Preformulation of a liquid dosage formulation of captopril for pediatric use: drug-excipient compatibility and stability studies

Janaina Da Silva Goes,Túlio Flávio Accioly De Lima E Moura Moura,Fernanda Nervo Raffin,Cícero Flávio Soares Aragão,Fátima Duarte Freire

doi:10.1590/s2175-97902019000218015

Janaina Da Silva Goes, Túlio Flávio Accioly De Lima E Moura Moura + Show 3 more

Open Access

https://doi.org/10.1590/s2175-97902019000218015

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Abstract

Currently, medications used in children are typically modified from pharmaceutical dosage forms designed for adults. Captopril is widely adapted to liquid formulations for use in hospitals. Its stability in the aqueous medium is reduced since it undergoes oxidation producing captopril disulfide (its main metabolite). The aim of this formulation study was to suggest favorable conditions for the development of a stable captopril formulation. The compatibility between the drug and excipients was evaluated by differential scanning calorimetry analysis (DSC). For studies in solution, different formulations were prepared according to a factorial design varying EDTA concentration, water purity and pH. The resultant formulations were stored at 60°C and analyzed over a twelve-day period using HPLC. The DSC curves obtained suggested, although not conclusive to elucidation, interactions of captopril with citric acid and sucralose. The stability study of these solutions revealed that the variables significantly influenced captopril content, which degraded at zero order kinetics and rates differing by a factor of up to 7 times, where pH proved the most influential factor. Interactions between variables were observed. Therefore, development of a stable captopril formulation is feasible provided EDTA and a buffering agent is used at suitable concentrations (0.08% and pH 3.85).

Highlights

The available medications are mostly developed for adults
Experimental planning was a useful tool to the pre-formulation study for the development of a liquid formulation of captopril
From the results of captopril contents obtained through the stress test, it can be stated that pH is the factor that has the most influence on the stability of the solutions

Summary

Introduction

The available medications are mostly developed for adults. the data on safe dose is often extrapolated for pediatric use. The lack of accurate and adequate information on the use of pediatric medicines or the lack of appropriate formulations for the indicated dosages led to the spread of the term “therapeutic orphans” when referring to children (Permala et al, 2010). Non-specific medicines for children can be classified as off-label, used with a different age, In various studies, captopril, an inhibitor of angiotensin converting enzyme (ECA) (Ferreira, 1998; Katzung, 2005), was cited as a necessary medicament in liquid form for the treatment of childhood arterial hypertension and heart failure (Peterlini, Chaud, Pedreira, 2003; Standing, Tuleu, 2005; Flores-Pérez, 2008; Santos et al, 2008; Costa, Lima, Coelho, 2009; Costa, Rey, Coelho, 2009). The antihypertensive treatment is initiated at dosages based on data obtained for adults (Salgado, Carvalhaes, 2003; Flynn, 2008)

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