Estudo químico-farmacêutico e avaliação da estabilidade de associações de oxitetraciclina e anti-inflamatórios não esteroidais em medicamentos veterinários
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2018-01-23
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Universidade Estadual Paulista (Unesp)
Resumo
O mercado farmacêutico veterinário tem crescido acentuadamente nos últimos anos, sendo liderado, principalmente, pelo segmento destinado aos animais de produção. As associações de oxitetraciclina com diclofenaco ou com piroxicam, na forma farmacêutica de soluções injetáveis, são amplamente empregadas na medicina veterinária. Apesar da importância clínica dessas associações, não foi encontrado na literatura científica nenhuma metodologia analítica capaz de quantificar simultaneamente esses fármacos nos medicamentos veterinários. Portanto, este trabalho objetivou desenvolver e validar métodos analíticos para determinação simultânea de oxitetraciclina associada ao diclofenaco de sódio ou ao piroxicam em soluções injetáveis veterinárias, empregando a Cromatografia Líquida de Alta Eficiência (CLAE) e Espectrofotometria no ultravioleta (UV). As matérias-primas desses fármacos foram caracterizadas por Cromatografia em Camada Delgada (CCD), Espectrofotometria na região do Ultravioleta (UV) e do Infravermelho (IV), Termogravimetria (TG), Calorimetria Exploratória Diferencial (DSC), Difração de Raios X (DRX), Microscopia Eletrônica de Varredura (MEV) e Cromatografia Líquida de Alta Eficiência acoplada à Espectrometria de Massas (CLAE-EM). O estudo de degradação forçada foi conduzido em condições hidrolíticas (alcalina, ácida, neutra e oxidativa) e fotolíticas, a estabilidade acelerada e de longa duração foram analisadas durante 6 meses (40 ± 2ºC) e 24 meses (30 ± 2ºC), respectivamente. A identificação dos produtos de degradação foi por EM e a avaliação da citotoxicidade in vitro foi através do ensaio de sulforrodamina B. Além disso, a compatibilidade fármaco-fármaco foi verificada através das técnicas de DSC, TG e espectrofotometria no IV. Os métodos analíticos por CLAE e espectrofotometria permitiram a determinação quantitativa e simultânea das associações avaliadas. Foram identificados seis produtos de degradação, sendo que o produto de degradação 5 apresentou atividade citotóxica moderada. Em relação à estabilidade acelerada e de longa duração, as amostras analisadas mostraram-se termicamente instáveis e os fármacos, na sua maioria, obedeceram à cinética de degradação de ordem zero. A avaliação de compatibilidade fármaco-fármaco sugeriu existir interações físico-químicas entre os fármacos. Os resultados deste trabalho ressaltam a importância das análises químico-farmacêuticas realizadas, pois elas são importantes ferramentas analíticas capazes de serem empregadas na rotina do controle de qualidade nas indústrias farmacêuticas, além de permitirem a previsão de alguns produtos de degradação dos fármacos que podem ser formados no ambiente.
The veterinary pharmaceutical market has grown markedly in the last years, being led, mainly, by the segment destined to the production animals. Fixed-dose combinations of oxytetracycline with diclofenac or piroxicam, available as injectable solutions, are widely used in veterinary medicine. Despite the clinical importance of these combinations, no analytical methodology could be found in the scientific literature capable of quantifying these drugs simultaneously in veterinary pharmaceuticals. Therefore, this work aimed to develop and validate analytical methods for the simultaneous determination of the oxytetracycline, diclofenac sodium and piroxicam in injectable veterinary solutions by High Performance Liquid Chromatography (HPLC) and UV spectrophotometry. The raw materials of these drugs were characterized by Thin Layer Chromatography (TLC), Ultraviolet (UV) and Infrared (IR) Spectrophotometry, Thermogravimetry (TG), Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD), Scanning Electron Microscopy (SEM) and High Performance Liquid Chromatography coupled to Mass Spectrometry (HPLC-MS). The forced degradation study was conducted under hydrolytic (alkaline, acid, neutral and oxidative) and photolytic conditions. The accelerated and the long term stability studies were carried out during 6 months (40 ± 2ºC) and 24 months (30 ± 2ºC), respectively. The identification of the degradation products was through MS and their in vitro cytotoxicity evaluation was carried out according to sulforhodamine B assay. Moreover, the drug-drug compatibility was verified by DSC, TG and IR spectrophotometry. HPLC and spectrophotometry validated methods allowed the simultaneous determination of the drugs under study. Six degradation products were identified, and the degradation product 5 showed moderate cytotoxic activity. Regarding to the accelerated and long-term stability, the analyzed samples were thermally unstable and the drugs mostly obeyed zero order degradation kinetics. The drug-drug compatibility evaluation suggested that there were physical-chemical interactions between the drugs. The results of this work highlight the importance of the chemical-pharmaceutical analyzes, once they are important analytical tools capable of being used in the routine of quality control in the pharmaceutical industries, contributing to the safety and efficacy of pharmaceutical products, besides allowing the prediction of some drug degradation products that can be formed in the environment.
The veterinary pharmaceutical market has grown markedly in the last years, being led, mainly, by the segment destined to the production animals. Fixed-dose combinations of oxytetracycline with diclofenac or piroxicam, available as injectable solutions, are widely used in veterinary medicine. Despite the clinical importance of these combinations, no analytical methodology could be found in the scientific literature capable of quantifying these drugs simultaneously in veterinary pharmaceuticals. Therefore, this work aimed to develop and validate analytical methods for the simultaneous determination of the oxytetracycline, diclofenac sodium and piroxicam in injectable veterinary solutions by High Performance Liquid Chromatography (HPLC) and UV spectrophotometry. The raw materials of these drugs were characterized by Thin Layer Chromatography (TLC), Ultraviolet (UV) and Infrared (IR) Spectrophotometry, Thermogravimetry (TG), Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD), Scanning Electron Microscopy (SEM) and High Performance Liquid Chromatography coupled to Mass Spectrometry (HPLC-MS). The forced degradation study was conducted under hydrolytic (alkaline, acid, neutral and oxidative) and photolytic conditions. The accelerated and the long term stability studies were carried out during 6 months (40 ± 2ºC) and 24 months (30 ± 2ºC), respectively. The identification of the degradation products was through MS and their in vitro cytotoxicity evaluation was carried out according to sulforhodamine B assay. Moreover, the drug-drug compatibility was verified by DSC, TG and IR spectrophotometry. HPLC and spectrophotometry validated methods allowed the simultaneous determination of the drugs under study. Six degradation products were identified, and the degradation product 5 showed moderate cytotoxic activity. Regarding to the accelerated and long-term stability, the analyzed samples were thermally unstable and the drugs mostly obeyed zero order degradation kinetics. The drug-drug compatibility evaluation suggested that there were physical-chemical interactions between the drugs. The results of this work highlight the importance of the chemical-pharmaceutical analyzes, once they are important analytical tools capable of being used in the routine of quality control in the pharmaceutical industries, contributing to the safety and efficacy of pharmaceutical products, besides allowing the prediction of some drug degradation products that can be formed in the environment.
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Oxitetraciclina, Diclofenaco de sódio, Piroxicam, Controle de qualidade, Estabilidade, Produtos de degradação, Oxytetracycline, Diclofenac sodium, Piroxicam, Quality control, Stability, Degradation products