Raman mapping of low-content active-ingredient pharmaceutical formulations. part II: statistically optimized sampling for detection of less than 1% of an active pharmaceutical ingredient

Several tablets are prepared with two forms of an active pharmaceutical ingredient (API) of which one (less than 1% w/w) is considered undesirable. The presence of this component is tested for by Raman microscopy in a series of mapping experiments. These experiments are conducted with a statistically based sampling routine in which the number of spectra to collect across the whole surface of a tablet is set so as to theoretically ensure spectral detection of the low-concentration form. Such experiments are then repeated a number of times to achieve approximately 95% confidence that the strictly limited number of sampling points suffice to detect the low-concentration form and that Raman microscopy is technically a reliable method for analytical analysis of this type.     

Raman chemical mapping of low-content active pharmaceutical ingredient formulations. III. Statistically optimized sampling and detection of polymorphic forms in tablets on stability

Several tablets of a formulation containing 1% w/w of the desired active pharmaceutical ingredient (API) form are spiked with minimal amounts of two different anhydrous polymorphs and an amorphous form. The amount of contaminant form was 2.5 to 10% of the total API concentration (0.025 to 0.1% w/w in the tablet), with five spiked tablets prepared. The presence of these contaminant particles are then identified using Raman microscopy/mapping. The entire surface of each of these tablets is Raman-probed through a grid based on our previous proposal (?a?i?, S.; Whitlock, M. Appl. Spectrosc.2008, 62, 916) about the minimal number of spectra to acquire that would guarantee identification of the targeted component (taking into account the limit of detection). All three forms have been clearly identified in the Raman mapping spectra of prepared "calibration" tablets; particularly of note is the 2.5% spike (0.025% w/w in the tablet) of the relatively weakly scattering amorphous form. The same method is then applied to packaged tablets on stability and demonstrates that none of the previously analyzed contaminant forms is detected, hence building confidence that the desired API form does not change during stability testing.     

Use of Raman microscopy and band-target entropy minimization analysis to identify dyes in a commercial stamp. Implications for authentication and counterfeit detection

Raman microscopy was used in mapping mode to collect more than 1000 spectra in a 100 microm x 100 microm area from a commercial stamp. Band-target entropy minimization (BTEM) was then employed to unmix the mixture spectra in order to extract the pure component spectra of the samples. Three pure component spectral patterns with good signal-to-noise ratios were recovered, and their spatial distributions were determined. The three pure component spectral patterns were then identified as copper phthalocyanine blue, calcite-like material, and yellow organic dye material by comparison to known spectral libraries. The present investigation, consisting of (1) advanced curve resolution (blind-source separation) followed by (2) spectral data base matching, readily suggests extensions to authenticity and counterfeit studies of other types of commercial objects. The presence or absence of specific observable components form the basis for assessment. The present spectral analysis (BTEM) is applicable to highly overlapping spectral information. Since a priori information such as the number of components present and spectral libraries are not needed in BTEM, and since minor signals arising from trace components can be reconstructed, this analysis offers a robust approach to a wide variety of material problems involving authenticity and counterfeit issues.     

Scanning electrochemical microscopy. 58. Application of a micropipet-supported ITIES tip to detect Ag+ and study its effect on fibroblast cells

We report the use of a micropipet-supported ITIES (interface between two immiscible electrolyte solutions, also called a liquid/liquid (L/L) or water/oil (W/O) interface) as a scanning electrochemical microscopy (SECM) tip to detect silver ion and explore Ag+ toxicity in living cells. A 1,2-dichloroethane solution containing a commercially available calixarene-based Ag+ ionophore (IV) was injected into a micrometer-size glass pipet to construct an Ag+-selective SECM tip. The local Ag+ concentration, down to the micromolar level, in the vicinity of living fibroblast cells, was monitored by SECM approach curves and through imaging of the uptake and efflux of Ag+ by living fibroblast cells in real time. The results show that several stages of interaction between Ag+ and fibroblast cells exist. Since a number of biological processes of cells are involved with non-redox-active ions, the work presented here provides a new way to explore cell metabolism, drug delivery, and toxicity assessment by SECM.     

Alternating current impedance imaging of high-resistance membrane pores using a scanning electrochemical microscope. Application of membrane electrical shunts to increase measurement sensitivity and image contrast

Whether an individual pore in a porous membrane can be imaged using scanning electrochemical microscopy (SECM), operated in ac impedance mode, is determined by the magnitude of the change in the total impedance of the imaging system as the SECM tip is scanned over the pore. In instances when the SECM tip resistance is small relative to the internal pore resistance, the total impedance changes by a negligible amount, rendering the pore invisible during impedance imaging. A simple solution to this problem is to introduce a low-impedance electrical shunt (i.e., a salt bridge) across the membrane. This principle is demonstrated by imaging polycarbonate membranes (6-12-microm thickness) containing between 1 and 2000 conical-shaped pores (60-nm- and 2.5-microm-diameter openings) using an approximately 1-microm-radius Pt tip. Theory and experiments show that image contrast (the change in ac current measured as the probe is scanned over the pore) is inversely proportional to the total resistance of the membrane and can be increased by a factor of approximately 50x by introducing a low-resistance electrical shunt across the membrane. Remarkably, SECM images of membranes containing a single high-resistance (approximately 1 G Omega) pore can only be imaged by short-circuiting the membrane. Image contrast also becomes independent of membrane resistance when an electrical shunt is used, allowing for more quantitative comparisons of the features in ac impedance images of different membranes.     

The effects of the switch from coal gas to natural gas on the accidental death rate: a study of the U.S.A. and Japan.

As the gas industries in the United States and Japan switched from toxic coal gas to nontoxic natural gas, the incidence of accidental deaths from domestic gas declined dramatically in both nations. Thus, improvements in public health occurred as incidental side effects of business decisions.