Overcoming Unpleasant Taste of Metformin Hydrochloride by Cold Extrusion/Spheronization Employing Solid Lipid Binders Gustavo F. Petrovick, Miriam Pein-Hackelbusch, Jörg Breitkreutz PSSRC Pharmaceutical Solid State Research Cluster Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University, Düsseldorf, Germany  +49 211 8114116  Gustavo.Petrovick@uni-duesseldorf.de INTRODUCTION Metformin hydrochloride is used in the treatment of type II diabetes mellitus. Tablet sizes and extreme bitter taste of this API, especially when tablets are splitted or crushed, have a negative impact on patient compliance. Solid lipids as excipients for oral dosage forms have advantages of lack of toxicity and good taste-masking attributes. Therefore, in the present study, a recently improved extrusion/spheronization method employing solid lipids should be applied to produce taste-masked pellets containing high drug loads of metformin HCl. RESULTS AND DISCUSSION A linearity range was observed for all sensors (fig. 1), beginning at concentrations of 0.50 mg·ml-1 until higher concentrations, indicating good sensor sensitivity towards metformin. A principal component analysis (PCA) was performed using the sensor responses for the formulations F1-F3 and F4-F6, separately. The PCA map for the pellets containing only hard fat as binder is depicted in fig. 2a. and for the pellets based on the ternary mixture in fig. 2b. Considering the first principal component (PC1), which contains most of tnses MATERIALS AND METHODS Extrusion of hard fat (Witocan® 42/44), ternary solid lipid mixtures containing 50-80% of metformin HCl (Table 1), and a drug-free control formulation (placebo) were performed using a co-rotating twin-screw extruder (Mikro 27GL-28D, Leistritz) at 33 °C (feed rate: 40 g·min-1, screw speed: 50 rpm, die plate: 91 dies with 0.5 mm in diameter and 1.35 mm length). Batches of 300 g extrudates were rounded using a spheronizer (RM 300, Schlüter), for 15.min at 1,500.rpm. The jacket temperature was set to 30 °C. Additionally, an IR light was used to heat the materials surface until 33 °C according to [1]. Taste-masking assessment of the pellets was performed using the Insent taste sensing system TS-5000Z. performedllets Fig. 1. Sensor responses to metformin hydrochloride which contains most of the information, the pellets F2, F3, F5 and F6 showed more similar responses to the drug-free formulation than to pure API, indicating an improvement on their taste-masking properties. As expected, samples, which released metformin over 60 s were located more closely to the pure API than those r …. more closely to pure API than those released over only 30 s due to a higher drug release at this time. Likewise, the higher the amount of lipids, the better the taste-masking properties toward metformin´s bitter taste. To allow a visual differentiation of all formulations, Euclidean distance was calculated and converted to % (fig. 3). The distance between pure API and the Placebo was considered as maximum taste change (from unpleasant to pleasant taste response). The pellets based on hard fat only (F1-F3) present a similar taste-masking pattern compared to pellets with the ternary lipid mixtures (F4-F6): the higher the amount of lipids, the better the taste-masked properties. A Table 1. Investigated formulations [%] F1 F2 F3 F4 F5 F6 Placebo Metformin HCl 80 70 50 - Witocan 42/44 20 30 15 22.5 37.5 100 Dynasan 114 2.5 3.75 6.25 Precirol ATO 5 B The used sensors are shown in Table 2. Measurement setup was performed according to [2]. API solutions (0.01 to 15 mg·ml-1) were analyzed prior to measurement for electronic tongue calibration. Pellets amount containing 500.mg metformin HCl were stirred in a glass beaker with 100 mL purified water at 37.°C. After 30 and 60 s the samples were filtered under pressure and measured. Fig. 2. PCA map for the pellets (A) F1 to F3 and (B) F4 to F6, containing the information of all 7 sensors, data was centered scaled Table 2: Electronic tongue set of sensors Sensor Corresponding taste sensation SB2AAE Umami SB2CT0 Saltiness SB2CA0 Sourness SB2AE1 Astringency SB2AC0 Bitterness of cationic substances SB2AN0 Bitterness of cationic or neutral substances SB2C00 Bitterness of anionic substances REFERENCES [1] Petrovick, G.F., et al., Eur J Pharm Biopharm 2015, 92, 15-21 [2] Woertz, K., et al., J Pharm Biomed Anal 2010, 51, 497-506 [3] Petrovick, G.F., et al., Int J Pharm 2016, 506, 361-370 Fig. 3. Euclidean distances to the drug-free pellet CONCLUSION Results of an electronic tongue evaluation proved that the investigated extrusion/spheronization technique employing solid lipid was suitable to overcome the unpleasant taste of metformin HCl producing taste-masked lipid pellets containing high drug load of this API. III ABCF Congress – 2016 – Porto Alegre, Brazil