This invention pertains to spectrometric instruments, such as spectrometric instruments for characterizing pharmaceutical heterogeneity.
Spectrometric techniques have been applied to monitoring mixing processes, such as the mixing of pharmaceutical blends. One approach has been to take a series of single spectra of a blend through a window in a mixing vessel. Mixing can then be carried out until this single measurement reaches an end point. This method is simple to implement, but it provides the user with relatively little information about the distribution of components of the mixture.
Another approach has been to acquire a series of near-infrared chemical images of a blend in a mixing vessel. These images can then be analyzed to derive statistical properties, such as the mean, standard deviation, kurtosis, or skew of the distribution, as described in more detail in published US application no. US2004-0211861, which is herein incorporated by reference. This approach can provide more information about the distribution of mixture components than does the single-measurement approach, but it can be relatively expensive to implement.
A number of different embodiments of the invention are presented in this application and in the attached claims.
In one general aspect, the invention features a spectroscopic method that includes acquiring a plurality of separate spectral measurements at different locations on a sample, evaluating results of the measurements based on one or more predetermined test criteria, categorizing information from measurements made at the different locations based on results of the step of evaluating, and reporting results that include information from both the step of acquiring and the step of categorizing.
In preferred embodiments the step of categorizing can be performed by rejecting one or more measurements that fail to satisfy the predetermined test criteria. The step of categorizing can be performed by classifying the measurements into a plurality of discrete categories. The step of categorizing can be performed by associating the measurements with categorization information. The predetermined test criteria can be statistical test criteria. The step of categorizing can include the steps of retaining measurements for the locations that meet the predetermined test criteria and rejecting measurements for the locations that fail to meet the predetermined test criteria. The method can further include the step of deriving one or more statistical properties of the categorized measurements. The step of deriving statistical properties can include a step of averaging the categorized measurements. The step of deriving statistical properties can include a step of obtaining a standard deviation for the categorized measurements. The step of deriving statistical properties can include a step of obtaining a kurtosis value for the categorized measurements. The step of deriving statistical properties can include a step of obtaining a skew value for the categorized measurements. The step of acquiring can include acquiring scout measurements and test measurements, with the step of categorizing including retaining information from test measurements at locations that satisfy the test criteria in the scout measurements. The measurements can include Raman measurements. The step of evaluating results of the measurements can be adapted to detect fluorescence, and the step of categorizing can be operative to reject measurements where fluorescence is detected. The step of evaluating can detect measurements that exceed a predetermined intensity threshold. The sample can be moved relative to the detector to allow the detector to acquire the separate spectroscopic measurements from the different locations. The steps of acquiring can be performed using at least one moving minor. The moving mirror can image at least a portion of an illuminated area of the sample onto an aperture between the sample and the detector. The steps of acquiring and deriving can be performed for a pharmaceutical mixture. The steps of acquiring and deriving can be performed for a pharmaceutical product. The steps of acquiring and deriving can be performed for a pharmaceutical intermediate. The steps of acquiring and deriving can be performed for a pharmaceutical dosage unit. The step of acquiring can acquire a Raman measurement. The sample can be moved relative to the detector to allow the detector to acquire the sampled spectroscopic measurements from the different locations. The size of the samples can be on the order of the milled ingredient size for a pharmaceutical mixture. The size of the samples can be on the order of the domain sizes of individual species in a pharmaceutical mixture. The size of the samples can be on the order of 10 microns. The size of the samples can be on the order of 125 microns. The size of the samples can range from 0.5 microns to 1000 microns.
In another general aspect, the invention features a spectroscopic apparatus for monitoring heterogeneity of a sample, that includes a sampling detector operative to acquire sampled spectroscopic measurements distributed over a range of different locations in a sample, a sequencer operative to cause the same sampling detector to successively acquire samples for each of a plurality of locations in the sample, and a spectral processor operative to derive from the sampled spectroscopic measurements a statistical measure of chemical heterogeneity.
In a further general aspect, the invention features a spectroscopic apparatus for monitoring heterogeneity of a sample, that includes means for acquiring sampled spectroscopic measurements distributed over a range of different locations in a sample, means for causing the sampling detector to successively acquire samples for each of a plurality of locations in the sample, and means for deriving from the sampled spectroscopic measurements a statistical measure of chemical heterogeneity.
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The system 10 includes one or more infrared illumination sources 16 directed toward a window 18 in the mixing vessel 14. One or more sampling detectors 20 are positioned near the vessel in such a way that they can acquire spectrometric samples through the window. A sequencer 22 can trigger acquisitions by the sampling detector, and a statistical processor 24 can receive the acquired samples.
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The acquisition process ends at the end of a final macro-sample (step 36). This can be the last of a predetermined number of macro-samples in a fixed sampling schedule. The system can also stop the process for other reasons, such as once certain predetermined mixing characteristics have been achieved, or when an error condition is detected.
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In a second implementation the illumination is as above, but an optical system which includes a scanning mirror images a portion of the illuminated area onto an aperture. This aperture is then imaged onto the slit of the spectrograph or onto a fiber bundle as described above. The spatial resolution is determined by the size of the aperture projected through the collection optics onto the sample. The aperture may consist of an iris, slit, wedge or a small mirror, positioned to pick off only a small portion of the sample image.
In a third implementation the oblique illumination is provided by the modulated light from a Fourier Transform (FT) interferometer, and the micromirror array selectively images a portion of the illuminated area directly into a single element detector.
In a fourth implementation the illumination is the modulated light from an FT interferometer, and an optical system which includes a scanning mirror images a portion of the illuminated area onto an aperture which is imaged directly onto a detector.
In a fifth implementation a beamsplitter is used to couple a collimated broadband beam into the collection path. The light is telescoped down and sent through an aperture, which is imaged to a spot on the sample by an optical system which incorporates a scanning mirror. Light from that spot follows the same path back to the beamsplitter and is then focused onto the slit of a spectrograph.
As before, the collimated broadband illumination source can be the modulated output of a Michelson interferometer, in which case the spectrograph is replaced by a single element detector.
Instead of telescoping the illumination beam to the size of a small aperture, the entire collimated excitation beam can illuminate a micromirror array oriented so that an minor in the ‘on’ state will direct a portion of the collimated incident beam to a corresponding spot on the sample, and the reflected light from that spot will be directed to the beamsplitter and then to either the slit of the spectrograph or into a detector in the case of FT illumination. The spot could also be brought to the sample through the use of an optical microscope.
In still another configuration, a spectrograph (or a detector for the case of FT modulated illumination) can be set up to collect light from a large area, and a small portion of that area can be illuminated oblique to the collection angle, either using a micromirror array or by again making use of the small aperture—scanning minor-lens combination described earlier.
Sampling at different locations can also be achieved by moving the material to be sampled instead of moving the sampling locations with respect to the instrument. A dosage unit could be rotated or tumbled, for example, in front of a single-point detector. A x-y stage could also be moved randomly with respect to a detector.
Sampling can also take place from different vantage points. Different sample locations could be acquired from opposite sides of a tablet, for example, by different detectors, optical conduits, mirrors, or other suitable arrangements.
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The sequencing of acquisitions can take place in any suitable manner. It can use a computer program or dedicated circuit or a combination of the two. It can also use other types of principles, such as optical, mechanical, or electro-optical principles. In the embodiment of
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The statistical techniques performed by the statistical processor 24 can be applied to raw spectral data, or derived values, such as chemical or physical properties. The statistical properties can be computed as the micro-samples are being acquired and/or after a full run.
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Acquiring measurements from differently sized locations can provide additional information about the distribution of particles in a sample. Measurements over large areas will generally be representative of a number of different particles and will therefore reflect an average for these particles. Measurements over areas that are similar in size to individual particles will tend to reflect a single species. As size decreases in a series of measurements, therefore, the acquired spectrum will generally evolve from showing a mixture of species to showing just spectral features corresponding to an individual species. Chemometric analysis techniques can also be applied to the series of measurements to derive more detailed information about particle size and relative ingredient concentrations.
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If the micro-sample meets the test criteria it is classified as passing (step 84). If the micro-sample does not meet the test criteria it is categorized as failing (step 86). The categorization of measurements can range from a simple pass-fail determination to a more complex multi-class categorization, or even a continuous categorization. The categorization process be performed in a variety of ways, such as retaining or discarding sample measurement values, storing different types of sample measurements in different parts of a data structure, or associating categorization information with each sample.
This categorization technique can be used in situations where one or more macro-sample is desired (see step 34). It is also possible to perform separate macro-sample runs for evaluation and final measurement purposes. A first scout pass might be performed to find outliers, for example, with a second pass then being performed to acquire measured values. The scout pass could be performed in a different way than the measurement pass (e.g., more quickly or with a different measurement range).
The categorized micro-sample data set can then be reported to the user or to another system component. This reporting step provides information from the measurement and its categorization. For example, it can include passing samples and exclude failing samples, it can weight some of the samples more heavily, or it can include categorization information associated with one or more the samples that can be used as a figure of merit.
The techniques described above can also be applied to determine the uniformity of a pharmaceutical compound that is in the form of dosage units. This approach can allow the system to acquire information about the uniformity of the mixture within each unit and/or across a lot of units, and the sampling can take place before or after the dosage units are packaged in transparent blister packs. Relevant techniques for this type of measurement can be found in U.S. Pat. No. 6,690,464, which is herein incorporated by reference. Staining techniques may also help to enhance the information received from some experimental runs. These techniques are described in U.S. application Ser. No. 11/265,796, published under WO2006044861, and herein incorporated by reference. Moreover, while the techniques presented above have been developed for use in the characterization of pharmaceuticals, they may also be applicable to other types of products, such as cosmetics or nutritional supplements. Coated goods, drug delivery systems, medical devices, and composite materials may also be inspected using systems according to the invention.
The present invention has now been described in connection with a number of specific embodiments thereof. However, numerous modifications which are contemplated as falling within the scope of the present invention should now be apparent to those skilled in the art. It is therefore intended that the scope of the present invention be limited only by the scope of the claims appended hereto. In addition, the order of presentation of the claims should not be construed to limit the scope of any particular term in the claims.
This application claims the benefit under 35 U.S.C. 119(e) of U.S. provisional application No. 61/295,688, filed on Jan. 15, 2010. It is also related to provisional application No. 60/860,345, filed on Nov. 20, 2006, provisional application No. 60/993,141, filed on Sep. 10, 2007, and non-provisional application No. 11/986,548, filed on Nov. 20, 2007, now U.S. Pat. No. 7,864,316. All of these applications are herein incorporated by reference.
Number | Date | Country | |
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61295688 | Jan 2010 | US |