Radiant energy – Photocells; circuits and apparatus – Optical or pre-photocell system
Reexamination Certificate
2000-11-03
2004-09-21
Allen, Stephone B. (Department: 2878)
Radiant energy
Photocells; circuits and apparatus
Optical or pre-photocell system
C356S318000, C356S432000
Reexamination Certificate
active
06794670
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a method of analysing a turbid pharmaceutical sample, e.g. a tablet, a capsule—especially a multiple unit pellet system (MUPS) tablet or capsule—or a similar sample forming a pharmaceutical dose. The invention also relates to an apparatus for performing such a method.
The present invention can optionally be combined with the invention and the spectrometric methods and set-ups as disclosed in applicant's copending International patent application WO99/49312, filed before the present application but unpublished on the priority date of the present application. Especially, the present invention can be combined with the technique disclosed therein for irradiating two opposite surfaces of an analysed sample, in order to obtain signals representative of the three-dimensional distribution of at least one component in the sample. The content of this International patent application is hereby incorporated by reference.
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 nm) where pharmaceutical tablets are relatively transparent (low molar absorptivity). Since light in this region can penetrate compressed powders several millimeters in depth, information on 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 U.S. Pat. No. 5,760,399, assigned to Foss NIRsystems 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 a 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 phramaceutical sample, in particular, a pharmaceutical tablet, capsule, bulk powder, or an equivalent pharmaceutical dose.
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; and
measuring the intensity of emitted radiation from the thus irradiated sample as a function of both the wavelength of the emitted radiation and the photon propagation time through said sample.
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 reflection 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 light. On the other hand, highly scattered photons (transmitted and/or reflected) exit with a substantial time delay. This means that all 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 light is captured by a time-integrated detection. Accordingly, the complementary information is lost in a conventional technique. For instance, a decrease in the registered light intensity may be caused by an increase in the sample absorption coefficient, but it may also be caused by a change in the sample scattering coefficient. However, the information about the actual cause is hidden, since all the emitted light has been time-integrated.
According to the invention and in contrast to such prior-art NMR 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. Especially, 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 NIR-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 establish quantitative analytical parameters of the sample, such as content, concentration, structure, homogeneity, etc.
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 well 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 (NIR) radiation of in the range corresponding to wavelengths of from about 700 to about 1700 nm, particularly from 700 to 1300 nm. However, the excitation beam of radiation may also include visible light (400 to 700 nm) and UV radiation. In this connection, it should also be stated that the term “excitation” should be interpreted as meaning “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
Folestad Staffan
Johansson Jonas
Josefson Mats
Sparen Anders
Allen Stephone B.
AstraZeneca AB
White & Case LLP
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