Enhancing Chemical Stability and Bioavailability of Aneratrigine Capsules via Dry Granulation: Addressing Stability Challenges in Sodium Bicarbonate-Containing Formulations for Clinical Development.

Abstract

<b>Background</b>: Aneratrigine, a potent selective Nav1.7 inhibitor, faced challenges in developing a clinically viable oral formulation due to its poor aqueous solubility in acidic gastric conditions (0.06 mg/mL at pH 1.2), leading to limited bioavailability in Phase 1 studies. <b>Methods:</b> To address this, a capsule formulation containing sodium bicarbonate (NaHCO₃) was developed to enhance dissolution via in situ pH modulation. However, production-scale wet granulation led to stability issues, such as capsule content discoloration and excessive degradant formation, attributed to NaHCO₃ decomposition under thermal and moisture stress. This raised the content pH and triggered degradation products not seen in initial compatibility tests. Consequently, dry granulation was adopted to minimize heat and moisture exposure. <b>Results:</b> The dry granulation process proved scalable, maintaining chemical integrity across laboratory (1.5 kg), pilot (5.4 kg), and commercial (25.9 kg) batches. The optimized formulation showed enhanced stability (total impurities < 0.05%) and improved dissolution (>80% at 30 min, pH 4.0). <b>Conclusions:</b> This work establishes a robust manufacturing platform that overcomes stability challenges in alkalizer-containing formulations, facilitating the successful advancement of aneratrigine to Phase 2a and providing a model for developing heat- and moisture-sensitive compounds.