QUALITY-BY-DESIGN-BASED DEVELOPMENT AND OPTIMIZATION OF WURSTER-COATED INDOMETHACIN EXTENDED-RELEASE PELLETS FOR MULTIPLE UNIT PELLET SYSTEM (MUPS) CAPSULES: IN VITRO CHARACTERIZATION AND COMPARATIVE DISSOLUTION EVALUATION

Abstract

Objective: the objective of the present investigation was to develop and optimize indomethacin extended release pellets for encapsulation into a multiple unit pellet system (MUPS) using a quality-by-design (QbD) approach. Extended-release pellets were prepared by Wurster fluid-bed coating employing ethyl cellulose as the rate-controlling polymer, with povidone and talc as formulation auxiliaries, to achieve a robust and reproducible sustained-release dosage form. Methods: An optimisation approach grounded in QbD and utilizing response surface methodology (RSM) was applied to analyse the effects of significant formulation variables on drug release characteristics. The independent factors for indomethacin release consisted of ethyl cellulose, povidone, and talc content. The formulations were meticulously characterized for their micromeritic properties, friability, drug content, and in vitro release performance and short term accelerated stability study. Results: The optimized indomethacin ER pellets filled into hard gelatin capsule (HGC) displayed a controlled release for a duration of 12 hours, effectively minimizing the initial burst and allowing for once-daily administration.  The optimized indomethacin ER pellets exhibited controlled release over 12 hours (97% at 12h), with dissolution comparable (f2 = 85, f1 = 3) to the marketed product (Indocap SR Tablets 75mg), meeting USP specifications in pH 6.2 phosphate buffer. The formulation demonstrated acceptable micromeritic properties (Carr's Index: 10.84) and stability under accelerated conditions (60±2°C for 28 days). Future investigations may include in vivo pharmacokinetic studies and stability assessments according to ICH guidelines to further confirm clinical importance and commercial viability. The f2 metric of dissolution data between test and reference product was found to be 85%, which shows similarity between test and reference products. Statistical analyses and response surface plots identified the content of ethyl cellulose of 8 mg per capsule, was found to be most critical material attribute for in vitro release of indomethacin. Conclusion: At 12 hours, the cumulative drug release reached 92–100%, fulfilling the sustained-release profile objectives. ANOVA confirmed a statistical significance (p = 0.0194). Factor effect screening demonstrated that ethyl cellulose (Factor A) exerted a statistically significant influence (p = 0.0065), whereas povidone K30 and talc exhibited negligible contributions.