Development of a Self-Emulsifying Lipid Based Formulation Using Clotrimazole as Model Compound M. Piest, A. Bernaerts, K. Rousou, M. V. Baest Patheon Inc. Purpose Goal is to demonstrate that our standard Lipid Based Formulation approach can be used to develop a SEDDS. Clotrimazole has poor aqueous solubility of 29.84 μg/ml and high log P of 6.1 [www.DrugBank.ca] and was selected as model drug. Methods Solubility of Clotrimazole was determined by UHPLC in >20 excipients covering medium and long chain triglycerides, lipid surfactants, and non-lipid cosolvents. Lead formulations were evaluated for aqueous dispersion by addition of 2 g formulation to 400 ml Simulated Gastric Fluid (SGF) in dissolution apparatus with Paddle at 37°C and 100 rpm. Duplicate samples were taken after 60 minutes and assayed by UHPLC. Lipid digestion screening was performed according to lipid digestion studies following the procedure described by the Lipid Formulation Classification System Consortium. In short 1 g lipid formulation is digested by pancreatin at pH 6.5 using a Metrohm Titrando to perform a pH-stat titration. Samples were collected after 0, 15, 30, 45, and 60 minutes, respectively. After adding the enzyme inhibitor to stop the digestion, samples are centrifuged at 14,000 rpm for 30 minutes at 37°C. Next, supernatant is collected for analysis by UHPLC and the 60 minute sample is analyzed by DLS. Results Capryol 90 was selected as main excipient as solubility of Clotrimazole was highest (15.26 ± 1.32 % w/w at 37°C after an excursion to 65°C for 24 hours). Labrasol was selected as a lipid surfactant. Next, different co-surfactants and stabilizers were investigated. Up to 24 prototype formulations were prepared by mixing excipients with Clotrimazole, heated to 80°C until dissolved. Addition of Phosal and Povidone were found to further increase the solubility to the target value of 20% w/w in the vehicle upon activation with a small amount of water. Five prototype formulations showed complete solubility at target 20% w/w concentration, also after three repeated freeze-thaw cycles. These were evaluated for aqueous dispersion in SGF and good recoveries of 80-85% were found by UHPLC assay for Clotrimazole after centrifugation. Formulations were subjected to lipid digestion studies to verify whether a stable emulsion could be formed under digestive intestinal conditions. Recoveries of Clotrimazole was again determined by UHPLC analysis after centrifugation and were found to be less than 7% after 60 minutes of lipid digestion. DLS results were poor due to sedimentation of the samples during analysis. Conclusion Clotrimazole is an antifungal, typically dosed as vaginal tablet or oral lozenge or topical cream, but Clotrimazole can also be used as a potential antimalarial drug. When administered orally Clotrimazole exhibited poor and erratic absorption from the gastrointestinal tract [Int. J. of Pharm., (2012), 431, 149–160]. We have developed five physically stable lipid based formulations containing ca 20% w/w of Clotrimazole. These formulations formed micro-emulsions upon aqueous dilution in SGF improving aqueous solubility suggesting that all five formulations can solubilize Clotrimazole in the gastric compartment. However, during lipid digestion at pH 6.5 aqueous solubility was reduced as the pKa of Clotrimazole is 6.62. This is suggesting that the drug will precipitate in the intestines as digestion takes place, which in turn may explain the variation in bioavailability observed in clinical studies. Thus we have demonstrated that tools such as lipid digestion and solubility in bio-relevant media are essential screening tools for lipid formulations and could provide additional insights to specific behavior of compounds in vivo.