Ab Initio Prediction of the Diversity of Second Harmonic Generation from Pharmaceutically Relevant Materials

Abstract

A model for predicting the anticipated second harmonic generation (SHG) activity of crystalline active pharmaceutical ingredients (APIs) was developed based on combining time-dependent Hartree−Fock calculations of the molecular building block with analytical theory for the predicted intensity from the lattice. Predicted trends agreed well overall with experimental measurements for 18 representative APIs. Inspection of the SHG images suggests that outliers from the predicted trends likely arose from the presence of trace SHG-active metastable crystal forms not considered in the predictions. The success of this relatively simple computational approach suggests a route for reliably predicting the anticipated SHG activities of API target molecules, which in turn can serve to indicate their potential compatibility with analysis by SHG.

Parts per Million Powder X-ray Diffraction

“…Fortuitously, previous experiments have shown a 7 orders of magnitude detectable dynamic range for the observed SHG intensity of 42 different APIs under comparable imaging conditions. 36 The SHG activity of RTV falls in the midrange of this scale, suggesting viable detection for the majority of homochiral crystalline APIs. From previous studies of common excipients, it is reasonable to suggest that the approach described herein will have few constraints arising from the selection of polymer matrices in amorphous solid dispersions.…”

“…The coverslips were then mounted on the goniometer for combined SHG and XRD analysis. RTV was chosen as a representative model system, in part because it exhibits midrange SHG activity compared to a suite of small molecule APIs 36 and the polymorphic purity of the commercial product is well established. 37 The RTV was used as received from the manufacturer.…”

Imaging the Nonlinear Susceptibility Tensor of Collagen by Nonlinear Optical Stokes Ellipsometry

“…In the experiments described in this work, the c ð2Þ l of the fiber can be measured, while the molecular tensor b ð2Þ of the triple helix is challenging to unambiguously access experimentally. Previous work has shown good agreement between ab initio predictions of molecular nonlinear susceptibility tensors, b ð2Þ and experimental results (36,42). Consequently, theoretical predictions of b ð2Þ for a single collagen triple helix were combined with experimental methods to determine c ð2Þ l for a fiber, for us to gain insight into helical organization within a fiber.…”

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

“…The most likely source of the background SHG is the microcrystalline cellulose, from which weak SHG activity has been reported previously. 28 Native cellulose as generated biologically has been shown to be SHG-active. 39 While the cellulosic materials commonly used as excipients in pharmaceutical formulations generally undergo substantial treatments before use, residual weak SHG from a sparse population of locally ordered domains may potentially contribute to the observed background.…”