This is the fourth contribution to NILQ's Reflections on Teaching series.

The solvent is the most important external influence on crystal morphology. Correctly interpreting solvent effects is essential to engineer the desired crystal morphology with specific properties. In this study, we propose a method based on quantum mechanical calculated gas phase interaction + Solvation Model Based on Density (SMD) calculated solvation free energy to predict the solvent‐modified bond energies to predict the morphology of crystals grown from solvents. We also calculate the solvent‐modified bond energy by combining molecular force fields, including the Generalized Amber Force Field and the Coulomb–London–Pauli force field (to calculate gas phase interaction) and SMD (to calculate solvation free energy). We validate these methods using mechanistic models to predict morphologies of four crystals grown from various solvents. Good agreement between the predicted crystal morphologies and the experimental results indicates the reliability of the proposed methods.

Steps play a crucial role in growth of crystal faces. The step velocity is a critical parameter within the growth models and is a function of the density of kinks, which are the most favorable sites of attachment along crystal steps. In this article, we introduce a symbolic-numerical computational tool to generalize the Simplified Steady-State Framework (SSSF), introduced in our earlier articles, to nonequilibrium kink density calculations for crystals with any number of molecules in the unit cell. The tool employs a graph theoretic approach for representation of the crystal surface kinetics, which allows digital implementation of the method for molecules of API complexity. The SSSF is based on identifying a small subset of most-probable surface events which dominate the surface kinetics. Our new model replaces Boltzmann statistics for kink density modeling with a fully nonequilibrium model that captures both the surface correlations between sites (via the use of conditional probabilities) as well as their dependence on supersaturation. The digital tool demonstrates the versatility of the theory for providing key growth parameters within crystal growth models for a wide range of crystals. The tool was successfully used to predict the crystal morphology for three organic compounds with four molecules in the unit cell, one forming platelets and the other two needle-like crystals.

A workflow for the digital design of crystallization processes starting from the chemical structure of the active pharmaceutical ingredient (API) is a multi-step, multi-disciplinary process. A simple version would be to first predict the API crystal structure and from it the corresponding properties of solubility, morphology, and growth rates, assume that the nucleation would be controlled by seeding, and then use these parameters to design the crystallization process. This is usually an over-simplification as most APIs are polymorphic, and the most stable crystal of the API alone may not have the required properties for development into a drug product. This perspective, from the experience of a Lilly Digital Design project, considers the fundamental theoretical basis of crystal structure prediction (CSP), free energy, solubility, morphology and growth rate prediction, and the current state of nucleation simulation. This is illustrated by applying the modeling techniques to real examples, olanzapine and succinic acid. We demonstrate the promise of using ab initio computer modeling for solid form selection and process design in pharmaceutical development. We also identify open problems in the application of current computational modeling and achieving the accuracy required for immediate implementation that are currently limiting the applicability of the approach.

Kink sites are a fundamental characteristic of steps found on crystals growing in layered regimes. For asymmetric organic molecules, kink densities are usually modeled at equilibrium, owing to a lack of understanding of nonequilibrium kink density behavior. Hence, crystal growth models approximate kink density at its equilibrium value despite observations showing its strong dependence on supersaturation. In this work, we develop a simplified steady-state framework for obtaining nonequilibrium kink densities and propose a pathway for predicting step velocity as a function of kink density for molecular crystals with Z = 2 growth units in the unit cell. The kink density and step velocity predictions are validated with kinetic Monte Carlo (kMC) simulation data from the literature. The overarching goal is translation of the framework to provide rapid predictions of crystal properties such as crystal shape, morphology, and size distribution.

This article reports innovations in mechanistic modeling and simulation approaches for noncentrosymmetric molecular crystals with two growth units in the unit cell (Z = 2). A simplified steady-state framework considers the kinetics of most likely surface processes to predict nonequilibrium kink densities and step velocities. Kinetic Monte Carlo methods are utilized to simulate the evolution of growing crystal surfaces and capture dynamic step behavior. These approaches are compared quantitatively for their predictions of kink densities and step velocity with respect to interaction anisotropy and supersaturation. The approaches are applied to morphology predictions of an active pharmaceutical ingredient, trimethoprim, followed by a detailed comparative analysis.

Crystal morphologies are governed by growth conditions, such as supersaturation and temperature, as well as by the bonding structures of growth units within the crystal lattice. The vast majority of organic crystals of interest exhibit noncentrosymmetric growth units, which feature anisotropic bonding interactions. Bonding anisotropy results in the presence of multiple distinct growth units within the unit cell that generate complex periodic bond chains and introduce edge stability phenomena, presenting a significant challenge for contemporary morphology prediction tools. Previous work has reported the use of kinetic Monte Carlo (kMC) simulations to predict the morphologies of organic centrosymmetric crystals. In this article, we consider the case of noncentrosymmetric molecules with two distinct growth units present in the unit cell (Z = 2). kMC simulations offer insight into noncentrosymmetric phenomena and provide a route to calculate relevant parameters such as step velocities and face growth rates as functions of the crystal anisotropy for different edge configurations. We employ these approaches to predict the crystal morphology of a triclinic polymorph of piracetam and discuss the extension of this approach to additional cases. We also discuss challenges inherent to modeling and simulating noncentrosymmetric crystal growth and explore rate rescaling techniques to accelerate rare event sampling and minimize computational requirements.

In this contribution the single crystal growth rates of four para substituted benzoic acids measured in toluene and isopropyl alcohol solutions are reported. Major objectives of the work have been to consider how such data might be correctly compared and how such comparisons may be related to underlying packing arrangements in the respective crystal structures. Morphological determinations formed an important part of the overall study. Consideration has been given to various practical issues arising from the varying solubility of the materials and growth rate dispersion among the measured crystal seeds. This provides suggestions as how best to measure growth rates for this purpose. The ultimate aims of such work have been to explore connections between growth and nucleation kinetics as well as to consider what such a data set might predict about the kinetics of other related molecules.

Foreign molecules in solution often disrupt crystal growth mechanisms and alter the crystal morphology. In this article, we predict crystal morphologies for molecules of interest by combining step velocity model theory, kinetic Monte Carlo simulations, and existing visualization frameworks. We first validate the methodology by comparing simulation results to verified step velocity models for crystal growth systems without impurities present. We then introduce impurities (both thermoneutral and energetically attractive/repulsive) to the system and examine the change in step behavior to inform impurity-mediated crystal growth models. We demonstrate the approach with a visualization of morphology for the centrosymmetric molecule naphthalene grown under a variety of growth conditions, including from impure solutions. We comment on the applicability of this approach for more complex structures, including noncentrosymmetric molecular growth units.

This work uses a dual absolute chemical potential route with a centroid reference for the dissolved molecules and an Einstein crystal reference for the solid. We use these calculations to predict the vapour pressure, solubility limit, and chemical potential driving forces for crystallization of napthalene (large and rigid) and succinic acid (floppy and anharmonic). We examine each source of error in the free energy calculations and demonstrate that the chemical potentials can be computed with an overall precision of ca. 0.05 kcal/mol, leading to solubility predictions with precision of ca. 10%. The precise calculations should facilitate studies of nucleation kinetics, growth kinetics, and efforts to develop accurate force fields.

All-atom force fields are important for calculating interaction energies between growth units to predict crystal morphology. Our group at UCSB developed the ADDICT morphology design software to predict crystal morphology using mechanistic growth models driven by the generalized Amber force field (GAFF). In this study, the universal force field (UFF), the consistent force field (CFF), and the Coulomb-London-Pauli (CLP) force field are incorporated into ADDICT. We systematically test the lattice energies and crystal morphologies of olanzapine, adipic acid, rubrene, biphenyl, and naphthalene using all these force fields. The unit cells for these crystals are represented by the original CSD experimental structure, as well as optimized structures. Considering the high accuracy of CLP, its wide range of applications, and the fact that ADDICT can automatically specify the atomic charge and type required for this force field, we find that CLP is the best all-atom model to drive morphology calculations.

Abstract In the first volume of this Yearbook, Professor Sevenster assessed the potential for Member States to maintain or introduce national measures more stringent than those in a European Community (EC) harmonization measure under Article 95(4)–(6) EC shortly after the entry into force of the Treaty of Amsterdam, and questioned whether it represented an example of the ‘Emperor ‘s New Clothes ‘. :is article revisits the provisions some seven years later and through focusing on their interpretation and application in the intervening period aims to assess the reality of the protections provided. It briefly outlines the genesis of the Treaty provisions in the Single European Act (SEA) and their major reform in the Treaty of Amsterdam (ToA).

Crystals with asymmetric growth units present a ubiquitous challenge for modeling crystal growth. We derive the crystal step edge velocity for steps with alternating rows of growth units (i.e., a row of A followed by a row of B growth units). We construct a free energy model for 1D nucleation of this two-tiered row and show that a single anisotropic interaction parameter and the supersaturation characterize the edge stability. A Fokker–Planck model captures the kinetics of nucleation and seamlessly connects the stable and unstable regimes, whereas previous models diverge near the transition between these cases. The 1D nucleation model leads to an expression that predicts the step velocity as a function of supersaturation and edge stability. We show that the model is in excellent agreement with kinetic Monte Carlo simulations.

Chemical engineering industrial practice has always forged ahead of chemical engineering science to cre-ate new processes and products driven mostly by the pull of society's desire for improved quality of life. The resulting processes have often left room for advances in process systems engineering and in chem-ical engineering science to explain subtle aspects of the chemical technologies, thereby leading the way to systematic process improvement. As process improvements move along the learning curve it raises the question, "what is the best process that can be achieved, and how close is the current process to that best case?" For reaction systems, Horn formulated this question in 1964, and Feinberg & Ellison an-swered it in 2001. In this article we state the method for calculating the ultimate productivity of a given reaction system and associated chemical kinetics and apply it to a simple industrial chemical process to make ethyl acetate from renewable bioethanol feedstock. The benchmarks provided by the method lead to useful practical pathways for driving innovation. (c) 2022 Elsevier Ltd. All rights reserved.

Crystal growth models depend on the density of kink sites along step edges, which are primary sites for surface integration of growth units. Since the kink density is a fundamental quantity in these growth models, disregarding its supersaturation dependence results in the loss of effects that get magnified at higher supersaturation. In this work, a simplified steady-state framework is developed for estimating the nonequilibrium kink density as a function of supersaturation. It involves balancing the rates of the dominant surface events that produce kinks with those that destroy kinks. The master equations obtained are solved simultaneously to yield closed-form expressions for the nonequilibrium kink density. Predicted step velocities are in excellent agreement with kinetic Monte Carlo simulations.

Crystal morphology modeling of organic molecular solvates and hydrates remains largely unexplored due to the complex intermolecular interactions and growth units involved in the attachment at surface sites. In this paper, we present a mechanistic model to predict the crystal morphology of olanzapine-methanol solvate and olanzapine dihydrate. This study provides mechanistic insight into predicting the crystal habits of solvates and hydrates for broader classes of organic molecules. In this model, we assume that olanzapine incorporated into the solid state as a cluster consists of a solute together with a stoichiometric number of solvent molecules. Binding energy calculations are used to identify the most probable growth unit clusters, which is an olanzapine-methanol tetramer for the methanol solvate crystal, and olanzapine-water hexamer for the dihydrate crystal. The close agreement between the experimentally observed and the predicted morphologies lends support to the utility of the model.

Free energies of crystals computed using a center of mass constraint require a finite-size correction, as shown in previous work by Polson et al. [J. Chem. Phys. 112, 5339-5342 (2000)]. Their reference system is an Einstein crystal with equal spring constants. In this paper, we extend the work of Polson et al. [J. Chem. Phys. 112, 5339-5342 (2000)] to the case of differing spring constants. The generalization is convenient for constraining the center of mass in crystals with atoms of differing masses, and it helps to optimize the free energy calculations. To test the theory, we compare the free energies of LiI and NaCl crystals from calculations with differing spring constants to those computed using equal spring constants. Using these center of mass finite size corrections, we compute the true free energies of these crystals for different system sizes to eliminate the intrinsic finite-size effects. These calculations help demonstrate the size of these finite-size corrections relative to other contributions to the absolute free energy of the crystals.

The Irish Supreme Court’s decision in McKelvey v Iarnród Éireann/ Irish Rail enters into the ongoing discussion of the ‘legalisation’ of workplace dispute resolution.

The central thesis of legal design is that service design principles and methods can be usefully applied to legal processes. This necessarily involves lawyers commissioning, participating in, and implementing design projects. This chapter examines anthropological and sociological accounts of professional practice and posits that there are some cultural hurdles to developing this law/design relationship. There are identifiable lawyerly attributes and mindsets derived from legal culture. This culture is not homogeneous but at its heart are themes of precedent, formality, and textual/verbal articulacy. Design has its own cultural tropes including flexibility, experimentation, and visual literacy. The cultural centres of law and design are some distance apart and this tension may be problematic for those seeking design interventions into law. These cultural constructs have significant power, but they also exhibit plasticity. The chapter concludes by examining the potential of both cultural change and exchange to ease the process of introducing human-centred design characteristics into legal practices.

Techno-economic analysis is an important part of evaluating potential chemical manufacturing ventures. A proposed conceptual process design gives the design engineer most of the information required to conduct these analyses. However, developing conceptual designs can be time consuming and expensive, especially given that most conceptual designs never see commercialization. In this work, we present a rapid screening methodology to generate screening-level economic metrics (NPV and NPV%) without dedicating significant time or resources to conventional chemical process design. This methodology uses ultimate bounds on reaction selectivity combined with the minimum work of separations to bypass the design procedure altogether. The methodology presented here provides a means to rapidly screen chemistries for their economic merit, compare a proposed process design to the best-case economic scenario, and compare potential projects competing for the same funding sources. In this article, we present the necessary theory and demonstrate the methodology. (C) 2020 Elsevier Ltd. All rights reserved.