Prospects and challenges in the synthesis of zeotype materials

Abstract

The recent emergence of stable, handheld ultrafast (~100 fs) laser sources has opened practical access to fundamentally new classes of nonlinear light-matter interactions for characterization crystallization phenomena. In this work, second order non-linear optical imaging of chiral crystals (SONICC) is investigated as a rapid (up to video rate), selective, and ultra-sensitive all-optical method for high-throughputs studies of active pharmaceutical ingredient (API) crystallization phenomena. SONICC relies on second harmonic generation (SHG), or the frequency doubling of light, which is forbidden in unordered media and most achiral salts, but allowed for the overwhelming majority of chiral crystals. This high specificity to chiral crystals combined with an insensitivity to optical scattering and an enormous (~8 decade) dynamic range of linear quantification open new opportunities for high-throughput screenings.Three proof-of-concept applications of SONICC will be demonstrated for characterization of API formulations; i) polymorph screening from the polarization-dependence of the SHG response, which provides up to 18 unique observables specific to a particular crystal compared to 3 for linear optics, ii) crystallization screening with reliable quantification of trace API crystallinity with sub-parts per million to parts per billion detection limits in powdered APIs and in amorphous polymer formulations (i.e.,4-7 orders of magnitude improvement over most current routine methods for powder analysis), and iii) direct determination of nucleation kinetics within powders and turbid matrices without significant loss of image quality from optical scattering (since only the unscattered incident light contributes to the detected signal). Quantitation and polarization analysis can be performed rapidly with high signal to noise on single crystals less than ~1 µm 3 in size, opening opportunities for performing screenings of hundreds or thousands of conditions with just a few milligrams of purified API when coupled to emerging ultrahigh-throughput microfluidic screening platforms. Furthermore, SONICC is directly compatible with most existing high-throughput screening plates that allow conventional optical imaging without modification. The absence of a background response from disordered media allows the development of simple image analysis algorithms for automated quantification of nucleation rates, crystal growth rates, and activation energies for nucleation.An overview of the methods and analysis will be presented, along with and a critical discussion of the strengths and limitations of SONICC for practical high-throughput screening and a summary of some of the challenges associated with the measurements. In addition, a description will be provided of the basic instrumentation required for SONICC, which is anticipated to be commercially available in the near future through partnership with Formulatrix.This presentation will cover the challenges in the preparation of discrete zeo-type molecular sieves with emphasis on their comp...