Obtenção de novas formas de cocristais de praziquantel: estrutura e propriedades
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Data
2023-12-19
Autores
Gaiotto, Cristina Aparecida Andrade Raymundo
Orientadores
Batista Junior, João Marcos [UNIFESP]
Tipo
Tese de doutorado
Título da Revista
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Resumo
Praziquantel (PZQ), (RS)-2-ciclo-hexilcarbonil-1,2,3,6,7,11b-hexa-hidro-4H-pirazino[2,1-a] isoquinolin-4-ona, é um fármaco antiparasitário comumente utilizado na medicina veterinária, assim como em humanos, sendo o fármaco de primeira escolha para doenças causadas por cestódeos e trematódeos. Em humanos, o PZQ apresenta eficácia de 80% em adultos e 70% em crianças, com efeitos adversos bem toleráveis. Contudo, um forte sabor metálico e amargo na língua (baixa palatabilidade) constitui uma barreira na aderência ao tratamento com esta substância, especialmente pelas crianças. O PZQ é administrado na forma de um racemato (mistura equimolar de enantiômeros), onde o enantiômero R é o eutômero (responsável pela atividade), enquanto o enantiômero S (distômero) está associado a efeitos adversos e é o principal responsável pelo forte sabor metálico e amargo do fármaco. A cocristalização pode ser uma boa estratégia para alterar propriedades físicas que impactem na palatabilidade do PZQ. Portanto, este trabalho visou a obtenção de estruturas multicomponentes de PZQ, tais como solvatos e cocristais. Os testes de triagem foram conduzidos experimentalmente com solventes de diversas classes química e cerca de 60 coformadores foram avaliados a fim de selecionar os mais adequados. Neste contexto experimental, foi possível ainda estimar o parâmetro de solubilidade de Hansen (HSP) para o PZQ a partir das forças das interações intermoleculares tabeladas para os solventes, estabelecer a predição para a formação de cocristais ou sistemas multicomponentes contendo o PZQ, o que resultou na obtenção de 6 novas formas de PZQ, sendo 3 cocristais e 3 complexos. As metodologias de evaporação lenta e moagem assistida por líquidos ou gotas do solvente (LAG), bem como reação de cristalização (RC) foram utilizadas para o preparo das amostras, que foram caracterizadas por difratometria de raios-X para pós e análises térmicas por DSC. A estrutura cristalina foi investigada com as técnicas espectroscópicas no infravermelho e Raman, enquanto a morfologia foi avaliada por estereomicroscopia. Por fim, a palatabilidade das formas multicomponentes foi investigada por meio de e-tongue e análises quimiométricas, revelando que os cocristais de rac-PZQ:Vanilina e R-PZQ:L-ácido málico são os mais promissores mascaradores de sabor.
Praziquantel (PZQ), (RS)-2-cyclohexylcarbonyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a] isoquinolin-4-one, is an antiparasitic drug commonly used in veterinary medicine, as well as in humans, being the drug of first choice for diseases caused by cestodes and trematodes. In humans, PZQ is 80% effective in adults and 70% in children, with well-tolerable adverse effects. However, a strong metallic and bitter taste on the tongue (low palatability) constitutes a barrier to the adherence to treatment with this substance, especially by children. PZQ is administered in the form of a racemate (equimolar mixture of enantiomers), where the R-enantiomer is the eutomer (responsible for activity), while the S-enantiomer (distomer) is associated with adverse effects and is mainly responsible for the strong metallic taste. and bitterness of the drug. Cocrystallization can be a good strategy to change physical properties that impact the palatability of PZQ. Therefore, this work aimed to obtain multicomponent structures of PZQ, such as solvates and co-crystals. The screening tests were conducted experimentally with solvents of different chemical classes and around 60 coformers were evaluated in order to select the most suitable ones. In this experimental context, it was also possible to estimate the Hansen solubility parameter (HSP) for PZQ based on the strengths of intermolecular interactions tabulated for the solvents, establish the prediction for the formation of cocrystals or multicomponent systems containing PZQ, which led to 6 forms of PZQ, 3 cocrystals and 3 complexes. The methodologies of slow evaporation and grinding assisted by liquids or drops of solvent (LAG), as well as crystallization reaction (RC) were used to prepare the samples, which were characterized by X-ray diffractometry for powders and thermal analysis by DSC. The crystalline structure was investigated using infrared and Raman spectroscopic techniques, while the morphology was evaluated using stereomicroscopy. Finally, the palatability of the multicomponent forms was investigated using e-tongue and chemometric analyses, revealing the cocrystals of rac-PZQ:Vaniline and R-PZQ:L-malic acid as the most promising flavor maskers.
Praziquantel (PZQ), (RS)-2-cyclohexylcarbonyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a] isoquinolin-4-one, is an antiparasitic drug commonly used in veterinary medicine, as well as in humans, being the drug of first choice for diseases caused by cestodes and trematodes. In humans, PZQ is 80% effective in adults and 70% in children, with well-tolerable adverse effects. However, a strong metallic and bitter taste on the tongue (low palatability) constitutes a barrier to the adherence to treatment with this substance, especially by children. PZQ is administered in the form of a racemate (equimolar mixture of enantiomers), where the R-enantiomer is the eutomer (responsible for activity), while the S-enantiomer (distomer) is associated with adverse effects and is mainly responsible for the strong metallic taste. and bitterness of the drug. Cocrystallization can be a good strategy to change physical properties that impact the palatability of PZQ. Therefore, this work aimed to obtain multicomponent structures of PZQ, such as solvates and co-crystals. The screening tests were conducted experimentally with solvents of different chemical classes and around 60 coformers were evaluated in order to select the most suitable ones. In this experimental context, it was also possible to estimate the Hansen solubility parameter (HSP) for PZQ based on the strengths of intermolecular interactions tabulated for the solvents, establish the prediction for the formation of cocrystals or multicomponent systems containing PZQ, which led to 6 forms of PZQ, 3 cocrystals and 3 complexes. The methodologies of slow evaporation and grinding assisted by liquids or drops of solvent (LAG), as well as crystallization reaction (RC) were used to prepare the samples, which were characterized by X-ray diffractometry for powders and thermal analysis by DSC. The crystalline structure was investigated using infrared and Raman spectroscopic techniques, while the morphology was evaluated using stereomicroscopy. Finally, the palatability of the multicomponent forms was investigated using e-tongue and chemometric analyses, revealing the cocrystals of rac-PZQ:Vaniline and R-PZQ:L-malic acid as the most promising flavor maskers.
Descrição
Citação
Gaiotto-Raymundo, C.A.A. OBTENÇÃO DE NOVAS FORMAS DE COCRISTAIS DE PRAZIQUANTEL: ESTRUTURA E PROPRIEDADES.