Storage stability of chocolate –based CDS formulations of midazolam and tramadol

INTRODUCTION Midazolam and tramadol are bitter drugs that are difficult to taste mask, which then leads to administrative difficulties in paediatric hospitals. We have developed a chewable chocolate-based delivery system (CDS) that provides palatable oral formulations of midazolam and tramadol with non-inferior bioavailability compared to standard of care products.1,2 This study aimed to determine the storage stability of the tramadol and midazolam CDS formulations, as tablets and oral liquids. METHOD CDS tablets of midazolam HCl (5 mg) and tramadol HCl (11.3 mg) were stored at ambient and refrigerated (4-8°C) temperatures as tablets or as oral liquids, which were prepared by melting the CDS tablets in hot water (2 ml per tablet) and adding compound hydroxybenzoate solution APF (1% v/v). Samples were analysed for drug content via high performance liquid chromatography on the date of manufacture, and on specified storage time points for up to 18 months for tablets and 70 days for oral liquids. In vitro drug release into 0.1 M HCl was also determined for the tablets, while the oral liquids were monitored for pH changes. Accelerated stability tests were conducted on midazolam and tramadol CDS tablets cut into quarter size and stored at 40°C. RESULTS CDS tablets of midazolam and tramadol were stable for up to 18 months storage at ambient temperature, with both types of tablets having residual drug content within 90-110% of the initial amount (Table 1). At all storage time points, the CDS tablets showed at least 80% cumulative drug release after 20 min in 0.1M HCl. When cut into quarter tablets and stored for 3 months at 40°C, the residual drug content was 103% and 92% for the midazolam and tramadol CDS tablets, respectively. Oral liquids stored at 4 - 8°C were stable for at least 70 days with regards to odour, pH and drug content (Figure 1), but the liquids were unstable to storage at ambient temperatures for >7 days, as indicated by a drop in pH and unpleasant odour. CONCLUSION The chocolate-based CDS tablet platform is stable for at least 18 months at ambient temperature when loaded with midazolam or tramadol. When transformed into the respective oral liquids by melting in water and adding an appropriate preservative, the CDS formulations are stable for at least 2 months when refrigerated, with no deterioration in drug content detected.