Differences in In Vitro Dissolution Rates Using Single-Point and Multi-Point Sampling

Abstract

INTRODUCTION In vitro dissolution testing is an important physicochemical tool used to measure drug release rates during both early and late stages of drug development. In both cases, a product-specific discriminating dissolution method is utilized as a quality control tool to evaluate batch-to-batch consistency and as a predictive means to gain a post-market bio-waiver in cases where there is in vitro–in vivo correlation or in vitro–in vivo relation. Developing rugged methods with appropriate discriminatory dissolution parameters is often a challenging objective regardless of the solubility of the compounds. Method development is further challenged when hydrodynamic effects within the vessel (1–4) impact method ruggedness. The hydrodynamic environment within the vessel can be affected by many variables including the position of the tablet (5, 6) and the presence and position of a measuring (7) or sampling probe (8). Thus, for poorly soluble drugs, it is challenging to develop an appropriate dissolution method that is rugged, discriminating, and maintains sufficient sink conditions. While implementing a dissolution method in a manufacturing quality control (QC) laboratory, we encountered a unique method ruggedness issue. Previously, we successfully transferred the validated discriminating dissolution method from our R&D facility to both a stability laboratory and a manufacturing QC laboratory. However, during the manufacturing validation campaign, several tablet batches exhibited slower dissolution rates in the QC laboratory when compared with the historical dissolution rates generated in the R&D and stability laboratories. Several of the process validation batches were at risk of proposed specification failure, which had required Stage II (S2) testing. An investigation was initiated to determine if the root cause of the low results was due to a method robustness or product quality issue. The drug product that exhibited this behavior was prepared using a BCS class II (low solubility and high permeability) compound in which dissolution was the Differences in In Vitro Dissolution Rates Using Single-Point and Multi-Point Sampling