D. R. Lu1 , E. C. Ware2 , 1ONDQA, CDER, FDA, 2University of Georgia
Background: The objective of this work was to implement an automated robotic approach to screen a large number of pharmaceutical salts using Biomek robotic workstation. The work represented the early attempt to use a high-throughput approach to preformulation studies.
Methods: Automation of Trazodone salt formation on Biomek workstation was performed using eight different crystallizing solvents and 13 different acids. A control program was set up to generate 104 Trazodone salts. The salts were observed under a polarized light microscope to determine crystallinity. After stepwise eliminations, the remaining salts were scaled-up for differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), hygroscopic, pH-solubility, density, surface area, and particle size analyses.
Results: Oils formed in several cases resulted in preliminary elimination of mesyl and esyl salts and four crystallizing solvents. Crystallinity was observed in 34 of 44 scaled-up Trazodone salts. PXRD, DSC, and hygroscopic analyses indicated a number of new salts that were comparable in physicochemical parameters to the reference HCl salt. Among the new Trazodone salts, the most interesting profile was from tosylate salt with a low solubility throughout the entire pH range. The solubility values range from 3 mg/mL at pH 1 to 0.2 mg/mL at pH 12.
Conclusions: The new tosylate salt gave a unique pH-solubility profile with low solubility over the entire pH range making it a potential candidate for a suspension or prolonged-action formulation. The high-throughput robotic process demonstrates its capability to increase the efficiency of pharmaceutical salt selection.