WO2004027398A1 - Method and apparatus for quantitative analysis of a turbid, pharmaceutical sample - Google Patents

Method and apparatus for quantitative analysis of a turbid, pharmaceutical sample Download PDF

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Publication number
WO2004027398A1
WO2004027398A1 PCT/GB2003/003619 GB0303619W WO2004027398A1 WO 2004027398 A1 WO2004027398 A1 WO 2004027398A1 GB 0303619 W GB0303619 W GB 0303619W WO 2004027398 A1 WO2004027398 A1 WO 2004027398A1
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WO
WIPO (PCT)
Prior art keywords
sample
radiation
excitation beam
pharmaceutical
intensity
Prior art date
Application number
PCT/GB2003/003619
Other languages
French (fr)
Inventor
Staffan Folestad
Jonas Johansson
Sune Svanberg
Christoffer Abrahamsson
Stefan Andersson-Engels
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Priority to AU2003255807A priority Critical patent/AU2003255807A1/en
Publication of WO2004027398A1 publication Critical patent/WO2004027398A1/en

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
    • G01N21/359—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using near infrared light
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
    • G01N21/3563—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light for analysing solids; Preparation of samples therefor
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility

Definitions

  • the present invention relates to a method for analysing a turbid pharmaceutical sample, e.g. a tablet, a capsule - especially a multiple unit pellet system (MUPS) - or a similar sample forming a pharmaceutical dose.
  • a turbid pharmaceutical sample e.g. a tablet, a capsule - especially a multiple unit pellet system (MUPS) - or a similar sample forming a pharmaceutical dose.
  • the invention also relates to apparatuses for performing such a method.
  • NIR near- infrared
  • Raman spectrometry is a recognised technique for performing a fast analysis of compounds.
  • the common feature of both these techniques is that they utilise light in the NIR wavelength region (700-2500 nm, specifically 700-1500 run) where pharmaceutical tablets are relatively transparent (low molar absorptivity). That is, Ught can in this region penetrate compressed powders several mm:s why information in the content can be obtained emanating from the bulk of the tablet and not only from the surface.
  • a practical advantage of using NIR radiation is that diode lasers can be used.
  • a method for use in quantitative analysis of a turbid sample there is provided a method for use in quantitative analysis of a turbid sample.
  • the method comprises the following steps: - providing an excitation beam of radiation;
  • the method according to the present invention may be used in quantitative analysis of a turbid element.
  • the method is used in quantitative analysis of a turbid pharmaceutical sample, such as but not limited to, a tablet, a granule, an encapsulated pellet, a capsule, a bulk powder, a powder, granules or an equivalent pharmaceutical material or compound; packaging for a pharmaceutical or an element forming part of a packaging for a pharmaceutical; a pharmaceutical device or an element forming part of a pharmaceutical device.
  • a turbid pharmaceutical sample such as but not limited to, a tablet, a granule, an encapsulated pellet, a capsule, a bulk powder, a powder, granules or an equivalent pharmaceutical material or compound
  • packaging for a pharmaceutical or an element forming part of a packaging for a pharmaceutical for a pharmaceutical
  • a pharmaceutical device or an element forming part of a pharmaceutical device The invention is based on the following principles.
  • optical properties are (i) the absorption coefficient, (ii) the scattering coefficient and (iii) the scattering anisotropy.
  • Photons that by coincidence travel along an essentially straight path through the sample and thus do not experience any appreciable scattering will exit the sample with a relatively short time delay.
  • Photons that are directly reflected on the irradiated surface will also present a relatively short time delay, in the case of measurements on reflected Ught.
  • the intensity of the emitted radiation from the sample is measured both as a function of the wavelength and as a function of the photon propagation time through said sample.
  • the inventive method can be said to be both wavelength- resolved and time-resolved. It is important to note that the method is time-resolved in the sense that it provides information about the kinetics of the radiation interaction with the sample.
  • time resolved means "photon propagation time resolved”.
  • the time resolution used in the invention is in a time scale which corresponds to the photon propagation time in the sample (i.e.
  • the photon transit time from the source to the detector which, as a consequence, makes it possible to avoid time- integrating the information relating to different photon propagation times.
  • the transit time for the photons may be in the order of 0,1-2 ns.
  • the term "time resolved" is not related to a time period necessary for performing a spatial scanning, which is the case in some prior-art NER-techniques where "time resolution" is used.
  • the invention makes it possible to estabUsh quantitative analytical parameters of the sample, in particular the density of the sample and/or the porosity of the sample. Therefore there is an analysis of density and/or an analysis of porosity.
  • the term 'analysis of porosity' is used herein to describe a quantitative or quaUtative determination of, for example but not limited to, the void volume, number of cavities, size of cavities or size distribution of cavities within the sample. These quantities affect the Ught scattering and thus the photon propagation profiles as measured in time- resolved spectroscopy.
  • the porosity is related both to inter-particle and intra-particle cavities and the cavities can be both closed or open with connections between them
  • Both the transmitted radiation and the reflected radiation from the irradiated sample comprise photons with different time delay. Accordingly, the time-resolved and wavelength resolved detection may be performed on transmitted radiation only, reflected radiation only, as weU as a combination of transmitted and reflected radiation.
  • the excitation beam of radiation used in the present invention may include infrared radiation, especially near infrared radiation (NIR) in the range corresponding to wavelengths of from about 700 to about 1700 nm, particularly form 700 to 1300 nm.
  • the excitation beam of radiation may also include visible light (400 to 700 nm) and UN radiation.
  • the term "excitation” should be interpreted as "illumination”, i.e. no chemical excitation of the sample is necessary.
  • the step of measuring the intensity as a function of photon propagation time is performed in time- synchronism with the excitation of the sample.
  • this time synchronism is implemented by using a pulsed excitation beam, presenting a pulse train of short excitation pulses, wherein each excitation pulse triggers the intensity measurement.
  • a pulsed laser system or laser diodes can be used. This technique makes it possible to perform a photon propagation time-resolved measurement of the emitted intensity (transmitted and/or reflected) for each given excitation pulse, during the time period up to the subsequent excitation pulse.
  • excitation pulses should have a pulse length short enough in relation to the photon propagation time in the sample and, preferably, much shorter than the photon propagation time.
  • the intensity detection of the emitted radiation associated with a given excitation pulse is time- synchronised with this pulse, and the detection of the emitted Ught from one pulse is completed before next pulse.
  • the data evaluation can be done in different ways. By defining the boundary conditions and the optical geometry of the set-up, iterative methods such as Monte Carlo simulations can be utilised to calculate the optical properties of the sample and indirectly content and structural parameters. Alternatively, a multivariate calibration can be used for a direct extraction of such parameters. In multivariate cahbration, measured data is utilised to estabUsh an empirical mathematical relationship to the analytical parameter of interest, such as the content or structure of a pharmaceutical substance. When new measurements are performed, the model can be used to predict the analytical parameters of the unknown sample, this can be used to estabUsh the density of the sample and/or the porosity of the sample.
  • the radiation source is intensity modulated in time.
  • frequency domain spectroscopy can be used for determining phase shift and/or modulation depth of the emitted radiation from the sample.
  • the phase and/or modulation depth of the emitted sample radiation is compared with those of the excitation radiation. That information can be used to extract information about the time delay of the radiation in the sample.
  • the emitted radiation can be measured for a multitude of wavelengths to obtain spectral information.
  • the above mentioned frequency domain spectroscopy is also a "time-resolved" technique according to the invention, since it also provides information about the kinetics of the photon interaction with the sample. With similar mathematical procedures as above, the same quantitative analytical information can be extracted, this can be used to estabUsh the density of the sample and/or the porosity of the sample.
  • a pulsed excitation beam according to the first embodiment, and an intensity modulated excitation beam according to the second embodiment share the common feature that they make it possible to identify - in said excitation beam - a specific "excitation time point" which can be used to trigger the detection of the emitted radiation from the sample, i.e. to time- synchronise the time-resolved detection with the excitation of the sample.
  • This can be performed by letting the pulsed or modulated beam trigger a photodetector or the equivalent, which in its turn triggers the detection unit via suitable time-control circuitry.
  • the time detection may be implemented by the use of a time-resolved detector, such as a streak camera. It may also be implemented by the use of a time-gated system, by which the detection of emitted radiation is performed during a limited number of very short time slices instead of the full time course. The time length of each such time slice is only a fraction of the detection time period during which the time resolved detection is performed for each excitation. By measuring several such "time slices" a coarse time resolution is achieved. An attractive alternative is to measure wavelength resolved spectra at two such time gates, prompt Ught and delayed light. Furthermore, time-resolved data may be recorded by means of other time-resolved equipment, transient digitizers or equivalent.
  • a Fourier transform detector is used, whereby a mirror is scanned back and forth producing an interferogram.
  • the interferogram will contain information about the Ught transmitted through the sample at aU wavelengths. Since an interferogram is used, aU wavelengths are monitored simultaneously. The result will be a spectrum of the transmitted Ught.
  • the Ught source is intensity modulated with a modulation driver at high frequency (MHz-GHz). The phase and the modulation depth of the detected signal and the modulation driver are compared and used as output signals. These will provide information about the time behaviour of the photon propagation through the sample.
  • phase difference and the modulation depth are measured by a scan in the Fourier space and not a scan in the wavelength domain.
  • Information about physicaUy relevant parameters, such as contents or particle size, of the sample can be extracted by deconvolution techniques and chemometric models. A multitude of modulation frequencies can be utilised for more accurate analysis.
  • intensity modulated Ught is directed onto a sample.
  • the transmitted or diffusely reflected Ught is detected by a fast detector and a second detector detects the Ught before irradiating the sample.
  • the signals from the two detectors are compared regarding the phase difference and modulation depth. These two values are registered for each wavelength in sequence and from these values information about, for example, contents can be extracted with deconvolution techniques and chemometric models.
  • the wavelength resolved detection may be implemented in many different, conventional ways. It may be implemented by the use of a multi-channel detector, such as microchannel plate or a streak camera.
  • light dispersive systems such as (i) a spectrometer, (u) a wavelength dependent beam splitter, (ui) a non-wavelength dependent beam splitter in combination with a pluraUty of filters for filtering each of respective components for providing radiation of different wavelength or wavelength band, (iv) a prism array or a lens system separating the emitted radiation from the sample into a pluraUty of components in combination with a pluraUty of filters, etc.
  • a spectrometer a wavelength dependent beam splitter
  • a non-wavelength dependent beam splitter in combination with a pluraUty of filters for filtering each of respective components for providing radiation of different wavelength or wavelength band
  • a prism array or a lens system separating the emitted radiation from the sample into a pluraUty of components in combination with a pluraUty of filters, etc.
  • apparatuses for performing the inventive method there is also provided apparatuses for performing the inventive method.
  • said apparatuses have the features as defined in the enclosed claims.
  • Figure la illustrates a set-up for performing a time-resolved and wavelength resolved analysis.
  • Figure lb illustrates an embodiment where the excitation and the coUection of emitted Ught are performed at the irradiation side only of the sample.
  • Figure 2 illustrates functional components for implementing the present invention.
  • Figure 3 a is a streak camera image, illustrating an experimental result of a wavelength-resolved and time-resolved tablet transmission measurement according to the invention.
  • Figure 3b is a 3D plot of the streak camera image in figure 3 a.
  • Figure 4a is a streak camera image, illustrating an experimental result of a time- resolved tablet transmission measurement according to the invention, in combination with spatial resolution.
  • Figure 4b is a 3D plot of the streak camera image in figure 4a.
  • Figure 5 is diagram illustrating experimental results from transmission measurements on two different tablet samples.
  • Figure 6 illustrates an alternative set-up for perforaiing a time-resolved and wavelength resolved analysis.
  • Figure 7 illustrates yet another alternative set-up for performing a time-resolved and wavelength resolved analysis.
  • Figure 8 is a diagram illustrating experimental results from measurements made with the set-up in figure 7.
  • the laser beam 14 thereby generated is amplified by a neodymium YAG amplifier stage 16 into an amplified laser beam 18.
  • the laser beam 18 is passed through a water filled cuvette 22 via a mirror Ml and a first lens system LI.
  • a sample to be analysed is schematically illustrated at reference numeral 24 and comprises a front surface 26 and a back surface 28.
  • the sample 24 is temporarUy fixed in a sample-positioning unit (not shown).
  • the excitation laser beam 20 is focused onto the front surface 26 of sample 24 via a lens system L2 L3 and mirrors M2-M4.
  • the transmitted laser beam 30 is coUected from the backside by lens system L4 L5 and focused into spectrometer 32.
  • the sample 24 may be a pharmaceutical, soUd tablet having a diameter of e.g. 9 mm.
  • the excitation beam 20 may be focused in a spot of about 1 mm.
  • the excitation beam may be focused on the whole sample, or scanned over the sample.
  • the apparatus is attached to for example a fluidised bed for remote sampling of a selected part of the contents in the bed.
  • the excitation beam 20 in this embodiment is time-pulsed into a pulse train of short, repetitive excitation pulses P.
  • the pulse length of each excitation pulse P is short enough and the time spacing between two consecutive excitation pulses P is long enough in relation to the transit time of the beam (i.e. in relation to the time taken for each pulse to be completely measured in time), such that any interference is avoided between the detected Ught from one given excitation pulse P render and the detected Ught from the next excitation pulse P n+1 .
  • the detected Ught beam 33 is passed via lens system L6/L7 to a time-resolved detection unit, which in this embodiment is implemented as a streak camera 34.
  • the streak camera 34 used in an experimental set-up according to figure la was a Hamamutsu Streak Camera Model C5680.
  • the streak camera 34 has an entrance slit (not shown) onto which the detected Ught beam 33 from the spectrometer 32 is focused. It should be noted that only a fraction of the Ught emitted from the sample is actuaUy coUected in the spectrometer 32 and, thereby, in the detection unit 34.
  • the emitted radiation 30 from the sample 24 is spectraUy divided in space, such that radiation received by the streak camera 34 presents a wavelength distribution along the entrance slit.
  • the incident photons at the sUt are converted by the streak camera into photoelectrons and accelerated in a path between pairs of deflection plates (not shown). Thereby, the photoelectrons are swept along an axis onto a microchannel plate inside the camera, such that the time axis of the incident photons is converted into a spatial axis on said microchannel plate. Thereby, the time in which the photons reached the streak camera and the intensity can be determined by the position and the luminance of the streak image.
  • the wavelength-resolution is obtained along the other axis.
  • the photoelectron image is read out by a CCD device 36, which is optically coupled to the streak camera 34.
  • the data coUected by the CCD device 36 is coupled to an analysing unit 38, schematically illustrated as a computer and a monitor.
  • the intensity of the emitted Ught is measured as a function of time in time- synchronism with each excitation of the sample.
  • the detection unit comprising the streak camera 34 and the associated CCD device 36 is time- synchronised with the repetitive excitation pulses P.
  • This time- synchronism is accomplished as foUows: each excitation pulse P of the laser beam 14 triggers a photodetector 42 or the equivalent via an optical element 40.
  • An output signal 43 from the photodetector 42 is passed via a delay generator 44 to a trig unit 46, providing trig pulses to the streak camera 34. In this manner, the photon detection operation of the streak camera is activated and de-activated at exact predetermined points in time after the generation of each excitation pulse P.
  • the evaluation and analysis of the coUected, time-resolved information can be done in different ways.
  • the coUected data information from each excitation is transferred from the streak camera 34 and the CCD device 36 to a computer 38 for evaluation of the information.
  • Monte Carlo simulations, multivariate caUbrations, etc as mentioned in the introductory part of this appUcation can be utUised in order to calculate the optical properties of the sample and, indirectly, content and structural parameters of the sample 24. This information can be used to estabUsh the density of the sample
  • FIG lb schematically illustrates how an excitation beam 20' corresponding to excitation beam 20 in figure la is focused via a lens L3' onto the front surface 26 of a sample 24.
  • the photons of each excitation pulse wiU be reflected both as directly reflected photons from the front surface 26 as weU as diffusely backscattered photons with more or less time delay.
  • This directly reflected radiation as well as the diffusely backscattered radiation is coUected by a lens L4' into a detection beam 30', corresponding to detection beam 30 in figure la.
  • Figure 2 schematicaUy discloses the main functional components in an embodiment for implementing the inventive method, including a radiation generation unit 100 (components 10, 12 and 16 in figure la), a sample positioning unit 102, one or more wavelength dispersive/selective elements 104 (component 32 in figure la), one or more detector units 106 (components 34 and 36 in figure la) and an analysing unit 108 (component 38 in figure la).
  • the water filled cuvette 22 producing white laser Ught in combination with the spectrometer 32 acting as a wavelength-dispersive element makes it possible to coUect data that is both wavelength-resolved and time-resolved.
  • Figures 3a and 3b Ulustrate the experimental result of such a detection.
  • FIG. 3a illustrates a streak camera image pasted into a time-wavelength diagram, the Ught portions correspond to high intensity values.
  • the left part of the image corresponds to detected photons having a relatively short time delay, whereas the right part of the image corresponds to photons with a relatively long delay time.
  • the 3D plot in figure 3b corresponds to the image in figure 3a.
  • This 3D plot clearly illustrates how the time-resolved spectroscopy according to the invention results in an intensity measurement as a function of both wavelength and photon propagation time. This 3D plot also clearly illustrate that the total information content as obtained by the present invention is significantly greater than the information obtainable with a conventional time- integrated detection.
  • wavelength-resolved spectra are measured at two time gates only - one for "prompt” light and one for "delayed" Ught.
  • the intensity-time diagram in figure 5 Ulustrates two experimental, time-resolved results from measurements on two different tablets. By selecting suitable time gates where the difference is substantial, one can easily distinguish different tablets from each other.
  • wavelength selective Ught sources such as diode lasers.
  • wavelength selective detectors such combinations of filters and detector diodes, can be used for each wavelength.
  • spatial resolved refers to a spatial resolution obtained for each excitation pulse.
  • EspeciaUy "spatial resolved” does not refer to a spatial resolution based on a scanning in time of the excitation beam in relation to the sample.
  • the Ught focused on the entrance sUt of the streak camera would be spatial resolved along the sUt, corresponding to a "slit" across the sample.
  • a streak camera image obtained by such a set-up is Ulustrated in figure 4a, and a corresponding 3D plot is Ulustrated in figure 4b.
  • figures 4a and 4b represent one pulse only; i.e. the spatial resolution illustrated does not correspond to any scanning of the excitation beam over the sample.
  • a further alternative set-up is Ulustrated in figure 6.
  • a modulation driver 50 intensity modulates 51 a Ught source 52.
  • the Ught source is intensity modulated with a high frequency (MHz-GHz).
  • the Ught source 52 preferably a Ught emitting diode (LED), emits an excitation beam 53 in broad range of wavelengths.
  • the excitation beam 53 reaches a beam splitter 54 where the excitation beam 53 is divided.
  • One part of the excitation beam 53 continues towards a mirror 56 where it is reflected back to the beam spUtter 54.
  • the other part of the excitation beam 53 continues towards a moving mirror 55 where it is reflected back to the beam splitter 54.
  • the two parts of the spUt excitation beam 53 are brought together again at the beam splitter 54 where they continue towards the sample 57.
  • the sample 57 is thus irradiated and the transmitted Ught detected by a detector 58.
  • an interferogram is produced. This interferogram contains information about the Ught transmitted through the sample at aU wavelengths.
  • the signal 60 from the modulation driver 50 is compared to the signal 59 from the detector 58 by a phase comparator 61. From the comparison in the comparator 61 information can be extracted with deconvolution techniques and chemometric models.
  • a further alternative set-up of the present invention is Ulustrated in figure 7.
  • the Ught source producing intensity modulated Ught is made up of an array of diode lasers 62.
  • the array of diode lasers 62 covers a wide range of wavelengths and a multiplexer 63 is used to scan the various diode lasers 62 in the array, i.e. the multiplexer 63 executes the scan through the different wavelengths.
  • the produced excitation beam travels through a set of mirrors, Ulustrated in figure 7 with one mirror 65, untU it reaches a beam splitter 66 where the excitation beam 64 is divided up into two beams 70 and 74.
  • One beam 74 irradiates the sample 67 and the transmitted Ught is detected by a photomultiplier 68.
  • the other beam 70 is directed directly to a photomultipUer 71 without irradiating the sample 67.
  • the two signals 69 and 72 produced by the photomultipliers 68 and 71 due to the incident beams are compared in a phase comparator 73. These two signals 69 and 72 are recorded for each wavelength in sequence according to the scanning of the diode laser array 62 by the multiplexer 63.
  • the diagram in figure 8 shows an example of the two signals 69 and 72 where the excitation sinus curve corresponds to the beam 70 detected by photomultiplier 71 in figure 7, i.e. the beam unaffected by the sample 67.
  • the beam 74, after irradiating the sample is the detection sinus curve in figure 8.
  • Information about physical parameters of the sample can be extracted from the type of diagram iUustrated in figure 8 by comparing the two sinus shapes.
  • the measurements can be carried out by remote sampling, i.e. the sample does not have to be positioned in specific means. Therefore, the apparatuses can be placed to measure the contents in a turbid, pharmaceutical sample flow and not only in a specifically selected sample, e.g. a tablet, or a capsule.
  • the pharmaceutical sample to be analysed may be a granule, an encapsulated peUet, a capsule, a bulk powder, a powder, granules or an equivalent pharmaceutical material; packaging for a pharmaceutical or an element forming part of a packaging for a pharmeutical; a pharmaceutical device or an element forming part of a pharmaceutical device.

Abstract

The present invention relates to a method and apparatuses for use in performing a quantitative analysis of a turbid pharmaceutical sample, e.g. a tablet, a capsule or a similar sample forming a pharmaceutical dose. A pharmaceutical, turbid sample (57) is irradiated with an excitation beam (53) of radiation, e.g. near infrared radiation. The intensity of emitted radiation from the sample (57) is detected as function of both the wavelength of the emitted radiation and the photon propagation time through said sample (57). Optionally, the intensity of the emitted radiation from the sample (57) is also detected in a spatially resolved manner. Preferably, the sample (57) is alnalysed with a Fourier transform spectrometer (54, 55, 56) comprising a moving a moving mirror (55) and producing an interferogram. The scanning speed of said moving mirror (55) is slower than the light source (52) modulation frequency. A phase comparator (61) compares signals from the modulation driver (50) and from the detector.

Description

METHOD AND APPARATUS FOR QUANTITATIVE ANALYSIS OF A TURBID, PHARMACEUTICAL SAMPLE
Field of the invention
The present invention relates to a method for analysing a turbid pharmaceutical sample, e.g. a tablet, a capsule - especially a multiple unit pellet system (MUPS) - or a similar sample forming a pharmaceutical dose. The invention also relates to apparatuses for performing such a method.
Background of the invention Non- invasive, non-destructible analysis of whole tablets can be carried out by means of near- infrared (NIR) or Raman spectrometry. Today, NIR spectroscopy is a recognised technique for performing a fast analysis of compounds. The common feature of both these techniques is that they utilise light in the NIR wavelength region (700-2500 nm, specifically 700-1500 run) where pharmaceutical tablets are relatively transparent (low molar absorptivity). That is, Ught can in this region penetrate compressed powders several mm:s why information in the content can be obtained emanating from the bulk of the tablet and not only from the surface. A practical advantage of using NIR radiation is that diode lasers can be used.
One example of such an analysis is described in US 5,760,399, assigned to Foss NIRsy stems Inc. This document discloses an instrument for performing a NIR spectrographic transmission measurement of a pharmaceutical tablet. This instrument is, however, capable of providing only limited information as to the content of a sample, typically the quantity of a particular component in a sample. This prior-art instrument cannot provide detailed information of, for example, the three-dimensional distribution of one or more components in a sample. The technical background on which this limitation is based will be further discussed in connection with the description of the present invention. The prior art also includes a significant amount of methods for optical imaging of human tissues, in particular for detecting disturbances of homogeneity, such as the presence of a tumour in human tissue. These methods are generally qualitative measurements, not quantitative, in the sense that they primarily focus on determining the presence and the location of an inhomogeneity. These prior-art methods are not suitable for performing a quantitative analysis on pharmaceutical, turbid samples, such as tablets and capsules, in order to determine e.g. content and structural parameters. Summary of the invention
According to a first aspect of the invention there is provided a method for use in quantitative analysis of a turbid sample.
According to the invention, the method comprises the following steps: - providing an excitation beam of radiation;
- irradiating a pharmaceutical, turbid sample with said excitation beam of radiation;
- detecting the radiation emitted from the thus irradiated sample;
- measuring the intensity of detected radiation from the irradiated sample as a function of both the wavelength of the emitted radiation and the photon propagation time through said sample or the phase difference; and
- utilising the measured intensity to establish the density and/or the porosity of the sample.
The skilled person in the art will appreciate that the method according to the present invention may be used in quantitative analysis of a turbid element. Preferably, the method is used in quantitative analysis of a turbid pharmaceutical sample, such as but not limited to, a tablet, a granule, an encapsulated pellet, a capsule, a bulk powder, a powder, granules or an equivalent pharmaceutical material or compound; packaging for a pharmaceutical or an element forming part of a packaging for a pharmaceutical; a pharmaceutical device or an element forming part of a pharmaceutical device. The invention is based on the following principles. A sample to be analysed by a spectrometric transmission and/or reflection measurement presents a number of so called optical properties. These optical properties are (i) the absorption coefficient, (ii) the scattering coefficient and (iii) the scattering anisotropy. Thus, when the photons of the excitation beam propagate through the turbid sample - in transmission and/or reflective mode - they are influenced by these optical properties and, as a result, subjected to both absorption and scattering. Photons that by coincidence travel along an essentially straight path through the sample and thus do not experience any appreciable scattering will exit the sample with a relatively short time delay. Photons that are directly reflected on the irradiated surface will also present a relatively short time delay, in the case of measurements on reflected Ught. On the other hand, highly scattered photons (transmitted and/or reflected) exit with a substantial time delay or phase difference. This means that aU these emitted photons - presenting different propagation times - mediate complementary information about the sample. In a conventional steady state (no time-resolution) measurement, some of that complementary information is added together since the emitted Ught is captured by a time- integrated detection. Accordingly, the complementary information is lost in a conventional technique. For instance, a decrease in the registered Ught intensity may be caused by an increase in the sample scattering coefficient. However, the information about the actual cause is hidden, since all the emitted Ught has been time- integrated. According to the invention and in contrast to such prior-art NTR spectroscopy with time- integrated intensity detection, the intensity of the emitted radiation from the sample is measured both as a function of the wavelength and as a function of the photon propagation time through said sample. Thus, the inventive method can be said to be both wavelength- resolved and time-resolved. It is important to note that the method is time-resolved in the sense that it provides information about the kinetics of the radiation interaction with the sample. Thus, in this context, the term "time resolved" means "photon propagation time resolved". In other words, the time resolution used in the invention is in a time scale which corresponds to the photon propagation time in the sample (i.e. the photon transit time from the source to the detector) and which, as a consequence, makes it possible to avoid time- integrating the information relating to different photon propagation times. As an illustrative example, the transit time for the photons may be in the order of 0,1-2 ns. EspeciaUy, the term "time resolved" is not related to a time period necessary for performing a spatial scanning, which is the case in some prior-art NER-techniques where "time resolution" is used. As a result of not time- integrating the radiation (and thereby "hiding" a lot of information) as done in the prior art, but instead time resolving the information from the excitation of the sample in combination with wavelength resolving the information, the invention makes it possible to estabUsh quantitative analytical parameters of the sample, in particular the density of the sample and/or the porosity of the sample. Therefore there is an analysis of density and/or an analysis of porosity.
The term 'analysis of porosity' is used herein to describe a quantitative or quaUtative determination of, for example but not limited to, the void volume, number of cavities, size of cavities or size distribution of cavities within the sample. These quantities affect the Ught scattering and thus the photon propagation profiles as measured in time- resolved spectroscopy. The porosity is related both to inter-particle and intra-particle cavities and the cavities can be both closed or open with connections between them
Both the transmitted radiation and the reflected radiation from the irradiated sample comprise photons with different time delay. Accordingly, the time-resolved and wavelength resolved detection may be performed on transmitted radiation only, reflected radiation only, as weU as a combination of transmitted and reflected radiation.
The excitation beam of radiation used in the present invention may include infrared radiation, especially near infrared radiation (NIR) in the range corresponding to wavelengths of from about 700 to about 1700 nm, particularly form 700 to 1300 nm. However, the excitation beam of radiation may also include visible light (400 to 700 nm) and UN radiation. In this connection, it should also be stated that the term "excitation" should be interpreted as "illumination", i.e. no chemical excitation of the sample is necessary. Preferably, the step of measuring the intensity as a function of photon propagation time is performed in time- synchronism with the excitation of the sample. In a first preferred embodiment, this time synchronism is implemented by using a pulsed excitation beam, presenting a pulse train of short excitation pulses, wherein each excitation pulse triggers the intensity measurement. To this end, a pulsed laser system or laser diodes can be used. This technique makes it possible to perform a photon propagation time-resolved measurement of the emitted intensity (transmitted and/or reflected) for each given excitation pulse, during the time period up to the subsequent excitation pulse.
In order to avoid any undesired interference between the intensity measurements relating to two subsequent pulses, such excitation pulses should have a pulse length short enough in relation to the photon propagation time in the sample and, preferably, much shorter than the photon propagation time.
To summarise, in this embodiment of the invention the intensity detection of the emitted radiation associated with a given excitation pulse is time- synchronised with this pulse, and the detection of the emitted Ught from one pulse is completed before next pulse. The data evaluation can be done in different ways. By defining the boundary conditions and the optical geometry of the set-up, iterative methods such as Monte Carlo simulations can be utilised to calculate the optical properties of the sample and indirectly content and structural parameters. Alternatively, a multivariate calibration can be used for a direct extraction of such parameters. In multivariate cahbration, measured data is utilised to estabUsh an empirical mathematical relationship to the analytical parameter of interest, such as the content or structure of a pharmaceutical substance. When new measurements are performed, the model can be used to predict the analytical parameters of the unknown sample, this can be used to estabUsh the density of the sample and/or the porosity of the sample. In an alternative embodiment the radiation source is intensity modulated in time.
Then, frequency domain spectroscopy can be used for determining phase shift and/or modulation depth of the emitted radiation from the sample. Thus, the phase and/or modulation depth of the emitted sample radiation is compared with those of the excitation radiation. That information can be used to extract information about the time delay of the radiation in the sample. Moreover, the emitted radiation can be measured for a multitude of wavelengths to obtain spectral information. It should be noted that the above mentioned frequency domain spectroscopy is also a "time-resolved" technique according to the invention, since it also provides information about the kinetics of the photon interaction with the sample. With similar mathematical procedures as above, the same quantitative analytical information can be extracted, this can be used to estabUsh the density of the sample and/or the porosity of the sample.
A pulsed excitation beam according to the first embodiment, and an intensity modulated excitation beam according to the second embodiment, share the common feature that they make it possible to identify - in said excitation beam - a specific "excitation time point" which can be used to trigger the detection of the emitted radiation from the sample, i.e. to time- synchronise the time-resolved detection with the excitation of the sample. This can be performed by letting the pulsed or modulated beam trigger a photodetector or the equivalent, which in its turn triggers the detection unit via suitable time-control circuitry.
The time detection may be implemented by the use of a time-resolved detector, such as a streak camera. It may also be implemented by the use of a time-gated system, by which the detection of emitted radiation is performed during a limited number of very short time slices instead of the full time course. The time length of each such time slice is only a fraction of the detection time period during which the time resolved detection is performed for each excitation. By measuring several such "time slices" a coarse time resolution is achieved. An attractive alternative is to measure wavelength resolved spectra at two such time gates, prompt Ught and delayed light. Furthermore, time-resolved data may be recorded by means of other time-resolved equipment, transient digitizers or equivalent.
In a further embodiment a Fourier transform detector is used, whereby a mirror is scanned back and forth producing an interferogram. The interferogram will contain information about the Ught transmitted through the sample at aU wavelengths. Since an interferogram is used, aU wavelengths are monitored simultaneously. The result will be a spectrum of the transmitted Ught. The Ught source is intensity modulated with a modulation driver at high frequency (MHz-GHz). The phase and the modulation depth of the detected signal and the modulation driver are compared and used as output signals. These will provide information about the time behaviour of the photon propagation through the sample. If the scanning speed of the moving mirror of the Fourier spectrometer is much slower than the Ught modulation frequency, a value for the phase difference and the modulation depth is obtained for each position of the moving mirror. Thus, the phase difference and the modulation depth are measured by a scan in the Fourier space and not a scan in the wavelength domain. Information about physicaUy relevant parameters, such as contents or particle size, of the sample can be extracted by deconvolution techniques and chemometric models. A multitude of modulation frequencies can be utilised for more accurate analysis.
In yet a further embodiment intensity modulated Ught is directed onto a sample. The transmitted or diffusely reflected Ught is detected by a fast detector and a second detector detects the Ught before irradiating the sample. The signals from the two detectors are compared regarding the phase difference and modulation depth. These two values are registered for each wavelength in sequence and from these values information about, for example, contents can be extracted with deconvolution techniques and chemometric models. The wavelength resolved detection may be implemented in many different, conventional ways. It may be implemented by the use of a multi-channel detector, such as microchannel plate or a streak camera. Use can be made of light dispersive systems, such as (i) a spectrometer, (u) a wavelength dependent beam splitter, (ui) a non-wavelength dependent beam splitter in combination with a pluraUty of filters for filtering each of respective components for providing radiation of different wavelength or wavelength band, (iv) a prism array or a lens system separating the emitted radiation from the sample into a pluraUty of components in combination with a pluraUty of filters, etc.
In accordance with a further aspect of the invention, there is also provided apparatuses for performing the inventive method. Preferably, said apparatuses have the features as defined in the enclosed claims.
Description of the drawings
The skilled person in the art wUl appreciate that the method and apparatus according to the present invention may be used in quantitative analysis of a turbid element. The invention above and other features and advantages of the invention are defined in the claims and described in greater detail below, as an example only, with reference to the accompanying drawings, which illustrate preferred embodiments.
Figure la illustrates a set-up for performing a time-resolved and wavelength resolved analysis. Figure lb illustrates an embodiment where the excitation and the coUection of emitted Ught are performed at the irradiation side only of the sample. Figure 2 illustrates functional components for implementing the present invention.
Figure 3 a is a streak camera image, illustrating an experimental result of a wavelength-resolved and time-resolved tablet transmission measurement according to the invention. Figure 3b is a 3D plot of the streak camera image in figure 3 a.
Figure 4a is a streak camera image, illustrating an experimental result of a time- resolved tablet transmission measurement according to the invention, in combination with spatial resolution.
Figure 4b is a 3D plot of the streak camera image in figure 4a. Figure 5 is diagram illustrating experimental results from transmission measurements on two different tablet samples.
Figure 6 illustrates an alternative set-up for perforaiing a time-resolved and wavelength resolved analysis.
Figure 7 illustrates yet another alternative set-up for performing a time-resolved and wavelength resolved analysis.
Figure 8 is a diagram illustrating experimental results from measurements made with the set-up in figure 7.
Description of preferred embodiments Referring now to figure la, an apparatus according to a first embodiment for performing a time-resolved analysis according to the invention comprises a Ti: sapphire laser 10 pumped by an argon laser 12. The laser beam 14 thereby generated is amplified by a neodymium YAG amplifier stage 16 into an amplified laser beam 18. In order to create an excitation beam 20 of "white" Ught, the laser beam 18 is passed through a water filled cuvette 22 via a mirror Ml and a first lens system LI.
A sample to be analysed is schematically illustrated at reference numeral 24 and comprises a front surface 26 and a back surface 28. The sample 24 is temporarUy fixed in a sample-positioning unit (not shown). The excitation laser beam 20 is focused onto the front surface 26 of sample 24 via a lens system L2 L3 and mirrors M2-M4. On the opposite side of sample 24, the transmitted laser beam 30 is coUected from the backside by lens system L4 L5 and focused into spectrometer 32. In the illustrated set-up, the sample 24 may be a pharmaceutical, soUd tablet having a diameter of e.g. 9 mm. The excitation beam 20 may be focused in a spot of about 1 mm. In other embodiments, the excitation beam may be focused on the whole sample, or scanned over the sample. In an alternative embodiment the apparatus is attached to for example a fluidised bed for remote sampling of a selected part of the contents in the bed. As schematically illustrated in figure la, the excitation beam 20 in this embodiment is time-pulsed into a pulse train of short, repetitive excitation pulses P. The pulse length of each excitation pulse P is short enough and the time spacing between two consecutive excitation pulses P is long enough in relation to the transit time of the beam (i.e. in relation to the time taken for each pulse to be completely measured in time), such that any interference is avoided between the detected Ught from one given excitation pulse P„ and the detected Ught from the next excitation pulse Pn+1. Thereby, it is possible to perform a time-resolved measurement on the radiation from one excitation pulse P at a time.
From the spectrometer 32, the detected Ught beam 33 is passed via lens system L6/L7 to a time-resolved detection unit, which in this embodiment is implemented as a streak camera 34. The streak camera 34 used in an experimental set-up according to figure la was a Hamamutsu Streak Camera Model C5680. Specifically, the streak camera 34 has an entrance slit (not shown) onto which the detected Ught beam 33 from the spectrometer 32 is focused. It should be noted that only a fraction of the Ught emitted from the sample is actuaUy coUected in the spectrometer 32 and, thereby, in the detection unit 34. As a result of passing through the spectrometer 32, the emitted radiation 30 from the sample 24 is spectraUy divided in space, such that radiation received by the streak camera 34 presents a wavelength distribution along the entrance slit.
The incident photons at the sUt are converted by the streak camera into photoelectrons and accelerated in a path between pairs of deflection plates (not shown). Thereby, the photoelectrons are swept along an axis onto a microchannel plate inside the camera, such that the time axis of the incident photons is converted into a spatial axis on said microchannel plate. Thereby, the time in which the photons reached the streak camera and the intensity can be determined by the position and the luminance of the streak image. The wavelength-resolution is obtained along the other axis. The photoelectron image is read out by a CCD device 36, which is optically coupled to the streak camera 34. The data coUected by the CCD device 36 is coupled to an analysing unit 38, schematically illustrated as a computer and a monitor.
In the set-up in figure la, the intensity of the emitted Ught is measured as a function of time in time- synchronism with each excitation of the sample. This means that the detection unit comprising the streak camera 34 and the associated CCD device 36 is time- synchronised with the repetitive excitation pulses P. This time- synchronism is accomplished as foUows: each excitation pulse P of the laser beam 14 triggers a photodetector 42 or the equivalent via an optical element 40. An output signal 43 from the photodetector 42 is passed via a delay generator 44 to a trig unit 46, providing trig pulses to the streak camera 34. In this manner, the photon detection operation of the streak camera is activated and de-activated at exact predetermined points in time after the generation of each excitation pulse P.
As mentioned above, the evaluation and analysis of the coUected, time-resolved information can be done in different ways. As schematically Ulustrated in figure la, the coUected data information from each excitation is transferred from the streak camera 34 and the CCD device 36 to a computer 38 for evaluation of the information. Monte Carlo simulations, multivariate caUbrations, etc as mentioned in the introductory part of this appUcation can be utUised in order to calculate the optical properties of the sample and, indirectly, content and structural parameters of the sample 24. This information can be used to estabUsh the density of the sample
In the embodiment shown in figure lb, it is the transmitted radiation - the beam 30 - which is detected in a time-resolved manner. However, the invention can also be implemented by detecting the radiation reflected from the sample. Figure lb schematically illustrates how an excitation beam 20' corresponding to excitation beam 20 in figure la is focused via a lens L3' onto the front surface 26 of a sample 24. The photons of each excitation pulse wiU be reflected both as directly reflected photons from the front surface 26 as weU as diffusely backscattered photons with more or less time delay. This directly reflected radiation as well as the diffusely backscattered radiation is coUected by a lens L4' into a detection beam 30', corresponding to detection beam 30 in figure la. As stated above, it is possible to combine the embodiments Ulustrated in figures la and lb into one single embodiment, where both transmitted and backscattered Ught is detected and analysed in a time-resolved and wavelength-resolved manner according to the invention.
Figure 2 schematicaUy discloses the main functional components in an embodiment for implementing the inventive method, including a radiation generation unit 100 (components 10, 12 and 16 in figure la), a sample positioning unit 102, one or more wavelength dispersive/selective elements 104 (component 32 in figure la), one or more detector units 106 (components 34 and 36 in figure la) and an analysing unit 108 (component 38 in figure la). The water filled cuvette 22 producing white laser Ught in combination with the spectrometer 32 acting as a wavelength-dispersive element makes it possible to coUect data that is both wavelength-resolved and time-resolved. Figures 3a and 3b Ulustrate the experimental result of such a detection. It should be noted that the time scale in both figure 3a and figure 3b illustrate the intensity variation over time for one pulse only, although the actual data used for producing these figures is based in accumulated data from many readings. The time axis in figures 3a and 3b is in nano second scale. Figure 3a illustrates a streak camera image pasted into a time-wavelength diagram, the Ught portions correspond to high intensity values. The left part of the image corresponds to detected photons having a relatively short time delay, whereas the right part of the image corresponds to photons with a relatively long delay time. The 3D plot in figure 3b corresponds to the image in figure 3a. This 3D plot clearly illustrates how the time-resolved spectroscopy according to the invention results in an intensity measurement as a function of both wavelength and photon propagation time. This 3D plot also clearly illustrate that the total information content as obtained by the present invention is significantly greater than the information obtainable with a conventional time- integrated detection.
In figure 3b, for each wavelength (such as for the wavelengths λl and λ2 as identified in figure 3b) there is a multitude of timely spaced intensity readings. Thus, for each wavelength it is possible to obtain a fuU curve of emitted (transmitted and/or reflected) intensity vs. propagation time. The form of these "time profiles" shown in figure 3b is dependent on the relation between the optical properties of the analysed sample. With such a time-resolved and wavelength-resolved spectroscopy, it is possible to obtain information for describing the Ught interaction with the sample. As an example, this provides the basis for determining an analytical concentration in a sample that is proportional to the absorption coefficient but not related to the scattering. As another example, one might want to measure an analytical quantity that correlates to the scattering properties of the sample instead.
As Ulustrated by the dashed lines tl and t2 in figure 3b, it is also possible to evaluate the emitted Ught by detecting the intensity during fixed time sUces. This would give a more coarse time resolution. In one embodiment, wavelength-resolved spectra are measured at two time gates only - one for "prompt" light and one for "delayed" Ught.
The intensity-time diagram in figure 5 Ulustrates two experimental, time-resolved results from measurements on two different tablets. By selecting suitable time gates where the difference is substantial, one can easily distinguish different tablets from each other.
As an alternative to the set-ups Ulustrated in figures la and lb, instead of using the water cuvette 20 in combination with the spectrometer 32, it is possible to use wavelength selective Ught sources, such as diode lasers. On the detector side, wavelength selective detectors, such combinations of filters and detector diodes, can be used for each wavelength.
It is possible to combine the invention with spatial-resolved intensity detection on the emitted Ught from the sample. In this context, the term "spatial resolved" refers to a spatial resolution obtained for each excitation pulse. EspeciaUy, "spatial resolved" does not refer to a spatial resolution based on a scanning in time of the excitation beam in relation to the sample. As an illustrative example, by removing the water cuvette22 and the spectrometer 32 in the figure la set-up, the Ught focused on the entrance sUt of the streak camera would be spatial resolved along the sUt, corresponding to a "slit" across the sample. A streak camera image obtained by such a set-up is Ulustrated in figure 4a, and a corresponding 3D plot is Ulustrated in figure 4b. In accordance with figures 3a and 3b discussed above, figures 4a and 4b represent one pulse only; i.e. the spatial resolution illustrated does not correspond to any scanning of the excitation beam over the sample. A further alternative set-up is Ulustrated in figure 6. A modulation driver 50 intensity modulates 51 a Ught source 52. The Ught source is intensity modulated with a high frequency (MHz-GHz). The Ught source 52, preferably a Ught emitting diode (LED), emits an excitation beam 53 in broad range of wavelengths. The excitation beam 53 reaches a beam splitter 54 where the excitation beam 53 is divided. One part of the excitation beam 53 continues towards a mirror 56 where it is reflected back to the beam spUtter 54. The other part of the excitation beam 53 continues towards a moving mirror 55 where it is reflected back to the beam splitter 54. The two parts of the spUt excitation beam 53 are brought together again at the beam splitter 54 where they continue towards the sample 57. The sample 57 is thus irradiated and the transmitted Ught detected by a detector 58. By scanning the moving mirror 55 back and forth, an interferogram is produced. This interferogram contains information about the Ught transmitted through the sample at aU wavelengths. By using an interferogram all wavelengths are monitored simultaneously and the result wUl be a spectrum of the transmitted Ught intensity. The signal 60 from the modulation driver 50 is compared to the signal 59 from the detector 58 by a phase comparator 61. From the comparison in the comparator 61 information can be extracted with deconvolution techniques and chemometric models.
A further alternative set-up of the present invention is Ulustrated in figure 7. In this embodiment the Ught source producing intensity modulated Ught is made up of an array of diode lasers 62. The array of diode lasers 62 covers a wide range of wavelengths and a multiplexer 63 is used to scan the various diode lasers 62 in the array, i.e. the multiplexer 63 executes the scan through the different wavelengths. The produced excitation beam travels through a set of mirrors, Ulustrated in figure 7 with one mirror 65, untU it reaches a beam splitter 66 where the excitation beam 64 is divided up into two beams 70 and 74. One beam 74 irradiates the sample 67 and the transmitted Ught is detected by a photomultiplier 68. The other beam 70 is directed directly to a photomultipUer 71 without irradiating the sample 67. The two signals 69 and 72 produced by the photomultipliers 68 and 71 due to the incident beams are compared in a phase comparator 73. These two signals 69 and 72 are recorded for each wavelength in sequence according to the scanning of the diode laser array 62 by the multiplexer 63. The diagram in figure 8 shows an example of the two signals 69 and 72 where the excitation sinus curve corresponds to the beam 70 detected by photomultiplier 71 in figure 7, i.e. the beam unaffected by the sample 67. The beam 74, after irradiating the sample, is the detection sinus curve in figure 8. Information about physical parameters of the sample can be extracted from the type of diagram iUustrated in figure 8 by comparing the two sinus shapes.
In either of the above embodiments the measurements can be carried out by remote sampling, i.e. the sample does not have to be positioned in specific means. Therefore, the apparatuses can be placed to measure the contents in a turbid, pharmaceutical sample flow and not only in a specifically selected sample, e.g. a tablet, or a capsule. The pharmaceutical sample to be analysed may be a granule, an encapsulated peUet, a capsule, a bulk powder, a powder, granules or an equivalent pharmaceutical material; packaging for a pharmaceutical or an element forming part of a packaging for a pharmeutical; a pharmaceutical device or an element forming part of a pharmaceutical device.
The foregoing is a disclosure of preferred embodiments for practicing the present invention. However, it is apparent that device incorporating modifications and variations wUl be obvious to one skUled in the art. Inasmuch as the foregoing disclosure is intended to enable one skUled in the art to practice the instant invention, it should not be construed to be limited thereby, but should be construed to include such modifications and variations as fall within its true spirit and scope.

Claims

1. A method for use in quantitative analysis of a turbid, pharmaceutical sample, comprising the foUowing steps: - providing an excitation beam of radiation with intensity light;
- irradiating a pharmaceutical, turbid sample with said excitation beam of radiation;
- detecting the radiation emitted from the thus irradiated sample (24, 57, 67);
- measuring the intensity of detected radiation from the irradiated sample (24, 57, 67) as a function of both the wavelength of the emitted radiation and the photon propagation time through said sample (24, 57, 67) or the phase difference; and
- utUise the measured intensity to estabUsh the density of said sample (24, 57, 67) and/or the porosity of the sample (24, 57, 67).
2. A method as claimed in claim 1, wherein said emitted radiation comprises transmitted radiation (30) from said sample (24, 57, 67).
3. A method as claimed in claim 1, wherein said emitted radiation comprises diffusely reflected radiation (30') from said sample (24, 57, 67).
4. A method as claimed in claim 1, wherein said emitted radiation comprises transmitted radiation (30) as weU as diffusely reflected radiation (20') from said sample (24, 57, 67).
5. A method as claimed in any of the claims 1-4, wherein said excitation beam (20,
53, 64) is a pulsed excitation beam presenting a pulse train of excitation pulses (P), and wherein the step of measuring the intensity as a function of the photon propagation time is performed in time synchronism with said excitation pulses (P).
6. A method as claimed in clahn 5, wherein said excitation pulses (P) have a pulse length shorter than the photon propagation time.
7. A method as claimed in claim 6, wherein said excitation pulses (P) have a pulse length selected short enough in relation to the photon propagation time such that any undesired interference between intensity measurements relating to two subsequent excitation pulses is prevented.
8. A method as claimed in any of the claims 1-4, wherein said excitation beam (20, 53, 64) is an intensity modulated excitation beam.
9. A method as claimed in claim 8, wherein the step of measuring the intensity as a function of the photon propagation time is performed by comparing the phase of the intensity modulated excitation beam (20, 53, 64) with the phase of the emitted radiation (30) form the sample (24, 57, 67).
10. A method as claimed in claim 8 or 9, wherein the step of measuring the intensity as a function of the photon propagation time is performed by comparing the modulation depth of the emitted radiation (30) for the sample (24, 57, 67).
11. A method as claimed in any of the claims 1-10, wherein said measuring of the intensity of emitted radiation (30) from the sample (24, 57, 67) as a function of time is performed by the use of a time-resolved detection unit.
12. A method a claimed in any of the claims 1-10, wherein said measuring of the intensity of the emitted radiation (30) from the sample (24, 57, 67) as a function of time is performed by the use of a phase-resolved detection unit.
13. A method as claimed in any of the claims 1-10, wherein said measuring of the intensity of emitted radiation (30) from the sample (24, 57, 67) as a function of time is performed by the use of a time-gated system.
14. A method as claimed in any of the preceding claims, wherein said step of measuring the intensity further includes a spatial-resolved detection of said intensity.
15. A method as claimed in any of the preceding claims, wherein said pharmaceutical, turbid sample is a soUd sample (24, 57, 67), in particular a tablet, a granule, an encapsulated peUet, a capsule, a bulk powder, a powder, granules or an equivalent pharmaceutical material; packaging for a pharmaceutical or an element forming part of a packaging for a pharmaceutical; a pharmaceutical device or an element forming part of a pharmaceutical device.
16. A method as claimed in claim 15, wherein said step of irradiating the sample with said excitation beam comprises the step of irradiating a first surface of the soUd sample (24, 57, 67).
17. A method as claimed in claim 15, wherein said step of irradiating the sample with said excitation beam (20, 53, 64) comprises the step of irradiating a first surface and a second surface of the soUd sample (24, 57, 67), especially oppositely-directed surfaces.
18. A method as claimed in claim 17, wherein the first surface and the second surface of the soUd sample are irradiated at different points in time.
19. A method as claimed in any of the claims 1-14, wherein said pharmaceutical, turbid sample is a dispersion.
20. A method as claimed in any of the preceding claims, wherein the excitation beam (20, 53, 64) comprises infrared radiation.
21. A method as claimed in claim 20, wherein the infrared radiation is in the near infrared radiation (NIR).
22. A method as claimed in claim 21, wherein the radiation has a frequency in the range corresponding to wavelengths of from about 700 to about 1700 nm, particularly from 700 to 1300 nm.
23. A method as claimed in any of the preceding claims, wherem the excitation beam (20, 53, 64) comprises visible Ught.
24. A method as claimed in any of the preceding claims, wherein the excitation beam (20, 53, 64) comprises UN radiation.
25. A method as claimed in any of the preceding claims, wherein the sample (57) is analysed with a Fourier transform spectrometer comprising a moving mirror (55).
26. A method as claimed in claim 25, wherein an interferogram is produced.
27. A method as claimed in any of the claims 25 and 26, wherein the scanning speed of said moving mirror (55) is slower than the Ught modulation frequency.
28. A method as claimed in any of the claims 1-24, wherein the intensity modulated excitation beam (64) is divided into two beams (70, 74) with a beam splitter (66), whereby one of said beams (70, 74) is detected after radiating the sample (67).
29. A method as claimed in claim 28, wherein the beams (70, 74) are detected by photomultipliers (68,71).
30. A method as claimed in claim 28 or 29, wherein the signals (69, 72) are compared in a phase comparator (73).
31. A method for use in an analysis of a turbid sample (24, 57, 67), wherein an excitation radiation is directed onto said sample (24, 57, 67) and wherein the intensity of emitted radiation (30) from the thus radiated sample (24, 57, 67) is measured as a function of both wavelength of the emitted radiation (30) and photon propagation time through said sample (24, 57, 67).
32. A method as claimed in any of the preceding claims, wherein remote sampling is performed.
33. A method as claimed in any one of the previous claims, wherein said excitation beam of radiatin comprises intensity modulated Ught.
34. An apparatus for use in quantitative analysis of a turbid pharmaceutical sample (57), comprising: - means (52) for generating an excitation beam (53) of radiation;
- means (50) for intensity modulating said excitation beam (53);
- means (54, 55, 56) for focusing said excitation beam (53) onto said sample(57);
- means (58) for detecting and measuring all wavelengths simultaneously.
35. An apparatus as claimed in claim 34, wherein said means for detecting and measuring comprises a time-resolved detection unit (58).
36. An apparatus as claimed in claim 34, wherein said means for detecting and measuring comprises a phase-resolved detection unit.
37. An apparatus as claimed in claim 34, wherein said means for detecting and measuring comprises a time-grated syste
38. An apparatus as claimed in any of the claims 33-37, further comprising means for performing a spatial-resolved detection and measurement of said intensity.
39. An apparatus as claimed in any of the claims 33-38, wherein said pharmaceutical, turbid sample is a soUd sample (57), in particular a tablet, a granule, an encapsulated peUet, a capsule, a bulk powder, a powder, granules or an equivalent pharmaceutical material; packaging for a pharmaceutical or an element forming part of a packaging for a pharmaceutical; a pharmaceutical device or an element forming part of a pharmaceutical device.
40. An apparatus as claimed in any of the claims 33-38, wherein said pharmaceutical, turbid sample is a dispersion.
41. An apparatus as claimed in claim 33, wherein the excitation beam (53) comprises infrared radiation.
42. An apparatus as claimed in claim 41, wherein the infrared radiation is in the near infrared radiation (NIR).
43. An apparatus as claimed in claim 33, wherein the radiation has a frequency in the range corresponding to wavelengths from about 700 to about 1700 nm, particularly 700 to 1300 nm
44. An apparatus as claimed in any of the claims 33-43, wherein the excitation beam (53) comprises visible Ught.
45. An apparatus as claimed in any of the claims 33-44, wherein the excitation beam (53) comprises UN radiation.
46. An apparatus as claimed in any of the claims 33-45, wherein said means (52) for generating an excitation beam (53) of radiation comprises one or more diode lasers.
47. An apparatus as claimed in any of the claims 33-45, wherein said means (52) for generating an excitation beam (53) of radiation comprises an intensity modulated lamp.
48. An apparatus as claimed in any of the claims 33-45, wherein said means (52) for generating an excitation beam (53) of radiation comprises an intensity modulated Ught emitting diode (LED).
49. An apparatus as claimed in any of the claims 33-48, wherein said means (50) for intensity modulating said excitation beam (53) is a modulation driver (50).
50. An apparatus as claimed in any of the claims 33-49, wherein said means (54, 55, 56) are parts of a Fourier spectrometer.
51. An apparatus as claimed in any of the claims 33-50, wherein a phase comparator (61) is arranged to compare signals from the modulation driver (50) and from the detector (58).
52. An apparatus as claimed in any of the claims 33-51, comprising means for positioning a turbid pharmaceutical sample (57).
53. An apparatus for use in quantitative analysis of a turbid pharmaceutical sample (67), comprising:
- means (62, 63) for generating an excitation beam (64) of radiation; - means (65, 66) for focusing said excitation beam (64) onto said sample(57);
- means (66) for spUtting said excitation beam into two beams (70, 74)
- means (68, 71) for detecting and measuring transmitted Ught and non- transmitted Ught respectively.
54. An apparatus as claimed in claim 53, wherein said means for detecting and measuring comprises a time-resolved detection unit.
55. An apparatus as claimed in claim 53, wherein said means for detecting and measuring comprises a phase-resolved detection unit.
56. An apparatus as claimed in claim 53, wherein said means for detecting and measuring comprises a time-grated system
57. An apparatus as claimed in any of the claims 53-56, further comprising means for performing a spatial-resolved detection and measurement of said intensity.
58. An apparatus as claimed in any of the claims 53-57, wherein said pharmaceutical, turbid sample is a soUd sample (67), in particular a tablet, a granule, an encapsulated peUet, a capsule, a bulk powder, a powder, granules or an equivalent pharmaceutical material; packaging for a pharmaceutical or an element forming part of a packaging for a pharmaceutical; a pharmaceutical device or an element forming part of a pharmaceutical device.
59. An apparatus as claimed in any of the claims 53-57, wherein said pharmaceutical, turbid sample is a dispersion.
60. An apparatus as claimed in claim 53, wherein the excitation beam (64) comprises infrared radiation.
61. An apparatus as claimed in claim 60, wherein the infrared radiation is in the near infrared radiation (NIR).
62. An apparatus as claimed in claim 53, wherein the radiation has a frequency in the range corresponding to wavelengths from about 700 to about 1700 run, particularly 700 to 1300 nm
63. An apparatus as claimed in any of the claims 53-62, wherein the excitation beam (64) comprises visible Ught.
64. An apparatus as claimed in any of the claims 53-63, wherein the excitation beam (64) comprises UN radiation.
65. An apparatus as claimed in any of the claims 53-64, wherein said means (62, 63) for generating an excitation beam (64) of radiation comprises one or more diode lasers.
66. An apparatus as claimed in any of the claims 53-64, wherein said means (62, 63) for generating an excitation beam (64) of radiation comprises an intensity modulated lamp.
67. An apparatus as claimed in any of the claims 53-64, wherein said means (62, 63) for generating an excitation beam (64) of radiation comprises an intensity modulated light emitting diode (LED).
68. An apparatus as claimed in claim 53, wherein said means (62, 63) for generating an excitation beam (64) of radiation is an array of diode lasers (62) and a multiplexer (63).
69. An apparatus as claimed in claim 53, wherein said means (68, 71) for detecting transmitted Ught and non-transmitted Ught are photomultipUers.
70. An apparatus as claimed in claim 53, wherein a phase comparator (73) is arranged to compare the signals (69, 72) from said means (68, 71) for detecting transmitted light and non-transmitted Ught.
PCT/GB2003/003619 2002-09-20 2003-09-09 Method and apparatus for quantitative analysis of a turbid, pharmaceutical sample WO2004027398A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2446026A (en) * 2007-01-29 2008-07-30 Teraview Ltd Analysis apparatus and method
WO2008136675A1 (en) * 2007-05-07 2008-11-13 Friesland Brands B.V. Method and apparatus for preparing cheese from milk

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4413908A (en) * 1982-03-05 1983-11-08 Bio-Rad Laboratories, Inc. Scanning interferometer control systems
US5021661A (en) * 1989-09-04 1991-06-04 Jeol Ltd. Time-resolved infrared spectrophotometer
US5440388A (en) * 1993-08-02 1995-08-08 Erickson; Jon W. Chemical analysis and imaging by discrete fourier transform spectroscopy
US6040914A (en) * 1997-06-10 2000-03-21 New Focus, Inc. Simple, low cost, laser absorption sensor system
WO2001022063A1 (en) * 1999-09-22 2001-03-29 Astrazeneca Ab Method and apparatus for spectrometric analysis of turbid, pharmaceutical samples
US6339222B1 (en) * 1998-11-12 2002-01-15 Kvaerner Canada Inc. Determination of ionic species concentration by near infrared spectroscopy

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4413908A (en) * 1982-03-05 1983-11-08 Bio-Rad Laboratories, Inc. Scanning interferometer control systems
US5021661A (en) * 1989-09-04 1991-06-04 Jeol Ltd. Time-resolved infrared spectrophotometer
US5440388A (en) * 1993-08-02 1995-08-08 Erickson; Jon W. Chemical analysis and imaging by discrete fourier transform spectroscopy
US6040914A (en) * 1997-06-10 2000-03-21 New Focus, Inc. Simple, low cost, laser absorption sensor system
US6339222B1 (en) * 1998-11-12 2002-01-15 Kvaerner Canada Inc. Determination of ionic species concentration by near infrared spectroscopy
WO2001022063A1 (en) * 1999-09-22 2001-03-29 Astrazeneca Ab Method and apparatus for spectrometric analysis of turbid, pharmaceutical samples

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2446026A (en) * 2007-01-29 2008-07-30 Teraview Ltd Analysis apparatus and method
US9201052B2 (en) 2007-01-29 2015-12-01 Teraview Limited Analysis apparatus and method
WO2008136675A1 (en) * 2007-05-07 2008-11-13 Friesland Brands B.V. Method and apparatus for preparing cheese from milk

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