Publicação
Thermodynamic studies of nicotinic acid
| Resumo: | The work presented in this thesis was carried out at the Molecular Energetics group from “Centro de Química e Bioquímica” of “Faculdade de Ciências da Universidade de Lisboa”. The general research goal of the group is the study of the relationship between the energetics of molecules or groups of molecules and their structure and reactivity. In the recent years, the laboratory where I worked devoted special attention to the study of organic molecular solids, in particular, to the way structural and morphological differences in crystals are reflected by their physical properties and energetics. At the time my thesis was planned, the group was particularly interested in compounds relevant for pharmaceutical applications, since the possibility of occurrence of polymorphs or solvates in these substances can have an important impact on their use as active pharmaceutical ingredients. Indeed, although the active molecule remains the same, different crystal forms can exhibit significantly different physical properties (e. g. melting point, solubility, and cohesive energy). For example, differences in solubility can significant affect the bioavailability of a drug. Nicotinic acid (niacin) seemed a good candidate for this kind of studies. It is a reasonably rigid molecule and has two hydrogen bond acceptor (N, C=O) and one donor (OH) centers. Hydrogen bonds strongly determine molecular organization and packing in the solid state. Thus, the possibility of more than one combination donor/acceptor for hydrogen interactions between molecules of nicotinic acid suggested that the compound could perhaps be prone to polymorphism, i.e. crystallize in more than one crystal form. Moreover, as stated in the Introduction and in other chapters of this thesis, nicotinic acid is a very important active pharmaceutical ingredient and is available on a fairly high scale (~100 g) at an affordable price. The starting point of the thesis was therefore, the investigation of polymorphism in this compound. Remarkably, the several attempts to obtain polymorphs or solvates (e.g. hydrates) by recrystallization from various solvents showed that, unlike its hydroxyl derivatives, nicotinic acid has a tendency to always crystallize in the same solid form, a result which is nevertheless interesting. The work that started as a quest for nicotinic acid polymorphism evolved into the following topics: (i) Structural, morphological, and energetic characterization of a nicotinic acid (NIST Standard Reference Material 2151) standard sample. The aim of this study, described in Chapter 3, was to obtain data, which could be used as references for intercomparison of different nicotinic acid samples, when trying to assess the effect of structural and morphological differences in the energetics of crystals. It also led to the determination of reliable enthalpies of formation of nicotinic acid in gaseous and crystalline states and to the corresponding enthalpy of sublimation, whose previously published values showed considerable discrepancies. (ii) Determination of equilibrium solubility of nicotinic acid in six solvents differing in polarity, polarizability, and hydrogen bond ability (water, ethanol, acetone, dimethyl sulfoxide, acetonitrile and diethyl ether), described in Chapter 4. Deviations from ideal solubility were analyzed based on the activity coefficients obtained for the compound in the different solvents. The observed solubility order (dimethyl sulfoxide >> water > ethanol > acetone > diethyl ether > acetonitrile) was interpreted in terms of descriptors of these solvents. Finally, it was found that both the nature of the solvent and the fact that nicotinic acid is predominantly zwitterionic in water and nonzwitterionic in the nonaqueous media did not affect the nature of the crystalline form in equilibrium with the solution, which always corresponded to the same monoclinic phase. (iii) The study of the influence of temperature and ionic strength on the acid dissociation constants of nicotinic acid. This study, included in Chapter 5, was motivated by the discrepancies observed in the values of these constants in the literature and by the fact that these data were required for the interpretation of the solubility and dilution/solution results presented in Chapters 4 and 6. (iv) Finally, Chapter 6 includes results of enthalpies of solution of nicotinic acid in water and enthalpies of dilution of aqueous nicotinic acid solutions. Combining these results, with the above mentioned acid dissociation constants, on Chapter 5, and the corresponding enthalpies of proton dissociation retrieved from the literature, it was possible to determine the standard molar enthalpies of formation at infinite dilution, of the three nicotinic acid species involved in the protonation/deprotonation equilibria. |
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| Autores principais: | Gonçalves, Elsa Marisa Duarte Rodrigues, 1978- |
| Assunto: | Ácido nicotínico Polimorfismo Termoquímica Energética Solubilidade Entalpias de diluição Teses de doutoramento - 2011 |
| Ano: | 2011 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | The work presented in this thesis was carried out at the Molecular Energetics group from “Centro de Química e Bioquímica” of “Faculdade de Ciências da Universidade de Lisboa”. The general research goal of the group is the study of the relationship between the energetics of molecules or groups of molecules and their structure and reactivity. In the recent years, the laboratory where I worked devoted special attention to the study of organic molecular solids, in particular, to the way structural and morphological differences in crystals are reflected by their physical properties and energetics. At the time my thesis was planned, the group was particularly interested in compounds relevant for pharmaceutical applications, since the possibility of occurrence of polymorphs or solvates in these substances can have an important impact on their use as active pharmaceutical ingredients. Indeed, although the active molecule remains the same, different crystal forms can exhibit significantly different physical properties (e. g. melting point, solubility, and cohesive energy). For example, differences in solubility can significant affect the bioavailability of a drug. Nicotinic acid (niacin) seemed a good candidate for this kind of studies. It is a reasonably rigid molecule and has two hydrogen bond acceptor (N, C=O) and one donor (OH) centers. Hydrogen bonds strongly determine molecular organization and packing in the solid state. Thus, the possibility of more than one combination donor/acceptor for hydrogen interactions between molecules of nicotinic acid suggested that the compound could perhaps be prone to polymorphism, i.e. crystallize in more than one crystal form. Moreover, as stated in the Introduction and in other chapters of this thesis, nicotinic acid is a very important active pharmaceutical ingredient and is available on a fairly high scale (~100 g) at an affordable price. The starting point of the thesis was therefore, the investigation of polymorphism in this compound. Remarkably, the several attempts to obtain polymorphs or solvates (e.g. hydrates) by recrystallization from various solvents showed that, unlike its hydroxyl derivatives, nicotinic acid has a tendency to always crystallize in the same solid form, a result which is nevertheless interesting. The work that started as a quest for nicotinic acid polymorphism evolved into the following topics: (i) Structural, morphological, and energetic characterization of a nicotinic acid (NIST Standard Reference Material 2151) standard sample. The aim of this study, described in Chapter 3, was to obtain data, which could be used as references for intercomparison of different nicotinic acid samples, when trying to assess the effect of structural and morphological differences in the energetics of crystals. It also led to the determination of reliable enthalpies of formation of nicotinic acid in gaseous and crystalline states and to the corresponding enthalpy of sublimation, whose previously published values showed considerable discrepancies. (ii) Determination of equilibrium solubility of nicotinic acid in six solvents differing in polarity, polarizability, and hydrogen bond ability (water, ethanol, acetone, dimethyl sulfoxide, acetonitrile and diethyl ether), described in Chapter 4. Deviations from ideal solubility were analyzed based on the activity coefficients obtained for the compound in the different solvents. The observed solubility order (dimethyl sulfoxide >> water > ethanol > acetone > diethyl ether > acetonitrile) was interpreted in terms of descriptors of these solvents. Finally, it was found that both the nature of the solvent and the fact that nicotinic acid is predominantly zwitterionic in water and nonzwitterionic in the nonaqueous media did not affect the nature of the crystalline form in equilibrium with the solution, which always corresponded to the same monoclinic phase. (iii) The study of the influence of temperature and ionic strength on the acid dissociation constants of nicotinic acid. This study, included in Chapter 5, was motivated by the discrepancies observed in the values of these constants in the literature and by the fact that these data were required for the interpretation of the solubility and dilution/solution results presented in Chapters 4 and 6. (iv) Finally, Chapter 6 includes results of enthalpies of solution of nicotinic acid in water and enthalpies of dilution of aqueous nicotinic acid solutions. Combining these results, with the above mentioned acid dissociation constants, on Chapter 5, and the corresponding enthalpies of proton dissociation retrieved from the literature, it was possible to determine the standard molar enthalpies of formation at infinite dilution, of the three nicotinic acid species involved in the protonation/deprotonation equilibria. |
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