Alguns cocristais de ciprofloxacino: síntese mecanoquímica, caracterização e ensaio de solubilidade
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Data
2019-03-01
Autores
Almeida, Amanda Cosmo de
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Universidade Estadual Paulista (Unesp)
Resumo
Tendo em vista a necessidade de se melhorar as propriedades físico-químicas de fármacos por parte da indústria farmacêutica, a cocristalização atua como um novo método capaz de melhorar tais propriedades, dentre elas a solubilidade aquosa. Uma vez que o Ciprofloxacino (CIP) pertence à classe 4 do Sistema de Classificação Biofarmacêutica, o que significa que o mesmo apresenta baixa solubilidade aquosa e baixa permeabilidade em biomembranas, o presente trabalho descreve a síntese e caracterização dos cocristais deste antibiótico. Os coformadores ácido pirazinóico (APZ), ácido p-aminobenzóico (PABA), ácido nicotínico (ANC) e ácido isonicotínico (AINC) foram escolhidos, devido a possíveis estabelecimentos de síntons com o API. Os cocristais foram obtidos através de método mecanoquímico (moagem à seco e assistida por solvente), com o auxílio de um moinho de bolas. A caracterização dos cocristais foi realizada através das seguintes técnicas: calorimetria exploratória diferencial (DSC), termogravimetria e analise térmica diferencial simultânea (TG-DTA), espectroscopia vibracional de absorção na região do infravermelho (IV) e difratometria de raios X do pó (DRXP). Através da análise térmica, espectroscópica e difratométrica foi possível verificar a formação de três cocristais e um sal, nas razões estequiométricas 1:1 (mol/mol), com e sem adição do solvente etanol. Além disso, foram construídos diagramas de fase binários, variando-se as razões molares entre API e coformador, afim de utilizar tal método para reafirmar a formação de cocristais. Um método de determinação analítica quantitativa do princípio ativo foi validado neste trabalho e um estudo da solubilidade dos cocristais formados entre o API e os ácidos nicotínico e isonicotínico foi realizado, verificando um aumento na solubilidade aquosa e em sistema tamponado de pH 6,8 para os cocristais em relação ao precursor CIP. Dessa forma, os cocristais formados foram capazes de uma melhoria nas propriedades físico-químicas do antibiótico utilizado nesse estudo.
In view of the need of improving physicochemical properties of drugs by the pharmaceutical industry, cocrystallization acts as a new method capable of improving such properties, among them the aqueous solubility. Since Ciprofloxacin (CIP) belongs to Class 4 of the Biopharmaceutics Classification System, which means that it has low aqueous solubility and low permeability in biomembranes, the present work describes the synthesis and characterization of the cocrystals of this antibiotic. The pyrazinoic (APZ), p-aminobenzoic (PABA), nicotinic (ANC) and isonicotinic (AINC) acids coformers were chosen due to possible synthons establishments with the API. The cocrystals were obtained by mechanochemical method (dry milling and liquid-assisted grinding), with the aid of a ball mill. The characterization of the cocrystals was carried out using the following techniques: differential scanning calorimetry (DSC), thermogravimetry and simultaneous differential thermal analysis (TG-DTA), infrared spectroscopy (IR) and powder X-ray diffractometry (PXRD). Through the thermal, spectroscopic and diffractometric analysis it was possible to verify the formation of three cocrystals and one salt, in the 1:1 (mol/mol) stoichiometric ratios with and without the addition of the ethanol. In addition, binary phase diagrams were constructed by varying the molar ratios between API and coformer in order to use such a method to reaffirm the formation of cocrystal. A method of quantitative analytical determination of the drug was validated in this work and a study of the solubility of the cocrystals formed between the API and the nicotinic and isonicotinic acids was carried out, verifying an increase in the aqueous solubility and in a buffered system of pH 6.8, comparing the cocrystals with the precursor CIP. Thus, the formed cocrystals were capable of an improvement in the physicochemical properties of the antibiotic used in this study.
In view of the need of improving physicochemical properties of drugs by the pharmaceutical industry, cocrystallization acts as a new method capable of improving such properties, among them the aqueous solubility. Since Ciprofloxacin (CIP) belongs to Class 4 of the Biopharmaceutics Classification System, which means that it has low aqueous solubility and low permeability in biomembranes, the present work describes the synthesis and characterization of the cocrystals of this antibiotic. The pyrazinoic (APZ), p-aminobenzoic (PABA), nicotinic (ANC) and isonicotinic (AINC) acids coformers were chosen due to possible synthons establishments with the API. The cocrystals were obtained by mechanochemical method (dry milling and liquid-assisted grinding), with the aid of a ball mill. The characterization of the cocrystals was carried out using the following techniques: differential scanning calorimetry (DSC), thermogravimetry and simultaneous differential thermal analysis (TG-DTA), infrared spectroscopy (IR) and powder X-ray diffractometry (PXRD). Through the thermal, spectroscopic and diffractometric analysis it was possible to verify the formation of three cocrystals and one salt, in the 1:1 (mol/mol) stoichiometric ratios with and without the addition of the ethanol. In addition, binary phase diagrams were constructed by varying the molar ratios between API and coformer in order to use such a method to reaffirm the formation of cocrystal. A method of quantitative analytical determination of the drug was validated in this work and a study of the solubility of the cocrystals formed between the API and the nicotinic and isonicotinic acids was carried out, verifying an increase in the aqueous solubility and in a buffered system of pH 6.8, comparing the cocrystals with the precursor CIP. Thus, the formed cocrystals were capable of an improvement in the physicochemical properties of the antibiotic used in this study.
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Palavras-chave
Cocristal, Ciprofloxacino, Análise térmica, Ciprofloxacin, Cocrystal, Thermal analysis