WO2008122597A1

WO2008122597A1 - Method and apparatus for analysis of a sample

Info

Publication number: WO2008122597A1
Application number: PCT/EP2008/054068
Authority: WO
Inventors: Roger Stuart Hutton
Original assignee: Glaxo Group Limited
Priority date: 2007-04-04
Filing date: 2008-04-03
Publication date: 2008-10-16
Also published as: GB0706664D0

Abstract

There is provided a method of analysing the structure of a sample. The method comprises identifying a sample; illuminating said sample with a pulse of broad beam electromagnetic radiation; detecting at least one property of said beam subsequent to illuminating the sample; and referencing said at least one property of the beam to derive structural information relating to the sample. The method is suitable for use in the continuous analysis of samples on a production line.

Description

Method and apparatus for analysis of a sample

Technical field

The present invention relates to a method and apparatus for determining structural characteristics of a sample by means of a pulse of broad beam illumination addressed thereat. In embodiments, the method is suitable for determining the structural characteristics of tablets or capsules on a continuous production line.

Background to the invention

During the manufacture of pharmaceutical solid dosage forms (e.g. tablets and capsules) on a production line it is necessary to monitor the three dimensional structural characteristics of all materials present. This can involve measuring the properties of thin surface layers, the properties of bulk material and in particular, checking for the presence of material defects. In one aspect, surface coatings are often applied to pharmaceutical solid dosage forms to modify their properties, and this can affect appearance and dissolution properties. The three dimensional properties of such materials need to be controlled to maintain consistent properties such as mechanical behaviour and dissolution properties, which may affect pharmaceutical performance characteristics.

Conventional methods for monitoring such three dimensional structural characteristics involve removing a sample (e.g. a tablet or a capsule) from the production line and then subjecting this sample to structural analysis away from the production line. Such methods involve a first inherent disadvantage that a sample removal step is necessitated, and a second inherent disadvantage that there is an inevitable time lag between removing the sample and then subjecting it to structural analysis. If any problems are detected, these may therefore have been allowed to continue on the production line whilst the sample removal and analysis steps are carried out 'off line', which can lead to greater production 'waste' in the situation where a problem has developed on the line. It is therefore desirable to conduct structural analysis of the sample 'on line', which is to say without the need to remove the sample from the production line. Optimally, analysis might be performed continuously in 'real time', which is to say without slowing down the production line in any way, thereby enabling immediate detection of any problems, which in turn can lead to immediate action to rectify the problems.

Known structural analysis methods including near infrared (NIR) spectroscopy and Raman spectroscopy have been described for use in the imaging of pharmaceutical solid dosage forms. Near infrared (NIR) spectroscopy is for example, described in G. Reich: Near-infrared spectroscopy and imaging: Basic principles and pharmaceutical applications, Advanced Drug Delivery Reviews. 57(8):1109-1143, 2005. Raman spectroscopy is for example, described in S. Wartewig and R. H. H. Neubert: Pharmaceutical applications of Mid-IR and Raman spectroscopy, Advanced Drug Delivery Reviews. 57(8):1144-1170. These methods are however, affected by light scattering and can only penetrate the surface of materials.

Pulsed optical methods in the THz region of the electromagnetic spectrum have also been described for use measuring the three dimensional nature of solid dosage forms and the properties of surface layers. These methods utilise narrowly focused THz beams and robotics in an image mapping operation. Thus, pulsed illumination directed sequentially at multiple points across a surface is used to build up a 3D map of a surface. For example, PCT Patent Application Publication No. WO-A- 2005/022130 describes the use of such mapping techniques to image the surface and layers or pharmaceutical tablet samples. Such image mapping methods have inherent speed limitations as the sample must be physically moved relative to (e.g. in front of) the interrogating beam of light. Full sample analysis therefore takes some minutes to conduct, which make such methods unsuitable for continuous analysis of samples on a production line. The inventor herein discloses a new method of analysing the structure of a sample.

Summary of the invention

According to one aspect of the present invention there is provided a method of analysing the structure of a sample comprising

(i) identifying a sample;

(ii) illuminating said sample with a pulse of a broad beam of electromagnetic radiation;

(iii) detecting at least one property of said beam subsequent to illuminating the sample; and

(iv) referencing said at least one property of the beam to derive structural information relating to the sample.

There is provided a method of analysing the structure of a sample. The method in particular enables the analysis of the three dimensional structure of a sample, including structural features of surfaces and layers of the sample.

In one preferred aspect, the sample is a solid dosage form such as a tablet or a capsule, such as of a pharmaceutical. In other aspects, the sample is in the form of a powder or suspension. In other aspects, the sample is a (e.g. pharmaceutical) dosage form within packaging (e.g. powdered medicament in a blister pack). In other aspects, the sample is another suitable sample for analysis including food, packaging and other solid or suspension forms. In embodiments, the method is employed to detect product defects including for example, tablet capping. The method may also be used to analyse (e.g. measure) the integrity and behaviour of multilayer tablets. Data obtained is characteristic of chemical and physical differences in the samples.

In embodiments, the method is used to analyse the thickness and/or packing of powders or suspensions (e.g. of medicament products, such as inhalable medicament products).

The method involves the step of identifying a sample for analysis. The identification of the sample is required only in order that the pulse of broad beam electromagnetic radiation may be suitably directed or aligned with the sample. Where the sample is one of many on a production line, the identification may involve identifying the sample pathway on the production line, again for suitable direction or aligning of the beam. In embodiments, the identifying step may involve the identification of a particular point of interest on the sample, which point of interest may, in embodiments, comprise all of the sample that is able to be illuminated by the beam, which may be the whole sample or a part of the sample, and which may depend on how the sample is presented to the beam.

The method involves the step of illuminating the sample with a pulse of broad beam electromagnetic radiation. The width of the broad beam is selected in part by reference to the sample and of any point of interest thereon. Suitably the beam width is comparable to one or more dimensions of the sample itself. The optimal beam width will be determined by what features are to be measured and the effect of surface curvature. Beam width may be controlled by optical setup of the detecting apparatus including for example, focus point, and optical F-number etc. The exact beam width for a particular sample type would be determined by investigation.

In embodiments, the width of the broad beam is comparable (e.g. approximately equal to) to that of a dimension of interest (e.g. width, length, diameter) of the sample, which may in embodiments be the maximum dimension thereof. Thus, the width of the broad beam is typically from 10 to 200%, particularly from 30 to 150%, such as from 80 to 120% of the relevant dimension (e.g. the maximum dimension) of the sample. Thus, for example if the sample to be analysed is a tablet of diameter 10mm, the beam may itself have a beam width of from 1 mm to up to 20mm, particularly from 3mm to 15mm, such as from 8 to 12mm. Such broad beam width compares to the narrow beams used in 3D-mapping methods, in which narrowly- focused beams are employed.

In embodiments, the width of the broad beam is selected such that the whole of a position of interest on the sample is illuminated thereby. In embodiments, that position of interest corresponds to the whole area of the sample that is accessible to illumination. That is to say, the whole of an area of a sample that may be illuminated by addressing the pulse of broad beam electromagnetic radiation thereat, and which thus, does not lie in the shadow of that broad beam.

The properties of the pulse of the broad beam electromagnetic radiation, including pulse width and pulse intensity, may be selected by reference to the sample to be analysed. Typically, the present method utilises a short illumination pulse.

In embodiments, only a single pulse of the broad beam electromagnetic radiation is employed to characterise the sample structure in the beam illumination area. If this is the only sample structure required to be characterised (or the whole sample is illuminated by the beam), then the sample as a whole is characterised (e.g. pass or fail) from that single pulse. If another sample structure of the same sample is required to be characterised, then another (i.e. a second) pulse of broad beam electromagnetic radiation may also be employed. However, a single pulse of broad beam electromagnetic radiation to characterise a sample as a whole is preferred. Thus, analysis is by means of a broad pulse, as compared to prior art beam mapping methods, which employ multiple narrow pulse measurements collated in mapped (e.g. mapped-out grid) fashion to analyse the overall structural characteristics of the sample.

The electromagnetic radiation is selected to have a suitable wavelength. In embodiments, the wavelength is in the visible, near infra red (NIR), microwave or Terahertz (THz) part of the spectrum. Typically microwave radiation has a frequency of from 10⁹ to 4 x 10¹⁰ Hz; TeraHertz radiation has a frequency of from 4 x 10¹⁰ to 4 x 10¹² Hz; infra red radiation has a frequency from 4 x 10¹² to 3 x 10¹⁴ Hz.

In an embodiment, the pulse of broad beam electromagnetic radiation has a pulse width of 100 fs, and may be generated with a repetition rate of 80 MHz.

Preferably, the broad beam of pulsed electromagnetic radiation is of TeraHertz (THz) radiation, for example of the pulse width and repetition rate specified in the previous paragraph.

Where the pulse of broad beam electromagnetic radiation is one of a series of such pulses (i.e. in a pulse train) which illuminates the sample, as may be the case where the pulse is produced by a laser device, for instance at the type of repetition rate mentioned above, only the property of that particular pulse in the pulse series need be detected. However, if desirable the same property of one or more of the other pulses in the series may also be detected and an average of the detected properties used for the referencing step. Where electronic signal processing is used to detect and reference the property, this averaging with plural pulses may be useful to reduce the effect of noise.

Typically, in the present method no additional illumination of the sample is required.

The method involves detecting at least one property of said beam subsequent to illuminating the sample. The property of the beam may be selected according to the analytical detail required. Suitable examples of properties that may be detected (i.e. measured) include beam reflectance, transmission, scattering or any combination thereof.

The source of illumination of the sample is generally a point source. The detector may in embodiments, be either a point source detector or an array detector (e.g. an array of detectors).

In embodiments, the present method involves detection of reflected and/or transmitted light. In this method an image of the surface is not generated. Source and detector need therefore not be collinear relative to each other, and the position of each will determine whether information on scattering, reflectance and/or transmission is obtained.

The method involves referencing the measured at least one property of the beam subsequent to illumination of the sample to derive structural information relating to that sample. Suitably, this reference involves computerised analysis (e.g. by graphical representation or by reference to look-up tables) of the measured at least one property. In one particular example, a measure is made of the signal standard deviation from inside the sample. This provides a measure of the average sample homogeneity. There are many ways the signal could be analysed, and it is usually the magnitude and profile that is important.

In one aspect, line shape properties (e.g. the width, height and/or shape properties) of the beam as a whole are measured. By 'line shape' herein it is meant the magnitude and profile of transmitted and/or reflected light pulses. The line shape is generally characteristic of the sample under study and provides an average of its properties.

By measuring line shape properties from a broadly illuminated area, scanning of the sample is not required. Thus, the measurement is inherently fast, preferably of the order of femto seconds. This type of measurement and analysis can therefore be used to interrogate either a part of a tablet sample or a complete tablet sample in one go. Such structural and chemical information is critical to tablet performance.

The method herein may be used to obtain information on structural properties of the sample such as: three dimensional (3D) structures via refractive index changes, and/or properties of surface layer(s) from scattering events and from absorption which in turn can be used to measure properties such as water content.

The use of a pulse of broad beam electromagnetic radiation for analysis of the structure of the sample means that mapping of the sample (i.e. using multiple point readings using a narrowly focused beam) is not required. Thus the present method is inherently fast and may therefore be performed on a moving sample or sequentially on a series of moving samples. The inherently fast nature of the method also lends it to being used for continuous monitoring of a production line such as in the context of 'on production line' analysis for real time release of products

Thus, according to another aspect of the present invention there is provided a method for analysing the structure of plural samples on a production line comprising applying the method described above to each of said plural samples.

The samples may be moving continuously on the production line when illuminated by the pulse of broad beam electromagnetic radiation. Alternatively, the samples may be stationary (e.g. parked) when illuminated by the pulse, for instance by step-wise movement of the samples on the production line.

In one aspect, each sample of the plural samples on the production line is presented in series and hence, the method is applied sequentially (i.e. along the series) to each sample of the plural samples. In embodiments, the method is repeated for each sample (e.g. at a particular point on the production line). In another aspect, the method is applied to two or more of said samples of the plural samples at a time.

It will be appreciated that the particular order and sequence of applying the method to each of the plural samples may be selected and configured to match the particular configuration of the production line of interest.

In embodiments, the illuminating step is synchronised with the movement (e.g. speed of presentation) of samples (e.g. at an illuminating station) on a production line. That is to say, in embodiments the step of illuminating each sample of the plural samples is synchronised with the movement of the plural samples on the production line.

In embodiments, the method herein is conducted in situ as the samples move on the production line itself ('on line analysis'). That is to say, a measuring station necessary for carrying out the method is located for analysis of the samples as they pass along the production itself.

In other embodiments, the samples are diverted from the production line to a measuring station spaced therefrom, but typically at a convenient position local thereto ('at line analysis'). That is to say, the apparatus necessary for carrying out the method is arranged for analysis of at least some of the samples at a position diverted from the production line, but typically local thereto. In one particular embodiment, the measuring station (e.g. an analyser) locates adjacent to a tablet press.

The present method can be used to rapidly determine the structure of a sample and may be used to analyse materials on a continuous production line. The present method is applicable to determinations involving solid dosage forms (e.g. tablets and capsules), in particular of a pharmaceutical, but may also be used for a wider range of samples (e.g. food or packaging samples). In embodiments, the present method is used to analyse the three dimensional structure of a sample (e.g. a table or capsule) and/or the properties of thin surface layers/coatings of a sample (e.g. a tablet or capsule). As the present method enables analysis measurements to be made very rapidly, potentially 100 % of all tablets/capsules (or other solid dosage samples) on a production line could be analysed thereby without the need for sample removal or any robotic sampling associated therewith.

The use of a pulse of broad beam of electromagnetic radiation provides a simple and convenient method to illuminate a sample. Importantly, the use of a pulse of a broad beam of electromagnetic radiation means that mapping of the sample (i.e. using multiple point readings using a narrowly focused beam) is not required. This is why the present method is inherently fast (e.g. of the order of femto seconds) and may therefore be used for continuous monitoring of a production line.

Brief Description of the Drawings

The invention will now be described with reference to the accompanying drawings in which:

Figure 1 shows a schematic representation of an instrument setup suitable for carrying out the method of the present invention;

Figure 2a shows a typical reflection signal from a single pulse of a narrow beam of electromagnetic radiation applied to a good tablet sample;

Figure 2b shows a typical reflection signal from a single pulse of a narrow beam of electromagnetic radiation applied to a defective tablet sample;

Figure 3a shows a simulated reflection signal from a single pulse of a broad beam of electromagnetic radiation applied to the complete surface of a good tablet sample; Figure 3b shows a simulated reflection signal from a single pulse of a broad beam of electromagnetic radiation applied to the complete surface of a defective tablet sample; and

Figure 4 shows a schematic representation of a production line setup arranged for carrying out the method of the present invention.

Detailed Description of the Drawings

Referring now to the drawings in more detail, Figure 1 shows a schematic representation of an instrument setup. This shows an experimental configuration, in which a pulse of a broad beam of TeraHertz (THz) radiation 42 is used to analyse a sample 10 in a reflection configuration. In more detail, ultra short pulse laser 45 communicates with Thz generator 40 to transmit a pulse of broad beam THz radiation 42 to the sample 10. The ultra short pulse laser apparatus may for example comprise a Ti: sapphire, Yb: Er doped fibre, Cr: LiSAF, Yb: silica, Nd : YLF, Nd: Glass, Nd : YAG or Alexandrite type of laser. The physical width 42 of the beam may be varied according to the size characteristics of the sample, but typically comprises from 10 to 200% of the maximum dimension of the sample 10. The beam width determines the area (and hence volume) of sample 10 that is interrogated. In the case that the complete sample 10 is illuminated, information on the entire sample is obtainable.

The detector 50 detects the THz radiation 52 after it is incident on the sample 10 and sends reflectance, transmittance and/or scattering data to computer 60 for analysis.

The detector 50 may either be a point detector or an array detector. The computer

60 typically includes a monitor and graphical user interface for display and monitoring of the data by an operative. The source 40, detector 50 and rapid-scan delay line 48 are both also controllable by the computer to enable different variations of the method and hence, different sets of data to be collected. Scanning delay line 48 is suitably a static delay, or a step-scan, which adjusts the relative path-lengths between the THz generator 40 and Thz detector 50 and the beams 42, 52.

Noting that the ultra short laser 45 will be producing a train of broad beam THz pulses (THz pulse train) incident on the same area of the sample, in accordance with the invention it is only necessary for a single THz pulse in the pulse train to be captured by the detector 50 and processed by the computer 60, e.g. by suitable configuration of the instrument setup. However, in accordance with the invention the instrument setup may also be configured so that a number of THz pulses in the pulse train are detected by the detector 50 and processed by the computer 60 to produce a pulse average. This averaging with plural pulses may be useful to reduce the effect of noise.

Suitable instrumentation of the type described with reference to Figure 1 is available commercially from Teraview Ltd of St John's Innovation Park, Cambridge, United

Kingdom under the trade name TPI lmaga 2000 imaging system. Instrumentation of this general type is also described (in relation to mapped analysis of tablets) in a paper entitled Non-destructive Analysis of Tablet Coating Thicknesses Using

Terahertz Pulsed Imaging by A J Fitzgerald, B E Cole, P F Taday published in Journal of Pharmaceutical Sciences, 2005, 94(1 ): 177-183, which is incorporated herein by reference.

Figures 2a and 2b show typical reflection signals from a single pulse of a narrow beam of THz radiation incident on respectively good and defective pharmaceutical tablet samples. In this instance, the incident THz beam is of beam width of 250 μm. Thus, the THz pulse is incident on a small section of the tablet. This narrow beam THz pulse can be produced by the instrument setup of Figure 1 when configured to produce a narrow THz beam.

The reflection of the THz beam by the sample is detected by a THz detector and plotted by a computer as shown in Figures 2a, 2b, where the Y-axis is the intensity (electric field strength) of the reflection (in arbitrary units) and the X-axis is the time- delay in the reflections reaching the THz detector which corresponds to the distance into the tablet at which reflections takes place.

In this case, the THz beam is reflected where there are changes in refractive index in the tablet sample, these being associated with the surface itself, surface coatings and defects within the bulk of the sample. The change in intensity of the reflected signal is representative of the tablet features giving rise to the refractive index changes in the tablet. In more detail, variations in the intensity of the reflection signal, that is to say the observed peaks and troughs, are related to differences in refractive index characteristics of the sample. Peaks/troughs at longer time-delays correspond to structural features extending deeper into the sample.

Thus, Figure 2a shows data that is obtained for a good tablet sample, where peak (a) is due to a surface reflection and area (b) is due to reflections within the tablet bulk due to refractive index changes within the tablet. Figure 2b shows data that is obtained for a defective tablet sample, where peak (c) is due to a surface reflection and peak (d) results from reflection by an internal defect in the tablet bulk.

Figures 3a and 3b show a simulated THz reflection signal that will result from an embodiment of the present invention. In this case, the simulated THz reflection signals are from illumination of a complete external surface of good (Figure 3a) and defective (Figure 3b) pharmaceutical tablet samples by a single pulse of a broad beam of THz radiation whose beam width is sufficient to illuminate the complete external surface. For instance, for a tablet sample having an external surface area with a maximum dimension of 1 cm, then the beam width (diameter) would also be of approximately 1 cm. The profiles shown by areas (a) and (b) are characteristic of each of the tablet's three dimensional properties (the earlier central peak again being due to reflection at the external surface, as in Figures 2a and 2b). Each simulated graphical plot is generated by carrying out the narrow beam measurements described with reference to Figures 2a and 2b across the complete external surface of the respective tablets and then averaging the reflection signals from the narrow beam mapping of the complete external surface to produce a simulation of the reflection signal which would result from incidence of a single pulse of a THz radiation beam whose width illuminates the complete external surface of the tablet. In the simulated broad beam reflection signal the intensity of the reflection signal for a given structural feature, in particular a surface and/or bulk feature, in the tablet is diminished compared to that observed for the corresponding structural feature in the narrow beam reflection signal, but is nonetheless still observable. Thus, it can be seen that there is an observable difference in the simulated reflection signals in areas (a) and (b) of Figures 3a and 3b which corresponds to there being no bulk defects in the tablet represented by Figure 3a, but bulk defects being present in the tablet represented by Figure 3b.

Figures 3a and 3b show that illuminating a tablet (or other sample) area, for example illuminating all or substantially all of a surface thereof, with a single pulse of a broad beam of THz radiation will produce a reflection signal containing data for characterising that sample, e.g. as either having or not having a defect. This method therefore enables sample data to be obtained rapidly.

It will be appreciated that by illuminating all or substantially all of a surface of a sample with the broad beam of electromagnetic radiation, all of the underlying volume of the sample is also characterised as the broad beam passes through the sample. Thus, it is not necessary to illuminate the whole external surface of a sample to characterise its bulk properties, but just to illuminate an external surface which overlies all, or a substantial proportion, of the bulk of the sample. Of course, in other instances, only a part of the sample may be of interest for characterising that sample, in which case the broad beam would typically only need to be incident on that part of the sample external surface overlying that part of the sample of interest. The method herein is applicable to the continuous monitoring of structural properties of samples on a production line. Figure 4 shows a representative production line set up arranged for this purpose, which may utilise the apparatus of the type described with reference to Figure 1 above. Belt 110 carries samples 120 (e.g. tablet samples) 5 along a forward direction 112. At measuring station 130, each sample 120 is subjected to a single pulse of broad beam THz radiation 142 originating from THz source 140. The bandwidth of the THz beam 142 corresponds roughly to the length of the sample 120 (or maximum dimension of the surface facing the beam 142). Reflected, transmitted and/or scattered radiation 152 from the sample is detected by 10 the detector 150, which sends reflectance, transmittance and/or scattering data to computer 160 for analysis, for instance to produce a reflection signal of the type described above with reference to Figures 3a and 3b.

The computer 160 typically includes a monitor and graphical user interface for

15 display and monitoring of the data by an operative. In practice, the computer 160 might also be configured to monitor and analyse the data and then automatically produce control signals (e.g. error signals or production line control signals) based on such analysis. For example, the computer might make reference to look-up tables or other data analysis algorithms, and such analysis may involve minimal or no user

20 intervention. The source 140 and detector 150 are both also controllable by the computer to enable different variations of the method and hence, different sets of data (e.g. repeat data) to be collected.

The belt 110 may move the samples 120 continuously through the measuring station 25 130, such that the THZ pulse 142 is incident on moving samples 120. Alternatively, the belt 110 advances the samples 120 step-wise through the measuring station 130; in other words, each sample 120 in turn is moved into the measuring station and held stationary thereat (i.e. parked), such that the THz pulse 142 is incident on stationary samples 120. 30 If the samples are moving continuously through the measuring station 130, and the THz pulse is in a THz pulse train supra, the computer 160 can synchronize selection of the THz pulses in the THz pulse train for detection and analysis with the speed of movement of the samples so that for each sample the same area (area of interest) is being characterised.

It will be appreciated that instead of using a pulse of broad beam THz radiation, the specific embodiments of the invention described above with reference to the Figures may use one of the other electromagnetic radiations described herein for the broad beam pulse for characterising the sample(s).

It will be further appreciated that the embodiments of the present invention described with reference to the Figures of drawings may be modified as elsewhere described or detailed herein, for instance in the 'Summary of the invention' and 'Claims' sections.

It will be also understood that the present disclosure is for the purpose of illustration only and the invention extends to modifications, variations and improvements thereto.

The application of which this description and claims form part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described therein. They may take the form of product, method or use claims and may include, by way of example and without limitation, one or more of the following claims:

Claims

1. A method of analysing the structure of a sample comprising

(i) identifying a sample;

2. A method according to claim 1 , wherein the sample is a pharmaceutical solid dosage form.

3. A method according to claim 2, wherein said pharmaceutical solid dosage form is a tablet or a capsule.

4. A method according to claim 1 , wherein the sample is in the form of a powder or suspension.

5. A method according to any of claims 1 to 4, wherein the beam has a width that is comparable to the maximum dimension of the sample.

6. A method according to claim 5, wherein said width of the beam is from 10 to 200% of the maximum dimension of the sample.

7. A method according to any of claims 1 to 5, wherein the width of broad beam is selected such that the whole of a position of interest on the sample is illuminated thereby.

5 8. A method according to claim 7, wherein said position of interest corresponds to the whole of the sample that is accessible to illumination or a single side of the sample.

9. A method according to any of claims 1 to 8, carried out with a single pulse of 10 the broad beam electromagnetic radiation.

10. A method according to any of claims 1 to 9, wherein said electromagnetic radiation is microwave radiation with a frequency of from 10⁹ to 4 x 10¹⁰ Hz.

15 11. A method according to any of claims 1 to 9, wherein said electromagnetic radiation is TeraHertz radiation with a frequency of from 4 x 10¹⁰- to 4 x 10¹² Hz.

12. A method according to any of claims 1 to 9, wherein said electromagnetic radiation is infra red radiation with a frequency from 4 x 10¹² to 3 x 10¹⁴ Hz.

20

13. A method according to any of claims 1 to 12, wherein the at least one property of the beam that is detected is selected from the group consisting of beam reflectance, transmission, scattering and any combination thereof.

25 14. A method according to any of claims 1 to 13, wherein at least one line shape property of the beam as a whole is detected.

15. A method according to claim 14, wherein said at least one line shape property is selected from the group consisting of width, height and shape properties of the 30 beam as a whole and any combination thereof.

16. A method according to any of claims 1 to 15, wherein the detector is a point detector.

17. A method according to any of claims 1 to 15, wherein the detector is an array 5 detector.

18. A method for analysing the structure of plural samples on a production line comprising applying the method according to any of claims 1 to 17 to each of said plural samples.

10

19. A method according to claim 18, wherein each sample of said plural samples on said production line is presented in series and the method according to any of claims 1 to 17 is applied sequentially to each sample of the plural samples.

15 20. A method according to either of claims 18 or 19, wherein the step of illuminating each said sample of the plural samples is synchronised with the movement of the plural samples on the production line.

21. A method according to any of claims 18 to 20, wherein the method according 20 to claims 1 to 17 is carried out at a measuring station locating on the production line.

22. A method according to any of claims 18 to 20, wherein at least some of the plural samples are diverted from the production line to a measuring station locating at a spaced position therefrom.

25

23. A method according to any of claims 18 to 22, wherein for each sample the method is carried out with a single said pulse.