Mid-Infrared Photothermal Imaging of Active Pharmaceutical Ingredients at Submicrometer Spatial Resolution

Abstract

Chemical imaging with sufficient spatial resolution to resolve microparticles in tablets is essential to ensure high quality and efficacy in controlled release. The existing modalities have the following disadvantages: they are time-consuming or have poor spatial resolution or low chemical specificity. Here, we demonstrate an epi-detected mid-infrared photothermal (epi-MIP) microscope at a spatial resolution of 0.65 μm. Providing identical spectral profiles as conventional infrared spectroscopy, our epi-MIP microscope enabled mapping of both active pharmaceutical ingredients and excipients of a drug tablet.

All-digital histopathology by infrared-optical hybrid microscopy

“…The concept of dynamic photothermal changes in morphology (34,35), force (36,37), or near-field coupling (38)(39)(40), using an atomic force microscope cantilever as local probe, has been reported for point-by-point IR measurements. Noncontact optical photothermal microscopy is more recent (41)(42)(43)(44)(45)(46)(47)(48)(49)(50) and typically utilizes a local IR illumination coincident with a highly focused visible probe beam to measure local refractive index change by beam scattered out of the angular acceptance of the objective lens. This method has been applied to chemical imaging of tissue and live cells (44,46,47), bacteria (48), and pharmaceutical tablets (49).…”

“…Noncontact optical photothermal microscopy is more recent (41)(42)(43)(44)(45)(46)(47)(48)(49)(50) and typically utilizes a local IR illumination coincident with a highly focused visible probe beam to measure local refractive index change by beam scattered out of the angular acceptance of the objective lens. This method has been applied to chemical imaging of tissue and live cells (44,46,47), bacteria (48), and pharmaceutical tablets (49). These point-scanning approaches, just as for point scanning FT-IR spectroscopy, involve long scan times (51).…”

Infrared Spectroscopy and Imaging at Nanometer Scale

“…This technique has been recently applied to image lipids and proteins of living cells, 45 polymer-coated MEMS device, 47 polymer particle, 48 and compounds mixtures like pharmaceutical drugs. 46 Although the technique cannot provide sub-100 nm spatial resolution, the technique is readily adaptable to routine confocal microscopy instrumentation. Figure 8 shows an example of the application of PTLM technique to visualize inhibitors and lipids in a single cell.…”

High-resolution infrared imaging of biological samples with third-order sum-frequency generation microscopy

“…The dimensions of this interaction volume are roughly equal to the diffraction-limited spot size of the tightly focused visible laser beam, thus offering a sub-µm imaging resolution. Recent implementations of the photothermal MIR microscopy technique have reached a lateral resolution in the 0.6 µm range [16,17], which is about an order of magnitude better than the resolution set by the IR-diffraction limit of the same lens.…”

“…[13,14] Another technique uses a secondary visible laser beam to probe the MIR-induced photothermal effect in the sample. [15][16][17] The heat induced refractive index changes in the sample affect the beam properties of the visible beam upon traversing the specimen, which can be captured with a visible photodetector. In both approaches, expensive MIR detectors can be avoided and replaced by more efficient and cost effective detectors in the visible/NIR.…”