Synthesis of novel double-ester polymeric drugs ; automated methods in preformulation development
Ware, Emily Childrey
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The purpose of part I was to synthesize novel polymeric drug conjugates by combining several orthoesters with N-[2-(hydroxypropyl)-methacrylamide] (HPMA), an analogue for methacrylamide (MA) bound anti-cancer drugs and MA bound targeting moieties, for targetable anti-cancer therapy. HPMA was reacted with various orthoesters in 1:4:2 molar ratios under basic conditions using the Michael addition reaction mechanism. Reaction progress was monitored with thin layer chromatography. No successful addition occurred due to amide delocalization of HPMA competing with enolate ion formation. Acetic anhydride protecting groups were placed on the hydroxyl hydrogen of HPMA to try to prevent this occurrence. HPMA was successfully modified and analyzed via H1NMR and LCMS, however the Michael addition reaction with orthoesters did not go to completion and byproducts together with leftover reactants made separation and purification difficult. The purpose of part II was to establish an automated approach to salt selection and preformulation development for a large number of Trazodone salts. Automated procedures were developed on a Biomek 2000 automation workstation with stacker and plate reader capabilities. Trazodone was dispensed into 96 well plates and an automated method was setup to form 104 Trazodone salts. Salts were observed under a polarized light microscope to determine crystallinity. After stepwise eliminations, the remaining salts were scaled-up and subjected to differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD) and hygroscopic, pH-solubility, density, surface area and particle size analyses. Oils formed in several cases resulting in the preliminary elimination of mesyl and esyl salts and 4 crystallizing solvents. Crystallinity was observed in 34 of the 44 scaled-up Trazodone salts. Analyses indicated a number of new salts, which were comparable in physicochemical parameters to the marketed HCl salt. Among them, the tosylate salt showed its uniqueness for new applications due to low solubility throughout the entire pH range making it a good candidate for a suspension or prolonged action formulation compared to the other salts. In addition, a thermally induced polymorph of the tosylate salt may be present with different properties than the tosylate salt. Automated procedures can be developed to increase the efficiency for pharmaceutical salt selection.