A multi-well setup with video-microscopy was used to study the influence of solvent on solubility, nucleation, and crystallization of an Active Pharmaceutical Ingredient (API): metformin hydrochloride (MET.HCI). Starting with 13 solvents covering a wide variety of polarity and proticity, we found 63 crystallization medium for MET.HCI solid generation: good solvents, good co-solvents and anti-solvent systems. For toxicological reasons, we limited the number of crystallization medium to 18: 3 good solvents (class 3), 3 good co-solvent systems and 12 anti-solvent systems. In order to study the influence of crystallization medium on nucleation temperature, crystal habit and polymorphism of MET.HCI, crystallization was studied by a cooling temperature method. Different crystal habits were observed by optical and scanning electron microscopies, and solid phase were characterized by X-ray powder diffraction, indicating that all the crystals correspond to the thermodynamic stable polymorphic form A of MET.HCI. Finally, the enthalpy of fusion and the melting temperature of MET.HCI were determined by DSC and confirmed the X-ray powder diffraction results. (C) 2016 Elsevier B.V. All rights reserved.