The subject of crystal engineering started in the 1970s with the study of topochemical reactions in the solid state. A broad chemical definition of crystal engineering was published in 1989, and the supramolecular synthon concept was proposed in 1995 followed by heterosynthons and their potential applications for the design of pharmaceutical cocrystals in 2004. This review traces the development of supramolecular synthons as robust and recurring hydrogen bond patterns for the design and construction of supramolecular architectures, notably, pharmaceutical cocrystals beginning in the early 2000s to the present time. The ability of a cocrystal between an active pharmaceutical ingredient (API) and a pharmaceutically acceptable coformer to systematically tune the physicochemical properties of a drug (i.e., solubility, permeability, hydration, color, compaction, tableting, bioavailability) without changing its molecular structure is the hallmark of the pharmaceutical cocrystals platform, as a bridge between drug discovery and pharmaceutical development. With the design of cocrystals via heterosynthons and prototype case studies to improve drug solubility in place (2000-2015), the period between 2015 to the present time has witnessed the launch of several salt-cocrystal drugs with improved efficacy and high bioavailability. This review on the design, synthesis, and applications of pharmaceutical cocrystals to afford improved drug products and drug substances will interest researchers in crystal engineering, supramolecular chemistry, medicinal chemistry, process development, and pharmaceutical and materials sciences. The scale-up of drug cocrystals and salts using continuous manufacturing technologies provides high-value pharmaceuticals with economic and environmental benefits.

Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs.

In the last decades, mechanochemical processing has emerged as a sustainable method for the large-scale production of a variety of nanomaterials. In particular, mechanochemical synthesis can afford well-dispersed metal-oxide nanoparticles, which are used in wide-ranging applications including energy storage and conversion, environmental monitoring, or biomedical uses. This article reviews recent progress in the mechanochemical synthesis of metal-oxide nanoparticles, explores reaction mechanisms, and contrasts the influence of chosen process parameters on the properties of end products. The role of choice of reaction pathway, as well as advantages and limitations compared to other synthesis methods are discussed. A prospect for future development of this synthetic method is proposed. Mechanochemistry is driven by mechanical energy input, which often alleviates the need for solvents or heating to achieve desired products. Here, the author reviews mechanochemical syntheses of metal-oxide nanoparticles, exploring reaction mechanisms, and contrasting the influence of process parameters on the properties of end products.

/pdf/mechanochemical-synthesis-of-metal-oxide-nanoparticles-1nhckrswph.pdf

Mechanochemical synthesis of metal oxide nanoparticles

Mechanochemistry provides an environmentally benign platform to develop more sustainable chemical processes by limiting raw materials, energy use, and waste generation while using physically smaller equipment. A continuously growing research community has been steadily showcasing examples of beneficial mechanochemistry applications at both laboratory and preparative scales. Given the yet unstandardised nature of mechanochemical processes compared to solution-based chemistry, scaling up is still a nascent discipline. The purpose of this review is to highlight similarities, differences and challenges of the various approaches that have been successfully applied for a range of chemical applications at various scales. We hope to provide a discussion starting point for those interested in further developing mechanochemical processes for commercial use and/or industrialisation.

Tinkering with Mechanochemical Tools for Scale Up.

The ability to rationally design and predictably construct crystalline solids has been the hallmark of crystal engineering research. To date, numerous examples of multicomponent crystals comprising organic molecules have been reported. However, the crystal engineering of cocrystals comprising both organic and inorganic chemical units is still poorly understood and mostly unexplored. Here, we report a new diverse set of higher-order cocrystals (HOCs) based on the structurally versatile-yet largely unexplored-phosph(V/V)azane heterosynthon building block. The novel ternary and quaternary cocrystals reported are held together by synergistic and orthogonal intermolecular interactions. Notably, the HOCs can be readily obtained either via sequential or one-pot mechanochemical methods. Computational modelling methods reveal that the HOCs are thermodynamically driven to form and that their mechanical properties strongly depend on the composition and intermolecular forces in the crystal, offering untapped potential for optimizing material properties.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ange.202101248

Mechanosynthesis of Higher-Order Cocrystals: Tuning Order, Functionality and Size in Cocrystal Design**

Cocrystal engineering is gaining interest across various disciplines since it can effectively tune the properties of solid substances via noncovalent synthesis by introducing new components into the lattice. Mechanochemistry is without a doubt the most valuable tool for the research of cocrystals, which combines the pursuit of efficient and sustainable process pathways with the exploration of supramolecular synthons that cannot be discovered using solution methods. In this review, concerning the significance of the mechanochemical synthesis of cocrystals, we begin by outlining the strategies for mechanochemical preparation of cocrystals. We then elaborate on the theoretical mechanisms of the mechanochemically induced formation of cocrystals and their polymorphs. On this foundation, several cross-fields in which mechanochemistry enhances the application value of cocrystal engineering are shown to overcome existing limitations, which are difficult or impossible to access using conventional solution methods. More importantly, we demonstrate that the introduction of new methods, such as cultivating single crystals from melt microdroplets, and new techniques, such as microelectron diffraction (Micro-ED), has harmoniously united the fields of cocrystal engineering and mechanochemistry. Finally, a brief conclusion and outlook are presented, including current challenges and future opportunities for the cooperation of mechanochemistry and cocrystal engineering. 

Mechanochemical Synthesis of Cocrystal: From Mechanism to Application

We have synthesized a completely new family of acyclic trimeric cyclodiphosphazane compounds comprising NH, Ni Pr, Nt Bu and NPh bridging groups. In addition, the first NH-bridged acyclic dimeric cyclophosphazane has been produced. The trimeric species display highly tuneable characteristics so that the distance between the terminal N(H)R moieties can be readily modulated by the steric bulk present in the bridging groups (ranging from ≈6 to ≈10 A). Moreover, these species exhibit pronounced topological changes when a weak non-bonding NH⋅⋅⋅π aryl interaction is introduced. Finally, the NH-bridged chloride binding affinities have been calculated and benchmarked along with the existing experimental data available for monomeric cyclodiphosphazanes. Our results underscore these species as promising hydrogen bond donors for supramolecular host-guest applications.

N-Bridged Acyclic Trimeric Poly-Cyclodiphosphazanes: Highly Tuneable Cyclodiphosphazane Building Blocks.

Inorganic macrocycles remain largely underdeveloped compared with their organic counterparts due to the challenges involved in their synthesis. Among them, cyclodiphosphazane macrocycles have shown to be promising candidates for supramolecular chemistry applications due to their ability to encapsulate small molecules or ions within their cavities. However, further developments have been handicapped by the lack of synthetic routes to high-order cyclodiphosphazane macrocycles. Moreover, current approaches allow little control over the size of the macrocycles formed. Here we report the synthesis of high-order oxygen-bridged phosphazane macrocycles via a “3 + n cyclisation” (n = 1 and 3). Using this method, an all-PIII high-order hexameric cyclodiphosphazane macrocycle was isolated, displaying a larger macrocyclic cavity than comparable organic crown-ethers. Our approach demonstrates that increasing building block complexity enables precise control over macrocycle size, which will not only generate future developments in both the phosphazane and main group chemistry but also in the fields of supramolecular chemistry. Cyclodiphosphazane macrocycles have demonstrated promising host-guest chemistry, but synthetic routes to highorder versions are lacking. Here the authors synthesise high-order oxygen-bridged phosphazane macrocycles via a modular cyclisation strategy.

/pdf/size-control-in-the-synthesis-of-oxo-bridged-phosphazane-iihiryauiu.pdf

Size-control in the synthesis of oxo-bridged phosphazane macrocycles via a modular addition approach

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Mechanosynthesis of Higher-Order Cocrystals: Tuning Order, Functionality and Size in Cocrystal Design**

N-Bridged Acyclic Trimeric Poly-Cyclodiphosphazanes: Highly Tuneable Cyclodiphosphazane Building Blocks.

Size-control in the synthesis of oxo-bridged phosphazane macrocycles via a modular addition approach