Chemometrics-Guided Pharmaceutical Cocrystal Screening: Structural Elucidation and Development of Gemfibrozil-Isonicotinamide Cocrystals

Abstract Raman spectroscopy combined with Principal Component Analysis was employed as a rapid triage tool to screen for cocrystal formation among three fibrate-class active pharmaceutical ingredients (bezafibrate, ciprofibrate, and gemfibrozil) paired with a panel of coformers under mechanochemical grinding. Gemfibrozil-isonicotinamide (GEM-INCT) emerged as the system with the most pronounced spectral departure from physical-mixture behavior, an outcome later corroborated by powder X-ray diffraction. A simplex-centroid mixture design across the ethanol/methanol/water compositional space guided crystallization toward single crystals suitable for X-ray analysis, leading to the first single-crystal structure of GEM-INCT: a 1:1 triclinic (P-1) adduct held together by the canonical carboxylic acid-pyridyl heterosynthon and cooperative amide−amide and amide−carbonyl N−H···O contacts that propagate into a one-dimensional hydrogen-bonded chain. Multivariate Curve Resolution-Alternating Least Squares modeling of the Raman time series revealed that liquid-assisted grinding substantially outpaced neat grinding in driving conversion, informing the design of a vortex-slurry process that affords a low-solvent, readily scalable route to gram quantities of the phase-pure cocrystal. Solubility measurements at pH 1.2 and 4.5 showed no equilibrium advantage relative to gemfibrozil, though dissolution kinetics at pH 4.5 were measurably faster for the cocrystal. These findings connect spectroscopic screening, solvent space optimization, and process design within a single cocrystal development pipeline.