Tuning energetic properties through co-crystallisation - a high-pressure experimental and computational study of nitrotriazolone: 4,4'-bipyridine.

We report the preparation of a co-crystal formed between the energetic molecule 3-nitro-1,2,4-triazol-5-one (NTO) and 4,4'-bipyridine (BIPY), that has been structurally characterised by high-pressure single crystal and neutron powder diffraction data up to 5.93 GPa. No phase transitions or proton transfer were observed up to this pressure. At higher pressures the crystal quality degraded and the X-ray diffraction patterns showed severe twinning, with the appearance of multiple crystalline domains. Computational modelling indicates that the colour changes observed on application of pressure can be attributed to compression of the unit cell that cause heightened band dispersion and band gap narrowing that coincides with a shortening of the BIPY π⋯π stacking distance. Modelling also suggests that the application of pressure induces proton migration along an N-H⋯N intermolecular hydrogen bond. Impact-sensitivity measurements show that the co-crystal is less sensitive to initiation than NTO, whereas computational modelling suggests that the impact sensitivities of NTO and the co-crystal are broadly similar.

Designer Gelators for the Crystallization of a Salt Active Pharmaceutical Ingredient-Mexiletine Hydrochloride.

We report an approach to obtain drug-mimetic supramolecular gelators, which are capable of stabilizing metastable polymorphs of the pharmaceutical salt mexiletine hydrochloride, a highly polymorphic antiarrhythmic drug. Solution-phase screening led to the discovery of two new solvated solid forms of mexiletine, a type C 1,2,4-trichlorobenzene tetarto-solvate and a type D nitrobenzene solvate. Various metastable forms were crystallized within the gels under conditions which would not have been possible in solution. Despite typically crystallizing concomitantly with form 1, a pure sample of form 3 was crystallized within a gel of ethyl methyl ketone. Various type A channel solvates were crystallized from gels of toluene and ethyl acetate, in which the contents of the channels varied from those of solution-phase forms. Most strikingly, the high-temperature-stable form 2 was crystallized from a gel in 1,2-dibromoethane: the only known route to access this form at room temperature. These results exemplify the powerful stabilizing effect of drug-mimetic supramolecular gels, which can be exploited in pharmaceutical polymorph screens to access highly metastable or difficult-to-nucleate solid forms.

Novel keto-enol tautomerism in 1,3,5-trihydroxybenzene systems.

We report a new synthesis of the water-soluble compound 1,3,5-trihydroxy-2,4,6-trimethylsulfonic acid (1), which exists in two tautomeric forms (60 : 40::enol%:keto%) and can be used as a proton conductor. Quantum chemical calculations show the importance of intramolecular hydrogen bonding and the presence of implicit MeOH solvent on the relative stabilities of the tautomers. 1 complexes with lanthanides through its sulfonato groups and forms a layered cage-like structure with one intramolecular and two intermolecular hydrogen bonds.

Ball-free mechanochemistry: in situ real-time monitoring of pharmaceutical co-crystal formation by resonant acoustic mixing.

Resonant acoustic mixing (RAM) is a new technology designed for intensive mixing of powders that offers the capability to process powders with minimal damage to particles. This feature is particularly important for mixing impact-sensitive materials such as explosives and propellants. While the RAM technique has been extensively employed for the mixing of powders and viscous polymers, comparatively little is known about its use for mechanosynthesis. We present here the first in situ study of RAM-induced co-crystallisation monitored using synchrotron X-ray powder diffraction. The phase profile of the reaction between nicotinamide and carbamazepine in the presence of a small amount of water was monitored at two different relative accelerations of the mixer. In marked contrast to ball-milling techniques, the lack of milling bodies in the RAM experiment does not hinder co-crystallisation of the two starting materials, which occurred readily and was independent of the frequency of oscillation. The reaction could be optimised by enhancing the number of reactive contacts through mixing and comminution. These observations provide new insight into the role of various experimental parameters in conventional mechanochemistry using liquid-assisted grinding techniques.

Trimeric cyclamers: solution aggregation and high Z' crystals based on guest structure and basicity.

Ureidosalicylic acid forms remarkable trimeric cyclamer-like crystal structures with either three or six independent molecules in the asymmetric unit as a result of the excess of hydrogen bond donors and guest inclusion within the centre of the cyclamer. The structures persist in solution in hydrogen bond acceptor solvents suggesting a role for solution pre-association in forming high Z' structures.

Cavity-containing supramolecular gels as a crystallization tool for hydrophobic pharmaceuticals.

We present two approaches to low-molecular-weight supramolecular gels bearing hydrophobic cavities based on calixarene-containing building blocks. Gels are formed by a calixarene based tetrahydrazide gelator or a co-gel of a calixarene diammonium salt and a bis-crown ether. The calixarene hydrophobic cavity enables the complexation of hydrophobic drug molecules in a generic fashion thus providing an anchor site on the surface of the gel fibre to initiate drug crystal nucleation and growth. This technique potentially represents a route to growth of hard-to-nucleate polymorphic modifications. The co-gel comprising two components holding together by non-covalent ammonium-crown ether interaction can be easily switched back to the sol state by adding competitive binding cations.

Pharmaceutical crystallization with nanocellulose organogels.

Carboxylated nanocellulose forms organogels at 0.3 wt% in the presence of a cationic surfactant. The resulting gels can be used as novel crystallization media for pharmaceutical solid form control, resulting in isolation a new sulfapyridine solvate, morphology modification and crystallization of an octadecylammonium salt of sulfamethoxazole.

Manipulating three-dimensional gel network entanglement by thin film shearing.

Vortex fluidic mediated shearing of supramolecular gels in thin films leads to complete disruption of fluorous bis-urea derived gels. Hydrocarbon analogues however, are only partially disrupted, which emphasizes the resistance of non-fluorous bis-urea gelators towards shear. The gel structures have been studied by combining the thin film shearing with small angle neutron scattering. This technique represents a novel approach to study the effects of external stimuli on self-assembled supramolecular gel networks.

Gelation by supramolecular dimerization of mono(urea)s.

Mono-ureido salicylic acid derivatives form hydrogen bonded dimers that mimic the gelation behaviour of covalently linked bis(urea)s. The 5-ureido salicylic acid isomers are much more effective gelators because of the lowered conjugation and less planar geometry, resulting in stronger urea···urea α-tape hydrogen bonding interactions.

Fluorous 'ponytails' lead to strong gelators showing thermally induced structure evolution.

Appending perfluoroalkyl substituents to bis(urea) gelators results in significantly decreased inter-chain interactions with markedly thinner fibres and hence more cross-linked and more transparent gels with potential applications in the crystallisation of fluorinated pharmaceuticals. Gel structure has been probed by detailed SANS measurements which indicate a surprising structure evolution on thermal cycling, not seen for hydrocarbon analogues. The SANS data are complemented by the single crystal X-ray structure of one fluorinated gelator.

Fluorescent carbon dot-molecular salt hydrogels.

The incorporation of functionalised carbon nanodots within a novel low molecular weight salt hydrogel derived from 5-aminosalicylic acid is reported. The carbon dots result in markedly enhanced gelation properties, while inclusion within the hydrophobic gel results in a dramatic fluorescence enhancement for the carbon nanomaterials. The resulting hybrid CD gels exhibit a useful sensor response for heavy metal ions, particularly Pb2+.

Correction: Fluorescent carbon dot-molecular salt hydrogels.

[This corrects the article DOI: 10.1039/C5SC01859E.].