Design and development of a delayed-release dose-flexible matrix tablet of tolfenamic acid for potential application in cancer therapy.
Abstract
Tolfenamic acid (TFA), a Biopharmaceutics Classification System (BCS) class II drug, exhibits dissolution-limited absorption and significant gastric irritation when administered as conventional immediate-release formulations, limiting its potential for high-dose and long-term applications, including emerging anticancer indications. The present study aimed to develop a delayed-release, dose-flexible matrix tablet of TFA using enteric polymers incorporated directly into the tablet matrix, eliminating the need for external enteric coating. A 2 × 3 factorial formulation screening design was employed to systematically evaluate the influence of enteric polymers (HPMC-AS, Eudragit S100, and cellulose acetate phthalate) and diluent/binder (microcrystalline cellulose, spray-dried mannitol, and lactose monohydrate) on acid resistance and buffer-stage drug release. Tablets were prepared by wet granulation and characterized for physicochemical properties, solid-state stability, surface morphology, chemical uniformity, assay, presence of impurities, disintegration, and two-stage dissolution performance. The optimized formulation maintained complete integrity in an acidic medium for 2 h with no drug release and achieved > 96% drug release in phosphate buffer (pH 8.2) in 3 h, meeting USP dissolution criteria. Solid-state analysis confirmed preservation of the crystalline form and the absence of drug-excipient incompatibility, while stability studies under accelerated and intermediate conditions demonstrated maintained physicochemical integrity and release performance. The developed matrix system provides a cost-effective and process-efficient alternative to conventional enteric coating and supports modular dose adjustment within a single strength, offering a promising platform for delayed-release, dose-flexible oral therapy suitable for combination regimens and personalized cancer treatment strategies.