Rational use of antioxidants in solid oral pharmaceutical preparations

Maísa Teodoro Celestino,Flávia Almada Do Carmo,Valeria Pereira De Sousa,Viviane Lione,Uiaran De Oliveira Magalhães,Aline Guerra Manssour Fraga,Carlos Rangel Rodrigues,Helena Carla Castro,Lucio Mendes Cabral

doi:10.1590/s1984-82502012000300007

Abstract

Antioxidants are currently used as efficient excipients that delay or inhibit the oxidation process of molecules. Excipients are often associated with adverse reactions. Stability studies can guide the search for solutions that minimize or delay the processes of degradation. The ability to predict oxidation reactions in different drugs is important. Methods: This study was conducted to assess the rational use of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite (SMB), propyl gallate (PG) and cysteine (CYS) in tablet formulations of simvastatin and ketoconazole. These antioxidants were evaluated according to stability parameters and the relationship between efficiency of the antioxidant and chemical structure of the drugs. Results were compared with DPPH tests and computational simulations. BHT was most efficient regarding simvastatin stability, and the most effective BHT concentrations for maintaining stability were 0.5 and 0.1%. In relation to ketoconazole, SMB was most efficient for maintaining content and dissolution profile. The evaluation by DPPH showed that the largest percentage of absorbance reduction was observed for PG, while SMB proved most efficient and had lower consumption of DPPH. The same pattern was observed, albeit with lower efficiency, for the other lipophilic antioxidants such as BHT and BHA. The results of the molecular modeling study demonstrated that electronic properties obtained were correlated with antioxidant activity in solution, being useful for the rational development of liquid pharmaceutical formulations but not for solid oral formulations. This study demonstrated the importance of considering stability parameters and molecular modeling to elucidate the chemical phenomena involved in antioxidant activity, being useful for the rational use of antioxidants in the development of pharmaceutical formulations.

Highlights

Excipients play a vital role in maintaining the expected pharmacological effect, modifying drug release rate and stability
The characterization tests demonstrated that the absence of lactose allowed for higher flux, lower adherence to the top punches of the compressor machine and greater reproducibility of results for hardness and sample weight, resulting in differences between formulations
The increased proportion of croscarmellose sodium, a disintegrant excipient, in the S2 formulation from 1.0 to 3.0% contributed to increased disintegration of the tablet and release of the active pharmaceutical ingredient (API), as expected

Summary

Introduction

Excipients play a vital role in maintaining the expected pharmacological effect, modifying drug release rate and stability. The stage of formulation development in early pre-formulation studies assessing physical and chemical interactions, such as incompatibilities between an active pharmaceutical ingredient (API) and excipients of interest, has become relevant (Peres-Filho et al, 2011) Such incompatibilities may affect drug stability and bioavailability, interfering with efficacy and safety (Rowland, Tozer, 2009). The efficacy, safety and stability of drugs administered in solid oral dosage forms are closely correlated with stability, as well as with solubility and permeability problems (Kommanaboyina, Rhodes, 1999; Murthy, GhebreSellassie, 1993) Physical factors such as light, heat and humidity can trigger or accelerate undesirable chemical reactions such as oxidation, hydrolysis, decarboxylation, racemization and photolysis, compromising drug stability. Oxidation rate is influenced directly by factors such as temperature, radiation and pH (Vadas, 2004)

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Results