Do metastable polymorphs always grow faster? Measuring and comparing growth kinetics of three polymorphs of tolfenamic acid.

The phenomenon of molecular crystal polymorphism is of central importance for all those industries that rely on crystallisation for the manufacturing of their products. Computational methods for the evaluation of thermodynamic properties of polymorphs have become incredibly accurate and a priori prediction of crystal structures is becoming routine. The computational study and prediction of the kinetics of crystallisation impacting polymorphism, however, have received considerably less attention despite their crucial role in directing crystallisation outcomes. This is mainly due to the lack of available experimental data, as nucleation and growth kinetics of polymorphs are generally difficult to measure. On the one hand, the determination of overall nucleation and growth kinetics through batch experiments suffers from unwanted polymorphic transformations or the absence of experimental conditions under which several polymorphs can be nucleated. On the other hand, growth rates of polymorphs obtained from measurements of single crystals are often only recorded along a few specific crystal dimensions, thus lacking information about overall growth and rendering an incomplete picture of the problem. In this work, we measure the crystal growth kinetics of three polymorphs (I, II and IX) of tolfenamic acid (TFA) in isopropanol solutions, with the intention of providing a meaningful comparison of their growth rates. First, we analyse the relation between the measured growth rates and the crystal structures of the TFA polymorphs. We then explore ways to compare their relative growth rates and discuss their significance when trying to determine which polymorph grows faster. Using approximations for describing the volume of TFA crystals, we show that while crystals of the metastable TFA-II grow the fastest at all solution concentrations, crystals of the metastable TFA-IX become kinetically competitive as the driving force for crystallisation increases. Overall, both metastable forms TFA-II and TFA-IX grow faster than the stable TFA-I.

Indigenous land-based approaches to well-being: The Sibi (River) program in subarctic Ontario, Canada.

The Albany River system holds a special significance for the Omushkego Cree of subarctic Ontario, Canada, embodying their cultural roots, history, and the Cree way of life and worldviews. Through the Sibi program, youth learned traditional fishing practices from Elders and on-the-land experts, gaining valuable knowledge on the land and river. The program addressed barriers to being on the land, while also creating a space for the transfer of Indigenous knowledge and revitalising community social networks. The program took place in the summer, following the Omushkego Cree's seasonal cycle and employed community-based participatory research approach. Photovoice and semi-structured interviews were used to identify elements of well-being from an Indigenous perspective. Regardless of age or experience, participants expressed positive emotions while being on the land, highlighting how strengthening social and community networks, intergenerational knowledge transfer, and fostering cultural continuity contribute to improved well-being. Program outcomes emphasize the importance of collaboration with communities to gain insights into their needs, priorities, and values, ultimately creating more sustainable and effective well-being programs. By fostering engagement and recognizing the environment's significance, sustainable and long-term solutions can be pursued to address challenges faced by communities, ultimately advancing health and well-being for both present and future generations.The Albany River system holds a special significance for the Omushkego Cree of subarctic Ontario, Canada, embodying their cultural roots, history, and the Cree way of life and worldviews. Through the Sibi program, youth learned traditional fishing practices from Elders and on-the-land experts, gaining valuable knowledge on the land and river. The program addressed barriers to being on the land, while also creating a space for the transfer of Indigenous knowledge and revitalising community social networks. The program took place in the summer, following the Omushkego Cree's seasonal cycle and employed community-based participatory research approach. Photovoice and semi-structured interviews were used to identify elements of well-being from an Indigenous perspective. Regardless of age or experience, participants expressed positive emotions while being on the land, highlighting how strengthening social and community networks, intergenerational knowledge transfer, and fostering cultural continuity contribute to improved well-being. Program outcomes emphasize the importance of collaboration with communities to gain insights into their needs, priorities, and values, ultimately creating more sustainable and effective well-being programs. By fostering engagement and recognizing the environment's significance, sustainable and long-term solutions can be pursued to address challenges faced by communities, ultimately advancing health and well-being for both present and future generations.

Indigenous Land-Based Approaches to Well-Being: The Niska (Goose) Harvesting Program in Subarctic Ontario, Canada.

Historically, goose harvesting provided a source of culturally significant, safe, and nutritious food for the Omushkego Cree of subarctic Ontario, Canada. Disruptions stemming from colonization and climate change have led to a decrease in harvesting, resulting in higher rates of food insecurity. The aim of the Niska program was to reconnect Elders and youth to revitalize goose harvesting activities and associated Indigenous knowledge within the community. The program and evaluation were built using a two-eyed seeing (Etuaptmumk) and community-based participatory research approach. Salivary cortisol, a biomedical measure of stress, was collected before (n = 13) and after (n = 13) participation in the spring harvest. Likewise, cortisol samples were collected before (n = 12) and after (n = 12) the summer harvest. Photovoice and semi-directed interviews were employed after the spring (n = 13) and summer (n = 12) harvests to identify key elements of well-being from an Indigenous perspective. The changes observed in cortisol levels for the spring (p = 0.782) and summer (p = 0.395) harvests were not statistically significant. However, there was a noteworthy increase in the subjective well-being observed through the qualitative measures (semi-directed interviews and photovoice), highlighting the importance of using multiple perspectives when assessing well-being, especially in Indigenous peoples. Future programs should incorporate multiple perspectives when addressing complex environmental and health issues, such as food security and environmental conservation, especially in Indigenous homelands worldwide.

Complex Growth of Benzamide Form I: Effect of Additives, Solution Flow, and Surface Rugosity.

Understanding crystal growth kinetics is of great importance for the development and manufacturing of crystalline molecular materials. In this work, the impact of additives on the growth kinetics of benzamide form I (BZM-I) crystals has been studied. Using our newly developed crystal growth setup for the measurement of facet-specific crystal growth rates under flow, BZM-I growth rates were measured in the presence of various additives previously reported to induce morphological changes. The additives did not have a significant impact on the growth rates of BZM-I at low concentrations. By comparison to other systems, these additives could not be described as "effective" since BZM-I showed a high tolerance of the additives' presence during growth, which may be a consequence of the type of growth mechanisms at play. Growth of pure BZM-I was found to be extremely defected, and perhaps those defects allow the accommodation of impurities. An alternative explanation is that at low additive concentrations, solid solutions are formed, which was indeed confirmed for a few of the additives. Additionally, the growth of BZM-I was found to be significantly affected by solution dynamics. Changes in some facet growth rates were observed with changes in the orientation of the BZM-I single crystals relative to the solution flow. Of the two sets of facets involved in the growth of the width and length of the crystal, the {10l̅} facets were found to be greatly affected by the solution flow while the {011} facets were not affected at all. Computational fluid dynamics simulations showed that solute concentration has higher gradients at the edges of the leading edge {10l̅} facets, which can explain the appearance of satellite crystals. {10l̅} facets were found to show significant structural rugosity at the molecular level, which may play a role in their mechanism of growth. The work highlights the complexities of measuring crystal growth data of even simple systems such as BZM-I, specifically addressing the effect of additives and fluid dynamics.

Indigenous Land-Based Approaches to Well-Being: The Amisk (Beaver) Harvesting Program in Subarctic Ontario, Canada.

The act of decolonizing knowledge systems involves recovering and renewing traditional, non-commodified cultural patterns, such as the sustenance of intergenerational relationships and traditional practices. A decline in beaver harvesting, which was once an integral part of the Omushkego Cree culture, has resulted in an overabundance of beavers and dams, which has negatively affected communities by increasing the local flooding events and impacting the water quality. The aim of the Amisk (beaver) program was to reconnect the Elders and youth to revitalize traditional on-the-land activities and, in the present case, beaver harvesting and associated activities within the community. The program and evaluation were built using a two-eyed seeing (Etuaptmumk) and community-based participatory research approach. Salivary cortisol, a biomedical measure of stress, was collected before and after participation in the program. Photovoice, along with semi-directed interviews, were employed to identify the key elements of well-being from a First Nations' perspective. For the beaver harvesting activities, the changes observed in the cortisol concentrations were not statistically significant (p = 0.094). However, the act of beaver dam removal was associated with a statistically significant increase in the post-participation cortisol concentration (p = 0.021). It was noteworthy that increased stress during the removal of the beaver dams-as indicated by the elevated post-activity cortisol levels-were not reflected in a decrease in the qualitative measures (semi-directed interviews and photovoice) of well-being from an Indigenous perspective. In fact, there was a noted increase in the subjective well-being of the participants, which highlights the importance of multiple perspectives when assessing well-being, especially in Indigenous peoples. However, the cortisol findings of the present pilot project need to be interpreted with caution, due to the limited sample sizes.

Two-Eyed Seeing and developmental origins of health and disease studies with indigenous partners.

Globally, mortality of Indigenous persons is greater than that of their non-Indigenous counterparts, which has been shown to be disproportionately attributable to non-communicable diseases. The historically subordinate position that Indigenous Knowledge (IK) held in comparison to Western science has shifted over the last several decades, with the credibility and importance of IK now being internationally recognized. Herein, we examine how Marsahall's (2014) Two-Eyed Seeing can foster collaborative and culturally relevant Developmental Origins of Health and Disease (DOHaD) studies for health and well-being by using '..the best in Indigenous ways of knowing…[and] the best in Western (or mainstream) ways of knowing…and learn to use both these eyes for the benefit of all.' At its core, Two-Eyed Seeing also includes the principles of ownership, control, access and possession, and Community-Based Participatory Research, which further reinforces the critical role of Indigenous peoples taking active roles in DOHaD research. Additionally, we also present a partnership model for working with Indigenous communities that includes the principles of respect, equity and empowerment. As researchers begin to fill the gap in Indigenous health, we outline how Two-Eyed Seeing should form the basis of DOHaD studies involving Indigenous communities. This model can be used to develop and guide projects that result in robust and meaningful participatory partnerships that have impactful uptake of research findings.

Harvest Programs in First Nations of Subarctic Canada: The Benefits Go Beyond Addressing Food Security and Environmental Sustainability Issues.

By breaking down barriers that impacted the ability of subarctic First Nations people to harvest waterfowl, the Sharing-the-Harvest program provided a safe, nutritious, and culturally appropriate food (i.e., geese) to James Bay Cree communities while also helping to protect the environment by harvesting overabundant geese. However, the impacts extend beyond those described above. Thus, the objectives of the present paper are twofold: to document the food sharing networks of the Sharing-the-Harvest program; and to examine the benefits associated with the harvest program beyond food security and environmental sustainability issues, as revealed through semi-directed interviews. In the regional initiative, harvested geese were shared with all James Bay communities; sharing is an important part of Cree culture. Where detailed information was collected, the goose-sharing network reached 76% of the homes in one of the communities. Likewise, in the local initiative, the goose-sharing network had a 76% coverage rate of the homes in the community. Although decreasing food insecurity was an important focus of the harvest-sharing programs, there were other benefits, from an Indigenous perspective, of being on the land, as identified by the Cree harvesters through semi-directed interviews (e.g., the transmission of Indigenous knowledge, the strengthening of social networks, and the feeling of wellness while out on-the-land). Thus, by participating in the on-the-land harvest programs, the Cree gained benefits beyond those solely related to strengthening food security and contributing in part to environmental sustainability. The Sharing-the-Harvest protocol has the potential to be adapted and employed by other Indigenous (or marginalized) groups worldwide, to help improve health and wellness, while, also protecting the environment from overabundant and/or invasive species.

Transforming Computed Energy Landscapes into Experimental Realities: The Role of Structural Rugosity.

We exploit the possible link between structural surface roughness and difficulty of crystallisation. Polymorphs with smooth surfaces may nucleate and crystallise more readily than polymorphs with rough surfaces. The concept is applied to crystal structure prediction landscapes and reveals a promising complementary way of ranking putative crystal structures.

Concerning Elusive Crystal Forms: The Case of Paracetamol.

Increasing commercial application of state of the art crystal structure prediction to aid solid form discovery of new molecular entities allows the experimentalist to target the polymorphs with desired properties. Here we remind ourselves that in this field the gap between such prediction and experimentation can be vast, the latter depending strongly on kinetic processes not accounted for in the computations. Nowhere is this gap more evident than in examples of so-called "elusive" polymorphs, forms that have been found difficult to crystallize, sometimes taking years to appear or sometimes disappearing altogether. In attempting to probe the origins of such phenomena this work targets a well-known, relatively simple molecule, paracetamol (PCM), and explores the structural and kinetic origins of its elusive nature. It is noted that in general comparisons of the kinetic factors (nucleation and crystal growth) between polymorphs have rarely been reported and of course in cases where one or more forms is "elusive" this will, by definition, be essentially impossible. PCM however offers a unique opportunity and we show how the recent discovery of the impact of metacetamol (MCM) in stabilizing PCM form II can be used to advantage, enabling otherwise impossible comparative kinetic experiments to be made. Resulting from this study we now appreciate that MCM has a selective impact in blocking the growth of the thickness and width of PCM form I while it has no impact on form II. This is interpreted in terms of strong adsorption of MCM on the {011} faces (width and thickness) of form I in orientations that inhibit crystal growth ("wrong" orientations). Of more significance here is the use of the additive in allowing an otherwise impossible comparison of linear growth rates of forms I and II. This leads to the appreciation that only through calculation of growth volumes can we finally appreciate how the relative growth kinetics lead inevitably to the elusive nature of Form II.

Can molecular flexibility control crystallization? The case of para substituted benzoic acids.

Despite the technological importance of crystallization from solutions almost nothing is known about the relationship between the kinetic process of nucleation and the molecular and crystal structures of a crystallizing solute. Nowhere is this more apparent than in our attempts to understand the behavior of increasingly large, flexible molecules developed as active components in the pharmaceutical arena. In our current contribution we develop a general protocol involving a combination of computation (conformation analysis, lattice energy), and experiment (measurement of nucleation rates), and show how significant advances can be made. We present the first systematic study aimed at quantifying the impact of molecular flexibility on nucleation kinetics. The nucleation rates of 4 para substituted benzoic acids are compared, two of which have substituents with flexible chains. In making this comparison, the importance of normalizing data to account for differing solubilities is highlighted. These data have allowed us to go beyond popular qualitative descriptors such 'crystallizability' or 'crystallization propensity' in favour of more precise nucleation rate data. Overall, this leads to definite conclusions as to the relative importance of solution chemistry, solid-state interactions and conformational flexibility in the crystallization of these molecules and confirms the key role of intermolecular stacking interactions in determining relative nucleation rates. In a more general sense, conclusions are drawn as to conditions under which conformational change may become rate determining during a crystallization process.

The importance of configurational disorder in crystal structure prediction: the case of loratadine.

Loratadine, an over-the-counter antihistamine medication, has two known monotropically related polymorphs, both of which feature disorder. A combined experimental and computational approach using variable temperature single crystal X-ray diffraction (VT-SCXRD) analysis and dispersion corrected density functional theory (DFT-D) reveals that the nature of the disorder in each form is markedly different and cannot be described by a simple isolated-site model with thermally populated conformations in either of the two cases. In Form I, the ethyl carbamate functionality adopts two different configurations, with adjacent moieties interacting along one-dimensional chains. The most stable arrangement features alternating configurations, but because of the low energetic cost of stacking faults, the domain sizes are short and an average crystal structure is observed experimentally. The configurational free energy of the disordered structure is lower than the energy of the two corresponding ordered crystal structures, but the energy decrease is dominated by the lower lattice energy of the alternating arrangement with a small entropic contribution. In Form II, the flexible cycloheptane bridge adopts two different configurations. The disorder is not an equilibrium property but is instead frozen-in during the crystallisation process. The configurational free energy of the disordered structure falls in between the lattice energies of the two corresponding ordered structures. The two ordered components of each disordered structure are all found in a crystal structure prediction (CSP) study with the GRACE programme. However, the experimentally observed stability relationship is only reproduced when the energy contribution of disorder is taken into account. The disordered model of Form I is found to be lower in energy than all the other predicted structures and there is no indication of a missing, thermodynamically more stable, form. The case of loratadine demonstrates that experimentally observed disorder close to 50/50 does not necessarily correspond to a free energy decrease by kT ln 2.

Aromatic stacking - a key step in nucleation.

Crystal nucleation from solution is of central importance in the chemical and biological sciences. Linking nucleation kinetics to the properties of solutes and solvents remains a grand-challenge in physical chemistry. Through a unique dataset of compounds able to self-assemble via both hydrogen-bonds and aromatic stacking, we are able to compare the importance of these two types of interaction in driving the nucleation process. Contrary to previous reports in which solution chemistry and hydrogen bonding have been seen as controlling factors, we are now able to show that cluster growth via aromatic stacking holds the key.

Crystallisation from a Water-in-Oil Emulsion as a Route to Enantiomer Separation: The Case of DL-Threonine.

The use of crystalliation as a means of separating enantiomers is well known. The utility of commonly applied seeding approaches is limited by the ultimate crystallisation of the antipode. Here we demonstrate how the combination of colloid science and crystal chemistry can lead to an emulsion based process yielding robust separation of a purified solid and impure liquid phases with ultimate product ee of up to 90 %. Threonine is used as a model to demonstrate the viability of the method but it is clear that extension to include, for example, simultaneous racemisation within the disperse phase is easily possible and would transform this from a separation to a preparation process.

Crystal nucleation from solutions--transition states, rate determining steps and complexity.

This introductory paper offers a contemporary view of crystal nucleation. We begin with a molecular interpretation of the transition state and then revisit the use of classical nucleation theory as a means of obtaining molecular scale information from kinetic data. Traditional physical organic chemistry has always utilised the combination of kinetics and thermodynamics in order to gain insight over reaction pathways. Here we demonstrate for the cases of sucrose and p-aminobenzoic acid how solution chemistry, crystallography and kinetics come together to provide self-consistent pictures of the molecular scale processes occurring during nucleation. In this and a number of other systems desolvation of specific functional groups is highlighted as the rate determining step. Finally we move on to discuss the question of complexity, both from a phase and molecular perspective.

Proton transfer and hydrogen bonding in the organic solid state: a combined XRD/XPS/ssNMR study of 17 organic acid-base complexes.

The properties of nitrogen centres acting either as hydrogen-bond or Brønsted acceptors in solid molecular acid-base complexes have been probed by N 1s X-ray photoelectron spectroscopy (XPS) as well as (15)N solid-state nuclear magnetic resonance (ssNMR) spectroscopy and are interpreted with reference to local crystallographic structure information provided by X-ray diffraction (XRD). We have previously shown that the strong chemical shift of the N 1s binding energy associated with the protonation of nitrogen centres unequivocally distinguishes protonated (salt) from hydrogen-bonded (co-crystal) nitrogen species. This result is further supported by significant ssNMR shifts to low frequency, which occur with proton transfer from the acid to the base component. Generally, only minor chemical shifts occur upon co-crystal formation, unless a strong hydrogen bond is formed. CASTEP density functional theory (DFT) calculations of (15)N ssNMR isotropic chemical shifts correlate well with the experimental data, confirming that computational predictions of H-bond strengths and associated ssNMR chemical shifts allow the identification of salt and co-crystal structures (NMR crystallography). The excellent agreement between the conclusions drawn by XPS and the combined CASTEP/ssNMR investigations opens up a reliable avenue for local structure characterization in molecular systems even in the absence of crystal structure information, for example for non-crystalline or amorphous matter. The range of 17 different systems investigated in this study demonstrates the generic nature of this approach, which will be applicable to many other molecular materials in organic, physical, and materials chemistry.

Nucleation of organic crystals--a molecular perspective.

The outcome of synthetic procedures for crystalline organic materials strongly depends on the first steps along the molecular self-assembly pathway, a process we know as crystal nucleation. New experimental techniques and computational methodologies have spurred significant interest in understanding the detailed molecular mechanisms by which nuclei form and develop into macroscopic crystals. Although classical nucleation theory (CNT) has served well in describing the kinetics of the processes involved, new proposed nucleation mechanisms are additionally concerned with the evolution of structure and the competing nature of crystallization in polymorphic systems. In this Review, we explore the extent to which CNT and nucleation rate measurements can yield molecular-scale information on this process and summarize current knowledge relating to molecular self-assembly in nucleating systems.