Physicochemical and Microbiological Stability of a New Oral Clonidine Solution for Paediatric Use

Abstract

Abstract Background As many drugs are unavailable for paediatric use, hospital pharmacies are often required to develop suitable formulations themselves. Clonidine is commonly used in paediatrics (in severe hypertension, in opiate withdrawal syndrome, in tics and Gilles de la Tourette syndrome or in anaesthetic premedication) but no appropriate formulation has been drawn up. The aims of this work were to develop an oral solution of clonidine dedicated to children and to assess its physicochemical and microbiological stability. Methods Formulation of an oral solution of clonidine hydrochloride suitable for neonates and paediatrics was developed using the active pharmaceutical ingredient (API), with as few excipients as possible and without any complex excipient vehicle. A stability study was made according to GERPAC-SFPC guidelines. At each point in time (D0, D1, D7, D15, D29, D60 and D90), visual aspect (limpidity), pH and osmolality were established. Clonidine concentration was quantified using a stability-indicating HPLC-UV-DAD method previously developed from a forced degradation study and validated according to SFSTP Pharma. Microbiological stability was also tested according to the European Pharmacopeia monograph with the best adapted method (by comparing membrane filtration and inclusion). Solutions were stored in amber glass bottles with an oral adapter for up to 3 months in two different conditions: 5 °C +/– 3 °C and at 25 °C +/– 2 °C with 60 % residual humidity (climatic chamber). Results The formulated oral solution is composed of API at a concentration of 10 µg/mL and of potassium sorbate (0.3 %), citric acid, potassium citrate (pH 5 buffer) and sodium saccharine (0.025 %). Forced degradation highlighted six degradation products and the method was validated in the acceptance limits of ± 5 %. On D29, the mean percentages of the initial clonidine concentrations (+/–standard deviation) were 92.95+/–1.28 % in the solution stored at 25 °C +/– 2 °C and 97.44+/–1.21 % when stored at 5 °C +/– 3 °C. On D90, means were respectively 81.82+/–0.41 % and 93.66+/–0.71 %. The visual aspect did not change. Physical parameters remained stable during the study: pH varied from 4.94 to 5.09 and osmolality from 82 to 92 mOsm/kg in the two conditions tested here. Membrane filtration appeared to be the more sensitive method. Whatever the storage conditions,<1 micro-organism/mL was identified (only environmental) with no detected E.coli. Conclusions This formulation is stable for at least 3 months at 5 °C +/– 3 °C in amber glass bottles and for one month when stored at room temperature. Microbiological stability was proven in accordance with the European Pharmacopeia.