Síntese, caracterização, estudo termoanalítico e avaliação da solubilidade dos novos cocristais de norfloxacino
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Data
2020-02-21
Autores
Ferreira, Patricia Osorio [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A baixa solubilidade em água faz com que grande parte das novas moléculas descobertas com grande potencial farmacológico pouquíssimas cheguem a fase de comercialização. Uma forma de melhorá-la assim como outras propriedades (estabilidade física e química, velocidade de dissolução e biodisponibilidade oral), é por meio da obtenção de cocristais farmacêuticos, que são definidos como cristais que se constroem a partir de dois componentes ou mais, estando no estado sólido em condições ambiente, sendo um fármaco e um coformador, que é uma substancia não prejudicial à saúde, podendo ser, inclusive outro fármaco. As publicações sobre cocristalização têm crescido nos últimos anos devido a melhora das propriedades dos fármacos e a possibilidade de obtenção de patentes. O fármaco escolhido para este trabalho é o norfloxacino, que possui baixa solubilidade aquosa e permeabilidade, o que o torna de interesse para esse estudo. O método de síntese escolhido foi o mecanoquímico, que vem ganhando bastante destaque por conta da reprodutibilidade e por ser um método verde. Foram obtidos cocristais utilizando os coformadores propostos, ácido isonicotínico, ácido nicotínico, ácido picolínico e sacarina, os quais foram caracterizados por análise térmica, espectrometria vibracional de absorção na região do infravermelho e difratometria de raios X do pó e suas estequiometrias confirmadas pelo diagrama de fases binário. Também foram realizados os ensaios de solubilidade aquosa e em tampões pH 3,0; 6,1 e 8,5. Obtendo-se aumento na solubilidade aquosa para todos os cocristais obtidos, não observando aumento significativo para pH 3,0 com exceção do sistema com ácido picolínico que aumentou 3 vezes, um aumento em pH 6,1, com exceção do sistema com ácido picolínico que não houve mudança significativa e uma diminuição da solubilidade em pH 8,5 para todos os cocristais obtidos. Além da avaliação microbiológica para aferição da potência dos cocristais com ácido isonicotínico e sacarina, frente ao micro-organismo Staphylococcus epidermidis, mostrando que a atividade do norfloxacino não foi afetada pela cocristalização.
The low solubility in water causes most of the new molecules discovered with great pharmacological potential, very few reach the commercialization stage. One way to improve it, as well as other properties (physical and chemical stability, speed of dissolution and oral bioavailability), is by obtaining pharmaceutical cocrystals, which are defined as crystals that are built from two or more components, being in the solid-state under ambient conditions, being a drug and a coformer, which is a substance that is not harmful to health, and may even be another drug. Publications on cocrystallization have grown in recent years due to improved properties of drugs and the possibility of obtaining patents. The drug chosen for this work is norfloxacin, which has low aqueous solubility and permeability, which makes it of interest for this study. The method of synthesis chosen was mechanochemical, which has been gaining prominence due to its reproducibility and because it is a green method. Cocrystals were obtained using the proposed coformers, isonicotinic acid, nicotinic acid, picolinic acid, and saccharin, which were characterized by thermal analysis, vibrational absorption spectrometry in the infrared region and powder X-ray diffractometry and their stoichiometries confirmed by the phase diagram binary. The aqueous solubility tests and pH 3.0 buffers were also performed; 6.1 and 8.5. Obtaining an increase in aqueous solubility for all crystals obtained, not observing a significant increase for pH 3.0, except for the system with picolinic acid which increased 3 times, an increase in pH 6.1, except for the system with picolinic acid, which there was no significant change and a decrease in solubility at pH 8.5 for all cocrystals obtained. In addition to the microbiological evaluation to measure the potency of the cocrystals with isonicotinic acid and saccharin, against the microorganism Staphylococcus epidermidis, showing that the activity of norfloxacin was not affected by cocrystallization.
The low solubility in water causes most of the new molecules discovered with great pharmacological potential, very few reach the commercialization stage. One way to improve it, as well as other properties (physical and chemical stability, speed of dissolution and oral bioavailability), is by obtaining pharmaceutical cocrystals, which are defined as crystals that are built from two or more components, being in the solid-state under ambient conditions, being a drug and a coformer, which is a substance that is not harmful to health, and may even be another drug. Publications on cocrystallization have grown in recent years due to improved properties of drugs and the possibility of obtaining patents. The drug chosen for this work is norfloxacin, which has low aqueous solubility and permeability, which makes it of interest for this study. The method of synthesis chosen was mechanochemical, which has been gaining prominence due to its reproducibility and because it is a green method. Cocrystals were obtained using the proposed coformers, isonicotinic acid, nicotinic acid, picolinic acid, and saccharin, which were characterized by thermal analysis, vibrational absorption spectrometry in the infrared region and powder X-ray diffractometry and their stoichiometries confirmed by the phase diagram binary. The aqueous solubility tests and pH 3.0 buffers were also performed; 6.1 and 8.5. Obtaining an increase in aqueous solubility for all crystals obtained, not observing a significant increase for pH 3.0, except for the system with picolinic acid which increased 3 times, an increase in pH 6.1, except for the system with picolinic acid, which there was no significant change and a decrease in solubility at pH 8.5 for all cocrystals obtained. In addition to the microbiological evaluation to measure the potency of the cocrystals with isonicotinic acid and saccharin, against the microorganism Staphylococcus epidermidis, showing that the activity of norfloxacin was not affected by cocrystallization.
Descrição
Palavras-chave
Química supramolecular, Norfloxacino, Química do estado sólido, Análise térmica, Solubilidade, Supramolecular Chemistry, Norfloxacin, Solid-state chemistry, Thermal analysis, Solubility