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Thesis (Ph.D. (Physics)) -- University of Limpopo, 2016 / Refer to the document / National Research Foundation

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Solid-liquid equilibrium in isomorphous amino acid systems has been investigated as a model for systems that form solid solutions. Solid- and liquid-phase compositions in L-valine + L-leucine, L-valine + L-isoleucine, and L-isoleucine + L-valine in water were measured over the entire range of solid composition, and it was shown (from mass balance and phase rule considerations) that these systems form solid solutions. The solid- phases resulting from isothermal and cooling crystallization experiments were also investigated using powder x-ray diffractometry which showed that homogeneous solid solutions could only be obtained in cooling crystallization experiments, whereas isothermal experiments generally produced inhomogeneous solids. This suggests that data reported in the literature from isothermal experiments may not represent true equilibrium values. Solid-phase activity coefficients were estimated using binary and ternary equilibrium data and the UNIFAC-Kuramochi model for liquid-phase nonidealities. The solid phases in the three systems investigated exhibited significant nonidealities that were correlated using the Margules model. The model parameters exhibited a linear relationship with the ratio of binary solubilities of the two solutes. Such simple relationship may be advantageous when solid-liquid equilibrium of thermally unstable solutes or components with unknown physical properties are crystallized.

Synthesis of a melatonin agonist for treatment of sleep disorders produced a pair of enantiomers, of which one is biologically active. Two polymorphs were discovered using the inactive enantiomer, conserving the active enantiomer for toxicological testing. Later studies with the active enantiomer yielded only the metastable form, despite more than 1000 attempts to isolate the stable form. The difficulty is surprising, since the stable form is favored by 0.7 kcal mol–1, which is toward the extreme for stability differences between organic polymorphs. Study of individual enantiomers allowed the phase behavior of polymorphs of greatly different energy to be examined without interconversion. A number of unusual features are noted. After the stable polymorph of the inactive enantiomer was nucleated, the metastable form became very difficult to isolate. The metastable form converts into a less soluble monohydrate structure in water, whereas the stable polymorph does not due to its reduced activity. Both chiral polymorphs are denser than the racemic crystalline form at low temperature, the stable form being at the extreme for chiral-racemic pairs. Free energy-temperature relations predict “spontaneous resolution” of the racemic crystalline form into a conglomerate mixture of stable polymorph at low temperature. The unusual characteristics of the system are explained by hydrogen bonding and conformational flexibility of the molecule. Ab initio calculations aid in understanding the relative contributions of these interactions to the lattice energies and the role that conformational energy differences play in the polymorphic stability. This system highlights the importance of the creation of the very first nuclei of a crystalline form. The reluctance of the stable form to nucleate is attributed to a large energy difference between polymorphic forms. The large interfacial tension for primary nucleation reduces the probability of forming clusters of size sufficient for favorable growth in the absence of heterogeneous nucleation. This study highlights how nucleation of a new form can revise the readily “accessible” region of a compound’s crystal form landscape.

Yes / Polymorphism in active pharmaceutical ingredients (APIs) can be regarded as critical for the potential that crystal form can have on the quality, efficacy and safety of the final drug product. The current contribution aims to characterize thermodynamic interrelationship of a dimorphic co-crystal, FI and FII, involving carbamazepine (CBZ) and saccharin (SAC) molecules. Supramolecular synthesis of CBZ-SAC FI and FII have been performed using thermo-kinetic methods and systematically characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), solubility and slurry measurements. According to Berger and Ramberger’s heat of fusion rule, FI (ΔHfus = 121.1 J/g, mp 172.5 °C) and FII (ΔHfus= 110.3 J/g, mp 164.7 °C) are monotropically related. The solubility and van’t Hoff plot results suggest that FI stable and FII metastable forms. This study reveals that CBZ-SAC co-crystal phases, FI or FII, could be stable to heat induced stresses, however, FII converts to FI during solution mediated transformation. / Authors would like to acknowledge UKIERI (TPR 26), EPSRC (EP/J003360/1, EP/L027011/1) for the support. Open Access funded by Engineering and Physical Sciences Research Council

Faculty of Science; School of Chemistry; PhD Thesis / ortho-Ethoxy-trans-cinnamic acid (OETCA) has been known to form three polymorphs - the α , β and γ polymorphs which crystallize in P1 (Z=2), R3 (Z=18) and C2/c (Z=8), respectively. These polymorphs have long been of interest from polymorphism and solid-state photoreactivity perspectives but have, until now, never been fully characterized. In this thesis the complete structures of these polymorphs and their photodimerization products are presented. In addition, a new polymorph, the α' polymorph [P1 (Z=6)], which is only obtainable from the α polymorph via a reversible solid-state phase transformation at 60 °C, has been discovered and characterised. In all the polymorphs of OETCA, the smallest building component is the hydrogen-bonded carboxylic acid R22(8) dimers. These dimers further aggregate via CH...O interactions to form a ribbon motif in the α , α' and γ polymorph structures. Structural and solid-state reactivity differences in these three polymorphs are therefore due to differences in the arrangement of these ribbons. With few exceptions, solid state [2+2] photodimerization reactions have been found to obey the topochemical principle. Such reactions occur with minimal structural movement in which the contact distance between reacting double bonds is between 3.5 and 4.2 Å. In this respect the solid-state reactivity of both the α and α' polymorphs is especially interesting and unusual, and indicate that significant movement - both molecular and structural - is possible and necessary for reactions to occur in these polymorphs. Both polymorphs yield the centrosymmetric dimer product 2,2' diethoxy-α-truxillic acid. Photodimerization in the layered structure of the α polymorph, where the double bond contact distance is at 4.54 Å beyond reasonable photodimerization distance, is probably initially enabled by crystal defects. While the α' polymorph is structurally very similar to the α polymorph it is instead composed of two reaction sites with double bond contact distances of 3.72 and 4.99 Å, respectively. This polymorph's solid-state reactivity has as a consequence been found to be temperature dependent, with only 66.7% conversion being achieved at 293 K and 100% conversion occurring at 343 K; reaction at 343 K involves both a significant conformation change in a reaction product as well as a heat and reaction driven phase change. In the γ polymorph the closest distance between the double bonds is 5.26 Å, which together with the structural rigidity imposed by its herring bone structure ensures that no photodimerization occurs. The β polymorph is really a solvate containing either benzene or thiophene within channels in the structure. The interactions between the solvent and OETCA molecules play an important role in maintaining the symmetry and integrity of the structure. The thiophene and benzene forms of the β polymorph are isomorphous and yield a mirror product (2,2'-diethoxy-β-truxinic acid) upon photodimerization - the molecules involved being related by a 4.0 Å translation along the unit cell c axis.

<p> The alkali metal dichromates show extensive polymorphism. The crystal structures of the polymorphs α-Na2Cr2O7, β-Na2Cr2O7, β1-Rb2Cr2O7 and P21/c NaRbCr2O7 have been determined with x-ray methods. Crystal data were determined for β2-Rb2Cr2O7, P1 Cs2Cr2O7 and the P21/c NaCsCr2O7.</p> <p> The dichromate ions found in this work have been compared with the dichromate ions found in other crystal structure determinations. The anions are described in terms of the bridging oxygen angles b and the torsion angles α1 and α2. Many of the dichromate ions are close to having C2v symmetry with values for α1 and α2 close to zero and bridging angles of around 124°. But there is a number of dichromates with α1 = -α2 and 0°<|α|<60° for which the bridging angle varies between 131° to 141°.</p> <p> The structures determined in this work are discussed as part of a unified description of thortveitite like and dichromate like structures in terms of layers of Y2O7 anions. In terms of this description and Brown and Calvo's classification a structure is proposed for the β2Rb2Cr2O7, while for the structure of NaCsCr2O7 it is suggested that it is isostructural to that of P21/c NaRbCr2O7. The phase transition of α-Na2Cr2O7 to β-Na2Cr2O7 is considered and it is suggested that a twisting thermal mode plays an important role in this as well as in other transitions.</p> / Thesis / Doctor of Philosophy (PhD)

No / The crystal structure of the I-phase of quinacridone was determined from non-indexed X-ray powder data by means of crystal structure prediction and subsequent Rietveld refinement. This I-phase is another polymorph than the -phase reported by Lincke [G. Lincke and H.-U. Finzel, Cryst. Res. Technol. 1996, 31, 441¿452.]. The crystal structures of the and polymorphs were determined from single crystal data. The knowledge of the crystal structures can be used for crystal engineering, i.e., for targeted syntheses of pigments having desired properties, especially for the syntheses of new red pigments.