Thermodynamic and structural study of tolfenamic acid polymorphs
Introduction
Tolfenamic acid (Fig. 1a) is a nonsteroidal anti-inflammatory drug (NSAID), belonging to the fenamate group compounds (niflumic, mefenamic and flufenamic acids). Fenamates are widely applied in medicine and veterinary as febrifugal and anti-inflammatory drugs [1], [2]. The most common opinion of the predominant mechanism of the action these drugs produce is inhibiting cyclo-oxygenases which catalyses the biosynthesis of prostaglandins in inflammation pathogenesis [3], [4], [5], [6].
The determination of the tolfenamic acid properties was the subject of previous research [7], [8], [9], [10], [11], [12], [13], [14], [15]. The pharmacodynamic and pharmacokinetic characteristics were investigated by Pedersen [7], whereas aqueous solubility by Bergstro et al. [8]. Recently there have been several papers about the analysis of the tolfenamic acid impact on the conductivity of ionic channels and opportunities to use this group of substances for Alzheimer disease treatment [9], [10], [11].
It is well known that most of the fenamates have several polymorphic forms. The tolfenamic acid is also a typical drug, which exhibits polymorphism. The literature on this subject described two polymorphic modifications: form I with space group P21/c (white form) [12] and form II, P21/n (yellow form) [13]. However, recently three new forms have been identified [14]: form III with space groups P21/c; form IV, P 1bar; form V, P 1bar. The analysis of IR spectrums of white and yellow polymorphic forms was carried out by Gilpin and Zhou [15]; however the question about the nature of the polymorphic modifications is still under discussion. Moreover, it should be noted that the thermodynamic and thermophysical aspects of the forms have not been studied yet. Furthermore, the sublimation and solvation processes of the tolfenamic acid in the solvents, imitating biological media, have not been investigated either. The present work is devoted to the abovementioned problems.
Section snippets
Compounds and solvents
The tolfenamic acid (2-[(3-chloro-2-methylphenyl)amino]benzoic acid, white form, C14H12ClNO2, MW 261.7, lot 110H0469, CAS 13710-19-5), flufenamic acid (2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid, C14H10F3NO2, FW 281.23, lot 122K1018, CAS 530-78-9) and niflumic acid (2-[3-(trifluoromethyl)anilino]nicotinic acid, C13H9F3N2O2, FW 282.2, lot 12K1486, CAS 4394-00-7) were purchased from the Sigma Chemical Co., Ltd., St. Louis, USA. The purity of the compounds was over 99.8%.
The methanol HPLC
Crystal structure analysis of the two forms of the tolfenamic acid
The crystal lattices characteristics of the white and yellow polymorphic forms of tolfenamic acid are presented in Table 1. The molecular packing architectures of the presented polymorphs are shown in Fig. 2.
As it has been mentioned by Andersen et al. [12], the color difference of the two modifications can be connected with conformational peculiarities of the molecules in the crystal lattices. The phenyl fragments of the outlined molecules are planar and the interplanar angle for the white form
Conclusion
We have studied two tolfenamic acid polymorphic modifications in the space groups P21/c (white form) and P21/n (yellow form), measured the temperature dependence of the white form vapor pressure by the transpiration method and calculated the thermodynamic parameters of the sublimation process. We have also estimated the difference between the crystal lattice energies of the two modifications by solution calorimetry. The crystal lattice energy of the yellow form was found to be 6.7 ± 1.2 kJ mol−1
Acknowledgments
We are grateful for the opportunity to carry out calculations by DMol3 program on the platform of Institute of Pharmacy of University of Tromsø, Norway. This study was supported by the Russian Foundation of Basic Research N 09-03-00057. The work was carried out within the frame of Agreement between the Russian and Polish Academies of Sciences.
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