Solubility enhancement of poorly-soluble active pharmaceutical ingredients (APIs) remains a scientific challenge and poses a practical issue in the pharmaceutical industry. The emergence of pharmaceutical cocrystals has contributed another dimension to the diversity of crystal forms available at the disposal of the pharmaceutical scientist. That pharmaceutical cocrystals are amenable to the design principles of crystal engineering means that the number of crystal forms offered by pharmaceutical cocrystals is potentially greater than the combined numbers of polymorphs, salts, solvates and hydrates for an API. The current spotlight and early-onset dissolution profile ("spring-and-parachute" effect) exhibited by certain pharmaceutical cocrystals draw attention to an immediate question: How big is the impact of cocrystals on aqueous solubility? The scientific literature and in-house data on pharmaceutical cocrystals that are thermodynamically stable in water are reviewed and analyzed for trends in aqueous solubility and melting point between the cocrystal and the cocrystal formers. There is poor correlation between the aqueous solubility of cocrystal and cocrystal former with respect to the API. The log of the aqueous solubility ratio between cocrystal and API has a poor correlation with the melting point difference between cocrystal and API. Structure-property relationships between the cocrystal and the cocrystal formers remain elusive and the actual experiments are still necessary to investigate the desired physicochemical properties. Crystal form (cocrystals, polymorphs, salts, hydrates and solvates) diversity is and will continue to be a contentious issue for the pharmaceutical industry. That the crystal form of an API dramatically impacts its aqueous solubility (a fixed thermodynamic property) is illustrated by the histamine H2-receptor antagonist ranitidine hydrochloride and HIV protease inhibitor ritonavir. For more than a century, the dissolution rate of a solid has been shown to be directly dependent on its solubility, cçterîs paribus. A century later, it remains impossible to predict the properties of a solid, given its molecular structure. If delivery or absorption of an API are limited by its aqueous solubility, aqueous solubility then becomes a critical parameter linking bioavailability and pharmacokinetics of an API. Since the majority of APIs are Biopharmaceutical Classification System (BCS) Class II (low solubility and high permeability) compounds, crystal form screening, optimization and selection have thus received more efforts, attention and investment. Given that the dissolution rate, aqueous solubility and crystal form of an API are intricately linked, it remains a scientific challenge to understand the nature of crystal packing forces and their impact upon physicochemical properties of different crystal forms. Indeed, the selection of an optimal crystal form of an API is an indispensable part of the drug development program. The impact of cocrystals on crystal form diversity is addressed with molecular and ionic targets in ellagic acid and lithium salts. A supramolecular heterosynthon approach was adopted for crystal form screening. Crystal form screening of ellagic acid yields molecular cocrystals, cocrystal solvates/hydrates and solvates. Crystal form screening of lithium salts (chloride, bromide and nitrate salts) afforded ionic cocrystals and cocrystal hydrates.

Complexos de rutênio, em razão da menor toxicidade e por poderem exibir atividade citotóxica ou antimetastática, tem sido considerados como alternativas potencialmente promissoras aos complexos de platina para tratamento de câncer. Nosso grupo de pesquisa tem investigado a interação de íons metálicos com fármacos anti-inflamatórios não esteroides (FAINEs) e já obteve sucesso na preparação de metalofármacos de dirutênio(II,III)-FAINEs, os quais se mostraram promissores com relação à atividade frente a modelos de glioma. Com a finalidade de contribuir para o entendimento das propriedades físico-químicas desses complexos, o presente trabalho teve como principal objetivo analisar propriedades consideradas particularmente essenciais a um potencial candidato a fármaco, tais como, estabilidade no estado sólido, lipofilicidade, solubilidade aquosa e dissolução intrínseca. Um complexo inédito de fórmula [Ru2Cl(feno)4], em que feno = fenoprofenato, foi sintetizado e caracterizado por meio de análise elementar, espectroscopia eletrônica, espectroscopia vibracional, difratometria de raios X, análise térmica e espectrometria de massas. Os complexos já testados anteriormente para atividade biológica, [Ru2Cl(ibp)4], ibp = ibuprofenato, e [Ru2(cet)4Cl], cet = cetoprofenato, foram analisados quanto à estabilidade no estado sólido por meio da determinação isotérmica de variação de massa. As lipofilicidades desses dois complexos, juntamente com a dos fármacos de origem e a do precursor sintético [Ru2(O2CH3)4Cl], foram avaliadas pelo método shake flask, e suas solubilidade aquosas foram investigadas em presença de co-solventes alcoólicos. Investigou-se ainda a velocidade de dissolução intrínseca do [Ru2Cl(ibp)4] que se encontra em estágio avançado de estudos biológicos. Os resultados obtidos trazem novas informações sobre o comportamento térmico dos complexos e sobre suas características biofarmacêutica. / Ruthenium complexes, mainly due to the lower toxicity and the cytotoxic and anti-metastatic activities, have been considered as potentially promising alternatives to platinum drugs for cancer treatment. Our research group has investigated the interactions of diruthenium metal cores with anti-inflammatory non-steroidal drugs (NSAIDs) and succeeded in preparing diruthenium(II,III)-NSAIDs metallodrugs which show promising activity against glioma models. With the aim of elucidating the physico-chemical properties of these complexes, the major objective of the present work was to investigate properties which are considered as essential for a potential candidate to drug, e.g., stability in the solid state, lipophilicity, aqueous solubility and intrinsic dissolution. A new complex of formula [Ru2Cl(feno)4], where feno = fenoprofen, was synthesized and characterized by elemental analysis, electronic spectroscopy, vibrational spectroscopy, X-rays difractommetry, thermal analysis and mass spectrometry. The complexes previously tested for biological properties, [Ru2Cl(ibp)4], ibp = ibuprofenate, and [Ru2(cet)4Cl], cet = cetoprofenate, were inv estigated for the stability in the solid state by isothermal thermogravimetry. The lipophilicity of the se complexes, as well as those of the parent drugs and of the precursor [Ru2(O2CH3)4Cl], was evaluated by the shake flask method, and their aqueous solubility in the presence of alcohol co-solvents was investigated. In addition, the intrinsic dissolution rate was determined for [Ru2Cl(ibp)4], which is undergoing advanced biological studies. The results provide important new information on the thermal behavior of the complexes and also on their biopharmaceutical propertie.

Complexos de rutênio, em razão da menor toxicidade e por poderem exibir atividade citotóxica ou antimetastática, tem sido considerados como alternativas potencialmente promissoras aos complexos de platina para tratamento de câncer. Nosso grupo de pesquisa tem investigado a interação de íons metálicos com fármacos anti-inflamatórios não esteroides (FAINEs) e já obteve sucesso na preparação de metalofármacos de dirutênio(II,III)-FAINEs, os quais se mostraram promissores com relação à atividade frente a modelos de glioma. Com a finalidade de contribuir para o entendimento das propriedades físico-químicas desses complexos, o presente trabalho teve como principal objetivo analisar propriedades consideradas particularmente essenciais a um potencial candidato a fármaco, tais como, estabilidade no estado sólido, lipofilicidade, solubilidade aquosa e dissolução intrínseca. Um complexo inédito de fórmula [Ru2Cl(feno)4], em que feno = fenoprofenato, foi sintetizado e caracterizado por meio de análise elementar, espectroscopia eletrônica, espectroscopia vibracional, difratometria de raios X, análise térmica e espectrometria de massas. Os complexos já testados anteriormente para atividade biológica, [Ru2Cl(ibp)4], ibp = ibuprofenato, e [Ru2(cet)4Cl], cet = cetoprofenato, foram analisados quanto à estabilidade no estado sólido por meio da determinação isotérmica de variação de massa. As lipofilicidades desses dois complexos, juntamente com a dos fármacos de origem e a do precursor sintético [Ru2(O2CH3)4Cl], foram avaliadas pelo método shake flask, e suas solubilidade aquosas foram investigadas em presença de co-solventes alcoólicos. Investigou-se ainda a velocidade de dissolução intrínseca do [Ru2Cl(ibp)4] que se encontra em estágio avançado de estudos biológicos. Os resultados obtidos trazem novas informações sobre o comportamento térmico dos complexos e sobre suas características biofarmacêutica. / Ruthenium complexes, mainly due to the lower toxicity and the cytotoxic and anti-metastatic activities, have been considered as potentially promising alternatives to platinum drugs for cancer treatment. Our research group has investigated the interactions of diruthenium metal cores with anti-inflammatory non-steroidal drugs (NSAIDs) and succeeded in preparing diruthenium(II,III)-NSAIDs metallodrugs which show promising activity against glioma models. With the aim of elucidating the physico-chemical properties of these complexes, the major objective of the present work was to investigate properties which are considered as essential for a potential candidate to drug, e.g., stability in the solid state, lipophilicity, aqueous solubility and intrinsic dissolution. A new complex of formula [Ru2Cl(feno)4], where feno = fenoprofen, was synthesized and characterized by elemental analysis, electronic spectroscopy, vibrational spectroscopy, X-rays difractommetry, thermal analysis and mass spectrometry. The complexes previously tested for biological properties, [Ru2Cl(ibp)4], ibp = ibuprofenate, and [Ru2(cet)4Cl], cet = cetoprofenate, were inv estigated for the stability in the solid state by isothermal thermogravimetry. The lipophilicity of the se complexes, as well as those of the parent drugs and of the precursor [Ru2(O2CH3)4Cl], was evaluated by the shake flask method, and their aqueous solubility in the presence of alcohol co-solvents was investigated. In addition, the intrinsic dissolution rate was determined for [Ru2Cl(ibp)4], which is undergoing advanced biological studies. The results provide important new information on the thermal behavior of the complexes and also on their biopharmaceutical propertie.

Cette étude s’attache à la caractérisation physico-chimique des contaminants des emballages alimentaires organiques, précisément les phtalates et les alkylphénols, en terme de solubilité aqueuse, coefficient de partage octanol-eau et pression de vapeur. Cette caractérisation se situe dans le cadre des règlementations REACH concernant l’identification des substances chimiques toxiques. Les mesures expérimentales de solubilité aqueuse sont effectuées par la méthode dynamique de saturation dans un intervalle de température [298.15-328.15K], celles du coefficient de partage octanol-eau avec la méthode « shake-flask » à 298.15. Les mesures de pression de vapeur sont réalisées avec la méthode dynamique de saturation dans un intervalle de température [313.15-423.15K] et validées avec la méthode statique. A partir de ces mesures, les coefficients de partage air-eau et octanol-air sont déterminés. En addition des mesures expérimentales, une prédiction de ces propriétés est effectuée avec les modèles thermodynamiques : UNIFAC originale, UNIQUAC, NRTL et COSMO-sac-dsp. A l’issue de ces résultats, une évaluation quantitative et qualitative de chacun des modèles est effectuée. Cette évaluation facilitera l’optimisation des paramètres de chacun des modèles des deux familles dans le but de créer un modèle de prédiction du phénomène de migration de l’emballage vers l’aliment / The aim of this study is the physical-chemical characterization of the organic food packaging contaminants, particularly phthalates and alkyl phenols, in terms of aqueous solubility, octanol-water partition coefficient and vapor pressure. This characterization falls within the scope of REACH regulations for the identification of chemical substances. The aqueous solubility measurements are performed using the dynamic saturation method in a temperature range of [298.15 – 328.15K], those of octanol-water partition coefficient with the “shake-flask” method at 298.15K. The vapor pressure measurements are carried out with the “dynamic saturation method” in a temperature range between 313.15 and 423.15K, and validated with the static method. These measurements are used in the determination of air-water and octnol-air partition coefficients. Beside experimental measurements, these poperties are predicted using thermodynamic models: UNIFAC originale, UNIQUAC, NRTL and COSMO-sac-dsp. A qualitative and quantitative evaluation is performed for each model. This evaluation will facilitate the optimization of the models’ parameters concerning phthalates and alkyl phenols in order to generate a model for the contaminants migration process

Solubility prediction usually refers to prediction of the intrinsic aqueous solubility, which is the concentration of an unionised molecule in a saturated aqueous solution at thermodynamic equilibrium at a given temperature. Solubility is determined by structural and energetic components emanating from solid-phase structure and packing interactions, solute–solvent interactions, and structural reorganisation in solution. An overview of the most commonly used methods for solubility prediction is given in Chapter 1. In this thesis, we investigate various approaches to solubility prediction and solvation model development, based on informatics and incorporation of empirical and experimental data. These are of a knowledge-based nature, and specifically incorporate information from the Cambridge Structural Database (CSD). A common problem for solubility prediction is the computational cost associated with accurate models. This issue is usually addressed by use of machine learning and regression models, such as the General Solubility Equation (GSE). These types of models are investigated and discussed in Chapter 3, where we evaluate the reliability of the GSE for a set of structures covering a large area of chemical space. We find that molecular descriptors relating to specific atom or functional group counts in the solute molecule almost always appear in improved regression models. In accordance with the findings of Chapter 3, in Chapter 4 we investigate whether radial distribution functions (RDFs) calculated for atoms (defined according to their immediate chemical environment) with water from organic hydrate crystal structures may give a good indication of interactions applicable to the solution phase, and justify this by comparison of our own RDFs to neutron diffraction data for water and ice. We then apply our RDFs to the theory of the Reference Interaction Site Model (RISM) in Chapter 5, and produce novel models for the calculation of Hydration Free Energies (HFEs).