Optimization and Characterization of Chlorthalidone Bilayer Tablets for Chronotherapeutic Pulsatile Drug Release

Pulsatile Drug Delivery System (PDDS) is defined as the rapid and transient release of drug molecules within a short time period immediately after a predetermined lag (off release) period. Blood pressure exhibits a well-documented circadian surge in the early morning hours — a window associated with peak cardiovascular morbidity. Chlorthalidone, a BCS Type-II thiazide-like diuretic with a plasma half-life of 40–60 hours, was selected as the model drug for a chronopharmacological pulsatile formulation. Nine bilayer press-coated tablet formulations (CHT-A through CHT-I) were prepared using Hydroxypropyl Methylcellulose K100M (HPMC) as the hydrophilic swelling polymer and Ethyl Cellulose (EC) as the hydrophobic rupturable membrane at varying weight ratios. Preformulation studies — including ATR-IR spectroscopy, Differential Scanning Calorimetry (DSC), and powder flow characterization — confirmed drug identity, thermal behaviour, and excipient compatibility. Scanning Electron Microscopy (SEM) was employed to characterize surface morphology. The core tablet exhibited a disintegration time of 185 seconds and 95.8% drug content. Formulation CHT-G (HPMC 150 mg: EC 250 mg) demonstrated the optimal 6-hour lag time followed by a burst release of 83.20% at hour 7. Korsmeyer-Peppas modelling (R² = 0.8545; n = 2.2082) identified super case-II swelling-controlled transport as the dominant release mechanism. The developed system offers a clinically promising chronopharmacological strategy for the management of morning-surge hypertension.