention also provides a controller and / or one or more other computer systems comprising computer program code configured to perform the method steps as described herein, as well as providing such computer program code and one or more computer readable media carrying such computer program code.

[0054] Embodiments of the present invention will now be described, by way of example only, with reference to the drawings in which: [Brief description of the drawings]

[0055] [Figure 1] FIG. 1 shows a schematic diagram of an apparatus for handling and optical interrogation and analysis of multiple pharmaceutical dosage forms. [Diagram 2] 2A-2C show some aspects of the dosage form handler of FIG. 1 in greater detail. [Figure 3a] FIG. 3 shows a dosage form that can be handled and analyzed using the apparatus of FIGS. 1 and 2, and the associated dosage form axes that can be identified by the machine vision system of the apparatus. [Figure 3b]FIG. 3 shows a dosage form that can be handled and analyzed using the apparatus of FIGS. 1 and 2, and the associated dosage form axes that can be identified by the machine vision system of the apparatus. [Figure 4a] FIG. 3 illustrates a method of operation of the apparatus of FIGS. 1 and 2. [Figure 4b] FIG. 3 illustrates a method of operation of the apparatus of FIGS. 1 and 2. [Diagram 5] FIG. 3 illustrates a method of operation of the apparatus of FIGS. 1 and 2. [Figure 6] FIG. 3 illustrates a method of operation of the apparatus of FIGS. 1 and 2. [Figure 7] FIG. 3 illustrates how a dosage form can be presented at the inspection location of the Raman analysis station of FIGS. 1 and 2 with a range of alignments, which differ in translation and / or rotation of the dosage form. [Figure 8] FIG. 3 illustrates how a dosage form can be presented at the inspection location of the Raman analysis station of FIGS. 1 and 2 with a range of alignments, which differ in translation and / or rotation of the dosage form. [Figure 9] FIG. 1 illustrates how the value of each property can be determined for two sub-dose portions of a single dosage form, which are typically separated by a surface groove or other dividing line. [Figure 10] FIG. 3 illustrates some technical details of how the apparatus of FIGS. 1 and 2 can be implemented. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0056] 1, there is shown generally an apparatus 10 for the spectral or other optical analysis of a pharmaceutical dosage form 12, in particular an oral solid dosage form such as a tablet or capsule, although other types of dosage forms or for that matter other kinds of objects may be analyzed using the apparatus.

[0057] The apparatus 10 is configured and operated to provide improved consistency of spectral or other optical analysis across batches of such dosage forms that are intended to be substantially identical. Although the dosage forms of a batch may typically be superficially identical or very similar in terms of, for example, shape, size and composition, they may nevertheless contain defects and / or variations, particularly in their internal chemical content and composition. It may be important to detect such defects and variations as part of the manufacturing process or other inspection scenario.

[0058] Pharmaceutical tablets are manufactured in a variety of shapes, sizes and colors. Some tablets may have several different colors. Tablet shapes include cylindrical or elliptical prisms, often with beveled edges, spherical, oval, diamond shaped, etc. Tablets are often embossed or debossed with markings such as alphanumeric codes and other symbols, slots to aid in division into multiple portions, and other surface features. Some tablets retain printed surface markings, including, for example, alphanumeric codes and other symbols. Tablets are manufactured in both coated and uncoated forms, where the surface layer contains a different composition relative to the underlying tablet core.

[0059] Pharmaceutical capsules, one particular form of which is the gel capsule, usually comprise an encapsulating sleeve that contains a pharmaceutical powder or sometimes a gel or fluid. The usual shape of the capsule is cylindrical with rounded ends, although other geometries, such as flattened cylindrical forms, are sometimes used. The encapsulating sleeve is usually formed by joining two opposing end faces, which often have different colors. The capsules are often printed with surface markings, such as alphanumeric codes and other symbols.

[0060] The inventors have found that, even if multiple such dosage forms of the same type or batch are superficially identical, various physical characteristics of the dosage forms as described above may affect the consistency of the results of optical analysis between them.For example, it has been found that consistency may be reduced when such dosage forms are presented to optical analysis with different orientations or rotations of their features relative to the optical analysis equipment.Some dosage forms may have sufficient symmetry around one axis of rotational symmetry such that the rotation of the dosage form around that axis is difficult to detect, at least visually, for example by a machine vision system, and in that case, the rotation around this axis does not effectively contribute at all to considering the rotational state of the dosage form during subsequent handling of optical analysis, but there are few dosage forms that may be desirable to optically analyze that do not inherently have such features or asymmetries.

[0061] An apparatus such as that shown in FIG. 1 can be used to provide automatic and sequential optical analysis of a plurality of such superficially identical or similar dosage forms with improved consistency of the optical analysis.

[0062] A typical application area may be monitoring the chemical composition of dosage forms sampled from a production line or other manufacturing process. The desired properties of the dosage form may include measurements or concentrations or amounts of one or more active ingredients or other components, and measurements or concentrations or amounts of polymorphic forms, hydrated forms, solvated forms, salt forms, and crystallinity of one or more such active ingredients or components. The presence or concentration of impurities may be detected as well.

[0063] The apparatus shown in Figure 1 is particularly configured to perform Raman spectral analysis of the dosage form 12. However, other types of spectral analysis or, more generally, optical analysis may be performed in addition or instead. To this end, the apparatus includes a Raman analysis station 20 configured to detect Raman spectral features 33 in probe light scattered within the dosage form 12 when the dosage form 12 is positioned at an inspection location 22 of that station.

[0064] The Raman analysis station 20 of FIG. 1 comprises a laser source 24 configured to generate a laser beam of probe light, typically infrared light, delivery optics 26 configured to direct the probe light to a dosage form 12 at an inspection location 22, collection optics 30 configured to receive the probe light after scattering, including Raman scattering, within the dosage form 12, and a detector 32 configured to detect Raman spectral features 33 of the dosage form present in the scattered probe light.

[0065] Typically, laser source 24 may operate in the near infrared, for example at about 700 nm to 1000 nm, as either a continuous wave source or a pulsed source. Suitable average optical output power delivered to dosage form 12 may be about 50 mW to 1200 mW, and suitable spot diameters of the probe light beam at dosage form 12 may be in the region of about 1 mm to 10 mm. Particularly small spot sizes may be avoided due to the risk of thermal damage to the dosage form being inspected.

[0066] When implementing Raman spectroscopy techniques, the collection optics 30 and / or detector 32 are typically designed to incorporate very good suppression of the wavelength band (i.e., fundamental wavelength) of the probe light as emitted by the laser source 24. The Raman scattering cross section is very small, so that in the absence of such suppression, the fundamental wavelength would likely adversely affect accurate detection of the Raman spectral features, even though their wavelengths may be spaced tens of nanometers or more from the laser waveband. This suppression can be achieved using one or more optical filters, such as a holographic notch filter in the collection optics 30, to suppress the laser waveband light elastically scattered through or around the pharmaceutical solid dosage form being examined.

[0067] Suppression of the laser waveband light in the collection optics 30 when detecting Raman spectral features 33 reduces the need to avoid stray probe light reflecting or scattering into the collection optics around the dosage form 12, as would otherwise be necessary when using infrared absorption spectroscopy and some other spectroscopic techniques. As a result, the dosage form to be inspected can be suspended at the inspection location 22 without the specific need for a carrier or other structure that provides an optical seal around the sides of the dosage form between the delivery optics 26 and the collection optics 30 to prevent such stray light. The dosage form can thus be suspended between the delivery optics and the collection optics without having to be seated in any holder or carrier.

[0068] Thus, the dosage form 12 can be held at the inspection location 22 in a "free space" configuration without the need for any particular optical barrier or optical seal around the dosage form. Furthermore, this allows for some design flexibility in the methods of transporting the dosage form to the inspection location 22, holding the dosage form at the inspection location 22, and removing the dosage form from the inspection location 22, as discussed in more detail below, for example, by using mechanical grippers to hold the dosage form through all of these steps. Similarly, the mechanical grippers discussed below do not need to be provided with light blocking baffles, for example in the form of a resiliently bending material.

[0069] The dosage form 12 may be presented at the inspection location 22 in a particular fixed position and rotational state (orientation / alignment) during optical inspection, or may be moved / rotated between a number of discrete positions with optical inspection performed at each discrete position, and / or moved in a scanning motion (including either or both translation and rotation) with optical inspection performed during the movement. Such movement may be performed using a dosage form handler, described in more detail below, for example, by moving the dosage form into the inspection location using a gripper 90. However, this geometry for optical analysis may alternatively or additionally be changed between the discrete inspection geometries, and / or by scanning using movement or adjustment of the delivery optics 26 of the Raman analysis station used to deliver the probe light to the dosage form and / or the collection optics 30 of the Raman analysis station used to collect the scattered light from the dosage form, or by a combination of these aspects.

[0070] Multiple optical measurements obtained in such a manner during presentation of a particular dosage form can be combined, for example, to obtain a more representative optical measurement of the dosage form. For example, by directing a laser spot at multiple different locations and / or scanning across a range of locations to inspect a particular dosage form, the optical measurements can be more representative of the entire bulk of the dosage form. Such techniques can also allow for smaller and / or more consistent laser spot sizes on the dosage form being used.

[0071] The detector 32 can be implemented in a variety of ways, for example as a spectrometer, such as a Kaiser Optical Technologies Holospec device, covering a waveband suitable for detecting the desired Raman spectral features 33. Coupling of the laser light from the laser source 24 to the delivery optics 26 and between the collection optics 30 and the detector 32 can typically be accomplished using optical fibers, although free space transmission configurations can also or instead be used.

[0072] Spectral data indicative of at least aspects of the detected Raman spectral features 33 may be passed from the detector 32 to an analyzer 34 that is configured to determine properties of the dosage form from the spectral data, such as the various chemical properties discussed above. The spectral data may typically take the form of a readout from a CCD or other imaging component of the detector 32, and the analyzer 34 may then be configured to detect aspects such as the magnitude of particular Raman spectral peaks and other features indicative of particular chemical components that are expected or anticipated in the dosage form under test, broader spectral matches with spectra or multiple spectral features of such components, for example by reference to one or more data libraries that define expected spectra and / or particular spectral features of such components.

[0073] The spectral data and / or determined properties of the tested dosage form may be used in a variety of ways, such as for local and / or remote storage, for transmission over a network, for further analysis, for use to control a process such as a manufacturing process used to make the tested dosage form, etc. In Figure 1, a local personal computer 36 is shown receiving the determined properties and may provide output of aspects of the determined properties to a person monitoring the apparatus 10, such as in the form of an indication of deviations of the determined properties from expected values, an audible or visual alert that draws the attention of such a person to a deviation that is sufficiently large, etc.

[0074] Typically, the probe light may be directed by delivery optics 26 to a first surface 40 of the dosage form 12 disposed at the inspection location 22, and the probe light scattered within the dosage form may then be collected from a second surface 41 spaced from the first surface. In this manner, the collected probe light will be scattered deep within the dosage form 12 being inspected, and the detected Raman spectral features 33 will be representative of the bulk properties of the dosage form.

[0075] Generally, the second surface 41 can be spaced apart from the first surface 40 such that forward scattering of the Raman scattering components of the probe light is transmitted to the second surface for collection and detection such that the dosage form is analyzed in a transmission scattering geometry or a forward scattering geometry. Although different configurations are possible, typically the second surface 41 can be on the opposite side of the dosage form relative to the first surface 40. An example of this is shown for a tablet dosage form 12' shown in an expanded view in FIG. 1. In this expanded view, the first surface 40 is a first planar surface of the tablet dosage form 12' and the second surface 41 is a second planar surface of the tablet dosage form 12' opposite the first surface 40. For some dosage forms, and more generally for tablet forms, each of the first and second surfaces can be substantially parallel, often circular, and spaced apart from each other by a sidewall.

[0076] Some ways in which a Raman analysis station 20 can be constructed and operated to perform analyses using such transmitted or forward scattering configurations are described in US Pat. No. 5,399,633, the contents of which are incorporated herein by reference for all purposes.

[0077] In some other configurations, the Raman analysis station 20 may additionally or alternatively be configured to perform Raman spectral measurements of the dosage form 12 in other configurations and modes, for example using a spatially offset Raman spectroscopy (SORS) mode of operation. In such modes, probe light is delivered to one or more incident surface regions of the dosage form 12 by the delivery optics 26, and collection optics 30 are used to collect scattered probe light from one or more collection surface regions laterally spaced from the incident region(s). Raman spectral features 13 are then detected in the collected light by detector 32.

[0078] The depth profile of the Raman scattering resulting in the Raman spectral features 13 in the collected light then depends on the lateral spacing. A single spacing between the incident and collection surface areas can be used, or Raman spectral features from multiple spacings can be combined to provide more detailed depth-dependent measurements, such as the Raman scattering profile and resulting spectral features as a function of depth within the dosage form. Details of this technique and various embodiments are discussed, for example, in WO 2006 / 061565 and GB 2541110. The contents of these WO and GB publications are incorporated herein by reference in their entirety for all purposes.

[0079] The Raman analysis station 10 may additionally or alternatively be configured to perform Raman analysis of the dosage form using other arrangements, configurations or techniques, and in some embodiments other spectral techniques, such as ultraviolet, visible, or infrared absorption or reflectance spectral techniques, fluorescence techniques, etc., may be used in addition to or instead of Raman spectroscopy. In some such modes of optical analysis, the delivery and collection optics may be separate, combined, or provided in other more complex forms having backscattering or transmission, or where other types of arrangements are used.

[0080] As already mentioned above, various asymmetries and features of the dosage form under test, such as the overall shape, surface, color features, debossed and embossed portions, and printed markings, can affect the outcome of the optical analysis, and there are few dosage forms that are essentially free of such asymmetries and features that it may be desirable to analyze optically.

[0081] When optically analyzing a dosage form 12 using, for example, the above-described Raman analysis station 20 implementing a transmission geometry, it has been found that variations in the orientation and position of the dosage form within the inspection location 22 cause variations and errors in the detected Raman spectral features 33 and, therefore, in the detected properties of the dosage form being inspected. Variations in the orientation of the dosage form being inspected can cause not only an overall change in the brightness of the collected light, but also variations in the relative intensities and apparent wavelengths of the various spectral features due to interactions with, for example, the placement and properties of the delivery optics, collection optics, and detector. Different orientations of the dosage form can also cause different distributions of both elastic and Raman scattering within the volume of the dosage form.

[0082] To achieve more consistent results in optical analysis among similar or essentially identical dosage forms, it has been found to be beneficial to present each such dosage form for optical analysis in the same orientation. Some specific exemplary situations are as follows: - If a batch of dosage forms contains tablets with particular debossing or printing or other markings on one flat surface, those markings should be consistently oriented for inspection, e.g., always facing up or always facing down and always rotated to the same orientation in a horizontal plane. - If a batch of dosage forms contains capsules with two ends, each of a different color, the ends should be oriented in the same and consistent manner; and - If a batch of dosage forms contains capsules with printing along a cylindrical sidewall, the printing should be consistently oriented.

[0083] The apparatus of FIG. 1 comprises a dosage source 42 configured to provide dosage forms to a dosage form handler 60. For example, the dosage source may comprise or be configured to receive one or more singulator hoppers 43, each configured to release one dosage form at a time under the control of a controller 50. In this manner, multiple batches of dosage forms may be loaded for analysis into separate singulator hoppers 43, each containing perhaps tens to hundreds of such dosage forms, and the controller may then provide for scheduled automated processing of these batches. Each such batch, or each of two or more of the singulator hoppers, may advantageously contain a different type of dosage form, e.g., dosage forms that differ in terms of any of geometry (size, shape, etc.), pharmaceutical content, marking, color, etc. The described apparatus is particularly beneficial in that it is capable of handling such different types of dosage forms without any specific physical transformation or modification to the apparatus, such that multiple different batches of dosage forms may be processed in a single operating session without user intervention.

[0084] The singulator hopper or hoppers can be configured to deliver the dosage forms to a feeding mechanism 44. The feeding mechanism 44 can include, for example, a carousel having a plurality of peripheral apertures each receiving one such dosage form 12, which rotates and transfers the received dosage forms from the dosage source 42 to the dosage handler 60 for discharge one at a time.

[0085] The dosage form handler 60 receives a series of dosage forms of the same type or batch from the dosage form source 42 and is then automatically operated by the controller 50 to consistently set at least some aspects of the rotational state of each such dosage form (e.g., the alignment of the dosage form's axis about its axis to a preferred direction and / or orientation of the dosage form) for presentation at the inspection location 22 of the Raman analysis station 20. In this manner, potential errors and variations in detected characteristics of the dosage forms that may otherwise result from inconsistencies in the rotational state at the inspection location 22 can be minimized or reduced. To this end, the controller can include or be provided with alignment / orientation data 52 that defines predefined or preferred rotational states, such as alignment and / or orientation, of dosage forms of each type or batch that can be delivered by the dosage form source to the dosage form handler 60 for use as described in more detail below.

[0086] After the optical analysis, the dosage form handler 60 performs a discharge operation. Typically, the discharge operation should allow each optically inspected dosage form to be uniquely and accurately identified or identified for possible further inspection or analysis. To this end, the dosage form handler 60 may place each inspected dosage form into a different cell of the discharge tray 45 in such a way that the cell used for that particular dosage form can later be identified, either manually or as part of a further automated process.

[0087] FIG. 2 shows generally how the dosage form handler 60 of FIG. 1 can be implemented to provide the desired improved consistency of alignment and / or orientation in the optical analysis of multiple dosage forms of a single type or batch. The dosage form handler 60 comprises a handling table 70 that provides a table surface 72 on which each dosage form 12 delivered from the dosage form source 42 can be manipulated. The table surface 72 can preferably be flat, i.e., substantially horizontal. The table surface 72 can be smooth or textured in some manner, in one or more regions or across the entire table surface 72. For example, a surface texture can be provided that allows the dosage forms 12 to be pushed or slid across the table surface 72 but prevents or reduces undesired rolling or other movement of the dosage forms. Suitable surface textures can include, for example, repeating small protrusions, such as pyramidal or conical shapes, repeating small depressions or dimples, and the like. Such features can have a height or depth and repeat period of, for example, less than about 1 mm.

[0088] The dosage form handler 60 shown in FIG. 2 comprises a rotation stage 74 having a rotation stage surface 75 configured to receive and rotate the dosage form 12 into a predetermined preferred alignment for gripping for subsequent transport to and analysis by the Raman analysis station 20. The rotation stage surface 75 may typically be flush with or form part of the table surface 72 of the handling table (and thus typically also be flat or substantially horizontal) to allow the dosage form 12 to be pushed across and onto the table surface 72, as discussed in more detail below. The rotation stage surface 75 is configured to rotate about a rotation stage axis 77. This rotation stage axis is substantially perpendicular to the rotation stage surface and the table surface, and thus typically is approximately vertical when the table surface is approximately horizontal. In other words, the rotation stage used to rotate the dosage form about an axis that is typically vertical provides the desired rotational alignment about that axis.

[0089] To achieve the preferred alignment, the dosage form handler 60 also includes a machine vision system 80 that detects at least some aspects of the rotational state of the dosage form, e.g., when present on the rotating stage surface 75, and passes the detected aspects to the controller 50, so that the preferred alignment of the dosage form can be achieved by rotating the rotating stage 74 through suitable control of a rotating stage motor 76 (which in some embodiments can be considered to be included with the rotating stage 74). For example, the machine vision system 80 can detect a starting alignment of the dosage form on the rotating stage surface and pass this starting alignment to the controller, which then rotates the rotating stage to bring the dosage form into the preferred alignment. In other embodiments, the machine vision system can monitor the alignment of the dosage form as the rotating stage is rotated, and the controller is then configured to stop rotation when the preferred alignment is achieved.

[0090] The machine vision system 80 may include at least one camera 82, typically pointed downward at the rotating stage and having a field of view that includes at least a portion of the rotating stage surface 75, and a machine vision processor 84 configured to receive one or more images of the dosage form 12 disposed on the rotating stage surface and detect desired characteristics of the dosage form 12 from those images, including aspects of its rotational state, such as alignment and orientation. Although depicted as a separate entity in Figure 2, the machine vision processor 84 may be provided as part of the controller 50, if desired.

[0091] The machine vision processor 84 can use features such as those described above, which can include, for example, shape, size, printed markings, surface embossed and debossed markings, color areas, etc., to detect aspects of the rotation as well as other characteristics of the dosage forms 12, such as the location of the dosage form on the rotation stage surface 75, and positive or negative identification of the dosage form as being of a particular type or from a particular batch, and can pass such detected characteristics to the controller 50, the analyzer 34, the personal computer 36, or other suitable element. For example, the controller 50 can control the dosage form handler 60 to handle the dosage form differently depending on which type of dosage form is detected, e.g., to orient the dosage form in a type-specific manner for optical analysis.

[0092] The machine vision system 80 can also be used to determine dosage form dimensions, such as the diameter of a circular dosage form in plan view, or more specific length and width dimensions of dosage forms in other planar shapes, such as oval, rectangular, or capsule shapes (which may require matching the dosage form dimensions to the desired dimensions). Other suitable measures can include surface area in plan view. The thickness of a dosage form between two generally planar opposing surfaces, such as the thickness of a tablet, can also be determined by the machine vision system, although this may require some manipulation of the dosage form to ensure that the edges of the dosage form are properly presented to the camera 82. In some cases, the machine vision system can make sufficient dimensional and / or area measurements to allow calculation of the dosage form's volume.

[0093] For a particular type or batch of dosage forms, a preferred alignment can be defined with respect to the dosage form axes of the dosage forms (e.g., in the alignment / orientation data 52 available to the controller). The dosage form axes of the dosage forms can be predefined and at least implicitly known from images of such dosage forms using the machine vision system 80. Rotating the dosage form to the preferred alignment on the rotational stage is then the same as rotating the dosage form's default dosage axis into alignment with a target axis that is parallel to the rotational stage surface, where the target axis can typically be fixed relative to the dosage form handler 60 or one or more other parts of the apparatus 10.

[0094] FIG. 3a shows how the dosage form axis 13 and thus the preferred alignment (i.e., orientation of rotation) of the dosage form can be defined. In this case, an essentially cylindrical capsule 12'' is shown as having a dosage form axis 13, which in this case corresponds to the axis of rotational symmetry of the cylinder. The preferred alignment of this capsule can be when the dosage form axis 13 is parallel to a target axis (not shown in this figure). If the capsule 12'' or other dosage form is not symmetrical with respect to reversal or reflection of the direction along this dosage form axis, for example if it has ends with different colors or other asymmetric features as shown in this figure, the preferred alignment may require the dosage form axis to be specifically parallel or anti-parallel to the target axis.

[0095] Since the alignment of the dosage form on the rotational stage can determine how the dosage form is gripped for transport to the inspection location, the selection of the dosage form axis can also take into account the expected stability of the hold by the gripper when gripped along or in a defined orientation relative to this axis.

[0096] Furthermore, if the capsule 12'' contains features that make the capsule asymmetric in rotation about the dosage form axis 13, such as printed lettering as shown in the figures, in addition to rotating the dosage form axis into the preferred alignment, it may be desirable to rotate the dosage form into a preferred rotational orientation about another axis that is substantially parallel to the dosage form axis or the surface of the rotational stage, for example using a gripper as described in more detail below.

[0097] FIG. 3b shows another example of how the dosage form axis 13 of tablet 12''' can be defined. Tablet 12''' has a snap line feature or division line 14 embossed on one of two opposing circular surfaces of tablet 12'''. In this case, the preferred orientation of rotation about the dosage form axis can be one in which the snap line faces in a particular direction, for example, either up or down, or possibly to the left or right in the figure.

[0098] Referring again to Figure 2, the dosage form handler 60 also includes elements for moving the rotated dosage form to an inspection location. In Figure 2, this element is provided by a gripper 90 configured to grip the dosage form 12 after rotation into a preferred alignment using the rotation stage and transport the gripped dosage form to the inspection location 22 of the Raman analysis station 20. These operations are under the control of the controller 50.

[0099] As the dosage form on the rotating stage is transported from a position where it is gripped by the gripper to a position where it is presented for analysis at the inspection location 22, the alignment and optionally other aspects of the dosage form's orientation can remain fixed or can be changed in a controlled, known manner to achieve consistent alignment and / or orientation of the dosage form at the inspection location. On the other hand, after optical analysis, there is typically little or no need to maintain a known or precise alignment or orientation of the dosage form during subsequent ejection operations.

[0100] The gripper 90 may also be configured to rotate the gripped dosage form in a preferred rotational orientation about a gripper axis of rotation 96, which may be, for example, an axis parallel to the rotating stage surface 75 (and thus typically a horizontal axis). This may be accomplished by using the gripper to grip the dosage form, lifting it above the rotating stage surface 75, rotating the dosage form, returning it to the rotating stage surface 75, and releasing the dosage form. Such a sequence may be used if it is preferred for the gripper to return to another rotational and / or translational state before gripping the dosage form again for transport to an inspection location. Alternatively, the gripper may rotate the dosage form after gripping and lifting without placing it back on the rotating stage surface, for example as part of a movement to transport the dosage form to an inspection location, or even at the inspection location. As another alternative, such lifting and / or replacing of the dosage form by the gripper may occur at one or more other portions of the table surface away from the rotation stage, which may in some configurations or operations obviate the need to lift the dosage form before rotation, for example when rotation is performed around an axis of symmetry of a cylindrical form.

[0101] Typically, the gripper 90 can include opposing jaws 92, 94 configured to close toward one another until they contact a dosage form, thereby gripping the dosage form. Although the dosage form axis can be defined in a variety of ways to accommodate the requirements of rotation into a preferred alignment using a rotation stage, as discussed above, the dosage form axis can conveniently be defined as the axis along which the gripper jaws approach to close until they contact the dosage form for gripping and transporting the dosage form to an inspection location.

[0102] As shown in FIG. 2, the gripper rotation axis 96 can also be parallel to the axis along which the gripper jaws close, and therefore can also be parallel to the target axis described above, which is the same as the dosage form axis when the dosage form is in the desired alignment on the rotary stage 74.

[0103] Each gripper jaw 92, 94 can be designed to function in a satisfactory manner with all anticipated dosage forms without the need to customize the shape for any particular dosage form or class of dosage forms and without the need to modify the gripper jaw. To this end, each gripper jaw can be provided with concave surfaces 98 that face each other and are presented to the dosage form for gripping the dosage form when the jaws approach each other. Each concave surface can have a radius of curvature suitable to provide a more stable grip of the typical dosage form being handled, for example a radius of curvature of about 3 mm to 10 mm.

[0104] More generally, a method of operating the apparatus may include the dosage form handler delivering each of a plurality of dosage forms of a first geometry (e.g., shape, size, etc.) to an inspection location for optical analysis, and thereafter, without deformation or alteration of the gripper jaws, delivering each of a plurality of dosage forms of a second, different geometry to the inspection location for optical analysis.

[0105] The machine vision system 80 is also configured to detect the orientation of rotation of the dosage form, e.g., about the gripper rotation axis and / or the dosage form axis, and pass this detected orientation to the controller, in order to control the gripper to rotate the dosage form to a preferred rotation orientation, e.g., as defined by the alignment / orientation data 52. This may be done as a starting orientation from which the controller can determine the amount of gripper rotation required, or as ongoing orientation detection as gripper rotation is occurring, or in other ways.

[0106] Overall translational movement of the gripper 90 is provided by multi-axis staging 100, which typically has three translational axes, to enable the gripper to move to a position on the table to grip the dosage form, lift the dosage form from the table, transport it to the inspection location 22, and complete the ejection operation. To this end, the machine vision system 80 is also configured to detect the lateral position of the dosage form on the rotary stage and pass the detected lateral position to the controller for controlling the gripper to grip the dosage form at the detected lateral position by suitable control of both the multi-axis staging 100 and the gripper jaws 92, 94.

[0107] The grippers can be configured such that when the jaws close towards each other, both gripper jaws move relative to the multi-axis staging 100. Alternatively, one jaw (e.g., distal jaw 92, on the side furthest from the staging 100 in FIG. 2) can be stationary relative to the staging 100 while the other jaw (e.g., proximal jaw 94, on the side closer to the staging 100 in FIG. 2) is configured to translate relative to the staging.

[0108] In addition to the rotating stage 74 and rotating stage surface 75, the handling table 70 may include other structures and areas for handling, analyzing, and otherwise processing the dosage forms. For example, as shown in FIG. 2, the handling table 70 may also include a scale 110 with a scale surface 112. The scale surface 112 is preferably flush with or forms part of the table surface 72 so that the dosage form can be slid or pushed across and onto the scale surface 112. The scale is coupled to the controller 50 so that the weight of the dosage form can be received from the scale for reporting to, for example, the personal computer 36 or other part of the device. The determined weight of the dosage form can be used along with other characteristics determined by the machine vision system and / or the analyzer 34, for example, to help determine whether the dosage form meets certain required specifications or whether the dosage form is of an expected type or from the correct batch.

[0109] Although the scale is depicted as separate in FIG. 2, in some embodiments it may be integrated into the rotation stage.

[0110] The handling table surface 72 as shown in Figure 2 also comprises a drop zone 120. The drop zone is an area of ​​the table surface 72 where a dosage form source is configured to place a dosage form for handling and analysis. Providing such a drop zone 120 separate from the weighing machine surface means that the impact of a dosage form drop onto the drop zone 120 does not adversely affect the accuracy of the weighing machine. Once a dosage form has been dropped onto the drop zone 120 by the dosage form source, it can be moved, for example by sliding or pushing, for subsequent weighing by the weighing machine 110.

[0111] Although part or all of the rotating stage surface 75 could in principle be used as a drop zone, robot layout and workflow considerations may make it advantageous to keep these areas separate.

[0112] The dosage form handler 60 may also include elements for pushing or sliding the dosage form across the table surface 72. In FIG. 2 this is shown as a box slider 130 that surrounds the dosage form in the plane of the table surface 72 or from a top perspective when in the proper position to push or slide the dosage form or when in the process of pushing or sliding the dosage form, although other forms of sliders that do not necessarily surround the dosage form may also be used. The exemplary box slider 130 shown in FIG. 2 provides a closed rectangular perimeter around the dosage form to be moved, although other forms may also be used, provided that the slider is useful for accurate positioning of the dosage form when required on the table surface 72. The box slider in FIG. 2 has a lateral dimension of approximately 30 mm to 60 mm along each side.

[0113] In particular, the box slider 130 can be controlled by the controller 50 to move to the drop zone 120 to receive a dosage form from the dosage form source 42 into the box slider 130. The box slider is then controlled to move the received dosage form to the weigher surface 112 for weighing and then to the rotary stage surface 75 for alignment and / or orientation before being transferred by the gripper 90 to the inspection location 22.

[0114] To deposit the dosage form on the rotating stage surface 73, the box slider 130 is provided with a translation axis, typically vertical, perpendicular to the table surface 72 so that the box slider can be lifted sufficiently to remove the dosage form. In addition, the box slider 130 is typically provided with two translation axes so that the dosage form can be moved to various locations on the table surface 72 as may be required by the manipulation process being performed.

[0115] Conveniently, the box slider can be mounted on the same multi-axis staging 100 as the gripper 90. For structural efficiency and use, the dosage form handler 60 can then be configured such that the drop zone 120, the weigher surface 112, and the rotary stage surface 75 are generally located in that order along a process axis 125 of the dosage form handler 60 as generally shown in FIG. 2, and the inspection location 22 of the Raman analysis station can then also be generally located further along the same process axis 125 from the rotary stage surface 75. The multi-axis staging 100 used to move the position of the gripper 90 can also provide the required movement of the box slider 130 along the process axis 125 between the drop zone 120, the weigher 110, and the rotary stage 74.

[0116] The process axis 125 may correspond to the primary axis of motion of the multi-axis staging 100, for example, by movement of the multi-axis staging along a rail 102 or similar structure extending along or parallel to the process axis 125. In practice, three separate axes of motion may be provided by the multi-axis staging in common to both the gripper and the box slider. In the configuration of FIG. 2, these provide for movement along the vertical depth and vertical process axes across the table surface. However, in some configurations, one or more of these axes may be provided separately for each of the gripper 90 and the box slider 130, for example, each of the gripper and the box slider may be provided with a separate vertical control axis or a separate depth control axis.

[0117] 4a, 4b and 5 illustrate, using flow diagrams, several ways in which the above-described apparatus may be automatically operated, for example by controller 50, to present dosage forms in a consistent rotational state, such as alignment and / or orientation, at an inspection location 22 of a Raman analysis station 20 or other spectral or optical analysis device. Although a particular sequence of process steps is illustrated and discussed, a subset of these steps may be used without all of the other steps, and the steps need not necessarily be used in the order described and illustrated.

[0118] In step 410 of Figure 4a, the dosage form is received on the rotating stage 74. The dosage form can be received on the rotating stage in a variety of ways, for example, as discussed above and below with respect to Figure 5.

[0119] In step 415, the rotational stage is rotated to rotate the dosage form about its axis of rotation 77, which is typically a vertical or substantially vertical axis. As discussed above, the amount of rotation required to achieve the preferred dosage form alignment can be determined using a machine vision system 80 that includes a camera having a field of view that includes some or all of the rotational stage 74. The preferred dosage form alignment can be achieved by aligning the dosage form's predetermined dosage form axis 13, which can be identified using the machine vision system, with a target axis that is typically fixed relative to a stationary portion of the apparatus, such as the machine vision system.

[0120] The dosage form is then gripped using the gripper 90 in the preferred alignment and picked up from the rotating stage in step 418. The dosage form is then transported by the gripper 90 in step 425 to the inspection location 22 of the optical analysis station for optical analysis in step 430. An optional step shown in FIG. 4a as step 420 may also be performed after rotation of the dosage form into the preferred alignment using the rotating stage, or in some cases prior to rotation. This additional step involves using the gripper 90 to rotate the dosage form into a preferred orientation about a gripper rotation axis 92. The gripper rotation axis 92 is typically inclined or substantially perpendicular to the rotating stage axis 77, and therefore may typically be horizontal or substantially horizontal and / or parallel to the rotating stage surface 72 on which the dosage form is supported.

[0121] Rotation to a preferred orientation can occur partially or completely while the dosage form is still on or just above the rotating stage, and / or during travel to the inspection location, and / or immediately upon arrival at the inspection location, for example, as illustrated by three alternative time points (a), (b) and (c) in FIG. 4a.

[0122] In this manner, the preferred dosage form alignment and / or orientation is preserved until optical interrogation at the inspection location is completed, despite any known subsequent rotation due to the controlled movement of the grippers, after which the dosage form may be released from the grippers' grasp.

[0123] Optical interrogation of the dosage form is performed in step 430, which may be, inter alia, Raman interrogation for Raman spectral features or other types of spectral or optical analysis as discussed elsewhere herein. Optical interrogation may be performed, inter alia, in a transmission configuration, for example, by directing laser probe light to a first surface region of the dosage form, collecting components of the laser probe light scattered within the dosage form from a second surface region of the dosage form that is opposite the dosage form from the first surface region, and detecting Raman or other spectral features in the collected light.

[0124] As noted above, during optical inspection, the dosage form may be presented using a gripper in a particular fixed position and rotational state (orientation / alignment) at the inspection location 22, or it may be moved / rotated between multiple discrete positions with optical inspection performed at each discrete position, and / or it may be moved in a scanning motion (including either or both translation and rotation) with optical inspection performed during the movement.

[0125] Finally, a characteristic of the dosage form is determined in step 435. Such a characteristic may be a chemical characteristic of the dosage form, such as the presence or proportion of a particular chemical species or chemical form, and such a characteristic may be determined from the detected Raman or other spectral features. Various notifications and / or alerts may then be automatically generated for the attention of an operator of the device, for example, an alert indicating that one or more characteristics of the dosage form are outside of a desired range.

[0126] By using a transmission geometry and using Raman spectroscopy, various useful chemical and compositional properties can be determined not only from the surface regions of the dosage form, but also from the internal bulk. However, such transmission analysis can be sensitive to precise rotational conditions such as alignment / orientation of the dosage form at the inspection location 22, and by using a rotational stage and / or gripper to provide proper alignment / orientation, and using the gripper to preserve that rotational condition (albeit with a subsequent known rotation), more consistent results of the Raman spectroscopy can be achieved.

[0127] The grippers may be used for other operations and actions in addition to those shown in FIG. 4a above. For example, either before or after the dosage form has been rotated into the preferred alignment, it may be necessary to "flip" the dosage form so that the preferred side of the dosage form faces upward and toward the camera 82. Such an operation may allow the machine vision system 80 to more fully determine or control the correct alignment of the dosage form, for example, when suitable markings are found on only one major side of the dosage form, in which case such a flip operation may be undertaken by the grippers prior to the rotation stage motion. In another example, as discussed below, the grippers may be used in presenting an edge of the dosage form to the machine vision system to aid in determining the dosage form's thickness.

[0128] A machine vision system 80 can be used to obtain various dimensional measurements of the dosage form while it is positioned on a rotating stage and / or held by a gripper. Typically, the machine vision system can include a camera 82 with a downward view onto the rotating stage, as shown in FIG. 2. Where the dosage form has two opposing major surfaces, as is common for tablets and some other forms, the downward viewing camera can be used to easily obtain plan view dimensions when the dosage form is lying with such major surfaces against the rotating stage, although the machine vision system 80 may also wish to determine the thickness between the two opposing major surfaces, which dimension is not visible to the camera in such a view. Such dosage forms can typically be tablets or the like with two opposing circular surfaces and a sidewall of approximately constant width extending between the surfaces, although other surface shapes and geometries may also be used.

[0129] To this end, gripper 90 may also be used, under control of a controller, to use machine vision system 80 to present an edge surface or sidewall of the dosage form to camera 82 of machine vision system 80 such that the thickness of the dosage form can be determined, for example, by machine vision processor 84. This may occur before or after step 415 in Figure 4a, depending, for example, on whether a particular rotational state of the dosage form is required for it to be picked up by the gripper.

[0130] In some examples, the gripper can be used to pick up the dosage form, rotate it, for example, 90 degrees, and then place the dosage form edge-down on the rotating stage. The gripper can then move out of the way to release the dosage form and provide a clearer view of the dosage form to the machine vision system. In other examples, the gripper can maintain a grip on the dosage form, but rotate it, for example, 90 degrees, to present an edge view to the machine vision system without placing the dosage form edge-down on the rotating stage. For some designs of gripper 90, a certain rotation may be required to ensure that a sufficiently clear view of the dosage form edge is still obtained.

[0131] In either case, a machine vision system is then used to obtain and output suitable dimensional data of the dosage form from the edge plot in order to determine the thickness of the dosage form.

[0132] If the dosage form is placed edge down on the rotating stage to determine the thickness after rotation step 415 of Figure 4a, it may be possible to pick up the dosage form again from this position using the grippers and proceed to steps 425, 430 and 435 of Figure 4a, and optionally also to step 420. However, the process of placing the dosage form edge down may instead require the dosage form to be returned on the rotating stage to a position with its major surface lying on the stage, either by direct handling using the grippers or by flipping the dosage form over in some manner, which may require repeating the rotation of the stage according to step 415 after determining the edge thickness.

[0133] Some ways in which such dimensional measurements can be performed are shown in FIG. 4b. In step 450, a dosage form having opposing major surfaces separated by an edge surface is received beneath a machine vision system camera 82. This may be step 410 in FIG. 4a where the dosage form is received on a rotating stage, but the dosage form may also be received on some other surface or part of the handling table 70. In step 455, the machine vision system camera 82 is used to detect the dimensions of the major surfaces of the dosage form in a plan view beneath the camera. Such dimensions may be the diameter of a circular dosage form, the length and width dimensions of an oval or rectangular tablet, the plan view surface area, etc. If the dosage form is also being manipulated in a manner such as FIG. 4a, step 455 may be performed before or after step 415 of rotating the dosage form into the preferred alignment.

[0134] In step 460, the dosage form is gripped using the gripper 90 and the dosage form is rotated so that the edge surface is presented to the machine vision system camera 82. For example, it can be rotated so that the portion of the edge surface closest to the camera is substantially horizontal, although other presentation angles relative to the camera that provide sufficient measurement accuracy can also be used. The gripper can then move away to lower the dosage form edge-down and provide the machine vision system with a clear view of the dosage form, or it can maintain its grip on the dosage form if maintaining its grip still provides a sufficiently clear view. In step 465, using the machine vision system, the thickness of the dosage form is detected using the visible width of the edge surface. If the dosage form is also being manipulated in a manner such as that of FIG. 4a, step 460 may be followed by repositioning the dosage form so that it is placed face down before performing rotation step 415, or by performing rotation step 415 again if necessary, or step 465 may be followed by step 425 (and optionally step 420) in which the dosage form is transported to an inspection location, without necessarily having to place the dosage form on the rotating stage again by the gripper.

[0135] FIG. 5 illustrates steps that may be performed automatically, for example under the control of controller 50, to provide a dosage form to rotating stage 74 so that a method such as FIG. 4a can be performed.

[0136] In step 510, the dosage form is received at the drop zone 120 of the handling table 70, which also comprises a rotating stage 74. The handling table 70 may also comprise a scale 110, which may be flush with or form part of the handling table so that the dosage form can be pushed or slid across the handling table between these stations. The drop zone is provided separately on the handling table 70 from the scale, if one is provided, so that the drop of the dosage form onto the handling table does not affect the subsequent performance of the scale. If the dosage form is dropped directly onto the scale, the scale may take some time to return to equilibrium, thereby slowing down the handling and optical analysis process.

[0137] The dosage forms may be delivered to the drop zone 120 by a dosage form source 42 as described elsewhere herein, which may itself comprise or be configured to receive one or more singulator hoppers 43, each capable of holding a batch of tens or hundreds of dosage forms of the same type and inspected in the same manner, and capable of delivering one such dosage form at a time to the drop zone.

[0138] In step 515, the dosage form received at the drop zone is transferred by sliding or pushing it across the handling table onto the weigher 110, if provided. The dosage form is then weighed in step 520 and then transferred by sliding or pushing it across the handling table onto the rotating stage in step 525. At this point, the steps of Figure 4a can then be performed.

[0139] The sliding or pushing of the dosage form across the handling table can be accomplished by a slider element, for example the box slider 130 shown in Figure 2. Such a box slider, encircling the dosage form in all horizontal directions, allows the dosage form to be dropped by the dosage form source 42 in step 510 without the risk of the dosage form bouncing away from the expected location or leaving the handling table entirely. The box slider also allows the dosage form to then be moved precisely in any horizontal direction under the control of the controller 50 to any desired position, for example the center of a weighing scale or the center of a rotation stage.

[0140] The described apparatus can also be used to perform automated series of tests on the same dosage form or a series of dosage forms of the same type. Such series of tests can be used, for example, to determine the operating characteristics of the apparatus, such as the accuracy and reproducibility of the presentation of the dosage form at the test location 22 and, therefore, the accuracy and reproducibility of the resulting optical analysis and determined properties of such type of dosage form. To this end, the described apparatus can be used, for example, to carry out a method as outlined in FIG.

[0141] 6, a dosage form is received at a handling table 70, e.g., at a drop zone 120 of the handling table, in step 610. The dosage form is then manipulated using a dosage form handler apparatus, e.g., including the use of one or more of a box slider 130, a weigher 110, a rotational stage 74, a gripper 90, and a multi-axis staging 100, as described above, in step 620. The dosage form is then presented at the inspection location 22, in step 630, by the gripper 90 in one or more preferred rotational states (combinations of orientation and alignment, as appropriate) and / or translational positions, for optical interrogation by detection of Raman spectral features using the Raman analysis station 20. As discussed above, such rotational states and / or positions may include only one such rotational state and position, or may include movement between a plurality of such configurations, where optical analysis is performed in each such configuration and / or sequentially during such movement in the form of a scanning operation.

[0142] At decision point 640, if the series of inspections is completed, then in step 650, the data received from the series of optical interrogations can be analyzed to determine one or more parameters of the handling, presentation and analysis process, but if not, then in step 660, the dosage form can be returned to the handling table 70, for example by using the gripper 90 to return the dosage form to the drop zone 120, after which the steps of handling and presentation to the Raman analysis station 20 are repeated using the same dosage form.

[0143] Rather than handling and presenting the same dosage form to the Raman analysis station 20 each time, the presented dosage form can be discarded and a new dosage form of the same type can be used for the next inspection sequence of Figure 6. Rather than presenting the dosage form in the same orientation, alignment and position each time, the dosage form handler can instead present the dosage form in a range of different such configurations.

[0144] Determining 650 the parameters of the handling, presentation, and analysis process can take a variety of forms, including one or more parameters that represent a measure of the variability of a property of the dosage form, such as the absolute amount of active pharmaceutical ingredient, under the assumption that the dosage form is presented at the Raman analysis station 20 using the same rotational conditions, alignment, and position each time.

[0145] If aspects of the dosage form during optical interrogation, such as its rotational state and position, are varied from presentation to presentation in order to inspect a range of such aspects, the parameters determined in step 650 may represent how adjusting such aspects affects the results of the optical analysis. Such parameters or results may then be used to design improved or optimized strategies for presenting the same or similar types of dosage forms at the inspection location 22.

[0146] The described apparatus can therefore be used to examine the effects of variability and determine the accuracy of optical measurement results due to a variety of different factors, including variability in handling and presentation of dosage forms and variability in optical measurements. The described apparatus can also be used to establish improved or optimized methods or handling and presentation of dosage forms.

[0147] The above described apparatus 10 configured to handle and analyze pharmaceutical dosage forms as discussed can typically enable Raman spectral interrogation of a single dosage form in about a few seconds to tens of seconds, with this time period depending on the signal to noise ratio required for detection of the Raman spectral features and the resulting accuracy of the chemical properties sought, what power levels of laser beam illumination of each dosage form are acceptable, and other factors such as the type of optics and optical detectors used. As a result, the dosage form handler should be configured to handle a series of dosage forms at the same speed or at a higher speed to maximize utilization of the optical analyzer. For example, if the dosage form source can be equipped with 10 singulator hoppers, each carrying 100 dosage forms, then with the improved accuracy of optical analysis resulting from the embodiments of the present invention discussed above, about 1000 dosage forms can be easily analyzed in a fully automated manner within a few hours.

[0148] Certain aspects of the described apparatus and methods may be implemented using computer program code executed on one or more suitable computer systems. Such computer systems will typically include one or more microprocessors for executing such computer program code, memory for storing such programs and associated data, and suitable input / output facilities including, for example, wired or wireless data connections, non-volatile storage, a visual display, and input devices such as a keyboard and mouse.

[0149] The controller 50 may include one or more suitable computer systems programmed to carry out the described operations, for example, by control of the dosage form source, grippers, rotary stage, multi-axis staging and other components in response to data received from the machine vision system, weighers, analyzers, 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 required data processing of the controller 50. In some embodiments, the machine vision system may utilize LabVIEW software (Laboratory Virtual Instrument Engineering Workbench) provided by National Instruments, Austin, Texas, to implement aspects such as identification of the particular type of dosage form, as well as various aspects of the position and orientation of the dosage form.

[0150] The analyzer may similarly be implemented using one or more computer systems employing suitable software that receive the spectral data signals from detector 32, analyze and process the spectral data signals in various ways, e.g., to reduce noise, convert them to a desired form, determine or measure specific spectral features, and match the detected spectral features to features of known or expected components or properties of the dosage form being tested. Libraries of spectral features that can be used for such comparisons are available, for example, from ST Japan or Sigma-Aldrich.

[0151] It has been discussed above how the gripper 90 can be used to move the dosage form 12 while taking multiple optical measurements through a range of alignments (changes in translational position and / or rotational orientation) of the dosage form in order to obtain a more representative optical measurement of the dosage form during presentation at the inspection location. To this end, FIG. 7 shows the dosage form 12 being gripped by the gripper while, for example, on the rotational stage 74 or other portion of the handling table surface 72 and transported by the gripper 90 to the inspection location 22 located within the Raman analysis station 20. These and other movements and motions by the gripper 90 can be performed by a controller, such as the controller 50 depicted in FIGS. 1 and 2, in combination with elements that provide suitable movement, such as the multi-axis staging depicted in FIG. 2.

[0152] 7 shows the delivery optics 26 and collection optics 30 already described above, with the dosage form 12 positioned at the inspection location 22 between these two. The delivery optics 26 is then configured to direct a beam of probe light 27 to a first surface region 710 of the dosage form, and the collection optics 30 is configured to receive the probe light from a second surface region 712 of the dosage form after scattering, or more specifically forward scattering, that has passed through the dosage form 12 from the first surface region to the second surface region.

[0153] In particular, the first surface region 710 and the second surface region 712 may be on opposite sides or opposing faces of the dosage form 12, such as on the respective first surface 40 and second surface 41 as already shown in Figure 1, such that the dosage form is inspected using a forward scattering configuration or a transmission configuration, although other configurations may be used, such as those discussed above.

[0154] 1 and discussed above is configured to receive the focused probe light from collection optics 30 and detect Raman spectral features in the focused probe light, such as Raman spectral features representative of the magnitude of multiple Raman spectral peaks, or more generally a full Raman spectrum representative of detected intensity or power as a function of wavenumber or wavelength. This data is then passed to analyzer 34, also discussed above. The analyzer is configured to use the Raman spectral features to determine one or more characteristics of the dosage form being tested, such as the relative concentration of a particular constituent of interest, such as an active pharmaceutical ingredient.

[0155] In some embodiments, a particular dosage form 12 is positioned at an inspection location and held stationary in a single configuration or alignment between the delivery and collection optics while the Raman spectral features are measured, and the Raman spectral features of that single alignment are then used to determine one or more properties of the dosage form. However, the inventors have realized that there may be some advantages to moving the dosage form within the inspection location while undergoing inspection, such that Raman spectral features are detected for a number of different such alignments or configurations. Such measurements of Raman spectral features may be made during one or more movements of the dosage form, or a combination of the two, at each of a number of discrete, usually stationary, alignments. Typically, all such alignments can be used to obtain Raman spectral features without removing the dosage form from the inspection location, although in some embodiments it may be desirable or appropriate to remove the dosage form from the inspection location between some alignments or groups of alignments. One such situation may be that after using one or more alignments, the dosage form is returned to a surface such as table surface 72 to rotate the gripper to use one or more further alignments, the dosage form is picked up again with the gripper in the rotated position, the gripper is used to invert the dosage form, and the dosage form is presented in an inverted (upside down) state at the inspection location.

[0156] Different alignments or configurations of the dosage form at the inspection location 22, whether discrete such alignments or continuous movement through a range of such alignments, can be provided by, inter alia, rotation of the dosage form about one or more selected axes, translation in one or more directions, or a combination of both. Such changes in the alignment of the dosage form at the inspection location result in a corresponding change in the position on the dosage form of one or both of the first surface region 710 and the second surface region 712, and thus a change in the scattering path of the probe light between the first and second surface regions, and thus a change in the representative volume of the dosage form inspected at each alignment.

[0157] Moving the gripper to present the dosage form in multiple alignments between the delivery and collection optics, and collecting the probe light from the second surface for each alignment, thus allows for a range of different scattering configurations and representative volumes of the dosage form to be inspected. The analyzer can then use the Raman spectral features from the various alignments in multiple ways to determine one or more properties of the dosage form using Raman spectral features detected during some or all of the alignments.

[0158] For example, in one mode of operation, the analyzer can process the detected Raman spectral features for each alignment or each of multiple groups or ranges of alignments to derive individual dosage form characteristics for each such alignment, group, or range, and then average or combine the obtained dosage form characteristics to obtain a single average dosage form characteristic that is more representative of the entire dosage form.

[0159] In another mode of operation, the analyzer can instead average or otherwise combine the Raman spectral features from each alignment, or each of multiple groups or ranges of alignments, with one another to determine a more representative set of Raman spectral features of the entire dosage form from which a more representative dosage form characteristic of the entire dosage form can be derived.

[0160] In other modes of operation, individual values ​​of a property of the dosage form may be determined for each of a plurality of different alignments, or groups or ranges of alignments, e.g., to determine individual values ​​of a property of the dosage form for each of two or more distinct portions of the dosage form. For example, such modes of operation may be used to detect individual values ​​for each of two or more frangibly separable portions of a pharmaceutical tablet defined by one or more division lines 14 or grooves in one or more faces of the tablet, such as, for example, the embossed snap line features typically seen in FIG. 3b.

[0161] Alignment of the dosage form at the inspection location can be more easily accomplished using the described configuration because of the use of Raman spectroscopy, which allows the dosage form to be held at the inspection location without the need for light baffles or other devices that strongly prevent the probe light from being directed around the dosage form and towards the probe light collection optics. This is in contrast to the use of infrared absorption spectroscopy, where leakage of the probe light around the dosage form is a much greater concern and typically requires the dosage form to be held in some sort of light-tight surrounding environment, making that type of optical inspection of the dosage form over a range of alignments (translational and / or rotational) more difficult. To this end, as discussed elsewhere, the gripper used in this embodiment can be configured to suspend the dosage form in essentially free space between the delivery and collection optics of the Raman analysis station, without the need for baffles or other specific light-blocking structures.

[0162] 7, the mechanical gripper (represented by a cross section through opposing jaws 94) is controlled to laterally translate the dosage form 12 between the delivery and collection optics such that a first surface region 710 translates across an upper surface 40 of the dosage form 12 while a second surface region 712 translates across a lower surface 41 of the dosage form. The dosage form can be held stationary in each of two or more particular such alignments and Raman spectral features can be detected for each such discrete alignment, and / or Raman spectral features can be detected during one or more episodes of continuous movement of the dosage form 12.

[0163] The depicted lateral translation allows for sampling of a larger volume of the dosage form while maintaining the use of a modest diameter probe light beam 27 (and thus the first surface area 710) that may be easier to provide in an optically consistent manner, while using a modest diameter second surface area that may also improve the consistency of light collection. To improve the consistency of probe light delivery and collection, it may be preferable to use optics with a fixed probe light spot size and a fixed focused spot size on the dosage form 12, and avoid telescope or other moving optics configurations. For example, the desired first surface area 710 or delivered light spot size may be less than about 3 mm in diameter, or less than about 2 mm.

[0164] Although an essentially lateral translation between two or more locations is depicted in Figure 7, these locations can be distributed in various ways, for example, in a line across the dosage form, in a spiral, using a two-dimensional array of equally spaced sampling points, etc. Although the translation in Figure 7 is depicted as 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 be particularly desirable to maintain the second surface region at a suitable focal distance from the collection optics to maintain constant collection characteristics.

[0165] In FIG. 8, it can be seen that the gripper is controlled to rotate the dosage form 12 about one or more axes. The one or more axes can be perpendicular to the optical axes of the delivery and collection optics as shown in FIG. 8, or can be other axes, or can include other axes. With respect to FIG. 7, the dosage form can be held stationary in each of two or more specific such alignments and Raman spectral features can be detected for each such discrete alignment, and / or Raman spectral features can be detected during one or more episodes of continuous movement of the dosage form 12. In FIG. 7, the rotation angle is depicted at about 30 degrees, but a range of alignments over a much smaller or larger angular range may be used. In some embodiments, the dosage form can be completely flipped or turned upside down between alignments such that one or more alignments involve the 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.

[0166] One or more such rotational movements can be combined with one or more translational movements (e.g., as shown in FIG. 7) to provide a plurality 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 resulting in different optical paths of scattering of the probe light through the sample for analysis, as discussed above.

[0167] When translation is used, the range of translation of the dosage form associated with providing multiple alignments can typically be on the order of a few mm, e.g., at least 2 mm. When rotation is used, the range of rotation of the dosage form associated with providing multiple alignments can vary widely, e.g., at least a few degrees or at least 10 degrees. One or more complete inversions of the dosage form can involve a range of rotation of about 180 degrees or about 360 degrees.

[0168] FIG. 9 is similar to FIGS. 7 and 8, but depicts the translation of a dosage form 12''' similar to that of FIG. 3b, but with a dividing line 14 or embossed snap line feature across the surface of the dosage form to facilitate dividing the dosage form into two portions, such as two half doses. In this case, the one or more alignments at which Raman spectral features are measured provide a first surface area and a second surface area in one half dose, and the one or more alignments at which Raman spectral features are measured provide a first surface area and a second surface area in the other half dose. In this manner, one or more properties of the dosage form can be determined for each half dose separately. Of course, some dosage forms may be similarly structured to divide into three or more separate doses, and one or more alignments corresponding to each such dose can be used to determine one or more properties of each such dose.

[0169] Figure 10 provides a detailed perspective view of an apparatus for implementing the dosage form handler 60 and several other embodiments shown in Figures 1 and 2. However, for clarity and convenience, Figure 10 does not explicitly show the dosage form source 42, controller 50, analyzer 34, and personal computer 36 seen in the previous figures.

[0170] The dosage form handler is generally depicted within the dashed balloon labeled 60. Multi-axis staging, generally depicted within dashed balloon 100, provides movement of gripper 90 and box slider 130 as necessary to carry out the handling processes described above with respect to handling table 70. A horizontal table surface 72 of handling table 70 includes a drop zone 120 where a dosage form source (not shown) drops dosage forms into box slider 130, a weigher surface 112 of weigher 110 to which box slider 130 moves dosage forms for metering, and a rotary stage surface 75 of rotary stage 74 to which box slider 130 moves dosage forms after metering. Rotary stage 74 is driven by a rotary stage motor 76.

[0171] The machine vision system includes a machine vision camera 82 with a field of view that covers some or all of the rotary stage surface 75 via a machine vision mirror 83 so that the machine vision system can detect at least the alignment of the dosage form lying in the plane of the handling table surface such that the dosage form can be aligned into a preferred alignment by rotation of the rotary table. The machine vision system preferably also detects further orientation information of the dosage form so that the dosage form can be rotated by a gripper 90 about a gripper rotation axis 92 to a desired rotational orientation. The gripper axis is parallel to the table surface 72. In FIG. 10, the rotation of the gripper is driven by a gripper rotation motor 99 through a belt drive.

[0172] The Raman analysis station is generally depicted within the dashed balloon 20 and comprises a laser source 24 generating a probe beam 27 of laser light, delivery optics 26, collection optics 30 and detector 32. The inspection location 22 in FIG. 10 is located near above the handling table 70. The drop zone 120, meter surface 112 and rotating stage surface 75 are generally distributed along the process axis 125, and the inspection location 22 is conveniently located beyond the rotating stage surface 75 along the same axis. The probe beam 27 of laser light is directed by the delivery optics 26 downwards towards the inspection location 22 above an aperture 73 through the handling table 70. The dosage form is held by the gripper 90 for optical analysis at the inspection location above the aperture 73, and collection optics 70, located partially below the handling table, receives the probe light scattered within the held dosage form through the aperture 73, thereby achieving a transmission configuration for the optical analysis.

[0173] The multi-axis staging 100 is configured to ride along rails 102 parallel to the process axis 125 to provide the required access by the box slider 130 to the drop zone 120, the weighing machine surface 112 and the rotary stage surface 75, and the required access by the gripper 90 to the rotary stage surface 75 and the inspection location 22. Vertical motion of the gripper 90 and the box slider 130 is provided by a common vertical axis mechanism of the multi-axis staging 100, and depth motion across the table surface perpendicular to the process axis 125 is provided by a common depth axis mechanism of the multi-axis staging.

[0174] Although particular embodiments of the present invention have been described with reference to the drawings, those skilled in the art will recognize that various changes and modifications can be made to these embodiments without departing from the scope of the invention. The claims as originally filed are as follows: Claim 1: 1. A method for automated analysis of pharmaceutical dosage forms, comprising: gripping the dosage form using a gripper; moving the gripper to bring the dosage form to an inspection location between delivery optics configured to direct probe light to a first surface region of the dosage form and collection optics configured to receive a probe from a second surface region of the dosage form after scattering through the dosage form; moving the gripper to present the dosage form in a plurality of alignments between the delivery optics and the collection optics, and collecting probe light from the second surface for each alignment; detecting a Raman spectral feature of the received probe light for each of the plurality of alignments; The method includes: Claim 2: 10. The method of claim 1, further comprising determining a characteristic of the dosage form using the Raman spectral features detected during some or all of the alignments. Claim 3: The method of claim 2 , wherein the characteristic is an average characteristic of the dosage form determined using Raman spectral features detected during all of the alignments. Claim 4: 3. The method of claim 2, wherein distinct values ​​of the property for each of two or more portions of the dosage form are determined using Raman spectral features collected during one or more alignments in which the first surface region and the second surface region are found in each such portion of the dosage form. Claim 5: 5. The method of claim 4, wherein the two or more portions of the tablet are defined by a dividing line provided on a surface of the tablet. Claim 6: 6. The method of claim 1, wherein at least one of the location of the first surface region on the dosage form and the location of the second surface region on the dosage form varies between each alignment. Claim 7: 7. The method of claim 1, wherein between each alignment, the gripper moves the dosage form by one or both of translation and rotation. Claim 8: The method of any one of claims 1 to 7, wherein at least some of the alignments form one or more continuous ranges of alignment during movement of the dosage form in which the Raman spectral features are detected in the received probe light. Claim 9: 9. The method of claim 1, wherein the second surface region is on an opposite side of the dosage form from the first surface region. Claim 10: 10. The method of claim 1, wherein the pharmaceutical dosage form is one or more of a tablet, a coated tablet, a capsule, a gel capsule, a solid dosage form, and an oral dosage form. Claim 11: 11. The method of claim 1, wherein moving the dosage form to provide the plurality of alignments comprises at least one of translating the dosage form through a distance of at least 2 mm and rotating the dosage form through at least 10 degrees. Claim 12: 1. An apparatus for automated analysis of pharmaceutical dosage forms, comprising: a mechanical gripper configured to grip the dosage form; a Raman analysis station having an inspection location and configured to detect Raman spectral features in probe light scattered within the dosage form when positioned at the inspection location; a controller configured to control the gripper to present the dosage form in a plurality of alignments within the inspection location and to control the Raman analysis station to collect probe light scattered within the dosage form and detect Raman spectral features in the collected probe light at each of the alignments; an analyzer configured to determine one or more properties of the dosage form from the detected Raman spectral features; An apparatus comprising: Claim 13: 13. The apparatus of claim 12, wherein the Raman analysis station comprises a delivery optical element configured to direct probe light to a first surface region of the dosage form when the dosage form is presented within the inspection location, and a collection optical element configured to receive probe light from a second surface region of the dosage form after forward scattering through the dosage form. Claim 14: 14. The apparatus of claim 13, wherein at least one of the location of the first surface region on the dosage form and the location of the second surface region on the dosage form moves between subsequent alignments. Claim 15: 15. An apparatus according to any one of claims 12 to 14, wherein the controller is configured to control the gripper to rotate and / or translate the dosage form between each alignment. Claim 16: An apparatus as described in any one of claims 12 to 15, wherein at least some of the alignments form one or more continuous ranges of alignment during movement of the dosage form in which the Raman spectral features are detected in the received probe light and used to determine one or more properties of the dosage form. Claim 17: 17. The apparatus of claim 12, wherein at least one of the one or more determined properties is an average property of the dosage form determined using the detected Raman spectral features from all of the alignments. Claim 18: 18. An apparatus according to any one of claims 12 to 17, configured to determine a different value of one of said properties for each of two or more portions of the dosage form using one or more alignments in which the probe light is largely scattered through each of such portions of the dosage form. Claim 19: a rotating stage having a rotating stage surface configured to receive the dosage form; a gripper configured to grip the dosage form; a Raman analysis station having an inspection location and configured to detect Raman spectral features in probe light scattered within the dosage form when positioned at the inspection location; a controller configured to control rotation of the rotational stage to rotate the dosage form into a preferred alignment while on the stage surface, control the gripper to grip the dosage form in the preferred alignment, and control the gripper to transport the gripped dosage form to the inspection location for Raman analysis; 1. An apparatus for analyzing a pharmaceutical dosage form comprising: Claim 20: The Raman analysis station comprises: a delivery optics configured to direct a probe light to a first surface region of the dosage form when disposed at the inspection location; a collection optic configured to receive the scattered probe light from a second surface region of the dosage form, the second surface region being spaced apart from the first surface region; and a detector configured to detect the Raman spectral feature in the received probe light; 20. The apparatus of claim 19, comprising: Claim 21: 21. The device of claim 20, wherein the second surface region is on an opposite side of the dosage form from the first surface region. Claim 22: 22. The apparatus of claim 20 or 21, wherein the gripper is configured to hold the dosage form at the inspection location for Raman analysis without having other structures between the delivery optical element and the collection optical element. Claim 23: 23. The apparatus of any one of claims 19 to 22, further comprising an analyzer configured to determine one or more properties of the dosage form from the detected Raman spectral features. Claim 24: 24. The apparatus of any one of claims 19 to 23, further comprising a machine vision system configured to detect the alignment of the dosage form when on the rotary stage surface and pass the detected alignment of the dosage form to the controller to control rotation of the rotary stage to rotate the dosage form into the preferred alignment. Claim 25: 25. The apparatus of claim 24, wherein the machine vision system is configured to detect an alignment of a pre-defined dosage form axis of the dosage form, and the preferred alignment comprises a preferred alignment of the dosage form axis. Claim 26: 26. The apparatus of claim 25, wherein the gripper is further configured to rotate the gripped dosage form about a gripper axis of rotation, and the controller is configured to control the gripper to rotate the dosage form about the gripper axis of rotation in a preferred rotational orientation while gripping the dosage form. Claim 27: 27. The apparatus of claim 26, wherein the gripper rotation axis is parallel to the rotary stage surface. Claim 28: 28. Apparatus according to claim 26 or 27, wherein the gripper rotation axis is parallel to the preferred alignment of the dosage form axis. Claim 29: 29. The apparatus of any one of claims 26 to 28, wherein the machine vision system is also configured to detect the rotational orientation of the dosage form about the gripper rotation axis and pass the detected rotational orientation to the controller for controlling the gripper when rotating the dosage form into the preferred rotational orientation. Claim 30: 30. The apparatus of claim 24, wherein the machine vision system is also configured to detect a lateral position of the dosage form on the rotating stage surface and pass the detected lateral position to the controller for controlling the gripper to grip the dosage form at the detected lateral position. Claim 31: 31. The apparatus of any one of claims 24 to 30, wherein the machine vision system is further configured to determine one or more dimensions of the dosage form. Claim 32: 32. The apparatus of claim 31, wherein the controller is configured to control the gripper to rotate the dosage form to present an edge of the dosage form to the machine vision system, the machine vision system configured to determine a thickness of the dosage form from the presented edge. Claim 33: 33. The apparatus of claim 32, wherein the controller is configured to control the gripper to place the dosage form edge-down on the rotary stage to determine a thickness of the dosage form by the machine vision system. Claim 34: 34. An apparatus according to any one of claims 19 to 33, wherein the gripper comprises opposing jaws configured to grip the dosage form between the jaws. Claim 35: 35. The apparatus of claim 34, wherein the opposing jaws are configured to grip the dosage form by gripping the dosage form along at least one of an axis parallel to the rotating stage surface and an axis aligned with the gripper axis of rotation. Claim 36: 36. Apparatus according to any one of claims 19 to 35, wherein the gripper is configured to remain in the preferred alignment when the dosage form is held at the inspection location for Raman analysis. Claim 37: 37. Apparatus according to any one of claims 19 to 36, wherein each jaw of the gripper comprises a concave surface presented to the dosage form for gripping the dosage form when the jaw grips the dosage form. Claim 38: 38. The apparatus of claim 19, wherein the controller is configured to control the gripper to place the dosage form in a predetermined cell of an output tray after detecting a Raman spectral feature in probe light scattered within the dosage form when positioned at the inspection location. Claim 39: Apparatus according to any one of claims 19 to 38, wherein the rotating stage surface forms part of a table surface of a handling table. Claim 40: 40. The apparatus of claim 39, further comprising a scale having a scale surface forming part of the table surface, the scale configured to measure a dosage form when positioned on the scale surface. Claim 41: 41. The apparatus of claim 39 or 40, further comprising a dosage form source configured to deposit a dosage form in a drop zone of the table surface, the drop zone being separate from the weighing device and optionally separate from the rotating stage surface. Claim 42: 42. The apparatus of claim 41, further comprising a slider configured to slide the dosage form across the table surface under the control of the controller, the controller configured to control the slider to slide the dosage form from the drop zone to the meter surface for metering and to slide the dosage form from the meter surface to the rotary stage surface. Claim 43: 43. The apparatus of claim 42, wherein the slider is a box slider configured to encircle a dosage form for sliding across the table surface. Claim 44: 44. The apparatus of claim 43, wherein the controller is configured to control the slider and the dosage source such that the dosage source places a dosage within the box slider at the drop zone. Claim 45: 45. The apparatus of claim 42, wherein both the gripper and the slider are coupled to multi-axis staging that provides movement along a process axis under the control of the controller to move the slider between the drop zone, the meter surface, and the rotary stage surface, and to move the gripper between the rotary stage surface and the inspection location of the Raman analysis station. Claim 46: 46. ​​The apparatus of any one of claims 19 to 45, further configured to present the dosage form in a plurality of different alignments through one or both of translation and rotation of the dosage form at the inspection location using the gripper for Raman analysis. Claim 47: a dosage form handler configured to place the dosage form in a preferred rotation in response to detection of the dosage form by a machine vision system; an optical analysis station for inspecting said dosage form in said preferred rotational state; 1. An apparatus for analyzing a pharmaceutical dosage form comprising: Claim 48: 48. The apparatus of claim 47, wherein the dosage form handler comprises a rotational stage configured to rotate the dosage form in response to the machine vision system. Claim 49: 49. The apparatus of claim 47 or 48, wherein the dosage form handler comprises a manipulator configured to one or more of: rotate the dosage form in response to the machine vision system and transport the dosage form to the optical analysis station for inspection. Claim 50: 50. The device of any one of claims 19 to 49, wherein the pharmaceutical dosage form is one or more of a tablet, a coated tablet, a capsule, a gel capsule, a solid dosage form, and an oral dosage form. Claim 51: 51. The device of any one of claims 19 to 50, wherein the pharmaceutical dosage form comprises one or more of a surface marking, a debossing, an embossing, a plurality of surface regions each having a different color, and a printed marking. Claim 52: 1. A method for automatically analyzing a pharmaceutical dosage form, comprising: Receiving the dosage form on a rotating stage; rotating the rotary stage to rotate the dosage form about a rotary stage axis into a preferred alignment; transporting the dosage form from the rotary stage to an inspection location of a spectral analysis station; optically interrogating the dosage form at the inspection location; and The method includes: Claim 53: 54. The method of claim 53, wherein the optical interrogation comprises spectral interrogation of the dosage form, the method further comprising determining one or more properties of the dosage form from results of the spectral interrogation. Claim 54: 55. The method of claim 53 or 54, wherein performing spectral interrogation comprises directing a laser probe light to a first surface region of the dosage form, collecting components of the laser probe light scattered within the dosage form from a second surface region of the dosage form that is opposite the dosage form from the first surface region, and detecting Raman spectral features in the collected light. Claim 55: 55. The method of any one of claims 52-54, wherein said transporting is effected by gripping the dosage form while in the preferred alignment using a gripper, transporting the gripped dosage form to the inspection location using the gripper, performing spectral interrogation of the gripped dosage form, and releasing the dosage form from the grip of the gripper. Claim 56: 56. The method of any one of claims 52 to 55, further comprising using the gripper to rotate the dosage form about a gripper axis of rotation to a preferred orientation. Claim 57: 57. The method of claim 56, wherein rotation of the dosage form about the gripper rotation axis occurs after rotation of the dosage form about the rotation stage axis using the rotation stage. Claim 58: 58. The method of claim 56 or 57, wherein the rotational stage axis and the gripper rotation axis are substantially perpendicular to each other. Claim 59: 59. The method of any one of claims 52 to 58, further comprising receiving the dosage form at a drop zone of a handling table, the handling table also comprising a weighing scale and the rotating stage; sliding the dosage form from the drop zone across the handling table to the weighing scale; weighing the dosage form using the weighing scale; sliding the dosage form from the weighing scale across the handling table to the rotating stage, rotating it into the preferred alignment, and then transporting it to the inspection location. Claim 60: 60. The method of any one of claims 52-59, wherein optically interrogating the dosage form at the inspection location comprises optically interrogating the dosage form at the inspection location at a plurality of different alignments. Claim 61: 1. A method for determining variability in handling and optical interrogation of a pharmaceutical dosage form, comprising: repeating the steps of any one of claims 52 to 60 for either a single dosage form or multiple dosage forms of the same type to perform a plurality of said optical interrogations; comparing results of the plurality of optical interrogations to determine at least one measure of variability in the handling and the optical interrogation of the dosage form; The method includes: Claim 62: loading a plurality of dosage forms each of a plurality of dosage form types, the dosage forms of each type being loaded into a separate hopper; Carrying out the steps of any one of claims 52 to 61 for each dosage form; Including, A method for automatically analyzing a plurality of pharmaceutical dosage forms, wherein receiving a particular dosage form on the rotating stage comprises receiving the dosage form from the hopper loaded with the dosage form. Claim 63: 1. A method for analyzing a pharmaceutical dosage form, comprising: in response to detection of the dosage form by the machine vision system, placing the dosage form in a preferred alignment and / or orientation using a dosage form handler; inspecting said dosage form in said preferred alignment and / or orientation within an optical analysis station; The method includes:

Claims

1. A method of manufacturing a device comprising: a rotary stage (74) having a rotary stage surface (75), the rotary stage surface configured to receive and rotate a dosage form about a rotary stage axis (77) perpendicular to the rotary stage surface; a gripper (90) configured to grip the dosage form, wherein the gripper has a gripper axis of rotation (96) that is parallel to the rotating stage surface; a Raman analysis station (20) having an inspection location (22) and configured to detect Raman spectral features in probe light scattered within the dosage form when positioned at the inspection location; a controller (50) configured to control rotation of the rotational stage to rotate the dosage form into a preferred alignment while on the stage surface, control the gripper (90) to rotate the dosage form into a preferred rotational orientation about the gripper rotation axis while gripping the dosage form, control the gripper to grip the dosage form in the preferred alignment and preferred orientation, and control the gripper to transport the gripped dosage form to the inspection location (22) for Raman analysis; 1. An apparatus for analyzing a pharmaceutical dosage form (12), comprising:

2. The apparatus of claim 1, wherein rotating the dosage form (12) in a preferred rotational orientation about the gripper axis of rotation (96) comprises flipping the dosage form over so that a preferred side of the dosage form faces upward either before or after the dosage form has been rotated into the preferred alignment.

3. The Raman analysis station (20) comprises: a delivery optics (26) configured to direct probe light to a first surface region of the dosage form (12) when disposed at the inspection location (22); a collection optic (30) configured to receive the scattered probe light from a second surface region of the dosage form (12), the second surface region being spaced apart from the first surface region; a detector (32) configured to detect the Raman spectral features in the received probe light, the second surface region being on an opposite side of the dosage form (12) from the first surface region; 3. The apparatus according to claim 1 or 2, comprising:

4. 4. The apparatus of claim 1, wherein the gripper (90) is configured to hold the dosage form at the inspection location for Raman analysis without having other structures between the delivery optics and the collection optics.

5. An apparatus as described in any one of claims 1 to 4, further comprising a machine vision system (80) configured to detect the orientation of rotation of the dosage form (12) around the gripper rotation axis (96) and pass the detected orientation of rotation to the controller (50) to control the gripper when rotating the dosage form in the preferred orientation of rotation.

6. An apparatus as described in any one of claims 1 to 5, wherein a machine vision system (80) is configured to detect the alignment of the dosage form (12) when on the rotating stage surface (75) and pass the detected alignment of the dosage form to the controller to control rotation of the rotating stage to rotate the dosage form into the preferred alignment.

7. 7. The apparatus of claim 6, wherein the machine vision system (80) is configured to detect alignment of a predefined dosage form axis (13) of the dosage form, and the preferred alignment comprises a preferred alignment of the dosage form axis.

8. 8. The apparatus of claim 1, wherein the gripper (90) comprises opposing jaws (94) configured to grip the dosage form (12) between the jaws, the opposing jaws (94) configured to grip the dosage form by gripping the dosage form along at least one of an axis parallel to the rotating stage surface and an axis along the gripper axis of rotation (96).

9. The apparatus of any one of claims 1 to 8, wherein the gripper (90) is configured to remain in the preferred alignment and preferred orientation when the dosage form is held at the inspection location for Raman analysis.

10. The apparatus of any one of claims 1 to 9, wherein the rotating stage (74) surface forms part of a table surface of a handling table (70), further comprising a weighing device (110) configured to weigh a dosage form when positioned on the weighing device surface, the weighing device having a weighing device surface (112) forming part of the table surface, and further comprising a dosage form source (42) configured to deposit a dosage form in a drop zone (120) of the table surface, the drop zone being separate from the weighing device and separate from the rotating stage surface.

11. a slider (130) configured to slide a dosage form across the table surface (72) under the control of the controller (50), the controller being configured to control the slider to slide the dosage form from the drop zone to the meter surface for metering and to slide the dosage form from the meter surface to the rotary stage surface; the slider is a box slider configured to encircle a dosage form for sliding across the table surface; 11. The apparatus of claim 10, wherein the controller is configured to control the slider and the dosage source such that the dosage source places a dosage within the box slider at the drop zone (120).

12. A method for automatically analyzing a pharmaceutical dosage form (12), comprising: Receiving (410) the dosage form on a rotating stage having a rotating stage surface; rotating the rotary stage (415) to rotate the dosage form into a preferred alignment about a rotary stage axis perpendicular to the rotary stage surface; before or after the step of rotating the rotary stage, using a gripper to rotate the dosage form about a gripper rotation axis (420) in a preferred orientation, where the rotary stage axis and the gripper rotation axis are perpendicular to each other; transporting the dosage form from the rotary stage to an inspection location of a spectral analysis station (425); optically interrogating the dosage form at the inspection location (430); The method includes:

13. The method of claim 12, wherein rotating (420) the dosage form in a preferred rotational orientation about the gripper axis of rotation comprises flipping the dosage form over so that a preferred side of the dosage form faces upward.

14. wherein the optical interrogation (430) comprises a spectral interrogation of the dosage form, the method further comprising determining (435) one or more properties of the dosage form from results of the spectral interrogation; 14. The method of claim 12 or 13, wherein performing spectral interrogation comprises directing a laser probe light to a first surface region of the dosage form, collecting components of the laser probe light scattered within the dosage form from a second surface region of the dosage form that is opposite the dosage form from the first surface region, and detecting Raman spectral features in the collected light.

15. Receiving (510) the dosage form at a drop zone of a handling table, the handling table also comprising a weighing device and the rotary stage; Sliding the dosage form from the drop zone across the handling table and into the meter (515); metering the dosage form using the meter (520); sliding the dosage form from the weighing machine across the handling table to the rotary stage, rotating it to the preferred alignment, and then transporting it to the inspection location (525); The method of any one of claims 12 to 14, further comprising:

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