Nucleation, the first step of crystallization, is stochastic at small volumes and becomes increasingly deterministic with increasing volume. Translating crystallization processes from the lab to commercial scale remains challenging due to the stochastic nature of nucleation at smaller scales, differences between crystallizer designs, and inconsistencies that arise during scale-up. This study examines how solution volume and agitation affect nucleation kinetics in the crystallization of griseofulvin in methanol. Induction time experiments were conducted at 1 and 100 mL scales using Crystal16 and EasyMax setups, respectively. These results were compared to previously reported experiments conducted at a 20 mL scale using a setup of magnetically stirred solutions, where the induction time was determined through visual analysis of video recordings. GSF nucleated as stable Form I under all investigated conditions. There is a transition from stochastic nucleation observed at 1 and 20 mL scales to a more deterministic process at the 100 mL scale. The nucleation rate exhibits a correlation with differing energy dissipation and solution volume conditions.

The effect of solvent on active pharmaceutical ingredient (API) nucleation behavior is system-dependent. A better understanding of the role of the solvent in nucleation could help predict and control crystallization. In this work, induction time experiments, spectroscopic analysis, and dynamic light scattering were used to explore the influence of solvent on the polymorphic landscape and the nucleation behavior of griseofulvin (GSF), a medium-sized, flexible, model API. Based on a total of 2960 induction time experiments, the relative ease of nucleation was characterized in three solvents commonly used in the pharmaceutical industry: methanol (MeOH), acetonitrile (ACN), and n-butyl acetate (nBuAc). GSF crystallized as stable Form I in MeOH and as solvated forms in both ACN and nBuAc. GSF nucleated most easily in ACN, followed by nBuAc, while nucleation was most difficult in MeOH. This order was found to correlate with increasing interfacial energy, which was found to be lower in ACN, intermediate in nBuAc, and higher in MeOH, based on a classical evaluation. However, in contrast to classical nucleation theory, which suggests that higher nucleation rates are associated with larger pre-exponential factors, the pre-exponential factor was found to be highest in MeOH, while it remained comparable in ACN and nBuAc. An analysis of the GSF solutions used in the nucleation studies confirmed the presence of mesoscale clusters in ACN and in nBuAc, but not in MeOH. The size and concentration of mesoscale clusters in ACN solution were higher than those in nBuAc, which could explain the higher nucleation rate observed in ACN if the nonclassical nucleation pathway is considered for these solvents.

Hypothesis: It is hypothesised in this work that mesoscale clusters will be present in both undersaturated and supersaturated solutions of organic pharmaceutical molecules. These clusters, being loose aggregates, could be sensitive to shear forces experienced during filtration. Thus, comparing the behaviour of these clusters alongside nanoparticles during filtration—an important sample treatment parameter during crystallization—will elucidate qualitative differences from solid, crystalline nanoparticles of similar size. Experiments: The impact of filtration with different pore sizes and membranes on (i) mesoscale clusters of flufenamic acid (FFA) ethanol solutions and (ii) aqueous FFA nanosuspensions was studied with dynamic light scattering and nanoparticle tracking analysis. Findings: FFA solutions, ranging from undersaturated to supersaturated, were found to form mesoscale clusters, where the cluster size and number concentration were independent of solute concentration. Under filtration stress, irrespective of pore size and membrane used, the mesoscale cluster peak disappeared from the size distribution with no detectable change in concentration. In contrast, similarly sized FFA nanoparticles were removed by filtration, causing a significant change in solute concentration and size distribution. Mesoscale clusters of FFA in ethanol constitute only a tiny fraction of the total solute concentration and possess poor light scattering properties, lower mass density than solid particles of similar size, and no clear phase boundary.

Hypothesis: The stabilization and isolation to dryness of drug nanoparticles has always been a challenge for nano-medicine production. In the past, the use of montmorillonite (MMT) clay carrier particles to adsorb drug nanoparticles and maintain their high surface area to volume ratio after isolation to dryness has proven to be effective. We hypothesise that the distribution of hydrophilic and hydrophobic patches on the clay's surface as well as its porosity/roughness, hinder the agglomeration of the drug nanoparticles to the extent that they retain their high surface area to volume ratio and display fast dissolution profiles. Experiments: In this work, the distribution of hydrophobicity and hydrophilicity, and the porosity/roughness, of the surface of selected silica carrier particles were varied and the impact of these variations on drug nanoparticle attachment to the carrier particle and subsequent dissolution profiles was studied. Findings: The fastest dissolution profiles at the highest drug nanoparticle loadings were obtained with a periodic mesoporous organosilane carrier particle which had a homogeneous distribution of hydrophobic and hydrophilic surface properties. Carrier particles with rough/porous surfaces and a combination of hydrophobic and hydrophilic patches resulted in nanocomposite powders with faster dissolution behaviour than carrier particles with predominantly either a hydrophobic or hydrophilic surface, or with non-porous/smoother surfaces.

The early stages of the molecular self-assembly pathway leading to crystal nucleation have a significant influence on the properties and purity of organic materials. This mini review collates the work on organic mesoscale clusters and discusses their importance in nucleation processes, with a particular focus on their critical properties and susceptibility to sample treatment parameters. This is accomplished by a review of detection methods, including dynamic light scattering, nanoparticle tracking analysis, small angle X-ray scattering, and transmission electron microscopy. Considering the challenges associated with crystallisation of flexible and large-molecule active pharmaceutical ingredients, the dynamic nature of mesoscale clusters has the potential to expand the discovery of novel crystal forms. By collating literature on mesoscale clusters for organic molecules, a more comprehensive understanding of their role in nucleation will evolve and can guide further research efforts.

The nickel metal hydride (NiMH) battery technology has been designed for use in electric vehicles, solar-powered applications and power tools. These batteries contain the critical and strategic raw materials cobalt, nickel and several rare earth elements (REE). When designing a battery recycling process, there are several choices to be made regarding end-products and process chemicals. The aim of this study is to investigate and compare the environmental and economic sustainability of different recycling options for NiMH batteries by taking projected market developments into consideration and by applying life cycle assessment and life cycle costing methods. The comparative study is limited to recovery of the REEs. Two hydrometallurgical processes for recovery of the REEs from the anode material are compared with extraction of REEs from primary sources in China. The processes compared are a high-temperature sulfation roasting process and a process based on hydrochloric acid leaching followed by precipitation of REE oxalates. By comparing the different recycling approaches, the hydrochloric acid process performs best. However, the use of oxalic acid has a large impact on the overall sustainability footprint. For the sulfation roasting process, the energy, sodium hydroxide and sulphuric acid consumption contribute most to the total environmental footprint.

This article is part of the discussion meeting issue 'Sustainable metals: science and systems'.

Crystal nucleation shapes the structure and product size distribution of solid-state pharmaceuticals and is seeded by early-stage molecular self-assemblies formed in host solution. Here, molecular clustering of salicylamide in ethyl acetate, methanol, and acetonitrile was investigated using photon correlation spectroscopy. Cluster size steadily increased over 3 days and with concentration across the range from undersaturated to supersaturated solutions. Solute concentration normalized by solubility provided more sensitive characterization of molecular-level conditions than concentration alone. In saturated solution, cluster size is independent of solvent, while at equal supersaturation, solvent-dependent cluster size increases as methanol < acetonitrile < ethyl acetate, commensurate with increasing nucleation propensity. In ethyl acetate, with largest prenucleation clusters, the driving force required for nucleation is lowest, compared to methanol with smallest clusters and highest driving force. To understand solvent-solute effects, we performed IR spectroscopy supported by molecular simulations. We observe solute-solvent interaction weakening in the same order: methanol < acetonitrile < ethyl acetate, quantifying the weaker solvent-solute interactions that permit the formation of larger prenucleation clusters. Our results support the hypothesis that nucleation is easier in weaker solvents because weak solute-solvent interactions favor growth of large clusters, as opposed to relying solely on ease of desolvation.

The impact of single or combinations of additives on the generation of nanosuspensions of two poorly water-soluble active pharmaceutical ingredients (APIs), fenofibrate (FF) and dalcetrapib (DCP), and their isolation to the dry state via antisolvent (AS) crystallization followed by freeze-drying was explored in this work. Combinations of polymeric and surfactant additives such as poly(vinyl alcohol) or hydroxypropyl methyl cellulose and sodium docusate were required to stabilize nanoparticles (∼200-300 nm) of both APIs in suspension before isolation to dryness. For both FF and DCP, multiple additives generated the narrowest, most-stable particle size distribution, with the smallest particles in suspension, compared with using a single additive. An industrially recognized freeze-drying process was used for the isolation of these nanoparticles to dryness. When processed by the liquid AS crystallization followed by freeze-drying in the presence of multiple additives, a purer monomorphic powder for FF resulted than when processed in the absence of any additive or in the presence of a single additive. It was noted that all nanoparticles freeze-dried in the presence of additives had a flat, flaky habit resulting in large surface areas. Agglomeration occurred during freeze-drying, resulting in micron-size particles. However, after freeze-drying, powders produced with single or multiple additives showed similar dissolution profiles, irrespective of aging time before drying, thus attenuating the advantage of multiple additives in terms of size observed before the freeze-drying process.

The nucleation in the p-hydroxybenzoic acid:glutaric acid 1:1 cocrystal (PHBA:GLU) system has been investigated in stoichiometric and non-stoichiometric acetonitrile solutions by induction time experiments. Utilizing the ternary phase diagram, the supersaturated non-stoichiometric solutions were created with compositions along the invariant point boundary lines. In all cases, the PHBA:GLU cocrystal was the nucleating phase, even though the non-stoichiometric solutions were also supersaturated with respect to the pure solid phases. The nucleation of the cocrystal from the mixed solutions is found to be more difficult than the nucleation of the pure compounds from the respective pure solutions, as captured by lower pre-exponential factors (A). However, if the driving force is defined per reactant molecule instead of per heterodimer, the cocrystal nucleation difficulty is close to that of the more difficult-to-nucleate pure compound. The difference in nucleation difficulty of the cocrystal from stoichiometric and non-stoichiometric solutions was captured by differences in the interfacial energy, while the pre-exponential factor remained unchanged. Apart from the pure GLU system, the relation between the experimentally determined pre-exponential factors for the different systems correlates with calculated values using theoretical expressions for volume-diffusion and surface-integration control.

This work presents two new solid forms, a polymorph and a solvate, of the antifungal active pharmaceutical ingredient griseofulvin (GSF). The novel forms were characterized by powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis, and their crystal structures were determined by single-crystal X-ray diffraction. The new polymorphic form (GSF Form VI) was obtained upon drying at room temperature the GSF-acetonitrile solvate. GSF Form VI is a relict structure related to reported solvates of GSF. Thermal stability studies show that Form VI is metastable and monotropically related to the stable GSF Form I. The new GSF-n-butyl acetate solvate was obtained by crystallization from an n-butyl acetate solution. The stoichiometry of the n-butyl acetate solvate is 1:0.5. The solvate loses the solvent from the crystal lattice at a temperature between 363.15 and 374.15 K.