Dissertations / Theses on the topic 'Polymorphism (crystallography)'

Thesis (Ph.D)--Chemical Engineering, Georgia Institute of Technology, 2009.<br>Committee Chair: Rousseau, Ronald; Committee Member: Meredith, Carson; Committee Member: Prausnitz, Mark; Committee Member: Teja, Amyn; Committee Member: Wilkinson, Angus. Part of the SMARTech Electronic Thesis and Dissertation Collection.

Spectroscopy is increasingly used to investigate and monitor the solid state forms of pharmaceutical materials and products. Spectroscopy�s speed, nondestructive sampling, compatibility with fibre optics and safety also make it attractive for in-line monitoring. In this thesis, the spectroscopic techniques Fourier transform Raman spectroscopy, terahertz pulsed spectroscopy and second harmonic generation were used to characterise and quantify polymorphism and crystallinity of pharmaceutical compounds. Where possible, the multivariate analysis technique partial least squares was used for quantitative analysis. Fourier transform Raman spectroscopy detects polarisability changes mainly associated with molecular vibrations. Terahertz pulsed spectroscopy is a new spectroscopic technique that operates between the infrared and microwave regions of the electromagnetic spectrum and detects dipole moment changes mainly associated with crystalline phonon vibrations in the solid state. Second harmonic generation is a nonlinear optical phenomenon that depends on the dipole moment in crystals and crystal symmetry. Several materials capable of existing in different solid state forms were used. FT-Raman spectroscopy was able to differentiate carbamazepine forms I and III, enalapril maleate forms I and II and γ-crystalline and amorphous indomethacin. Combined with partial least squares the technique could quantify binary mixtures of CBZ forms I and III with a limit of detection as low as 1%, and mixtures of enalapril maleate with a limit of detection of as low as 2%. Terahertz pulsed spectroscopy obtained very different spectra for carbamazepine forms I and III, enalapril maleate forms I and II, γ-crystalline and amorphous indomethacin, crystalline and supercooled thermotropic liquid crystalline fenoprofen calcium, three forms of lactose, and five forms of sulphathiazole. At present the modes in the spectra cannot be attributed to specific phonon modes. Quantitation of binary mixtures of different forms of a compound using partial least squares analysis usually resulted in a limit of detection of about 1%. Second harmonic generation was used to quantify binary mixtures of different forms of enalapril maleate and lactose, as well as binary mixtures of enalapril maleate form II and polyvinylpyrrolidone. A quantitative relationship was present for each of the mixtures, however the limits of detection were usually above 10%. The high value is probably due to the machine being a prototype and univariate analysis associated with a single output variable. Future improvements to the apparatus and measurement parameters are likely to reduce the limits of detection. Ranitidine hydrochloride polymorphs could also be differentiated using second harmonic generation, however γ-crystalline and amorphous indomethacin and forms I and III of carbamazepine could not. The methods used in this thesis were successfully used for qualitative and quantitative analysis of polymorphism and crystallinity of pharmaceutical compounds. TPS and SHG are useful additions to the range of experimental techniques that can be used to investigate and monitor properties of pharmaceutical solids.

Polymorphism can influence every aspect of the properties of a solid including the shelf life, dissolution rate, solubility, formulation properties and processing properties of a solid drug. A deeper understanding of polymorphism and related solid state properties would ensure an improved quality of the materials used throughout drug preparation, dosage form formulation and clinical trials. Therefore, determination of the existence of polymorphs and pseudopolymorphs, characterization of different solid state forms and their respective properties, and controlling the existing form in the resulting formulation all form part of a rapidly growing field within pharmaceutical research and industry. Carbamazepine (CBZ) was the model drug used in this study. FT-Raman spectroscopy was chosen as a main investigative technique in this study to evaluate its potential in monitoring (pseudo)polymorphic conversions in aqueous suspensions in the absence or presence of various pharmaceutical excipients. Partial least squares analysis (PLS) was used for quantitative analysis of the spectral data. Earlier it has been found that CBZ converts rapidly to the dihydrate (DH) when exposed to humidity or water, and this has been reported to be the main reason for the sometimes observed greatly decreased bioavailability of marketed CBZ tablets. In this study, the conversion kinetics of CBZ (forms I, II and III) to DH in aqueous suspension were found to be first order kinetics with an unconverted portion (R� [greater than or equal to] 0.95), where the crystal morphology appeared to play a more important role in its conversion kinetics than the polymorphic form. The influence of pharmaceutical excipients on the conversion of CBZ in aqueous suspension was also explored. For excipients such as methylcellulose (MC), hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) which have both a low solubility parameter (< 27.0 MPa[1/2]) and strong hydrogen bonding groups, complete inhibition of the conversion of CBZ was possible even at a very low concentration (0.1 % w/v). Raman spectroscopy showed its high applicability in investigating CBZ conversion kinetics and screening of excipient effects in aqueous environment. It was demonstrated that Raman has a robust nature in quantitative analysis since problems such as different particle size, morphology, and spatial distribution of the two solid state forms of the drug seemed not to have significant influence on Raman scattering. This study has also clarified the relative importance of many contributing factors (type of crystalline form (CBZ or DH), crystal morphology, surface area, and excipient interactions with drug particles) influencing the in vitro dissolution of CBZ. The solid state characterization approach taken in this study will provide a deeper insight into the dissolution performance of drugs and should thus lead to a better understanding of in vitro/in vivo behavior of drugs.

This thesis describes the effect of pressure on crystal structures that are in some way unusual. The aim was to investigate whether pressure could be used to force these ‘structural oddities’ to conform to more conventional behaviour. In many cases pressure-induced phase transitions were observed, and the driving forces of these are considered. L-serine monohydrate crystallises with layers of hydrogen bonded serine molecules. Layers are linked together by H-bonds from the donor atoms of water molecules. The orientation of the water molecules between the layers is uncommon for other layered hydrates in the CSD. A single crystal of serine hydrate undergoes a pressure-induced phase transition at 5 GPa, which is characterised by a rotation of the water molecules to an orientation which is more frequently observed. PIXEL calculations show that the transition is driven by the PV term in the equation G = U - TS + PV. An attempt to reproduce the transition in another layered hydrate with a similar topology was partially successful in the compression of S-4-sulfo-L-phenylalanine monohydrate, which undergoes a similar phase transition at 1 GPa. Methyl 2-(9H-carbazol-9-yl)benzoate crystallises unusually with eight molecules in the asymmetric unit (Z’ = 8). Compression of a single crystal results in a phase transition at ca. 5 GPa to give a Z’ = 2 polymorph. The PV term is an important contributor to the driving force of the transition. The geometries of the molecules in phase-II are significantly less stable than in phase-I, and as pressure is released on phase-II the need to adopt a more stable molecular conformation eventually outweighs the PV advantage. The Z’ = 8 structure is eventually re-established at 4.6 GPa. This work illustrates how low Z’ polymorphs of the same structure are not always the thermodynamically more stable forms. When recrystallised in situ from a 4:1 by volume solution of methanol and ethanol, a new polymorph of salicylamide is obtained at 0.2 GPa. The ambient pressure phase appears in the CSD to contain a number of abnormally short H…H contacts. We find this model to be incorrect, and have re-determined the structure to find no short H…H contacts. PIXEL and DFT calculations indicate that the high-pressure polymorph is favoured over the ambient phase by the PV term, the zero point energy and entropy. Low completeness that often occurs as a result of shading from the high-pressure cell was improved by the inclusion of multiple crystals within the sample chamber. Bianthrone changes colour from yellow to green on grinding, though this does not occur when subjected to hydrostatic pressure to 6.5 GPa. There is, however, a subtle colour change from bright yellow to dark orange as pressure is applied, and it is likely that this is caused by changes in the - stacking distances. This work highlights how a system can react differently to hydrostatic and non-hydrostatic conditions.

A new approach to the investigation of the optical properties of polytypic minerals that combines spindle stage techniques, X-ray diffraction methods, electron microprobe analysis, and dielectric tensor calculations has been developed and applied to zinc sulfides and chloritoids. For the first time, X—ray diffraction studies of natural anisotropic zinc sulfides have documented the simultaneous occurrence of twinning and stacking disorder along more than one of the four symmetry equivalent <111> directions of sphalerite. Precession photographs of optically anisotropic zinc sulfides are characterized by twin—equivalent diffraction maxima and diffuse diffraction streaking along lattice rows with (h-k) ≠ 3n (equivalent hexagonal indices) in one or two <111> directions. A system of linear equations has been used to calculate the approximate volume fractions of each twin domain and the sphalerite host domain. Dielectric tensor calculations have been performed to illustrate that mixtures of cubic and hexagonal zinc sulfide may be optically biaxial if the intergrowth occurs along more than one of the symmetry equivalent <111> directions of sphalerite (cubic). The dependence of the optical properties upon the chemical variation and polytypic intergrowth in the Hg-Fe chloritoids has been investigated. The effects of the variation in chemical composition of specific polytypic compositions were analyzed first. The refractive indices of 10 approximately pure 2M₂ Hg-Fe chloritoids show strong correlations (R² ≥ 0.094) to the proportion of Hg cations in the H(1B) site, Hg/(Hg + Fe + Hn) - HGN. Correlations between the optical orientation angles and HGN were weaker (R² ≤ 0.87). The optical orientation is very sensitive to small variations in the polytypic composition, especially orientation angles that have fixed values in 2M₂ chloritoid. The parameter showing the most sensitivity is ∠ X ⋀ b, which is 0° in an ideal 2M₂ chloritoid, but increases to about 6° for a chloritoid containing 10% by volume 1Tc polytype. The sum of ∠ Y ⋀ c* and ∠ Z ⋀ c* for an ideal 2M₂ chloritoid has a value of 90°, whereas a chloritoid with 10% 1Tc has a sum of 92°. Although not as sensitive as ∠ X ⋀ b, this parameter can be determined with only a spindle stage or universal stage. The observed dependence of the optical properties on polytypic intergrowth and chemical variation has been modeled using dielectric tensor calculations based on the properties of a 1Tc layer and assuming that the 2M₂ polytype is derived by twinning the 1Tc polytype about [010] with an (001) composition plane.<br>Ph. D.

6,6’-Dimethoxygossypol (DMG) is a natural product of the cotton variety Gossypium barbadense and a derivative of gossypol. Gossypol has been shown to form an abundant number of clathrates with a large variety of compounds. One of the primary reasons why gossypol can form clathrates has been because of its ability to from extensive hydrogen bonding networks due to its hydroxyl and aldehyde functional groups. Prior to this work, the only known solvate that DMG formed was with acetic acid. DMG has methoxy groups substituted at two hydroxyl positions, and consequently there is a decrease in its ability to form hydrogen bonds. Crystallization experiments were set up to see whether, like gossypol, DMG could form clathrates. The following results presented prove that DMG is capable of forming clathrates (S1 and S2) and two new polymorphs (P1 and P2) of DMG have been reported.

Esta tesis se basa fundamentalmente en el estudio in situ del polimorfismo de triacilgliceroles (TAGs) mayoritarios de aceites y grasas alimentarios, la determinación del comportamiento de fases de algunas de sus mezclas binarias, y la aplicación del polimorfismo como herramienta para la autentificación de productos alimentarios. Se ha llevado a cabo la caracterización polimórfica de los TAGs POP, OPO, POO, POL, SOO, OOO y OOL, básicamente utilizando una combinación de calorimetría diferencial de barrido y difracción de rayos X con radiación sincrotrón (SAXD y WAXD). Así, se han podido monitorizar los procesos dinámicos de cristalización y las transiciones polimórficas cuando las muestras se sometían a diferentes velocidades de enfriamiento y calentamiento. Los resultados obtenidos son directamente aplicables a procesos de cristalización de aceites y grasas alimentarios, con la finalidad de obtener las propiedades deseadas del producto final, utilizando los tratamientos térmicos más eficientes. Para comprender las interacciones intermoleculares que tienen lugar entre TAGs, se ha determinado los diagramas de fases de las mezclas PPO-OPO, PPO-POO y POO-OPO. Se ha observado un comportamiento eutéctico para el sistema PPO-OPO, mientras que en los sistemas PPO-POO y POO-OPO se formaba un compuesto molecular (co-cristal) metaestable, que tendía a separarse en los componentes de origen. Mediante el uso de difracción de rayos X con micro-haz de radiación sincrotrón, se han analizado las microestructuras heterogenias de mezclas de POP-OPO. El estudio de estos agregados cristalinos esferulíticos es directamente aplicable a procesos de fraccionamiento del aceite de palma. Con la finalidad de comprender muestras grasas más complejas, se ha caracterizado el complejo comportamiento polimórfico de mezclas multi-componente de 3 a 6 TAGs. Para el caso particular del aceite de oliva, el comportamiento polimórfico viene básicamente determinado por los TAGs mayoritarios, mientras que los componentes minoritarios parecen desarrollar un papel menos crucial. Finalmente, se ha aplicado el comportamiento polimórfico como herramienta para la autentificación y detección de fraudes en productos alimentarios. Ha sido posible determinar adiciones fraudulentas de aceite de avellana en aceite de oliva virgen extra en concentraciones inferiores al 5%, y se han podido establecer diferencias muy significativas en grasas de jamones Ibéricos de las categorías cebo y bellota.<br>Lipids, together with proteins and carbohydrates are major nutrients and also employed as lipophilic materials in food, cosmetic and pharmaceutical industries. Alimentary and industrial fats and oils (such as vegetable oils, margarine, chocolate, and confectionery fats) mainly consist of triacylglycerols (TAGs), whose molecules involve different types of fatty acid moieties. TAGs show a complicated crystallization behavior. The physicochemical properties of a TAG molecule are determined by the nature and compositions of the three fatty acid moieties. These properties must be studied not only in their pure systems but also in mixed systems. In particular, studies on binary mixture systems provide valuable information about molecular interactions among different lipid materials. This PhD thesis is based on the study of the in situ polymorphic characterization of the main TAGs of some vegetable and animal fats and oils, some of their mixtures and the use of the polymorphic behavior of edible fats and oils as a tool to determine their authentication. The polymorphic study of the triacylglycerols POP, OPO, POO, POL, SOO, OOO and OOL was in situ characterized by mainly using differential scanning calorimetry (DSC) and synchrotron radiation X-ray diffraction (SR-XRD) with SAXD and WAXD simultaneous measurement. The combined usage of DSC and SR-XRD or laboratory-scale X-ray diffraction enabled us to monitor the occurrence and transformation behavior at different rates of cooling and heating. The results obtained are closely related to actual crystallization processes of edible fats and oils, in which most functional polymorphic forms can be obtained by applying the most efficient thermal treatments. We also determined the phase behavior of binary mixtures of mixed-acid TAGs containing palmitic and oleic fatty acids (i.e. PPO-OPO, PPO-POO and POO-OPO). PPO-OPO system revealed an eutectic behavior, whereas PPO-POO and POO-OPO were molecular compound-forming. Long incubation periods were needed in order to thermodynamically stabilize the binary mixtures, and the results demonstrated that molecular compounds of PPO-POO and POO-OPO were metastable and tended to separate into the pure TAG components. On the other hand, microstructures of spherulites of POP-OPO binary mixtures were analyzed in neat liquid and solution (n-dodecane) systems by using synchrotron radiation microbeam X-ray diffraction (SR-mu-XRD). Due to a molecular compound formation at the 50:50 concentration ratio, 75POP:25OPO and 25POP:75OPO compositions were characterized to study how the microstructures of spherulites of the TAGs mixtures are determined when the molecular compound crystals and POP or OPO component crystals can be formed competitively. Studies of these heterogeneous microstructures in neat liquid and solution are applicable to palm oil fractionation processes by dry and solvent methods. In an attempt to make an approach to complex natural fatty samples, such as olive oil, the polymorphism of multicomponent mixtures (from 3 to 6 TAG components) was analyzed and discussed. Thus, we observed that the polymorphic behavior of an extra virgin olive oil from the Arbequina olive variety was mainly influenced by its main TAGs, whereas apparently minor components did not develop a crucial role. Furthermore, we also used the polymorphic behavior of natural fat and oils (virgin and extra virgin olive oil, and Iberian ham fat) as a tool to determine authenticity (different ham categories depending on the fattening system used) and detection of adulterations (fraudulent additions of hazelnut oil in olive oil). The combined use of DSC and preliminary chemometric calculations permitted determining fraudulent additions of raw hazelnut oil in an extra virgin olive oil (Arbequina) at concentrations below 5%. On the other hand, highly significant differences were detected in the polymorphic behavior of Iberian ham fat from the bellota and cebo categories.

Magister Pharmaceuticae - MPharm<br>In this study, new solid supramolecular derivatised forms of bis(adamantine-1-aminium) carbonate (ADTCO3) were prepared. ADTCO3 is a derivative of amantadine used for Parkinson’s disease and has antiviral properties against influenza-A, dengue fever and pharmacological activity towards Parkinson’s disease. The new forms prepared were polymorphic and co-crystal forms of ADTCO3. Polymorphism is a phenomenon where the ability of a substance to exist in two or more crystalline forms occurs when crystallised under different conditions and co-crystallization is the process of formation of multicomponent crystals of a drug substance. New solid forms often display different mechanical, physicochemical and thermal properties that can remarkably influence the bioavailability, hygroscopicity and stability of active pharmaceutical ingredients (APIs). For the formation of polymorphs of ADTCO3, techniques such as dry grinding, solvent-drop grinding, co-precipitation, sublimation and vapour diffusion were applied. For the development of co-crystals and/or complex formation, ADTCO3 was treated in combination with ten selected co-formers viz; benzoic acid, 4-hydroxybenzoic acid, cinnamic acid, 4-hydroxycinnamic acid, succinic acid, tartaric acid, salicylic acid, L-glutamic acid, citric acid monohydrate and L-glutaric acid using similar techniques as applied in the polymorphism study. The first four co-formers were selected for their potential biological activity and the latter six were selected for their generally regarded as safe (GRAS) status. All products were isolated and characterized using different analytical techniques to assess the thermal behaviour of the products by hot stage microscopy (HSM), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). FTIR spectroscopy and proton-nuclear magnetic resonance (1HNMR) were used to identify and determine the purity of the parent compounds and the modified forms. X-ray powder diffraction was used to determine the formation of a new phase and single crystal X-ray diffraction was applied at the initial stages to identify ADTCO3 by its unit cell parameters. Furthermore, the Cambridge Structural Database (CSD) and other resources were used to generate information on the molecular structures of all elucidated parent compounds, their polymorphs and reported co-crystals. Four different polymorphic forms of ADTCO3 were identified (viz. ADTCO3 Forms I to IV) and sixteen co-crystals (viz. ADTCO3BA1 to ADTCO3BA5, ADTCO3HBA, ADTCO3CIN, ADTCO3HCIN, ADTCO3SUC, ADTCO3LTTA, ADTCO3SA, ADTCO3CA, ADTCO3GLA, ADTCO3GA) were synthesised. Of the sixteen co-crystals 5 were identified as ADTCO3BA “salt” co-crystal polymorphic forms and 2 as ADTCO3SUC co-crystal polymorphic forms. Two solvated “salt” co-crystal forms were also identified, namely; ADTCO3GLA and ADTCO3LTTA. ADTCO3GLA had a mass loss of 10.3% (n = 2.4) and ADTCO3LTTA had a mass loss of 5.25% (n = 0.86). Finally, the rest of the co-crystals ADTCO3HBA, ADTCO3CIN, ADTCO3HCIN, ADTCO3SA, ADTCO3CA and ADTCO3GA all crystallised as “salt” co-crystals.

Thesis (Ph.D.)--Chemical Engineering, Georgia Institute of Technology, 2009.<br>Committee Chair: Dr Rousseau, Ronald W; Committee Co-Chair: Dr Grover Gallivan, Martha; Committee Member: Dr Realff, Matthew; Committee Member: Dr Garmestani, Hamid; Committee Member: Dr Nenes, Athanasios.

Une large hystérèse centrée autour de la température ambiante constitue l'un des objectifs principaux de la recherche sur les matériaux commutables fonctionnels. Dans le domaine très étudié de la conversion de spin, un tel comportement apparaît très rarement. Un nouveau composé, le complexe [Fe(PM-PeA)2(NCSe)2] présentant une large hystérèse autour de la température ambiante a été synthétisé, sous forme de monocristal et de poudre. Ce composé a été la base de deux axes de recherche. Le premier concerne l’étude multi-échelles des relations structure-propriétés en combinant la diffraction des rayons X sur poudre et sur monocristal, à température variable. Un focus tout particulier a été fait sur l’échelle microstructurale, très peu explorée à ce jour. Pour la première fois,la taille des domaines cohérents et le taux de microdéformations, ont été quantifiés pour un composé moléculaire discret à conversion de spin. Le deuxième axe concerne l’investigation de la transition de spin induite par la pression. L’étude in situ par diffraction des rayons X sur monocristal a permis une caractérisation complète de la structure cristalline des deux états de spin, sous pression. Par la suite, un suivi fin de la transition de spin, révélant une piezo-hystérèse, a été fait grâce à la diffraction des rayons X sur poudre, sous pression in situ à l’aide du rayonnement synchrotron. Les expériences couplant pression et température ont donné accès à des informations cruciales, telles que la variation des modules d’élasticité avec la température, les effets de la température sur la pression de transition, le caractère coopératif de la transition et la largeur de la piezo-hystérèse<br>Spin crossover (SCO) compounds with a large hysteresis centered around room temperature (RT) are being constantly pursued although such behavior is very rare and most often noticed in coordination networks. In this context, a new molecular discrete compound, the complex [Fe(PM-PeA)2(NCSe)2], showing a large SCO hysteresis spanning RT has been synthesized in both singlecrystal and powder forms. Then, two research lines emerged. The first one concerns the multi-scales study of the structure-properties relationships, combining single-crystal and powder X-ray diffraction at variable temperature. A particular focus has been made on the microstructural scale, almostunexplored until now. For the first time, the coherent domain sizes and the micro-deformation rate has been quantified for a molecular discrete SCO compound. The second part of this work investigates in detail the pressure-induced SCO. The in situ single-crystal X-ray diffraction studies has been carried out to perform a complete characterization of the crystal structure under pressure. Thereafter, an accurate high-pressure X-ray diffraction measurement on the powder, with a synchrotron radiation,provides a fine track of the pressure-induced SCO and showed a piezo-hysteresis. Experiments coupling pressure and temperature brought crucial information pertaining to variation of bulk moduli withtemperature, the piezo-hysteresis width, the temperature dependence of the pressure transition and pressure-induced SCO abruptness, are provided in detail for the first time

Throughout this thesis, we have studied ZnO and its properties in a bottom-up manner through a dimensionality range starting from 0D nanoparticles to 3D bulk phases. For the 0D clusters and the 2D nanofilms studied we also considered the effect of a support in models designed to study ZnO thin film growth on the Ag(111) surface. In chapter 3, we have studied ZnO nanoclusters on a Ag support and compared their properties with free space ZnO nanoclusters. In this chapter we highlighted the importance of the presence of the support during the global optimization of the clusters (i.e. as opposed to global optimization of the clusters in free space and then introducing a support). Our results show that the presence of the support strongly affects the energetic stability ranking of the nanocluster isomers. More drastically, after a certain cluster size, the support also stabilizes selectively 2D type structures, which are not stable in free space, with respect to the 3D clusters. The extra stabilization of supported 2D clusters is attributed mainly to the contact area, which is evidently greater for 2D clusters where all the atoms can interact with the surface. The importance of the contact are is also observed for 3D clusters, as ellipsoid bubbles or inflated double layer clusters being of lower energy than more spherical clusters on the support whereas the latter, more symmetric 3D clusters are more stable in free space. Matching of the cluster structure with the surface morphology was found to be another factor determining cluster stability. The Zn3O3 sixmembered ring, which is one of the main motifs for both 3D and 2D clusters, matches best with the Ag(111) surface because it follows the same six-fold (C6) symmetry (or its trigonal C3 subgroup with a three-fold axis, taking into account the distinction between Zn and O atoms). However because of the lattice size differences, such matching dies away for larger ZnO clusters. The preferential stabilities of the 2D structures of ZnO clusters can be seen as the initial stages of thin film growth and is found to be in line with the experimentally observed layered ZnO sheets on the Ag(111) surface. In Chapter 4, we have considered a full 2D-ZnO sheet on Ag(111) surface and also investigated also how H atoms interact with it. Following our results for ZnO nanoclusters on the Ag surface, we highlighted the importance of the degree of 2D-ZnO:Ag(111) unit cell commensurability for calculating accurate sheeton-substrate binding energies. We have found a 8:9 commensurate monolayer to be more favored with interatomic potentials and a 7:8 commensurate monolayer with DFT calculations, where the latter is found in experiment. Our calculations showed no evidence of charge transfer or covalent bonding between the Ag(111) surface and the 2D-ZnO sheet, but did show that the ZnO sheet and the Ag(111) surface exhibit small structural distortions in order to maximize their mutual interaction. Calculations of the unsupported 2D-ZnO sheet interacting with hydrogen provided strong evidence for H forming a low energy Zn 4s–H 1s multi center bonding state when passing through a Zn3O3ring of the 2D-ZnO sheet, thus allowing for relatively facile H transport through the sheet. In chapter 5, we have extended our study of supported 2D ZnO nanofilms with higher coverage models, including triangular islands on top of two full monolayers, prepared to model the experimental system. Our results showed that the triangular adlayer islands induce a transition to the WZ structure in the island core and in local region in the two layers immediately below the island core. The islands are also found to have BCT-structured reconstructions on their edges and T1-structured reconstructions on their corners. These models are found to better match the experimental structural data for the experimental 2.7 ML Ag-supported ZnO film with respect to models assuming a purely layered or a purely WZ structure. In chapter 6, we focused on 4ML nanofilms and compared bulk and the 4 ML nanofilm poymorphism of ZnO. Our results revealed that the stability range of nanofilms and their energetic ordering are radically different than that of bulk polymorphs. We have developed a method to generate a wide range of new low energy nanofilm and bulk polymorphs using nets as a basis, and showed that there exist at least three nanofilm structures with trigonal basal plane symmetry compatible epitaxial growth on fcc metal (111) surfaces that are more stable than layered-ZnO. While confirming the previous theoretical studies predicting the BCT-ZnO phase as being the lowest energy free-standing nanofim for small thicknesses, we obtained a range of structurally related and near energetically degenerate phases, indicating there exists BCT polytypism. With increasing thickness we found that atomically reconstructed wz-ZnO becomes more stable than BCT-ZnO for ~14 MLs, and is always more stable than non-reconstructed wz-ZnO. We have also stressed the influence of strain on polymorphism by showing that BCT-ZnO and layered-ZnO nanofilms are unstable to novel polymorphs under in-plane strain. Together with the T1 structures and BCT structures which were also predicted as reconstructions on island corners in the previous chapter, our results strongly suggest that many new nanofilm polymorphs should be experimentally accessible, and in some cases, may have even already been observed. In chapter 7, we focused on bulk polymorphism and, specifically, investigated the effect of nanoporosity. Our results showed that both energetic instability and band gap increase with nanoporosity and we predicted that nanoporosity could induce band gap increases of up to ~1.5 eV relative to wurtzite ZnO. We showed that the band gap increase is related with bandwidth changes in the conduction band and the valance band. We suggested that the underlying physical mechanism for this effect is that introducing nanoporosity, and thus periodic internal void space, restricts extended orbital overlaps and thus decreases bandwidths. Due to the generality of this argument, we expect that nanoporosity could similarly affect bandgap values in a wide range of materials and could be employed as a band gap engineering method.<br>El treball de recerca desenvolupat en aquesta tesi es centra en ZnO, un dels semiconductors de tipus II-VI amb un ampli ventall d’aplicacions. En les estructures (ZnO)n suportades, s’observa que la presència del suport afecta l’ordre d’estabilitats dels mateixos però de manera molt més dràstica afecta selectivament les estructures bidimensionals (2D) que, a partir d’una certa grandària, en fase gas són menys estables que les tridimensionals (3D). Els càlculs per a la làmina 2D-ZnO aïllada interaccionant amb l’hidrogen proporcionen una forta evidència per a la formació d’un estat d’enllaços multi-centres de baixa energia quan passa a través de l’anell de Zn3O3 de la làmina 2D-ZnO, permetent així de forma relativament fàcil el transport d’hidrogen a través de la làmina. Quan canviem a models amb illes mes grans, observem reconstruccions estructurals a l’interior i sota l’illa formada per una nova capa incompleta. L’interior de les illes triangulars adopta estructura WZ i esta rodejada per vores amb estructures BCT i cantonades amb estructura T1. S’ha observat que aquests models presenten en un millor acord estructural amb les dades experimentals per el cas de les lamines formades per 2.7 ML que no pas respecte als models que assumeixen una estructura purament grafítica o purament WZ. Hem generat un ampli rang de polimorfs de ZnO basats en lamines hexagonals inspirades en l’enumeració de les seves xarxes subjacents característiques i evaluant l’estabilitat del sòlid “bulk” i les nano-lamines d’aquestes estructures mitjançant calculs ab initio. Hem observat un ampli polimorfisme d’estructures de baixa energia en les nano-lamines amb un ordre d’estabilitat totalment diferent al del sòlid “bulk”. A partir d’aquestes bases generals hem pogut tenir un millor coneixement de les transicions estructurals observades durant el creixement epitaxial i les prediccions d’estabilitat de les nano-lamines en variar-ne el gruix i la pressió exercida. Hem conclòs els nostres resultats explicant que la nanoporositat està inextricablement connectada tant amb la Erel com amb el ΔEgap i hem predit que la nanoporositat pot induir un increment en el band gap de fins a ~1.5 eV relatius a la wurtzita ZnO. Comprovant també la generalitat d’aquest fenomen, pe’l CdS i pel CdSe suggerim que la nanoporositat pot ser emprada com un mètode genèric d’enginyeria de band gap per materials funcionals morfològicament i electrònicament.

Made available in DSpace on 2014-06-11T19:29:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-08-21Bitstream added on 2014-06-13T18:58:39Z : No. of bitstreams: 1 nascimento_nm_me_araiq.pdf: 692107 bytes, checksum: 18300527e76c2d41a696df746f92f483 (MD5)<br>Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)<br>Devido a contradições presentes na literatura quanto à natureza dos complexos dos metais do quarto período da tabela periódica com o ligante tris(2-hidroxietil)amina (trietanolamina) (TEAH3), uma reinvestigação foi feita consistindo na exploração das possibilidades do ligante em formar dímeros ou até polímeros com a propriedade de polimorfismo com sais dos metais de transição Co2+ e Cu2+. Com o metal representativo Zn2+, os compostos não apresentaram a propriedade de se cristalizarem em mais de uma estrutura cristalográfica distinta. Os complexos [MCl(TEAH2)] foram preparados a partir de misturas de soluções de MCl2 e TEAH3 em várias proporções, e os produtos foram caracterizados pela espectroscopia no infravermelho e difratometria de raios-X (em pó e em monocristal). Durante as tentativas de obtenção de monocristais dos complexos [MCl(TEAH2)] (M=Co, Cu, Zn) em álcool isoamílico, observou-se a oxidação inusitada do ligante TEAH2 coordenado, obtendo-se derivados de fórmula geral [M(bic)2] (M=Co, Cu, Zn). A determinação da estrutura molecular e cristalina do monocristal de [Cu(bic)2] obtido foi realizado pelo Prof. Dr. Carlos B. Pinheiro, da Universidade Federal de Minas Gerais (UFMG)<br>Due to contradictions in the literature as to the nature of the complexes of metals of the fourth period of the periodic table with the ligand tris(2- hydroxyethyl) amine (triethanolamine) (TEAH3), a reinvestigation was made consisting in exploring the possibilities of the ligand to form dimers or even polymers with the property of polymorphism with salts of transition metals Co2+ and Cu2+. With the metal representative Zn2+, the compounds did not show the property to crystallize in more than one different crystal structure. The complexs [MCl(TEAH2)] were prepared from mixtures of solution of MCl2 and TEAH3 in various proportions, and the products were characterized by infrared spectroscopy and X-ray diffraction (powder and single crystal). During attempts to obtain crystals of the complexes [MCl(TEAH2)] (M = Co, Cu, Zn) in isoamyl alcohol, was observed unusual oxidation of TEAH2 coordinated that yield derivatives of formula [M(bic)2] (M = Co, Cu, Zn). The determination of crystal and molecular structure of the single crystal of [Cu(bic)2] obtained was carried out by Professor. Dr. Carlos B. Pinheiro, Universidade Federal de Minas Gerais (UFMG)

Made available in DSpace on 2014-06-11T19:30:20Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-02-18Bitstream added on 2014-06-13T21:00:51Z : No. of bitstreams: 1 bezzon_vdn_me_bauru.pdf: 5934071 bytes, checksum: bd5d8e0bb1eb9f7d625e556c89e14940 (MD5)<br>Polimorfismo é a propriedade de moléculas cristalizarem em mais de uma forma cristalina, o que pode afetar suas propriedades físico-químicas. Esse fenômeno está presente também em fármacos, e a avaliação de matérias-primas para manter o controle do polimorfo presente em comprimidos comercializados tem um papel importante na indústria farmacêutica. A identificação e o controle de formas polimórficas podem ser realizadas utilizando diversas técnicas, dentre as quais: Análise térmica, espectroscopia na região do infra-vermelho, espectroscopia Raman e a difração de raios X por policristais (DRXP). Esta última é uma técnica que permite a caracterização de fases cristalinas, quantificação de amorfo utilizando padrões internos, e por meio do método de Rietveld o refinamento de estrutura cristalina e a quantificação das fases presentes na amostra. No entanto, alguns fatores limitam a identificação e quantificação das fases em misturas em análises por DRXP, e estão relacionados a parâmetros estruturais da amostra como a baixa simetria e grande volume da cela unitária, á características físicas como forma e tamanho dos cristalinos, e resolução dos difratômetros que são definidas pela geometria, fendas, monocromatização do feixe e sistema de detecção<br>Polymorphism is the property of molecules to crystallize in more than one crystal form, which may affect physicochemical properties. This phenomenon is also present in pharmaceuticals, and evaluation of raw materials to maintain the control of the polymorph present in tables plays an important role in the pharmaceutical industry. The identification and control of polymorphic forms can be performed using various techniques, among which Thermal analysis, infrared spectroscopy, Raman spectroscopy and X-ray powder diffraction. The latter is a technique that allows among things characterization of crystalline phases, quantification of amorphous using internal standards and, by means of Rietveld method, refinement of the crystal structure and quantification of phases present in the sample. However, several factors limit the identification and quantification of the phases in mixtures, and are related to structure parameters of the sample, such as low symmetry and large unit cell volume, the physical characteristics such as crystallite size and shape, and the resolution of diffractometers which are defined by the geometry, slits, beam monochromatization and detection system

Orientador: Carlos de Oliveira Paiva Santos<br>Coorientador: Marcelo Ornaghi Orlandi<br>Banca: Selma Gutierrez Antonio<br>Banca: Humberto Gomes Ferraz<br>O Programa de Pós-Graduação em Ciência e Tecnologia de Materiais, PosMat, tem caráter institucional e integra as atividades de pesquisa em materiais de diversos campi da Unesp<br>Resumo: Polimorfismo é a propriedade de moléculas cristalizarem em mais de uma forma cristalina, o que pode afetar suas propriedades físico-químicas. Esse fenômeno está presente também em fármacos, e a avaliação de matérias-primas para manter o controle do polimorfo presente em comprimidos comercializados tem um papel importante na indústria farmacêutica. A identificação e o controle de formas polimórficas podem ser realizadas utilizando diversas técnicas, dentre as quais: Análise térmica, espectroscopia na região do infra-vermelho, espectroscopia Raman e a difração de raios X por policristais (DRXP). Esta última é uma técnica que permite a caracterização de fases cristalinas, quantificação de amorfo utilizando padrões internos, e por meio do método de Rietveld o refinamento de estrutura cristalina e a quantificação das fases presentes na amostra. No entanto, alguns fatores limitam a identificação e quantificação das fases em misturas em análises por DRXP, e estão relacionados a parâmetros estruturais da amostra como a baixa simetria e grande volume da cela unitária, á características físicas como forma e tamanho dos cristalinos, e resolução dos difratômetros que são definidas pela geometria, fendas, monocromatização do feixe e sistema de detecção<br>Abstract: Polymorphism is the property of molecules to crystallize in more than one crystal form, which may affect physicochemical properties. This phenomenon is also present in pharmaceuticals, and evaluation of raw materials to maintain the control of the polymorph present in tables plays an important role in the pharmaceutical industry. The identification and control of polymorphic forms can be performed using various techniques, among which Thermal analysis, infrared spectroscopy, Raman spectroscopy and X-ray powder diffraction. The latter is a technique that allows among things characterization of crystalline phases, quantification of amorphous using internal standards and, by means of Rietveld method, refinement of the crystal structure and quantification of phases present in the sample. However, several factors limit the identification and quantification of the phases in mixtures, and are related to structure parameters of the sample, such as low symmetry and large unit cell volume, the physical characteristics such as crystallite size and shape, and the resolution of diffractometers which are defined by the geometry, slits, beam monochromatization and detection system<br>Mestre

Resumo: Devido a contradições presentes na literatura quanto à natureza dos complexos dos metais do quarto período da tabela periódica com o ligante tris(2-hidroxietil)amina (trietanolamina) (TEAH3), uma reinvestigação foi feita consistindo na exploração das possibilidades do ligante em formar dímeros ou até polímeros com a propriedade de polimorfismo com sais dos metais de transição Co2+ e Cu2+. Com o metal representativo Zn2+, os compostos não apresentaram a propriedade de se cristalizarem em mais de uma estrutura cristalográfica distinta. Os complexos [MCl(TEAH2)] foram preparados a partir de misturas de soluções de MCl2 e TEAH3 em várias proporções, e os produtos foram caracterizados pela espectroscopia no infravermelho e difratometria de raios-X (em pó e em monocristal). Durante as tentativas de obtenção de monocristais dos complexos [MCl(TEAH2)] (M=Co, Cu, Zn) em álcool isoamílico, observou-se a oxidação inusitada do ligante TEAH2 coordenado, obtendo-se derivados de fórmula geral [M(bic)2] (M=Co, Cu, Zn). A determinação da estrutura molecular e cristalina do monocristal de [Cu(bic)2] obtido foi realizado pelo Prof. Dr. Carlos B. Pinheiro, da Universidade Federal de Minas Gerais (UFMG)<br>Abstract: Due to contradictions in the literature as to the nature of the complexes of metals of the fourth period of the periodic table with the ligand tris(2- hydroxyethyl) amine (triethanolamine) (TEAH3), a reinvestigation was made consisting in exploring the possibilities of the ligand to form dimers or even polymers with the property of polymorphism with salts of transition metals Co2+ and Cu2+. With the metal representative Zn2+, the compounds did not show the property to crystallize in more than one different crystal structure. The complexs [MCl(TEAH2)] were prepared from mixtures of solution of MCl2 and TEAH3 in various proportions, and the products were characterized by infrared spectroscopy and X-ray diffraction (powder and single crystal). During attempts to obtain crystals of the complexes [MCl(TEAH2)] (M = Co, Cu, Zn) in isoamyl alcohol, was observed unusual oxidation of TEAH2 coordinated that yield derivatives of formula [M(bic)2] (M = Co, Cu, Zn). The determination of crystal and molecular structure of the single crystal of [Cu(bic)2] obtained was carried out by Professor. Dr. Carlos B. Pinheiro, Universidade Federal de Minas Gerais (UFMG)<br>Orientador: Adelino Vieira de Godoy Netto<br>Coorientador: Stanlei Ivair Klein<br>Banca: Alexandre de Oliveira Legendre<br>Banca: Vinicius Caliman<br>Mestre

This work concerns the interrelationship between thermodynamic, kinetic and structural aspects of crystal polymorphism. It is both experimental and theoretical, and limited with respect to compounds to substituted monocyclic aromatics. Two polymorphs of the compound m-aminobenzoic acid have been experimentally isolated and characterized by ATR-FTIR spectroscopy, X-ray powder diffraction and optical microscopy. In addition, two polymorphs of the compound m-hydroxybenzoic acid have been isolated and characterized by ATR-FTIR spectroscopy, high-temperature XRPD, confocal Raman, hot-stage and scanning electron microscopy. For all polymorphs, melting properties and specific heat capacity have been determined calorimetrically, and the solubility in several pure solvents measured at different temperatures with a gravimetric method. The solid-state activity (ideal solubility), and the free energy, enthalpy and entropy of fusion have been determined as functions of temperature for all solid phases through a thermodynamic analysis of multiple experimental data. It is shown that m-aminobenzoic acid is an enantiotropic system, with a stability transition point determined to be located at approximately 156°C, and that the difference in free energy at room temperature between the polymorphs is considerable. It is further shown that m-hydroxybenzoic acid is a monotropic system, with minor differences in free energy, enthalpy and entropy. 1393 primary nucleation experiments have been carried out for both compounds in different series of repeatability experiments, differing with respect to solvent, cooling rate, saturation temperature and solution preparation and pre-treatment. It is found that in the vast majority of experiments, either the stable or the metastable polymorph is obtained in the pure form, and only for a few evaluated experimental conditions does one polymorph crystallize in all experiments. The fact that the polymorphic outcome of a crystallization is the result of the interplay between relative thermodynamic stability and nucleation kinetics, and that it is vital to perform multiple experiments under identical conditions when studying nucleation of polymorphic compounds, is strongly emphasized by the results of this work. The main experimental variable which in this work has been found to affect which polymorph will preferentially crystallize is the solvent. For m-aminobenzoic acid, it is shown how a significantly metastable polymorph can be obtained by choosing a solvent in which nucleation of the stable form is sufficiently obstructed. For m-hydroxybenzoic acid, nucleation of the stable polymorph is promoted in solvents where the solubility is high. It is shown how this partly can be rationalized by analysing solubility data with respect to temperature dependence. By crystallizing solutions differing only with respect to pre-treatment and which polymorph was dissolved, it is found that the immediate thermal and structural history of a solution can have a significant effect on nucleation, affecting the predisposition for overall nucleation as well as which polymorph will preferentially crystallize. A set of polymorphic crystal structures has been compiled from the Cambridge Structural Database. It is found that statistically, about 50% crystallize in the crystallographic space group P21/c. Furthermore, it is found that crystal structures of polymorphs tend to differ significantly with respect to either hydrogen bond network or molecular conformation. Molecular mechanics based Monte Carlo simulated annealing has been used to sample different potential crystal structures corresponding to minima in potential energy with respect to structural degrees of freedom, restricted to one space group, for each of the polymorphic compounds. It is found that all simulations result in very large numbers of predicted structures. About 15% of the predicted structures have excess relative lattice energies of &lt;=10% compared to the most stable predicted structure; a limit verified to reflect maximum lattice energy differences between experimentally observed polymorphs of similar compounds. The number of predicted structures is found to correlate to molecular weight and to the number of rotatable covalent bonds. A close study of two compounds has shown that predicted structures tend to belong to different groups defined by unique hydrogen bond networks, located in well-defined regions in energy/packing space according to the close-packing principle. It is hypothesized that kinetic effects in combination with this structural segregation might affect the number of potential structures that can be realized experimentally. The experimentally determined crystal structures of several compounds have been geometry-optimized (relaxed) to the nearest potential energy minimum using ten different combinations of common potential energy functions (force fields) and techniques for assigning nucleus-centred point charges used in the electrostatic description of the energy. Changes in structural coordinates upon relaxation have been quantified, crystal lattice energies calculated and compared with experimentally determined enthalpies of sublimation, and the energy difference before and after relaxation computed and analysed. It is found that certain combinations of force fields and charge assignment techniques work reasonably well for modelling crystal structures of small aromatics, provided that proper attention is paid to electrostatic description and to how the force field was parameterized. A comparison of energy differences for randomly packed as well as experimentally determined crystal structures before and after relaxation suggests that the potential energy function for the solid state of a small organic molecule is highly undulating with many deep, narrow and steep minima.<br>QC 20110527

This work has two principal sections. The first section is a study of the hydrogen bonding in a series of urea inclusion compounds, utilising neutron diffraction methods and a novel technique for growing neutron diffraction-suitable single crystals. The second section focusses on high pressure crystallography as a technique for exploring polymorphic landscapes, of a series of acid-base co-crystals, and the well-known active pharmaceutical ingredient 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY). Single crystal neutron structures at several temperatures have been determined for -phase urea inclusion compounds containing hexadecane, 1,6-dibromohexane and 2,7-octanedione guests. The neutron structure of the ‘partial channel’ co-crystal of urea and DMF is also reported. This includes an in-depth discussion and analysis of the structure and bonding of this urea series, in particular, how the guest compound affects the symmetry and hydrogen bonding of the host urea network. Additionally, the challenge of obtaining crystals suitable for neutron diffraction is addressed and a new heating/cooling device to aid crystallisation is presented. Pyridine and formic acid have been crystallised at differing ratios by both cryo-crystallisation and compression in a diamond anvil cell. Mixtures of the liquids in 1:1, 1:2 and 1:4 ratios all crystallise at high pressure, while only the 1:1 and 1:4 compositions were crystallised by in situ low temperature capillary crystallisation. The 1:2 structure crystallised by high pressure is a previously unknown co-crystal of pyridine - formic acid. For the 1:4 mixture, a new polymorph has been identified at a pressure of 14.2 kbar with a distinctly different structure and bonding pattern to that of the previously reported low temperature form. Five new co-crystals of 2,6-dimethylpyridine (DMP) with formic acid (FA) were crystallised by application of pressure in a diamond anvil cell and by in situ cryo-crystallisation. Mixtures in ratios 1:1, 1:2 and 1:3 of DMP: FA have been crystallised via both methods. Both the 1:2 and 1:3 co-crystals exhibit high pressure/low temperature polymorphism. ROY has been crystallised from acetone solution using a diamond anvil cell. The needle-like form obtained, named ONP shows similarities with the ORP, ON and Y forms, determined by Raman spectroscopy. The ONP crystals were recovered from the pressure cell by freezing with liquid nitrogen. Synchrotron X-ray data were collected on the sample, although no structure solution and refinement was possible. The unit cell of the ONP shows a crystallographic relationship to the ORP form.

This thesis is a multidisciplinary study of the solid state of squaric acid derivatives which combines approaches from areas such as crystal engineering, supramolecular chemistry and crystallography. The structural preferences in the solid state of this family of compounds has been analyzed, new crystalline materials derived from squaric acid have been designed in order to study new supramolecular synthons and relevant chemical phenomena such as template effect, preorganization, cooperativity and electrostatic compression have been explored. In summary, 47 polymorphs, solvates, cocrystals and salts from 22 squaric acid derivative compounds have been obtained and 31 crystal structures have been solved and analyzed. Several experimental techniques such as differential scanning calorimetry, thermogravimetry, thermomicroscopy, NMR spectroscopy and X­ray diffraction have been used for the analysis of the squaric acid derivatives synthesized. In this sense, the optimization of a methodology for solving crystal structures from laboratory powder X­ray diffraction data by means of direct space methods has permitted to overcome the difficulty of growing good quality single crystals of disecondary squaramides. Squaramides are interesting compounds due to their double donor­acceptor hydrogen bond character. In this work, their structural characteristics in the solid state have been studied and cooperativity in hydrogen­bonded catemers has been observed to play a crucial role in defining the robust solid­state head­to­tail synthon in the anti/anti conformation of disecondary squaramides, overriding the preferred association mode anti/syn observed in solution. Consequently, the self­assembling of the squaramide rings is a very strong binding motif, which has been proven difficult to be perturbed by other competing functional groups in the solid state. Taking into account these characteristics, two different cocrystal design strategies have been developed: the first one considering the preorganization of a monosquaramide ester via intramolecular hydrogen bonding, and the second one, more successful, considering that secondary squaramides can act as molecular scaffolds which, with a suitable functionalization of their substituents, new multicomponent solids have been obtained with coformers interacting via peripheral hydrogen bonding. Moreover, the analysis of the hydrogen bonding donor/acceptor parameters (a and ß) has been conducted with some model compounds with the aim of explaining their structural preferences in the solid state. Understanding the preference of a functional group for a particular synthon is mandatory in order to design new crystalline materials. In this sense, an unprecedented squaramide helical topology driven by the head­to­tail interaction has been reported, revealing its potential use in the field of crystal engineering and supramolecular chemistry. In a second stage of this thesis, further inside has been given to squaric acid derivatives through the design of zwitterionic squaramides. This has permitted the analysis of the electrostatic compression phenomenon which is responsible for a robust dimeric supramolecular synthon which also allows the formation of multicomponent solids. Finally, a collaborative research has been conducted on the theoretical and experimental of the main interactions shown by squaric acid and amidosquaric acid salts in the solid state. In summary, it can be concluded that the squaric/squaramide functional group, poorly studied in the solid state, has interesting properties which can be potentially exploited for the design and synthesis of new and diverse crystalline materials.<br>Aquesta tesi presenta un estudi multidisciplinar de l’estat sòlid de derivats de l’àcid esquàric, enmarcat en diferents àrees com l’enginyeria cristal•lina, la química supramolecular i la cristal•lografia. Les esquaramides són compostos interessants per la seva capacitat doble donadora/acceptora d’enllaços d’hidrogen. En aquest treball s’han analitzat les característiques estructurals de les esquaramides en l’estat sòlid i s’han dissenyat nous materials cristal•lins derivats de l’àcid esquàric per tal d’estudiar nous sintons supramoleculars. L’estudi de la capacitat acceptora/donadora de compostos model a través de la determinació teòrica dels paràmetres d’enllaç d’hidrogen (a i ß), ha permès la racionalització dels aspectes estructurals d’aquesta família de compostos. A més, a través d’aquest estudi, s’han explorat fenòmens químics de rellevància com l’efecte template i la preorganització pel disseny de sals i cocristalls, la cooperativitat, responsable del sintó observat en estat sòlid de les diesquaramides secundàries, així com la compressió electrostàtica identificada en esquaramides zwitteriòniques i sals de l’àcid esquàric. En resum s’han obtingut 47 polimorfs, solvats, cocristalls i sals de 22 derivats de l’àcid esquàric i s’han resolt i analitzat 31 estructures cristal•lines. Per a l’anàlisi de les espècies sintetitzades s’han utilitzat diferents tècniques experimentals com la calorimetria diferencial d’escaneig, la termogravimetria, la termomicroscòpia, l’espectroscòpia de ressonància magnètica nuclear i la difracció de raigs X de pols i de monocristall. En aquest sentit, l’optimització de la metodologia de resolució d’estructures cristal•lines a partir de dades de difracció de raigs X de laboratori a través de mètodes d’espai directe ha permès superar les dificultats que presenten les esquaramides secundàries a cristal•litzant monocristalls de qualitat. A partir dels resultats d’aquesta tesi doctoral es pot concloure que el grup funcional esquàric/esquaramida, poc estudiat en l’estat sòlid, té unes propietats potencialment explotables en el disseny i la síntesi de nous i diversos materials cristal•lins.

L'effet LIESST (Light-Induced Excited Spin-State Trapping) apparaît comme l'un des phénomènes les plus prometteurs et les plus excitants pour les dispositifs applicatifs basés sur les complexes à transition de spin (TS). Cependant, la compréhension fondamentale du LIESST doit encore être approfondie avant toute conception rationnelle. Par exemple, il est encore très difficile d'établir les relations structure-propriétés, bien que cette approche soit cruciale pour découvrir des matériaux à TS ayant une température de relaxation T(LIESST) élevée. L'objectif de ce travail est donc de comprendre comment augmenter la valeur de T(LIESST) vers une plage de température de la vie quotidienne. Nous avons choisi de l’atteindre en tentant d’augmenter la distorsion de la sphère de coordination du métal par deux stratégies basées sur la chimie : i) influer à l'échelle moléculaire via des contraintes stériques induites par des ligands halogénés et ii) moduler la contrainte moléculaire via du polymorphisme. La partie I présente quelques aspects fondamentaux et les parties II et III sont consacrées à la synthèse, à la cristallographie et aux études (photo)magnétiques des nouveaux composés moléculaires, y compris des polymorphes, de la famille [Fe(PM-L)2(NCX)2]. Ces nouveaux composés offrent tout d'abord un large éventail de comportements innovants, comme par exemple des expansions volumiques négatives ou nulles à la TS et l'absence de transition à plusieurs étapes malgré des sites métalliques indépendants au sein du cristal. Ces travaux élargissent considérablement la richesse des perspectives du phénomène de TS. De plus, l'examen approfondi des paramètres pertinents pour l’obtention d’un T(LIESST) élevé, tel que discutés dans la partie IV, apporte de nouvelles caractéristiques et prouve définitivement que toutes les échelles physiques doivent être prises en compte, ce qui conduit à proposer un concept multi-échelle de l'effet LIESST<br>The Light-Induced Excited Spin-State Trapping effect (LIESST) appears as one of the most promising and exciting phenomena for applicative devices based on Spin-CrossOver (SCO) complexes. However, the fundamental understanding of the LIESST effect must be yet deeply completed prior to any rational design of any efficient material. For instance, it is still a great challenge to establish the structure-properties relationships corresponding to the LIESST process, though this approach is crucial to discover SCO materials with a high relaxation temperature T(LIESST). The target of this work is therefore to understand how to increase T(LIESST) towards a daily-life temperature range. We choose to reach this goal by increasing the distortion of the metal coordination sphere through two chemistry-based strategies: i) playing at the molecular scale via steric strains produced by halogen-substituted ligands and ii) controlling the molecular stress through polymorphism. Part I displays some fundamental knowledge on SCO and Part II and III are devoted to the synthesis, crystallography and (photo)magnetic studies of new molecular compounds, including polymorphs, of the [Fe(PM-L)2(NCX)2] family. First these new compounds offer a large panel of innovative behaviours, such as, for instance, negative or zero volume expansions at the SCO and the absence of multi-step transition despite independent metal sites within the crystal. This work enlarges significantly the richness of the SCO based perspectives. Second, the deep examination of the relevant parameters to high T(LIESST) as discussed in Part IV brings new features and, overall, definitively proves that all physical scales must be taken into account, leading to a multiscale concept of the LIESST effect

Salt formation provides a means of altering the physicochemical and resultant biological characteristics of a drug entity without modifying its molecular structure. Many published reviews have indicated the importance of the selection of the most appropriate salt form. This work is an investigation into the salt formation of two heterocyclic drugs. This is done by the physicochemical and the crystallographic studies of 19 high resolution single crystal diffraction studies. The particular targets of the work are the selection of the most appropriate salt forms, investigations into the tautomerism and polymorphism (or pseudopolymorphism) and an understanding of the interactions most likely between these heterocyclic drugs and their specific receptor sites. Section 1 describes the effect of protonation on the absorption of drugs, the rationale for using various salt forms and the resultant effect this has on a number of physicochemical properties of the parent compound. Section 2 is a description of the experimental techniques used in the physicochemical investigations and in crystal structure determination. In Sections 3 and 7, the preparation and characterisation of the salts and modifications of the two heterocyclic drugs, GU and IM is described. In Sections 4 and 8, the physicochemical investigations into the hygroscopicity and solid-state stabilities of the salts of GU and IM is described. Van't Hoff solubility studies are used to determine the enthalpies of solution and where appropriate the relative thermodynamic stabilities of the various phases produced. The structures of 19 of the salts or modifications of GU and IM, together with their packing and hydrogen bonding interactions is described in Sections 5 and 9. Sections 6 and 10 describe the ionisation properties of these molecules. Both the guanidine and imidazole moieties of GU and IM, respectively, are tautomeric, the particular form(s) found in these investigations and the effect of protonation is discussed. The conformations of these structures are discussed and the effect of protonation, especially on the puckering of the piperazine ring, is described.

La salut ha estat sempre una de les principals preocupacions de la societat, i més encara amb la situació de pandèmia actual produïda pel virus (SARS-CoV-2) s’és conscient de que portar un estil de vida amb bons hàbits alimentaris influeix directament en la salut, existint nombroses investigacions que així ho demostren. Per tant, l’adquisició de nutrients adequats juga un paper vital en el manteniment de la funció normal del cos i la prevenció de malalties, sobretot aquelles que estan relacionades amb l’envelliment (malalties cardiovasculars, neurodegeneratives, diabetis tipus II, així com diversos tipus de càncer). És per això que la demanda d'aliments funcionals que promouen la salut ha rebut una àmplia atenció, tant entre professionals de la salut com entre el públic en general, emergint així nous conceptes com els nutracèutics. El terme nutracèutic combina dues paraules "nutrient" i "farmacèutic" i va ser introduït per Stephen DeFelice, metge endocrinòleg, l'any 1989. DeFelice defineix el compost nutracèutic com "aquell aliment o part d'un aliment que proporciona un benefici en la salut, incloent-hi la prevenció o el tractament d'una malaltia ". Desafortunadament, la majoria d'aquests compostos solen presentar propietats fisicoquímiques limitants, com ara una baixa biodisponibilitat oral, baixa solubilitat i en alguns casos baixa estabilitat química. El pterostilbé, l'ubiquinol i la vitamina D3 són tres compostos nutracèutics coneguts per les seves importants funcions bioquímiques i nutricionals. Lamentablement no sempre es poden aprofitar completament els seus potencials beneficis ja que presenten una baixa biodisponibilitat oral en el cas del pterostilbé i inestabilitat química com en els casos de l’ubiquinol i la vitamina D3. En la present tesi doctoral es descriu el descobriment, la síntesi i la caracterització de noves formes sòlides cristal·lines, en particular cocristalls amb millora de les propietats fisicoquímiques d'aquests tres compostos nutracèutics. Els cocristalls presenten avantatges respecte als compostos de partida en quant a biodisponibilitat i estabilitat i han demostrat ser alternatives amb potencial aplicabilitat industrial. Per a aquest estudi es van utilitzar diferents tècniques experimentals com ara la mòlta, la suspensió, la cristal·lització i l'evaporació lenta. Dels més de 1.500 experiments de cribatge, s’han obtingut 25 noves formes cristal·lines, entre ells polimorfs i cocristalls dels tres compostos nutracèutics. Les estructures cristal·lines d’11 de les noves formes han estat resoltes i analitzades en detall. En particular, dues d'elles s'han resolt mitjançant mètodes d’espai directe amb dades de difracció de raigs X de pols. A més, s’han utilitzat diverses tècniques computacionals, com ara l'anàlisi de les interaccions intermoleculars, el càlcul de l’energia reticular, la construcció de superfícies de potencial electrostàtic molecular (MEP) i superfícies de Hirshfeld per tal d’aprofundir en el coneixement a nivell cristal·logràfic i supramolecular dels 3 principis actius nutracèutics.<br>Health has always been one of the main concerns of society, and even more so with the current pandemic situation caused by the virus (SARS-CoV-2). It is well accepted that following a lifestyle with good eating habits directly influences health, as numerous studies prove. Therefore, acquisition of the right nutrients plays a vital role in maintaining normal body function and preventing disease, especially those related to aging (cardiovascular disease, neurodegenerative diseases, type II diabetes, as well as different types of cancer). This is why the demand for functional foods that promote health has received widespread attention, both among health professionals and the general public, thus emerging new concepts such as nutraceuticals. The term nutraceutical, combining two words "nutrient" and "pharmaceutical", was introduced by Stephen DeFelice, an endocrinologist, in 1989. DeFelice defines the nutraceutical compound as "food or part of a food that provides a benefit in the health, including the prevention or treatment of a disease”. Unfortunately, most of these compounds tend to show limiting physicochemical properties, such as low oral bioavailability, low solubility, and in some cases low chemical stability. Pterostilbene, ubiquinol and vitamin D3 are three nutraceutical compounds known for their important biochemical and nutritional functions. Unfortunately, their potential benefits cannot always be fully exploited as they have low oral bioavailability in the case of pterostilbene and chemical unstability in the case of ubiquinol and vitamin D3. The present PhD thesis describes the discovery, synthesis and characterization of new crystalline solid forms, in particular cocrystals with improved physicochemical properties of these three nutraceutical compounds. Cocrystals can show certain advantages over parent compounds in terms of bioavailability and stability and have proven to be alternatives with potential industrial applicability. Different experimental techniques such as grinding, slurry, reaction crystallization and solution crystallization were used for this study. From more than 1,500 screening experiments, 25 new crystalline forms have been discovered, including polymorphs and cocrystals of the three nutraceutical compounds. The crystal structures of 11 out of the new forms have been determined and analyzed in detail. In particular, two of them have been solved by means of direct space methods from powder X-ray diffraction data. In addition, several computational techniques have been used, such as the analysis of intermolecular interactions, the calculation of lattice energies, molecular electrostatic potential surfaces (MEPS), and Hirshfeld surfaces in order to get deeper insight and knowledge at crystallographic and supramolecular level of the 3 active nutraceutical principles.<br>La salud ha sido siempre una de las principales preocupaciones de la sociedad, y más aún con la situación de pandemia actual producida por el virus (SARS-CoV-2) se es consciente de que llevar un estilo de vida con buenos hábitos alimentarios influye directamente en la salud, existiendo numerosas investigaciones que así lo demuestran. Por lo tanto la adquisición de los nutrientes adecuados juega un papel vital en el mantenimiento de la función normal del cuerpo y la prevención de enfermedades, sobre todo aquellas que están relacionadas con el envejecimiento (enfermedades cardiovasculares, neurodegenerativas, diabetes tipo II, así como varios tipos de cáncer). Es por ello que la demanda de alimentos funcionales que promueven la salud ha recibido una amplia atención, tanto entre profesionales de la salud como entre el público en general, emergiendo así nuevos conceptos como los nutracéuticos. El término nutracéutico combina dos palabras "nutriente" y "farmacéutico" y fue introducido por Stephen DeFelice, médico endocrinólogo, en el año 1989. DeFelice define el compuesto nutracéutico como "aquel alimento o parte de un alimento que proporciona un beneficio en la salud, incluyendo la prevención o el tratamiento de una enfermedad ". Desafortunadamente, la mayoría de estos compuestos suelen presentar propiedades fisicoquímicas limitantes, tales como una baja biodisponibilidad oral, baja solubilidad y en algunos casos baja estabilidad química. El pterostilbeno, el ubiquinol y la vitamina D3 son tres compuestos nutracéuticos conocidos por sus importantes funciones bioquímicas y nutricionales. Lamentablemente no siempre se pueden aprovechar completamente sus potenciales beneficios ya que presentan una baja biodisponibilidad oral en el caso del pterostilbeno e inestabilidad química en el caso del ubiquinol y la vitamina D3. En la presente tesis doctoral se describe el descubrimiento, la síntesis y la caracterización de nuevas formas sólidas cristalinas, en particular cocristales, con mejoras en las propiedades fisicoquímicas de estos tres compuestos nutracéuticos. Los cocristales presentan ventajas respecto a los compuestos de partida en cuanto a biodisponibilidad y estabilidad y han demostrado ser alternativas con potencial aplicabilidad industrial. Para este estudio se utilizaron diferentes técnicas experimentales tales como la molienda, la suspensión, la cristalización y la evaporación lenta. De los más de 1.500 experimentos de cribado, se han obtenido 25 nuevas formas cristalinas, entre ellas polimorfos y cocristales de los tres compuestos nutracéuticos. Las estructuras cristalinas de 11 de las nuevas formas han sido resueltas y analizadas en detalle. En particular, dos de ellas se han resuelto mediante métodos de espacio directo a partir de datos de difracción de rayos X de polvo. Además, se han utilizado diversas técnicas computacionales tales como el análisis de las interacciones intermoleculares, el cálculo de la energía reticular, la construcción de superficies de potencial electrostático molecular (MEP) y superficies de Hirshfeld con el fin de profundizar en el conocimiento a nivel cristalográfico y supramolecular de los 3 principios activos nutracéuticos.

Aquesta tesi descriu el disseny, optimització i implementació de metodologies d’screening versàtils per a la recerca de noves formes sòlides de compostos orgànics. La certesa d’estar desenvolupant la forma sòlida d’un principi actiu més adient per a ser formulada només es pot tenir quan es realitza un estudi complert de l’estat sòlid del compost. El coneixement de quines són les diferents formes sòlides en les que pot existir un compost, de les interaccions intermoleculars que estabilitzen les seves xarxes cristalꞏlines, així com la manera d’obtenir-les i la seva caracterització són els objectius de l’estudi de l’estat sòlid d’un compost. En aquest treball s’ha establert una metòdica de treball semi-automàtica de cerca de noves formes sòlides que és capaç d’adaptar-se a les demandes de la indústria farmacèutica i que a l’hora és modulable en el temps, en funció del progrés de l’estudi. El disseny i l’optimització de les metodologies d’screening s’han desenvolupat a partir de la combinació dels coneixements multidisciplinaris adquirits de diferents àrees com són els estudis d’estat sòlid, la cristalꞏlografia i l’enginyeria cristalꞏlina. L’aplicació i validació qualitativa de les metodologies s’ha realitzat a través de l’estudi de tres casos pràctics amb compostos amb interès farmacèutic. S’han descobert 48 noves fases cristalꞏlines: polimorfs, solvats, sals, híbrids i cocristalls dels tres principis actius estudiats i s’han resolt i analitzat 20 estructures cristalꞏlines. Per a l’anàlisi i caracterització dels diferents sòlids cristalꞏlins descoberts s’han utilitzat diferents tècniques experimentals com la calorimetria diferencial d’escaneig, la termogravimetria, l’espectroscòpia de ressonància magnètica nuclear, la difracció de raigs X de pols i de monocristall, la sorció dinàmica de vapors i la termomicroscòpia. El gran nombre de formes sòlides descobertes dels tres principis actius ha permès aprofundir en l’estudi de diversos fenòmens de gran rellevància dins del camp de l’estat sòlid farmacèutic: la generació de formes sòlides a partir de la desolvatació de solvats que emmascaren la seva existència, el morfotropisme, la formació de compostos híbrids sal-cocristall, les interaccions intermoleculars anió-anió o la constatació que l’aparició de productes secundaris condicionen la recerca de noves formes sòlides.<br>This Thesis describes the design, optimization and implementation of screening methodologies for the research of new solid forms or organic compounds. It is possible to be sure about the most suitable solid form of an API to be developed only when a comprehensive solid-state study has been conducted. The main objective of such a study is to understand the polymorphic landscape, the intermolecular interactions that stabilize the crystal lattice together with the methodologies to prepare the solid forms of interest. In this work, a semi-automatic work methodology for the research of new solid forms adaptable to the pharmaceutical industry needs has been developed starting from a combination between multidisciplinary knowledge in the areas of crystallography and crystal engineering. The application and qualitative validation of the methodologies has been conducted through the study of three active pharmaceutical ingredients. In this sense, 48 new crystal forms (polymorphs, solvates, salts, hybrid salt/cocrystals and cocrystals) have been discovered and 20 crystal structures have been solved. Differential scanning calorimetry, thermogravimetry, powder and single crystal X-ray diffraction, nuclear magnetic ressonance, thermomicroscopy and dynamic vapour sorption have been used to analyse and characterize the new solid forms. The high number of new solid forms discovered in this work has allowed to get a deeper insight in phenomena of great relevance in the field of pharmaceutical solid state, such as the production of new solid forms from solvates, the morphotropism, the formation of hybrid salt/cocrystals, the anion/anion intermolecular interaction and the importance of secondary products for the discovery of new solid forms.<br>Esta tesis describe el diseño, optimización e implementación de metodologías de screening versátiles para la búsqueda de nuevas formas sólidas de compuestos orgánicos. La certeza de estar desarrollando la forma sólida de un principio activo más adecuada para ser formulada sólo se puede tener cuando se realiza un estudio completo del estado sólido del compuesto. El conocimiento sobre cuáles son las diferentes formas sólidas en las que puede existir un compuesto, de las interacciones intermoleculares que estabilizan sus redes cristalinas, así como la manera de obtenerlas y su caracterización, son los objetivos del estudio de estado sólido del mismo. En este trabajo se ha establecido una metódica de trabajo semi-automática de búsqueda de nuevas formas sólidas que es capaz de adaptarse a las demandas de la industria farmacéutica y que a su vez es modulable en el tiempo, en función del progreso del estudio. El diseño y optimización de las metodologías de screening se han desarrollado a partir de la combinación de los conocimientos multidisciplinares adquiridos de diferentes áreas como son los estudios de estado sólido, la cristalografía y la ingeniería cristalina. La aplicación y verificación cualitativa de las metodologías se ha realizado a través del estudio de tres casos prácticos con compuestos de interés farmacéutico. Se han descubierto 48 nuevas fases cristalinas: polimorfos, solvatos, sales, híbridos y cocristales de los tres principios activos estudiados y se han resuelto y analizado 20 estructuras cristalinas. Para el análisis y caracterización de los diferentes sólidos cristalinos descubiertos se han utilizado diferentes técnicas experimentales como la calorimetría diferencial de barrido, termogravimetría, espectroscopía de resonancia magnética nuclear, difracción de rayos X de polvo y de monocristal, sorción dinámica de vapor y termomicroscopía. El gran número de formas sólidas descubiertas de los tres principios activos ha permitido profundizar en el estudio de diversos fenómenos de gran relevancia dentro del campo del estado sólido farmacéutico: la generación de formas sólidas a partir de la desolvatación de solvatos que enmascaran su existencia, el morfotropismo, la formación de compuestos híbridos sal- cocristal, las interacciones intermoleculares anión-anión o la constatación de que la aparición de productos secundarios condicionan la búsqueda de nuevas formas sólidas.

La mesure de couplage dipolaire permet d’accéder à la structure tridimensionnelle d’un composé solide. Cependant, en présence d’une forte densité de spins couplés, le phénomène de troncature dipolaire rend difficile l’obtention de ces informations par RMN du solide. Ce problème peut être affranchi par l’étude de spins rares en abondance naturelle. En effet, avec une abondance naturelle de 1.1 %, la probabilité que trois 13C soient couplés, et avec elle la troncature dipolaire, devient négligeable. Une méthodologie basée sur la séquence de recouplage dipolaire POST-C7 permet d’accéder à des informations structurales d’échantillons en abondance naturelle sensibles à la fois à la conformation moléculaire et à l’empilement cristallin par mesure de couplages dipolaires 13C-13C. La sensibilité de détection des signaux RMN 13C est augmentée à l’aide la polarisation dynamique nucléaire ce qui permet de réduire considérablement les temps d’expériences. De plus, la séquence de recouplage R20_9_2 aidée de supercycles s’est montrée être plus robustes que POST-C7 face à de fortes anisotropies de déplacement chimique ou de forts couplages hétéronucléaires 1H-13C. La seconde problématique abordée concerne l’attribution de signaux 13C. En effet, il existe seulement quelques exemples de détermination de connectivités 13C -13C en abondance naturelle. Nous montrons ici que des spectres de corrélations dipolaires 13C-13C peuvent être obtenus en quelques jours à l’aide de la séquence de recouplage R20_9_2. Contrairement aux méthodologies basées sur le couplage J, notre séquence requiert un temps d’excitation DQ plus court ce qui la rend adaptée à l’étude de solides désordonnés<br>Measurment of dipolar coupling provides 3D structural information of powder samples. However, in practice, the high density of spins in organic compounds prevents the measurements of long-range dipolar couplings in solid-state NMR by the so-called dipolar truncation effect. The study of rare spins on natural abundance allows to overcome this problem. In fact, with a natural abundance of 1.1 %, the probability for three 13C to be coupled is negligible. We developed a methodology based either on the dipolar recoupling NMR pulse sequence POST-C7 or on the dramatic increase in sensitivity provided by dynamic nuclear polarization. We demonstrated that its methodology provides a measure of 13C-13C dipolar couplings in natural abundance powder samples and that the so-obtained distance information is sensitive to both molecular conformation and crystal packing of powder samples. Moreover, we show that the recoupling pulse sequence R20_9_2 is more robust to strong chemical shift anisotropy and also to strong 1H-13C heteronuclear dipolar couplings than POST-C7. The second challenge involves 13C signal assignment for natural abundance. In fact, there are only a few examples of 13C-13C correlation spectra obtained for natural abundance samples. Here, we show that 13C-13C correlation spectra sequence based on the reintroduction of 13C−13C dipolar couplings can be obtained with standard MAS probe and within few days using R20_9_2 pulse sequence. Contrary to pulse sequences based on 13C-13C J coupling, our pulse sequence requires shorter DQ excitation time and hence, is more suitable for samples having short T2 relaxation times such as amorphous solids

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science 6 February 2017, Johannesburg.<br>Polymorphism is not only limited to single component systems. Co-crystals have exhibited polymorphism and various polymorphic co-crystals have been reported. Polymorphism in co-crystals presents an expansion of the optimization space around a pharmaceutical compound and also offers the opportunity to develop novel patentable material. Polymorphism of pharmaceutical co-crystals was investigated by means of an exhaustive data mining survey and the formation of polymorphic co-crystals. The search was performed using the Cambridge Structural Database (CSD). The search aimed to find and tally neutral pharmaceutical co-crystals which are polymorphic. The survey of the CSD showed that 14% of the pharmaceutical co-crystals were polymorphic. The co-crystal of theophylline and 3,4-dihydroxybenzoic acid was found to be polymorphic and the novel polymorph was synthesized and characterized. The co-crystals were characterized by x-ray crystallographic techniques and Differential Scanning Calorimetry. The single crystals of carbamazepine and cinnamic acid was grown and characterized by SCXRD for the first time. The single crystal data was able to show that the hydrogen bonding packing that was modelled in the literature is incorrect.<br>MT2017

A Dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science. 21 May 2015<br>Crystal polymorphism is the capacity of a solid crystalline form to exist in more than one structural arrangement. In the pharmaceutical setting investigations into the polymorphic forms of potential drugs are of vital importance since different crystalline forms can affect bioavailability, mechanical, thermal, and chemical properties. One such example is isonicotinic acid-(1-phenylethylidene) hydrazide (IPH), a derivative of the popular drug isoniazid (used as first line treatment against Mycobacterium tuberculosis) was found to crystallise in six different polymorphic forms. Each crystal structure was determined using X-ray diffraction techniques and including the thermal phase relationships of the polymorphic compound were delineated. In addition to polymorph elucidation, isonicotinic acid-(1-phenylethylidene) hydrazide was modified with –OH and –NH2 at various aromatic positions, creating geometric pyridyl isomers. In-depth studies of these pyridyl isomers revealed a diverse range of supramolecular aggregates. Preliminary thermal screening suggests that only a small selection of these pyridyl isomers present potential polymorphic activity for further study.

Long-chain molecules are widely used in many commercial products, including waxes, oils, fats and soaps. This study focuses on the primary n-alkylammonium chlorides that have applications as surfactants, detergents and as models for bio-membranes. The specific topic of this investigation is the polymorphism of three series of n-alkylammonium halides. Polymorphism is the ability of a substance to exist in more than one crystal form. Due to the conformational flexibility of the long alkyl chain and the forces (hydrogen bonding and van der Waals interactions) dictating the packing in these compounds, more than one type of molecular packing is possible, resulting in the crystallization of various polymorphs for each compound. Various investigations of the polymorphism of n-alkylammonium halides have been published in the scientific literature. This includes mainly studies on the polymorphism and structures of n-alkylammonium chlorides. Only a few reports on investigations of the polymorphism of n-alkylammonium bromides were found in the literature, but no investigation of the polymorphism of n-alkylammonium iodides could be located. This study is limited to the medium chain length primary n-alkylammonium halides, CnH2n+1N+H3X- where n = 11 to 18 (except 17) and X = Cl, Br and I. It is expected that in this chain length range, both packing forces (hydrogen bonding and van der Waals interactions) will play a role in dictating the molecular packing. It was attempted to crystallize the maximum number of polymorphs of each compound by extensive variation of the crystallization conditions. The parameters varied include crystallization temperature, solvent and crystallization method. Information regarding the polymorphism of a compound crystallized under specific conditions were collected by the complementary techniques of X-ray diffraction and thermal analysis. X-ray diffraction is the ideal technique to study polymorphism because the result of such an investigation is the three-dimensional packing in the crystal structure. Due to the wide scope of the investigation, only the polymorphic forms stable at room temperature were investigated. The single crystal X-ray technique allows the determination of the crystal structure of a polymorph, but due to the tendency of the compounds to crystallize in thin plates, very few single crystals of good diffraction quality were obtained. Nine crystal structures were, however, determined. Most polymorphic forms were available as polycrystalline powders. The new techniques for crystal structure determination from powder data were employed to determine two crystal structures from powder diffraction data, although at lower precision, and further refined them by the Rietveld technique. Conventional X-ray powder diffraction is well suited to the identification of polycrystalline materials. The technique does not give direct information regarding the structural nature of the polymorph, but gives a unique fingerprint for each polymorphic form. All polymorphs that were obtained by the various crystallization techniques were characterised by X-ray powder diffraction, and the unique long Summary iispacing of each polymorphic form was determined from the position of the low angle diffraction peaks in the diffraction pattern. Linear correlations between the chain lengths and long spacings were used to search for the presence of isostructural series amongst the phases. More than one isostructural series could be identified for each homologous series of compounds. Thermal analysis techniques were employed to determine the phase transition temperatures and enthalpies of phase transitions occurring at temperatures above room temperature. In this investigation the thermal behaviour of polymorphs were investigated by differential scanning calorimetry (DSC), thermo-gravimetric analysis (TGA) and hot stage microscopy (HSM). A stepwise melting behaviour that includes various solid-solid phase transitions was observed for all compounds studied. The sequence of phase transitions that occur with an increase in temperature were found to be unique to a specific polymorphic form. Thermogravimetric analysis provided information regarding the incorporation of solvent in the crystal lattice by monitoring the change of sample weight with increase in temperature. Hot stage microscopy allowed the visual observation of changes occurring in the morphology and texture of the sample with temperature. This investigation contributed a large amount of information to the pool of knowledge on the crystalline phases of the n-alkylammonium halides. Up to now, not much structural data on the crystal forms of these compounds were available in the literature. In this study, complex patterns of crystal packing and phase transitions were revealed. Six isostructural series of n-alkylammonium chlorides were identified, three of which have not been reported previously, and the crystal structure of one of the novel forms was determined. Four isostructural polymorphic forms of n-alkylammonium bromides were identified. Only two forms have been reported previously in the literature. Six crystal structures of compounds with a novel crystal form were determined. For the homologous series of n-alkylammonium iodides, four novel isostructural series were identified, and one structure was determined. Relationships between chain lengths and structural parameters like long spacings, unit cell parameters and phase transition temperatures were determined and expressed as mathematical functions. An analysis of all the known structures (structures reported in the literature and structures determined in this investigation) indicated that different molecular conformations and hydrogen bonds are responsible for differences in the packing, as expressed in the formation of polymorphs. A choice of anion for a specific compound (chloride, bromide or iodide) influenced not only the cell volume, as would be expected, but also dictated the preferential formation of pseudo-polymorphs and complex hydrogen bonding networks in the crystals themselves. Phase transition temperatures were found to be not simply a function of chain length, but to be significantly influenced by the anion and polymorphic form present.<br>Prof. G.J. Kruger

The thesis entitled "Phase Behaviour in Crystalline Solids: Exploring the Structure Guiding Factors via Polymorphism, Phase Transitions and Charge Density Studies" consists of five chapters divided into two parts. A basic introductory section describes the topics relevant to the work and the methods and techniques utilized. Part A contains two chapters that discuss the structural aspects related to polymorphism, solvatomorphism, conformational preferences and phase transitions exhibited by active pharmaceutical ingredients (APIs). It also discusses the structure-property correlations in API crystal forms and the possible utility of second harmonic generation (SHG) for their bulk characterization. Part B has three chapters that discuss experimental and theoretical charge density analyses of intra-and intermolecular interactions that play structure guiding roles in some of the APIs discussed in Part A. The main focus of the present work is to characterize the interaction patterns devoid of strong classical hydrogen bonds. The case studies include multifurcated C - H …O hydrogen bonds, the “carbon bonding” and chalcogen interactions involving Se and S atoms. In addition to charge density studies, in situcryocrystallography and molecular complexation experiments have been employed to examine structural consequences of chalcogen bonding. Further, Appendices 1 and 2 describe phase transition studies on the inorganic mineral kröhnkite and its high temperature phase transitions leading to novel inorganic structural types. Part A: Polymorphism and phase behaviour in Active Pharmaceutical Ingredients (APIs) Chapter 1 discusses case studies of polymorphism, supramolecular preference sand phase transitions exhibited by active pharmaceutical ingredients (APIs). Section 1.1 deals with the polymorphism of an anti-oxidant drug candidate ebselen and its hydroxyl derivative. The potential of organoselenium compounds to form a Se…O chalcogen bonded supramolecular recognition unit (synthon) has been established in these polymorphs and its generality is substantiated with the help of a Cambridge Structural Database (CSD) analysis. Section 1.2 demonstrates the utility of the ‘chalcogen bonded supramolecularsynthon’ in generating molecular complexes of APIs. A series of salts and co-crystals of the amyotrophic lateral sclerosis drug Riluzole have been synthesized in order to evaluate the structure directing role of S…O chalcogen bonded synthon in their crystal structures. Section 1.3adescribes the generation of polymorphs and solvatomorphs of the antidepressant drug candidate fenobamand associated phase transitions. The tautomeric preference in this molecule has been rationalized from the crystal structure analysis and abinitioenergy calculations. Further, section 1.3b utilizes chemical derivatization as a means to experimentally simulate thetautomeric preference and molecular conformations in several derivatives of fenobam and thiofenobam. Section 1.4 describes the issue of solvatomorphism and the generation of the fifth solvatomorph of gallic acid, its structural complexity and temperature induced phase transitions. The ability of solvent water molecules to drive structural diversity, by forming ‘hydration synthons’,is demonstrated in this case. Chapter 2 presents a novel methodology for the detection of polymorphic impurities in APIs based on second harmonic generation (SHG).The SHG based method has been employed to polymorphic mixtures of fenobam, hydrochlorothiazide, pyrazinamide, tolbutamide, curcumin, febuxostat and nimesulide.The conventional methods such as powder X-ray diffraction (profile fitting analysis), FT-IR, Raman spectroscopy and thermal analysesto detect the presence of polymorphic impuritiesin bulk API samples are employed on the mixtures of these API samples and the impurity detection limits are compared with the proposed SHG methodology. The APIs used in these case studies were screened for their SHG efficiency using quantum chemical calculations of hyperpolarizability and HOMO-LUMO charge redistribution behaviour. Further, a correlation with the crystal symmetry, relative packing arrangement of molecules and the observed SHG efficiency have been discussed in of some of these cases. Part B: Exploring the nature and structural consequences of nonbonding interactions in molecular crystals Chapter 3 discusses the electron density features of quasi-trifurcated CH…Cl/CH…O interaction motifs leading to ‘carbon bonding’ and a trifurcated CH…O hydrogen bond motif. Section 3.1 describes the experimental and theoretical charge density analyses of quasi-trifurcated CH…Cl and CH…O motifsand investigates the existence of “carbon bonding” in solid state. The experimental charge density evidence for “carbon bonding” have been analyzed in cases of fenobam and dimethylamine: 4-hydroxybenzoic acid complex. The existence of this unconventional interaction, which roughly mimics the transition state geometry of SN2 (bimolecular nucleophilic substitution) reaction, is further established by a CSD analysis. Section 3.2 describes the experimental and theoretical charge density analyses of ferulic acid and compares the topological features associated with a trifurcated CH…O hydrogen bond motif, with corresponding strong classical OH…O hydrogen bonds. The study demonstrates the “Gulliver effect” of weak interactions in charge density terms. Charge density based interaction energy calculations via EPMM and EML methods have been utilized in this context to evaluate the relative strength of such interactions. Chapter 4 discusses the charge density features of intermolecular chalcogen bonding interactions involving selenium and sulphur atoms.Section 4.1 describes the experimental and theoretical charge density analyses of ebselen and its hydroxyl derivative. The charge density characterization of the conserved chalcogen bond synthon (discussed in chapter 1, section 1.1) has been carried out and electronic nature and geometric dependence of Se…O interactions have been explored. The mechanism of drug action of ebselen has been correlated with the experimentally observed charge density distribution around the intramolecular SeC and SeN bonds. Section 4.2 explores the homochalcogen interactions such as S…SandSe…Se in phenol analogues. In situ cryocrystallographic studies on thiophenol, selenophenol and their solid solutions are described. Veggard’s law-like behaviour observed in these solid solutions have been rationalized and the S…S and Se…Sehomochalcogen interactions have been evaluated in these liquid systems which are devoid of any other packing forces such as strong hydrogen bonds. Chapter 5 discusses the conformation locking potential of intramolecular S…O chalcogen bonding in sulfadrugs. Section 5.1 discusses conformation locking in the antibioticdrugsulfamethizole. A two pronged approach has been adopted in the study; a) generation of cocrystals and salts of sulfamethizole for the ‘experimental simulation’ of the molecular conformation, b) evaluation of charge density distribution around the intramolecular S…O interaction region in sulfamethizole. Section 5.2 describes the effect of ‘simple hybridized orbital geometry’ in the formation of intramolecular S…O chalcogen bonding. The experimental charge density analysis of the carbonic anhydrase inhibitor drug acetazolamide has been carried out and the two different intramolecular S…O geometries have been compared in terms of the charge density topology. The analysis highlights the advantage of “orbital geometry” consideration over the conventional distance-angle criteria in assessing nonbonded interactions.

Three distinct aspects, disorder, polymorphism and co-crystal formation have been addressed in molecular crystals in terms of intra- and intermolecular interactions involving halogens, weak hydrogen bonds and van der Waals interactions. A basic introductory chapter highlights the importance of these three aspects followed by a foreword to the contents. Chapter 1 employs in situ cryo-crystallization techniques to study the crystal and molecular structures of compounds which are liquids at room temperature. Section 1.1 deals with the crystal structure analyses of low melting chloro- and bromo-substituted anilines which reveal both the importance of hydrogen bonds and weak interactions involving different halogens. The halogen⋅⋅⋅halogen interactions are compared with fluorine and iodine substituted compounds to bring out the relevance of both size and polarizability characteristics. Section 1.2 describes the crystal structures of benzyl derivative compounds utilizing the concept of in situ cryo-crystallization. This analysis brings out the correlation between acidity of benzyl derivative compounds with its preference of either a (sp2)C-H⋅⋅⋅π or (sp3)C-H⋅⋅⋅π interactions in the crystal packing. Chapter 2 consists of two sections dealing with the preference of halogen⋅⋅⋅halogen interactions in supramolecular chemistry. Section 2.1 discusses a statistically large number of crystal structures in halogen substituted benzanilide compounds. It reveals the importance of hetero halogen F⋅⋅⋅X (Cl, Br), homo halogen X⋅⋅⋅X (F, Cl, Br, I), C-X⋅⋅⋅π and C-H⋅⋅⋅F interactions in terms of their directionality and preferences to complement a primary N-H⋅⋅⋅O hydrogen bond in directing the three-dimensional supramolecular assembly. Section 2.2 deals with solvent induced polymorphism which highlights the role of weak interactions in two case studies. The preference and directionality of C-H⋅⋅⋅F and Cl⋅⋅⋅Cl interactions lead to dimorphic modifications in case of 3-chloro-N-(2-fluorophenyl)benzamide whereas in case of 2-iodo-N-(4-bromophenyl)benzamide the interactions are through C-H⋅⋅⋅π and I⋅⋅⋅I contacts. Further, the analysis is supported using morphological evidence, DSC (Differential scanning calorimetry) and Powder X-ray diffraction data. Chapter 3 has three sections, concentrating on disorder and its consequence in crystal structures. Section 3.1 discusses the apparent shortening of the C(sp3)–C(sp3) bond analysed via a variable temperature X-ray diffraction study in racemic 1,1′-binaphthalene-2,2′-diyl diethyl bis(carbonate). Variable temperature single crystal X-ray diffraction studies show that the shortening is entirely due to positional disorder and not due to thermal effects. A supercell formation at T≤150 K depicts the formation of a Z'= 2 structure. Section 3.2 deals with crystal structure analysis of Ethyl-4-(2-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate which clarifies the discrepancy in the higher value of the residual electron density in the literature in terms of positional disorder of fluorine at ortho sites. The existence of fluorine atom at the para position on the phenyl ring of another isomeric molecule leads to disorder induced conformational polymorphism through the involvement of the ethyl group. The static disorder of ethyl group which is associated with only one molecule (Z′=2) could be resolved at 120 K. This supports the results of the previous section (3.1). Section 3.3 reports crystal structure analysis of disordered fluorine in benzanilide compounds. The preference of interactions involving fluorine in either ortho sites or meta sites could be one of the reasons for the positional disorder of both possible sites. With one of the structure showing high Z′ value due to differences in the occupancy of disordered fluorine atom. CSD (Cambridge Structural Database) analysis indicates that the percentage of disorder in halogenated crystal structures having halogen atom at either ortho site or meta site decreases from fluorine to iodine. Further, the analysis points out that the disorder in fluorine containing compounds is mostly localized at the fluorine position whereas for other halogenated disordered structures, the disorder appears at other parts of the molecule. Chapter 4 discusses co-crystal formation and analysis of intermolecular interactions. It consists of two sections. Section 4.1 discusses co-crystal formation of nicotinamide with benzoic acid and seven other derivatives by changing the functional group at different positions of benzoic acid. Hydroxyl (-OH) group at 4/3-postion of benzoic acid prefers phenol⋅⋅⋅pyridine synthon when at 2-position it prefers acid⋅⋅⋅pyridine synthon. The preference of amide anticatemer over dimer synthon is supported by additional C-H⋅⋅⋅O hydrogen bonds. In case of 3,5-dinitro-2-hydroxy benzoic acid, the disorder in hydroxyl (-OH) group at ortho site leads to salt formation. Section 4.2 describes co-crystal study of adenine and thymine (AT) as free nucleobases. This result reveals the formation of AT (2:1) complex with both Hoogsteen and “quasi-Watson-Crick” hydrogen bonds. The hydrogen bonded bases using the Hoogsteen and the “quasi-Watson-Crick” interactions generate a hexagonal supramolecular motif. Four water molecules are located inside the hexagonal void of this complex. A high temperature study on the same crystal shows that at 313K, one of the water molecules escapes from the lattice resulting in the small change in unit cell parameters. However, the space group remains the same and the hexagonal void remains unaltered. With further increase in temperature, the crystal deteriorates irreversibly which clearly brings out the importance of water molecule in the molecular recognition of adenine-thymine complex. Chapter 5 discusses crystal structure analysis of trans-atovaquone (antimalarial drug), its new polymorph form including one stereoisomer (cis) and five other derivatives with different functional groups. Based on the conformational features of these compounds and the characteristics of the nature of hydrogen bonding and other weak intra and intermolecular interactions, docking studies with cytochrome bc1 complex provide valuable insight into the atomistic details of protein-inhibitor interactions. The docking results reveal that atovaquone and its derivatives, owing to their nature of hydrogen bond and the propensity towards the formation of weaker hydrogen bonds involving the chlorine atom as well appear as good candidates for drug evaluation.

The thesis entitled “Structure-function control in organic co-crystals/salts via studies on polymorphism, phase transitions and stoichiometric variants” consists of five chapters. The main emphasis of the thesis is on two aspects, one to characterize co-crystal polymorphism in terms of propensity of intermolecular interactions to form co-crystals/salts or eutectics. The other aspect is to explore the feasibility of using such co-crystals/salts to exhibit properties like proton conduction, dielectric and ferroelectric behaviour. Gallic acid and its analogues possess functionalities to provide extensive hydrogen bonding capabilities and are chosen as the main component while the coformers are carefully selected such that they either accept or reject the hydrogen bonding offered. Such co-crystallization experiments therefore provide an opportunity to unravel the intricate details of the formation of crystalline polymorphs and/or eutectics at the molecular level. Further these co-crystal systems have been exploited to evaluate proton conductivity, dielectric and ferroelectric features since the focus is also on the design aspect of functional materials. In the context of identifying and utilizing Crystal Engineering tools, the discussions in the following chapters address not only the structural details but identify the required patterns and motifs to enable the design of multi-component co-crystals/salts and eutectics. In particular, the presence/absence of lattice water in gallic acid has been evaluated in terms of importing the required physical property to the system. Chapter 1 discusses the structural features of tetramorphic anhydrous co-crystals (1:1; which are synthon polymorphs) generated from a methanolic solution of gallic acid monohydrate and acetamide, all of which convert to a stable form on complete drying. The pathway to the stable form (1:3 co-crystal) is explained based on the variability in the hydrogen bonding patterns followed by lattice energy calculations. Chapter 2A studies the presence/absence and geometric disposition of hydroxyl functionality on hydroxybenzoic acids to drive the formation of co-crystal/eutectic in imide-carboxylic acid combinations. In Chapter 2B the crystal form diversity of gallic acid-succinimide co-crystals are evaluated with major implications towards the design and control of targeted multi-component crystal forms. The co-crystal obtained in this study shows a rare phenomenon of concomitant solvation besides concomitant polymorphism and thus making it difficult to obtain a phase-pure crystal form in bulk quantity. This issue has been resolved and formation of desired target solid form is demonstrated. Thus, this study addresses the nemesis issues of co-crystallization with implications in comprehending the kinetics and thermodynamics of the phenomenon in the goal of making desired materials. Chapter 3 focuses on the systematic co-crystallization of hydroxybenzoic acids with hexamine using liquid assisted grinding (LAG) which show facile solid state interconversion among different stoichiometric variants. The reversible interconversion brought about by varying both the acid and base components in tandem is shown to be a consequence of hydrogen bonded synthon modularity present in the crystal structures analyzed in this context. In Chapter 4A, the rationale for the proton conduction in hydrated/anhydrous salt/co-crystal of gallic acid - isoniazid is provided in terms of the structural characteristics and the conduction pathway is identified to follow Grotthuss like mechanism which is supplemented by theoretical calculations. Chapter 4B describes an extensive examination of the hydrated salt of gallic acid-isoniazid which unravels the irreversible nature of the dielectric property upon dehydration and suggests that the “ferroelectric like” behaviour is indeed not authenticated. This chapter brings out the significance role of lattice water in controlling the resulting physical property (dielectric/ferroelectric in this case). Chapter 5 describes the structural features of two hydrated quaternary salts of hydroxybenzoic acids-isoniazid-sulfuric acid and the phase transitions at both low and high temperatures are shown to be reversible. Single Crystal to Single Crystal (SCSC) in situ measurement corroborated by thermal and in situ Powder X-ray Diffraction studies proves the claim. Further, the properties exhibited by these materials are also governed by lattice water content.

Crystal engineering underlies the essence of natural affiliation between the molecule on the one side and the crystal as a supramolecular assembly on the other. Molecular recognition is the fundamental cause for this efficient transformation and if we consider the crystal as a supramolecular entity then it is not at all difficult to conceive crystallization as an outstanding example of molecular recognition. In general, organic compounds often facilitate closed packed crystal structures as described by A. I. Kitaigorodskii in the form of the close packing principle but based on chemical features, there is still a small window to understand, to rationalize and to fashion new crystal structures. Extending the chemical viewpoint as first proposed by J. M. Robertson, the supramolecular synthon model as a descriptor of collective crystal structures has been invoked that enables one to trail the molecular behaviour from an entropy dominated situation in solution to an enthalpy driven progression in the solid state. After 20 years, the concept of the supramolecular synthon has stood the test of time because of its simplicity and effectiveness towards the implementation in complex crystal structures and has led the scientific community to further handle complex and interesting ideas in structural chemistry and supramolecular synthesis. The complexity of dynamic and progressive behavior of molecules during crystallization may be understood by the analogous argument of protein folding; both these complex phenomena decode the emergence of multiple metastable forms before the final structures are attained. These intermediate kinetically driven species may be high energy polymorphs and pseudopolymorphs of the compound in question or semicompact random globules for proteins. Understanding the role of these species in their respective processes is of critical importance in elucidating mechanisms. As an alternative approach, crystal structure prediction (CSP) is also of fundamental importance in the context of understanding the crystallization process. All energy based computational methods of CSP address this problem by scanning the multi-dimensional energy hypersurface. This is performed by computing lattice energy changes with respect to parameters like unit cell dimensions, space group symmetry and the positional coordinates of atoms in the asymmetric unit. Further, the computational prediction of the crystal structure of an organic compound results in several choices, and it is possible that a collection of some of these when taken together forms a pattern that mimics the course of the crystallization process very much in the manner that structure correlation mimics covalent bond breaking and making. With all these developments, one is truly at the stage today when any experimental or computed crystal structure is just that, a crystal structure of the molecule in question and it is part of a complex and dynamic structural space which may include a part of the supramolecular reaction trajectory for crystallization itself. Accordingly, this thesis emphasizes the importance of kinetic events during crystallization and proposes some strategies to access the inaccessible domains of this structural space of a given compound. I have exploited the supramolecular synthon model to understand the kinetics of the crystallization process and have further extended this understanding towards the isolation of stoichiometric ternary solids. The synthon model also helps one to provide a logical step to explore these remote domains of the complex hyperenergy surface that have collectively been termed as the crystal structure landscape of the compound in question. The precise descriptions of the chapters are mentioned below. Chapter 2 describes fluorosubstitution as a unique chemical probe to explore the high energy crystal structures of benzoic acid in ambient conditions. This landscape exploration of benzoic acid is based on the robust (kinetically favoured) supramolecular homosynthon as well as consistent fluorosubstitution in native compound. This analysis is also supported by synthon based crystal structure prediction which is one of the best ways of monitoring high energy virtual crystal structures. Chapter 3 extends the idea of landscape exploration towards multicomponent systems. The incorporation of an additional compound during crystallization facilitates even complex kinetic environments but using fluorosubstitution as a chemical probe, it again helps to analyse the high energy virtual domains of the given multicomponent system. Similar to chapter 2, the landscape exploration of multicomponent system is also based on the robust (kinetically favoured) supramolecular heterosynthon as well as consistent fluorosubstitution in the native multicomponent system. Chapter 4 emphasizes the importance of synthon modularity as a chemical probe to traverse in the crystal structure landscape of the given multicomponent system. Here, I have quantified the role of the definitive synthon, by using the supramolecular synthon based fragment approach (SBFA), in the emergence of polymorphism in cocrystals. In latter part of this chapter, I utilized this collective kinetic information in order to realize the combinatorial nature of the crystallization process and showed the complex combinatorial synthesis of ternary solids which itself is considered to be an arduous exercise. Chapter 5 discusses the importance of kinetic information which were fetched from the corresponding multicomponent landscapes and were further utilized for combinatorial synthesis of ternary solids. Although the combinatorial idea is well established in solution, this chapter highlights the first experimental evidence of this idea in the solid state and shows preferred amplification of certain supramolecular synthons from corresponding libraries in the supersaturated crystallizing medium. Chapter 6 extends the combinatorial idea of crystallization even further by using highly flexible organic compounds that collectively provide larger structural space during crystallization. Using the delicate kinetic information about the molecular and supramolecular features, this chapter describes the preferential selection of molecular conformation and supramolecular synthons from the supersaturated solution during the molecule→crystal pathway. In summary, the idea of the crystal structure landscape provides an extended interpretation about some of the complex ideas namely, crystal energy landscape and polymorphism in modern crystal engineering. The crystallization of an organic compound often depends upon intrinsic chemical features and accordingly one selects optimized crystallization routes in the corresponding landscape through decisive experimental conditions. As a final note, the idea of the crystal structure landscape enables one to (at least qualitatively) understand the importance of crystallization kinetics which is understandably a difficult task.

The thesis entitled “Organic fluorine in crystal engineering: Consequences on molecular and supramolecular organization” consists of six chapters. The main theme of the thesis is to address the role of substituted fluorine atoms in altering the geometrical and electronic features in organic molecules and its subsequent consequences on crystal packing. The thesis is divided into three parts. Part I deals with compounds that are liquids under ambient conditions, crystal structures of which have been determined by the technique of in situ cryocrystallography. Part II demonstrates the utilization of in situ cryocrystallography to study kinetically trapped metastable crystalline phases that provide information about crystallization pathways. In part III, crystal structures of a series of conformationally flexible molecules are studied to evaluate the consequences of fluorine substitution on the overall molecular conformation. The genesis and stabilization of a particular molecular conformation has been rationalized in terms of variability in intermolecular interactions in the crystalline state. Part I. In situ cryocrystallography: Probing the solid state structures of ambient condition liquids. Chapter 1 discusses the crystal structures of benzoyl chloride and its fluorinated analogs. These compounds have been analysed for the propensity of adoption of Cl···O halogen bonded dimers and catemers. The influence of conformational and electronic effects of sequential fluorination on the periphery of the phenyl ring has been quantified in terms of the most positive electrostatic potential, VS,max (corresponding to σ-hole) on the Cl-atom. It is shown that fluorine also exhibits “amphoteric” nature like other heavier halogens, particularly in presence of electron withdrawing groups. Although almost all the derivatives pack through C–H···O, C–H···F, C–H···Cl, Cl···F, C–H···π and π···π interactions, the compound 2,3,5,6-tetrafluorobenzoyl chloride exhibited a not so commonly observed Cl···O halogen bonded catemer. On the other hand, the proposed Cl···O mediated dimer is not observed in any of the structures due to geometrical constraints in the crystal lattice. Chapter 2 presents the preferences of fluorine to form hydrogen bond (C–H···F) and halogen bonds (X···F; X= Cl, Br, I). Crystal structures of all three isomers of chloro-, bromo-and iodo-fluorobenzene have been probed in order to gain insights into packing interactions preferred by fluorine and other heavier halogens. It has been observed that homo halogen…halogen (Cl···Cl, Br···Br and I···I) contacts prevail in most of the structures with fluorine being associated with the hydrogen atom forming C–H···F hydrogen bond. The competition between homo and hetero halogen bonds (I···I vs I···F) is evident from the packing polymorphism exhibited by 4-iodo fluorobenzene observed under different cooling protocols. The crystal structures of pentafluoro halo (Cl, Br, I) benzenes were also determined in order to explore the propensity of formation of homo halogen bonds over hetero halogen bonds. Different dimeric and catemeric motifs based on X···F and F···F interactions were observed in these structures. Chapter 3 focuses on the effect of different cooling protocols in generating newer polymorphs of a given liquid. The third polymorph (C2/c, Z'=6) of phenylacetylene was obtained by sudden quenching of the liquid filled in capillary from a hot water bath (363 K) to the nitrogen bath (< 77 K). Also, different polymorphs were obtained for both 2¬fluoro phenylacetylene (Pna21, Z'=1) and 3-fluoro phenylacetylene (P21/c, Z'=3) when crystallized by sudden quenching in contrast to the generally followed method of slow cooling which results in isostructural forms (P21, Z'=1). The rationale for these kinetically stable “arrested” crystalline configurations is provided in part II of the thesis. Part II. Tracing crystallization pathways via kinetically captured metastable forms. Chapter 4 explains the utilization of the new approach of sudden quenching of liquids (detailed in chapter 3) to obtain kinetically stable (metastable) crystalline phases that appear to be closer to the unstructured liquids. Six different examples namely, phenylacetylene, 2-fluorophenylacetylene, 3-fluorophenylacetylene, 4-fluorobenzoyl chloride, 3-chloro fluorobenzene and ethyl chloroformate are discussed in this context. In each case, different polymorphs were obtained when the liquid was cooled slowly (100 K/h) and when quenched sharply in liquid nitrogen. The relationship between these metastable forms and the stable forms (obtained by slow cooling) combined with the mechanistic details of growth of stable forms from metastable forms provides clues about the crystallization pathways. Part III. Conformational analysis in the solid state: Counterbalance of intermolecular interactions with molecular and crystallographic symmetries. Chapter 5 describes the crystal structures of a series of conformationally flexible molecules namely, acetylene and diacetylene spaced aryl biscarbonates and biscarbamates. While most of the molecules adopt commonly anticipated anti (transoid) conformation, some adopt unusual cisoid and gauche conformations. It is shown that the unusually twisted conformation of one of the compounds [but-2-yne-bis(2,3,4,5,6¬pentafluorocarbonate)] is stabilized mainly by the extraordinarily short C–H···F intermolecular hydrogen bond. The strength of this rather short C–H···F hydrogen bond has been authenticated by combined single crystal neutron diffraction and X-ray charge density analysis. It has also been shown that the equi-volume relationship of H-and F-atoms (H/F isosterism) can be explored to access various possible conformers of a diacetylene spaced aryl biscarbonate. While biscarbonates show variety of molecular conformations due to absence of robust intermolecular interactions, all the biscarbamates adopt anti conformation where the molecules are linked with antiparallel chains formed with N–H···O=C hydrogen bonds. Chapter 6 presents a unique example where the commonly encountered crystallographic terms namely, high Z' structure, polymorphism, phase transformation, disorder, isosterism and isostructuralism are witnessed in a single molecular species (parent compound benzoylcarvacryl thiourea and its fluorine substituted analogs). The origin of all these phenomenon has been attributed to the propensity of formation of a planar molecular dimeric chain mediated via N–H···O [R2 (12)] and N–H···S [R2 (8)] dimers.

Crystal engineering offers a rational way of analyzing crystal structures and designing new structures with properties. The supramolecular synthon concept was introduced in 1995 and has shown versatility and utility in the design of molecular solids. Chapter 1 gives a general introduction about the development of the concept of supramolecular synthons over the years which has seen a transition from synthesis to structures and dynamics. This thesis focuses on the later phase of the development of the concept of supramolecular synthons. Chapter 2 introduces the idea of structural landscape and describes a structural landscape of a conformationally flexible molecule, orcinol, and explores the synthon preferences of this particular molecule towards cocrystal formation. Chapter 3 explores a combinatorial matrix to show both global and local features of a structural landscape. Chapter 4 takes a component of this landscape namely 4,4'-bipyridine and 4-hydroxybenzoic acid and shows the occurrence of synthon polymorphism in cocrystals which originates from the interplay of geometrical and chemical factors. Chapter 5 introduces a four step method for the identification of multiple synthons by FTIR spectroscopy. Along with, it shows that the rarity of synthon polymorphism is not a case of overlooking of crystals in the process of selecting good looking crystals. Chapter 6 takes a series of dihalogenated phenols and indicates that the Br prefers type II. This chapter also explains elastic bending on the basis of halogen bonds. Chapter 7 attempts to explore the Cl/Br isostructurality in the light of type I and type II contacts and concludes that Cl/Br isostructurality arises from a geometrical model and therefore it is quite similar to Cl/Me isostructurality. Chapter 8 attempts to analyze the class of trichlorophenols and reveals structural modularity in this class of compounds. The modularity of 3,4,5-trichlorophenol is explored in crystal design in chapter 9 in terms of LSAM (Long Range Synthon Aufbau Module) A subsequent study in solution by NMR reveals the presence of LSAM in solution and establishes a hierarchy of the dissociation of its components. The concept of supramolecular synthon has come a long way from being a tool in a crystal engineer’s toolbox to a structural unit responsible for crystallization and therefore offer multiple possibilities both in terms of structures and dynamics. This thesis attempts to explore some of these possibilities based mainly on the concepts of structural landscape and halogen bonds which are blended with the concept of supramolecular synthons.

Structural studies of peptides are of great importance in developing novel and effective biomaterials ranging from drugs and vaccines to nano materials with industrial applications. In addition, they provide model systems to study and mimic the protein conformations. The ability to generate folded intramolecularly hydrogen bonded structures in short peptides is essential for peptide design strategies, which rely on the use of folding nuclei in the construction of secondary structure modules like helices and β-hairpins. In these approaches, conformational choices at selected positions are biased, using local stereochemical constraints, that limit the range of accessible backbone torsion angles. X-ray crystallographic studies of designed peptides provide definitive proof of the success of a design strategy, and provide essential structural information that can be utilized in the future design of biologically and structurally important polypeptides. Recent trends in peptide research focus on the incorporation of β-, γ- and higher homologs of the α-amino acid residues in designed peptides as they confer more proteolytic stability to the polypeptides. X-ray crystallographic studies of such modified peptides containing non-protein residues are essential, since information on the geometric and stereochemical properties of modified amino acids can only be gathered from the systematic structural studies of synthetic peptides incorporating them. This thesis reports a systematic study of the structures and conformations of amino acid derivatives and designed peptides containing stereochemically constrained α-, β- and γ-amino acid residues and the structural studies of polymorphic peptide helices. The structures described in thesis contain the Cα,α-dialkyalted α-residues α-aminoisobutyric acid (Aib) and 1-aminocyclohexane-1-carboxylic acid (Ac6c), the β-amino acid residue 1-aminocyclohexane acetic acid (β3,3Ac6c) and the γ-amino acid residue 1-aminomethylcyclohexaneacetic acid (gabapentin, Gpn). The crystal structure determination of peptides incorporating conformationally constrained α-, β- and γ- amino acid residues permitted the characterization of new types of hydrogen bonded turns and polymorphs. The studies enabled the precise determination of conformational and geometric parameters of two ω-amino acid residues, gabapentin and β 3,3Ac6c and provided detailed information about the conformational excursions possible for peptide molecules. This thesis is divided into 10 chapters. Chapter 1 gives a general introduction to the stereochemistry of the polypeptide chain, description of backbone torsion angles of α- and ω- amino acid residues and the major secondary structures of α-peptides, β-peptides, γ-peptides and hybrid peptides. A brief introduction to polymorphism and weak interactions, in particular aromatic interactions, is also provided, followed by a discussion on X-ray diffraction and solution to the phase problem. Chapter 2 describes the crystal structures of gabapentin zwitterion and its eight derivatives (Ananda, Aravinda, Vasudev et al., 2003). The crystal structure of the gabapentin zwitterions determined in this study is identical to that previously reported (Ibers, J. A. Acta Crystallogr. 2001, C57, 641-643). Eight of the nine achiral compounds crystallized in centrosymmetric space groups P21/c, C2/c or Pbca, while one derivative (Tos-Gpn-OH) crystallized in non-centrosymmetric space group Pna21 with four independent molecules in the asymmetric unit.The structural studies presented in this chapter reveal that the geminal substituents on the Cβ atom limits the values of dihedral angles θ1 and θ2 to ±60°, resulting in folded backbone conformations in all the examples. Intramolecular hydrogen bonds with 7-atoms in the hydrogen bond turn (C7) are observed in three derivatives, gabapentin hydrochloride (GPNCL), Boc-Gpn-OH (BGPNH) and Piv-Gpn-OH (PIVGPN), while a 9-atom hydrogen bonded turn (C9) is observed in Ac-Gpn-OH (ACGPH). Unique structural features, such as an unusual anti conformation of the COOH group (in ACGPH) and positional disorder of the cyclohexane ring (in BGPNN), indicating the co-existence of both the interconvertible chair conformations, are revealed by the crystal structure analyses. Chapter 3 describes the structural characterization of novel hydrogen bonded conformations of homo oligomers of Gpn. The crystal structures of three peptides, Boc-Gpn-Gpn-NHMe (GPN2), Boc-Gpn-Gpn-Leu-OMe (GPN2L) and Boc-Gpn-Gpn-Gpn-Gpn-NHMe (GPN4) provide the first crystallographic characterization of two new families of polypeptide structures, the C9 helices and C9 ribbons (Vasudev et al., 2005, 2007), in which the molecular conformations are stabilized by contiguous C9 turns formed by the hydrogen bonding between the CO group of residue (i) and the NH group of residue (i+2). The C9 hydrogen bond is characterized by a specific combination of the four torsion angles for the Gpn backbone, with the torsion angles θ1 and θ2 adopting g+/g+ or g /g- conformations. The structural analysis also permits precise determination of hydrogen bond geometry for the C9 structures, which is highly linear in contrast to the analogous γ-turn hydrogen bonds in α-peptides. A comparison of the backbone conformations in the three peptides reveals two classes of C9 hydrogen bonded secondary structures, namely C9 helices and C9 ribbons. The packing arrangement in these γ-peptides follows the same patterns as the helix packing in crystals of α-peptides. Chapter 4 describes ten crystal structures of short hybrid peptides containing the Gpn residue (Vasudev et al., 2007). In addition to the C7 and C9 hydrogen bonded turns which are defined by the backbone conformations at the Gpn residue, hybrid turns defined by a combination of backbone conformations at the α and γ-residues or at the β and γ-residues have been determined. Peptides Boc-Ac6c-Gpn-OH (ACGPH), Piv-Pro-Gpn-Val-OMe (PPGPV) and Boc-Val-Pro-Gpn-OH (VPGPH) reveal molecular conformation stabilized by intramolecular C9 hydrogen bonds, while Boc-Ac6c-Gpn-OMe (ACGPO) and Boc-Gpn-Aib-OH (GPUH) are stabilized by a C7 hydrogen bonded turn at the Gpn residue. An αγ hybrid turn with 12 atoms in the intramolecular hydrogen bonded rings (C12 turns) has been observed in the tripeptide Boc-Ac6c-Gpn-Ac6c-OMe (ACGP3), while βγ hybrid turns with 13 atoms in the hydrogen bonded ring (C13 turns) have been characterized in the tripeptides Boc-βLeu-Gpn-Val-OMe (BLGPV) and Boc- βPhe-Gpn-Phe-OMe (BFGPF). The two βγ C13 turns belong to two different categories and are characterized by different sets of backbone torsion angles for the β and γ residues. A γα C10 hydrogen bond, which is formed in the N→C direction (NHi ••• COi+2), as opposed to the regular hydrogen bonded helices of α-peptides, has also been observed in BFGPF. The Chapter provides a comparison of the backbone torsion angles of the Gpn residue in various hydrogen bonded turns and a brief comparison of the observed hydrogen bonded turns with those of the α-peptides. Chapter 5 describes the crystal structures of three αγ hybrid peptides which show C12/C10 mixed hydrogen bond patterns (Vasudev et al., 2007, 2008a; Chatterjee, Vasudev et al.,2008a). The insertion of gabapentin in the predominantly α-amino acid sequences in Boc-Ala-Aib-Gpn-Aib-Ala-OMe (AUGP5) and Boc-Leu-Gpn-Aib-Leu-Gpn-Aib-OMe results in the observation of helices stabilized by αα C10 (310-turn) and αγ C12 turns. The tetrapeptide Boc-Leu-Gpn-Leu-Aib-OMe reveals a novel conformation, stabilized by C12 (αγ) and C10 (γα) hydrogen bonds of opposite hydrogen bond directionalities. The conformations observed in crystals have been extended to generate C12 helix and C12/C10 helix with alternating hydrogen bond polarities in ( αγ)n sequences. The structure determination of three crystals, providing five molecular conformations, presented in this chapter provides the first crystallographic characterization of two types of helices predicted for the regular αγ hybrid peptides from theoretical calculations. The crystal structure of Boc-Ala-Aib-Gpn-Aib-Ala-OMe also provides an example for the co-existence of left-handed and right-handed helix in the asymmetric unit. Chapter 6 describes the structural studies of αγ hybrid peptides containing Aib and Gpn residues, and is divided into two parts. The first part presents the crystal structure analysis of peptides of sequence length 2 to 4, with alternating Aib and Gpn residues, and illustrates the conformational variability in αγ hybrid sequences as evidenced by the observation of conformational polymorphs (Chatterjee, Vasudev et al., 2008b; Vasudev et al., 2007; Ananda, Vasudev et al., 2005). The peptide Boc-Gpn-Aib-NHMe (GUN), Boc-Aib-Gpn-Aib-OMe (UGU), Boc-Gpn-Aib-Gpn-Aib-OMe (GU4O), Boc-Aib-Gpn-Aib-Gpn-OMe (UG4O) and Boc-Aib-Gpn-Aib-Gpn-NHMe (UG4N), all of which are potential candidates for exhibiting αγ C12 hydrogen bonds, reveal molecular conformations stabilized by diverse hydrogen bonded turns such as C7, C9, C12 and C17 in crystals. The conformational heterogeneity in this class of hybrid peptides is further evidenced by the observation of three polymorphs in the monoclinic space group P21/c for the tetrapeptide Boc-Aib-Gpn-Aib-Gpn-NHMe (UG4N), providing four independent peptide molecules adopting two distinct backbone conformations. In one polymorph, C12 helices terminated with an unusual three residue ( γαγ) C17 turn is observed, while the unfolding of helical conformation by solvent insertion into the backbone is observed in the other two polymorphs. The studies indicate the possible utility of Gpn residue in stabilizing locally folded conformations in the folding pathway, thus permitting their crystallographic characterization in multiple crystal forms. A discussion of the structural and conformational features of Gpn residues determined from all the crystal structures is presented in the Chapter, along with a φ-ψ plot for the Gpn residue. Part 2 of Chapter 6 describes the crystal structures of two octapeptides, Boc-Gpn-Aib-Gpn-Aib-Gpn-Aib-Gpn-Aib-OMe (GU8) and Boc-Leu-Phe-Val-Aib-Gpn-Leu-Phe-Val-OMe (LFVUG8), featuring C12 turns at the Aib-Gpn segments (Chatterjee, Vasudev et al., 2009). GU8 folds into a C12 helix flanked by C9 hydrogen bonds at both the termini, while LFVUG8 adopts β-hairpin conformation with a chain-reversing C12 turn at the central Aib-Gpn segment. A remarkable feature of the Aib-Gpn turn in the β-hairpin structure is the anti conformation about the Cβ-Cα (θ2) bond, which is the only example of a Gpn residue not adopting gauche conformation for both θ1 and θ2. The crystal structures of the two peptides, mimicking the two major secondary structural elements of α-peptides in hybrid polypeptides, permits a comparative study of the mode of molecular packing in crystals of α-peptides and hybrid peptides. The chapter also discusses theoretical calculations on αγ hybrid sequences, which reveal new types of C12 hydrogen bonded turns. Chapter 7 describes the crystal structures of conformationally biased tert-butyl derivatives of Gpn. The crystallographic characterization of the E (trans) and Z (cis) isomers of the residue,three protected derivatives and a tripeptide provides examples of C7 and C9 hydrogen bonded conformations, suggesting that the C7 and C9 hydrogen bonds can be formed by Gpn residues with both the chair conformations of the cyclohexane ring. Chapter 8 describes the systematic structural studies of the derivatives and peptides of the stereochemically constrained β- amino acid residue, β3,3Ac6c (Vasudev et al., 2008c). The backbone torsion angles φ and θ adopt gauche conformation in majority of the examples, owing to the presence of a cyclohexane ring on the Cβ atom. In contrast to Gpn, β3,3Ac6c does not show strong preference for adopting intramolecularly hydrogen bonded conformations. Of the 16 crystal structures determined, intramolecular hydrogen bonds involving the β-residue are observed only in 4 cases. The amino acid zwitterion (BAC6C), the hydrochloride (BACHCL) and the dipeptide Boc-β3,3Ac6c-β3,3Ac6c-NHMe (BAC62N) form N-H•••O hydrogen bonds with 6-atoms in the hydrogen bond ring (C6 turns). An αβ hybrid C11 hydrogen bonded turn is characterized in the dipeptide Piv-Pro-β3,3Ac6c-NHMe, which is distinctly different from the C11 hydrogen bonds observed in αβ hybrid peptide helices. Several unique structural features such as a dynamic disorder of the hydrogen atom of the carboxylic acid group (in BBAC) and cis geometry of the urethane bond (in BBAC, BAC62N and BPBAC) have been observed in this study. A comparison of the backbone conformations of β3,3Ac6c with other β- amino acid residues is also provided. Chapter 9 describes the crystallographic characterization of a new polymorph of gabapentin monohydrate and crystal structures of the zwitterions of E and Z isomers of tert-butylgabapentin and its hydrochloride and hydrobromide (Vasudev et al., 2009). A comparison of the crystal structures of the monoclinic form (Ibers, J. A. Acta Crystallogr. 2001, C57, 641-643) of gabapentin monohydrate and the newly characterized orthorhombic form reveals identical molecular conformations and intermolecular hydrogen bond patterns in both the polymorphs. The two polymorphs show differences in the orientation of molecules constituting a layer of hydrophobic interactions between the cyclohexyl side chains. A comparison of the packing arrangements of the zwitterionic amino acid molecules in the crystal structures of gabapentin monohydrate, the tert-butyl derivatives and other co-crystals of gabapentin that had been characterized so far, is provided which would facilitate prediction of new polymorphs of the widely used drug molecule, Gpn. Chapter 10 describes the crystallization of α-peptide helices in multiple crystal forms (Vasudev et al., 2008b). Crystal structures of two peptides, Boc-Leu-Aib-Phe-Phe-Leu-Aib-Ala-Ala-Leu-Aib-OMe (LFF), Boc-Leu-Aib-Phe-Ala-Leu-Ala-Leu-Aib-OMe (D1) in two crystal forms and the crystal structure of a related sequence, Boc-Leu-Aib-Phe-Ala-Phe-Aib-Leu-Ala-Leu-Aib-OMe (D10) permit an analysis of the molecular conformation and packing patterns of peptide helices in crystals. The two polymorphs of LFF, crystallized in the space groups P21 and P22121, reveal very similar molecular conformation (α/310-helix) in both the polymorphic crystals; the two forms differ significantly in the pattern of solvation. The crystal structure determination of a monoclinic (P21) and an orthorhombic polymorph (P21212) of D1 provides five different peptide conformations, four of which are α-helical and one is a mixed 310/α-helix. The crystal structure determination of the three peptides provide an opportunity to compare the nature and role of aromatic interactions in stabilizing molecular conformation and packing and its significance in the observation of polymorphism. An analysis of the Cambridge Structural Database and a model for nucleation of crystals in hydrophobic peptide helices are also discussed.