INVESTIGATING THE ROLE OF MOLECULAR INTERACTIONS IN POLYMORPHISM OF MEFENAMIC ACID IN ETHYL ACETATE SOLUTION
DOI:
https://doi.org/10.11113/jt.v79.11322Keywords:
Crystallization, COMPASS, hydrogen bonding, molecular dynamics simulation, mefenamic acidAbstract
Mefenamic acid, a widely used nonsteroidal anti-inflammatory and analgesic agent, is one of the active pharmaceutical ingredients that exhibit polymorphisms. This study reports a combined experimental and molecular dynamics simulation study of mefenamic acid crystallization in ethyl acetate. The solid-state characterization of the polymorph produced using Fourier transform infrared spectroscopy (FTIR), X-Ray powder diffractometer (XPRD), and differential scanning calorimetry (DSC) analysis show the characteristic of Form I, which were N-H stretching at 3313cm-1, two endothermic  peaks, and significant XPRD peaks at 6.3°, 13.8°, 15.9°, 21.3°, and 26.3°. The molecular dynamics simulations were performed using COMPASS force field available in the Material Studio 5.5 simulation package. The simulations were run for equilibration with a time step of 1 fs for a period of 250 ps and 2000 ps simulation in NVE (constant number of atoms, volume and energy) and NPT (constant number of atoms, pressure and temperature) thermodynamic ensemble, respectively. The trajectory files from the simulation were analyzed for radial distribution function (RDF) to investigate the intermolecular interactions. The simulation results showed strong solute-solute and solute-solvent interactions, which were O1MA•••H15MA and O1EA•••H15MA. These findings revealed the presence of hydrogen bonds that contributes to the solvation and formation of hydrogen motif in polymorphic Form I of mefenamic acid during crystallization with ethyl acetate as a solvent.
References
Brittain, H. G. 2007. Polymorphism and Solvatomorphism. Journal of Pharmaceutical Science. 96: 705-728.
Adam, F. 2012. An Examination into the Influence and Change of Solution Structure on the Polymorphic Behaviour of 2,6-Dihydroxybenzoic Acid. Institute of Particle Science and Engineering: University of Leeds, Leeds.
Lee, E .H. 2014. A Practical Guide to Pharmaceutical Polymorph Screening & Selection. Asian Journal of Pharmaceutical Sciences. 9(4): 163-175.
Heinz, A., C. J. Stracchan, K. C. Gordon, and T. Rades. 2009. Analysis of Solid-State Transformations of Pharmaceutical Compunds Using Vibrational Spectroscopy. Journal of Pharmaceutical Pharmacology. 61: 971-988.
Marques, M. P. M., R. Valero, S. F. Parker, J. Tomkinson, and L. A. Batista de Carvalho. 2013. Polymorphism in Cisplatin Anticancer Drug. The Journal of Physical Chemistry B. 117(21): 6421-6429.
SeethaLekshmi, S. and T. N. Guru Row. 2012. Conformational Polymorphism in a Non-Steroidal Anti-Inflamatory Drug Mefenamic Acid. Crystal Growth & Design. 12: 4283-4289.
Cesur, S. and S. Gokbel. 2008. Crystallization of Mefenamic Acid and Polymorphs. Crystal Research & Technology. 43: 720-728.
Panchagnula, R., R. Sundaramurthy, O. Pillai, and S. Agrawal. 2004. Solid-State Characterization of Mefenamic Acid. Journal of Pharmaceutical Science. 93: 1019-1029.
Gilpin, R. K. and W. Zhou. 2005. Infrared Studies of the Polymorphic States of the Fenamates. Journal of Pharmaceutical and Biomedical Analysis. 37(3): 509-515.
Cunha, V. R., C. M. lzumi. P. A. Petersen, A. Magalhaes, M. L. Temperini, H. M., Petrilli, V. R. Constantino, V. R. 2014. Mefenamic Acid Anti-Inflammatory Drug: Probing Its Polymorphs by Vibrational (IR and Raman) and Solid-State NMR Spectroscopies. The Journal of Physical Chemistry B. 118(16): 4333-4344.
Hamad, S., C. Moon, C. R. A. Catlow, A. T. Hulme, and S. L. Price. 2006. Kinetic Insights into the Role of the Solvent in the Polymorphism of 5-Fluorouracil from Molecular Dynamics Simulations. Journal of Physical Chemistry B. 110(7): 3323-3329.
Abdul Mudalip, S. K., M. R. Abu Bakar, P. Jamal, and F, Adam. 2013. Solubility and Dissolution Thermodynamic Data of Mefenamic Acid Crystals in Different Classes of Organic Solvents. Journal of Chemical & Engineering Data. 58(12): 3447-3452.
vanGunsteren, W. and H. A. Berendsen. 1990. Computer Simulation of Molecular Dynamics: Methodology, Applications, and Perspectives. Angewandte Chemie International Edition in English. 29(9): 992-1023.
Mullin, J. W. 2001. Crystallization. 4th edition. Oxford: Butterworth-Heinemann.
Surov, A. O., I. V. Terekhova, A. Bauer-Brandl, and G. L. Perlovich. 2009. Thermodynamic and Structural Aspects of Some Fenamate Molecular Crystals. Crystal Growth & Design. 9: 3265-3272.
Gonza´lez, B., N. Calvar, E. Go'mez, E. and A. K. Domi'nguez. 2009. Density, Dynamic Viscosity, and Derived Properties of Binary Mixtures of Methanol or Ethanol with Water, Ethyl Acetate, and Methyl Acetate at T = (293.15, 298.15, and 303.15). Journal of Chemical Thermodynamics. 39(12): 1578-1588.
Allen, M. P. and D. J. Tildesey. 1991. Computer Simulation of Liquids. New York: Oxford University Press.
Nose, A. S. 1984. A Unified Formulation of the Constant Temperature Molecular Dynamics Methods. Journal of Chemical Physics. 81(1): 511-519.
Beredsen, H. J. C.1984. Molecular-Dynamics with Coupling to an External Bath. Journal of Chemical Physics. 81(8): 3684-3690.
Ho, R., Naderi, M. J. Y. Heng, D. R. Williams, F. Thielmann, P. Bouza, and D. J. Burnett. 2012. Effect of Milling on Particle Shape and Surface Energy Heterogeneity of Needle-Shaped Crystals. Pharmaceutical Research. 29(10): 2806-2816.
Romero, S., B. Escalera, and P. Bustamante. 1999. Solubility Behavior of Polymorphs I and II of Mefenamic Acid in Solvent Mixtures. International Journal of Pharmaceutics. 178: 193-202.
Park, K., J. M. B. Evans, and A. S. Myerson. 2003. Determination of Solubility of Polymorphs Using Differential Scanning Calorimetry. Crystal Growth & Design. 3(6): 991-995.
Craig, D. Q. M. and G. A. K. 2007. Thermal Ananlysis of Pharmaceuticals. Boca Raton: CRC Press, Taylor & Francis Group.
Kato, F., M. Otsuka, and Y. Matsud. 2006. Kinetic Study of the Transformation of Mefenamic Acid Polymorphs in Various Solvents and Under High Humidity Conditions. International Journal of Pharmaceutics. 321(1): 18-26.
Sun, H. 1998. COMPASS: An ab Initio Force-Field Optimized for Condensed-Phase Applications Overview with Details on Alkane and Benzene Compounds. The Journal of Physical Chemistry B. 102(38): 7338-7364.
Ingebrigtsen, T. S., T. B. Schroder, and J. C. Dyre. 2012. What is Simple Liquid? Physical Review X. 2(1): 011011.
Davey, R. and J. Garside. 2002. From Molecules to Crystallizers: An Introduction to Crystallization. United States: Oxford University Press Inc.
Downloads
Published
Issue
Section
License
Copyright of articles that appear in Jurnal Teknologi belongs exclusively to Penerbit Universiti Teknologi Malaysia (Penerbit UTM Press). This copyright covers the rights to reproduce the article, including reprints, electronic reproductions, or any other reproductions of similar nature.
