Single Particle Nonlinear Optical Imaging of Trace Crystallinity in an Organic Powder

Abstract

Microscopic characterization of crystallinity in powders can reveal information lost in ensemble-averaged measurements. Nonlinear optical imaging based on second harmonic generation (SHG) provides rapid and highly selective detection of individual chiral microcrystals, enabling insights into the fundamental mechanism of action for the observed crystallinity loss of an organic powder induced by mechanical grinding. Using griseofulvin as the model compound, the results from second order nonlinear optical imaging of chiral crystals (SONICC) compared favorably with those of powder X-ray diffraction (PXRD) over the linear dynamic range of the PXRD measurements. However, the SHG measurements demonstrated three decade improvements in linear dynamic range. The detection limit of SHG was estimated to be 4 ppm crystallinity in the powder. The rate of crystallinity loss induced by milling followed a first order process with a half-life of 15 ± 1 min. Recrystallization of cryomilled powder is ~40 times faster than that prepared by melt-quenched powder, suggesting that the disordered state obtained by exhaustive cryomilling appears to contain ordered domains that are larger than the critical nucleation size, but below the detection limit of SONICC. The presence of such domains provides a barrier-less nucleation source resulting in rapid crystallization, the kinetics of which depends only on crystal growth.

Water–solid interactions in amorphous maltodextrin-crystalline sucrose binary mixtures

“…The majority of chiral crystals, when in the presence of intense optical electromagnetic fields, will produce SHG, which is the frequency-doubling of the incident light 34 . The custom-built SONICC instrument utilizes beam scanning with a resonant vibrating mirror (Electro-Optical Products, 8 kHz) on the fast-axis, and a galvanometer (Cambridge Technologies) for slow-axis scanning, significantly reducing the possibility of laser-induced photo-damage 35 . The instrument was configured to acquire 200 sweeps per line with the laser for four fields of view via an automated xyz stage (Prior Scientific OptiScan).…”

“…The signals were amplified with Ortec 9305 amplifiers, directed into photon-counting cards (PMS− 400A, Becker and Hickl GmbH). The acquisition software utilized Labview, and the images acquired were analyzed using ImageJ software 35,36 . Five z-planes were acquired for each field of view of 600 × 600 µm with a 10×objective (Nikon 0.3 NA).…”

Selective Imaging of Active Pharmaceutical Ingredients in Powdered Blends with Common Excipients Utilizing Two-Photon Excited Ultraviolet-Fluorescence and Ultraviolet-Second Order Nonlinear Optical Imaging of Chiral Crystals

“…17, 18 Each technique has its own strengths and limitations, including: a relatively high limit of detection for XRPD (>~1% typically), 5, 19 long analysis times for NMR, 16 interference by excipients and subsampling with Raman, 13, 20, 21 relatively small fields of view and the inability to probe sub-surface details for SEM. 1,7,10,22 Consequently, sensitive detection of crystallinity at low loadings deep within tablets and powders represents an important niche not easily addressed by existing common methodologies.…”

“…19, 29, 30 Initial investigations of APIs, specifically griseofulvin, produced high signal to noise (on the order of 10,000:1) with low excitation powers (25–75 mW), with both kinetics and trace crystallinity probed. 19 SONICC, utilizing second harmonic generation (SHG), relies on the frequency doubling of light upon the interaction with non-centrosymmetric crystals of specific classes, which include most chiral crystals. 31 Previously, ensemble-averaged SHG was utilized as a tool for monitoring API distributions.…”

Drop printing of pharmaceuticals: Effect of molecular weight on PEG coated‐naproxen/PEG 3350 solid dispersions

“…It is a useful tool for the examination of crystalline samples, allowing for high signal-to-noise measurements, with low limits of detection. 22–24 SHG involves the frequency-doubling of light upon interaction with certain classes of noncentrosymmetric crystals. 23 It has recently been applied to quantify crystallinity without the need for any additional sample processing.…”