Abstract

QUALITY DESIGN OF TABLET FORMULATION OF ENANTIOPURE AMLODIPINE BESYLATE IN RELATION TO ICH Q8 GUIDELINES

Silvia Kocova El-Arini*

ABSTRACT

As a consequence of the FDA regulations regarding chiral switch, numerous active pharmaceutical ingredients (API’s) originally marketed as racemic molecules are reaching the market as single active enantiomers. But because the enantiopure counterparts of chiral drugs represent new entities, lack of science-based quality design can lead to failed product and thus the advantage of using the active enantiomer will be lost. In this study the guidelines of ICH Q8 were implemented for quality design of pharmaceutical dosage form of the active enantiomer of amlodipine besylate by analyzing the critical properties and drug-excipients interactions which are relevant to the development of the formulation and the selection of the manufacturing process. To insure that chiral inversion did not occur during the development process or upon exposure to stressed conditions the HPLC method was adopted using specific chiral column. It was found that the enantiopure amlodipine besylate (S-AB) was not stable in multicomponent mixtures with acidic excipients although they are components of the marketed dosage form of the racemic drug. Therefore understanding the solid-state interactions of acid-sensitive API, such as S-AB with excipients of high surface acidity is of primary importance in preventing incompatibility during the formulation development process. The difference in drug-excipient interactions between the racemic and the enantiopure amlodipine besylate requires rigorous control of the components of the formulation design space in order to obtain dissolution profiles with good similarity factors.

Keywords: ICH Q8 guidelines, formulation design space, S-amlodipine besylate, drug-excipient interactions, surface acidity, dissolution profile, chiral inversion.