A scalable, transferable, cooling crystallisation route to the elusive, metastable, form II of the API acetaminophen (paracetamol) has been developed using a multicomponent “templating” approach, delivering 100% polymorphic phase pure form II at scales up to 120 g. Favourable solubility and stability properties are found for the form II samples.

A transferable, simple, method for producing previously elusive and novel polymorphic forms of important active pharmaceutical ingredients (APIs; paracetamol (acetaminophen), piroxicam and piracetam) is demonstrated. Nitrogen heterocyclic co-molecules are employed to influence the self-assembly crystallisation process in a multi-component environment. Previously unknown solvates have also been synthesised by this method.

Nine hydrogen bonded networks of N-phenylurea and 5-nitroisophthalic acid, with solvent inclusion properties, have been engineered and their thermal stabilities studied. Solvent guests of methanol, ethanol, acetonitrile, acetone, THF, ethyl acetate and water have been included into the hydrogen bonded host networks in pockets and channels via interaction with a carboxylic acid group of the host. Two non-solvated N-phenylurea 5-nitroisophthalic acid complexes (NS1 2:1 and NS2 1:1) were also formed. Thermal studies of the inclusion materials revealed guest release and conversion to NS1, in all but one case, and conversion of one non-solvated form to the other (NS2 to NS1). The carboxylic acid:amide hydrogen bond synthon R22(8) was shown to be a robust synthon for network formation whilst guest molecules are suggested to have a role in templating the overall network geometry.

A total of 18 molecular complexes of chloranilic acid (H2CA) and various isomeric dimethylpyridine (lutidine) bases (B) in a 1:1 and 1:2 stoichiometric ratio have been prepared and characterised structurally; 10 of the structural determinations used high resolution crystallography. Since proton transfer between the acid and base occurs in all the crystalline forms, they are most appropriately described as salts between the lutidinium cations [BH+] and the chloranilate mono- and dianions [HCA−] and [CA2−]. The formation of bifurcated or non-bifurcated charge-assisted hydrogen bonds is described and the influence of the different functional groups on symmetrical or asymmetrical bifurcated hydrogen bond formation are investigated. Previously unreported salts of the composition [BH+][HCA−] with 2,3- and 3,5-lutidine, and [BH+]2[CA2−] with 2,3-, 2,4-, 2,5-, 2 ,6- and 3,4-lutidine are reported, as well as di- and trihydrate forms of the latter salt type with 2,4- and 3,4-lutidine respectively. For the 2,4- and 3,5-lutidines only, molecular complexes containing co-existing charged and neutral chloranilic acid molecules are also observed. The charge delocalisation in the chloranilate anions, which has an influence on the hydrogen bond distances, is confirmed by the deformation density plots, atomic net charge calculations and the density at the bond critical points. The QTAIM molecular graphs, which show the presence of bifurcated or non-bifurcated hydrogen bonds, are highly dependent on the exact refinement model. Lattice energy calculations based on the experimental charge densities also show a high dependence on the refinement strategy, while theoretical lattice energy calculations using different approaches provide no consistency in the rank order stabilities. We conclude that neither experimental nor theoretical approaches are currently sufficiently accurate to determine a definitive stability order for such isomeric complexes.

The effect of the triblock copolymer Pluronic P123 (PP123) on the growth of succinic acid crystals from aqueous solutions is reported at two batch process scales: 10 and 350 mL. The presence of small quantities of PP123 is shown to modify the crystal morphology from plate-like crystals to block-like crystals, in a fully reproducible manner. Increasing the quantity of polymer present, or the concentration of succinic acid used, produces needle-like crystals that are less favorable for processing. In-line process analytical tools (FBRM, PVM, and Raman) were implemented for the larger volume batch processes, allowing the crystallization to be monitored in real time. The effect of the polymer on the metastable zone width (MSZW) has also been determined in designing the crystallization experiments and is presented. In addition, the effect of the individual blocks of the copolymer, poly(ethylene glycol) and poly(propylene glycol), on the crystal morphology was examined, and these findings, together with face indexing and knowledge of the underlying crystal structure, have allowed a possible mechanism to be constructed for the interaction of the polymer with the crystal surface. This mechanism is supported by subsequent recrystallization experiments following washing of the block-like crystals with a nonpolar solvent.

The deuterated molecular complexes of isonicotinamide with oxalic acid crystallise in two polymorphs, which are found to be distinct from the two polymorphs of the hydrogenous complexes previously reported. This phenomenon is known as isotopomeric polymorphism, is rarely observed in molecular materials and in particular the presence of multiple polymorphic forms of each isotopic material observed here appears to be unprecedented. The four polymorphic forms are found to exhibit different degrees of hydron transfer. Unlike the hydrogenous forms, the deuterated polymorphs do not show short, strong hydrogen bonding between the acid and the pyridine base. Periodic electronic structure calculations establish an energy scale for the polymorphism in these isotopomeric polymorphs.

Reacting equimolar quantities of 5-allenyl-1,3-benzenedicarboxylic acid (H2abd) with lead(II) acetate trihydrate in N,N-dimethylformamide (DMF) under solvothermal conditions results in formation of a metallogel with a critical gelation percentage of 1% w/v. Elemental analysis performed on the gel provided a molecular composition ratio of [Pb(abd)(H2O)]n (1). Viewing the gel by scanning electron microscopy (SEM) identified an entangled network of cross-linked nano-fibres. 1H-NMR aliquots of hydrated lead(II) acetate added to a solution of H2abd in deuterated DMF allows inferences to be made about solution-state behaviour that occurs during the initial gel aggregation stage. Under non-solvothermal conditions, combining H2abd and hydrated lead(II) acetate resulted in formation of single crystals suitable for X-ray diffraction, which were identified as a 3D coordination polymer with composition [Pb(abd)(DMF)] (2). Structural features observed within this 3D coordination polymer provide the basis for assigning the molecular structure to the fibrils present within gel 1. This assertion is supported by comparable vibrational profiles taken from a sample of dried gel 1 to that of crystalline 2, and the matching of early solution-state 1H-NMR spectroscopic trends to later solid-state observations.

The influence of weak hydrogen bonds on the crystal packing of a series of heavy and transition metal coordination polymers synthesized using the ligand 5-ethynyl-1,3-benzenedicarboxylic acid (H2ebdc) has been evaluated. Five coordination polymers were prepared and crystallographically characterized. These comprise two 1D chains, [Pb(ebdc)(DMSO)2] (1) and [Pb(ebdc)(DMF)] (2), two 2D nets, [Cu3(ebdc)(H2O)1.5(MeOH)0.5]·6H2O (3) and [Pb2(ebdc)2(DMF)4]·H2O (4), and a single 3D framework, [HNEt3][Zn3(μ3-OH)(μ2-H2O)(ebdc)3(MeOH)0.67(H2O)0.33]·MeOH·1.33H2O (5). The crystal structure of the free acid ligand form, H2ebdc·H2O, is also reported. Within the lead(II) coordination structures, ethynyl-derived C–H···O interactions are consistently found to provide the dominant influence over the crystal packing, as determined by solid-state structural analysis in combination with vibrational spectroscopy. The influence of weak hydrogen-bonding effects on the crystal packing of the transition metal coordination polymers that contain lattice water and methanol molecules was found to be far less prominent, which is interpreted in terms of the greater prevalence of strong hydrogen-bond donors and acceptors forming O–H···O interactions within these crystalline lattices.

Polymorphism in drug compounds can cause significant problems for industrial-scale production and so a method for restricting the conformational freedom of the target compound whilst retaining desired chemical properties is highly beneficial to the pharmaceutical industry. Co-crystallisation is commonly used to alter the structure of an active pharmaceutical ingredient (API) without affecting its activity. A comprehensive co-crystal screen of four fenamic acid derivatives affords a strictly limited number of co-crystals. These show no evidence of polymorphism, although some of the parent APIs exhibit significant polymorphism. Two of these co-crystals, of mefenamic acid and tolfenamic acid with 4,4′-bipyridine, were previously unknown and are studied using X-ray diffraction. Co-crystals from this screen are fully characterised and display comparable solubility and stability with respect to the parent APIs; no phase transformations have been identified. A range of crystallisation techniques, including cooling and grinding methods, are shown to afford single polymorphic forms for each of the co-crystals.

5-Ethynyl-1,3-benzenedicarboxylic acid (H2ebdc) reacted with lead(II) acetate trihydrate yields a 1D ladder network, [Pb(ebdc)(MeOH)]2·H2O (1). Removing crystals of 1 from the mother liquor results in a facile single crystal to single crystal transition, yielding 2D [Pb(ebdc)] net (2) with a change in space group from I2/a to P.

The potential of neutron powder diffraction (NPD) to provide vital information on the determination of accurate hydrogen positions in organic molecular crystals is demonstrated through the study of a series of hydrogen bonded molecular complexes with relevance in crystal engineering. By studying complexes designed to contain short, strong hydrogen bonds, the findings are shown to be of particular importance in the study of proton transfer, and the often critical distinction between neutral complexes and salts in these molecular materials. The use of combined NPD and single crystal X-ray diffraction is shown to be particularly potent in this area.

A series of twelve multi-component molecular crystals of the active pharmaceutical ingredient (API) piroxicam (PX) have been synthesised and their structures analysed with respect to their supramolecular motifs and degree of intermolecular hydrogen transfer observed on formation of the various complexes. The multi-component crystals of PX formed with a series of basic N-heterocycles are contrasted with those formed with strong haloanilic acids, with PX found to adopt different ionisation states. The effect of the formation of these multi-component molecular crystals on the physical property of solubility, often crucial in API formulation, has been investigated and these solubility determinations are compared with those of the parent PX material. Enhanced solubility is evident in some of the multi-component crystals formed.

The synthesis and crystal structures of a series of six magnesium pyridinecarboxylic and dicarboxylic acid complexes are reported. These complexes have been prepared to establish the nature of the hydrogen-bonding within this series and to investigate the potential of using these complexes as precursors in the self-assembly of network materials. Two Mg picolinic acid complexes (Mg1, Mg2) display a 1:2 metal:ligand ratio and are polymorphic. A Mg isonicotinic acid complex (Mg3) is a constitutional isomer of Mg1 and Mg2, while a 1:1 Mg picolinic acid complex (Mg4) is also reported and compared to the other members of the series. The set of complexes reported is completed by the synthesis and structural characterisation of two complexes containing the 2,4-pyridinedicarboxylic acid (2,4pdca) ligand, both a 1:1 (Mg5) and 1:2 (Mg6) Mg 2,4pdca acid complex, in which the presence of the additional carboxylate functionality provides clearer potential to form materials with extended network structures.

The carboxylic acid dimer is a frequently observed intermolecular association used in crystal engineering and design, which can show proton disorder across its hydrogen bonds. Proton disorder in benzoic acid dimers is a dynamic, temperature-dependent process whose reported occurrence is still relatively rare. A combination of variable temperature X-ray and neutron diffraction has been applied to demonstrate the effect of local crystalline environment on both the degree and onset of proton disorder in 3,5-dinitrobenzoic acid dimers. Dimers which have significantly asymmetric local intermolecular interactions are found to have a higher onset temperature for occupation of a second hydrogen atom site to be observed, indicating a greater energy asymmetry between the two configurations. Direct visualization of the electron density of hydrogen atoms within these dimers using high resolution X-ray diffraction data to characterize this disorder is shown to provide remarkably good agreement with that derived from neutron data.

4-Phenoxyphenol is a simple organic molecule that crystallizes as a porous material with channels running throughout the structure. The channels are constructed by a 6-fold hydrogen bonded ring and can host solvent molecules incorporated during crystal growth, with a minimum channel diameter of 5.8–5.9 Å; each channel usually contains a single solvent molecule per unit cell. The hydrogen bonded ring shows surprising flexibility, being able both to breathe and to sustain its crystalline integrity even when grown with empty pores. This is particularly surprising given that the remainder of the interactions within the crystal structure are C–H···π interactions and are weak in nature. It is also possible to grow “dry” porous 4-phenoxyphenol crystals by using a bulky solvent in the recrystallization.

A series of nineteen piroxicam (PX) molecular complexes with mono-substituted benzoic acid co-molecules are reported. The piroxicam molecule can exist in two possible tautomers, one of which is zwitterionic; the PX tautomer obtained in these complexes is not related to the type of substituent or substitution position. Instead, a correlation is seen between the pKa of the benzoic acid co-molecule and the preference towards a particular PX tautomer. The complexes with 2-, 3- and 4-fluorobenzoic acids exhibit the rare phenomenon of tautomeric polymorphism. DSC measurements have been used to identify the most thermodynamically stable polymorph in these cases and this has been rationalised by consideration of the intermolecular interactions in the crystal structures. The complexes containing zwitterionic piroxicam (PXZ) display a highly predictable and reproducible four-molecule tetrameric hydrogen bonding pattern whereas the complexes containing non-ionised piroxicam have more than one possible hydrogen bonding synthon.

The phenomenon of solid-state proton migration within molecular complexes containing short hydrogen bonds is investigated in two dimethylurea–oxalic acid complexes. Extensive characterisation by both X-ray and neutron diffraction shows that proton migration along the hydrogen bond can be induced in these complexes as a function of temperature. This emphasises the subtle features of the hydrogen bond potential well in such short hydrogen bonded complexes, both intrinsically and in the effect of the local crystalline environment. Based on these findings, the synthesis and analysis of a series of solid-state molecular complexes is shown to be a potential route to designing materials with tuneable proton migration effects.

A highly interactive research-led learning session for chemistry undergraduates is described, which aims to lead students to an awareness of the applications of crystallography technique through a mentored hands-on crystal structure solution and refinement session. The research-based environment is inherent throughout the 4.5 h program and is emphasized by several features in the learning experience.Keywords: Analytical Chemistry; Crystals/Crystallography; Curriculum; Hydrogen Bonding; Molecular Properties/Structure; Problem Solving/Decision Making; Undergraduate Research; Upper-Division Undergraduate; X-Ray Crystallography;

A simple route to crystallization of the pharmaceutically important paracetamol form II is reported. The method is based around multicomponent crystallization techniques, involving various second components containing carboxylic acid groups and a range of solvents. These crystallization experiments do not produce multicomponent molecular complexes, but instead they provide the conditions in which the metastable paracetamol form II is reliably produced in 100% yields and with stability of greater than one year. To date, batches of paracetamol form II have been produced easily on the 100 mg scale with clear potential for bulk production.

A transferable, simple, method for producing previously elusive and novel polymorphic forms of important active pharmaceutical ingredients (APIs; paracetamol (acetaminophen), piroxicam and piracetam) is demonstrated. Nitrogen heterocyclic co-molecules are employed to influence the self-assembly crystallisation process in a multi-component environment. Previously unknown solvates have also been synthesised by this method.

A scalable, transferable, cooling crystallisation route to the elusive, metastable, form II of the API acetaminophen (paracetamol) has been developed using a multicomponent “templating” approach, delivering 100% polymorphic phase pure form II at scales up to 120 g. Favourable solubility and stability properties are found for the form II samples.

The phenomenon of solid-state proton migration within molecular complexes containing short hydrogen bonds is investigated in two dimethylurea–oxalic acid complexes. Extensive characterisation by both X-ray and neutron diffraction shows that proton migration along the hydrogen bond can be induced in these complexes as a function of temperature. This emphasises the subtle features of the hydrogen bond potential well in such short hydrogen bonded complexes, both intrinsically and in the effect of the local crystalline environment. Based on these findings, the synthesis and analysis of a series of solid-state molecular complexes is shown to be a potential route to designing materials with tuneable proton migration effects.

5-Ethynyl-1,3-benzenedicarboxylic acid (H2ebdc) reacted with lead(II) acetate trihydrate yields a 1D ladder network, [Pb(ebdc)(MeOH)]2·H2O (1). Removing crystals of 1 from the mother liquor results in a facile single crystal to single crystal transition, yielding 2D [Pb(ebdc)] net (2) with a change in space group from I2/a to P.