Understanding the structure of matter in the solid state could be considered as being one of ‘the big questions’ in chemistry. Whereas the structural behaviour of molecules in the gas phase is relatively well-understood, this is not the case for the condensed phase due to the complexity of short and long-range intermolecular interactions. The purpose of the work in this thesis is to examine the structural response of solid molecular materials to stimuli of extreme pressure and temperature. L-alanine crystallises as a zwitterion in the space group P212121. Neutron powder diffraction and X-ray single crystal diffraction data show that the a and caxes are very similar in length. The a-axis is more compressible than the c-axis, and at ca. 2 GPa the cell becomes metrically tetragonal, however the underlying symmetry is still orthorhombic. The structure remains in a compressed form of the ambient phase up to 9.87 GPa. Previous Raman and energy dispersive powder diffraction studies have interpreted changes in spectra at ca. 2 and 9 GPa as phase transitions. The diffraction data and DFT calculations described here suggest that these are in fact due to changes in conformation of the ammonium group. L-alanine shows remarkable resistance to the effects of pressure but something must happen to the structure if pressure continues to be increased. Neutron powder diffraction has been used to obtain high-pressure data for L-alanine up to 15.46 GPa. These are the highest-pressure diffraction data reported for any amino acid. Above ca. 15 GPa, L-alanine undergoes a reversible transition to an amorphous phase through volume collapse of the crystal, driven by the need to minimise the PV term in the Gibbs free energy equation, as opposed to relieving destabilising contacts. It is currently the only amino acid known to undergo a transition of this type. The co-crystal of methylpyridine and pentachlorophenol (MP-PCP) forms in the space group P-1. When the phenolic proton is deuterated (MP-PCP-d) it exhibits isotopic polymorphism, crystallising in the space group Cc. Structures of the two other combinations of isotope and space group, i.e MP-PCP in Cc and MP-PCP-d in P-1 have not yet been determined. We demonstrate that these polymorphs can be obtained using high-pressure and low-temperature conditions predicted by thermodynamics. The use of in-situ crystallisation at pressure has driven MP-PCP to pack with Cc symmetry, minimising the PV term in the Gibbs free energy equation. Low-temperature crystallisation causes MP-PCP-d to form in P-1 due to this phase being favoured by vibrational enthalpic and entropic contributions. Aniline is a liquid under ambient conditions but freezes at 267 K in the monoclinic space group P21/c. It can also be frozen by pressure (ca. 0.8 GPa) in the orthorhombic space group Pna21. Neutron powder diffraction shows that on decompression the orthorhombic form transforms to the monoclinic phase at 0.3 GPa, owing to the monoclinic packing being less dense. PIXEL calculations provide an insight into the intermolecular energies of the orthorhombic crystal up to 7.301 GPa. They show that dispersive forces are more dominant than the hydrogen bonds, one of which becomes destabilising at higher pressure. Thermodynamic calculations estimating the relative stabilities of the two polymorphs prove inconclusive owing to improper treatment of dispersion interactions by Density Functional Theory calculations. The structural behaviour of cyclohexane in the crystalline (P21/c) and plastic phases (Fm3m) has been studied using neutron total scattering data and Reverse Monte Carlo (RMC) modelling. Atomistic models show that the molecules exhibit correlated motion as they prepare to undergo transformation on heating. Inclusion of I(t) data in the RMC refinements is shown to be important as when it is not accounted for, the RMC method is incapable of distinguishing the form of the disorder in the plastic phase. Molecular motion in this phase is shown to be correlated through the avoidance of short intermolecular D···D contacts. The ordered and disordered solid phases of oxalyl chloride (space groups P21/c and Pbca respectively) have been studied by neutron total scattering and modelled using a Reverse Monte Carlo approach. Atomistic models show that on heating, the atoms vibrate out of the plane of the molecule until 245 K where they show approximately isotropic vibration owing to reduced steric restriction. This may provide the molecules with the freedom they require to rotate and undergo the solidsolid transition. The onset of disorder has also been partially predicted by molecular dynamics simulations. RMC modelling does not provide satisfactory atomic configurations of the disordered solid phase due to an unrealistic distribution of intermolecular chlorine-chlorine contacts. This study presents an example of a flexible, 3-atom-type system that may be too complex for analysis by the RMC method.

There is heightened interest to diversify the range of crystal forms exhibited by active pharmaceutical ingredients (APIs) in the pharmaceutical industry. The crystal form can be regarded as the Achilles' heel in the development of an API as it directly impacts the physicochemical properties, performance and safety of the API. This is of critical importance since the crystal form is the preferred method of oral drug delivery by industry and regulatory bodies. The ability to rationally design materials is a lucrative avenue towards the synthesis of functional molecular solids with customized physicochemical properties such as solubility, bioavailability and stability. Pharmaceutical cocrystals have emerged as a new paradigm in pharmaceutical solid form development because they afford the discovery of novel, diverse crystal forms of APIs, generate new intellectual property and modify physicochemical properties of the API. In addition, pharmaceutical cocrystals are amenable to design from first principles of crystal engineering. This dissertation focuses on the crystal engineering of multi-component crystal forms, in particular pharmaceutical cocrystals and crystalline hydrates. It addresses: (i) the factors involved in the selection of cocrystal formers (ii) design strategies for APIs that exhibit complexity, (iii) the role of water molecules in the design of multi-component crystal forms and (iv) the relationship between the crystal structure and thermal stability of crystalline hydrates. In general, cocrystal former libraries have been limited to pharmaceutically acceptable substances. It was investigated to expand this library to include substances with an acceptable toxicity profile such as nutraceuticals. In other words, can nutraceuticals serve as general purpose cocrystals formers? The model compounds, gallic acid and ferulic acid, were selected since they possess the functional moieties carboxylic acids and phenols, that are known to form persistent supramolecular synthons with complementary functional groups such as basic nitrogen and amides. The result yielded pairs of cocrystals and revealed the hierarchical nature of hydrogen bonding between complementary functional groups. In general, pharmaceutical cocrystals have been designed by determining the empirical guidelines regarding the hierarchy of supramolecular synthons. However, this approach may be inadequate when considering molecules that are complex in nature, such as those having a multiplicity of functional groups and/or numerous degrees of conformational flexibility. A crystal engineering study was done to design multi-component crystal forms of the atypical anti-psychotic drug olanzapine. The approach involved a comprehensive analysis and data mining of existing crystal structures of olanzapine, grouped into categories according to the crystal packing exhibited. The approach yielded isostructural, quaternary multi-component crystal forms of olanzapine. The crystal forms consist of olanzapine, the cocrystal former, a water molecule and a solvate. The role of water molecules in crystal engineering was addressed by investigating the crystal structures of several cocrystals hydrates and their related thermal stability. The cocrystal hydrates were grouped into four categories based upon the thermal stability they exhibit and it was concluded that no structure/stability correlations exist in any of the other categories of hydrate. A Cambridge Structural Database (CSD) analysis was conducted to examine the supramolecular heterosynthons that water molecules exhibit with two of the most relevant functional groups in the context of active pharmaceutical ingredients, carboxylic acids, and alcohols. The analysis suggested that there is a great diversity in the supramolecular heterosynthons exhibited by water molecules when they form hydrogen bonds with carboxylic acids or alcohols. This finding was emphasized by the discovery of two polymorphs of gallic acid monohydrate to it the first tetramorphic hydrate for which fractional coordinates have been determined. Analysis of the crystal structures of gallic acid monohydrate polymorphs revealed that forms I and III exhibit the same supramolecular synthons but different crystal packing and forms II and IV exhibit different supramolecular synthons. Therefore, the promiscuity of water molecules in terms of their supramolecular synthons and their unpredictable thermal stability makes them a special challenge in the context of crystal engineering.

No / Solvent influences on the crystallization of polymorph and hydrate forms of the nootropic drug piracetam (2-oxo-pyrrolidineacetamide) were investigated from water, methanol, 2-propanol, isobutanol, and nitromethane. Crystal growth profiles of piracetam polymorphs were constructed using time-resolved diffraction snapshots collected for each solvent system. Measurements were performed by in situ energy dispersive X-ray diffraction recorded in Station 16.4 at the synchrotron radiation source (SRS) at Daresbury Laboratory, CCLRC UK. Crystallizations from methanol, 2-propanol, isobutanol, and nitromethane progressed in a similar fashion with the initial formation of form I which then converted relatively quickly to form II with form III being generated upon further cooling. However, considerable differences were observed for the polymorphs lifetime and both the rate and temperature of conversion using the different solvents. The thermodynamically unstable form I was kinetically favored in isobutanol and nitromethane where traces of this polymorph were observed below 10°C. In contrast, the transformation of form II and subsequent growth of form III were inhibited in 2-propanol and nitromethane solutions. Aqueous solutions produced hydrate forms of piracetam which are different from the reported monohydrate; this crystallization evolved through successive generation of transient structures which transformed upon exchange of intramolecular water between the liquid and crystalline phases

Thesis (PhD (Chemistry and Polymer Science))--Stellenbosch University, 2008. / Novel gold(I) trithiophosphite complexes were synthesised by utilising the ligands P(SR)3 (R = Me, Ph) and 1,2-bis(1,3,2-dithiaphospholan-2-ylthio)ethane (2L). Reaction with (tht)AuCl or (tht)AuC6F5 readily yielded the corresponding complexes (RS)3PAuX and 2L(AuX)2 (X = Cl, C6F5) as well as {Au[P(SMe)3]2}CF3SO3. Structural characterisation by X-ray diffraction revealed linear complexes in part associating by Au…Au and/or Au…S contacts, two polymorphs of one compound associating by either Au…S interactions or p-stacking was also obtained. (MeS)3PAuCl and (MeO)3PAuCl were found to be isostructural in the solid state. The complex chloro[tris(4-methylthiazol-2-yl)phosphane]gold, A, was used to probe the electronic influence tris(azol-2-yl)phosphanes exert upon gold(I) by substituting the chloride with various thiolates. In contrast to Ph3PAuCl, only NCS– and PhC(O)S– afforded stable compounds which could be attributed to a weaker donating capability of the tris- (azolyl)phosphane ligand class. The compounds A and chloro[tris(thiazol-2-yl)phosphane]- gold, B, were shown to crystallise in 4 new polymorphs and solvates bringing the total to an exceptional seven. Among the solid-state structures of A the rare instance of a polymorph and a thf solvate not exhibiting aurophilic interactions as opposed to the original structure were observed. Complex B was shown to crystallise in polymorphs where dimers are associated either by Au…Au or Au…Cl interactions but otherwise exhibit similar arrangements of the ligand, this set of polymorphs is unprecedented amongst gold complexes. An NMR experiment proved that tris(thiazolyl)phosphane complexes are subject to hydrolysis under alkaline conditions. A trimeric gold(I) heterometallacycle, obtained by reacting (tht)AuCl with 4,4-dimethyl-2-(2- thienyl)oxazoline deprotonated at C-5 of the thiophene ring, was structurally characterised. Intramolecular Au…S interactions were found to be present which precluded interaction of the gold atoms with other metal centres such as Me3CNCAuCl or AgNO3. A second solvate obtained additionally exhibits Au…Au interactions. The scope of uncommon bis-imine coordination to AuI was expanded by utilising 1,2-bis(1-imidazolylmethyl)-2,4,6-trimethylbenzene (2L) to synthesise the [Au2(μ-2L)2]2+ cation. The triflate salt forms the first porous crystal structure of gold and the co-crystallised solvent could be partially removed by evacuation at elevated temperatures. Utilising a ditopic phosphite ligand instead of the commonly used ditopic phosphane ligands, a new cationic species of the type [Au2(μ-2L)3]2+ was characterised in the solid state for the first time. Finally, employing 2-phenylthiazole and 1-(thiazol-2-yl)piperidine which can be deprotonated at C-5 of the thiazole ring, Fischer-type pentacarbonyltungsten carbeniate complexes were prepared and structurally characterised. Starting from these complexes, the analogous Fischertype methoxycarbene as well as carbyne complexes could be obtained by alkylation and formal oxide abstraction, respectively. The latter products readily formed dinuclear adducts with AuCl. A Fischer-type methoxycarbene could be transferred to AuI affording the first such gold(I) complex exhibiting Au…Au interactions in the solid state as well as a rare agostic Au…H interaction which was examined by low-temperature 1H NMR measurements. Transfer of the carbeniate ligand derived from 1-(thiazol-2-yl)piperidine to Ph3PAu+ afforded an aurated thiazole product (by an unprecedented loss of CO) which may be represented as a pseudoabnormal azolylidene complex owing to W(CO)5-coordination at a distant nitrogen. The carbeniate originating from 2-phenylthiazole, on the other hand, afforded, by rare W(CO)5- trapping and without CO-loss, a pseudo Fischer-type carbene complex. Carbene transfer to gold was complemented by the first transfers of rNHC ligands from chromium and tungsten to gold(I) affording a novel class of complexes, all of which were structurally characterised. This work bridges the unnatural divide created between Fischer and N-heterocyclic carbene complexes.

Pharmaceutical solids tend to exist in different physical forms termed as polymorphs. Issues about pharmaceutical systems are mainly concerned with the active ingredient's physico-chemical stability and bioavailability. The main aim of this study is to investigate the non-bonded interactions in pharmaceutical solids that govern the physical pharmaceutics performance of such materials and through the use of structural techniques and correlation of these results with crystal structural database to establish the presence of physical motifs in selected systems. Structural motifs were identified by the use of single crystal and crystal packing analysis on diverse range of pharma-relevant materials including chalcones, cryptolepines, biguanides and xanthines. These selected systems were validated using functional group and molecular analysis and correlating them to the Cambridge Structural Database. Crystallization studies are done on these selected systems as well as exploiting those using synthetic analogues. A total of 51 crystal structures were investigated including 16 new structure determinations. Addition synthesis of new xanthines to investigate novel intermolecular patterns was also undertaken. The understanding and exploitation of intermolecular interactions involving hydrogen bonds and coordination complexation during packing can be used in the design and synthesis of solid state molecular structures with desired physical and chemical properties.

A molecule can crystallise in more than one crystal structure, a common phenomenon in organic compounds known as polymorphism. Different polymorphic forms may have significantly different physical properties, and a reliable prediction would be beneficial to the pharmaceutical industry. However, crystal structure prediction (CSP) based on the knowledge of the chemical structure had long been considered impossible. Previous failures of some CSP attempts led to speculation that the thermodynamic calculations in CSP methodologies failed to predict the kinetically favoured structures. Similarly, regarding the stabilities of co-crystals relative to their pure components, the results from lattice energy calculations and full CSP studies were inconclusive. In this thesis, these problems are addressed using the state-of-the-art CSP methodology implemented in the GRACE software. Firstly, it is shown that the low-energy predicted structures of four organic molecules, which have previously been considered difficult for CSP, correspond to their experimental structures. The possible outcomes of crystallisation can be reliably predicted by sufficiently accurate thermodynamic calculations. Then, the polymorphism of 5- chloroaspirin is investigated theoretically. The order of polymorph stability is predicted correctly and the isostructural relationships between a number of predicted structures and the experimental structures of other aspirin derivatives are established. Regarding the stabilities of co-crystals, 99 out of 102 co-crystals and salts of nicotinamide, isonicotinamide and picolinamide reported in the Cambridge Structural Database (CSD) are found to be more stable than their corresponding co-formers. Finally, full CSP studies of two co-crystal systems are conducted to explain why the co-crystals are not easily obtained experimentally.

A presente dissertação visa fazer um recorte sobre a constituição do sujeito a partir do masoquismo erógeno e os seus desdobramentos. A afirmativa de Freud em 1923 que seria a partir do masoquismo erógeno que poderíamos ter o testemunho do momento mítico da fusão entre pulsão de vida e pulsão de morte, revela uma articulação importante entre o masoquismo e a constituição do sujeito. O masoquismo passa ser uma fonte privilegiada para compreender aquilo que temos de mais arcaico na vida psíquica. A metodologia utilizada nesse estudo foi uma pesquisa bibliográfica histórica conceitual da obra freudiana. A releitura que Lacan promove sobre os escritos de Freud serviram para auxiliar em um aprofundamento sobre o tema em questão. Apesar do masoquismo erógeno ser um conceito introduzido apenas após a descoberta do conceito de pulsão de morte em 1920, partiremos do início da elaboração da teoria pulsional de Freud em 1905. Isto porque esse estudo, ao investigar o percurso freudiano demonstrou que os conceitos na psicanálise são conceitos construídos através da experiência clínica e que, portanto, surgem com enigmas que com tempo vão assumindo um contorno teórico mais elaborado. Desde os Três ensaios sobre a teoria da sexualidade (1902/2006c), ao conceituar sobre o masoquismo, Freud aponta para enigmas que apenas em 1920 puderam ser mais elucidados. Os conceitos de sexualidade perverso-polimorfa, pulsão sado-masoquista e fantasia masoquista contribuíram para pensarmos em um alargamento da noção de masoquismo possibilitando a flexibilização desse termo para além de uma visão moralista que ao classificar como uma perversão sexual busca a sua patologização / The main objective of this dissertation is to rethink how the subjects constitute themselves through the concept of erogenous masochism. Freudian statement (1923) that the erogenous masochism was a witness of the early moments where there was a fusion between life drive and the death drive reveals the straight bond between the notion of masochism and emergency of the subjects in the psychoanalytical theory. Therefore, masochism is a privileged source for the understanding of ancient aspects of mental life onset. The methodology used through this research was a conceptual-historic bibliographic investigation of the complete works of Sigmund Freud, the father of psychoanalyses. Lacans interpretation of the Freudians writings contributes to this discussion. This research starts at 1905 with the Three Essays on the Theory of Sexuality, even though Freud only mentions erogenous masochism after he elaborates the notion of the existence of a death drive. The importance of showing the whole process in which Freud would build the psychoanalytical concepts is to demonstrate that they were forged through the psychoanalytical practice, and that at the beginning it presents itself as an enigma and with time it acquires more consistence. Since Three Essays on the Theory of Sexuality, Freud raised important questions about masochism that were only better understood after 1920. Concepts such as perverse polymorph sexuality, sadomasochism and Fantasy help to acknowledge an enlargement of this notion in the psychoanalyses theory. Hence, allowing a new understanding in the concept of masochism other then the moralist version that sees it as pathology.

A presente dissertação visa fazer um recorte sobre a constituição do sujeito a partir do masoquismo erógeno e os seus desdobramentos. A afirmativa de Freud em 1923 que seria a partir do masoquismo erógeno que poderíamos ter o testemunho do momento mítico da fusão entre pulsão de vida e pulsão de morte, revela uma articulação importante entre o masoquismo e a constituição do sujeito. O masoquismo passa ser uma fonte privilegiada para compreender aquilo que temos de mais arcaico na vida psíquica. A metodologia utilizada nesse estudo foi uma pesquisa bibliográfica histórica conceitual da obra freudiana. A releitura que Lacan promove sobre os escritos de Freud serviram para auxiliar em um aprofundamento sobre o tema em questão. Apesar do masoquismo erógeno ser um conceito introduzido apenas após a descoberta do conceito de pulsão de morte em 1920, partiremos do início da elaboração da teoria pulsional de Freud em 1905. Isto porque esse estudo, ao investigar o percurso freudiano demonstrou que os conceitos na psicanálise são conceitos construídos através da experiência clínica e que, portanto, surgem com enigmas que com tempo vão assumindo um contorno teórico mais elaborado. Desde os Três ensaios sobre a teoria da sexualidade (1902/2006c), ao conceituar sobre o masoquismo, Freud aponta para enigmas que apenas em 1920 puderam ser mais elucidados. Os conceitos de sexualidade perverso-polimorfa, pulsão sado-masoquista e fantasia masoquista contribuíram para pensarmos em um alargamento da noção de masoquismo possibilitando a flexibilização desse termo para além de uma visão moralista que ao classificar como uma perversão sexual busca a sua patologização / The main objective of this dissertation is to rethink how the subjects constitute themselves through the concept of erogenous masochism. Freudian statement (1923) that the erogenous masochism was a witness of the early moments where there was a fusion between life drive and the death drive reveals the straight bond between the notion of masochism and emergency of the subjects in the psychoanalytical theory. Therefore, masochism is a privileged source for the understanding of ancient aspects of mental life onset. The methodology used through this research was a conceptual-historic bibliographic investigation of the complete works of Sigmund Freud, the father of psychoanalyses. Lacans interpretation of the Freudians writings contributes to this discussion. This research starts at 1905 with the Three Essays on the Theory of Sexuality, even though Freud only mentions erogenous masochism after he elaborates the notion of the existence of a death drive. The importance of showing the whole process in which Freud would build the psychoanalytical concepts is to demonstrate that they were forged through the psychoanalytical practice, and that at the beginning it presents itself as an enigma and with time it acquires more consistence. Since Three Essays on the Theory of Sexuality, Freud raised important questions about masochism that were only better understood after 1920. Concepts such as perverse polymorph sexuality, sadomasochism and Fantasy help to acknowledge an enlargement of this notion in the psychoanalyses theory. Hence, allowing a new understanding in the concept of masochism other then the moralist version that sees it as pathology.

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No. of bitstreams: 2 Tese - Cameron Capeletti da Silva - 2017.pdf: 3293032 bytes, checksum: 714ecd70f3ac6d81018c08280d885007 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-12-13 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / A branch of lamivudine crystal engineering deals with its protonable pyrimidine-based nitrogen being a recipe of crystallization with acids. In this context and in relation to the drug lamivudine, ten new crystalline phases were prepared and their crystal structures were elucidated by single crystal X-ray diffraction. In addition, two of them were also characterized by infrared spectroscopy (IR) and other three were characterized by TG and DSC thermal analysis. Thus, this study shows an interesting example of chiral recognition even without chiral resolution. Lamivudine (R)-mandelate and (S)-mandelic acid cocrystal of lamivudine (R)-mandelate trihydrate showed the enantiopreference between lamivudine cation and the (R)-mandelandelate anion in both salt and cocrystal of salt phases through the robust synthon 2-aminopyridine-carboxylate. The present study shows how two solid forms of lamivudine with mandelic acid were used as a model to distinguish between the nature of a salt or cocrystal of salt. This happened because specific information obtained from IR spectra allowed the identification of ionized and neutral forms of mandelic acid directly in the spectrum of the cocrystal of salt. Furthermore, the formation of crystalline forms of lamivudine resembling a DNA structure was investigated due to its great structural value. After crystallization experiments three crystalline structures of lamivudine that mimics DNA structure were obtained and named as lamivudine duplex IV, V and VI, respectively. In the duplex IV of lamivudine the counterions are responsible for opening the two strands due to their hydrogen bonding pattern. The theoretical approach has shown that there is not an energetic tendency regarding the formation of lamivudine duplex with aliphatic organic acids or lamivudinium salts with aromatic acid. Thus, the preference of lamivudine in the assembly of double-helix structures with aliphatic organic acids rather than aromatic acids has been rationalized based on the amount of acid used during the synthesis. In addition, four other salts were also prepared by crystallizing lamivudine with the L-tartaric, sulfuric and perchloric acids, where the two-point synthon described by the graph set R22(8) prevailed. On the other hand, in the structure of lamivudine perchlorate monohydrate neither the two-point synthon nor the three-point one was observed. Finally, the first anhydrous polymorph of lamivudine was reported. This new polymorphic phase of lamivudine is anhydrous as well as form II. In addition to being a new solid phase of alleged commercial interest, the polymorphic form IV of lamivudine also reinforces the importance of performing an extensive screening of the crystallization conditions of new crystalline modifications of active pharmaceutical ingredients. / Um ramo da engenharia de cristais de lamivudina lida com sua base nitrogenada pirimidina, a qual pode ser protonada, sendo assim um alvo de cristalização com ácidos. Nesse contexto, e com relação ao fármaco lamivudina, dez novas fases cristalinas foram preparadas e suas estruturas cristalinas foram elucidadas por difração de raios X por monocristal. Além disso, duas delas também foram caracterizadas por espectroscopia no infravermelho (IV) e outras três foram caracterizadas termicamente por TG e DSC. Desse modo, esse estudo mostra o interessante exemplo de reconhecimento quiral mesmo sem resolução quiral. O (R)-mandelato de lamivudina e o co-cristal (S)-mandélico de (R)-mandelato de lamivudina trihidratado revelaram a enantiopreferência da conexão entre o cátion (lamivudina)+ e o ânion (R)-mandelato- em ambas fases de sal e co-cristal de sal através do sínton robusto de dois pontos 2-aminopiridina-carboxilato. O presente estudo mostra que as duas formas sólidas de lamivudina com ácido mandélico foram utilizadas como modelo para distinguir entre a natureza de um co-cristal de sal e de um sal. Isso porque informações específicas obtidas dos espectros de IV tornaram possível identificar ambas as formas ionizadas e neutra do ácido mandélico diretamente no espectro do co-cristal de sal. Ainda, investigou-se a formação de formas cristalinas de lamivudina que se assemelham a estrutura de DNA devido a seu grande valor estrutural. Após os experimentos de cristalização foram obtidas três estruturas cristalinas de lamivudina semelhantes a estrutura de DNA denominadas de dupla hélice de lamivudina IV, V e VI. Na dupla hélice de lamivudina IV os contra-íons são responsáveis pela abertura da dupla fita devido ao seu padrão de ligação de hidrogênio. A abordagem teórica mostrou que não há uma tendência energética com respeito a formação de duplex de lamivudina com ácidos orgânicos alifáticos ou de sais de lamivudina com ácidos aromáticos. Desse modo, a preferência da lamivudina em montar estruturas cristalinas de dupla hélice com ácidos orgânicos alifáticos ao invés de ácidos aromáticos foi racionalizada com base na quantidade de ácido usada durante a síntese. Além disso, também foram preparados outros quatro sais ao cristalizar lamivudina com os ácidos L-tartárico, sulfúrico e perclórico, onde o sínton de dois pontos descrito pelo conjunto gráfico R22(8) prevaleceu. Por outro lado, na estrutura do perclorato de lamivudina monohidratado nem o sínton de dois pontos e nem o de três pontos foram observados. Por fim, o primeiro polimorfo anidro de lamivudina foi reportado. Essa nova fase polimórfica de lamivudina é anidra assim como a forma II. Além de ser uma nova fase sólida de suposto interesse comercial, a forma polimórfica IV de lamivudina também reforça a importância de se realizar uma varredura extensiva das condições de cristalização de novas modificações cristalinas de insumos farmacêuticos ativos.

Pharmaceutical solids tend to exist in different physical forms termed as polymorphs. Issues about pharmaceutical systems are mainly concerned with the active ingredient's physico-chemical stability and bioavailability. The main aim of this study is to investigate the non-bonded interactions in pharmaceutical solids that govern the physical pharmaceutics performance of such materials and through the use of structural techniques and correlation of these results with crystal structural database to establish the presence of physical motifs in selected systems. Structural motifs were identified by the use of single crystal and crystal packing analysis on diverse range of pharma-relevant materials including chalcones, cryptolepines, biguanides and xanthines. These selected systems were validated using functional group and molecular analysis and correlating them to the Cambridge Structural Database. Crystallization studies are done on these selected systems as well as exploiting those using synthetic analogues. A total of 51 crystal structures were investigated including 16 new structure determinations. Addition synthesis of new xanthines to investigate novel intermolecular patterns was also undertaken. The understanding and exploitation of intermolecular interactions involving hydrogen bonds and coordination complexation during packing can be used in the design and synthesis of solid state molecular structures with desired physical and chemical properties.