Direct compression tablet formulation of trimetazidine through systematic screening of oxalate salts

Salt formation has been extensively used to modulate and improve the properties of active pharmaceutical ingredients (API), such as solubility, stability and mechanical properties. Tablets of the anti-angina drug, trimetazidine (TMZ) are currently manufactured using the wet granulation process, rather than the more cost-effective direct compression method. In an effort to address the two main challenges associated with the commercial dihydrochloride salt (TMZ-2HCl), i.e., poor flowability and high hygroscopicity, we have screened and prepared three new oxalate (Oxa) salts of TMZ, i.e., TMZ:Oxa 2:1 (hemi-salt), 1:1 (mono-salt), and 1:2 (di-salt). All of the three salts exhibited improved solid-state properties over TMZ-2HCl, including flow, tabletability, and stability against high humidity. Among the three salts, the TMZ-Oxa (1:2) di-salt demonstrates overall superior properties, establishing it as the most promising alternative crystal form. Consequently, using the di-salt, we developed a direct compression tablet formulation that shows potential for commercial manufacturing.