Multimodal Nonlinear Optical Imaging for Sensitive Detection of Multiple Pharmaceutical Solid-State Forms and Surface Transformations

Abstract

Two nonlinear imaging modalities, coherent anti-Stokes Raman scattering (CARS) and sum-frequency generation (SFG), were successfully combined for sensitive multimodal imaging of multiple solid-state forms and their changes on drug tablet surfaces. Two imaging approaches were used and compared: (i) hyperspectral CARS combined with principal component analysis (PCA) and SFG imaging and (ii) simultaneous narrowband CARS and SFG imaging. Three different solid-state forms of indomethacin-the crystalline gamma and alpha forms, as well as the amorphous form-were clearly distinguished using both approaches. Simultaneous narrowband CARS and SFG imaging was faster, but hyperspectral CARS and SFG imaging has the potential to be applied to a wider variety of more complex samples. These methodologies were further used to follow crystallization of indomethacin on tablet surfaces under two storage conditions: 30 °C/23% RH and 30 °C/75% RH. Imaging with (sub)micron resolution showed that the approach allowed detection of very early stage surface crystallization. The surfaces progressively crystallized to predominantly (but not exclusively) the gamma form at lower humidity and the alpha form at higher humidity. Overall, this study suggests that multimodal nonlinear imaging is a highly sensitive, solid-state (and chemically) specific, rapid, and versatile imaging technique for understanding and hence controlling (surface) solid-state forms and their complex changes in pharmaceuticals.

Understanding Dissolution and Crystallization with Imaging: A Surface Point of View

“…The storage-induced changes in surface morphology were slower for the tablets stored at 30 °C/75% RH, and many observed particles on these tablets had needle-like morphology. 18 …”

“…The separation between green and yellow regions is based on the intensity ratios of CARS peaks at 1652 and 1676 cm –1 so that the regions having SFG activity and the CARS peak at 1652 cm –1 are colored green (α-indomethacin), and the regions having SFG activity and CARS peak at 1676 cm –1 are colored yellow (ε-indomethacin). Panel (a) has been reprinted with permission from Novakovic et al 18 Copyright 2017 American Chemical Society. am = amorphous.…”

“…The surface crystallization of the amorphous indomethacin tablets during storage was also imaged. 18 Briefly, the tablets stored at lower humidity crystallized predominately to the γ-indomethacin, whereas the tablets stored at higher humidity crystallized mostly to the α-form. Some small areas of the nondominant polymorph, not detected with ATR-FTIR or Raman spectroscopies, were also observed.…”

Discriminating polymorph distributions in pharmaceutical tablets using stimulated Raman scattering microscopy

“…Over the last decades, coherent Raman imaging techniques such as coherent anti‐Stokes Raman scattering (CARS) and stimulated Raman scattering (SRS) have emerged, taking advantage of the high (×10 6 ) enhancement due to the coherent addition of the vibrational emitters . These techniques have spread over many fields to image cells, tissues, plants, cosmetics, nanoparticle drugs, and pharmaceutical compounds . However, only one study has been reported on polymorph imaging and identification using CARS .…”

Calibration-Free Second Harmonic Generation (SHG) Image Analysis for Quantification of Trace Crystallinity Within Final Dosage Forms of Amorphous Solid Dispersions

“…Complementary NLO methods including coherent anti-Stokes Raman (CARS) imaging involving interactions from multiple beams have also been demonstrated for compositional analysis of pharmaceutical materials. 31,32 In general, CARS lacks the symmetrydictated selectivity of even-ordered NLO processes, although multimodal imaging integrating both SHG and CARS has the potential to recovers such information. 32 Despite successes in detection, precise quantification of residual crystallinity by SHG continuously spanning a wide dynamic range of crystalline content remains challenging.…”