Vinpocetine: Polymorph and Solvate Screening Supports a Monomorphic Crystal Landscape

The solid-state landscape of pharmaceutical compounds is often characterized by the occurrence of polymorphs, hydrates, and solvates, which may significantly influence their physicochemical and biopharmaceutical properties. In contrast, some active pharmaceutical ingredients exhibit a remarkable resistance to crystal form diversification, despite extensive experimental investigation. In the present work, vinpocetine was subjected to an extensive solid-form screening campaign aimed at exploring its propensity to generate alternative polymorphs, hydrates, and solvates. Mechanochemical experiments were performed under neat grinding and liquid-assisted grinding conditions using a broad range of organic solvents and water, including two-step milling procedures and formulations containing surfactants. Additional investigations included high-energy planetary milling, high-pressure compaction, exposure to controlled humidity, thermal cycling, slurry-bridging experiments in various media, and crystallization after mechanochemical neutralization of vinpocetine salts. The resulting solids were systematically characterized by powder X-ray diffraction, and thermal and morphological analyses. In all cases, the recovered solid corresponded to the commercially available crystalline form of vinpocetine, with no evidence of alternative polymorphs, solvates, or hydrates. These results demonstrate the unusual robustness of vinpocetine crystal structure across a wide range of mechanical, thermal, and solventmediated conditions. Notably, this behavior contrasts with the well-established ability of vinpocetine to form numerous salts and salt cocrystals, suggesting that solid-state diversification in this compound is primarily driven by proton-transfer processes rather than by neutral polymorphism or solvent incorporation. The present study provides experimentally defined boundaries for the solid-state landscape of vinpocetine and contributes valuable data for future crystal-form prediction and pharmaceutical development studies. Beyond the specific findings reported herein, the systematic documentation of both successful and unsuccessful experimental outcomes represents a valuable source of experimentally validated positive and negative data that may support the future development and validation of AI-assisted crystal-form prediction tools.