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Following the computational prediction that 3-hydroxybenzoic acid (3HBA) could exist in more than the two literature polymorphs, an experimental investigation targeting computationally generated structures was performed. The third polymorph III, solved from powder X-ray diffraction data, and the literature form II share a common hydrogen-bonded ladder motif in contrast to the carboxylic acid dimer based form I. The two metastable polymorphs (II and III) are storage stable if phase pure and monotropically related to form I. Calorimetric measurements and (lattice) energy minimisations revealed that the three polymorphs are close in energy.

The solid form landscape of brucine sulphate (BS) was elucidated, resulting in three hydrate forms (HyA–C) and amorphous BS. Interconversion of the hydrates of BS with small changes in the relative humidity complicated identifying and characterising the solid forms. The hydrate obtained from crystallisation experiments (from water), HyA, is the only solid form described in the literature. The other two hydrates were produced by dehydration starting from the known hydrate. HyA contains 6.5 to 7.4 molecules of water per BS and is only stable in the relative humidity (RH) range ≥26% at room temperature (RT). HyB is only observable in a very narrow RH window (22–25%) at RT and shows a hexahydrate stoichiometry. At RH values ≤20%, the third hydrate, HyC, forms. Similar to HyA, the latter hydrate shows a variable water content of five or less water molecules per BS. Removal of the essential water molecules stabilising the hydrate structures causes the collapse to the amorphous state, a process which was not completed within 3.5 years of storing HyC under driest conditions (approx. 0%) at room temperature. Only the combination of intermolecular interaction and electronic structure calculations with thermal analytical techniques, X-ray diffraction, IR spectroscopy and gravimetric moisture (de)sorption studies and careful control of the external conditions allowed the discovery and rationalisation of the three hydrates of BS. The investigations on BS were complemented with an exploitation of the Cambridge Structural Database (CSD) to unravel the incidence of hydrates of sulphate salts. The analysis indicates that 56.5% of the sulphate salts (C, H, N, O, and S atoms only) are hydrate structures, with higher hydrates being more commonly present amongst sulphate salts than amongst all organic hydrates.

Experimental and theoretical characterisation and studies of the stability of heterobicyclic thiazinium salts (bicyclic 2-mercaptoimidazolium chlorides and bromides) were performed to rationalise and understand the influence of the counterion (Cl−↔ Br−) and the replacement of CH by N on crystal packing, the influence of the anion on the moisture and temperature dependent stability, and the racemisation behaviour of the imidazo-thiazinium chloride. Six compounds were synthesised and for five of the compounds the structures were solved from single-crystal X-ray diffraction data. The structural features of the sixth compound could be derived from powder X-ray diffraction data comparisons. An exchange of the Cl−anion by Br−does not influence the crystal packing of the racemic thiazinium salt but increases its moisture dependent stability. In contrast, replacing the imidazole moiety of the cation by a triazole or tetrazole moiety results in distinct packing arrangements of the investigated bromide salts, although,substitution calculations suggest that isostructural packing arrangements might exist. The binary melting point phase diagram was constructed to confirm the nature of the racemic species of the thiazinium chloride, and differential scanning calorimetry and lattice energy minimisations were used to estimate the enthalpy difference between the racemic and enantiopure crystals, rationalising the high tendency of racemisation of the enantiopure compound.

Dapsone (DDS) shows a rich solid form landscape, comprising five anhydrates, one hydrate and 15 solvates. The four isostructural DDS hemisolvates, with dichloromethane, acetonitrile, nitromethane and dimethyl sulfoxide as guest molecules, obtained by cooling crystallisation, slurry or solvent vapour diffusion experiments were investigated in this study. Experimental (thermal analysis and X-ray diffraction) and computational studies (lattice, intermolecular and stability energy calculations) were undertaken to rationalise and understand (hemi)solvate formation, stability and phase transitions occurring during the desolvation of the solvates. It was found that DDS⋯solvent interactions and the shape/size of the solvent molecules are critical for solvate formation. Careful control of the experimental crystallisation and storage conditions were required for identifying and characterising solvates that are unstable at ambient conditions. The solvent molecules of the hemisolvates are located at isolated-sites and form strong hydrogen bonds and/or interactions involving dispersion forces. The isostructurality of the four hemisolvates was confirmed by single crystal X-ray diffraction determinations and modelling, i.e. solvent exchange calculations. Furthermore, the formation of either the hemi- or monosolvate stoichiometry was rationalised on the basis of lattice energy calculations.

3-(3-Methylimidazolium-1-yl)propanoate (OOCEMIM), the related zwitterion of the parent ionic liquid [HOOCEMIM] [Cl], crystallises in two hydrated and one neat (AH) solid-state forms. All three forms can be produced directly in solution crystallisation experiments and their single crystal structures as well as the temperature- and moisture dependent interconversion pathways between the forms were unravelled. The OOCEMIM molecule adopts an elongated high energy conformation in both the mono- (Hy1) and dihydrates (Hy2), with water⋯OOCEMIM interactions contributing significantly to the lattice energy. A substantial conformational rearrangement of OOCEMIM is observed upon dehydration, resulting in a bent low energy conformation in the anhydrous form. Each of the three OOCEMIM solid-state forms shows a limited existence range. The anhydrous form AH can only be preserved at very dry atmospheric conditions (at 25 °C). The exposure of AH to elevated water vapour conditions results in a fast transformation to Hy1, which then transforms to Hy2 at relative humidities (RH) above 18%. Increasing the RH above 40% leads to deliquescence of the zwitterion. Hy1 and Hy2 melt at 90 °C and 61 °C (peritectic dissociation temperature), respectively, whereas AH melts and decomposes at 172 °C. The measured transformation enthalpies between the three solid-state forms, derived from differential scanning and isothermal calorimetry experiments, are in excellent agreement with the 0 K PBE-TS and PBE-D2 lattice energy differences. Knowledge about the interconversion pathways and stability ranges of the OOCEMIM solid-state forms is essential for handling the compound.

The solid forms emerging from an experimental screening programme of 1,10-phenanthroline (o-phen), a heavily used bidentate ligand, and interconversion pathways of its two neat forms, the monohdyrate (Hy1) and four solvates with acetone, chloroform, dichloromethane and 1,2-dichloroethane are described. The solvates, identified and characterised with thermoanalyical methods, are unstable when removed from the mother liquor and desolvate at room temperature depending on the relative humidity (RH) to anhydrate I° (AH I°) or transform to Hy1. At ambient conditions Hy1, a stoichiometric channel hydrate, is the thermodynaically most stable o-phen solid form. The enthalpically stabilised Hy1 melts at 102 °C or dehydrates to AH I° at RH < 10% at 25 °C. The potential energy difference between Hy1 and AH I° was calculated to be approx. 15 kJ mol–1. The second anhydrate polymorph (AH II) can be obatined from the quench cooled melt of o-phen, but is unstable at ambient conditions and transforms wihtin minutes to either AH I° or Hy1. The two neat polymorphs are enantiotropically related and water-free o-phen transforms to Hy1 at RH > 16%. The structural and stablity features of the solid forms, in paricular Hy1, are unravelled by a combination of experimental (thermal analysis, moisture sorption/desorption and storage experiments, infrared spectroscopy and powder X-ray diffraction) and computational modelling (crystal structure prediction and lattice energy calculations), providing a consistent picture why o-phen forms a very stable Z’ = 3 channel hydrate.

A computational search for polymorphs of cytosine, 5-flucytosine and a 1 : 1 mixture of the two substances not only rationalised the preferred packing arrangements but also enabled the finding and characterisation of cytosine/5-flucytosine solid solutions. The structures of the new solid forms were determined by combining laboratory powder X-ray diffraction data and computational modelling.

Crystal structure prediction studies indicated the existence of an unknown high density monohydrate structure (Hy1B°) as the global energy minimum for 4-aminoquinaldine (4-AQ). We thus performed an interdisciplinary experimental and computational study elucidating the crystal structures, solid form inter-relationships, and kinetic and thermodynamic stabilities of the stable anhydrate (AH I°), the kinetic monohydrate (Hy1A) and this novel monohydrate polymorph (Hy1B°) of 4-AQ. The crystal structure of Hy1B° was determined by combining laboratory powder X-ray diffraction data and ab initio calculations. Dehydration studies with differential scanning calorimetry and solubility measurements confirmed the result of the lattice energy calculations, which identified Hy1B° as the thermodynamically most stable hydrate form. At 25 °C the equilibrium of the 4-AQ hydrate/anhydrate system was observed at an aw (water activity) of 0.14. The finding of Hy1B° was complicated by the fact that the metastable but kinetically stable Hy1A shows a higher nucleation and growth rate. The presence of an impurity in an available 4-AQ sample facilitated the nucleation of Hy1B°, whose crystallisation is favored under hydrothermal conditions. The value of combining experimental with theoretical studies in hydrate screening and characterisation, as well as the reasons for hydrate formation in 4-AQ, are discussed.

Polymorphs of 4-aminoquinaldine (4-AQ) have been predicted in silico and experimentally identified and characterised. The two metastable forms, AH (anhydrate) II and AH III, crystallise in the trigonal space group [Formula: see text] and are less densely packed than the thermodynamically most stable phase AH I° (P21/c ). AH II can crystallise and exist both, as a solvent inclusion compound and as an unsolvated phase. The third polymorph, AH III, is exclusively obtained by desolvation of a carbon tetrachloride solvate. Theoretical calculations correctly estimated the experimental 0K stability order, confirmed that AH II can exist without solvents, gave access to the AH III structure, and identified that there exists a subtle balance between close packing and number of hydrogen bonding interactions in the solid state of anhydrous 4-AQ. Furthermore, the prevalence of void space and solvent inclusion in [Formula: see text] structures is discussed.

The ability of the pharmaceutically acceptable cocrystallising agents, succinic acid and 4-aminobenzoic acid, to form cocrystals with ten small organic molecules with hydrogen bonding acceptors but no donors, was investigated by grinding, hot-stage microscopy and solution based crystallisation experiments. The reproducible results obtained by different methods showed that only six cocrystals formed. The crystal structures of the four novel cocrystals, succinic acid·2,2′-bipyridine (1 : 1, P21/c, I), succinic acid·diphenylcyclopropenone (1 : 2, P21/c, II), 4-aminobenzoic acid·antipyrine (1 : 1, P21, III) and 4-aminobenzoic acid·phenazine (1 : 2, P, IV), are reported. The computed crystal energy landscapes of the cocrystals and their components show why succinic acid·1,4-dicyanobenzene did not form a cocrystal as well as predicting the observed structure of succinic acid·2,2′-bipyridine as the most stable. The most stable hypothetical structures of a 1 : 1 succinic acid·1,4-dicyanobenzene cocrystal are closely related to those of the components. The results demonstrate that cocrystal formation requires both hydrogen bonding and close packing, and so markedly non-planar pharmaceuticals will be quite specific in the steric and hydrogen bonding disposition requirement of coformers.

The study describes the solid state behaviour, and the thermal and structural features of four monosolvates of cinacalcet hydrochloride with acetic acid, chloroform, 1,4-dioxane, and tetrachloromethane, and summarises the transformation and production pathways of the seven crystal forms of this promising drug compound (calcimimetic). The solvates were identified and characterised by hot-stage microscopy, differential scanning calorimetry, thermogravimetric analysis, FT-infrared and Raman spectroscopy, powder diffractometry, and the structure of the acetic acid solvate was determined by single crystal X-ray diffraction. All solvates are unstable when removed from the mother liquor and desolvate to form II. To our knowledge, phase pure samples of this metastable but kinetically stable form are only obtainable via desolvation of one of the solvates.Thermoanalytical data and a conformation and packing analysis of the acetic acid solvate and the polymorphs indicate that the desolvation is a destructive process forming an isotropic intermediate state with high molecular mobility. Therefore the desolvation process results in the kinetic form II, which is structurally less similar to the solvate than the thermodynamically stable form III°. The study demonstrates that in spite of strong structural similarities between a solvate and a polymorph we can obtain a polymorph with less structural resemblance to the solvent adduct if the structure collapses during the desolvation process.