Formulation and Optimization of Ramipril-Hydrochlorothiazide Bilayer Tablets for Sequential Release Using Factorial Design

Abstract

A bilayer tablet combining a rapid‑release segment of ramipril (5 mg) with a sustained‑release segment of hydrochlorothiazide (12.5 mg) was developed to improve hypertension management. A 3² full‑factorial design was employed, varying the total polymer content (HPMC K4M + HPMC K100M) in the sustained‑release layer (22.22–38.89 %) and the amount of croscarmellose sodium in the immediate‑release layer (3.33–10 %). Pre‑formulation studies confirmed the identity and purity of both drugs (FTIR peaks at 3420 cm⁻¹ and 1740 cm⁻¹ for ramipril; 3360 cm⁻¹ and 1340 cm⁻¹ for hydrochlorothiazide) and showed no significant interaction with the selected excipients. Powder blends exhibited acceptable flow properties (Carr’s index 17–23 %, angle of repose 27–32°). All tablets met compendial specifications for weight (299–301 mg), hardness (6.2–7.2 kg·cm⁻²), friability (<1 %) and drug content (98–101 %). In vitro release demonstrated >85 % ramipril release within 30 min, with formulation F9 achieving 99.6 % in 20 min. Hydrochlorothiazide release extended over 12 h, ranging from >94 % at 10 h (F1–F3) to ~80 % at 12 h (F7–F9). Release kinetics best fitted the Korsmeyer‑Peppas model (R² > 0.99, n = 0.50–0.68), indicating a combined diffusion‑swelling mechanism. Formulation F5 (30.56 % polymer, 6.67 % disintegrant) was identified as optimal, showing a disintegration time of 9.4 min, swelling of 168 % at 8 h, and stability for three months under accelerated conditions (40 °C/75 % RH, f₂ > 94). The results demonstrate that increasing disintegrant levels accelerates ramipril release, while higher polymer concentrations sustain hydrochlorothiazide delivery, providing a convenient once‑daily antihypertensive therapy.

Keywords: bilayer tablet, ramipril, hydrochlorothiazide, immediate release, sustained release, HPMC, croscarmellose sodium, factorial design, dissolution kinetics, stability.