Enhanced Stability of Ramipril in Nanoemulsion Containing Cremophor-EL: A Technical Note

Abstract

Nanoemulsions are thermodynamically stable, transparent (or translucent) dispersions of oil and water stabilized by an interfacial film of surfactant and co-surfactant molecules having the droplet size less than 100 nm (1–3). Thermodynamic stability of nanoemulsions offer advantages over unstable dispersions, such as emulsions and suspensions, because they can be manufactured with little energy input (heat or mixing) and have a long shelf life (4). Ramipril, a potent antihypertensive drug, is almost completely converted to its active metabolite ramiprilat by hydrolytic cleavage of the ester group in the liver which has about six times angiotensin-converting enzyme (ACE) inhibitor activity of ramipril (1). Ramipril and ramiprilat inhibit ACE and lowers blood pressure effectively (5,6). Formulation of ramipril dosage form leads to a decrease in the assay of ramipril due to mechanical stress, compression, manufacturing processes, excipients, storage conditions, heat, moisture, and alkaline pH (7–9). Since the drug is highly lipophilic (log p 3.32), it was presumed that keeping it in lipophilic environment might increase its stability. In our experiments, when nanoemulsion formulation of ramipril was prepared using distilled water as an aqueous phase, ramipril was found to be degraded as its concentration decreased rapidly. A stable formulation of ramipril was claimed by a patent in which the drug was mixed with a physiologically tolerated buffer that ensures that a pH in the weakly acidic to weakly alkaline range is set up in a pharmaceutical formulation in the presence of moisture (10). Therefore, the aim of the present study was to perform pH degradation studies using different standard buffer solutions official in Indian Pharmacopoeia (I.P. 1996) as an aqueous phase in order to improve stability of ramipril in nanoemulsion formulation. The dose of ramipril varies between 2.5 and 20 mg, and the frequently prescribed dose is 5 mg for the adult. Therefore, for the present study, 5 mg/ml dose was selected for the development of nanoemulsion formulation.