Development and Optimization of a Biphasic-Release Acetazolamide Tablet-in-Tablet Formulation

High-altitude illness (HAI) poses health risks to individuals at high altitudes, and acetazolamide (ACZ) is the only Food and Drug Administration (FDA)-approved prophylactic drug. Conventional immediate-release (IR) tablets and extended-release (ER) capsules do not simultaneously provide early drug availability and prolonged coverage. This study aimed to develop a biphasic-release ACZ tablet-in-tablet (ACZ-TIT) formulation as a proof-of-concept oral dosage form integrating IR and ER.

ACZ-excipient compatibility was assessed using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD), and solubility was evaluated in physiologically relevant media. Formulation optimization was performed via single-factor studies and response surface methodology (RSM). Quality control included weight, hardness, friability, content, and related substances. In vitro dissolution studies were conducted, and drug release kinetics were analyzed using multiple models.

No new incompatibility signals were observed between ACZ and the selected excipients, and only small solubility differences were found across the tested media. ACZ-TIT showed a biphasic-release profile, with 25.3% drug release at 0.5 h and 86.5% at 10 h. Physical properties were within pharmacopeial limits (weight variation ≤ 2.65%, hardness 112.0 ± 21.2 N, friability 0.18%, and assay relative standard deviation < 1.2%), and the related substances were found to be within the specified limits. Release kinetics were best described by the Ritger-Peppas model (R² = 0.993), supporting diffusion-dominated ER.

ACZ-TIT may provide rapid initial release followed by sustained exposure, which could help address limitations of currently available ACZ dosage forms. In vivo pharmacokinetic and clinical studies are still required to establish clinical applicability.