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Energética de polimorfos e co-cristais
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A Engenharia de Cristais tem, nos últimos anos, emergido como uma disciplina focada na síntese seletiva de novas fases sólidas com estequiometria, empacotamento, morfologia e propriedades físicas (e.g. solubilidade) direcionadas para aplicações específicas. Um dos problemas centrais em indústrias como a farmacêutica ou a agroquímica, é o facto de muitos dos compostos orgânicos que são desenvolvidos serem demasiado insolúveis em meios aquosos para poderem cumprir adequadamente o fim a que se destinam. Uma das técnicas mais promissoras para melhorar a solubilidade de compostos orgânicos consiste na síntese de cristais multicomponentes (cristais contendo duas ou mais moléculas diferentes na rede cristalina). Durante o desenvolvimento deste tipo de materiais é essencial avaliar a sua estabilidade relativamente aos seus componentes sólidos puros, para garantir que não se decompõem durante o período de armazenamento. A entalpia da reação (A:B )(cr) A(cr) B(cr) b → + b , que reflete a diferença de energia de rede entre o co-cristal e seus precursores A e B, é um parâmetro importante para esta avaliação. Uma forma simples de o determinar é através da medição de entalpias de dissolução. O presente trabalho teve por objetivo utilizar esse tipo de medidas para avaliar a influência da estequiometria na estabilidade (entálpica) relativa de cristais multicomponentes constituídos por precursores com interesse farmacêutico. Para o efeito, foi desenvolvida uma célula calorimétrica adaptável a um calorímetro LKB 2277 Thermal Activity Monitor que permite trabalhar com quantidades de amostra <20 mg. A nova célula foi testada em termos de qualidade e sensibilidade do sinal calorimétrico. A precisão e exatidão das determinações foram avaliadas usando como reação padrão a dissolução de cloreto de potássio em água desionizada. Foi ainda usada como teste a determinação da diferença entálpica entre as formas polimórficas I e II da 4’-hidroxiacetofenona (HAP), o trs m → H (II I) , com base em medidas de entalpia de dissolução em DMSO. Todos estes ensaios foram realizados a 298,15K. Os testes de dissolução de cloreto de potássio permitiram obter uma entalpia de dissolução molar padrão de o sln m H =17,40±0,06kJ·mol -1 , em excelente acordo com o valor calculado a partir de dados retirados das Tabelas NBS, o sln m H =17,40±0,11kJ·mol-1 . O estudo da dissolução dos polimorfos da HAP conduziu a o trs m → H (II I) =0,48±0,10kJ∙mol-1 , também em excelente acordo com a literatura, o trs m → H (II I) =0,49±0,13kJ∙mol-1. A nova célula foi testada em termos de qualidade e sensibilidade do sinal calorimétrico. A precisão e exatidão das determinações foram avaliadas usando como reação padrão a dissolução de cloreto de potássio em água desionizada. Foi ainda usada como teste a determinação da diferença entálpica entre as formas polimórficas I e II da 4’-hidroxiacetofenona (HAP), o trs m → H (II I) , com base em medidas de entalpia de dissolução em DMSO. Todos estes ensaios foram realizados a 298,15K. Os testes de dissolução de cloreto de potássio permitiram obter uma entalpia de dissolução molar padrão de o sln m H =17,40±0,06kJ·mol -1 , em excelente acordo com o valor calculado a partir de dados retirados das Tabelas NBS, o sln m H =17,40±0,11kJ·mol-1 . O estudo da dissolução dos polimorfos da HAP conduziu a o trs m → H (II I) =0,48±0,10kJ∙mol-1 , também em excelente acordo com a literatura, o trs m → H (II I) =0,49±0,13kJ∙mol-1, H (MA:LPhe ) =447,3±7,4kJ·mol-1 , o Lat m H (MA:DLPhe) =278,2±4,3kJ·mol-1 e o Lat m 2 H (MA:DLPhe ) =447,1±7,4kJ·mol-1 . Neste caso é interessante notar que as diferenças de entalpia de rede entre os pares de estequiometria 1:1 e 1:2 são aproximadamente iguais à entalpia de sublimação do precursor responsável pela diferença de estequiometria: o Lat m 2 − H (MA:Phe ) o o Lat m sub m H H (MA:Phe) (Phe).
Crystal Engineering has, in recent years, emerged as a discipline focused on the selective synthesis of new solid phases with stoichiometry, packaging, morphology and physical properties (e.g. solubility) for specific applications. A main problem in industries such as pharmaceuticals or agrochemicals is that many of the organic compounds that are developed are too insoluble in water to serve their proper function. One of the most promising techniques for improving the solubility of organic compounds is the synthesis of multi-component crystals (crystals containing two or more different molecules in the crystalline lattice). During the development of this type of materials it is essential to assess their stability in relation to their pure solid components to ensure that they do not decompose during the storage period. The standard molar enthalpy of the reaction (A:B )(cr) A(cr) B(cr) b → + b , which reflects the difference in lattice energy between a given co-crystal and its precursors, is an important aspect to for this evaluation. A simple way to determine this parameter is by measuring dissolution enthalpies. The aim of this work was to use such measures to assess the influence of stoichiometry on the relative stability (enthalpic) of multi-component crystals composed by precursors of pharmaceutical interest. For this purpose, a calorimetric cell adaptable to a LKB 2277 Thermal Activity Monitor was developed, which allows working with sample quantities <20mg. The new cell was evaluated in terms of quality and sensitivity. The accuracy and precision of the calorimetric system was evaluated using as standard reaction the dissolution of potassium chloride in water. It was also used as a test the determination of the enthalpic difference between the polymorphs I and II of 4’-hydroxyacetophenone (HAP) in DMSO. All these tests were performed at 298,15K. The potassium chloride dissolution tests led to a standard molar dissolution enthalpy of o sln m H =17,40±0,06 kJ·mol-1 , in excellent agreement with the calculated from NBS Tables, o sln m H =17,40±0,11kJ·mol-1 . The dissolution of the HAP polymorphic system led to o trs m → H (II I) =0,48±0,10kJ∙mol-1 , also agreeing with the literature, o trs m → H (II I) =0,49±0,13kJ∙mol-1 . In order to study the energy of multicomponent pairs of crystals with different stoichiometries (A:B/A:B2), compounds based on maleic acid (MA) and fumaric acid (FA), and the amino acids phenylalanine (Phe) and valine (Val) were synthesized by mechanochemistry. The multi-component crystals obtained with a 1:1 ratio were (L refer to the enantiomer L and DL the racemic mixture): FA:LPhe, FA:DLPhe, MA:LPhe, MA:DLPhe, MA:LVal, and MA:DLVal; and with a 1:2 ratio: FA:LVal2, FA:DLVal2, MA:LPhe2, and MA:DLPhe2. In the case of MA:LPhe2, crystals were also obtained by crystallization in water, which allowed the determination of the molecular and crystalline structure by single crystal X-ray diffraction (SCXRD). During the thesis it was possible to study the energy of the following two pairs of stoichiometry 1:1 and 1:2: MA:LPhe/MA:LPhe2 and MA:DLPhe/MA:DLPhe2. The results of the measurements of the enthalpy reaction dissociation of these compounds in their precursors, at 298,15K, obtained by solution calorimetry, were: o r m H (MA:LPhe) =7,58±0,21kJ·mol-1 , o r m 2 H (MA:LPhe ) =16,08±0,28kJ·mol-1 , o r m H (MA:DLPhe) =7,55±0,22kJ·mol-1 and o r m 2 H (MA:DLPhe ) =15,87±0,47 kJ·mol-1 . These results indicate that, enthalpically, the systems are stable in relation to their decomposition in the precursors since the process is always endothermic. It also suggests that, at least in this limited number of cases, additivity is approximately observed since o o r m 2 r m H H (MA:Phe ) 2 (MA:Phe) . It was also possible to obtain the following values of lattice enthalpies: o Lat m H (MA:LPhe) =278,2±4,3kJ·mol-1 , o Lat m 2 H (MA:LPhe ) =447,3±7,4kJ·mol-1, H (MA:DLPhe) =278,2±4,3kJ·mol-1 e o Lat m 2 H (MA:DLPhe ) =447,1±7,4kJ·mol-1 . In this case it is interesting to note that the differences in lattice enthalpy between the 1:1 and 1:2 stoichiometry pairs are approximately equal to the sublimation enthalpy of the precursor responsible for the stoichiometry difference: o o o Lat m 2 Lat m sub m − H H H (MA:Phe ) (MA:Phe) (Phe) .
Crystal Engineering has, in recent years, emerged as a discipline focused on the selective synthesis of new solid phases with stoichiometry, packaging, morphology and physical properties (e.g. solubility) for specific applications. A main problem in industries such as pharmaceuticals or agrochemicals is that many of the organic compounds that are developed are too insoluble in water to serve their proper function. One of the most promising techniques for improving the solubility of organic compounds is the synthesis of multi-component crystals (crystals containing two or more different molecules in the crystalline lattice). During the development of this type of materials it is essential to assess their stability in relation to their pure solid components to ensure that they do not decompose during the storage period. The standard molar enthalpy of the reaction (A:B )(cr) A(cr) B(cr) b → + b , which reflects the difference in lattice energy between a given co-crystal and its precursors, is an important aspect to for this evaluation. A simple way to determine this parameter is by measuring dissolution enthalpies. The aim of this work was to use such measures to assess the influence of stoichiometry on the relative stability (enthalpic) of multi-component crystals composed by precursors of pharmaceutical interest. For this purpose, a calorimetric cell adaptable to a LKB 2277 Thermal Activity Monitor was developed, which allows working with sample quantities <20mg. The new cell was evaluated in terms of quality and sensitivity. The accuracy and precision of the calorimetric system was evaluated using as standard reaction the dissolution of potassium chloride in water. It was also used as a test the determination of the enthalpic difference between the polymorphs I and II of 4’-hydroxyacetophenone (HAP) in DMSO. All these tests were performed at 298,15K. The potassium chloride dissolution tests led to a standard molar dissolution enthalpy of o sln m H =17,40±0,06 kJ·mol-1 , in excellent agreement with the calculated from NBS Tables, o sln m H =17,40±0,11kJ·mol-1 . The dissolution of the HAP polymorphic system led to o trs m → H (II I) =0,48±0,10kJ∙mol-1 , also agreeing with the literature, o trs m → H (II I) =0,49±0,13kJ∙mol-1 . In order to study the energy of multicomponent pairs of crystals with different stoichiometries (A:B/A:B2), compounds based on maleic acid (MA) and fumaric acid (FA), and the amino acids phenylalanine (Phe) and valine (Val) were synthesized by mechanochemistry. The multi-component crystals obtained with a 1:1 ratio were (L refer to the enantiomer L and DL the racemic mixture): FA:LPhe, FA:DLPhe, MA:LPhe, MA:DLPhe, MA:LVal, and MA:DLVal; and with a 1:2 ratio: FA:LVal2, FA:DLVal2, MA:LPhe2, and MA:DLPhe2. In the case of MA:LPhe2, crystals were also obtained by crystallization in water, which allowed the determination of the molecular and crystalline structure by single crystal X-ray diffraction (SCXRD). During the thesis it was possible to study the energy of the following two pairs of stoichiometry 1:1 and 1:2: MA:LPhe/MA:LPhe2 and MA:DLPhe/MA:DLPhe2. The results of the measurements of the enthalpy reaction dissociation of these compounds in their precursors, at 298,15K, obtained by solution calorimetry, were: o r m H (MA:LPhe) =7,58±0,21kJ·mol-1 , o r m 2 H (MA:LPhe ) =16,08±0,28kJ·mol-1 , o r m H (MA:DLPhe) =7,55±0,22kJ·mol-1 and o r m 2 H (MA:DLPhe ) =15,87±0,47 kJ·mol-1 . These results indicate that, enthalpically, the systems are stable in relation to their decomposition in the precursors since the process is always endothermic. It also suggests that, at least in this limited number of cases, additivity is approximately observed since o o r m 2 r m H H (MA:Phe ) 2 (MA:Phe) . It was also possible to obtain the following values of lattice enthalpies: o Lat m H (MA:LPhe) =278,2±4,3kJ·mol-1 , o Lat m 2 H (MA:LPhe ) =447,3±7,4kJ·mol-1, H (MA:DLPhe) =278,2±4,3kJ·mol-1 e o Lat m 2 H (MA:DLPhe ) =447,1±7,4kJ·mol-1 . In this case it is interesting to note that the differences in lattice enthalpy between the 1:1 and 1:2 stoichiometry pairs are approximately equal to the sublimation enthalpy of the precursor responsible for the stoichiometry difference: o o o Lat m 2 Lat m sub m − H H H (MA:Phe ) (MA:Phe) (Phe) .
Descrição
Tese de mestrado em Química, Universidade de Lisboa, Faculdade de Ciências, 2021
Palavras-chave
Calorimetria Célula Calorimétrica Cristais Multicomponentes Ácido Maleico Aminoácidos Teses de mestrado - 2021