Purpose: To study drug release rates during in-vitro self-emulsification process for systems containing the weak acid ibuprofen as a function of the aqueous medium pH
Methods: Microemulsion anhydrous pre-concentrate formulations were prepared by dissolving using ibuprofen (10 mg and 40 mg) in 100 mg of peppermint oil and 400 mg of a surfactant mixture of Kolliphor PS 80 and Kolliphor EL (4:1 w/w). Each pre-concentrate formulation was introduced into of aqueous buffer solutions (pH 2 and pH 7, each at 23 and 37C) with moderate stirring to form microemulsions by self-emulsification. The total mixture volume was 100 mL. Simultaneously, the free drug concentration in the aqueous phase of the mixture was measured as a function of time using dynamic PMD.
Dynamic PMD was performed by immersing probes in the mixture of pre-concentration plus aqueous buffer. Phosphate buffer (10mM) at pH 7 was pumped through the PMD probes as the dialysate medium. After starting PMD sampling, the pre-concentrate was added to the buffer to begin the self-emulsification. PMD samples were taken every 12 seconds (8 seconds resting time + 4 seconds pumping time) for the first 2 minutes, then every minute for 3 minutes, then every two minutes for 6 minutes. The PMD probe window volume was 2.85 µL, the flush rate was 150 µL /min, the resting time was 8 seconds, and the volume of each collected PMD sample 10 µL. The free drug concentration CD,f was calculated from the equation Cs/FR where Cs was the experimental value of the sample and value of FR which was derived from previously performed dynamic probe calibration experiments. The values of FR taken for these experiments were 0.0428 for 23C and 0.0615 for 37C.
Results: The results of the PMD data are shown in the figures. During self-emulsifying, the dissolved drug fraction rose rapidly then plateaued, reaching approximately 10% in the first 1-2 minutes (Figure 1), while it reached nearly 85% in the first 1-2 minutes with pH 7 buffer (Figure 2). In all cases, the percentage drug release from microemulsion pre-concentrate to bulk aqueous media was found to be only 10 – 20 % at pH 2, but was 70 – 80 % at pH 7. This was attributed to the ibuprofen solubility, which is a weak acid (pKa ~ 4.5) and hence more soluble in the aqueous phase at pH 7 than at pH 2.
Conclusion: It was anticipated that the self-microemulsion process will be very rapid, but the time to occur the process has never been measured. Through the measurement of free drug concentration by dynamic PMD technique, how fast these rates were determined. It is projected that this information can be potentially important for formulating both topical and oral delivery systems and can provide new insight in dosage form design.