Solid materials with multiple observable phases can restructure in response to a change in temperature, fundamentally altering the materials' properties. This temperature-mediated solid transformation occurs primarily because of a difference in entropy between the two crystal forms. In this study, we examine for the first time the ability of classical point-charge molecular dynamics simulations to compute entropy and enthalpy differences between solid forms of a range of organic molecules and ultimately predict temperaturemediated restructuring events. Twelve polymorphic organic small molecule systems with known temperature-mediated transformations were modeled with the point-charge OPLS-AA potential. Relative entropies and free energies between different solid forms were estimated by computing the stability as a function of temperature from 0 K up to ambient conditions using molecular dynamics simulations. These simulations correctly found the experimental high temperature solid form to have an entropy larger than that of the low temperature form in all systems examined. The magnitude of the temperature/entropy contributions to the free energy at ambient conditions is generally larger than the change in enthalpy difference. We also find that free energy differences between polymorphs computed with a less expensive quasi-harmonic approximation are within 0.07 kcal•mol −1 at all temperatures up to 300 K in the small rigid molecules examined. However, the molecular dynamics free energies deviate from the quasi-harmonic approximation in the more flexible molecules and systems with disordered crystals by as much as 0.37 kcal•mol −1 . Finally, we demonstrate that at ambient conditions multiple lattice energy minima can convert into the same crystal ensemble due to easily kinetically accessible transitions between similar structures when thermal motions are present.

ergy differences as large as 0.5 kcal/mol between unit and supercells loosely correlated with differences in anisotropic thermal expansion. These larger system sizes are computationally more accessible because our cheaper 1D variant of anisotropic QHA, which gives free energies within within 0.02 kcal/mol of the fully anisotropic approach at all temperature studied. The errors between MD and experiment are 1-2 orders of magnitude larger than those seen between QHA and MD, so the quality of the force field used is still of primary concern, but this study illustrates a number of other important factors that must be considered to obtain quantitative organic crystal thermodynamics.

Direct-acting antiviral regimens have transformed therapeutic management of hepatitis C across all prevalent genotypes. Most of the chemical matter in these regimens comprises molecules well outside the traditional drug development chemical space and presents significant challenges. Herein, the implications of high conformational flexibility and the presence of a 15-membered macrocyclic ring in paritaprevir are studied through a combination of advanced computational and experimental methods with focus on molecular chameleonicity and crystal form complexity. The ability of the molecule to toggle between high and low 3D polar surface area (PSA) conformations is underpinned by intramolecular hydrogen bonding (IMHB) interactions and intramolecular steric effects. Computational studies consequently show a very significant difference of over 75 Å 2 in 3D PSA between polar and apolar environments and provide the structural basis for the perplexingly favorable passive permeability of the molecule. Crystal packing and protein binding resulting in strong intermolecular interactions disrupt these intramolecular interactions. Crystalline Form I benefits from strong intermolecular interactions, whereas the weaker intermolecular interactions in Form II are partially compensated by the energetic advantage of an IMHB. Like Form I, no IMHB is observed within the receptor-bound conformation; instead, an intermolecular H-bond contributes to the potency of the molecule. The choice of metastable Form II is derisked through strategies accounting for crystal surface and packing features to manage higher form specific solid-state chemical reactivity and specific processing requirements. Overall, the results show an unambiguous link between structural features and derived properties from crystallization to dissolution, permeation, and docking into the protein pocket.

We present a novel approach to efficiently implement thermal expansion in the quasiharmonic approximation (QHA) for both isotropic and more importantly, anisotropic expansion. In this approach, we rapidly determine a crystal's equilibrium volume and shape at a given temperature by integrating along the gradient of expansion from zero Kelvin up to the desired temperature. We compare our approach to previous isotropic methods that rely on a brute-force grid search to determine the free energy minimum, which is infeasible to carry out for anisotropic expansion, as well as quasi-anisotropic approaches that take into account the contributions to anisotropic expansion from the lattice energy. We compare these methods for experimentally known polymorphs of piracetam and resorcinol and show that both isotropic methods agree to within error up to 300 K. Using the Grüneisen parameter causes up to 0.04 kcal/mol deviation in the Gibbs free energy, but for polymorph free energy differences there is a cancellation in error with all isotropic methods within 0.025 kcal/mol at 300 K.Anisotropic expansion allows the crystals to relax into lattice geometries 0.01-0.23 kcal/mol lower in energy at 300 K relative to isotropic expansion. For polymorph free energy differ-ences all QHA methods produced results within 0.02 kcal/mol of each other for resorcinol and 0.12 kcal/mol for piracetam, the two molecules tested here, demonstrating a cancellation of error for isotropic methods.We also find that when expanding in more than a single volume variable, there is a nonnegligible rate of failure of the basic approximations of QHA. Specifically, while expanding into new harmonic modes as the box vectors are increased, the system often falls into alternate, structurally distinct harmonic modes unrelated by continuous deformation from the original harmonic mode. arXiv:1712.00936v3 [cond-mat.mtrl-sci]

Cell-based therapies are emerging as the next frontier of medicine, offering a plausible path forward in the treatment of many devastating diseases. Critically, current methods for antigen positive cell sorting lack a high throughput method for delivering ultrahigh purity populations, prohibiting the application of some cell-based therapies to widespread diseases. Here we show the first use of targeted, protective polymer coatings on cells for the high speed enrichment of cells. Individual, antigen-positive cells are coated with a biocompatible hydrogel which protects the cells from a surfactant solution, while uncoated cells are immediately lysed. After lysis, the polymer coating is removed through orthogonal photochemistry, and the isolate has >50% yield of viable cells and these cells proliferate at rates comparable to control cells. Minority cell populations are enriched from erythrocyte-depleted blood to >99% purity, whereas the entire batch process requires 1 h and <$2000 in equipment. Batch scale-up is only contingent on irradiation area for the coating photopolymerization, as surfactant-based lysis can be easily achieved on any scale.