Avaliação da estabilidade da Finasterida, estudos de compatibilidade fármaco-excipientes e controle de qualidade das formulações farmacêuticas sólidas do mercado
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Data
2020-05-29
Autores
Sousa, Igo Pinheiro Lopes e
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Universidade Federal do Espírito Santo
Resumo
Finasteride is a specific competitive inhibitor of the enzyme 5-alfarreductase, an intracellular enzyme responsible for the conversion of testosterone to dihydrotestosterone, used in the treatment of benign prostatic hyperplasia, prostate cancer and androgenetic alopecia. There are reports of crystalline polymorphism for the drug, but there are no studies of forced degradation or compatibility of commercial pharmaceutical formulations. The drug belongs to class II of the Biopharmaceutical Classification System and dissolution is the limiting step of bioavailability, this fact being an indication of the importance of further studies in relation to compatibility with excipients, degradation mechanisms, and kinetics of these possible chemical reactions, as that any changes directly influence absorption. The efficacy and safety of drugs containing finasteride depends directly on the assessment of its intrinsic stability and on compatible and stable formulations. Initially, the methodology for determining the drug was developed and optimized by High Performance Liquid Chromatography and subsequently subjected to validation tests as described in RDC 166/2017. The mobile phase was composed of acetonitrile, methanol and water, in the proportion of 26:39:35, in a flow of 1.2 mL.min-1 , under a temperature of 30 ºC, and octadecylsilane column (RP-18) of 250 x 4.6 mm, 5 µm, and detection at 210 nm. Then, forced degradation studies were conducted to assess the stability of finasteride, and it was evaluated by chromatography; study of degradation kinetics; studies of drug-excipient compatibility, using thermoanalytical techniques, thermogravimetry and differential thermal analysis; in addition to the quality control of market formulations. The analytical method optimized by High Performance Liquid Chromatography was subjected to the tests required in the legislation for validation, which pointed out that the method was approved in terms of the required parameters. Therefore, considered selective in relation to degradation products and placebo, linear in the working range of 0.07 to 0.13 mg.mL-1, precise, exact with an average recovery percentage of 99.97% and robust, with its detection limit of 4.46 µg.mL-1 and quantification limit of 13.52 µg.mL-1, acceptable and consistent for the present work. Finasteride has been shown to be stable under different stress conditions evaluated, except in the condition of basic hydrolysis, at extreme pH above 12.7. Thus, the degradation kinetics in liquid medium was calculated from this point, with the t90 obtained being 32.64 hours, at pH 12.7. Drug-excipient compatibility studies were performed by thermal analysis and demonstrated that the excipients starch, pregelatinized starch, stearic acid, croscarmellose sodium, microcrystalline cellulose, crospovidone, silicon dioxide, sodium starch glycolate, polyethylene glycol 6000, iron oxides red and yellow, and talc are compatible with finasteride. Among these, the excipients ethylcellulose, hydroxypropylmethylcellulose, sodium lauryl sulfate, Opadry YS-1-7006, polyvinylpyrrolidone K30 and titanium dioxide showed some interaction with the drug, which after complementary studies by X-Ray Diffraction it was possible to confirm compatibility in drug-excipient relationship, with an interaction with crystalline drug change. In addition to these, lactose and magnesium stearate proved to be incompatible, according to the TGA and DTA curves and, to ensure the safety of the formulation, it is suggested to replace these excipients with others of the same property, respectively mannitol and stearic acid. Among the market formulations submitted to quality control, only the two formulations manipulated did not reach the minimum quality requirements established by the pharmacopoeial specifications, respectively regarding dissolution and content uniformity tests. Still, in relation to the dissolution profile, only Lab 4 was considered a pharmaceutical equivalent to the reference laboratory. But even so, it was possible to notice some similarity in the dissolution curve of the other laboratories of the pharmaceutical specialties. Among the objectives achieved, considering the relevance of the tests and results obtained, this work provides bases for the development of safer formulations, containing finasteride, making it possible to devise drugs that can achieve the legal and clinical expectations imposed on them, especially from the point of view technological
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Finasterida , Análise térmica , Controle de qualidade , Estudo de compatibilidade , Finasteride , Thermal analysis , Quality control , Compatibility study