Kinetic Trapping of Metastable Amino Acid Polymorphs

Abstract

Second harmonic generation (SHG) microscopy measurements indicate that inkjet-printed racemic solutions of amino acids can produce nanocrystals trapped in metastable polymorph forms upon rapid solvent evaporation. Polymorphism impacts the composition, distribution, and physico-kinetic properties of organic solids, with energetic arguments favoring the most stable polymorph. In this study, unfavored noncentrosymmetric crystal forms were observed by SHG microscopy. Polarization-dependent SHG measurement and synchrotron X-ray microdiffraction analysis of individual printed drops are consistent with formation of homochiral crystal production. Fundamentally, these results provide evidence supporting the ubiquity of Ostwald’s Rule of Stages, describing the hypothesized transitioning of crystals between metastable polymorphic forms in the early stages of crystal formation. Practically, the presence of homochiral metastable forms has implications on chiral resolution and on solid form preparations relying on rapid solvent evaporation.

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

“…Recent studies of metastable homochiral crystallization from racemic solutions supports the relative ease with which such unfavored crystal forms can be routinely produced. 33 This argument is further supported by the much weaker SHG response observed from crystals of the achiral molecule loratadine, which occupies a centrosymmetric C 2c space group and has no viable pathway to produce metastable homochiral crystal forms. Measurements for loratadine, which forms a centrosymmetric and SHG-inactive lattice, were also included to indicate the lower noise-floor limits of the instrument.…”

Orodispersible films: Towards drug delivery in special populations

“…Newman and colleagues recently employed Second Harmonic Generation (SHG) microscopy-guided synchrotron powder X-ray diffraction to detect 100 ppm crystalline ritonavir in a hydroxypropyl methylcellulose (HPMC) matrix (Newman et al, 2015), while SHG microscopy-coupled confocal Raman spectroscopy enabled analysis of trace crystallites of paclitaxel in lyophilized Abraxane powder . Such analyses on printed films probably offer solid-state distribution in printed dots and their homogeneity (Chowdhury et al, 2014).…”

Synchronous-digitization for video rate polarization modulated beam scanning second harmonic generation microscopy

“…All experiments were performed on a custom built microscope described in detail previously 9,13–15 . In short, a 80 MHz ~100 fs MaiTai Ti:Sapphire laser (SpectraPhysics) operating at 800nm was used, with average powers between 20–220mW at the sample.…”

“…Polarization based SHG imaging has also seen success in characterization of inorganic materials 7–9 , in surface analysis 10,11 and crystal domain imaging 12 .…”