The aim of this study was to compare the specific characteristics of the S-enantiomer and the racemate of amlodipine besylate (AB) in order to design a robust and stable formulation of the active S-enantiomer which will guarantee continuous performance of the unichiral version of amlodipine. Preformulation studies showed that the S-enantiomer and the racemate exhibit different crystal morphology, particle size distribution and higroscopicity. The S-enantiomer exhibited significantly lower melting temperature compared to the racemate which was in accordance with its higher water solubility and its increased intrinsic dissolution rate. The thermograms of S-amlodipine besylate indicated that dehydration and melting occur at almost the same time and the dehydration event overlaps with the melting peak. Forced degradation tests conducted on both substances showed high levels of degradation into amlodipine related substance D as well as other impurities. Tablets prepared with S-AB, simulating originator's formulation, failed in stability tests due to drug incompatibility with calcium hydrogen phosphate. Therefore, a tablet formulation based on excipients which were confirmed compatible with S-AB was developed and optimized using full factorial design to obtain a dissolution profile comparative to the brand product. Stability studies conducted at 40 °C/75% relative humidity (RH) confirmed that appearance, drug content and drug release of the optimized tablet formulation remained within the recommended limits.