Cocrystallization of Nutraceuticals

Cocrystallization has emerged over the past decade as an attractive technique for modification of the physicochemical properties of compounds used as active pharmaceutical ingredients (APIs), complementing more traditional methods such as salt formation. Nutraceuticals, with associated health benefits and/or medicinal properties, are attractive as coformers due to their ready availability, known pharmacological profile, and natural origin, in addition to offering a dual therapy approach. Successful studies of favorably altering the physicochemical properties of APIs through cocrystallization with nutraceuticals are highlighted in this review. Many of the key functional groups commonly seen in nutraceuticals (e.g., acids, phenols) underpin robust supramolecular synthons in crystal engineering. This review assesses the structural data available to date across a diverse range of nutraceuticals, both in pure form and in multicomponent materials, and identifies the persistent supramolecular features present. This insight will ultimately enable predictive and controlled assembly of functional materials incorporating nutraceuticals together with APIs

Crystal Landscape of Primary Aromatic Thioamides

The crystal landscape of a series of primary aromatic thioamides is described, displaying similar characteristic intermolecular hydrogen-bonding interactions in the solid state to those observed in their widely studied amide analogues, including R₂²(8) dimers and C(4) chains. In a number of cases, high <i>Z</i>′ values were observed in the structures. On the basis of the observed solid-state features, the thioamide functional group, which is a strong hydrogen-bond donor and moderate acceptor, offers considerable potential as a key moiety for crystal engineering

Crystal Landscape of Primary Aromatic Thioamides

The crystal landscape of a series of primary aromatic thioamides is described, displaying similar characteristic intermolecular hydrogen-bonding interactions in the solid state to those observed in their widely studied amide analogues, including R₂²(8) dimers and C(4) chains. In a number of cases, high <i>Z</i>′ values were observed in the structures. On the basis of the observed solid-state features, the thioamide functional group, which is a strong hydrogen-bond donor and moderate acceptor, offers considerable potential as a key moiety for crystal engineering

Preparation and characterisation of solid state forms of paracetamol-O-glucuronide

The synthesis and crystallisation of the pharmaceutically important metabolite, paracetamol-O-glucuronide, is described. Hydrated and anhydrous forms of the target molecule have been characterised by PXRD, DSC and TGA. In addition, a methanol solvate has been analysed, including single crystal analysis, which represents the first structure solution for this system

Investigating CS···I Halogen Bonding for Cocrystallization with Primary Thioamides

Cocrystallization utilizing halogen bonding involving the thiocarbonyl functional group of a series of primary aromatic thioamides has been investigated. The well-known organoiodide 1,4-diiodotetrafluorobenzene was utilized as the halogen bond donor and the CS···I halogen bond was established as a robust supramolecular synthon in these systems. Weak N–H···S hydrogen bonding involving the thioamides influences the overall supramolecular architectures, meaning that there is a diverse range of structural motifs and cocrystal stoichiometries observed. The majority (60%) of the cocrystals obtained have a 2:1 ratio of thioamide/organiodide with the latter present over an inversion center. The higher ratio of organoiodide seen in the other cocrystals is achieved by additional I···I and I···π halogen bonding. The CS···I halogen bond is replaced by N···I halogen bonding in the one cocrystal containing a pyridyl-substituted thioamide. The ability of the thioamides to form cocrystals and the strength of the halogen bond were influenced by the nature of the substituents on the aromatic ring, with derivatives containing electron donating groups most likely to form cocrystals. Calculated molecular electrostatic potential values on the sulfur atom in the thioamides corroborate these experimental results

Diversity in a simple co-crystal: racemic and kryptoracemic behaviour

The crystal structure containing (+/-)-3-methyl-2-phenylbutyramide with salicylic acid is the first example of a kryptoracemate co-crystal. It exhibits the first temperature mediated reversible single-crystal to single-crystal transition between two kryptoracemate forms, in addition to crystallising in another, racemic, form. Theoretical calculations and structural analysis reveal that there are only small differences in both energy and packing arrangements between the three forms. These results suggest that co-crystals can be an opportunity to investigate kryptoracemate behaviour.The crystal structure containing (+/-)-3-methyl-2-phenylbutyramide with salicylic acid is the first example of a kryptoracemate co-crystal. It exhibits the first temperature mediated reversible single-crystal to single-crystal transition between two kryptoracemate forms, in addition to crystallising in another, racemic, form. Theoretical calculations and structural analysis reveal that there are only small differences in both energy and packing arrangements between the three forms. These results suggest that co-crystals can be an opportunity to investigate kryptoracemate behaviour

Insight into the Mechanism of Formation of Channel Hydrates via Templating

Cocrystallization of modafinil, <b>1</b>, and 1,4-diiodotetrafluorobenzene, <b>2</b>, in toluene leads to the formation of a metastable modafinil channel hydrate containing an unusual hydrogen bonded dimer motif involving the modafinil molecules that is not seen in anhydrous forms of modafinil. Computational methodologies utilizing bias drift-free differential evolution optimization have been developed and applied to a series of molecular clusters and multicomponent crystals in the modafinil/water and modafinil/water/additive systems for the additive molecules <b>2</b> or toluene. These calculations show the channel hydrate is less energetically stable than the anhydrous modafinil but more stable than a cocrystal involving <b>1</b> and <b>2</b>. This provides theoretical evidence for the observed instability of the channel hydrate. The mechanism for formation of the channel hydrate is found to proceed via templating of the modafinil molecules with the planar additive molecules, allowing the formation of the unusual hydrogen-bonded modafinil dimer. It is envisaged that the additive is then replaced by water molecules to form the channel hydrate. The formation of the channel hydrate is more likely in the presence of <b>2</b> compared to toluene due to the destabilizing effect of the larger iodine molecules protruding into neighboring modafinil clusters

Design and Synthesis of Ternary Cocrystals Using Carboxyphenols and Two Complementary Acceptor Compounds

A strategy combining a ditopic hydrogen-bond donor with two different hydrogen-bond acceptor molecules is proposed for the assembly of simple trimeric building blocks used in the construction of ternary cocrystals. The crystallization of each of three different low symmetry carboxyphenols (3-hydroxybenzoic acid, 6-hydroxy-2-naphthoic acid, and ferulic acid) with acridine and 2-amino-4,6-dimethylpyrimidine yielded ternary cocrystals where the three components are joined by phenol-pyridine and carboxylic acid-amidine synthons. The use of p<i>K</i>_a values, beta values, and synthon histories in the selection of the acceptor compounds is discussed. Significant challenges to the growth of the desired ternary products from solution were presented by competing crystalline phases, including the individual components, a variety of binary phases, salts, and hydrates. Molecular electrostatic potentials were used to analyze the donating and accepting abilities of the competing synthons

Synthesis of Cyclic α‑Diazo-β-keto Sulfoxides in Batch and Continuous Flow

Diazo transfer to β-keto sulfoxides to form stable isolable α-diazo-β-keto sulfoxides has been achieved for the first time. Both monocyclic and benzofused ketone derived β-keto sulfoxides were successfully explored as substrates for diazo transfer. Use of continuous flow leads to isolation of the desired compounds in enhanced yields relative to standard batch conditions, with short reaction times, increased safety profile, and potential to scale up

Demonstrating the Influence of Solvent Choice and Crystallization Conditions on Phenacetin Crystal Habit and Particle Size Distribution

Phenacetin was used as a model pharmaceutical compound to investigate the impact of solvent choice and crystallization conditions on the crystal habit and size distribution of the final crystallized product. The crystal habit of phenacetin was explored using crash-cooling crystallization (kinetically controlled) and slow evaporative crystallization (thermodynamically controlled) in a wide range of organic solvents. In general, a variety of needle-type shapes (needles, rods, or blades) were recovered from fast-cooling crystallizations, in contrast to hexagonal blocks obtained from slow evaporative crystallizations. The solubility of phenacetin was measured in five solvents from 10–70 °C to allow for the design of larger-scale crystallization experiments. Supersaturation and the nucleation temperature were independently controlled in isothermal desupersaturation experiments to investigate the impact of each on crystal habit and size. The crystal size (needle cross-sectional area) decreased with increasing supersaturation because of higher nucleation rates at higher supersaturation, and elongated needles were recovered. Increasing the nucleation temperature resulted in the production of larger crystals with decreased needle aspect ratios. Antisolvent phenacetin crystallizations were developed for three solvent/antisolvent systems using four different antisolvent addition rates to simultaneously probe the crystal habit and size of the final product. In general, increasing the antisolvent addition rate, associated with increased rate of generation of supersaturation, resulted in the production of shorter needle crystals