Investigation of the Dissolution Characteristics of Nifedipine Extended-Release Formulations Using USP Apparatus 2 and a Novel Dissolution Apparatus

INTRODUCTION Nifedipine is a calcium-channel blocking agent that is widely used in the treatment of angina pectoris and systemic hypertension (1). The pharmacokinetics and pharmacodynamics of nifedipine have been investigated in numerous studies (2–4). Clinical experiences gained with oral nifedipine formulations with immediate-release (IR) characteristics clearly show that a steep rise in the drug plasma concentration results in an increase in heart rate and drug-specific side effects (5–7). Therefore, it has been generally accepted that extended-release (ER) formulations are most efficient for routine hypertension therapy with nifedipine. The ER dosage forms should primarily reduce the occurrence of steep rises in plasma concentration of the drug. Another important therapeutic goal that can be achieved with ER formulations is the improvement of chronic therapy compliance by prolongation of the dosing intervals. ABSTRACT The aim of our studies was to investigate the dissolution characteristics of six extended-release nifedipine tablets with a dosage strength of 20 mg that are marketed in the European Union. All investigated products were homogenous matrix tablets having identical dosing regimens. The products can be substituted for originator products and other ER generic formulations of the same drug load. In the present study, the formulations were tested using USP Apparatus 2 at 50 rpm, which is one of the standard conditions specified by the USP for nifedipine ER tablets. Moreover, investigations under intensified stress conditions were performed with Apparatus 2 at 100 rpm, as well as in a novel biorelevant dissolution stress-test device. A complementary characterization of the integrity of the tablet matrices was performed using a standard disintegration test apparatus. In the applied experimental settings, drug dissolution from all tested formulations proceeded very fast with liberation of at least 15 mg of drug within the first two hours of analysis. The increase in stirring rate from 50 to 100 rpm in Apparatus 2 did not substantially accelerate the dissolution process. Moreover, it was noticed that the tablet matrices had poor mechanical stability and very rapid disintegration behavior under all experimental settings. The disintegration times measured in the standard disintegration test were less than 10 min. The results clearly show that the dissolution characteristics of all tested products are a function of the properties of the drug substance and not the dosage forms. It became obvious that none of the tested formulations fulfilled USP requirements for nifedipine ER tablets specified for Apparatus 2 at 50 rpm. However, the products are marketed in the European Union where the USP quality criteria are not mandatory but only advisable. In our interpretation, such dissolution characteristics bear a potential risk of dosage-form-related interactions in vivo.