Eutectic Mixture as a Novel Approach to Improve Compression Properties of Metformin Hydrochloride

Metformin hydrochloride (MET), an antidiabetic medication, possesses poor compression properties and severe elastic recovery, hindering its formulation via direct compaction. This study engineered MET eutectic mixture and cocrystals using freeze-drying and evaluated them for overcoming these compression liabilities and minimizing punch sticking propensity. Niacinamide (NI), a flexible carboxamide micronutrient beneficial in diabetes management, was evaluated alongside D-Mannitol (MAN), a brittle polyol benchmark excipient, at 1:1 and 1:2 molar ratios. Solid-state characterization (PXRD, FTIR, DSC and TGA) confirmed that both adjuvants yield a eutectic mixture at a 1:1 ratio and a distinct cocrystal phase at a 1:2 ratio. Morphologically, the MET-NI systems exhibited unique layered microstructures. Mechanical profile assessment showed that MET-NI eutectic mixture and cocrystals drastically improved MET plasticity, showing significantly reduced yield pressure via Heckel analysis compared to their corresponding physical mixtures. Consequently, the MET-NI systems displayed enhanced compactibility and tabletability, producing mechanically stable tablets at high drug-coformer loadings (99.5% w/w). Conversely, the MET-MAN formulations exhibited dominant brittle deformation, resulting in severe tablet lamination and capping at compaction pressures exceeding 150 MPa. Furthermore, punch sticking assessment revealed that the enhanced internal tablet strength (API:coformer - API:coformer bonding interaction) of MET-NI eutectics and cocrystals reduced punch sticking mass up to 10-fold compared to the physical mixture. This work demonstrates that particle engineering, particularly utilizing eutectic mixture approach via freeze-drying with flexible carboxamides like niacinamide, presents a highly viable approach for modifying the micromechanical properties of problematic drugs to facilitate seamless large-scale direct compaction manufacturing.