Trimetazidine HCl is the first cytoprotective anti-ischemic agent which, in contrast to classical antanginal drugs, is effective to ward off heart attack by enhancing the heart’s energy producing function rather than weakening the heart act. Clopidogrel bisulfate plays a central role as a platelet inhibitor in acute coronary syndromes, interventional cardiology and in secondary prevention of ischemic events in patients with myocardial infarction. The aim of this work was to develop a sustained release formulation of trimetazidine hydrochloride microspheres and immediate release formulation of clopidogrel bisulphate layer–tablet which were planned to be used for future preparation of bilayer tablets of the two drugs. Trimetazidine HCl microspheres were prepared by the emulsification-solvent evaporation technique using ethyl cellulose as retardant polymer at different drug: polymer ratio while clopidogrel layer-tablet was prepared and optimized by using different concentrations of crospovidone as disintegrant by direct compression method using a compression force of 15 kg/cm2 while. The 1:2 drug: polymer microspheres formulation showed the highest entrapment efficiency and production yield and a sustained drug release for up to 12 hr. On the other hand, the clopidogrel layer-tablet formulation containing 4% crospovidone showed the highest rate and extent of drug release.