Multicomponent Chemical Imaging of Pharmaceutical Solid Dosage Forms with Broadband CARS Microscopy

Abstract

We compare a coherent Raman imaging modality, broadband coherent anti-Stokes Raman scattering (BCARS) microscopy, with spontaneous Raman microscopy for quantitative and qualitative assessment of multicomponent pharmaceuticals. Indomethacin was used as a model active pharmaceutical ingredient (API) and was analyzed in a tabulated solid dosage form, embedded within commonly used excipients. In comparison with wide-field spontaneous Raman chemical imaging, BCARS acquired images 10× faster, at higher spatiochemical resolution and with spectra of much higher SNR, eliminating the need for multivariate methods to identify chemical components. The significant increase in spatiochemical resolution allowed identification of an unanticipated API phase that was missed by the spontaneous wide-field method and bulk Raman spectroscopy. We confirmed the presence of the unanticipated API phase using confocal spontaneous Raman, which provided spatiochemical resolution similar to BCARS but at 100× slower acquisition times.

Mapping Chemistry, Composition, and Dynamics with Coherent Raman Imaging

“…Examples in biology include mechanisms of intercellular signaling [9], and adhesion strategies of mollusks [10]. We have also been able to use this imaging modality to chemically map pharmaceutical preparations, finding rare, but potentially important features in drug phase that were not visible to spontaneous Raman imaging due to their small size [11].In addition to chemical contrast, it appears that it will be possible to derive a contrast mechanism based on materials dynamics from CRI methods. Recent advances in our understanding of motion in solids allows us to predict dynamic properties of these systems over 12 orders of magnitude in time with just a few parameters derived from picosecond timescale measurements [12].…”

Coherent anti-Stokes Raman scattering microscopy for pharmaceutics

“…These techniques are capable of determining the relative stability of polymorphs by investigating the energies involved in phase changes between various polymorphs [33]. Thermal analysis is based on the principle that a physical change in a material is associated with a release or absorption of heat.…”

“…Fussell et al [31] extended this dissolution concept by building an intrinsic flow-through dissolution setup which allowed correlation of surface solid-state changes occurring during dissolution with changes in drug dissolution rate. Slipchenko et al [32] and Hartshorn et al [33] focused on studying complex oral dosage forms containing APIs combined with a number of excipients.…”

“…Hartshorn et al [33] applied broadband CARS. Both groups reported that their respective optical techniques were capable of rapidly imaging the distribution of the API and excipients on the surface of the tablet.…”

Contrast in coherent Raman scattering microscopy

“…Second, narrowband CARS signals are typically detected on monolithic detectors such as photomultiplier tubes (PMTs) and bulk photodiodes (PDs). These detectors have bandwidths on the order of tens to hundreds of megahertz, allowing exceptionally fast imaging, while even the best broadband CARS microscope is limited to read-out speeds of about 10 kilohertz [66].…”