A Study Showcasing Crystal Medley of Metformin Free Base: Virtual and Experimental Insights

Objective: The present work reports the existence of polymorphism in metformin free base applying virtual and experimental approach. Methods: The experimental screening of various polymorphs of metformin free base has been coupled with virtual approach resulting in isolation of three distinct crystal phases from different solvents/ or solvent mixtures. The virtual screening of polymorphs was performed using Polymorph Predictor module of BIOVIA Material Studio (MS) software. A state-of-the-art approach was undertaken utilizing integrated molecular modeling and Monte Carlo simulation technology. The sophisticated tools were used to characterize the experimentally isolated forms such as Differential Scanning Calorimetry (DSC), Fourier Transform Infra-Red Spectroscopy (FTIR), Powder X Ray Diffraction (PXRD) and optical microscopy. Lattice energy landscape was examined to look for these observed forms. Crystal morphology study was conducted to analyse Morphologically Important (MI) facets. Results: A list of potential polymorphs of the drug molecule was generated with varied lattice constants using MS. Crystal energy landscape obtained from the study provided systematic energy ranking to the polymorphs. DSC of these forms exhibited endothermic peaks at 134.01, 111.24 and 79.84°C respectively indicating them to be different forms of metformin base. Structure determination from powder patterns showed that although all the forms, form I, II and III crystallize out in same triclinic space group, P-1 but they possessed different crystallographic parameters and hydrogen bonding patterns. The predicted results were quite complacent with experimental observations with respect to lattice parameters. The three observed forms have been found as local minima in the lattice energy landscape of potential polymorphs. Conclusion: The study explained the practical relevance of Crystal Structure Prediction (CSP) in studying the potential polymorphs of a drug molecule by successfully predicting various polymorphs of metformin free base. Out of all predicted polymorphs, three polymorphs were actually isolated experimentally. The information generated about the existence of multiple forms of metformin free base provides an opportunity to select and scale-up the desired crystal form well suited on bioavailability and stability grounds. The process can be escalated further to preclinical study, to emerge as an invaluable technology in future in increasing the efficiency of drug development process.