Patent Description:
<CIT> discusses the need for manufacturers of pharmaceutical products to monitor properties of tablets and other dosage formulations as they are produced. Traditionally, this has been achieved by taking samples from a batch of products to a laboratory for post-production testing. <CIT> discusses using Raman spectral analysis of pharmaceutical tablets on the production line itself. A laser beam is directed to a Raman probe in front of which a tablet is positioned. A small proportion of the illumination photons are inelastically Raman scattered in the surface region of the illuminated tablet. Backscattered Raman photons are collected by the probe and are directed to a spectrograph for analysis.

Another Raman probe which could be used to analyse pharmaceutical tablets is discussed in <CIT>.

The techniques used in this prior art yield an analysis of only a very limited portion of a tablet, because the backscattered Raman radiation originates from a small region around the point of incidence of the laser beam. Even if a wide area probe, such as that described in <CIT> is used, and almost all of the Raman radiation originates from a thin surface layer of the tablet. Therefore, characteristics of material in the interior or at other surfaces of the tablet are undetected.

In <CIT> a continually changing surface region of a tablet is exposed to an incident laser beam through a conical aperture through which scattered Raman photons are also detected. The surface region is continually changed by rotating the tablet behind the apex of the conical aperture and varying the distance from the centre of rotation to the conical apex. However, the Raman signal is still heavily biased towards the illuminated surface of the tablet.

The use of Raman spectroscopy to evaluate solid-state forms present in tablets is discussed in <NPL>. Properties of interest include salt formation, solvate formation, polymorphism, and degree of crystallinity.

<CIT> relates to a sample presentation apparatus for use in analysing equipment for pharmaceutical products. <CIT> relates to a sample arrangement for spectrometry, especially Raman spectrometry.

<NPL>) discloses a method of recording Raman spectra.

It would be desirable to provide methods for analysis of pharmaceutical dosage formulations, such as tablets, in which the Raman radiation detected and analysed to carry out the analysis represents more than just a surface region.

It would also be desirable to be able to apply such methods to manufacture and testing of pharmaceutical dosage formulations.

The invention seeks to address problems of the related prior art.

We describe a method of probing a sample, in particular the bulk or interior, or an interior portion of a sample, and especially of a diffusely scattering or turbid sample, by directing incident radiation at a first surface, surface region, area or portion of the sample, collecting forward scattered radiation from a second surface, surface region, area or portion of the sample, and detecting Raman radiation, arising from Raman scattering of said incident radiation within said sample, in the collected radiation. This may be applied to the mass production of a plurality of similar discrete objects, by carrying out these steps on each object and, for each object, analysing the detected Raman radiation to determine one or more characteristics of each object.

Advantageously, the forward scattered Raman radiation contains information from the full scattering depth between the first and second surface regions. In contrast, use of a backscattering geometry only provides information from a shallow depth beneath the illuminated surface. The method may particularly be applied to diffusely scattering solid samples.

In particular, the invention provides a method of determining one or more properties of the bulk of each of a plurality of tablet pharmaceutical dosage formulations on a mass production line as set out in claim <NUM>.

Using this method, the analyzed Raman signal is less representative of the surface of the dosage formulation and more representative of the whole contents of the formulation, and therefore more representative of the material to which a subject given the formulation will be exposed, for example after digestion. In particular, a region of impurity away from the illuminated surface may be detected. Properties which may be detected in this way include the presence of different polymorphs, hydrated forms, solvates, and salt forms, in particular of active pharmaceutical substances. Other properties include the presence of remnant chemical reagents and other impurities.

Analysis may be based on proximity of a measured Raman signal to an ideal or predefined template, on analytical decomposition of detected Raman spectra using known spectra of likely impurities, or by analysing features such as spectral shifts and widths of spectral lines and peaks.

The pharmaceutical dosage formulation may be a coated tablet. The method is used to analyze a tablet dosage formulation contained within a blister pack.

When the Raman radiation is collected from said second surface, it has been scattered through the dosage formulation from the first surface, so that the first and second surfaces mutually define a transmission, or forward scattering geometry.

In addition to detecting and analysing forward scattered Raman radiation, the method may also include collecting backscattered radiation, detecting Raman radiation in said backscattered radiation, and using the results of the detection in determining one or more properties of the formulation.

Typically, the dosage formulation will be held or supported in a carrier. This carrier may have one or more inner surfaces facing said dosage formulation, and at least part of these surfaces may be mirrored so that radiation is reflected back into the formulation to increase the amount of detected Raman radiation and improve the sensitivity of the method. In particular, a suitably mirrored enclosure will have the effect of improving the degree to which the detected Raman radiation reflects properties of the whole formulation.

The carrier may comprise a first aperture through which the first surface of said dosage formulation is exposed to said incident radiation, and a second aperture through which Raman radiation is received from the second surface of said dosage formulation.

Typically, the incident radiation is generated using one or more lasers.

Spectral information, such as line strengths, widths, or full spectra, obtained from the detected Raman light, may be used in a variety of ways for further analysis, such as by comparison with template or "ideal" spectral information, by decomposition into two or more known or expected spectral data groups or spectra, or by measuring line shifts in frequency or width.

Apparatus for putting the claimed methods of the invention into effect are also described, for example apparatus for analysing a pharmaceutical dosage formulation, comprising a carrier for retaining a dosage formulation, illumination optics arranged to direct incident radiation to a first surface region of a said formulation, and reception optics arranged to receive and detect transmitted Raman radiation from a second surface region of said formulation, the second region surface being spaced from said first surface region.

The illumination optics may be as simple as a laser source abutted against or directed at the first surface region, or more sophisticated arrangements could be used. Typically, the reception optics will comprise collection optics, and a spectrometer, filters or other spectral selection apparatus arranged to detect or isolate one or more elements, wavelengths or other aspects of said Raman radiation. For example, a Fourier Transform spectroscopy arrangement could be used, or one or more suitable spectral filters with one or more suitable photo detectors.

Typically, the apparatus will also comprise an analyser implemented as a computer, dedicated electronics, or some mix of the two, and arranged to derive one or more properties of the dosage formulation from said detected Raman radiation. Typically, the apparatus will also comprise a laser source for generating the incident, or probe radiation.

Reference will now be made to the accompanying drawings of which:.

Referring now to <FIG> there is shown a pharmaceutical dosage formulation in the form of a tablet <NUM>, which is held in a carrier <NUM> such that at least part of each of the upper <NUM> and lower <NUM> surfaces of the tablet are exposed. The carrier may be provided, for example, as part of a production line or a post-production testing facility. Light generated by a laser <NUM> is directed to illumination optics <NUM> above the carrier which cause the upper surface of the tablet to be exposed to the laser light. Receiving optics <NUM> are disposed below the carrier arranged to receive light scattering out of the lower surface of the tablet. This light is directed to a spectrographic detector <NUM>, and results from the spectrographic detector <NUM> are passed to a computer implemented analyser <NUM>.

Suitable wavelengths for the incident laser light are around the near infrared part of the spectrum, for example at <NUM> with a laser power of about <NUM> mW as used in the example discussed below in the "Experimental Example" section, where further details of suitable optical arrangements for the illumination, receiving and detection optics can be found. However, any other suitable wavelengths may be used.

Some of the photons of the incident laser light undergo Raman scattering in the tablet. The production of Raman photons having particular wavelengths depends on the chemical structure of the tablet, so that chemical properties of the tablet such as polymorph types, degrees of hydration and the presence of impurities and undesired salt and solvate forms can be deduced by analysing the scattered Raman photons. The computer analyser <NUM> uses the spectral results from the detector <NUM> in this way to deduce one or more properties of the tablet. These properties could be used, for example, to reject a tablet because of excessive levels of a particular polymorph or impurity.

A number of different properties which can be determined using the invention are discussed in the related prior art, such as <NPL>, and in references cited therein.

Most of the Raman photons backscatter towards the illumination optics. Almost all of the backscattered Raman photons have been produced close to the illuminated upper surface of the tablet, so only allow properties of that surface region to be deduced. Raman photons also scatter forwards and emerge from the lower surface of the tablet. Although the number of forward scattered Raman photons is small compared with the number of backscattered photons, these forward scattered photons originate from a relatively even range of depths throughout the tablet, so allow bulk properties of the tablet as a whole to be deduced. The spectrographic detector could take a variety of known forms such as a conventional spectrograph, a Fourier Transform spectrograph, or one or more filters in conjunction with one or more photo detectors.

In <FIG> an alternative construction of the carrier is illustrated. In this example, surfaces of the carrier abutting the tablet <NUM> are mirrored either in full or in part so as to reflect photons, which might have otherwise been absorbed at the carrier, back into the tablet. The density of photons within the tablet is thereby increased, and so is the intensity of Raman photons collected by receiving optics <NUM>. The degree to which the carrier encloses the tablet may vary, for example providing only small apertures for illumination of the tablet and to receive forward scattered Raman photons. The carrier <NUM> of <FIG> is divided into upper <NUM> and lower <NUM> portions, and the tablet is accepted between the portions, but other geometries could be used. This mirroring may be used in other described arrangements.

<FIG> illustrates an arrangement in which the illumination optics <NUM> also comprises receiving optics to collect backscattered Raman photons. These are passed to a separate spectrographic detector <NUM>, or alternatively to the detector <NUM> used to detect forward scattered photons, for detection and subsequent analysis. In this way, forward scattered and back scattered photons may be detected and analysed at the same time, or at different times, and these various alternatives may be used in other described arrangements.

In the arrangements illustrated in <FIG> the tablet is of generally rectangular cross section, perhaps <NUM> across and <NUM> deep, and circular when viewed from above. In <FIG>, which does not illustrate an embodiment of the invention, the tablet is spherical and therefore contained in a suitably adapted carrier <NUM>. <FIG> also illustrates that to derive bulk properties of the tablet using a transmission geometry it is not necessary to place the illumination and receiving optics in confrontation, directly across a tablet, although this may frequently be a preferred configuration for evenly distributed sampling of the tablet bulk. In the arrangement of <FIG> the illumination optics face downwards and the receiving optics collect light emerging from an aperture in the side rather than the bottom of the carrier, transverse to the direction of illumination. Generally, however, the surface of the tablet illuminated by the illumination optics should at least be separated or spaced from the surface from which scattered light is received by the receiving optics.

Because the general method described herein has reduced sensitivity to surface composition, it may be used to determine characteristics of a turbid medium such as a tablet when within an envelope such as packaging, for example a tablet already packaged for distribution and sale in a blister pack. This is illustrated in <FIG> in which a tablet <NUM> within a blister pack is probed using illumination and receiving optics <NUM>, <NUM> disposed laterally across the width of a tablet. This arrangement is useful in the conventional case of the upper membrane <NUM> of the blister pack being or comprising a metal or metalised foil, or other layer transmitting insufficient of the illumination photons. Comparing this arrangement with that of <FIG>, the blister pack is acting as carrier <NUM>. The lower blister pack membrane <NUM> is preferably translucent or transparent, for example being partly or wholly formed of a translucent white plastic, to enable light to pass sufficiently for the technique to work. If both the upper and lower membranes <NUM>, <NUM> allowed sufficient light to pass, an arrangement of optics more like that of <FIG> could be used.

A Monte Carlo model was used to simulate the transport of illumination and Raman photons scattering within a turbid medium such as the pharmaceutical tablet <NUM> of <FIG>. The model was used to calculate the relative intensities of backscattered and forward scattered Raman photons as a function of their depth within the turbid medium. Briefly, both the elastically (illumination) and non-elastically (Raman) scattered photons were individually followed as they propagated through the medium in random walk-like fashion in three-dimensional space. A simplified assumption was made that in each step a photon propagated in a straight line over a distance t and thereafter its direction was fully randomised at the next scattering event. Although this picture is simplistic from the standpoint of individual scattering events, photons propagating through a turbid medium typically have to undergo a number of scattering events (e.g. <NUM>-<NUM>) before their original direction of propagation becomes fully scrambled. This is due to the fact that individual scattering events are often strongly biased towards the forward direction. However, it has been shown that for large propagation distances such as those pertinent to the bulk analysis of tablets, as of interest here, the individual multiple scattering events can be approximated as a single composite event occurring over the 'randomisation length' t (<NPL>). This simplified assumption enables analysis of large propagation distances with modest computational expense.

The propagation distance, t, over which the photon direction is randomised, can be crudely approximated as the transport length of the scattering medium (lt) (<NPL>) which is defined in a similar manner as the average distance photons must travel within the sample before deviating significantly from their original direction of propagation. The transport length is typically an order of magnitude longer than the mean free scattering length (ls) of photons in the medium; the precise relation is ls = (<NUM>-g)lt , where g is the anisotropy for the individual scattering event. In the present model it was also assumed that the wavelength of light propagating through the medium was substantially shorter than the scattering length ls.

The modelled sample <NUM> is illustrated in <FIG>. The sample was considered to extend to infinity in x and y directions, with an air-medium interface located at the top surface <NUM> z=<NUM> and bottom surface <NUM> z=d3, where z is a Cartesian coordinate normal to the interface plane. The sample was modelled as a uniform turbid medium apart from an intermediate-layer <NUM> having a different Raman signature to represent a heterogenous impurity, the intermediate layer having a thickness d2 with a top surface located at depth d1. The overall modelled sample thickness was d3 (d3>=d1+d2). That is, the bulk sample medium was located at depths z1 such that d1>z1><NUM> and d3>z1>(d1+d2), and the intermediate layer of a different Raman signature at depths z2 such that d1+d2<z2<d1. In the simulations reported herein the parameters d2 and d3 were fixed at <NUM> and <NUM> respectively, and d1 was varied from <NUM> to <NUM> to represent different depths of the interlayer <NUM> within the bulk of the sample <NUM>.

The model assumed that all the illumination photons were first placed at a depth equal to the transport length lt and symmetrically distributed around the origin of the co-ordinate system x,y. The beam radius of the incident light r was <NUM> and the beam was given a uniform 'top-hat' intensity profile with all the photons having equal probability of being injected into the sample at any point within its cross-section. In the model, the Raman light was collected firstly at the top sample surface <NUM> from the illumination area of the incident light, and separately on the opposite side of the sample <NUM> symmetrically around the projection axis of the top collection/laser illumination area.

The laser beam photons were propagated through the medium by translating each individual photon in a random direction by a step t. At each step there was a given probability that the photon would be converted to a Raman photon. The absorption of photons was assumed to be insignificant in this simulation. This parameter is expressed as optical density for the conversion of laser beam photons to Raman light. That is, for example, an optical density (OD) of <NUM> or <NUM> per <NUM> corresponds to the <NUM>-fold or <NUM>-fold decrease of the number of illumination photons through conversion to Raman photons, respectively, passing through an overall propagation distance of <NUM>. The optical density accounting for the conversion of illumination photons into Raman photons was set to <NUM> per mm-. Although this value is higher than that of real conversion, it only affects the absolute number of Raman photons, and not the spatial dependencies of concern in the studied regime. When an illumination photon is converted into a Raman photon the layer where this occurred is identified and recorded. Raman photons are propagated in the same fashion as illumination photons. A dominant mechanism for photon escape exists at the sample-to-air interfaces <NUM>,<NUM>, as all the laser photons emerging from the sample at these interfaces do not return back into the sample and are effectively lost from the migration process. A Raman photon emerging at the top or bottom interface within the collection aperture of radius <NUM> centred on the axis of the laser beam are separately counted as detected Raman photons. Any photon emerging from the sample is eliminated from further calculations.

The numerical code for putting the model into effect was written in Mathematica <NUM> (Wolfram Research). <NUM>,<NUM> simulated photons were propagated, each over an overall distance of <NUM> which is in line with typical migration times observed in Raman spectroscopy in the absence of absorption. The step size used was t = <NUM> (i.e. <NUM> steps was used). This corresponds to a sample formed from a powder having particle sizes of <NUM> and <NUM> diameter for the anisotropy of <NUM> and <NUM>, respectively. It was checked that upon these times the vast majority of photons were lost at sample-to-surface interfaces. This process was repeated <NUM>-times. Hence the overall number of propagated photons was <NUM><NUM> with the total number of steps considered being approximately <NUM><NUM>. All the detected Raman photons in these repeated runs were summed up.

The number of Raman photons originating in the intermediate layer <NUM> and collected as backscattered photons at the upper surface <NUM>, and transmitted photons at the lower surface <NUM>, are shown in <FIG>. The graphs show the number of backscattered and transmitted photons for eight different depths d1 of the intermediate layer <NUM> ranging from at the top surface where d1=<NUM> to at the bottom surface where d1=<NUM>.

From <FIG> it is clear that the collection of Raman photons in backscattering geometry even from an aperture as large as <NUM> in diameter leads to an extremely strong bias towards the surface layers of the sample. The repositioning of the <NUM> thick intermediate layer from the illuminated surface to a depth of <NUM> reduces the Raman backscatter intensity by <NUM>%. In most practical applications the Raman signal will already have become swamped by the Raman or fluorescence signal originating from the surface region of the medium. At a depth of <NUM> the Raman signal originating from the intermediate layer has fallen by <NUM> orders of magnitude from its original level at the zero depth. On the other hand the dependence of the intensity of transmitted Raman photons exhibits only a weak dependence on the position of the intermediate layer within the sample. As the intermediate layer is moved between depths of <NUM> and <NUM> the corresponding Raman signal varies only by a factor of about <NUM>. The absolute intensity of the Raman signal from the intermediate layer is only about <NUM>-times lower than that of the bulk medium making detection relatively straightforward. Therefore the transmission geometry clearly provides a more representative sampling of the bulk of the sample interior than the conventional backscattering geometry, while permitting a satisfactory sensitivity.

For backscattering geometry, the model also reveals that an increase in sample thickness from <NUM> to <NUM> results in a <NUM>% increase of the Raman signal detected in the backscattering geometry. In simplistic terms, this could be wrongly interpreted as extra Raman photons (amounting to <NUM> % of the overall Raman signal observed for <NUM> tablet) being produced in the extra <NUM> thickness added to the top <NUM> sample layer. However, the model of a <NUM>-thick sample indicates that <NUM> % of Raman signal originates in the top <NUM> layer and only <NUM> % originates within the remaining <NUM> of sample thickness. The extra <NUM> of material not only contributes with extra production of Raman photons but also reduces the loss of Raman photons originated within the <NUM>-layer at the lower surface <NUM>. Thus the increase in backscattered Raman photons through the addition of a further <NUM> of sample is also accomplished by returning Raman photons originating near the upper surface back towards the upper surface from where they may emerge and be collected. In the same way, some illumination photons are scattered back towards the upper surface <NUM> allowing them to originate still more Raman photons within the top <NUM> layer.

In an experimental arrangement, a two-layer sample was composed of a paracetamol tablet (<NUM>, thickness <NUM>, circular diameter <NUM>, Tesco, PL Holder: The Wallis Laboratory Ltd. FOP234 MH/DRUGS/<NUM>) placed against a <NUM> thick fused silica cuvette with <NUM> windows filled with trans-stilbene ground powder. The cell width and length were <NUM> and <NUM>. Some measurements were taken with an illumination laser beam directed at the tablet, and some at the cuvette, in each case taking measurements of both backscattered and forward scattered (transmitted) Raman photons.

The illumination laser beam was generated using an attenuated <NUM> mW temperature stabilised diode laser operated at <NUM> (Micro Laser Systems, Inc, L4 <NUM>-<NUM>-TE). The laser power at the sample was <NUM> mW and the laser spot diameter was about <NUM>. The beam was spectrally purified by removing any residual amplified spontaneous emission components from its spectrum using two <NUM> band pass filters (Semrock). These were slightly tilted to optimise their throughput for the <NUM> laser wavelength. The beam was incident on the sample at about <NUM> degrees. The beam was polarised horizontally at the surface. The incident spot on the sample surface was therefore elliptical with the shorter radius being <NUM> and the longer <NUM>.

Raman light was collected using a <NUM> diameter lens with a focal length of <NUM>. The scattered light was collimated and passed through a <NUM> diameter holographic notch filter (<NUM>, Kaiser Optical Systems, Inc) to suppress the elastically scattered component of light. The filter was also slightly tilted to optimise suppression for the <NUM> elastic scatter. A second lens, identical to the first, was then used to image, with a magnification of <NUM>:<NUM>, the sample surface onto the front face of an optical fibre probe. The laser illumination spot was imaged in such a way so that it coincided with the centre of the probe axis. Two more filters (<NUM> diameter holographic notch filter, <NUM>, Kaiser Optical Systems, Inc, and an edge filter, <NUM>, Semrock) were used just before the probe to suppress any residual elastically scattered light that passed through the first holographic filter.

The fibre probe was comprised of <NUM> fibres placed tightly packed at the centre of the probe. The fibres were made of silica with a core diameter of <NUM>, cladding diameter of <NUM> and numerical aperture of <NUM>. Sleeves were stripped on both ends for tighter packing of the fibres. The bundle was custom made by C Technologies Inc. The Raman light was propagated through the fibre systems with a length of about <NUM> to a linear fibre end oriented vertically and placed in the input image plane of a Kaiser Optical Technologies Holospec f# = <NUM> NIR spectrograph with its slit removed. In this orientation the fibres themselves acted as the input slit of the spectrograph. Raman spectra were collected using a deep depletion liquid nitrogen cooled CCD camera (Princeton Instruments, SPEC10 400BR LN Back-Illuminated Deep Depletion CCD, <NUM> x <NUM> pixels) by binning the signal from all the <NUM> fibres vertically. The Raman spectra were not corrected for the variation of detection system sensitivity across the detected spectral range.

Results obtained using this experimental arrangement are shown in <FIG> and <FIG>. <FIG> shows spectra obtained from a conventional backscattering geometry applied to the two layered sample with the paracetamol illuminated (curve <NUM>) and the cuvette illuminated (curve <NUM>). Backscatter results for the paracetamol only (curve <NUM>) and the cuvette only (curve <NUM>) are also shown for reference. <FIG> shows spectra obtained using the transmission geometry with the paracetamol illuminated (curve <NUM>) and the cuvette illuminated (curve <NUM>), with transmission results for the paracetamol only (curve <NUM>) and the cuvette only (curve <NUM>) are also shown for reference.

It is clear from <FIG> that using the backscattering geometry only Raman signal from the directly illuminated component of the sample is seen. Even by subtracting the pure Raman spectrum of the top layer it was not possible to detect the spectrum of the sample sublayer, which is in line with predictions using the Monte Carlo model described above. In contrast, in the transmission geometry results of <FIG> a relatively constant Raman intensity ratio between the surface and sublayer is observed irrespective of which component of the sample is illuminated.

<FIG> demonstrates how, in an environment where tablets are being tested, an anomalous layer will be detected irrespective of its position relative to the illuminating radiation. If the paracetamol tablet used in this experiment had a thick layer of an impurity at the back, a conventional backscattering approach would not be able to detect its presence. The transmission geometry approach would detect the impurity layer irrespective of its depth within the sample.

The backscatter and transmission measurements using the paracetamol tablet without the cuvette show that the diminishment of the overall Raman intensity when going from the conventional backscattering to the transmission geometry was only by a factor of <NUM>, thereby still allowing short exposure times to be used with reasonable sensitivity. Notably, a good Raman signal was observed in the transmission geometry even through a stack of two paracetamol tablets (<NUM> thick) and it was still detectable through a stack of three paracetamol tablets (<NUM> thick), with the signal diminishing by a factor of <NUM> and <NUM> respectively, compared with only one tablet monitored in the transmission geometry. The large illumination areas applicable in transmission geometry with pharmaceutical tablets and other dosage formulations also make it possible to use substantially higher laser powers without damaging the sample. This can be used to achieve further reductions in exposure times if required, in particular if combined with large area receiving optics.

The same experimental arrangement was used to obtain a conventional backscatter Raman spectrum, and a transmission Raman spectrum, for a variety of different pharmaceutical capsules, having a variety of different coloured shell sections. Generally, the coloured capsule shells induced a large degree of fluorescence which had a deleterious effect on the signal to noise ratio of the measured Raman spectra. Spectra measured using a Sudafed (RTM) Dual Relief capsule coloured green, using a ten second exposure time, as shown in <FIG>. The upper curve is a spectrum obtained using the conventional backscatter geometry, with any Raman spectral features of the pharmaceutical ingredients completely obscured by a fluorescence signal. The lower curve is a spectrum obtained using the described forward scattering geometry and although weaker than the backscatter signal, the useful Raman spectral peaks are very clearly visible.

A number of different Raman spectroscopy techniques may be used to enhance detection of the expressed Raman spectral features, including resonance Raman spectroscopy.

Claim 1:
A method of determining one or more properties of the bulk of each of a plurality of tablet pharmaceutical dosage formulations (<NUM>) on a mass production line, comprising:
exposing a first surface (<NUM>) of said dosage formulation to incident radiation using illumination optics (<NUM>);
receiving and detecting Raman scattered elements of said incident radiation from a second surface (<NUM>) of each said formulation using receiving optics (<NUM>), said second surface being spaced from said first surface; and
determining one or more of said properties of each said formulation from the corresponding said detected Raman scattered elements,
wherein each dosage formulation is a tablet already packaged in a blister pack and the illumination optics and receiving optics are disposed laterally across the width of the tablet
wherein for each said dosage formulation the second surface is on an opposite side of said dosage formulation (<NUM>) to said first surface.