ABSTRACT:
Background: Migraine attacks frequently show circadian variation, and conventional immediate-release oral dosage forms may not provide drug exposure at the most therapeutically relevant time. Rimegepant, a calcitonin gene-related peptide (CGRP) receptor antagonist, is an effective agent for acute and preventive migraine therapy; however, a programmed oral delivery system may improve chronotherapeutic targeting. Objective: This study aimed to formulate, optimize and evaluate rimegepant pulsatile tablets designed to provide a defined lag phase followed by rapid drug release. Methods: Tablets were prepared by direct compression using microcrystalline cellulose, lactose, crospovidone, hydroxypropyl methylcellulose (HPMC), ethyl cellulose, magnesium stearate and talc. A two-factor, three-level experimental design was applied to evaluate the influence of crospovidone and HPMC concentrations on disintegration/lag time and percent drug release. Preformulation studies, UV spectrophotometric analysis, FTIR, DSC, precompression evaluation, post-compression testing, in vitro dissolution and accelerated stability studies were performed. Results: Rimegepant showed acceptable organoleptic properties, a melting range of 150-153 °C and maximum absorbance at 260 nm. FTIR and DSC results indicated the absence of major drug-excipient incompatibility. The prepared batches exhibited disintegration/lag times ranging from 49 to 80 min and drug release from 70% to 91%. The optimized formulation F9, containing 24 mg crospovidone, 25 mg HPMC and 39 mg ethyl cellulose, showed thickness of 2.4 mm, hardness of 2.9 kg/cm², friability of 0.40%, drug content of 99.2%, disintegration/lag time of 49 min and drug release of 91%. After 3 months of accelerated stability testing, F9 retained 98.3% drug content and 88% drug release. Conclusion: The optimized rimegepant pulsatile tablet demonstrated satisfactory pharmaceutical quality, improved release performance and short-term stability, indicating its potential for further development as a chronotherapeutic system for migraine management.