Optimizing Chlorthalidone Bioavailability through Advanced Co-Processing Techniques with Excipients

Abstract

Chlorthalidone, a widely used antihypertensive agent, presents significant challenges in formulation development due to its poor solubility and moderate permeability, which limit its bioavailability. This study aimed to enhance the physicochemical properties of Chlorthalidone through co-processing with selected excipients to improve its formulation efficiency and therapeutic performance. A series of preformulation studies, including solubility, partition coefficient, melting point determination, and micromeritic properties, were conducted to evaluate the suitability of Chlorthalidone for tablet formulation. Solubility tests in various media revealed that Chlorthalidone exhibits pH-dependent solubility, performing optimally in acidic environments. The partition coefficient (log P) of 1.9 confirmed moderate lipophilicity, further emphasizing the need for advanced formulation strategies to enhance bioavailability. Nine formulations (F1-F9) were prepared using excipients such as starch, sodium glycolate (SGG), xylitol, mannitol, and microcrystalline cellulose (MCC), and their micromeritic properties were analyzed. Among these, formulation F5 demonstrated the best flowability and compressibility, with a Hausner ratio of 0.82 and a Carr’s index of 11.00%, making it the most promising candidate for tablet production. Advanced co-processing techniques, including solid dispersion and hot-melt extrusion, were explored to improve Chlorthalidone's dissolution profile and overall bioavailability. The study concludes that strategic excipient selection and innovative formulation techniques offer promising pathways to optimize Chlorthalidone’s bioavailability, ensuring better therapeutic outcomes for patients.