First Development, Optimization, and Stability Control of a Pediatric Oral Atenolol Formulation.

Liquid formulations can be used in children of different ages by varying the volume of the administered dose in order to ensure an exact dosage. The aim of this work was to develop and to optimize a safe liquid atenolol formulation and to carry out the corresponding chemical and microbiological stability studies. A Plackett-Burman design was used to determine the factors that could be critical in the development of the formulations, and a central composite design was used to determine the optimal working conditions. As a result of these analyses, three formulations were selected and their stability studied in three storage conditions, 4, 25, and 40°C. After 6 months of stability testing, the optimal systems showed no pH change or atenolol loss; however, only glycerin-based formulations showed no microbial development. These systems, employing excipients in a range that the EMA has recommended, showed chemical and microbiological stability for at least 6 months even at the worst storage conditions.

Design, synthesis, and in vitro kinetics study of atenolol prodrugs for the use in aqueous formulations.

Based on DFT, MP2, and the density functional from Truhlar group (hybrid GGA: MPW1k) calculations for an acid-catalyzed hydrolysis of nine Kirby's N-alkylmaleamic acids and two atenolol prodrugs were designed. The calculations demonstrated that the amide bond cleavage is due to intramolecular nucleophilic catalysis by the adjacent carboxylic acid group and the rate-limiting step is determined based on the nature of the amine leaving group. In addition, a linear correlation of the calculated and experimental rate values has drawn credible basis for designing atenolol prodrugs that are bitterless, are stable in neutral aqueous solutions, and have the potential to release the parent drug in a sustained release manner. For example, based on the calculated B3LYP/6-31 G (d,p) rates, the predicted t1/2 (a time needed for 50% of the prodrug to be converted into drug) values for atenolol prodrugs ProD 1-ProD 2 at pH 2 were 65.3 hours (6.3 hours as calculated by GGA: MPW1K) and 11.8 minutes, respectively. In vitro kinetic study of atenolol prodrug ProD 1 demonstrated that the t1/2 was largely affected by the pH of the medium. The determined t1/2 values in 1N HCl, buffer pH2, and buffer pH 5 were 2.53, 3.82, and 133 hours, respectively.

Desenvolvimento, caracterização e avaliação de um sistema osmótico do tipo bicamada / Development, characterization and evaluation of a bilayer osmotic release system

Os comprimidos osmóticos do tipo bicamada ou "push pull" são sistemas reservatórios constituídos de um núcleo bicamada, circundado por uma membrana semipermeável e com um orifício de liberação perfurado a laser que permitem a liberação do fármaco através da cinética de ordem zero. Este sistema possui a vantagem de apresentar uma liberação controlada e não influenciada pelos fatores fisiológicos do trato gastrointestinal, permitindo aplicações terapêuticas para novos fármacos e inclusive para fármacos já existentes. O presente projeto contemplou as etapas de desenvolvimento, caracterização e avaliação de um sistema osmótico do tipo bicamada ou "push pull", para veiculação do atenolol, um beta bloqueador de grande importância na terapia antihipertensiva. Após a padronização e validação da metodologia analítica, estudos de compatibilidade entre o fármaco e os excipientes através da análise calorimétrica e espectroscopia no infravermelho (pré-formulação), a produção, a caracterização da membrana de revestimento e, por fim, a avaliação do desempenho dos núcleos osmóticos foram realizados. Assim, três lotes, com 4kg cada, foram produzidos para determinação do peso médio e do ferramenta I adequados, além da proporção entre os excipientes da formulação. O processo de compressão deu origem aos núcleos osmóticos do tipo bicamada que foram submetidos à avaliação físico-química como determinação do peso médio, da dureza, da friabilidade e da espessura. Além disso, padronizou-se o processo de revestimento dos núcleos com membrana semipermeável e avaliou-se o perfil de captação de água dos núcleos resultantes (Swelling)...

Hydrogen-bonding interactions in the 4-aminobenzoic acid salt of atenolol monohydrate.

Atenolol {or 4-[2-hydroxy-3-(isopropylamino)propoxy]phenylacetamide} crystallizes with 4-aminobenzoic acid to give the salt {3-[4-(aminocarbonylmethyl)phenoxy]-2-hydroxypropyl}isopropylammonium 4-aminobenzoate monohydrate, C14H23N2O3(+) x C7H6NO2(-) x H2O. In the crystal structure, the water molecule, the carboxylate group of 4-aminobenzoate, and the hydroxy and ether O atoms of atenolol form a supramolecular R3(3) (11) heterosynthon. Three other types of supramolecular synthons link the asymmetric unit into a two-dimensional structure.

An efficient asymmetric synthesis of (S)-atenolol: using hydrolytic kinetic resolution.

Enantiomerically pure (S)-atenolol was prepared by using (R,R) salen Co(III) complex for the resolution of terminal epoxide. This process was carried out at room temperature in excellent enantio selectivity. The method can be applied for large-scale preparation of (S)-atenolol without any problem.