Dissolution Testing of a Controlled-Release Capsule Formulation: Challenges and Solutions Using a Semi-Automated Dissolution System

Abstract

A controlled-release formulation was developed using enteric-coated beads in a hard gelatin capsule shell. This formulation requires two-stage dissolution testing at low and neutral pH. Because of high toxicity and limited stability of the active pharmaceutical ingredient in aqueous solution at room temperature, it is preferable to limit the analyst’s contact with the sample solutions during testing, and aliquots from the dissolution vessel need to be quickly filtered and refrigerated immediately after sampling. To meet these challenges, a semi-automated dissolution method was developed and validated. Dissolution samples are withdrawn and filtered into vials in the HPLC sample compartment where the temperature is controlled at 4 °C. A fast HPLC method was developed with a 3-min run per injection, enabling analysis of the samples within a very short time after collection, thereby decreasing the sample storage time and potential for degradation. An evaluation was also conducted for comparison of serial and parallel operation of two dissolution baths for the two-stage testing. Serial operation was chosen for this method and applied with a medium-exchange technique, which is safe, robust, easy to perform, compliant with USP, and gives enhanced productivity. INTRODUCTION Enteric coating is a widely used technique for controlled-release oral formulation of pharmaceutical products, specifically for delayed release (1). The formulation purposely limits drug release in the stomach, but facilitates release in the neutral environment of the intestine. It enables protection of the drug from the acidic gastric fluid to prevent possible degradation, as well as protection of the stomach from the drug to avoid possible irritation and adverse effects. The enteric materials are usually applied to substrates like tablets, pellets, or beads. The coated pellets and beads are further filled into a capsule shell (2–5). During development of an oncology drug at BristolMyers Squibb, the technology of coating on beads was applied to make a controlled-release capsule formulation. The physiochemical properties of this drug posed significant challenges for the formulation development, especially its instability in various conditions including (1) in an aqueous acidic environment,( 2) during the process of granulation, and (3) when in contact with enteric coating materials. To overcome these challenges, the enteric-coated beads were developed with multiple different coating layers. This formulation uses sugar spheres as the core substrate. The first coating layer on the sphere is a mixture of the drug and excipient. The second layer coating is an Opadry film that prevents drug from contacting the next layer, the final enteric coating. After the final enteric coating is applied, the beads are filled into a hard gelatin capsule shell (Figure 1). The various dosage strengths of the capsules are made using different fill weights. Evaluation of enteric-coated beads has been performed in both gastric and intestinal media (5, 6). A two-stage dissolution test is specified in USP General Chapter Dissolution (7), in which the integrity of the enteric coating is determined in an acidic environment and the drug release is measured in a neutral environment. The test can be performed using either medium-addition or mediumexchange methods; both start with an acid stage in 0.1 N hydrochloric acid for two hours and follow with a buffer stage in phosphate buffer at pH 6.8 for 45 min or a specific time as needed for the individual drug product. The quality of the dosage form is ensured by meeting USP accep*Corresponding author. e-mail: xujin.lu@bms.com Figure 1. Enteric-coated beads for controlled-release formulation. dx.doi.org/10.14227/DT200213P6