A selective RP-HPLC method for separation and determination of potential related impurities (starting materials and by-products of synthesis, and degradants) of apremilast drug substance has been developed and validated. The separation was accomplished on a Cosmosil C-18 (250 mm × 4.6 mm, 5 μm) column connected to a photodiode array (PDA) detector using optimized mixture of 0.05% trifluoroacetic acid, methanol and acetonitrile under gradient elution. Two major degradant impurities found in force degradation study of apremilast drug substance. Both degradants were characterized preliminarily by HPLC-MS studies and synthesized in laboratory. Structure was evidenced by NMR spectroscopy, mass spectrometry and FT-IR. HPLC method was developed for quantification of the synthesized impurities along with starting materials. This method can be used for the quality control testing of drug substance. The performance of the method was validated according to the ICH guide lines for specificity, limit of detection, limit of quantification, linearity, accuracy, precision, ruggedness and robustness.