Process development to overcome drug substance agglomeration and restore dissolution performance

Dissolution testing is performed to understand the rate and extent of drug release for assurance of in vivo bioavailability. In this case study, an immediate-release tablet of an investigational BCS Class II compound exhibited slow and incomplete dissolution at pH 4.5 and 6.8, indicating a risk of reduced exposure in patients with elevated gastric pH. To diagnose and remediate the issue, we evaluated three factors: (1) drug substance particle size (milled versus unmilled), (2) formulation wettability via incorporation of a surfactant alongside water-soluble versus insoluble fillers, and (3) shear mixing of the powder blend. Dissolution profiles for tablets containing milled and unmilled drug were comparable, and the addition of a surfactant did not improve performance. Subsequent investigation identified presence of drug agglomerates as the root cause of slow dissolution. Introducing a simple shear deagglomeration step as a pre-blend step markedly enhanced dissolution, allowing the clinical formulation composition to be retained and avoiding re-formulation and associated timeline impacts.