Doctor of Philosophy / Department of Chemistry / Christer Aakeröy / Physical properties of bulk solids are typically governed by the molecular arrangement of individual building blocks with respect to each other in the crystal lattice. Thus the ability to synthesize molecular crystals with pre-organized connectivities allows for the rational design of functional solids with desirable and tunable physical properties. A thorough understanding of the various intermolecular interactions that govern the solid-state architectures is an important pre-requisite for the rational design of molecular solids. In order to understand the role of molecular geometric complementarity in the design of solid-state architectures, we explored the structural landscape of two isomeric pyridine based acceptors (3N and 4N) with binding sites oriented along different directions, i.e. parallel and at angle of 60° respectively, with a series of even chain diacid (colinear binding sites) and odd chain diacid (binding sites oriented along 120°) using co-crystallization technique. The results obtained shows a striking correlation between the observed solid state architecture and geometric complementarity of interacting species. Combinations of 3N with odd and 4N with even chain diacid produced 1-D chains whereas 3N with even and 4N with odd chain diacid generated 0-D ring architectures. In order to exploit the possibility of fine-tuning physical properties using co-crystallization techniques, solubility measurements were performed on 3N and 4N co-crystals with the diacids. The results show that the solubilities of 3N and 4N in the co-crystal form were very different from their solubility in the pure form. Also, there was a strong correlation observed between the solubility of the co-crystals and their corresponding co-formers, i.e. diacids. To explore the dependence of crystal structure on a physical property such as melting point, we synthesized co-crystals of 3,3‟-azopyridine and 4,4‟-azopyridine with a series of even chain diacids. Structural consistency was obtained within the two groups of co-crystals. In both groups, 1-D chains were formed with the diacid as the primary building block. However, In the series of 3,3‟-azopyridine co-crystals, the co-crystal with succinic acid showed a different solid-state packing arrangement (although the primary building block was same as others) compared to the others in the same series. This difference is also reflected as a deviation in the melting point, while the others in the series showed a perfect correlation between the structural consistency and melting point behavior. It was also observed that the co-crystals of 4,4‟-azopyridine displayed higher melting points than co-crystals of 3,3‟-azopyridine which could be due to the differences in the overall packing of the crystal which is a combination of different intermolecular interactions that exist between molecules in the solid state. Using bi-functional donors (with both hydrogen and halogen bond donors on same backbone), we investigated the relative strengths of hydrogen and halogen bond donors in the presence of two isomeric acceptors, 3,3‟-azopyridine and 4,4‟-azopyridine, which exhibit geometric bias in their binding-site orientation. Based on the crystal structures, we noticed a preferential binding of hydrogen bond donors with 3,3‟-azopyridine and both hydrogen and halogen bond donors with 4,4‟-azopyridine. This shows that the two types of donors are very comparable and their binding preference is governed by the geometric complementarity between the donor-acceptor pair. Finally, we explored the scope of using co-crystallization for tuning the physical properties of two agrochemicals, cyprodinil and terbuthylazine. The crystal structures of the actives with a series of even chain diacids displayed structural consistency in the primary motifs within the two groups, while few differences were observed in the packing arrangement and secondary interactions. By forming co-crystals we were able to improve the solubility and melting point of cyprodinil, while ensuring that the hygroscopicity of the active was unaltered.

Calcium ions have important roles in cellular processes including intracellular signaling, protein folding, enzyme activation and initiation of programmed cell death. Cells maintain low levels of calcium in their cytosol in order to regulate these processes. When activation of calcium-dependent processes is needed, cells can release calcium stored in the endoplasmic reticulum (ER) into the cytosol to initiate the processes. This can also initiate formation of plasma membrane channels that allow entry of additional calcium from the extracellular milieu. The change in calcium levels is referred to as calcium flux. A key protein involved in initiation of calcium flux is Stromal Interaction Molecule 1 (STIM1), which has recently been identified as a sensor of ER calcium levels. STIM1 is an ER transmembrane protein that is activated by a drop in ER calcium levels. Upon activation, STIM1 oligomerizes with a plasma membrane protein, ORA1, to form calcium-selective plasma membrane channels. Dysregulation of calcium flux has been reported in cancers, autoimmune diseases and other diseases. STIM1 is a promising target in drug discovery due to its key role early in calcium flux. Here we review the involvement and importance of STIM1 in diseases and we discuss STIM1 as a viable target for drug discovery using computational chemistry methods to rapidly identify new molecules to target STIM1. Herein, computational techniques were used to understand the mechanistic role of STIM1 and virtual screening is in process to discover potential inhibitors of STIM1 activity. Also mutational analysis on STIM1 was performed computationally to see the effect it had on the protein computationally. It has been found that tumor cells and tissues, compared to normal cells, have higher levels of copper and possibly other metal ions. This presents a potential vulnerability of tumor cells that can serve as a physiological difference between cancer cells and normal cells and allows design of compounds that selectively target tumor cells while sparing normal cells. Recently we have identified compounds that have potential to inhibit the proteasome in tumor cells and induce cell death by mobilizing endogenous tumor copper resulting in in cellulo activation of the compound. These compounds hence act as pro-drugs, becoming active drugs in tumor cells with high copper content but remaining essentially inactive in normal cells, thereby greatly reducing adverse effects in patients. Such use would be of significant benefit in early detection and treatment of cancers, in particular, aggressive cancers such as pancreatic cancer which is usually not detected until it has reached an advanced stage. Six compounds were identified following virtual screening of the NCI Diversity Set with our proteasome computer model followed by confirmation with a biochemical assay that showed significant inhibition of the proteasome by the compounds in the presence of copper ions. In a dose response assay, NSC 37408 (6, 7-dihydroxy-1-benzofuran-3-one), our best compound, exhibited an IC50 of 3µM in the presence of 100 nM copper. Chagas’ Disease, a parasitic disease caused by the parasite Trypanosma Cruzi, is endemic to Latin America. The disease manifests itself in a short acute phase and a long chronic phase. Current treatments are effective only in the acute phase and are not used in the chronic phase due to toxicity of the drugs. Hence a new drug discovery approach was chosen for this disease. Cruzain is the major etiologic enzyme involved in the disease and is only present in the parasite. It is also an enzyme expressed by the parasite in both phases. Herein, a novel peptoid library containing hydromethylketones was constructed and screened against a virtual structure of cruzain. The peptoids thus found through this drug discovery effort can be used as potential drug candidates against cruzain. Computational techniques will help achieve a high degree of specificity and aid in proposing assays for determining compounds with high activity Alzheimer disease is the most common form of dementia. Its pathogenesis incorporates many potential targets for treatment. Among the targets identified, Apolipoprotein E4 (apoE4) is especially interesting due to its catalytic role in the degradation and clearance of amyloid beta (Aβ), a risk factor for Alzheimer disease. ApoE exists in 3 isoforms which directly impact its functionality in the body. There are characteristic structural differences between them. In ApoE4 ionic interactions exist between Arg-61 and Glu-255 residues, unlike the other isoforms. Hence interruption of this interaction by inhibitors may change the structure of apoE4 to a more linear structure as observed in the other isoforms. Virtual screening of the NCI diversity set on an energy minimized protein virtual structure was performed to identify potential small molecule inhibitors and to gain further understanding of interactions that can be targeted to inhibit this protein. From the top ligands in the NCI diversity set, a peptide library was designed to target the protein. Previous research has indicated that liquid assisted grinding (LAG) is efficient and reliable for cocrystal formation when compared to solvent crystallization and dimethyl formamide is the best solvent for grinding. Herein, we report the comparison of four screening processes: Slurry, solvent crystallization, LAG and dry grinding. Thirty-eight crystal forms containing the Narom··· COOH, Narom···OH supramolecular heterosynthons were screened in the process, and it was observed that slurry methodology is as efficient and reliable in forming cocrystals as solution crystallization. Twenty-four new crystal forms were also isolated herein. LAG was found to be more efficient as compared to dry grinding and was successful in the formation of twenty-five crystal forms of the thirty-eight screened. Dimethyl formamide still remains the best solvent for LAG. All our slurry experiments were performed in water and it was found that water can be used reliably for this method for compounds within a wide range of solubility, thereby increasing the versatility and usability of this method for future screening procedures.

Yes / A comprehensive study of the thermal behavior of the 1:1 and 2:1 benzoic acid/isonicotinamide cocrystals is reported. The 1:1 material shows a simple unit cell expansion followed by melting upon heating. The 2:1 crystal exhibits more complex behavior. Its unit cell first expands upon heating, as a result of C–H···π interactions being lengthened. It then is converted into the 1:1 crystal, as demonstrated by significant changes in its X-ray diffraction pattern. The loss of 1 equiv of benzoic acid is confirmed by thermogravimetric analysis–mass spectrometry. Hot stage microscopy confirms that, as intuitively expected, the transformation begins at the crystal surface. The temperature at which conversion occurs is highly dependent on the sample mass and geometry, being reduced when the sample is under a gas flow or has a greater exposed surface area but increased when the heating rate is elevated.

Yes / Properties of a matter are intrinsically dependent upon the internal arrangement of molecules in the solid state. Therefore, knowledge of 3-dimensional structure of the matter is prerequisite for structure-property correlations and design of functional materials. Over the past century, X-ray crystallography has evolved as a method of choice for accurate determination of molecular structure at atomic resolution. The structural information obtained from crystallographic analysis paved the way for rapid development in electronic devices, mineralogy, geosciences, materials science, pharmaceuticals, etc. Knowledge of the structural information of active pharmaceutical ingredients (APIs) is prerequisite for rational drug design and synthesis of new chemical entities for development as new medicines. Over the past two decades, X-ray crystallography has played a key role in the design of pharmaceutical cocrystals-crystalline solids containing an API and one or more of pharmaceutically acceptable coformers. These materials have proved promising for fine-tuning several important properties of APIs. This short review highlights the history of crystallography, early breakthroughs, and the role of crystallography in understanding physicochemical properties of pharmaceutical cocrystals. / S. Aitipamula gratefully acknowledges the financial support from the Institute of Chemical and Engineering Sciences of A*STAR (Agency for Science, Technology and Research), Singapore. V. R. Vangala thanks Royal Society of Chemistry for Researcher Mobility Grant (2015/17).

Yes / New multicomponent solid forms of sildenafil have been discovered by means of a combined virtual/experimental cocrystal screening. Coformer selection of candidates was conducted based on an in silico screening method from a database of more than 2000 organic compounds, and the intensive experimental screen produced 23 new solid forms. Since the 12 coformers chosen have a combination of phenol and carboxylic acid groups, a variety of cocrystals, salts, and hybrid salt-cocrystals were discovered and characterized.

Neste trabalho, foi realizado o estudo termoanalítico e a caracterização no estado sólido da interação química entre o cetoprofeno (CET) e alguns compostos orgânicos (benzamida (BA), picolinamida (PA), nicotinamida (NA), isonicotinamida (INA), pirazinamida (PZA), ácido salícílico (SA) e ácido benzoico (BA)), visando a obtenção de cocristais. A mecanoquímica foi utilizada como método de preparação dos compostos sólidos, e os mesmos foram analisados por calorimetria exploratória diferencial (DSC), espectroscopia de infravermelho com transformadas de Fourier (FTIR), e difração de raios X de pó (XRPD). A escolha dos compostostos orgânicos (co-formadores) foi baseada em suas estruturas moleculares, de modo que aqueles selecionados para esse trabalho possuíssem uma estrutura molecular capaz de possibilitar a formação de síntons moleculares adequados à formação dos cocristais desejados. A análise dos resultados obtidos permitiu verificar que, nas condições experimentais utilizadas, todas as misturas estudadas formaram apenas compostos eutéticos. Entretanto, embora os diagramas de fases e os experimentos de DSC, raios X e FTIR tenham confirmado apenas a obtenção de compostos eutéticos entre o cetoprofeno e os co-formadores estudados, o método do contato de Kofler indicou a formação de um cocristal entre o cetoprofeno e nicotinamida. Assim sendo, o trabalho realizado até agora abre portas para investigações futuras, nomeadamente, com relação aos estudos de termomicroscopia relativos aos demais sistemas estudados neste trabalho. / In this work, we performed the thermoanalytical study and characterization at the solid state on the chemical interaction between ketoprofen (CET) and some organic compounds (benzamide (BA), picolinamide (PA), nicotinamide (NA), isonicotinamide (INA), pyrazinamide (PZA), salicylic acid (SA) and benzoic acid (BA)), aimed at obtaining cocrystals. The mechanochemical method was used for the preparation of solid compounds, and they were analyzed by differential scanning calorimetry (DSC), infrared spectroscopy with Fourier transform (FTIR), and X-ray powder difraction (XRPD). The choice of the organic compounds (co-formers) was based on their molecular structures, so that those selected for this work possess a molecular structure able to allow the formation of molecular synthons suitable for cocrystals formation. The analysis of the results has shown that under the experimental conditions used, all systems studied has formed only eutectic compounds. However, although the phase diagrams and DSC experiments, X-ray and FTIR have confirmed obtaining only eutectic compounds between ketoprofen and co-formers studied, the method of contact Kofler has indicated the discovery of a new co-crystal formed between ketoprofen and nicotinamide. Therefore, the work done so far opens the door to future research in particular with regard to thermomicroscopy studies related to other systems studied in this work.

Neste trabalho, foi realizado o estudo termoanalítico e a caracterização no estado sólido da interação química entre o cetoprofeno (CET) e alguns compostos orgânicos (benzamida (BA), picolinamida (PA), nicotinamida (NA), isonicotinamida (INA), pirazinamida (PZA), ácido salícílico (SA) e ácido benzoico (BA)), visando a obtenção de cocristais. A mecanoquímica foi utilizada como método de preparação dos compostos sólidos, e os mesmos foram analisados por calorimetria exploratória diferencial (DSC), espectroscopia de infravermelho com transformadas de Fourier (FTIR), e difração de raios X de pó (XRPD). A escolha dos compostostos orgânicos (co-formadores) foi baseada em suas estruturas moleculares, de modo que aqueles selecionados para esse trabalho possuíssem uma estrutura molecular capaz de possibilitar a formação de síntons moleculares adequados à formação dos cocristais desejados. A análise dos resultados obtidos permitiu verificar que, nas condições experimentais utilizadas, todas as misturas estudadas formaram apenas compostos eutéticos. Entretanto, embora os diagramas de fases e os experimentos de DSC, raios X e FTIR tenham confirmado apenas a obtenção de compostos eutéticos entre o cetoprofeno e os co-formadores estudados, o método do contato de Kofler indicou a formação de um cocristal entre o cetoprofeno e nicotinamida. Assim sendo, o trabalho realizado até agora abre portas para investigações futuras, nomeadamente, com relação aos estudos de termomicroscopia relativos aos demais sistemas estudados neste trabalho. / In this work, we performed the thermoanalytical study and characterization at the solid state on the chemical interaction between ketoprofen (CET) and some organic compounds (benzamide (BA), picolinamide (PA), nicotinamide (NA), isonicotinamide (INA), pyrazinamide (PZA), salicylic acid (SA) and benzoic acid (BA)), aimed at obtaining cocrystals. The mechanochemical method was used for the preparation of solid compounds, and they were analyzed by differential scanning calorimetry (DSC), infrared spectroscopy with Fourier transform (FTIR), and X-ray powder difraction (XRPD). The choice of the organic compounds (co-formers) was based on their molecular structures, so that those selected for this work possess a molecular structure able to allow the formation of molecular synthons suitable for cocrystals formation. The analysis of the results has shown that under the experimental conditions used, all systems studied has formed only eutectic compounds. However, although the phase diagrams and DSC experiments, X-ray and FTIR have confirmed obtaining only eutectic compounds between ketoprofen and co-formers studied, the method of contact Kofler has indicated the discovery of a new co-crystal formed between ketoprofen and nicotinamide. Therefore, the work done so far opens the door to future research in particular with regard to thermomicroscopy studies related to other systems studied in this work.

Despite the advent of alternative dosage forms, solid dosage forms constitute a major proportion of dosage forms not only on the market, but also in many pharmaceutical companies’ pipelines. This is because of their superior stability and ease of manufacturing relative to other dosage forms. Although solid dosage forms have been the topic of discussion for decades, the process of compaction of these dosage forms is considered an art rather than science because of the empiricism that exists in this area. With the introduction of Quality by Design (QbD), it is imperative that the drug development process is guided by structured scientific principles. It has been hypothesized that crystal structure of organic solids plays a pivotal role in understanding the properties, processing and eventually performance of solids. In this regard, the intermolecular interactions within a solid play a paramount role in dictating the materials response to stress. One important parameter that is weakly addressed in the literature is the concept of strength of intermolecular interactions. In the current work, we utilize the concept of elasticity as a metric for strength of intermolecular interactions. We introduce powder Brillouin light scattering; an inelastic light scattering technique to measure the elasticity of organic solids and try to correlate the mechanical moduli extracted from the spectra to the compaction performance of solids. We hypothesize that any redistribution of intermolecular interactions would be reflected in the BLS spectrum of these materials and the material properties can be used to explain the differences in compaction performance. Before we tested our hypothesis, we validated our powder BLS technique using aspirin as model system. We then applied the same analysis to four model systems that involved different ways of reorganizing the intermolecular interactions upon subtle modifications to the molecular structure. In Chapter 4, we investigated the effect of alkyl chain length and crystal structure on the mechanical properties and compaction performance of p-aminobenzoic acid (PABA) and its esters. For the entire ester series, a similar hydrogen bonding pattern was observed with strong N-H…O (carbonyl) and supportive N-H…N interactions. While the ethyl and butyl esters exhibited a layered structure, the methyl ester displayed a 3-D isotropic structure. The crystal structure for PABA exhibited a three-dimensional, quasi-isotropic distribution of the hydrogen-bonding interactions that connected the PABA dimers. The powder BLS spectra for these materials revealed low velocity shear modes for the layered structures and a spectrum consistent with an isotropic structure for Me-PABA and PABA. This was in good agreement with the compressibility behavior under load, with Et-PABA and Bu-PABA more compressible than PABA. However, due to greater particle-particle adhesion, PABA compacts showed greater tensile strength at higher pressures. The moduli calculated also showed that both Et-PABA and Bu-PABA had lower shear and Young’s modulus relative to the other materials. Attachment energies corroborated the above results. These studies showed that weak dispersive forces play an important role in understanding material properties. In Chapter 5, a series of nitrobenzoic derivatives were used to study the effect of secondary interactions on the crystal reorganization and material properties. The materials used in the study include p-nitrobenzoic acid (4-NBA), m-nitrobenzoic acid (3-NBA, 4-chloro-3-nitrobenzoic acid (Cl-NBA), 4-bromo-3-nitrobenzoic acid (Br-NBA), and 4-methyl-3-nitrobenzoic acid (Me-NBA). Crystal structures of the materials revealed different organization of C-H…O interactions. Two types of C-H…O interactions were prevalent namely C-H…O (nitro) and C-H…O (carboxy). The reorganization of these two types of interactions led to different packing motifs and different mechanical behavior. These structural features were reflected in their mechanical properties assessed by powder Brillouin light scattering. Cl-NBA and Br-NBA displayed an isotropic spectrum similar to polystyrene and aspirin. 3-NBA, 4-NBA and Me-NBA displayed different spectra from Cl-NBA and Br-NBA with high frequency tailing in the longitudinal mode distribution indicating a specific direction of extended molecular interactions. The Young’s modulus and shear modulus followed the order: 3-NBA < Me-NBA< 4-NBA < Cl-NBA < Br-NBA. The maximum longitudinal modulus Mmax was the highest for 3-NBA and was significantly greater than rest of the materials. From the compaction studies, it was observed that the tabletability followed the rank order 3-NBA > 4-NBA > Me-NBA ≈ Br-NBA ≈ Cl-NBA which is the same order as Mmax. 3-NBA by virtue of its low shear and Young’s modulus to be the most compressible material, but the compressibility rank order was 4-NBA > Me-NBA ≈ 3-NBA > Cl-NBA > Br-NBA. However, 3-NBA by virtue of its greater particle-particle adhesion was the most compactable material. The yield pressures obtained from Heckel plots revealed that 4-NBA and Me-NBA were relatively more plastic when compared to the other materials. This study demonstrated that subtle changes to the molecular structure can result in drastically different crystal packing which in turn would influence the mechanical properties and the compaction performance of organic solids. In Chapter 6, we investigated the effect of cocrystallization on the compaction performance of caffeine(CAF). The series of halo-nitrobenzoic acids (F-NBA, Cl-NBA and 3-NBA) were used as coformers. The cocrystals CAF: F-NBA, CAF: Cl-NBA and CAF: NBA Form 1 adopted a flat layered structure that can undergo deformation with ease. This increased the compressibility of the cocrystals relative to CAF. In addition to the improved compressibility, by virtue of increased particle-particle contacts, the cocrystals also displayed superior tabletability. In contrast to the layered structures adopted by the three cocrystals, the CAF: NBA Form 2 displayed a columnar structure that exhibited resistance to stress. The compressibility and the tabletability of CAF: NBA Form 2 was significantly compromised when compared to that of Form1. All the compaction characteristics of the cocrystals were in good agreement with moduli and parameters obtained from powder BLS spectra. The layered materials showed the presence of low velocity shear modes corroborating the earlier studies. There was a clear difference in the spectra of the polymorphs, indicating that powder BLS can be used for mechanical screening of polymorphs. In Chapter 7, we examined the effects of crystal structure and coformer functionality on the compaction performance of theophylline (THY). The coformers employed include 4-fluoro-3-nitrobenzoic acid (FNBA), acetaminophen (APAP), and p-aminobenzoic acid (PABA). While THY-APAP and THY-FNBA exhibited layered structures, the THY-PABA displayed a interdigitated columnar structure. Powder BLS spectra showed the presence of low frequency shear modes relative to THY for all the three cocrystals. However, the order of frequencies followed: THY-FNBA < THY-APAP < THY-PABA. The shear modulus calculated followed the order THY-APAP≈ THY-FNBA < THY < THY-PABA which is in agreement with the crystal structures discussed. The Young’s modulus followed the order THY-FNBA < THY-APAP < THY < THY-PABA. The two layered structures (THY-APAP, THY-FNBA) showed distinct compaction performance (similar compressibility but different compactability and tabletability). The layered structures were more compressible than THY which is hypothesized to undergo deformation through multiple mechanisms. THY-PABA showed poor compaction properties. This highlights the fact that although the coformer (PABA) is molecularly similar to FNBA, the resultant cocrystals are structurally and mechanically distinct. These observations were well supported by the moduli calculated from powder BLS studies. The order of yield pressures obtained from Heckel analysis followed the same order as shear modulus. The tensile strength of the compacts of the cocrystals level off at around 150 MPa but the tensile strength of THY compacts continues to increase. From a manufacturing perspective the cocrystals can prove to be a better option as they as more compactable at higher porosities or they possess greater tabletability at low compaction pressures. Overall, we have used model systems to demonstrate that the redistribution of intermolecular forces upon point substitution or cocrystallization have a dramatic effect on the material properties. It is also worth noting that elasticity along with plasticity can provide important information about the strength of interactions which would help in understanding the role of weak intermolecular forces in the performance of organic materials. To gain a better perspective of the compaction process and move towards a QbD approach, it is also imperative to understand the link between crystal structures, intermolecular interactions which is possible with the help of novel characterization techniques (BLS, AFM).

Crystal engineering is a rapidly developing area of research with goals aimed at designing molecular solids with desired physical and chemical properties. By utilizing reliable intermolecular interactions, the principles of supramolecular chemistry are exploited in the solid state in order to achieve favorable arrangements of molecules in a crystal lattice. We have applied crystal engineering strategies to further develop the strategy of template-directed reactivity in the solid state. An evaluation of catechol, a regioisomer of the commonly used resorcinol template, was performed. Co-crystallization of the template candidate with a bis-pyridyl olefin produced a discrete self-assembled architecture wherein hydrogen-bonded dimers of catechol pre-organize the olefins for a [2+2] photodimerization in the solid state. The dimerization was determined to proceed quantitatively and X-ray studies of a partial single-crystal-to-single-crystal reaction supported the hypothesis of the reaction proceeding exclusively within the discrete assemblies, despite the infinite stacking of the olefins. A study of substituent effects on the conformational bias of additional catechol- based template candidates was carried out. Candidates with bulky substituents a the 3- and 4-positions were observed to adopt a favorable syn-anti or syn-gauche conformer in most cases. Though conformational bias was induced and discrete assembly achieved, only one of the synthesized cocrystals met the geometric requirements for a photodimerization, however, extended UV exposure produced no evidence of product formation. We discuss the fortuitous discovery of a catechol-based cocrystal system that produces an infinite linear assembly. The fluorine atom of 3-fluorocatechol was observed to be too small to induce conformational bias in the template candidate. However, the system was observed to progress through a three-step solvent-mediated phase transformation. The second and third crystal phases were isolated and characterized by single-crystal X-ray diffraction. The X-ray data revealed that the zig-zag assembly of the first phase spontaneously transforms to a double helix topology in the second phase, before transforming to the final phase, which exhibits a quadruple helix topology. In our studies of pharmaceutical cocrystals, we sought to perform a systematic study of the solid-state behavior of the anti-cancer drug 5-fluorouracil. Inspired by previously published cocrystal structures, we performed co-crystallization experiments with a small series of structurally similar coformers. Comparison of the three structures revealed an inconsistent degree of synthon disruption between the coformers. Curiously, one of the cocrystals obtained displayed a packing arrangement consistent with the requirements of a [2+2] cycloaddition. Irradiation of the sample with UV light resulted in the quantitative formation of a cross-photocycloaddition product. The product was characterized as a pyrimidine-fused cyclobutane, the first reported synthetic derivative of 5-fluorouracil obtained from a solid-state reaction. Lastly, we utilize crystal engineering strategies to study the behavior of 2- iodohippuric acid, a common radio-imaging target. The pharmacokinetic properties of 2- iodohippuric acid make it an ideal target for renal imaging. We sought to approach a solid formulation of the target in a similar manner to that of a drug or other metabolized pharmaceutical. In doing so, we hoped to study the compound’s behavior in the solid state so that we may eventually use co-crystallization as a means of altering the properties of the target for the purpose of generalizing its use in imaging the body.

Cocrystals have attracted much interest in recent years. It was once thought that cocrystals could be a means to prevent polymorphism but many recent examples of cocrystal polymorphism have been discovered and reported. In this contribution, we present a survey of polymorphic cocrystals. Polymorphism is the ability of a specific chemical compound to crystallize in more than one crystalline form. Polymorphs have different arrangements of the molecules in the given crystal lattice and may exhibit different characteristics such as packing properties, thermodynamic properties, spectroscopic properties, kinetic properties, surface properties, and mechanical properties. Polymorphs can be classified in various groups such as crystalline, amorphous, hydrates, and solvates. The main characterization methods used in this thesis are X-ray diffraction and solid-state NMR spectroscopy. The concept of variable stoichiometry cocrystallization is explored in halogen-bonded systems. Three novel cocrystals of 1,4-diiodotetrafluorobenzene and 3-nitropyridine with molar ratios of 1:1, 2:1, and 1:2, respectively, are prepared by slow evaporation methods. Powder X-ray diffraction experiments carried out on the 1:1 and 2:1 cocrystals confirm that gentle grinding does not alter the crystal forms. 1H → 13C and 19F →13C cross-polarization magic angle spinning (CP/MAS) NMR experiments performed on powdered samples of the 1:1 and 2:1 cocrystals are used as spectral editing tools to select for either the halogen bond acceptor or donor, respectively. I also describe the formation of a new cocrystal of 1, 3, 5-trifluoro-2, 4, 6-triiodobenzene and piperazine with a 2:1 molar ratio that was prepared by the slow evaporation method. In addition of that, I have prepared the cocrystal (1,4- VII diiodotetrafluorobenzene)(coumarin ) already reported. After preparation and purification process of this compound, I obtained a small amount powder, but could not characterize it by solid-state NMR; rather I performed powder X-ray diffraction to study this compound. Overall, this work contributes new examples to the field of polymorphism in halogen-bonded systems and to variable stoichiometry cocrystal engineering with halogen bonds.