Optics: measuring and testing – By dispersed light spectroscopy – With raman type light scattering
Reexamination Certificate
2003-01-09
2003-11-25
Font, Frank G. (Department: 2877)
Optics: measuring and testing
By dispersed light spectroscopy
With raman type light scattering
C356S309000, C356S073000
Reexamination Certificate
active
06654118
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method and apparatus for the analysis of pharmaceutical specimens. More particularly, to a method and apparatus for nondestructively obtaining the molecular data for a chemical component on the surface of or within the matrix of a pharmaceutical specimen.
BACKGROUND OF THE INVENTION
For analyzing a pharmaceutical specimen, it would be useful to be able to simultaneously determine the position for a chemical component on the surface or within the matrix of the specimen and its corresponding molecular data. Such position-related data could be used as the baseline profile for the pharmaceutical specimen at a given time and could allow analysis at a later time to determine changes of the chemical composition of the specimen. Information gained from analysis of a chemical profile could aid a pharmaceutical formulator in identifying any needed refinements to the formulation or manufacturing process. Additionally, it is desirable to examine the pharmaceutical specimen before and after selected manufacturing steps and at various timepoints during a stability study. Therefore, a nondestructive and reproducible analysis method is needed.
Some of the currently used analysis methods provide information on either the physical structure or elemental components of surface defects. Commonly used non-destructive structural analysis techniques include light microscopy (LM), infrared (IR) absorption spectroscopy and scanning electron microscopy (SEM).
LM is a comparatively simple technique that provides a relatively low resolution image of a specimen and can be used to detect surface particles of about 0.5 microns in diameter. LM enables locating a small area on the surface of a pharmaceutical specimen from which molecular data may obtained from the surface or from within the matrix of the specimen. LM has limited use in a pharmaceutical application, though, because it is not possible to find and focus on a single submicron chemical component. Manually searching for a small area using a microscope is extremely difficult, if not impossible for a smaller target within the region, with submicron targets simply not visible by light microscopy.
The technique of IR absorption spectroscopy is a commonly-used nondestructive technique for obtaining molecular identification of materials. IR absorption spectroscopy involves detecting molecular vibrations, or vibrations characteristic of atoms which are bonded together. Incident radiation which has the same frequency as a molecular vibration in the material is absorbed. The result of the measurement is typically a plot of transmitted radiation intensity versus wavenumber (reciprocal of wavelength) of the radiation, showing many transmission dips corresponding to vibrational mode frequencies. Coupling between vibrations involving different parts of a molecule results in a complex spectrum which provides a distinctive signature for the particular chemical compound and phase being measured. However, the water peak typically present using the IR technique limits the usefulness of IR in obtaining molecular data from a pharmaceutical specimen. Another problem with the IR technique is the spot size of the incident beam. Wavelengths of the vibrations used for identification of most chemical compounds are in the mid-infrared range, from approximately 2 microns to 25 microns. Because the wavelength of the incident radiation must match that of the vibrations to obtain an absorption spectrum, the incident radiation used in IR absorption measurements is also in the wavelength range of 2 microns to 25 microns. The spot size of a beam of radiation is related to its wavelength such that the lower limit of the spot size is on the order of the wavelength. Therefore, the area illuminated by the incident radiation in an IR absorption measurement and the area from which the resulting absorption signal is collected can be on the order of 25 microns in diameter. Because many of the chemical components of a pharmaceutical specimen are of submicron size, this illumination area is much too large for isolation of a particular element for analysis. To be useful for analysis of submicron-sized particles, an illumination area having a diameter of less than one micron is needed. Accordingly, the use of the typical infrared means of detection, IR absorption spectroscopy, is also limited in a pharmaceutical application because the water peak can obscure or hide spectra of interest and the area from which molecular data is collected is not small enough.
In SEM, a beam of primary electrons is directed at the surface of a specimen and emitted secondary electrons are detected in order to form a topographical image of the surface at a higher resolution than LM. Pharmaceutically interesting SEM subjects are nearly always nonconductive to the SEM beam, though, unless conductively coated. The conductive coating provides a source of secondary electrons that are excited by the primary SEM beam and subsequently detected to provide the surface image. The conductive coating material, however, obscures the surface of a pharmaceutical specimen and prevents obtaining molecular data from the specimen's surface. The coating also prevents obtaining molecular data from within the matrix of the specimen. Additionally, SEM requires that the specimen be placed in a vacuum chamber. The vacuum chamber is maintained at a negative pressure of up to 10
−5
Torr to remove any water vapor and, thus, reduce distortion. As a result of the vacuum, however, the specimen becomes dehydrated and cannot be used for analysis again at a later date. Standard SEM is therefore only useful for topographic analysis, with limited usefulness for reproducibly obtaining molecular data from the surface or within the matrix of a pharmaceutical specimen.
Another topographic analysis technique is scanning probe microscopy (SPM). SPM comprises a family of techniques in which a probe is held extremely close to a surface and scanned with high resolution and accuracy (tenths of nanometers). Some interaction between the probe and the surface is then measured. In the case of scanning tunneling microscopy, for example, tunneling current is measured. Another commonly used SPM technique in structural characterization is atomic force microscopy (AFM), in which the force between the probe and surface is measured. Typical applications include measurement of roughness, pinholes and other topographical features on a specimen. SPM techniques and applications have limited usefulness, though, for obtaining molecular data from the surface or within the matrix of a pharmaceutical specimen.
Other nondestructive techniques commonly used for elemental analysis include Auger emission spectroscopy (AES) and X-ray fluorescence spectroscopy (XRF). Like SEM techniques, AES techniques involve directing a beam of primary electrons at the specimen. Instead of forming an image using detected secondary electrons emitted by atoms on the upper surface, AES techniques measure the energy levels of the emitted electrons to determine elemental components of surface structures. In XRF techniques, a beam of primary X-rays is directed at the surface and the energy levels (or corresponding wavelengths) of resultant secondary X-rays emitted by atoms of elements on and just under the surface are measured. Atoms of elements in target materials emit secondary X-rays with uniquely characteristic energy levels (or corresponding wavelengths). Thus the elemental components of materials on and just under the surface may be determined from the measured energy levels (or wavelengths) of emitted secondary X-rays. The techniques for elemental analysis also have limited usefulness for obtaining the type of detailed chemical component data (i.e., other than elemental data) needed for pharmaceutical applications. For example, a technique such as AES or XRF might identify the presence of a chemical element on a surface, but would not be able to determine the molecular data for chemical components in a subsurface layer having a different
Font Frank G.
Lauchman Layla
Ortho-McNeil Pharmaceutical , Inc.
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