Zoomlab™-Guided Co-crystal Engineering of Nilotinib for Improved Dissolution

Abstract

Nilotinib (NH), a second-generation tyrosine kinase inhibitor for chronic myelogenous leukemia (CML), exhibits poor aqueous solubility and low intestinal permeability, classifying it as a Biopharmaceutics Classification System (BCS) Class IV drug. This study aimed to enhance NH solubility and dissolution through co-crystallization, guided by computational and experimental approaches. BASF's ZoomLab™ platform was utilized for rational coformer selection using the solubility parameter difference (Δδv) method. Validation with paracetamol and posaconazole datasets established 5 MPa0.5 as the optimal Δδv threshold. Pyroglutamic acid (PG) emerged as the most suitable coformer and was co-crystallized with NH via liquid-assisted grinding (LAG). Solid-state characterization (PXRD, DSC, FTIR, SEM) confirmed formation of Nilotinib-Pyroglutamic acid co-crystal (NH-PGCC). The co-crystal displayed significantly improved wettability and a 3.23-fold increase in solubility in 0.1 N HCl compared to pure NH. Although rapid phase transformation occurred within 3 minutes, PEG 6K stabilized the supersaturated state, improving dissolution. The optimized NH-PGCC capsule achieved 75% drug release in 15 minutes, significantly outperforming marketed formulations (Tasigna® and Nilotirel®) and reduction of crystallinity was less than 2% in 6 months, suggesting stability of co-crystal. This study successfully demonstrates the applicability of ZoomLab™ in coformer prediction and formulation development for solubility enhancement of poorly soluble drugs.

Key Points